INTRODUCTION Thrombotic microangiopathy (TMA)
The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis
TMA after transplantation can be classified into either:
(1) De novo TMA,
(2) Recurrent TMA,
In this review, the author shall try to discuss the main differences between the two categories in the pathophysiology, clinical course and available approaches of prevention and treatment.
DE NOVO TMA
Factors triggers De novo TMA after renal transplant:
(1) Antibody mediated rejection (AMR);
(2) Immunosuppressive-associated TMA: (CNI) or (mTORi), single or combined;
(3) Other medications: e.g., (anti-VGFI);
(4) Viral infection: e.g., HCV, CMV, BK and parvovirus;
(5) Genetic abnormalities in the complement cascade;
(6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation;
(7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA).
Which is more prevalent, de novo or recurrent TMA?
Reynolds et al, in a (USRDS)-based study, declared that the number of recurrent TMA cases was only 12 compared to 112 patients with de novo TMA,
Langer et al reported the incidence of de novo TMA to be 1.5%. However, the incidence of de novo TMA is mentioned to be as high as 3%-14%
de novo TMA is more prevalent after kidney transplantation and presumably underestimated.
Graft loss rate of 40% is reported in de novo TMA within a couple of years of diagnosis
Etiopathogenesis of de novo TMA AMR and medications are the two main causes of de novo TMA.
In addition, the role of complement abnormalities is becoming more apparent with one study
. Calcineurin-induced TMA:
Three underlying mechanisms
(1) Loss of the normal balance between the vasodilator peptides (e.g., (PG) E2 and (PG12)) and the vasoconstrictor peptides (e.g., thromboxane A2 and endothelin)
(2) CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity
(3) Microparticle production from endothelial cells, a known effect of CyA that can result in activation of the AP
three trap points have been speculated to oppose the role of CNI:
(1) Patients utilizing CNI to maintain immunosuppression represent more than 95% of kidney transplant recipients (KTR), and only a small percentage can develop TMA, which suggests the presence of another underlying predisposing factor
(2) CNI withdrawal in de novo TMA does not always guarantee a favorable graft outcome
(3) A USRDSbased study demonstrates a significantly higher incidence of TMA in the group of KTR that was not under CNI maintenance therapy (11.9/1000/year), as compared to those on CNI maintenance (5.0/1000/year).
mTOR inhibitor-associated TMA:
The following explanations have been given:
(1) mTORi has antiangiogenic properties, and can decrease renal expression of (VEGF) with death of the endothelial progenitor cells.
(2) The VEGF inhibition has been recently proven to be associated with reduced renal levels of complement factor H (CFH)
(3) Repair of endothelial injury could be hampered by mTORi use
(4) the procoagulant and the antifibrinolytic activity of mTORi might play additional roles in de novo TMA development
interpretation of these data may be limited by the fact that mTORi itself, e.g., sirolimus, may be used as a rescue medication in the case of diagnosis of CNI-induced TMA
Fortin et al reported that the highest risk of de novo TMA was in the group using CNI and mTORi,
Nava et al studied 396 KTR, 36 (7.3%) developed TMA and 17 of them were drug-related. Not only were the drug levels of CNI and mTORi higher in the TMA group, but the sum of both drug levels in the TMA group was also higher.
AMR-associated de novo TMA:
Endothelial cells are a well-known target of allo-immune response.
The peritubular capillary (PTC) C4d staining has been reported to be present in 16.2% of biopsied recipients with TMA
Satoskar et al reported an incidence of 55% of de novo TMA patients who express diffuse PTC C4d positivity.
Several less common etiologies have been reported :
1. Viral infection, e.g., CMV, BK virus, parvovirus, HCV virus,
2. antiviral medications, e.g., ribavirin and interferon and disseminated histoplasmosis.
3. Ischemia-reperfusion injury
4. (ADAMTS13) deficiency another rare risk factor
Complement gene mutations:
Chua et al observed C4d deposits in more than 88% and C4d with localized C5b-9 in about 60% of 42 biopsy samples from patients with histologically confirmed diagnosis of TMA
Le Quintrec et al reported the presence of genetic mutations in CFH, (CFI) or both in 29% of their studied de novo TMA patients, 25% showed low (CFB) and/or low C3, suggesting an AP complement activation.
Clinical manifestations :
TMA could develop at any time in the post transplantation course, however this syndrome is mostly encountered in the first 3-6 mo post transplantation.
Salient features: TMA manifestations are quite variable and can vary from a limited form confined to the kidney to a full blown systemic variant
The systemic form of TMA consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI).
Features of MAHA include raised (LDH), drop in (HB) and decreased haptoglobin with schistocytes on peripheral blood smear.
Localized (limited) TMA is usually presented later in TMA course, as compared to the systemic form, which can be explained by the urgency of the systemic type, necessitating the diagnostic allograft biopsy
When a renal transplant recipient has significant renal dysfunction and the biopsy does not show any acute rejection, one must suspect two possibilities: (1) TMA or (2) Renal artery stenosis.
The histopathologic changes are usually non-specific but vary in the acutestatus to the chronic angiopathic changes.
RECURRENT TMA AFTER RENAL TRANSPLANTATION Etiology of recurrent TMA aHUS;
(TTP);
autoimmune diseases: e.g., scleroderma and SLE , with or without anti-phospholipid antibody syndrome.
Recurrence of TMA in the allograft depends on the underlying type involving the native kidney.
For example, mutational abnormality involving CFH and CFI, The reported rate of aHUS recurrence approached 70%-90%
(MCP) keeps aHUS recurrence lower unless other mutational gene defects have been associated
The global rate of recurrence in aHUS patients is reported to be as high as 60%.
Untreated patients develop graft loss at a rate of 90%, with 80% of them occurring in the first year
TTP:
Genetic or acquired lack of ADAMTS13 has been recognized.
Serological evaluation of ADAMTS13 activity is now feasible.
complete distinction between the two clinical entities is not always possible because of overlap in manifestations.
SLE
can develop TMA in 5%-10% with documented recurrence after kidney transplantation
PATHOPHYSIOLOGY OF TMA RECURRENCE
Current classification of TMA includes the following
1. Primary hereditary TMA: Includes mutations in ADAMTS13, MMACHC (cb1c deficiency), or in genes encoding complement components.
Primary acquired TMA: Autoantibodies to ADAMTS13 or to CFH.
2. Infection-associated TMA:
(STEC-HUS) and pneumococcal HUS
3. Secondary TMA:
e.g., pregnancy-associated TMA
or de novo TMA after transplantation,
The most common complement mutation in aHUS is CFH, with 40% of cases inherited and 25% sporadic
THERAPY OF POST-TRANSPLANT TMA Treatment of de novo TMA
is highly dependent on diagnosis as well as the patient’s response.
The following approaches have been suggested:
(1) Immunosuppressive medication management:
Satoskar et al, denied any difference in outcomes between temporary discontinuation, dose modulation, withdrawal or continuation of CyA
Whatever the situation would be, the withdrawal of the offending agent should be the first line in treating de novo TMA,
(2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG):
In 2003, Karthikeyan et al reported a graft salvage rate with PE approaching 80%.
Two benefits have been postulated for this type of therapy:
• Removal of the platelet aggregation factors, e.g., thromboxane A2
• the simultaneous replenishment of the deficient factors, e.g., PGI2-stimulating factor
In AMR-associated TMA, 100% response has been reported to be associated with PE/IVIG therapy in five solid organ transplantation with systemic TMA with no evidence of relapse after withdrawal of the culprit agent (e.g., tacrolimus) in a recent study;
(3) Belatacept:
A promising alternate option that allows withdrawal of the offending drug incriminated in TMA evolution.
The first case report in 2009 documented TMA resolution after belatacept therapy used for immunosuppression in post-transplantation TMA due to CNI-induced endothelial toxicity
belatacept has nothing to do with the underlying endothelial derangement, its role is only to replace/displace the culprit drug
(4) Complement inhibition:
Eculizumab was proven to be effective in treatment as well as in prevention of recurrent aHUS after renal transplantation
anti-complement therapy has been suggested to have a fundamental role in the management of de novo post-transplantation TMA.
This efficacy has been also documented in patients with refractory AMR with TMA
Cornell et al reported no difference in death-censored graft survival or biopsy finding at one year when they compared the outcome of eculizumab-treated patients with controls
the use of this vital biological agent should be confined to a specified subset of de novo TMA patients, presumably:
(1) AMR-associated TMA;
(2) Patients who became PE-dependent;
(3) Refractory hemolysis persists despite maximum doses of PE therapy.
Treatment of recurrent TMA Recommendations for recurrent TMA:
most of the recommendations about recurrence and therapeutic advices relied primarily on case reports (level 4 evidence) as well as experts’ opinions (level 5 evidence) .
(1) The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3
(2) All patients with primary or suspected aHUS, should be surveyed for all complement components and its related proteins
(3) Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation
(4) Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy
(5) Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation
Prevention of aHUS:
(1) ischemia-reperfusion injury, viral infection and immunosuppressive medications, should be avoided;
(2) Certain relations have been reported between CNI use and aHUS recurrence, which is not confirmed by other authors, even the usual substitute in such a case (an mTOR) is not innocent and can induce recurrence;
(3) We cannot depend solely on PE therapy in management of aHUS recurrence
Prophylactic use of rituximab proved to be efficacious as anti-CFH-antibodies, the beneficial effect of rituximab can be enhanced by adding PE therapy
(5) The anti-C5 monoclonal antibiotic eculizumab has been reported to be used successfully to prevent aHUS recurrence in patients with CFH, CFH/CFHR1 hybrid genes as well as with C3 gene mutations
Therapeutic protocols for aHUS recurrence:
Once the diagnosis of primary aHUS has been established, complement blockade therapy should be instituted.
Duration of therapy:
There is not enough data supporting life-long therapy for aHUS.
should be permitted to optimize renal recovery and satisfy TMA resolution.
Kidney transplantation without eculizumab prophylaxis:
Verhave et al described therapeutic protocol consisted of:
Basiliximab for induction,
tacrolimus in low dose,
and prednisone and mycophenolate mofetil as immunosuppressive in addition to a statin.
No recurrence or rejection has been observed after 16-21 mo.
Treatment of DGKE mutation associated TMA:
Azukaitis and colleagues reported the feasibility of kidney transplantation in five patients with no recurrence after transplantation.
RENAL TRANSPLANTATION Timing
Renal transplantation should be postponed six months after institution of dialysis, as limited kidney recovery can occur several months after commencing eculizumab therapy
Disappearance of the extrarenal manifestations as well as resolution of TMA hematological parameters
Risk of kidney donation
Two risks have been reported to be associated with living-related kidney donation:
(1) Recurrent disease in the recipient;
(2) De novo disease in the donor, if he/she is a genetic mutation carrier
Research targets
The following agents are under investigation:
(1) The anti-C3b blocker,
(2) The anti-C3 convertase monoclonal antibodies
Level 5
Naglaa Abdalla
2 years ago
Types of TMA after transplantation :
(1) De novo TMA,
(2)Recurrent TMA,
De novo TMA is more prevalent than recurrent TMA. Causes of De novo TMA:
1- Calcineurin-induced TMA.
2- mTOR inhibitor-associated TMA
3- AMR-associated de novo TMA
4- Viral infection, e.g., CMV infection
5- antiviral medications, e.g., ribavirin and interferon Clinical manifestations:
Timing: TMA could develop at any time in the post
transplantation course, but is mostly occurred in the first 3-6 mo post transplantation.
Salient features:
TMA manifestations are quite variable. The systemic form
of TMA consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI).
Features of MAHA include raised lactic acid dehydrogenase (LDH), drop in hemoglobin
(HB) and decreased haptoglobin with schistocytes on peripheral blood smear.
Localized (limited) TMA is usually presented later in TMA course, as compared to the
systemic form. Causes of recurrent TMA :
1- aHUS
2- TTP Current classification of TMA :
1- Primary hereditary TMA: Includes mutations in
ADAMTS13, MMACHC (cb1c deficiency), or in genes encoding complement components.
2- Primary acquired TMA: Autoantibodies to ADAMTS13
or to CFH, which occurs with homozygous CFHR3/1 deletion.
3- Infection-associated TMA: Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) and pneumococcal HUS have distinct mechanisms that result in TMA; in other infections, the processes are ill-defined and sometimes can trigger manifestations of the primary
TMA.
4- Secondary TMA
Treatment :
This mainly depends on the cause.
-Immunosuppressive medication management: the role of immunosuppressive
medications (e.g., CNI or mTORi) has been reported in the literature, with a documented
better response after switching from one CNI member to another or to an mTORi.
-Plasmapheresis (PE) and intravenous immunoglobulins (IVIG)
-Belatacept
-Complement inhibition: Eculizumab
Wadia Elhardallo
2 years ago
Ø Post-transplant TMA can occur as a recurrence of the disease involving the native kidney or as de novo disease with no evidence of previous involvement before transplant.
Ø Management of both diseases varies from simple maneuvers, e.g., plasmapheresis, drug withdrawal or dose modification, to lifelong complement blockade, which is rather costly.
De novo TMA:
Ø the incidence of de novo TMA is mentioned to be as high as 3%-14% , precipitating factors have been identified in the context of renal transplantation that trigger the development of de novo TMA:
(1) Antibody mediated rejection (AMR)
(2) Immunosuppressive-associated TMA: Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi), single or combined;
(3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI)
(4) Viral infection: e.g., HCV, CMV, BK and parvovirus
(5) Genetic abnormalities in the complement cascade
(6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation; and
(7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA)
Ø Clinical manifestations:
1) Timing: TMA could develop at any time ,mostly encountered in the first 3-6 mo post transplantation.
2) Manifestations: are quite variable and can vary from a limited form confined to the kidney to a full blown systemic variant. The systemic form of TMA consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI). Features of MAHA include raised lactic acid dehydrogenase (LDH), drop in hemoglobin (HB) and decreased haptoglobin with schistocytes on peripheral blood smear. Localized (limited) necessitating the diagnostic allograft biopsy,
Ø The prognosis of post-transplant de novo TMA is quite poor for the patient and as well as the allograft. About one half of the patients loses their graft within the first two years after diagnosis
Recurrent TMA after renal transplantation:
Ø Etiology of recurrent TMA : aHUS; thrombotic thrombocytopenic purpura (TTP); and autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus, with or without anti-phospholipid antibody syndrome
Ø Current classification of TMA includes the following
1) Primary hereditary TMA: Includes mutations in ADAMTS13, MMACHC (cb1c deficiency), or in genes encoding complement components.
2) Primary acquired TMA: Autoantibodies to ADAMTS13 or to CFH, which occurs with homozygous CFHR3/1 deletion.
3) Infection-associated TMA: Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) and pneumococcal HUS have distinct mechanisms that result in TMA; in other infections, the processes are ill-defined and sometimes can trigger manifestations of the primary TMA.
4) Secondary TMA: Presents in a variety of conditions, and
Therapy of post-transplant TMA
Institution of therapeutic options is highly dependent on diagnosis as well as the patient’s response. therapeutic maneuvers should be individualized for each patient. The following approaches have been suggested:
(1) Immunosuppressive medication management
(2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG)
(3) Belatacept: A promising alternate option that allows withdrawal of the offending drug incriminated in TMA evolution
(4) Complement inhibition: Eculizumab, an anti-C5 agent, blocks the lytic C5b-9 membrane attack complex generation.
Level 5
Rehab Fahmy
2 years ago
TMA post transplant is either denovo or recurrent
Denovo TMA could be 2ry to :
1- Immunosuppression (CNI and Mtor inhibitors)
2- Acute rejection (AMR)
3- Viral anfection (CMV)
4- phenotypical changes in case of C3 glomerulopathy
5- genetic abnormality ADAMS 13,or deficiency of Factor H in complement pathway
Recurrent:
TTP or atypical HUS
In som cases it is not known before transplantation that TMA is the original cause of ESRD
Diag:
Cl manifestation: either limited or systemic (AKI ,MAHA and thrombocytopenia)
Biopsy :could come with acute rejection with positive C4D staining
In case of graft dysfunction >no rejection ,and no cause You should suspect TMA or Rena artery stenosis.
prevention:
in case of recurrent TMA :ECulizumab
treatment:
plasmapheresis
Belatacept
Eculizumab
Hamdy Hegazy
2 years ago
Please summarize this article TMA post-transplant incidence is 5.6 cases/1000 renal transplants with 50% mortality within 3 years. Types of TMA: De-novo TMA and Recurrent TMA. De-novo TMA is more common post-transplant than recurrent TMA which has better prognosis. Definition and causes: acquired or genetic disorder in the alternate pathway that can be caused by: AMR, CNI, m-TOR inhibitors, CMV, BKV, Parvo-virus, HCV, shift from C3GN to a-HUS post-transplant and missed diagnosis of TMA in native kidney. Clinical presentation: within first 3-6 months, classical triad: renal dysfunction without acute rejection, TMA, renal artery stenosis. It can present with limited manifestations. Recurrent TMA causes: a-HUS, TTP, SLE, Scleroderma. Extra-renal manifestations of TMA: digital gangrene, cerebral artery thrombosis, MI, GIT, Pulmonary thrombosis. Treatment of TMA: de novo TMA: 1- Change IS medications. 2- Plasma exchange and IVIG. 3- Eculizumab. 4- Belatacept. Recurrent TMA: 1- Avoid IRI, viral infection, IS triggered TMA. 2- Rituximab. 3- Eculizumab
What is the level of evidence provided by this article? level 5
Ahmed Omran
2 years ago
TMA can occur in the form of recurrence TMA of the disease involving the native kidney or in the form of de novo disease with no evidence of previous involvement before transplant.
De novo TMA is more common compared with recurrent TMA
Atypical hemolytic uremic syndrome is a sporadic disease that results from complement dysregulation with alternative pathway increased activity.
Several factors trigger the recurrence of TMA , or de novo TMA:
Drug induced like CNI induced TMA , m Tor inhibitors like sirolimus AMR and acute TMA viral infections eg CMV, genetic mutation variants &C3 nephropathy overlapping with TMA
Recurrent TMA can occur as early as first 3-6 months following transplantation either as a HUS , TTP , autoimmune disease with renal limited or as part of systemic manifestation essentially hematological; like typical MAHA with thrombocytopenia and uremia , both de novo or recurrent TMA following transplantation correlated with poor graft outcome.
Treatment of TMA depends on the underlying cause: if drug induced to stop the offending IS.
Plasmaphereses , IVIG if TMA is associated with AMR.
Eculizumab is the drug of choice for recurrence TMA including a HUS
level of evidence 5 ;narrative review article.
Dalia Ali
2 years ago
Thrombotic microangiopathy (TMA) is a debilitating complication of kidney transplantation that is associated with poor patient and graft outcomes. The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis[1]. TMA after transplantation can be classified into either:De novo TMA, i.e., developed for the first time without any evidence of the disease before transplant; and Recurrent TMA, i.e., native kidneys failed as a result of TMA and it came back in renal transplantation.
DE NOVO TMA
In the presence of acquired or genetic dysregulation of the alternative complement pathway (AP), a number of precipitating factors have been identified in the context of renal transplantation that trigger the devel- opment of de novo TMA. These factors include the following: (1) Antibody mediated rejection (AMR); (2) Immunosuppressive-associated TMA: Calcineurin in- hibitors (CNI) or mTOR inhibitors (mTORi), single or combined; (3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI); (4) Viral infection: e.g., HCV, CMV, BK and parvovirus; (5) Genetic abnormalities in the complement cascade; (6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation; and( 7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA)
Etiopathogenesis of de novo TMA
AMR and medications are the two main causes of de novo TMA.
Calcineurin-induced TMA: The link between CNI (CyA and tacrolimus) administration and the evolution of de novo TMA is not a new concept.
mTOR inhibitor-associated TMA: mTORi can inhibit cell cycle progression and proliferation. Both sirolimus and everolimus have been reported to be implicated in the pathogenesis of de novo TMA.
AMR-associated de novo TMA: The role of AMR in the development of post-transplant TMA is commonly reported and well-recognized. Endothelial cells are a well-known target of allo-immune response.
Complement gene mutations: Chua et al reported that renal complement activation is the common de- nominator in such a heterogeneous condition. They observed C4d deposits in more than 88% and C4d with localized C5b-9 in about 60% of 42 biopsy samples from patients with histologically confirmed diagnosis of TMA from a heterogenous group of patients
Relation to TMA evolution: The AP depends on two main regulators: CFH and CFI. CFH has the ability to inhibit the C3 cleaving enzyme C3bBb. Moreover, it can serve as co-factor for FI, and the latter has the ability to inactivate C3b.
Clinical manifestations
Timing: TMA could develop at any time in the post transplantation course[5,43], however this syndrome is mostly encountered in the first 3-6 mo post trans- plantation. This is probably when the CNI immuno- suppressive trough levels are relatively higher
Salient features: TMA manifestations are quite variable and can vary from a limited form confined to the kidney to a full blown systemic variant[4,6,44]. The systemic form of TMA consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI). Features of MAHA include raised lactic acid dehydrogenase (LDH), drop in hemoglobin (HB) and decreased haptoglobin with schistocytes on peripheral blood smear.
Prognosis of de novo TMA:
The prognosis of post- transplant de novo TMA is quite poor for the patient and as well as the allograft. About one half of the patients loses their graft within the first two years after diagnosis
RECURRENT TMA AFTER RENAL TRANSPLANTATION
Etiology of recurrent TMA
aHUS; thrombotic thrombocytopenic purpura (TTP); and autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus, with or without anti-phospholipid antibody syndrome
aHUS: Recurrence of TMA in the allograft depends on the underlying type involving the native kidney. Overactivation of the AP is known to be the underlying etiology of aHUS. By far, aHUS is the most common diagnosis in TMA associated with recurrence. Risk of recurrence is greatly dependent on the underlying associ- ated abnormality
TTP: TTP is the second recognized etiology in TMA.
Genetic or acquired lack of ADAMTS13 has been recognized. For a long period, differentiation between TTP and HUS relied primarily on the presence of neurologic manifestation in TTP and renal dysfunction in HUS to settle the diagnosis. Serological evaluation of ADAMTS13 activity is now feasible.
PATHOPHYSIOLOGY OF TMA RECURRENCE
The AP is constitutively active and is, therefore, fine- tuned. The regulatory components exist either in the serum (fluid phase) or attached onto cell membranes. CFH is the main inhibitor of the AP. CFH has the ability to work in fluid phase as well as on cell surfaces. Furthermore, CFH can act as a co-factor to CFI[59,60]. Regulatory components on cell surfaces, or “membrane regulators” include the following: (1) Membrane cofactor protein (MCP/CD46); (2) Complement receptor 1 (CR1/ CD35); (3) Decay accelerating factor (DAF/CD55); and (4) Protectin (CD59), which prohibits MAC formation
Current classification of TMA includes the following
Primary hereditary TMA:
Includes mutations in ADAMTS13, MMACHC (cb1c deficiency), or in genes encoding complement components.
Primary acquired TMA:
Autoantibodies to ADAMTS13 or to CFH, which occurs with homozygous CFHR3/1 deletion.
Infection-associated TMA:
Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) and pneumococcal HUS have distinct mechanisms that result in TMA; in other infections, the processes are ill-defined and sometimes can trigger manifestations of the primary TMA.
Secondary TMA:
Presents in a variety of conditions, and in many conditions the culprit mechanisms are usually multifactorial or unknown.
The most common complement mutation
in aHUS is CFH, with 40% of cases inherited and 25% sporadic . Furthermore, not only CFH has its impact on TMA evolution, but the CFH-related genes (CFHR1-5) have additional roles. Through deletion, hybrid protein formation and duplication of these genes, the endothelial cell surface becomes denuded from its protective shield, and consequently aHUS may supervene
The risk of aHUS recurrence could be four times higher with CFH mutations or with the carriers of CFH/ CFHR1 hybrid genes.On the other hand, the impact of CFI mutations is controversial. While early reports about CFI mutations documented a high rate of recurrence and graft loss
Clinical assessment of aHUS: Any HUS that is not due to STEC-HUS has been called aHUS. The recent progress in understanding the pathophysiology and the underlying genetic factors led to the current classification of aHUS
Acute vs chronic lesion?
Timing of an aHUS episode is not easily predictable. Many patients are at persistent risk of recurrence. In medical genetics, penetrance of any disease-causing mutation means the percentage of subjects with genetic mutations who can express clinical symptoms
Extrarenal manifestation: Twenty percent of aHUS patients can express extrarenal manifestations in the form of digital gangrene, cerebral artery thrombosis, myocardial infarction, in addition to ocular, GIT, pul- monary and neurologic involvement. Drusen formation is not common in aHUS
Laboratory investigations and differential diagnosis: Once the diagnosis of aHUS is suspected, exclusion of ADAMTS13 activity is urgently mandated to exclude TTP diagnosis. In children, TTP is less common; therefore, eculizumab therapy should be instituted early without waiting for the results of ADAMTS13 activity.
Complement assessment in aHUS: Before com- mencing plasma therapy, serum complement com- ponent should be thoroughly evaluated. C3 is low in 30% of aHUS patients and, therefore cannot be used as a screening criteria for aHUS
Panel of genetic testing: The diagnostic list of genes of aHUS should include at least CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE
Rationale for genetic screening: The current progress in understanding the underlying genetic background of aHUS and its molecular basis makes it paramount to
provide a full detailed genetic map before transplant, and the following explanations have been given: (1) Determination of the actual cause of the disease that allows for correct genetic counseling; (2) Drawing the plan of disease management; (3) Evaluating the expected response for therapy; and (4) Defining the prognostic course as well as patient and allograft survival.
Interpretation of the genetic variants: Genetic mutations can be interpreted as: (1) Benign; (2) Likely benign; (3) Variant of uncertain significance; (4) Likely pathogenic; or (5) Pathogenic, according to the international guidelines
Acquired drivers of aHUS: The FH autoantibodies are the best reported example. It is typically characterized by homozygosity for delCFHR3-CFHR1
Diagnosis of aHUS recurrence: A full detailed clinical history is usually warranted. A proven tissue diagnosis with light microscopy (LM), immunofluorescence (IF) and electron microscopy (EM) studies supporting the diagnosis of aHUS in the native kidney should be available.
THERAPY OF POST-TRANSPLANT TMA
Treatment of de novo TMA
In view of the extreme heterogenicity of the mechanisms related to variable etiologies of TMA, therapeutic ma- neuvers should be individualized for each patient. Institution of therapeutic options is highly dependent on diagnosis as well as the patient’s response. The following approaches have been suggested: (1) Immuno- suppressive medication management: the role of im- munosuppressive medications (e.g., CNI or mTORi) has been reported in the literature, with a documented better response after switching from one CNI member to another or to an mTORi) dose modulation, withdrawal or continuation of CyA in man- agement of de novo TMA.
(2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG): The following rationales have been addressed in favor of PE/IVIG therapy
(3) Belatacept: A promising alternate option that allows withdrawal of the offending drug incriminated in TMA evolution.
(4) Complement inhibition: Eculizumab, an anti-C5 agent, blocks the lytic C5b-9 membrane attack complex generation.
On the other hand, Cornell et al reported no difference in death-censored graft survival or biopsy finding at one year when they compared the outcome of eculizumab-treated patients with positive cross matching with controls, even though the incidence of acute AMR was less in the eculizumab group. So, in view of these conflicting results as well as considering the high cost of the drug, the use of this vital biological agent should be confined to a specified subset of de novo TMA patients, presumably: (1) AMR-associated TMA; (2) Patients who became PE-dependent; and (3) Refractory hemolysis persists despite maximum doses of PE therapy. However, more efforts are still warranted to declare the best way to utilize this unique agent and which subset of TMA patients are the best candidates for this costly drug. An urgent need for new biomarkers is also warranted for early detection of complement overactivity
Treatment of recurrent TMA
Recommendations for recurrent TMA: First of all, it is worthy to remember that most of the recommendations about recurrence and therapeutic advices relied primarily on case reports (level 4 evidence) as well as experts’ opinions (level 5 evidence) rather than on randomized controlled trials (level 1b evidence). (1) The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3 (2) All patients with primary or suspected aHUS, should be surveyed for all complement components and its related proteins; (3) Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation; (4) Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange the- rapy and (5) Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation
Prevention of aHUS: The following strategies are suggested to decrease/prevent aHUS: (1) Complement activity incited by an injury to endothelium, e.g., ischemia-reperfusion injury, viral infection and immuno- suppressive medications should be avoided; (2) Certain relations have been reported between CNI use and aHUS recurrence which is not confirmed by other authors even the usual substitute in such a case (an mTOR) is not innocent and can induce recurrence (3) We cannot depend solely on PE therapy in man- agement of aHUS recurrence for several reasons: PE failed to prevent aHUS recurrence in many cases
Prophylactic complement blockade: Gene abnor- malities have been reported to be associated with aHUS recurrence in 80% of patients
Therapeutic protocols for aHUS recurrence: Once the diagnosis of primary aHUS has been established, complement blockade therapy should be instituted. The available data points to two strategies: (1) Minimal dosage to establish complement blockade; and (2) Dose withdrawal scheme
FH autoantibody-driven aHUS: Anti-cellular therapy is recommended, with close monitoring of the antibody titer
Duration of therapy: There is not enough data sup- porting life-long therapy for aHUS. Cessation of therapy appears to be plausible in certain situations
Unanswered questions: There is paucity of information about this biological agent, e.g., what is the most optimal dose? What are the ideal dose-intervals? For how long should this kind of costly therapy be continued
What impact does this agent have on the spectrum of renal transplantation
Kidney transplantation without eculizumab pro- phylaxis:
They received living donor kidney with therapeutic protocol consisted of: Basiliximab for induction, tacrolimus in low dose, and prednisone and mycophenolate mofetil as immunosuppressive in addition to a statin. Additional precautions include lowering the blood pressure and minimizing the cold ischemic time.
Treatment of DGKE mutation associated TMA:
The role of complement blockade here is questionable.
RENAL TRANSPLANTATION
Timing
Renal transplantation should be postponed six months after institution of dialysis, as limited kidney recovery can occur several months after commencing eculizu- mab therapy
Risk of kidney donation
Two risks have been reported to be associated with living-related kidney donation: (1) Recurrent disease in the recipient; and (2) De novo disease in the donor, if he/she is a genetic mutation carrier[169]. Any po- tential donor proved to exhibit alternative pathway dysregulation should be excluded. On the other hand, any potential living-related donor devoid of complement gene abnormalities can be permitted
CONCLUSION
The impact of TMA, either de novo or recurrent, on allograft longevity is underestimated. The spectrum of the culprit genes implicated in the evolution of TMA is currently expanding. Despite the landmark breakthrough of immense efficacy of complement blockade therapy, the outlook of this devastating syndrome remains poor if the diagnosis is delayed. In contrast, the recurrent TMA is much more optimistic if there is timely intervention by complement blockade before permanent damage sets in. More efforts targeting genetic mutation management as well as the advent of early predictors of TMA recurrence are warranted for better disease control and, thereby, better patient and allograft outcome
Level 5
Mu'taz Saleh
2 years ago
Introduction
Thrombotic microangiopathy (TMA) is a debilitating complication of kidney transplantation that is associated with poor patient and graft outcomes. with incidence of 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis
TMA after transplantation can be classified into either:
(1) De novo TMA, i.e., developed for the first time without any evidence of the disease before transplant;
(2) Recurrent TMA, i.e., native kidneys failed as a result of TMA and it came back in renal transplantation
Precipitating factors for De novo TMA development
(1) Antibody mediated rejection (AMR);
(2) Immunosuppressive-associated TMA: (CNI) or mTOR inhibitors (mTORi),
(3) Other medications: e.g.,(anti-VGFI);
(4) Viral infection: e.g., HCV, CMV, BK and parvovirus;
(5) Genetic abnormalities in the complement cascade;
(6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation;
(7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA
Clinical manifestations
Timing: TMA could develop at any time in the post transplantation course but most commonly in the 1st 3-6 month due to high level of immunosupression
Clinical features: could be a symptomatic , limited form confined to the kidney or a full blown systemic variant
systemic form :
thrombocytopenia,
microangiopathic hemolytic anemia (MAHA) : raised (LDH), drop in (HB) and decreased haptoglobin with schistocytes on peripheral blood smear
acute kidney injury (AKI)
2.. Localized (limited) TMA , suspected when there is significant renal dysfunction
and the biopsy does not show any acute rejection,
The prognosis of post transplant de novo TMA is quite poor for the patient and as well as the allograft
Recurrent TMA causes :
aHUS;
TTP
autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus,
The current classification of TMA includes the following:
• Primary hereditary TMA
• Mutations in ADAMTS13, MMACHC
• Primary acquired TMA
• Autoantibodies to ADAMTS13
• Infection-associated TMA
• Shiga toxin-producing Escherichia coli-HUS, pneumococcal HUS
• Secondary TMA
Multifactorial
• Drug induced TMA
• Malignancy-associated TMA
• De novo TMA after solid organ transplantation
• TMA with autoimmune diseases
• TMA with glomerular diseases
Treatment of de novo TMA involves adjusting the immunosuppressant medications, plasmapheresis, intravenous immunoglobulins, belatacept (an immunosuppressive co-stimulatory blocker against CD80 and CD86 surface ligands), eculizumab (an anti-C5 agent that blocks the complement pathway).
Prevention of recurrent TMA is important, and the following strategies can be used:
1. Complement activity incited by an injury to the endothelium should be avoided (e.g. viral infections, immunosuppressive medications)
2. Substitution of CNIs
3. Plasmapheresis cannot suffice as the sole treatment
4. Use of eclizumab.
Therapeutic protocols for aHUS recurrence include complement blockade therapy with minimal dosage to establish complement blockade and a dose withdrawal scheme.
The duration of therapy should be enough time for renal recovery and TMA resolution.
Renal transplantation should be delayed for 6 months after starting dialysis and eclizumab therapy. Recurrent disease in the recipient and de novo disease have been recognized as risks for living related kidney donation.
Level of evidence: V
saja Mohammed
2 years ago
TMA can occur as a recurrence TMA of the disease involving the native kidney or as
de novo disease with no evidence of earlier involvement before transplant.
De novo TMA is more common than recurrence TMA
Atypical hemolytic uremic syndrome is a sporadic disease that results from complement dysregulation with alternative pathway overactivity,
many factors can triggers the recurrence of TMA , or denovo TMA
Drug induced like CNI induced TMA , M tor inhibitors like sirolimus and everolimus
AMR and acute TMA
viral infections like CMV
Genetic mutation variants
C3 nephropathy overlap with TMA
recurrence of TMA can occur as early as first 3-6 months post transplantation either as a HUS , TTP , autoimmune disease with renal limited or as part of systemic manifestation mainly hematological; like typical MAHA with thrombocytopenia and uremia , both denovo or recurrence TMA after transplantation associated with poor graft outcome
treatment of TMA
depends on the underlying cause if drug induced need to stop the offending IS
plasmaphereses , IVIG in case of TMA with AMR
Eculizumab is the drug of choice for recurrence TMA including a HUS
level of evidence 5 ( narrative review )
Asmaa Khudhur
2 years ago
TMA
Incidence of post-transplant TMA is 5.6 cases per 1000 KT recipients per year .
Classified either De Novo TMA or Recurrent TMA.
De Novo is more prevalent than recurrent TMA.
There are many factors that trigger the occurrence of De Novo TMA including:
1-AMR
2-CNIs induced TMA or mTOR inhibitors
3- Drugs
4- viral infection
5-Genetic abnormalities
6-shift of C3 Glomerulopathy to TMA post transplantation
7- missed diagnosis of TMA as a cause of primary GN disease . Clinical manifestations: TMA developed at any time but mostly in the first 3-6 months post transplantation.
It can be limited form or systemic form.
The systemic form consists of the triad of thrombocytopenia, microangiopathic hemolytic anemia , and AKI.
MAHA features include raised LDH , drop in Hb , and decrease in haptoglobin with schistocytes on peripheral blood smear.
The localized form occurs later in TMA course.
The prognosis of De Novo TMA is poor for the patients as well as allograft. Recurrent TMA after KT :
It’s either due to aHUS ,TTP, autoimmune diseases . The spectrum of TMA :
1- primary hereditary: aHUS with complement gene mutation, TTP with ADAMTS13 mutation.
2- primary acquired: TTP with ADAMTS13 autoantibodies, aHUS with FH autoantibodies.
3-infection associated: STEC-HUS, pneumococcal HUS , HIV- associated TMA and other infections.
4- secondary TMA : drug induced, De Novo TMA , pregnancy induced, malignancy-associated, TMA with severe HT , TMA with GN diseases , TMA with autoimmune diseases and TMA after bone marrow transplantation .
5- TMA due to unknown causes. Therapy of post KT TMA : Treatment of De Novo TMA
1- withdrawal of the offending agents.
2- PEX and IVIG
3- Belatacept which is an immunosuppressive co-stimulatory blocker against CD80 and CD86 surface ligands and CD80 on T cells.
4- complements inhibitors: Eculizumab an anti-C5 agent. Treatment of recurrent TMA
1-genetic screening include CFH, CFI, CFHR, CFB, MCP and C3.
2-surveyed all patients with primary or suspected aHUS for all complements .
3- MCP associated mutations patients may be safe for kidney donation.
4-patients with aHUS with no genetic mutation can proceed for kidney transplantation.
5-patients with polygenic pattern aHUS should be handle with caution in case of living donation.
Level of evidence: V
Wael Jebur
2 years ago
Thrombotic microangiopathy TMA post transplantation is often encountered with significant consequences on the allograft and recipient in survival.
Classically presented with ideopathic impaired allograft function, however systemic manifestation triad of thrombocytopenia TCP, microangiopathic hemolytic anemia MAHA, and allograft dysfunction.
It might be recurrent and or de novo TMA.
De novo TMA is more common and linked to several etiologies and predisposing factors
as follows:
Acute antibody mediated rejection ABMR:
as its affecting endothelial cells, promoting microangiopathic thrombosis.
It was found related to C4d deposition in peritubular capillaries.
Iatrogenic:
1-owing to the dependence on Calcineurin inhibitors Cyclosporin and Tacrolimus:
with several putative mechanisims linked to platelets stimulation and endothelial cell dysfunction.
2-Sirulimus:
3-Sirulimus and CNI combination.
Manal Malik
2 years ago
Summary of Thrombotic microangiopathy after renal transplantation- Current insights in de novo and recurrent diseaseIntroduction:
TMA is one of the causes of poor patient and graft outcomes post-renal transplantation. It could be :
1. De novo TMA
2. Recurrent TMA
In this review, we will try to discuss the main difference between the two categories in the pathophysiology, clinical cause, and available approach of prevention and treatment. De Novo TMA:
Acquired genetic dysregulation of the alternative complement pathway
Trigger factors include:
1. Antibody-mediated rejection
2. Immunosuppression associated TMA, CNI, or mTUR inhibition 3-anti-VGFI
3. Viral infection HCV, CMV, BK, and parvovirus
4. Genetic abnormalities in the complement cascade
5. C3 glomerulopathy with ESRD
6. Missed changes of TMA
CNI-induced TMA:
We== explain the role of CNI in TMA dependent:
1. Loss of the normal balance between the vasodilator peptide
2. CNI-induced platelet activation
3. Microparticle production from endothelial cells
mTOR inhibitor-associated TMA explanation:
1. mTOR has angiogenic properties and can decrease renal expression of vascular endothelial growth factor
2. the VEGF inhibition has been recently proven to be associated with reduced renal levels of complement factor H
3. repair of endothelial injury could be happened by mTOR use
4. the procoagulant and antifibrinolytic activity of mTOR AMR-associated de novo TMA:
Endothelial cells is the target of all-immune response. The peritubular capillary(PTC) c4d staining
Other causes less common:
1. viral infection e.g CMV infection, BK virus, parvovirus, chronic hepatic virus
2. ischemic reperfusion injury
3. ADAMTSII3 deficiency
4. C3 glomerulopathy Complement gene mutation:
Genetic mutation mCFH, complement factor cFI or both in 29% de novo TMA patients 25% for complement factor B( FB) Relation to TMA evolution:
The AP depends on two regulators CFH and CFI Clinical features:
Common in the first 3-6 month post-transplantation
Systemic form:
1. Thrombocytopenia
2. MAHA
3. AKI
Features of MAHA:
1. High LDH
2. Low drop Hb
3. Decrease haptoglobin
4. Schistocytes on peripheral blood smear
If the renal transplant biopsy does not show any acute rejection suspect two possibilities:
1. TMA OR
2. Renal artery stenosis
Active thrombosis and glomerular ischemia Chronic stage:
Basement membranes undergo duplication Prognosis of de novo TMA:
Relapse 54% of systemic TMA develop dialysis requiring AKI and 38% lost their graft Recurrent TMA after renal transplantation: Etiology of recurrent TMA:
TTP, aHUS, autoimmune disease(SLE and Scleroderma with or without APLs
aHus is most cause of recurrent TMA is about 70-90% rate
TTP is second cause of TMA cause of lack of ADAM TSI is ==recurrence after transplantation Pathology:
Endothelial injury present with fibrin/platelet plugging and intraluminal fibrin are not always seen in renal allograft biopsy Non-thrombotic features:
1. Denuded and swelling endothelium
2. Mesangiolysis
3. GBM double contour
4. Electrolucent matrial in the subendothelial Pathophysiology of TMA recurrence:
CFH is the main in== of the AP and co factor CRI and disturbance of regularly complement lead to complement activation Classification of TMA:
1. Primary hereditary TMA: mutation in AD AMTSIB, MMACHC or in gene encoding complement component
2. Primary acquired TMA: autoantibodies to AbAMB or to CFI which occurs with homozygous (FHR3) 1 deletion
3. Infection associated TMA shiga toxin produce Ecoli-HUS and pneumococcal HUS
4. Secondary TMA: mechanism multifactorial or unknown Role of DGKE mutation:
Most of a HUS is CFH with 40% of cases inherited and 25% sporadic
The risk of a HUS recurrence could be four time higher with CFH mutation Role of diacylglycerol kinase( DGKE) mutation:
DGKE associated acute renal failure, thrombocytopenia, and haemolytic anaemia Environmental triggers:
aHus triggers factors:
· Anti HLA antibodies
· Viral infection
· Ischemic-reperfusion injury
· Immunosuppression medications Clinical associated of a Hus: Acute vs chronic lesion:
Timing of an a Hus episode is not easily predictable
Many patients at risk of recurrence
Late presentation of aHus reflect the impact of the environmental triggers
TMA can be diagnosed by tissue biopsy without thrombocytopenia
Compliment inhibition can improve glomerular perfusion and maintain kidney function Extrarenal manifestation:
aHus 20% of patients have:
1. Digital gangrene
2. Cerebral artery thrombosis
3. Myocardial infarction
4. Ocular, GIT, pulmonary, and neurologic involvement Laboratory investigations and differential diagnosis:
Exclusion of ADAMB13 (TTP1) once a Hus suspected Complement assessment in a Hus:
C3 is low in 80% of a Hus patients
CD46 surface expression as functional parameters. Genetic testing:
Gene of a Hus : CFH, CFI,C3,CFB, THBD Rationale for genetic screening:
Full genetic map before transplantation because of the following factors:
1. Know the actual cause of the disease that allows for genetic counselling
2. Put plan of management
3. Evaluating the expected response for therapy
4. affecting the prognostic course as well as patient and allograft survival Genetic variants:
Genetic mutation can be as:
1. Benign
2. Likely benign
3. Variant of uncertain significance
4. Likely pathogenic
5. Pathogenic according to the international guidelines
Genetic designation also has its impact on therapeutic plans, response to therapy as well as the chance for a Hus recurrence Diagnosis of a Hus recurrence:
History is crucial to be elaborated
Tissue diagnosis:
1. Light microscopy
2. Immunofluorescence
3. Electron microscopy
Biochemical and genetic investigations if a Hus suspected should be any on include:
1. Anti-CFH-AB
2. MCP screening on the peripheral blood WBCs
3. Examination of the recombination in CFHR region
4. Screening of the genetic mutations related to CFH, CFI, CFB, C3, and MCP Therapy of posttransplant TMA: Treatment of de novo TMA:
Therapeutic options:
1. Immunosuppressive medication management( switch for CNI to other agents)
2. Plasmapheresis (PE) and intravenous immunoglobulin IVIG now replaced by eculizumab
3. Belatacept promising option therapy
4. Complement inhibition
Eculizumab an anti-C5b-9 membrane attack complex generation
Use for treatment and prevention of recurrent a Hus after renal transplantation
Biological agent use ( eculizumab) should be to specific subset of De Novo TMA patients:
1. AMR-associated TMA
2. Patient who became PE-dependent and
3. Refractory haemolysis Treatment of recurrent TMA: Recommendation for recurrent TMA:
1. The minimal list of genetic screening should be included CFH, CFI,CFHR,CFB, MCP, and C3
2. All patients with primary or suspected a Hus should be survey for all complement component and its related proteins
3. Isolated MCP-associated mutation safe for kidney donation
4. Patient with a Hus and no definite genetic mutation can proceed for kidney transplantation under the umbrella of plasma exchange therapy
5. Polygenetic pattern for a Hus patients should be handled with extreme caution in case of living donation Prevention of a Hus:
This steps suggest to prevent a Hus:
1. Avoid complement activation by viral infection, immunosuppression medication and ischemic-reperfusion injury
2. A CNI use although uncertain
3. PE failed to prevent a Hus recurrence
4. Use eculizumab to prevent a Hus recurrence in patients with CFH, CFHRI by genes as well as with C3 gene mutation Prophylactic:
Complement blockage in a Hus after exposure to triggers such as infection although lack enough evidence Therapeutic protocols:
For a Hus recurrence:
If diagnosis is confirm primary a Hus complement blockage therapy should be initiated:
1. Minimal dosage to complement blockage
2. Dose withdrawal scheme
Although both are lack of evidence
FH autoantibody-driven-a Hus:
Anti-cellular therapy is recommended
No enough data supporting life long therapy for a Hus
There is case series herald the possibility of successful kidney transplantation in recent a Hus without the need for prophylactic eculizumab through decrease cold ischemic time decreasing the risk of rejection Treatment of DGKE mutation associated TMA:
The role of complement blockage here is questionable
evidence level5
CARLOS TADEU LEONIDIO
2 years ago
Please summarise this article
Thrombotic microangiopathy (TMA) is one of the most devastating sequalae of kidney transplantation. Post-transplant TMA can occur as a recurrence of the disease involving the native kidney or as de novo disease with no evidence of previous involvement before transplant. De novo TMA is more common and its prognosis is poorer than recurrent TMA; the latter has a genetic background, with mutations that impact disease behavior and, consequently, allograft and patient survival. When a renal transplant recipient has significant renal dysfunction and the biopsy does not show any acute rejection, one must suspect two possibilities: (1) TMA or (2) Renal artery stenosis.
DE NOVO TMA
In the presence of acquired or genetic dysregulation of the alternative complement pathway (AP), a number of precipitating factors have been identified in the context of renal transplantation that trigger the development of de novo TMA. These factors include the following: (1) Antibody mediated rejection (AMR); (2) Immunosuppressive-associated TMA: Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi), single or combined; (3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI); (4) Viral infection: HCV, CMV, BK and parvovirus; (5) Genetic abnormalities in the complement cascade; (6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation; and (7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA).
Features:
– Occurs at any time post-transplantation, but is most common between 3-6 months.
– The systemic form of TAM consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (increase in lactic acid dehydrogenase (LDH), decrease in hemoglobin (HB) and decrease in haptoglobin with schistocytes in the peripheral blood smear), and acute kidney injury .
– Post-transplant de novo TMA prognosis is quite poor for the patient and also for the allograft., about half of the patients lose the graft in the first two years after.
RECORRENTE TMA
aHUS; thrombotic thrombocytopenic purpura (TTP); and autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus, with or without anti-phospholipid antibody syndrome.
Current classification of TMA includes the following:
– Primary hereditary TMA: Includes mutations in ADAMTS13, MMACHC (cb1c deficiency), or in genes encoding complement components.
-Primary acquired TMA: Autoantibodies to ADAMTS13 or to CFH, which occurs with homozygous CFHR3/1 deletion.
– Infection-associated TMA: Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) and pneumococcal HUS have distinct mechanisms that result in TMA; in other infections, the processes are ill-defined and sometimes can trigger manifestations of the primary TMA.
– Secondary TMA: Presents in a variety of conditions, and in many conditions the culprit mechanisms are usually multifactorial or unknown.
Diagnosis of aHUS recurrence:
A full detailed clinical history is usually warranted. A proven tissue diagnosis with light microscopy (LM), immunofluorescence (IF) and electron microscopy (EM) studies supporting the diagnosis of aHUS in the native kidney should be available. However, once diagnosis of aHUS is suspected, a full battery of biochemical, genetic as well as pathological investigations of the AP should be accomplished, including the following: (1) Estimation of the anti-CFH AB; (2) MCP screening on the peripheral blood WBCs; (3) Examination of the recombination in CFHR region; and (4) Screening of the genetic mutations related to CFH, CFI, CFB, C3, and MCP.
Treatment of de novo TMA In view of the extreme heterogenicity of the mechanisms related to variable etiologies of TMA, therapeutic maneuvers should be individualized for each patient. The following approaches have been suggested: – 1- Immunosuppressive medication management: the role of immunosuppressive medications (e.g., CNI or mTORi) has been reported in the literature, with a documented better response after switching from one CNI member to another or to an mTORi) – 2 – Plasmapheresis (PE) and intravenous immunoglobulins (IVIG) – 3 – Belatacept: A promising alternate option that allows withdrawal of the offending drug incriminated in TMA evolution. Belatacept is an immunosuppressive co-stimulatory blocker against CD80 and CD86 surface ligands and CD28 on T cells – 4 – Complement inhibition: Eculizumab, an anti-C5 agent, blocks the lytic C5b-9 membrane attack complex generation.
Treatment of recurrent TMA
Recommendations for recurrent TMA: First of all, it is worthy to remember that most of the recommendations about recurrence and therapeutic advices relied primarily on case reports as well as experts’ opinions rather than on randomized controlled trials. Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy.
What is the level of evidence provided by this article?
Level 5 – because this a narrative review
rindhabibgmail-com
2 years ago
Thrombotic microangiopathy post-transplantation has a poor prognosis up to 50% will end up with graft loss with in two years.
It could be recurrent or de novo. To confirm the recurrent need genetic testing like CFHR, MCP, CFH and CFI with C3 level. There could be multiple factor of triggering for de novo, usually they present with low platelets, raising creatinine, and features of MAHA.
Treatment is accordingly if by complement cascade blockade, immunosuppression dose modification, PLEX, high dose IVIG, eculizumab and newer agents like belatacept.
Level V.
Hinda Hassan
2 years ago
1. Please summarise this article
Thrombotic microangiopathy might occur in the kidney allograft in 2 forms: either de novo or recurrent TMA. De novo are more common than recurrent TMA.
De novo TMA
It can occur at any time post kidney transplantion but mostly occur in the first 3-6 months.
Triggering factors are : AMR, drug associated(CNI, mTORi, ribavirin, interferon and anti-VGFI associated), viral associated(HCV,CMV,BK and parvovirus), complement gene mutation and native kidney diseases (C3 glomerulopathy and missed TMA diagnosis).
Clinical features may vary from classical triad (low platelets, AKI and MAHA) or localized. Renal biopsy will reveal endothelial cell injury in the active stage with thrombosis ,fibrinoid necrosis and glomerular ischaemia. While the finding in the chronic stage are dublication of the basement membrane.. once diagnosed, the primary cause of renal disease need to be established as aHUS can be treated with eculizumab.
It has poor prognosis as 50% of patients will lose the graft within the first 2 years.
Recurrent TMA
The causes could be aHUS ,TTP, SLE or scleroderma. The most common one is aHUS followed by TTP. The renal biopsy will show thrombotic and non thrombotic features.. recurrence occur due to alterastion in the protective regulatory components of the complement system.
The current classification of TMA:
· Primary heiditory:
1. aHUS with complement gene mutations.
2. TTP with ADAMTS13 mutations.
3. cblC deficiency mediated TMA.
4. DGKE-associated TMA.
· Primary acquired
1. TTP with ADAMTS13 autoantibodies.
2. aHUS with FH autoantibodies.
· infection associated
1. STEC- HUS.
2. Pneumococcal HUS ( distinct mechanisms result in TMA ).
3. HIV-associated TMA.
4. Other infections ( ill defined, infection may trigger manifestation of a primary TMA ).
· Secondary
1. Drug-induced TMA.
2. De novo TMA after SOT.
3. Pregnancy-associated TMA (HELLP).
4. Malignancy-associated TMA.
5. TMA with severe HT.
6. TMA with glomerular diseases (MN, MPGN, FSGS, IgAN, AAV).
7. TMA with autoimmune diseases ( e.g. SLE, CAPS, SRC). 8. TMA after bone marrow transplant
Treatment of de novo TMA:
1- Immunosuppressive medication management ( switching from one CNI member to another or to an mTORi)
2- Plasmapheresis (PE) and intravenous immunoglobulins
3- Belatacept
4- Complement inhibition: Eculizumab
Treatment of recurrent TMA:
· The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3
· All patients with primary or suspected aHUS, should be surveyed for all complement components and its related proteins
· Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation
· Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy
· Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation
Prevention of aHUS is through avoiding complement activation, elicited by ischemia-reperfusion injury, viral infection and immunosuppressive medications, and prophylactic use of rituximab , anti-CFH-antibodies and eculizumab
Therapeutic protocol is use of complement blockade therapy and dose withdrawal scheme
What is the level of evidence provided by this article?
Level V
MICHAEL Farag
2 years ago
What is the level of evidence provided by this article? Level V; review article
INTRODUCTION Thrombotic microangiopathy (TMA) is a debilitating complication of kidney transplantation that is associated with poor patient and graft outcomes. TMA after transplantation can be classified into either: (1) De novo TMA, i.e., developed for the first time without any evidence of the disease before transplant; and (2) Recurrent TMA, i.e., native kidneys failed as a result of TMA and it came back in renal transplantation. Factors that trigger the development of de novo TMA (1) Antibody mediated rejection (AMR); (2) Immunosuppressive-associated TMA: Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi), single or combined; (3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI); (4) Viral infection: e.g., HCV, CMV, BK and parvovirus; (5) Genetic abnormalities in the complement cascade; (6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation; and (7) Missed diagnosis
of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA) Graft loss rate of 40% is reported in de novo TMA within a couple of years of diagnosis. Clinical features of TMA TMA is mostly encountered in the first 3-6 months post transplantation. This is probably when the CNI immunosuppressive trough levels are relatively higher; however, it can happen at any time post-transplant TMA manifestations are quite variable and can vary from a limited form confined to the kidney to a full blown systemic variant. The systemic form of TMA consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI) Prognosis of de novo TMA: The prognosis of posttransplant de novo TMA is quite poor for the patient and as well as the allograft THERAPY OF POST-TRANSPLANT TMA Treatment of de novo TMA – (1) The withdrawal of the offending agent should be the first line in treating de novo TMA, a fundamental step that ultimately results in correction of the hematological profile. – (2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG) – (3) Belatacept: A promising alternate option that allows withdrawal of the offending drug incriminated in TMA evolution – (4) Complement inhibition: Eculizumab, an anti-C5 agent. Treatment of recurrent TMA (1) Minimal dosage to establish complement blockade; and (2) Dose withdrawal scheme The following strategies are suggested to decrease/prevent aHUS: (1) Complement activity incited by an injury to endothelium, e.g., ischemia-reperfusion injury, viral infection and immunosuppressive medications[127], should be avoided; (2) Certain relations have been reported between CNI use and aHUS recurrence[ (3) PE therapy with rituximab (4) The anti-C5 monoclonal antibiotic eculizumab
Huda Saadeddin
2 years ago
Introduction
Thrombotic microangiopathy (TMA) is a debilitating complication of kidney transplantation that is associated with poor patient and graft outcomes.
TMA after transplantation can be classified into either:
1) De novo TMA, i.e., developed for the first time without any evidence of the disease before transplant
2) Recurrent TMA, i.e., native kidneys failed as a result of TMA and it came back in renal transplantation.
Contrary to what was believed in the past, de novo TMA is more common and its prognosis is poorer. On the other hand, recurrent TMA relies on a wide base of genetic backgrounds, with mutation errors differing in their impact on disease behavior and consequently on allograft and patient survival.
In this review, we shall try to discuss the main differences between the two categories in the pathophysiology, clinical course and available approaches of prevention and treatment.
DE NOVO TMA
a number of precipitating factors have been identified in the context of renal transplantation that trigger the development of de novo TMA.
These factors include the following:
1) Antibody mediated rejection (AMR)
2) Immunosuppressive-associated TMA: Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi), single or combined
3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI)
4) Viral infection: e.g., HCV, CMV, BK and parvovirus
5) Genetic abnormalities in the complement cascade
6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation
7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA)
the incidence of de novo TMA to be 1.5%. However, the incidence of de novo TMA is mentioned to be as high as 3%-14%. It is clear that de novo TMA is more prevalent after kidney transplantation and presumably underestimated.
Graft loss rate of 40% is reported in de novo TMA within a couple of years of diagnosis.
Etiopathogenesis of de novo TMA
AMR and medications are the two main causes of de novo TMA.
The risk of development of TMA with combined CNI and mTORi protocols is higher than using mTORi alone, an effect that has been documented in several studies.
The role of AMR in the development of post-transplant TMA is commonly reported and well-recognized
Several less common etiologies have been reported to be involved in TMA pathogenesis and include:
Viral infection, e.g., CMV infection, BK virus, parvovirus, chronic hepatitis C virus (with or without anti-cardiolipin seropositivity)
antiviral medications, e.g., ribavirin and interferon
disseminated histoplasmosis.
Ischemia-reperfusion injury can augment complement-associated injury through complement activation.
An acquired disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiencyanother rare risk factor- has been shown in one case to represent post-transplant TMA
The systemic form of TMA consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI).
Features of MAHA include raised lactic acid dehydrogenase (LDH), drop in hemoglobin (HB) and decreased haptoglobin with schistocytes on peripheral blood smear.
In the absence of renal biopsy, many cases can be misdiagnosed as hypertensive nephrosclerosis.
Consequently, a prompt testing for genetic mutations should be accomplished to unmask an underlying complement dysregulation and avoid missing the diagnosis of a recurrent aHUS.
This approach has key therapeutic implications, since de novo TMA has limited therapeutic options, in contrast to recurrent aHUS after transplantation, which has a better chance of C-5 blockade through the monoclonal antibody eculizumab, an effective therapeutic agent not only for treatment, but also for prevention of recurrence.
To compare systemic versus localized TMA, Schwimmer et al reported that 54% of systemic TMA develops dialysis-requiring AKI and 38% lost their grafts.
RECURRENT TMA AFTER RENAL TRANSPLANTATION
Etiology of recurrent TMA
aHUS; thrombotic thrombocytopenic purpura (TTP); and autoimmune diseases
Therapeutic protocols for aHUS recurrence:
Once the diagnosis of primary aHUS has been established, complement blockade therapy should be instituted.
The available data points to two strategies:
1) Minimal dosage to establish complement blockade
2) Dose withdrawal scheme[142] . Both options, however, lack enough evidence and require precise monitoring of complement blockade
Level V
Sahar elkharraz
2 years ago
Thrombotic microangiopathy (TMA) is serious complications post transplant leading to poor graft survival and outcome.
It’s account 5.6 cases per 1000 patients annually and mortality rate is around 50% of cases diagnostic with Thrombotic microangiopathy (TMA). There’s tow types of Thrombotic microangiopathy (TMA); de novo and recurrence of original renal disease. Since advantage of eculuzmab anti C5 monoclonal in preventing of Thrombotic microangiopathy (TMA) and role of renal biopsy prior to transplant help to diagnosis and treated. However not all transplanted cases underwent biopsy. This article focus on differentiate between de novo and recurrence of Thrombotic microangiopathy (TMA) in clinical courses and prognosis between tow types and role of renal biopsy to differentiate between them.
aDe novo TMA: It’s due to dysregulation of alternative complement pathways.
It’s may be genetic or due to precipitating factors like (1) Antibody mediated rejection. (2) Immunosuppressive-associated TMA: Calcineurin inhibitors or mTOR inhibitors (mTORi), single or combined; (3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI); (4) Viral infection: e.g., HCV, CMV, BK and parvovirus (5) Genetic abnormalities in the complement cascade; (6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation; and (7) Missed diagnosis of TMA in the native kidney as a cause of ESRD ( recurrence of TMA).
This study shows the risk if de novo TMA is more prevalent post transplant in comparison to recurrence of TMA in recipient with previous aHUS.
Pathophysiology is mainly due to abnormal compelement pathways and the risk factors associated with AMR and immunosuppressive medication. Drug induced TMA: calcinurine inhibitors may contribute to abnormal balance between vasodilator peptide ( prostaglandin and prostacyclin) and vasoconstrictor peptide ( thromboxane A and endothelin. leading to renal vasoconstriction and renal ischemic and endothelial injury.
another factor is platelets activation and pro coagulant and anti-fibrinolytic activity contribute to ischemic reperfusion injury.
Microparticle production from endothelial cells results from cyclosporine leading to TMA.
MTori drug associated with TMA especially sirolimus and everolimus because mTori lead to inhibition of vascular endothelial growth factors which are provoke TMA ; also this factors associated with reduced renal levels of complement factor H which carry risk of TMA.
procoagulant and the antifibrinolytic activity of mTORi might play important roles in de novo TMA development. mTori has procoagulant and the antifibrinolytic effects lead to TMA.
AMR recognized by presence of peritubular capillary Cd4 stanning which is strongly associated with TMA.
Other cases are viral infection and antiviral drug and C3 glomerular disease associated with TMA also acquired member 13 (ADAMTS13) deficiency also contribute for development of TMA .
This study shows there’s overlap between aHUS and TMA with deference mechanism and genetic mutations and complement and the coagulation-fibrinolysis cascades activation are associated with TMA.
Clinical presentation may appear at any time post transplant but mainly between 3 to 6 months post transplant.
Clinical classic triad’s presented with thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI). high LDH and low hemoglobin and haptoglobin. Sometimes there’s acute kidney dysfunction with vague symptoms and biopsy but the most possible diagnosis is TMA and renal artery stenosis.
In the active chronic
stage, there is evidence of endothelial cell injury with
platelet aggregation (thrombosis), fibrinoid necrosis and
glomerular ischemia. In the chronic stage, the basement
membranes undergo duplication and multilayering with
increased matrix layers and vessel wall cells.
The best treatment in de novo TMA is C5 monoclonal blocker’s.
Prognosis of de novo TMA is poor to graft and patients. Recurrence of TMA:
Overactivation of the alternative pathways is recognized cause of aHUS. The risk of recurrence is greatly dependent on the underlying associated abnormality.
aHUS recurrence approached 70%-90%.
Thrombotic thrombocytopenia:
It’s associated with TMA. it’s mainly genetic or acquired due to deficiency of ADAMTS13.
differentiation between TTP and HUS relied primarily on the presence of neurologic manifestation in TTP and renal dysfunction in HUS. The study shows the presence of AKI in more than half of TTP patients (with low ADAMTS13 activity) and 50% progression of CKD and even ESRD is highly suspect TMA. it’s due to recurrent of autoimmune disease like lupus nephritis which associated with TMA.
Spectrum of TMA:
Primary hereditary:
1. aHUS with complement gene mutations.
2. TTP with ADAMTS13 mutations.
3. cblC deficiency mediated TMA.
4. DGKE-associated TMA.
Primary acquired:
1. TTP with ADAMTS13 autoantibodies.
2. aHUS with FH autoantibodies
Infection causes:
C-staphylococcus HUS.
2. Pneumococcal HUS
3. HIV-associated TMA.
Secondary TMA:
Drug-induced TMA.
2. De novo TMA after SOT.
3. Pregnancy-associated TMA (HELLP).
4. Malignancy associated TMA.
5. TMA with severe HT.
6. TMA with glomerular diseases (MN, MPGN, FSGS, IgAN, AAV)
TMA with autoimmune diseases (e.g. SLE, CAPS, SRC).
8. TMA after bone marrow transplant
Extra renal manifestations of HUS is digital gangrene, cerebral artery thrombosis, myocardial infarction, ocular, GIT, pul- monary and neurologic involvement. Laboratory studies:
Complement assessment in aHUS: C3 is low and CD46 surface activity should be assessed because it’s a marker help in therapy guide.
Panel of genetic testing:
The diagnostic list of genes of aHUS should include at least CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE.
Genotyping workup should also include CFH-H3 and MCP ggaac haplotypes. to differentiate between acquired and genetic. Treatment of post transplant TMA:
Treatment of de novo TMA: Shift of calcinurine inhibitors ( cyclosporine); to mTOR temporary and 2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG)
Belatacept is co-stimulatory blocker against CD80 and CD86 surface ligands and CD28 on T cells.
4) Complement inhibition: Eculizumab, an anti-C5 agent, blocks the lytic C5b-9 membrane attack complex generation.
Prevention of aHUS:
High risk (50-100%): Who has
Previous early recurrence./ Pathogenic mutations1 Gain-of function mutations
those should be received Prophylactic eculizumab
Start on the day of transplantation to prevent severe recurrence.
Moderate risk:
No mutation identified/
Isolated CFI mutations/
Insignificant complement gene mutation:
those patients should be receive Prophylactic eculizumab or plasma exchange.
Low risk:
Isolated MCP mutations
Persistently negative FH autoantibodies. those patients no need for prophylaxis
It is level 5
amiri elaf
2 years ago
# Please summarise this article
# INTRODUCTION
*Thrombotic microangiopathy (TMA) is a disable complication of renal transplantation that is associated with poor patient and graft survival.
*The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis.
*TMA after transplantation can be classified into either:
(1)De novo TMA
(2)Recurrent TMA
# DE NOVO TMA
The factors that trigger the development of de novo TMA. Include the following:
*AMR
*Immunosuppressive-associated TMA:
(CNI) or mTOR inhibitors (mTORi), single or combined
*Other medications: e.g.(anti-VGFI)
*Viral infection: e.g., HCV, CMV, BK and parvovirus
*Genetic abnormalities in the complement cascade
*Phenotypical shift of C3 glomerulopathy (with ESRD), to
an aHUS post transplantation
*Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA).
# Etiopathogenesis of de novo TMA
*AMR and medications are the two main causes of de novo TMA.
*The role of complement abnormalities is becoming more apparent
# Calcineurin-induced TMA:
(1) Loss of the normal balance between the vasodilator peptides.
(2) CNI-induced platelet activation, pro-coagulant and anti fibrinolytic activity.
(3) Microparticle production from endothelial cells, a known effect of CyA that can result in activation of the AP.
*The trap points have been speculated to oppose the role of CNI:
(1) Patients utilizing CNI to maintain immunosuppression represent more than 95% of (KTR), and only a small percentage can develop TMA.
(2) CNI withdrawal in de novo TMA does not always
guarantee a favorable graft outcome.
(3) A USRDS based study demonstrates higher incidence of TMA in the KTR that was not under CNI compared to those on CNI maintenance.
# mTOR inhibitor-associated TMA:
* Both sirolimus and everolimus have been reported to be implicated in the pathogenesis of de novo TMA.
*The following explanations have been given:
(1) mTORi has antiangiogenic properties decrease renal expression of (VEGF) with death of the endothelial progenitor cells.
(2) The VEGF inhibition associated with reduced renal levels of (CFH).
(3) Repair of endothelial injury could be hampered by mTORi use
(4) The procoagulant and the antifibrinolytic activity of mTORi might play additional roles in de novo TMA development.
*The risk of development of TMA with combined CNI and mTORi protocols is higher than using mTORi alone
#AMR-associated de novo TMA:
*The role of AMR in the development of post-transplant TMA is by:
Endothelial cells are a well-known target of allo-immune response.
*The (PTC) C4d staining has been reported to be present in 16.2% of biopsied recipients with TMA.
* Satoskar et al reported an incidence of 55% of de novo TMA patients who express diffuse PTC C4d positivity.
*The clustering of both AMR and TMA would predict much worse graft outcome.
Other causes involved in TMA pathogenesis (Viral infection and antiviral medications).
# Clinical manifestations Timing:
*In the first 3-6 mo post transplantation.
*The systemic form of TMA consists of the classic triad of thrombocytopenia, (MAHA) and (AKI). Features of MAHA include raised (LDH), drop in (HB) and decreased haptoglobin with schistocytes on peripheral blood smear.
*Localized (limited) TMA is usually presented later in TMA course.
* When a KTR has significant renal dysfunction and the biopsy does not show any AR, one must suspect two possibilities:
(1) status to the chronic angiopathic changes
(2) Renal artery stenosis.
*The patient mortality rate of 50% after three years of diagnosis.
*To compare systemic versus localized TMA, Schwimmer
et al reported that 54% of systemic TMA develops dialysis-requiring AKI and 38% lost their grafts.
#RECURRENT TMA AFTER RENAL TRANSPLANTATION Etiology of recurrent TMA
*aHUS
*(TTP)
*Aautoimmune diseases
# aHUS:
*It is depends on the underlying type involving the native kidney.
*aHUS is the most common diagnosis in TMA associated with recurrence, the reported rate of aHUS recurrence approached 70%-90%.
*(MCP), a transmembrane complement regulatory component that is produced by kidney endothelial cells even in post-transplant period, keeps aHUS recurrence lower unless other mutational gene defects have been associated.
*Untreated patients develop graft loss at a rate of 90%, with 80% of them occurring in the first year.
# TTP:
*TTP is the second recognized etiology in TMA.
*Genetic or acquired lack of ADAMTS13 has been recognized.
*The differentiation between TTP and HUS relied primarily on the presence of neurologic manifestation in TTP and renal dysfunction in HUS to settle the diagnosis.
#Pathology:
* aHUS is a variety of TMA that represents the tissue response to an ongoing endothelial injury.
*Thrombotic features, e.g., fibrin/platelet plugging and intraluminal fibrin are not always seen in renal allograft biopsy.
*Non-thrombotic features can appear as denuded and swollen endothelium, mesangiolysis, glomerular basement membrane double contour, as well as accumulation of electrolucent material in the subendothelium.
*Arterial and arteriolar intraluminal fibrin, myxoid intimal thickening as well as concentric myointimal proliferation have also been described.
#PATHOPHYSIOLOGY OF TMA RECURRENCE
The CFH is the main inhibitor of the AP, has the ability to work in fluid phase as well as on cell surfaces and act as a co-factor to CFI.
*Regulatory components on cell surfaces, or “membrane regulators” include the following:
(1) Membrane cofactor protein
(2) Complement receptor 1
(3) Decay accelerating factor
(4) Protectin, which prohibits MAC formation.
# Current classification of TMA
*Primary hereditary TMA
*Primary acquired TMA
*Secondary TMA
# Clinical assessment of aHUS:
*Any HUS that is not due to STEC-HUS has been called aHUS.
*The term “primary HUS” used when there is underlying abnormality in the AP, underlying complement abnormality need a trigger factor(infection, surgery, medications, pregnancy, so that aHUS can clinically manifest.
#Acute vs chronic lesion?
*Penetrance in aHUS is age-related, by age 70, penetrance reaches
64%
* Certain patients may express more than one genetic determines the magnitude of disease penetrance.
*The late presentation of aHUS reflects the impact of the environmental triggers.
# Extrarenal manifestation:
*Twenty percent of Ahus patients can express extrarenal manifestations in the form of digital gangrene, cerebral artery thrombosis, myocardial infarction, in addition to ocular, GIT, pulmonary and neurologic involvement
# Laboratory investigations and differential diagnosis:
*Complement assessment in aHUS
*Panel of genetic testing
*Rationale for genetic screening
#Interpretation of the genetic variants:
Genetic mutations can be interpreted as:
(1) Benign
(2)Likely benign
(3) Variant of uncertain significance
(4)Likely pathogenic
(5) Pathogenic, according to the international guidelines.
# Diagnosis of aHUS recurrence:
* A full detailed clinical history is usually warranted.
*A proven tissue diagnosis with (LM), (IF) and (EM).
*Once diagnosis of aHUS is suspected, a full battery of biochemical, genetic as well
as pathological investigations of the AP, including the following:
(1) Estimation of the anti-CFH AB
(2) MCP screening on the peripheral blood WBCs
(3) Examination of the recombination in CFHR region
(4) Screening of the genetic mutations related to CFH, CFI, CFB, C3, and MCP.
# THERAPY OF POST-TRANSPLANT TMA
Treatment of de novo TMA
(1) Immunosuppressive medication management
(2) Plasmapheresis and intravenous immunoglobulins
(3) Belatacept
(4) Complement inhibition
# Treatment of recurrent TMA
(1) The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3.
(2) All patients with primary or suspected aHUS, should be surveyed for all complement components and its related proteins.
(3) Patients with isolated MCP associated mutations may be safe for kidney donation.
(4) Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy.
(5) Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation.
# Prevention of aHUS:
(1) Complement activity incited by an injury to endothelium should be avoided.
(2) Certain relations have been reported between CNI use and aHUS recurrence in such a case (an mTOR) is not innocent and can induce recurrence.
(3) Not depend solely on PE therapy in management of aHUS recurrence because PE failed to prevent aHUS recurrence in many cases.
(4) The anti-C5 monoclonal antibiotic (eculizumab).
# What is the level of evidence provided by this article?
*Level 5
Mohammed Sobair
2 years ago
Please summarise this article
Thrombotic microangiopathy :
TMA posttransplant either de novo or recurrent TMA in an isolated manner.
Associated with poor patient and graft outcomes.
The incidence is 5.6 cases per 1000 renal transplant recipients per year with a 50%
mortality rate three years after diagnosis.
DE NOVO TMA:
Risk factors:
Genetic or acquired dysregulation of the alternative complement pathway.
(1) AMR.
(2) Immunosuppressive-associated TMA: CNI or mTOR.
(3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-
VGFI).
(4) Viral infection: e.g., HCV, CMV, BK and parvovirus; antiviral medications, e.g.,
ribavirin and interferon and disseminated histoplasmosis.
(5) Genetic abnormalities in the complement cascade.
(6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post
transplantation.
(7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent
TMA).
De novo TMA is more prevalent after kidney transplantation and presumably
underestimated. Graft loss rate of 40%.
Etiopathogenesis of de novo TMA:
AMR and medications are the two main causes of de novo TMA.
Complement mutational abnormality in one third.
Calcineurin-induced TMA:
Suggested mechanism:
1-Due to imbalance between vasodilatation and constriction peptides, results in
arteriolar vasoconstriction, renal ischemia and establishment of endothelial injury.
2- CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity.
3- 3) Microparticle production from endothelial cells.
mTOR:
Has antiangiogenic properties, and can decrease renal expression of VEGF with death
of the endothelial progenitor cells.
(2) The VEGF inhibition has been recently proven associated with reduced renal levels
of complement factor H (CFH).
(3) Repair of endothelial injury could be hampered by mTOR.
(4) The procoagulant and the ant fibrinolytic activity of mTOR might play additional
roles.
AMR-associated de novo TMA:
A role of humoral rejection in the evolution of post-transplant TMA is suggested.
Complement gene mutations:
renal complement activation is the common denominator in such a heterogeneous
condition.
Multiple mutational gene varieties related to complement and the coagulation-fibrinolysis
cascades have been recently recognized in TMA patients
They observed C4d deposits in more than 88% and C4d with localized C5b-9 in about
60% .
reported the presence of genetic mutations in CFH, Complement Factor(CFI) or both in
29% of their studied de novo TMA patients, 25% showed low Complement Factor B
(CFB) and/or low C3, suggesting an AP complement activation.
Clinical manifestations :
Timing:
Any time in the post transplantation course.
Mostly encountered in the first 3-6 month post transplantation.
Salient features:
TMA :
A limited form confined to the kidney.
Systemic variant, MAHA, ARF and thrombocytopenia.
The histopathologic:
Changes are usually non-specific but vary in the acute from chronic.
In the active stage, there is evidence of endothelial cell injury with platelet aggregation
(thrombosis), fibrinoid necrosis and glomerular ischemia.
In the chronic stage, the basement membranes undergo duplication and Multilayering
with increased matrix layers and vessel wall cells, which ultimately ends in the unique
onionskin formation.
Prognosis of de novo TMA:
The prognosis of posttransplant de novo TMA is quite poor for the patient and as well as
the allograft. About one-half of the patients loses their graft within the first two years
after diagnosis.
RECURRENT TMA AFTER RENAL TRANSPLANTATION:
Etiology of recurrent TMA:
AHUS.
Thrombotic thrombocytopenic purpura.
Autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus, with or
without anti-phospholipid antibody syndrome.
AHUS:
Recurrence approached 70%-90%.
Over activation of the AP is known to be the underlying etiology of aHUS.
Mutational abnormality involving CFH and CFI, regulatory complement components
produced by the liver, results in aberrant CFH and CFI.
Additional MCP mutations (> 22percentage), is reported.
Untreated patients, however, ultimately develop graft loss at a rate of 90%, with 80% of
them occurring in the first year.
TTP:
Genetic or acquired lack of ADAMTS13 has been recognized.
Pathology:
aHUS is a variety of TMA .
PATHOPHYSIOLOGY OF TMA RECURRENCE:
The AP is constantly regulated, disturbance of this regulatory leads to complement
activation with subsequent endothelial cell derangement.
Both genetic aberrations as well as autoantibodies can be involved in this process.
There is Role of diacylglycerol kinase-ε (DGKE) mutations.
Current classification of TMA includes:
Primary hereditary TMA: Includes mutations in ADAMTS13, MMACHC (cb1c
deficiency), or in genes encoding complement components.
Primary acquired TMA: Autoantibodies to ADAMTS13 or to CFH, which occurs with
pathogenic; or (5) Pathogenic, according to the international guideline.
Acquired drivers of aHUS:
The FH autoantibodies. It is typically characterized by homozygosity for delCFHR3-
CFHR1.
Test results need to be confirmed after two weeks if positive.
Diagnosis of aHUS recurrence:
A full detailed clinical history .
Histopathology.
Test of alternative pathway:
(1) Estimation of the anti-CFH AB; (2) MCP screening on the peripheral blood WBCs.
(3) Examination of the recombination in CFHR region; and (4) Screening of the genetic
mutations related to CFH,
CFI, CFB, C3, and MCP.
Treating de novo TMA:
1-withdrawal of the offending agent should be the first line in treating de novo TMA.
(2) Plasmapheresis and intravenous immunoglobulins.
3) Belatacept.
(4) Complement inhibition: Eculizumab
In special subset of de novo TMA patients, presumably:
(1) AMR-associated TMA; (2) Patients who became PE-dependent; and (3) Refractory
hemolysis persists despite maximum doses of PE therapy.
Treatment of recurrent TMA Recommendations for recurrent TMA:
Prevention of aHUS:
Ischemia-reperfusion injury, viral infection and immunosuppressive medications, should
be avoided.
Prophylactic use of rituximab proved to be efficacious as anti-CFH-antibodies
, the beneficial effect of rituximab can be enhanced by adding PE therapy.
The anti-C5 monoclonal antibiotic Eculizumab has been reported to be used
successfully to prevent aHUS recurrence in patients with CFH, CFH/CFHR1 hybrid
genes as well as with C3 gene mutation.
Therapeutic protocols for aHUS recurrence:
Complement blockade therapy should be instituted.
Two strategies: (1) Minimal dosage to establish complement blockade.
(2) Dose withdrawal scheme.
FH autoantibody-driven aHUS:
Anti-cellular therapy is recommended.
Duration of Therapy:
Enough time, should be permitted to optimize renal recovery and satisfy TMA resolution
. Treatment of DGKE mutation associated TMA:
Many cases experienced disease remission with no specific therapy.
Timing renal transplantation:
Should be postponed six months after institution of dialysis, as limited kidney recovery
can occur several months after commencing Eculizumab therapy.
What is the level of evidence provided by this article?
Level of evidence V
Theepa Mariamutu
2 years ago
Thrombotic microangiopathy (TMA)
significant complication of kidney transplant recipients, associated with poor graft prognosis. classified into either de novo TMA or recurrent TMA.
De novo TMA is more prevalent than recurrent TMA and even more prevalent after kidney transplantation.
De novo TMA
triggered by many factors, such as antibody mediated rejection (AMR), immunosuppressive-associated TMA: calcineurin inhibitors (CNI), mTOR inhibitors (mTORi), anti-vascular endothelial growth factor inhibitors, viral infections (HCV, CMV, BK and parvovirus), genetic abnormalities in the complement cascade, phenotypical shift of C3 glomerulopathy and a missed diagnosis of TMA in the native kidney.
CNI can induce TMA by three possible mechanisms
It could be because of the loss of the normal balance between the vasodilator peptides (for example prostaglandin and prostacyclin) and the vasoconstrictor peptides (thromboxane A2 and endothelin) – results in arterial vasoconstriction, renal ischemia, and endothelial injury.
CNI induces activation of platelets, pro-coagulant and anti-fibrinolytic activity which may cause the evolution of TMA.
Microparticle production from endothelial cells can also induce TMA evolution.
mTORi have antiangiogenic properties and these effects have been implicated in TMA pathogenesis, but the exact role is still unknown. Endothelial cells are a well-known target of allo-immune response and hence the role of AMR in post transplantation is well known.
TMA could develop at commonly occurs in the first 3 to 6 months post the transplantation. It usually manifests as the classic triad of thrombocytopenia, microangiopathic haemolytic anaemia and acute kidney injury.
A renal biopsy will not show acute rejection, the histopathologic changes are usually non-specific.
In the active stage- evidence of endothelial cell injury with thrombosis, fibrinoid necrosis and glomerular ischemia.
In the chronic stage, the basement membranes undergo duplication and layering that leads to a unique onion skin formation.
Recurrent TMA
may be caused by atypical haemolytic uremic syndrome (aHUS), thrombotic thrombocytopenic purpura (TTP) and autoimmune diseases (such as scleroderma and systemic lupus erythematous).
Renal allograft -depends on the type involving the native kidney.
TTP is the second most common cause of recurrent TMA. It has been recognized that the cause is a lack of ADAMTS13. It could be either genetic or acquired. Histopathology shows ongoing endothelial injury.
can occur at any time, it is not easy to predict and therefore the patients are at a constant risk of recurrence.
may also manifest in other forms such as digital gangrene, cerebral artery thrombosis and myocardial infarction.
The current classification of TMA includes the following:
• Drug induced TMA
• Malignancy-associated TMA
• De novo TMA after solid organ transplantation
• TMA with autoimmune diseases
• TMA with glomerular diseases
Treatment of de novo TMA involves adjusting the immunosuppressant medications, plasmapheresis, intravenous immunoglobulins, belatacept (an immunosuppressive co-stimulatory blocker against CD80 and CD86 surface ligands), eculizumab (an anti-C5 agent that blocks the complement pathway).
Prevention of recurrent TMA is important, and the following strategies can be used:
1. Complement activity incited by an injury to the endothelium should be avoided (e.g. viral infections, immunosuppressive medications)
2. Substitution of CNIs
3. Plasmapheresis cannot suffice as the sole treatment
4. Use of eclizumab.
Therapeutic protocols for aHUS recurrence include complement blockade therapy with minimal dosage to establish complement blockade and a dose withdrawal scheme.
The duration of therapy should be enough time for renal recovery and TMA resolution.
Renal transplantation should be delayed for 6 months after starting dialysis and eclizumab therapy. Recurrent disease in the recipient and de novo disease have been recognized as risks for living related kidney donation.
Level of evidence: V
Tahani Ashmaig
2 years ago
Thrombotic microangiopathy after renal transplantation: Current insights in de novo and recurrent disease ________________________ Summary ◇INTRODUCTION ▪︎Thrombotic microangiopathy (TMA) is a debilitating complication of kidney transplantation that is associated with poor patient and graft outcomes. It can be classified into categories:
(1) De novoTMA
(2) Recurrent TMA
Since renal biopsy of native kidney is not performed in many patients with ESRD, missed diagnosis of TMA prior to kidney transplant
is likely.
▪︎The aim of this review is to discuss the main differences between the
two categories in the pathophysiology, clinical course & available approaches of prevention and treatment. DE NOVO TMA
▪︎In the presence of acquired or genetic dysregulation of the alternative complement pathway, a number of precipitating factors have been identified in the context of renal transplantat that trigger the development of de novo TMA.
(1) Antibody mediated rejection (AMR).
(2) Immunosuppressive-associated TMA: (CNI) or (mTORi), single or
combined.
(3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI).
(4)Viral infection: e.g., HCV, CMV, BK and parvovirus.
(5) Genetic abnormalities in the complement cascade.
(6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation.
(7) Missed diagnosis
of TMA in the native kidney as a cause of ESRD (i.e.,
recurrent TMA). ◇ Clinical manifestations Timing:
TMA could develop at any time (mostly in the first 3-6 mo post transplantation). Salient features: TMA manifestations varies from limited form (confined to the kidney and presented later in TMA course) to a full blown systemic variant (classical triad of thrombocytopenia, MAHA and AKI).
▪︎Features of MAHA include raised LDH, drop in HB and decreased haptoglobin with schistocytes on peripheral blood smear.
▪︎Localized (limited) TMA is usually presented later in TMA course
◇ DD of TMA:
(1)AR or (2) Renal artery stenosis. Histopathologic changes: ▪︎Active stage: evidence of endothelial cell injury with
platelet aggregation, fibrinoid necrosis and glomerular ischemia.
▪︎Chronic stage: the basement membranes undergo duplication and multilayering with increased matrix layers and vessel wall cells, which
ultimately ends in the unique onion skin formation Prognosis of de novo TMA: is quite poor for the patient
◇ Etiology of recurrent TMA
HUS; TTP; andautoimmune diseases: e.g., scleroderma & SLE, with or without APS.
◇ THERAPY OF POST-TRANSPLANT TMA Treatment of de novo TMA
▪︎Therapeutic maneuvers must be individualized for each patient.
▪︎Institution of therapeutic options is highly dependent on diagnosis as well as the patient’s response.
▪︎The following approaches have been suggested:
(1) Immunosuppressive medication management:
better response after switching from one CNI member to another or to an mTORi). Withdrawal of the offending agent should be the first line in treating de novo TMA.
(2) PE/IVIG therapy
(3) Belatacept: a promising alternate option
(4) Complement inhibition: Eculizumab, in the management of aHUS, Treatment of recurrent TMA Recommendations for recurrent TMA:
(1) The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3;
(2) All patients with primary or suspected a HUS, should be surveyed for all complement components and its related proteins;
(3) Patients with isolated MCP associated mutations may be safe for kidney donation;
(4) Patients with documented a HUS and with lack of definite
genetic mutations can proceed in renal transplant
under the umbrella of intensive PE therapy; and
(5) Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation[80]. CONCLUSION
▪︎Post-transplant TMA can occur as a recurrence of the disease involving the native kidney or as
de novo disease with no evidence of previous involvement
before transplant.
▪︎While atypical hemolytic uremic syndrome
is a rare disease that results from complement
dysregulation with alternative pathway overactivity, de
novo TMA is a heterogenous set of various etiologies
and constitutes the vast majority of post-transplant TMA cases.
▪︎Management of both diseases varies from simple maneuvers, e.g. , plasmapheresis, drug withdrawal or dose
modification, to lifelong complement blockade, which israther costly. ▪︎Careful donor selection and proper recipient
preparation, including complete genetic screening, would
be a pragmatic approach. ▪︎Novel therapies, e.g. , purified products of the deficient genes, though promising in theory, are not yet of proven value.
_______
♧ Level of evidence: V
Marius Badal
2 years ago
Summary of the article:
The article dealt with Thrombotic microangiopathy (TMA) after renal transplantation. This pathology has severe complication of the transplant kidney that is associated with poor patient and graft outcomes. It has been noted that the incidence of TMA is about 5.6 cases per 1000 renal per year. It is estimated that there is a 50 % mortality rate about 3 years post-diagnosis.
Classification of TMA
1) De novo TMA. There was no evidence of the disease before the transplant.
2) Recurrent TMA. Before transplantation, the patient had the same and return after transplantation.
The Novo TMA is more prevalent.
Possible causes of TMA:
1) AMR
2) IS-associated TMA with medications like CNI, mTORi
3) Possible viral infections like CMV, BK HCV
4) Possible genetic abnormalities.
5) TMA not diagnosed pre-transplant
The physiopathology of TMA:
Medications:
A) CNI-INDUCED TMA
1) CNI-induced TMA: it causes arteriolar vasoconstriction and renal ischemic that result in causing endothelial lesions.
2) CNI can cause platelet activation and anti-fibrinolytic activity
3) There may be microparticle production from endothelial cells that can result in the activation of the AP.
B) MTORi-induced TMA
1) It causes antiangiogenic properties that reduce kidney expression for VEGF
2) It decreases kidney CFH levels
3) It affected endothelial repair
C) AMR associated with de novo TMA
1) The endothelial cell is being targeted by the alloimmune response
2) The presence of PTC C4d
D) Complement gene mutation. It has shown that mutation of a specific gene for CFH, and CFI has caused TMA and low C3 also.
How does TMA manifest itself:
T can occur at any time but mostly at around 3-6 months after transplantation.
It can present with the triad of thrombocytopenia, MAHA, and AKI.
Will need an allograft biopsy.
It should be noted that the TMA prognosis is poor and about 50% of the recipient can lose their graft after a period of two years.
In the case of recurrent TMA what can be the causes?
a) aHUS are the most common cause.
It has a recurrence of about 60 %
The possible graft loss is 90%
b) TTP
It has a recurrent rate of 5-10% and it can be presented in two forms genetic or acquired due to the lack of ADAMTS13.
c) Autoimmune diseases: scleroderma and SLE
The most recent classification of TMA:
1) Primary hereditary TMA
2) Primary acquired TMA
3) Infection-associated TMA
4) Secondary TMA
The treatment of post-transplant de novo TMA:
1) Discontinue the agent that may be the cause
2) Immunosuppressive medications can be switched from one to a different one.
3) The use of plasmapheresis
4) Belatacept use
5) Eculizumab
Treatment of recurrent TMA:
1) The use of prophylactic complement blockade.
2) Treatment of aHUSs
Renal Transplantation:
Kidney transplantation should be postponed for about 6 months after the institution of dialysis because kidney recovery can occur several months after commencing the eculizumab treatment.
The prerequisite of renal transplant is the disappearance of extra-renal manifestation and hematological resolution of TMA.
The risk of kidney donation has been grouped into two different risks.
1) De novo disease in the donor
2) Recipient may have recurrent disease.
In conclusion: TMA can present itself either de novo or recurrent and can have a negative effect on the graft which is graft loss. This is the reason why it must be identified soon and treated.
The level of the article is V
Jamila Elamouri
2 years ago
summary:
Thrombotic microangiopathy (TMA) is a serious complication of transplantation. it is associated with poor outcomes. It occurs in 5.6 cases per 1000 cases with 50% mortality. Graft loss rate in de novo TMA reaches 40%.
TMA types:
a- De novo TMA i.e TMA developed for the first time
b- Recurrent TMA i.e., native kidney failed as a result of TMA and it comes back in renal transplantation, and because biopsy of the native kidney is not performed in many patients with ESRD, TMA diagnosis is likely missed prior to transplantation.
The distinction between these two entities has clear clinical and therapeutic implications, especially with the advance of the drug eculizumab, an anti-C5 monoclonal antibody which is highly effective in the treatment and prevention of atypical HUS. De novo TMA
A number of factors trigger the development of de novo TMA in the presence of acquired or genetic dysregulation of the alternative complement pathway (AP). These factors include:
1- AMR
2- Immunosuppressive-associated TMA: CNI or mTORi, single or combined
3- Other medications: e.g, anti-vascular endothelial growth factor inhibitors (anti-VGFI).
4- Viral infection: HCV, CMV, BK and parvovirus
5- Genetic abnormalities in the complement cascade
6- Phenotypical shift of C3 GN (with ESRD) to an aHUS post-transplantation.
7- Missed diagnosis of TMA in the native kidney (recurrent TMA). Which is more prevalent, de novo or recurrent TMA?
De novo TMA is more prevalent after kidney transplantation and it seems to be underestimated. Although; recurrent TMA has 36.5 times risk of recurrence in recipients with ESRD due to hemolytic
uremic syndrome (HUS) as compared to other etiologies. Etiopathogenesis of de novo TMA AMR and medications are main causes of de novo TMA. Underlying complement abnormalities determined in one third of patients in one study. i- Immunosuppression medications
1- Calcineurin-induced TMA: mechanism is:
a- Loss of equilibrium between the vasodilators (PG E2 , PG12) and vasoconstrictors (thromboxane A2, endothelin), which results in arteriolar vasoconstriction, renal ischemia and establishment of endothelial injury.
b- CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity especially with the presence of endothelial injury due to AMR, ischemia-reperfusion injury or any etiology.
c- Microparticle production from endothelial cells, as effect of CyA that can result in activation of AP. The role of CNI in TMA has been speculated to be opposed by many points:
1- 95% of recipients use CNI as maintenance therapy and only a small number can develop TMA which suggests presence of another underlying factor.
2- CNI withdrawal in de novo TMA does not always results in good graft outcome.
3- USRDS based study shows a significantly higher incidence of TMA in the group of KTR that was not under CNI maintenance therapy (11.9/1000/year), as compared to those on CNI maintenance (5.0/1000/year).
2- .mTOR inhibitor-associated TMA:
Mechanisms: 1- mTORi has antiangiogenic properties, and decrease renal expression of vascular endothelial progenitor cells. 2- The VEGF inhibition has been recently proven to be associated with reduced renal level of complement factor H (CFH), patients with CFH genetic mutations are susceptible to develop de novo TMA with mTORi. 3- mTORi can obstruct repair of endothelial injury. 4- The procoagulant and the antifibrinolytic activity of mTORi might play roles in de novo TMA.
ii- AMR-associated de novo TMA:
Endothelial cellsare a well-known target of allo-immune response. Peritubular capillary (PTC) C4d staining (which is a marker of AMR) has been reported to be present in 16.2% of biopsied patients with TMA. The incidence of TMA is 55% in those express diffuse PTC C4d positivity. v- Viral infections:
BK, CMV, HCV, parvovirus iv- antiviral medications
Ribavirin and interferon V-Disseminated histoplasmosis Vi- Ischemia-reperfusion injury. vii- acquired disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency. viii- recipient with C3 GN as a cause of ESRD can undergo phenotypic shift to de novo TMA post-transpamtation. ix- Complement gene mutations: Renal complement activation is the common denominator in TMA development. Genetic mutations in CFH, Complement FactorⅠ (CFI) or both occurs in de novo TMA patients, low Complement Factor B (CFB) and/or low C3, suggesting an AP complement activation. Relation to TMA evolution: CFH and CFI are main regulators for AP. CFH inhibit the C3 cleaving enzyme C3bBb. And it acts as co-factor for FI. CFI has the ability to inactivate C3b. Inactivation of these proteins either due to genetic mutations or development of neutralizing antibodies, can trigger an uncontrolled AP activity, leading to endothelial injury which is the pathogenic base of TMA. Clinical manifestation Timing: TMA can develop at any time post-transplantation. However; it is more common in the first 3-6 months, when the CNI trough levels are relatively high. Salient feature: a- Systemic form of TAM: Consists of a classical triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI). b- Localized (limited) TMA: Usually presented late with graft dysfunction, necessitating graft biopsy. When graft biopsy shows no evidence of rejection, TMA or renal artery stenosis should be excluded. The histopathologic changes In the active stage, there is evidence of endothelial cell injury with platelet aggregation (thrombosis), fibrinoid necrosis and glomerular ischemia. In the chronic stage, the basement membranes undergo duplication and multilayering with increased matrix layers and vessel wall cells, which ultimately ends in the unique onion skin formation. Once TMA diagnosed underlying cause of ESRD in the native kidney should be searched for, with prompt testing for genetic test mutations to discover any complement dysregulation and avoid missing the diagnosis of recurrent aHUS. As eculizumab; monoclonal, C5 blockade antibodies is effective treatment, and can be used also in prevention of recurrent TMA.
Prognosis of de novo TMA: 50% of the recipients loss their graft within 2 years from the diagnosis. A patient mortality rate of 50% after three years of diagnosis. Recurent TMA after renal transplantation: Etiology: Atypical HUS, thrombotic thrombocytopenic purpura (TTP), and autoimmune diseases. A HUS: Overactivation of the AP is known to be the underlying etiology of aHUS. By far, aHUS is the most common diagnosis in TMA associated with recurrence. The reported rate of aHUS recurrence approached 70%-90%. Etiology: mutational abnormality involving CFH and CFI. Untreated patients, however, ultimately develop graft loss at a rate of 90%, with 80% of them occurring in the first year. TTP is the second recognized etiology in TMA. Genetic or acquired lack of ADAMTS13 has been recognized. In the past the differentiation between the TTP and aHUS was depending on the presence of neurological involvement in TTP and renal dysfunction in aHUS. Serology test for ADAMTS13 activity is now feasible. Overlap between the both condition exist. PATHOPHYSIOLOGY OF TMA RECURRENCE
It is increasingly recognized that complement dysregulation is the fundamental etiology involved in TMA evolution. Both genetic aberrations as well as autoantibodies can be involved in this process. Usually, there is (are) an inciting environmental trigger factor(s). Classification of TMA
1- primary:
1. aHUS with complement gene mutations.
2. TTP with ADAMTS13 mutations.
3. cblC deficiency mediated TMA.
4. DGKE-associated TMA.
2- primary acquired:
1.TTP with ADAMTS13 autoantibodies.
2. aHUS with FH autoantibodies.
3- Infection associated:
1. STEC- HUS.
2. Pneumococcal HUS (distinct mechanisms result in TMA).
3. HIV-associated TMA.
4. Other infections (ill defined, infection may trigger a primary TMA).
4- Secondary TMA
1. Drug-induced TMA.
2. De novo TMA after SOT.
3. Pregnancy-associated TMA (HELLP).
4. Malignancy-associated TMA.
5. TMA with severe HT.
6. TMA with glomerular diseases (MN, MPGN, FSGS, IgAN, AAV).
7. TMA with autoimmune diseases (e.g. SLE, CAPS, SRC).
8. TMA after bone marrow transplant
CFH, CFI, CFB, C3, MCP, THBD, and CFHR1 del mutation all play role in aHUS. DGKE mutation may play a fundamental role in regulating thrombosis in renal tissues. Environmental triggers:
Anti-HLA antibodies, viral infection, ischemia-reperfusion injury and immunosuppressive medications. Acute vs chronic lesion?
Timing of an aHUS episode is not easily predictable. Many patients are at persistent risk of recurrence. Penetrance in aHUS is age-related, by age 70, penetrance reaches 64%. The late presentation of aHUS reflects the impact of the environmental triggers. Current use of eculizumab has an impact on the natural history of aHUS. Complement inhibition improves glomerular perfusion. Withdrawal of this agent, cause complement reaction with endothelium. Extrarenal manifestation:
20% of patients have extrarenal manifestations:
digital gangrene, cerebral artery thrombosis, myocardial infarction, in addition to ocular, GIT, pulmonary and neurologic involvement. Laboratory investigations and differential diagnosis:
ADAMTS13 activity is urgently mandated to exclude TTP diagnosis.
Eculizumab therapy should be instituted early without waiting for the results of ADAMTS13 activity.
Complement assessment in aHUS: serum complement should be thoroughly evaluated before any therapy. C3 level cannot be used as a screening criteria for aHUS. Because its low in 30% of cases. CD46 expression assessed by flow cytometry. Functional parameters and activation markersshould be also determined. Their role in treatment guide needs further study. Panel of genetic testing: The diagnostic list of genes of aHUS should include at least CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE.
Full-detailed genetic mapping, allows proper diagnosis and therapeutic plans, and helps in genetic counseling, particularly in living related-donation. Rationale for genetic screening:
Full genetic map before transplantation is important as it helps:
1- Determine the actual cause of the disease, so allows for correct genetic counseling.
2- Planning disease management.
3- Expecting response for therapy. 4- Define prognosis. Interpretation of the genetic variants:
according to the international guidelines: genetic mutation typed as:
(1) Benign; (2) Likely benign; (3) Variant of uncertain significance;
(4) Likely pathogenic; or (5) Pathogenic. Acquired drivers of aHUS: The FH autoantibodies are the best reported example. If anti-CHF autoantibody is positive, confirmation test should be repeated 2 weeks later, and on regular base. Diagnosis of aHUS recurrence:
Once diagnosis of aHUS is suspected, a detailed clinical history is needed. As well, full biochemical, genetic and pathological investigations of the AP should bedone, including:
(1) Estimation of the anti-CFH AB;
(2) MCP screening on the peripheral blood WBCs;
(3) Examination of the recombination in CFHR region; and
(4) Screening of the genetic mutations related to CFH, CFI, CFB, C3, and MCP.
Although; genetic screen is difficult and complex, it is so important to determine the outcome. Therapy of TMA post-transplantation:
Treatment should be individualized.
The following approaches have been suggested:
(1) Immunosuppressive medication management: the role of immunosuppressive medications (e.g., CNI or mTORi) has been reported in the literature, with a documented better response after switching from one CNI member to another or to an mTORi). But this approach is not universal. The withdrawal of the offending agent should be the first line in treating de novo TMA, as it corrects the hematological abnormalities.
(2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG)
(3) Belatacept: A promising agent, allows withdrawal of the offending drug contributes in TMA evolution.
(4) Complement inhibition: Eculizumab, the use of this vital biological agent should be confined to a specified subset of de novo TMA patients, presumably: (1) AMR-associated TMA; (2) Patients who
became PE-dependent; and (3) Refractory hemolysis persists despite maximum doses of PE therapy. More efforts are needed to clarify the best way to utilize this costly drug. Treatment of recurrent TMA Recommendations for recurrent TMA based on case report and expertise opinion are: 1- Genetic screen includes: CFH, CFI, CFHR, CFB, MCP and C3 at least. 2- All patients with primary or suspected aHUS, should be surveyed for all complement components and its related proteins. 3- Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation. 4- Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy. 5- Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation. Prevention of aHUS:
1. Endothelial injury caused by ischemia-reperfusion injury, viral infection and immunosuppression should be avoided.
2. a reported relation between aHUS and CNI has been recognized, although, the usual substitute in such case (mTORi) is nor free of this and can induce recurrent aHUS.
3. PE failed to prevent aHUS recurrence in many cases, so it is not the sole therapy. Beneficial effect of rituximab can be enhanced by adding PE therapy.
4. The anti-C5 monoclonal antibiotic eculizumab has been reported to be used successfully. Duration of therapy: There is not enough data supporting life-long therapy for aHUS. Renal transplant Timing six months after initiation of dialysis, as limited kidney recovery can occur months after given eculizumab. Disappearance of the extrarenal manifestations as well as resolution of TMA hematological parameters are the prerequisite for kidney transplantation. Risk of donation:
Any potential donor proved to exhibit alternative pathway dysregulation should be excluded.
level 4
Huda Mazloum
2 years ago
● TMA after transplantation can be classified into either:
(1) De novo TMA
(2) Recurrent TMA
DE NOVO TMA
● factors trigger de novo TMA include:
(1) Antibody mediated rejection (AMR)
(2) Immunosuppressive-associated TMA (CNI) or (mTORi)
(3) Others e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI)
(4) Viral infection: e.g., HCV, CMV, BK and parvovirus
(5) Genetic abnormalities in the complement cascade
(6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation
(7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA)
● the risk of posttransplant TMA recurrence was 36.5 times higher in kidney transplant recipients
● the incidence of de novo TMA to be 1.5%.
● de novo TMA is more prevalent than recurrent TMA after kidney transplantation
● Graft loss rate of 40% is reported in de novo TMA within a couple of years of diagnosis
● AMR and medications are the two main causes of de novo TMA.
● highest risk of de novo TMA was in the group using CNi and mTORi
● TMA is mostly encountered in the first 3-6 mo post transplantation.
● Prognosis of de novo TMA: quite poor for the patient and as well as the allograft. ● Recurrence rate in aHUS patients is as high as 60%.
● graft loss in 90%, with 80% of them occurring in the first year
● TTP recurrence after transplantation
● lupus nephritis, wherein patients can develop TMA in 5%-10% with documented recurrence after kidney transplantation
● complement dysregulation is the fundamental etiology involved in TMA evolution.
● Primary hereditary TMA: Includes mutations in complement components.
● Primary acquired TMA: Autoantibodies
● Infection-associated TMA: STEC-HUS and pneumococcal HUS
● Secondary TMA: pregnancy-associated TMA or de novo TMA after transplantation, may associated with genetic predisposition
● The process of aHUS recurrence can be triggered by anti-HLA antibodies , viral infection, ischemia-reperfusion injury and immunosuppressive medications
● Penetrance in aHUS is age-related, by age 70, penetrance reaches 64%
● Laboratory investigations
ADAMTS13 activity
Complement assessment in aHUS: C3 , CD46 ,CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE , CFH-H3 and MCP
● Treatment of de novo TMA :
** withdrawal of the offending agent
** Plasmapheresis (PE)
** intravenous immunoglobulins (IVIG)
** Belatacept: its role is only to replace the culprit drug
** Eculizumab, an anti-C5 agent use in :
(1) AMR-associated TMA
(2) Patients who became PE-dependent
(3) Refractory hemolysis persists despite maximum doses of PE therapy
● Prevention of aHUS:
** avoid injury to endothelium, e.g., ischemia-reperfusion injury, viral infection and immunosuppressive medications
** Certain relations have been reported between CNI use and aHUS recurrence in such a case (an mTOR) is not innocent and can induce recurrenc
** Adding rituximab ti PE therapy
** Anti-C5 monoclonal eculizumab
● Treatment of DGKE mutation associated TMA: feasibility of kidney transplantation with no recurrence after transplantation.
● RENAL TRANSPLANTATION
** Renal transplantation should be six months after institution of dialysis
** Disappearance of the extrarenal manifestations
** resolution of TMA hematological parameters are the prerequisite for kidney transplantation.
● Two risks to be associated with living-related kidney donation:
(1) Recurrent disease in the recipient
(2) De novo disease in the donor, if he/she is a genetic mutation carrier
● “Liver transplantation” may be reserved for patients with liverderived complement protein aberrations, particularly in patients poorly responding to complement blockade
● Future therapy
(1) Purified products of the deficient genes
(2) C3 convertase inhibitors
● Research targets
(1) The anti-C3b blocker, compstatin analog Cp40
(2) The anti-C3 convertase monoclonal antibodies
● Level : 5
Assafi Mohammed
2 years ago
Summary of the article “Thrombotic microangiopathy after renal transplantation- Current insights in de novo and recurrent disease”
This is a narrative review article, addressing de novo and recurrent TMA in the post-transplant period. De novo TMA Precipitating factors in the context of renal transplantation:
· Antibody mediated rejection (AMR).
· Immunosuppressive-associated TMA: CNI or mTOR inhibitors (mTORi), single or combined.
· Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI).
· Viral infection: e.g., HCV, CMV, BK and parvovirus.
· Genetic abnormalities in the complement cascade.
· Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation.
· Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA).
· An acquired disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency another rare risk factor, has been shown in one case to represent post-transplant TMA.
· Complement gene mutations: CFH, Complement FactorI(CFI), low Complement Factor B (CFB) and/or low C3, suggesting an AP complement activation.
De novo TMA; Prevalence
· According to USRDS-based study, the risk of post- transplant TMA recurrence was 36.5 times higher in kidney transplant recipients with ESRD due to hemolytic uremic syndrome (HUS) as compared to other etiologies (29.2% vs 0.8%).
De novo TMA; Clinical manifestations
1. TMA could develop at any time in the post transplantation course, and is mostly encountered in the first 3-6 mo post-transplantation.
2. Salient features:
· TMA manifestations are quite variable and can vary from a limited form confined to the kidney to a full blown systemic variant. The systemic form of TMA consists of the classic triad of:
a) Thrombocytopenia
b) Microangiopathic Hemolytic Anemia (MAHA)
c) Acute kidney injury (AKI) Localized (limited) TMA is usually presented later in TMA course, as compared to the systemic form, necessitating the diagnostic allograft biopsy.
De novo TMA; Prognosis
· The prognosis of post- transplant de novo TMA is quite poor for the patient and as well as the allograft.
· About one half of the patients loses their graft within the first two years after diagnosis.
· The USRDS-based report presented by Reynolds et al, reported a patient mortality rate of 50% after three years of diagnosis.
· Schwimmeret al reported that 54% of systemic TMA develops dialysis-requiring AKI and 38% lost their grafts.
· None of the patients with localized TMA developed TMA-related early graft loss or required dialysis.
De novo TMA; treatment
Therapeutic maneuvers should be individualized for each patient. The following approaches have been suggested:
· Immuno- suppressive medication management.
· Plasmapheresis (PE) and intravenous immunoglobulins (IVIG).
· Belatacept: A promising alternate option that allows withdrawal of the offending drug incriminated in TMA evolution.
· Complement inhibition: Eculizumab, an anti-C5 agent, blocks the lytic C5b-9 membrane attack complex generation.
Recurrent TMA after renal transplantation Recurrent TMA; Etiology
1. aHUS; The global rate of recurrence in aHUS patients is reported to be as high as 60%. Untreated patients, however, ultimately develop graft loss at a rate of 90%, with 80% of them occurring in the first year. Recurrence of TMA in the allograft depends on:
a) The underlying type involving the native kidney.
b) Overactivation of the AP is known to be the underlying etiology of aHUS.
c) Mutational gene defects;
· involving CFH and CFI, regulatory complement components produced by the liver, results in aberrant CFH and CFI.
· Membrane co-factor protein (MCP), a transmembrane complement regulatory component that is produced by kidney endothelial cells even in post-transplant period, keeps aHUS recurrence lower unless other mutational gene defects have been associated. 2. Thrombotic Thrombocytopenic Purpura (TTP);
· Either due to genetic or acquired lack of ADAMTS13.
· Zafraniet al documented the presence of AKI in more than half of TTP patients (with low ADAMTS13 activity) and 50% progression of CKD and even ESRD.
3. Autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus, with or without anti-phospholipid antibody syndrome.
· e.g.; lupus nephritis,wherein patients can develop TMA in 5%-10% with documented recurrence after kidney transplantation.
TMA; Current classification: includes the following:
1. Primary hereditary TMA:Includes mutations in ADAMTS13, MMACHC (cb1c deficiency), or in genes encoding complement components.
2. Primary acquired TMA:Autoantibodies to ADAMTS13 or to CFH, which occurs with homozygous CFHR3/1 deletion.
3. Infection-associated TMA:Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) and pneumococcal HUS have distinct mechanisms that result in TMA; in other infections, the processes are ill-defined and sometimes can trigger manifestations of the primary TMA.
4. Secondary TMA:Presents in a variety of conditions.
· Drug-induced TMA.
· De novo TMA after SOT.
· Pregnancy-associated TMA (HELLP).
· Malignancy-associated TMA.
· TMA with severe HT.
· TMA with glomerular diseases (MN, MPGN, FSGS, IgAN, AAV).
· TMA with autoimmune diseases (e.g. SLE, CAPS, SRC).
· TMA after bone marrow transplant. Recurrent TMA; treatment Recommendations for recurrent TMA(level 4 evidence):
· The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3.
· All patients with primary or suspected aHUS, should be surveyed for all complement components and its related proteins.
· Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation.
· Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy.
· Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation.
Prevention of aHUS:
The following strategies are suggested to decrease/prevent aHUS:
· Complement activity incited by an injury to endothelium, e.g., ischemia-reperfusion injury, viral infection and immuno- suppressive medications, should be avoided.
· Certain relations have been reported between CNI use and aHUS recurrence, which is not confirmed by other authors, even the usual substitute in such a case (an mTOR) is not innocent and can induce recurrence.
· We cannot depend solely on PE therapy in management of aHUS recurrence for several reasons:
a) PE failed to prevent aHUS recurrence in many cases.
b) PE cannot guarantee prevention of aHUS recurrence after cessation of therapy.
c) Many cases under PE therapy were proved to develop “subclinical” aHUS recurrence, which means that PE therapy cannot influence complement activity.
d) Prophylactic use of rituximab proved to be efficacious as anti-CFH-antibodies, the beneficial effect of rituximab can be enhanced by adding PE therapy.
· The anti-C5 monoclonal antibiotic eculizumab has been reported to be used successfully to prevent aHUS recurrence in patients with CFH, CFH/CFHR1 hybrid genes as well as with C3 gene mu- tations.
TMA and renal transplantation:
1. Timing
· Renal transplantation should be postponed six months after institution of dialysis., as limited kidney recovery can occur several months after commencing eculizu- mab therapy.
· Disappearance of the extrarenal manifestations as well as resolution of TMA hematological parameters are the prerequisite for kidney transplantation.
· The magnitude of risk of recurrence can be utilized to guide the necessity of anti-complement blockade.
2. Risk of kidney donation
Two risks have been reported to be associated with living-related kidney donation:
1. Recurrent disease in the recipient.
2. De novo disease in the donor, if he/she is a genetic mutation carrier.
3. Any potential donor proved to exhibit alternative pathway dysregulation should be excluded.
4. Any potential living-related donor devoid of complement gene abnormalities can be permitted.
5. “Liver transplantation” may be reserved for patients with liver- derived complement protein aberrations, particularly in patients poorly responding to complement blockade .
3. Future therapy ;
· Purified products of the deficient genes.
· C3 convertase inhibitors.
What is the level of evidence provided by this article?
This is a narrative review article
Level of evidence grade 5.
Abdul Rahim Khan
2 years ago
Please summarise this article
Thrombotic microangiopathy is a devastating complication after renal transplant.
Types-
Denovo
Recurrent
Denovo TMA is more common than recurrent. It has poor prognosis that recurrent. Typical Haemolytic uremic syndrome is rare. Denovo TMA is a heterogenous set of various etiologies and constitutes the vast majority of post-transplant TMA cases.
Denovo TMA
Common aetiological factors include-
Antibody mediated rejection
Immunosuppressive-associated TMA: Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi
Viral infection: e.g., HCV, CMV, BK and parvovirus
Genetic abnormalities in the complement cascade-Phenotypical shift of C3 glomerulopathy HUS post transplantation
Missed diagnosis of TMA in the native kidney as a cause of ESRD
Etiopathogenesis.
Calcineurin-induced TMA-
Underlying mechanisms include-
Loss of the normal balance between the vasodilator peptides and prostacyclin and the vasoconstrictor peptides
CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity
Microparticle production from endothelial cells.
mTOR inhibitor-associated TMA
mTORi has antiangiogenic properties
The VEGF inhibition has been recently proven to be associated with reduced renal levels of complement factor H
Repair of endothelial injury could be hampered by mTORi use.
AMR associated De Novo TMA.
Presentation.
Can present anytime but usually 3-6 months.
Systemic form may have thrombocytopenia, hemolytic anemia and AKI
In case of graft dysfunction when biopsy does not show rejection then suspect TRAS or TMA.
Treatment of Denovo TMA
Immunosuppressive medication- CNI or mTORi
Plasmapheresis (PE) and intravenous immunoglobulins (IVIG
Belatacept
Complement inhibition: Eculizumab, an anti-C5 agent
Treatment of recurrent TMA
The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3
All patients with primary or suspected aHUS, should be surveyed for all complement components
Patients with isolated MCP associated mutations may be safe for kidney donation
Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange
Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation
What is the level of evidence provided by this article?
Level V
hussam juda
2 years ago
INTRODUCTION
· Thrombotic microangiopathy (TMA) after transplantation can be classified into either: De novo TMA and Recurrent TMA
· Missed diagnosis of TMA pre-transplant may happen as biopsy not done in ESKD patients
· As anti C5 monoclonal antibody(eculizumab), is highly effective in prevention and treatment of atypical hemolytic uremic syndrome (aHUS), it worth while to diagnose TMA pre-transplantation
· This review will discuss the main differences between the two categories in the pathophysiology, clinical course and available approaches of prevention and treatment.
DE NOVO TMA
· precipitating factors: (1) Antibody mediated rejection (AMR); (2) CNI or mTORi, single or combined; (3) anti-VGFI (4) HCV, CMV, BK and parvovirus infection (5) Genetic abnormalities in the complement cascade; (6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation; and (7) Recurrence of missed TMA
· The incidence of de novo TMA may reach 3%-14% and more prevalent than recurrent TMA, however the risk of posttransplant TMA recurrence was 36.5 times higher in kidney transplant recipients with ESRD due to HUS as compared to other etiologies
Calcineurin-induced TMA: suggested mechnisms:
1. Loss of the normal balance between the vasodilator peptides and the
vasoconstrictor peptides
2. CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity
3. Microparticle production from endothelial cells
Points against CNI involvement in TMA:
1. 95% of transplant patients on CNI, while small percentage develop TMA
2. CNI withdrawal does not improve graft outcome all the time
3. A USRDSbased study demonstrates a significantly higher incidence of TMA in the group of KTR that was not under CNI maintenance therapy, as compared to those on CNI maintenance
mTOR inhibitor-associated TMA: suggested explanation:
1. mTORi has antiangiogenic properties, and can decrease renal expression of VEGF with death of the endothelial progenitor cells
2. The VEGF inhibition may be associated with reduced renal levels of complement factor H, and those with CFH genetic mutations are more susceptible to develop de novo TMA, particularly with mTORi exposure
3. Repair of endothelial injury could be inhibited by mTORi use
4. The procoagulant and the antifibrinolytic activity of mTORi
AMR-associated de novo TMA:
· The peritubular capillary C4d staining has been reported to be present in 16.2% of biopsied recipients with TMA
Clinical manifestations
· Timing: it could occur at any time, but mostly in the first 3-6 mo post transplantation
· Salient features: classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI)
-MAHA: raised LDH, drop in Hb, decreased haptoglobin with schistocytes on peripheral blood smear
· TMA should be suspected in recipient with impaired graft function with no rejection in biopsy
· Histopathology:
-In active stage of TMA: endothelial cell injury with platelet aggregation (thrombosis), fibrinoid necrosis and glomerular ischemia
– In the chronic stage: the basement membranes undergo duplication and multilayering with increased matrix layers and vessel wall cells ( ends with onion skin formation) Prognosis of de novo TMA:
· About one half of the patients loses their graft within the first two years after diagnosis
· patient mortality is about 50% after three years of diagnosis
RECURRENT TMA AFTER RENAL TRANSPLANTATION Etiology of recurrent TMA: aHUS; TTP; and autoimmune diseases: e.g., scleroderma and SLE, with or without anti-phospholipid antibody syndrome aHUS:
· aHUS is the most common diagnosis in TMA associated with recurrence
· recurrence rate 70%-90% in CFH and CFI mutations
· Membrane co-factor protein (MCP), lower aHUS recurrence
· 90% of untreated patients loose their gtrafts TTP:
· TTP is the second recognized etiology in TMA
· Genetic or acquired lack of ADAMTS13 has been recognized
· complete distinction between TTP and HUS is not always possible because of overlap in manifestations and 50 % of TTP patients may have low ADAMTS13 activity
PATHOPHYSIOLOGY OF TMA RECURRENCE
· “membrane regulators” are: (1) Membrane cofactor protein (2) Complement receptor 1 (3) Decay accelerating factor and (4) Protectin (CD59), which prohibits MAC formation
· Any disturbance in one of those will lead to complement activation with subsequent endothelial cell derangement Current classification of TMA: 1. Primary hereditary TMA: Includes mutations in ADAMTS13, MMACHC (cb1c deficiency), or in genes encoding complement components. 2. Primary acquired TMA: Autoantibodies to ADAMTS13 or to CFH, which occurs with homozygous CFHR3/1 deletion. 3. Infection-associated TMA: STEC-HUS, pneumococcal, and other infections 4. Secondary TMA: e.g., pregnancy-associated TMA or de novo TMA after transplantation
· The most common complement mutation in aHUS is CFH, with 40% of cases inherited and 25% sporadic
· The risk of aHUS recurrence could be four times higher with CFH mutations or with the carriers of CFH/ CFHR1 hybrid genes
· Any HUS that is not due to STEC-HUS has been called aHUS Acute vs chronic lesion?
· Penetrance in aHUS is age-related, by age 70, penetrance reaches 64%
· The late presentation of aHUS reflects the impact of the environmental triggers
Extrarenal manifestation: digital gangrene, cerebral artery thrombosis, myocardial infarction, in addition ocular, GIT, pulmonary and neurologic involvement
Laboratory investigations and differential diagnosis:
· Urgent ADAMTS13 activity
· 5% of STEC-HUS patients have no prodromal diarrhea and 30% of complement-mediated aHUS patients can present with a diarrheal prodrome
· C3 is low in 30% of aHUS patients and, therefore cannot be used as a screening criteria for aHUS
· CD46 surface expression should be assessed by flow cytometry
· The diagnostic list of genes of aHUS should include at least CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE
· Rationale for genetic screening: a full detailed genetic map before transplant should be done as may help in diagnosis, plan, treatment, and prognosis
· Interpretation of the genetic variants: (1) Benign (2) Likely benign (3) Variant of uncertain significance (4) Likely pathogenic (5) Pathogenic Diagnosis of aHUS recurrence:
· tissue diagnosis with LM, IF and electron microscopy
· Estimation of the anti-CFH AB
· MCP screening on the peripheral blood WBCs
· Examination of the recombination in CFHR region
· Screening of the genetic mutations related to CFH, CFI, CFB, C3, and MCP THERAPY OF POST-TRANSPLANT TMA Treatment of de novo TMA
· switching from one CNI member to another or to an mTORi
· Plasmapheresis and IVIG. Effictive in treating patients with TTP and previously was first line therapy for aHUS
· Belatacept: its role is only to replace/displace the offending drug
· Eculizumab, an anti-C5 agent, effective in treatment and in prevention of recurrent aHUS after renal transplantation, but it has high cost and should be confined to a specified patient:
(1) AMR-associated TMA; (2) Patients who became PE-dependent; and (3) Refractory hemolysis persists despite maximum doses of PE therapy Treatment of recurrent TMA
Recommendations for recurrent TMA:
(1) The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3
(2) All patients with primary or suspected aHUS, should be surveyed for all complement components and its related proteins;
(3) Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation;
(4) Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy
(5) Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation Prevention of aHUS:
1) Avoid complement activity (ischemia-reperfusion injury, viral infection and immunosuppressive medications
2) Trial with substitution of CNI with mTORi, but may recures
3) PE failed to prevent aHUS recurrence in many cases, and even “subclinical” aHUS recurrence in patients under PE therapy
4) The anti-C5 monoclonal antibiotic eculizumab has been used successfully to prevent aHUS recurrence
Kidney transplantation without eculizumab prophylaxis:
Can be successful through minimizing cold ischemic time, decreasing the risk of rejection and, thereby, providing endothelial protection
RENAL TRANSPLANTATION Timing
· Renal transplantation should be postponed six months after institution of dialysis
· We should wait for disappearance of the extrarenal manifestations and resolution of TMA hematological parameters Risk of living kidney donation:
1. Recurrent disease in the recipient
2. De novo disease in the donor, if he/she is a genetic mutation carrier Future therapy
1. Purified products of the deficient genes
2. C3 convertase inhibitors Research targets
1. The anti-C3b blocker, compstatin analog Cp40
2. The anti-C3 convertase monoclonal antibodies CONCLUSION
· TMA, either de novo or recurrent, effect on allograft is underestimated
· Genes involved in TMA etiology is currently expanding
· complement blockade therapy effective in early stages
· The recurrent TMA have better prognosis if complement blockade drugs given before permanent damage
Evidence 5
Hadeel Badawi
2 years ago
TMA is a debilitating complication of kidney transplantation that is associated with poor patient and graft outcomes.
The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year, with a 50% mortality rate three years after diagnosis.
Post-transplant TMA classification:
– De novo TMA, no evidence of the disease before transplant more prevalent
– Recurrent TMA came back in renal transplantation.
Differentiation is crucial as it will have clear clinical and therapeutic implications.
DE NOVO TMA Trigger the development of de novo TMA:
– AMR.
-IS-associated TMA: CNI or mTORi, single or combined
-Other medications: anti-VGFI
-Viral infection: e.g., HCV, CMV, BK and parvovirus
-Genetic abnormalities in the complement cascade.
-Phenotypical shift of C3 glomerulopathy (with ESRD) to an aHUS post-transplantation.
-Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA).
Pathogenesis of de novo TMA Calcineurin-induced TMA
– Arteriolar vasoconstriction and renal ischemia that results in endothelial injury
– CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity
– Microparticle production (CyA) from endothelial cells that can result in activation of the AP.
mTOR inhibitor-associated TMA
-Antiangiogenic properties decrease renal expression of VEGF with the death of the endothelial progenitor cells.
-Reduce renal levels of CFH
-Repair of endothelial injury could be hampered
-Procoagulant and the antifibrinolytic activity
AMR-associated de novo TMA
– Endothelial cells are the target of alloimmune response.
– PTC C4d staining has been reported in 16.2% of biopsied recipients with TMA.
– Both AMR and TMA would predict much worse graft outcomes.
Complement gene mutations
The presence of genetic mutations in CFH, CFI or both in 29% of de novo TMA patients, 25% showed low CFB and/or low C3,
suggesting an AP complement activation.
Clinical manifestations Timing: can occur at any time, mostly encountered in the first 3-6 m post-transplantation. Salient features:
– variable and can vary from a limited form confined to the kidney to a full-blown systemic variant.
– The systemic form consists of the classic triad of thrombocytopenia, MAHA and AKI.
– Localized (limited) usually presented later, necessitating the diagnostic allograft biopsy.
Prognosis of de novo TMA
De novo TMA is relatively poor for the patient and the allograft. About 50 % of the patients lose their graft within the first two years after diagnosis.
RECURRENT TMA AFTER RENAL TRANSPLANTATION
Etiology of recurrent TMA aHUS:
-The most common diagnosis in TMA associated with recurrence
-Risk of recurrence depends on the underlying type involving the native kidney
– Global rate of recurrence as high as 60%, graft loss at a rate of 90%,
Thrombotic thrombocytopenic purpura (TTP)
– Genetic or acquired lack of ADAMTS13
– Recurrence risk 5%-10%
Autoimmune diseases: scleroderma and SLE, with or without APLA
PATHOPHYSIOLOGY OF TMA RECURRENCE
Complement dysregulation is the fundamental etiology involved in TMA evolution. Both genetic aberrations, as well as autoantibodies can be involved in this process. Usually, there is (are) an inciting environmental trigger factor(s).
The current classification of TMA includes the following
Primary hereditary TMA
Primary acquired TMA
Infection-associated TMA
Secondary TMA
THERAPY OF POST-TRANSPLANT TMA
Treatment of de novo TMA
-IS management: documented better response after switching from one CNI to another or mTORi
– The withdrawal of the offending agent should be the first line in treating de novo TMA.
– Plasmapheresis (PE) and IVIG.
– Belatacept: an alternate option that allows withdrawal of the offending drug
– Complement inhibition: Eculizumab.
Treatment of recurrent TMA Prophylactic complement blockade: Gene abnormalities have been reported to be associated with aHUS recurrence in 80% of patients
Therapeutic protocols for aHUS recurrence
The available data points to two strategies:
-Minimal dosage to establish complement blockade
– Dose withdrawal scheme Duration of therapy: There is not enough data supporting life-long therapy for aHUS. Cessation of therapy appears to be plausible in certain situations
RENAL TRANSPLANTATION Timing:
Should be postponed six monthsafter the institution of dialysis, as limited kidney recovery can occur several months after commencing eculizumab
Prerequisite for transplantation
The disappearance of the extrarenal manifestations
Resolution of TMA hematological parameter. Risk of kidney donation
Any potential donor proven to exhibit AP dysregulation should be excluded. Future therapy
-Purified products of the deficient genes;
-C3 convertase inhibitors
Level of evidence 5 narrative review.
KAMAL ELGORASHI
2 years ago
Summary of the Article;
Thrombotic Microangiopathy is a very risky complication post donation that is associated with poor patient and graft survival. Incidence rate is about 5.6 cases /1000 KT/year, with 50% mortality rate after 3 years post donation. Classification;
De novo TMA, develop for first time with no previous evidence of TMA pre-transplant.
Recurrent TMA; native kidney failed as a result of proved diagnosis of TMA and recur again post transplantation.
TMA of grafted kidney post Tx, as a recurrence of undiagnosed TMA pretransplantation, and been the cause of failure.
De novo TMA; Factors cause development of De novo TMA;
Phenotypical shift of C3 glomerulopathy, (with ESRD), to an aHUS post Tx.
Missed diagnosis of TMA pre- transplantation in the native kidney as a cause of ESKD, (recurrent TMA).
The most prevalent;
Reynolds et al.; in the US Renal Data System (USRDS)-based study; Recuurent TMA was only 12, while 112 cases with De novo TMA, so the of De novo TMA was 36.5 higher incidence than recurrent TMA, as a cause of ESKD due to HUS, as compared to other aetiologies, (29.2% vs 0.8%).
Langer et al.; De novo TMA was 1.5%, however the incidence is high as 3%-14%.
Graft loss rate about 40% reported in De novo TMA.
CNI induce TMA;
Mechanism of explanation;
Loss of normal balance between the vasodilator, (PGE2, prostacyclin), and the vasoconstrictors (thromboxane A2, Endothelin), result in arteriolr vasoconstriction, renal ischemia, and endothelial injury.
CNI- induce platelet activation, procoagulant, and anti-fibrinolytic activity noticed to be involve in TMA incidence.
Microparticle production from endothelial cells, as side effects of CyA, lead to Ap activation, which results in TMA.
Points which against CNI induce TMA;
More than 95% Tx recipients take CyA as pillar of IS medication, and small number develop TMA, so other possibilities are suggested.
CNI withdrawal always not affect the graft outcome.
USRDS-based study, reported a high incidence of De novo TMA in non-CNI based IS regiment, compared to that on maintenance CNI therapy.
mTOR inhibitor-ass TMA; Both sirolimus and everolimus had TMA incidence reports, explained as follow;
Decreade VEGF expression with death of endithelial progenitor cells as a result of antiangiogenic property of mTORi.
mTOR as a result reduce VEGF expression, with resultant reduce CFH, those patients are more susceptible to de novo TMA.
mTOR use hamper endothelial injury repair.
mTOR property of procaagulant and antifibrinolytic play an important role in TMA development.
AMR-ass de novo TMA; Commonly reported and well noticed, as endothelial cell are the target site of allo-immune response, C4d staining present in 16.2% of biopsies with TMA. Clinical manifestation; Timing; Ocurr at any time, but commonly reported at 3-6 month post Tx. Features.
Systemic; present with classical triad, (Thrombocytopenia, MAHA, AKI).
Limited to kidney.
Prognosis of de novo TMA;
Diagnosis is poor for both recipient and graft.
50% lost their garft within 2 years of diagnosis.
50% mortality rate after 3 years of diagnosis.
54% of systemic TMA develop AKI require dialysis, and 38% lost their graft.
Localize TMA do not develop early graft loss or required dialysis.
Both types ass with poor long term graft survival.
Switch from one CNI to another or to mTOR, as way to stop offending agent.
PE and IVIG.
Balatacept; CD80 and CD86 blocker.
Eculizumab; anti-CD5 agents, a complemant inhibition, as large number of TMAs ass with complement activation.
Treatment of Recurrent TMA;
The minimum list of genetic screening should be done, (CFH, CFI, CFHR, CFB, MCP, and C3).
aHUS suspected cases should do all complement component survey.
Isolated CMP ass mutation can be safe for donation.
Documented aHUS with no evident genetic mutation can be donate under umbrella of intensive PE therapy.
Polygenic pattern should be considered with the extreme caution in case of living donation.
Renal transplantation; Timing;
Should be postpended 6 month after initiation of dialysis because of renal failure due to TMA, Conduct transplantation after disappearance of systemic manifestation and TMA hematological parameters. Conclusion;
The impact or whether type of TMA on grafted kidney outcome is underestimated.
Delayed diagnosis is rather fatal and can lead to graft loss. Early starting management with complement blockade before permanent endothelial damage is much hoping in recurrent TMA.
Level of evidence; level ((V)) article review
Rihab Elidrisi
2 years ago
It is very aggressive disease which tends to occurs post RTX as De novo TMA
we have two type Denovo and recurrent TMA
De novo TMA, post RTX can be triggered by AMR OR immunosuppression medications like CNI,viral infection like CMV,BKV,HCV.
CNI can produce TMA via three potential pathways. Loss of the normal equilibrium between vasodilator peptides (such as prostaglandin and prostacyclin) and vasoconstrictor peptides (thromboxane A2 and endothelin) may be the cause of arterial vasoconstriction, renal ischemia, and endothelial damage. CNI causes platelet activation, procoagulant and antifibrinolytic action, which may contribute to the development of TMA
It typically appears as the traditional triad of thrombocytopenia, microangiopathic hemolytic anemia (characterized by an increase in LDH and a reduction in hemoglobin), and acute kidney damage.
Recurrent TMA
: Viral infection, e.g., CMV infection, BK virus, parvovirus, chronic hepatitis C virus.
antiviral medications, e.g., ribavirin and interferon.
disseminated histoplasmosis.
Ischemia-reperfusion injury.
(ADAMTS13) deficiency.
C3 glomerulopathy disease in a native kidney can undergo phenotypical shift and present after kidney transplantation as de novo TMA.
What is the level of evidence provided by this article? Level 5
Mohamad Habli
2 years ago
Introduction
Thrombotic microangiopathy is a severe post-kidney transplantation complication linked with a poor allograft prognosis. It can be divided into de novo TMA and recurrent TMA. De novo TMA is more common than recurrent TMA, and it is considerably more common following a kidney transplant.
TMA is categorized into De novo TMA and recurrent TMA
De novo TMA
It can be triggered by a variety of factors, including AMR, immunosuppressive-associated TMA, CNI, mTORi, anti-vascular endothelial growth factor inhibitors, viral infections (HCV, CMV, BK, and parvovirus), genetic abnormalities in the complement cascade, phenotypical shift of C3 glomerulopathy, and a missed diagnosis of TMA in the native cell. These variables are typically accompanied by acquired or inherited impairment of the alternative complement pathway.
CNI can produce TMA via three potential pathways. Loss of the normal equilibrium between vasodilator peptides (such as prostaglandin and prostacyclin) and vasoconstrictor peptides (thromboxane A2 and endothelin) may be the cause of arterial vasoconstriction, renal ischemia, and endothelial damage. CNI causes platelet activation, procoagulant and antifibrinolytic action, which may contribute to the development of TMA. TMA evolution can also be induced by endothelial cell microparticle generation. mTORi have antiangiogenic capabilities, and these actions have been linked to the pathophysiology of TMA, although their precise involvement is still understood. Endothelial cells are a well-known target of allo-immune response, and the involvement of AMR in post-transplantation is also well-established.
TMA could develop at any time after a transplant, although it is more prevalent in the first 3 to 6 months after the transplant. It typically appears as the traditional triad of thrombocytopenia, microangiopathic hemolytic anemia (characterized by an increase in LDH and a reduction in hemoglobin), and acute kidney damage. A kidney biopsy will not reveal acute rejection, as histopathologic alterations are typically non-specific. Thrombosis, fibrinoid necrosis, and glomerular ischemia are signs of endothelial cell damage during the active phase. In the chronic phase, basement membranes undergo replication and stacking, resulting in the creation of a characteristic onion peel.
After a diagnosis of TMA has been made, immediate treatment of the potential cause should be undertaken. Unfortunately, both the patient and the graft have a bad prognosis. It may also necessitate dialysis and has the potential to cause patient death.
Recurrent TMA
It may result from atypical hemolytic uremic syndrome, thrombotic thrombocytopenic purpura , or autoimmune illnesses.The recurrence of TMA after the transplant depends on the subtype affecting the original kidney. It is known that the fundamental cause of aHUS is the overactivation of the AP. The most prevalent cause of TMA TTP is the second most prevalent cause of repeated TMA. A deficiency in ADAMTS13 has been identified as the reason. It could be bought or inherited. Histopathology demonstrates persistent endothelial damage. Typically, the AP is active and includes strict regulatory components. Any perturbation involving any of the defensive processes will result in complement activation and endothelial cell derangement. This condition is referred to as complement dysregulation. It can occur at any time, is difficult to predict, and so patients are at risk of recurrence at all times. Additionally, it may appear as digital gangrene, cerebral artery thrombosis, or myocardial infarction.
Once the diagnosis of aHUS is suspected, the diagnosis of TTP must be ruled out by excluding ADAMTS13 activity. Flow cytometry should be used to determine the surface expression of CD46. Include CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5, and DKGE on the diagnostic list of genes for aHUS. Genetic testing enables accurate genetic counseling, planning for disease management, evaluation of the anticipated response to treatment, and determination of the prognosis for the allograft and patient survival. A comprehensive clinical history is required for the diagnosis of recurrent aHUS. Studies involving light microscopy, immunofluorescence, and electron microscopy should be able to provide a conclusive tissue diagnosis.
Interpretation of genetic variants
Genetic mutations may be perceived as
– benign
– Likely benign.
-Variant with unknown significance.
– Probably pathogenic
– pathogenic.
Diagnosis of aHUS recurrence:
1- A comprehensive clinical history is generally required.
2-An established tissue diagnosis with (LM), (IF), and (EM) investigations to support the diagnosis of aHUS in the native kidney should be provided.
3-Once aHUS is detected, a comprehensive battery of biochemical, genetic, and histological examinations of the AP should be performed.
Prophylaxis against the recurrence of atypical hemolytic uremic syndrome in allografts based on a risk assessment strategy
High risk (50-100%): a history of early recurrence, pathogenic mutations, or gain-of-function mutations. Prophylactic eculizumab start on the day of transplantatioecause of the risk of severe recurrence and restricted time for treatment.
Moderate risk: no detected mutations, isolated CFI mutations, or insignificant complement gene mutations. suggested prophylaxis with eculizumab or plasma exchange.
Low risk: isolated MCP mutations or persistently negative FH autoantibodies. No need for prophylaxis
Huda Al-Taee
2 years ago
De novo TMA:
Precipitating factors:
Antibody-mediated rejection.
Immunosuppressive-associated TMA: CNI, mTORi, single or combined.
Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI).
Viral infection: e.g., HCV, CMV, BK and parvovirus.
Genetic abnormalities in the complement cascade.
Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post-transplantation.
Missed diagnosis of TMA in the native kidney as a cause of ESRD.
De novo TMA is more prevalent after kidney transplantation and is presumably underestimated. A graft loss rate of 40% is reported in de novo TMA within a couple of years of diagnosis.
Etiopathogenesis of de novo TMA
Calcineurin-induced TMA:
Three underlying mechanisms could explain the role of CNI in TMA development:
Loss of the normal balance between the vasodilator peptides (e.g., prostaglandin E2 and prostacyclin) and the vasoconstrictor peptides (e.g., thromboxane A2 and endothelin), results in arteriolar vasoconstriction, renal ischemia and establishment of endothelial injury,
CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity have been shown to be involved in TMA evolution, particularly so, with an injured endothelium due to AMR, ischemia-reperfusion injury or any other aetiology.
Microparticle production from endothelial cells, which can result in activation of the AP, a well-known mechanism that is implicated in TMA evolution.
mTOR inhibitor-associated TMA:
Mechanism:
mTORi has antiangiogenic properties and can decrease renal expression of vascular endothelial growth factor with the death of the endothelial progenitor cells.
VEGF inhibition has been recently proven to be associated with reduced renal levels of complement factor H. Patients with underlying CFH genetic mutations are more susceptible to develop de novo TMA, particularly with mTORi exposure.
Repair of endothelial injury could be hampered by mTORi use.
the procoagulant and the antifibrinolytic activity of mTORi might play additional roles in de novo TMA development.
AMR-associated de novo TMA:
Endothelial cells are a well-known target of alloimmune response.
The peritubular capillary C4d staining has been reported to be present in 16.2% of biopsied recipients with TMA.
clustering of both AMR and TMA would predict a much worse graft outcome.
Other causes:
: Viral infection, e.g., CMV infection, BK virus, parvovirus, chronic hepatitis C virus.
antiviral medications, e.g., ribavirin and interferon.
disseminated histoplasmosis.
Ischemia-reperfusion injury.
(ADAMTS13) deficiency.
C3 glomerulopathy disease in a native kidney can undergo phenotypical shift and present after kidney transplantation as de novo TMA.
Complement gene mutations:
A study reported the presence of genetic mutations in CFH, CFI or both in 29% of their studied de novo TMA patients; 25% showed low CFB and/or low C3, suggesting an AP complement activation.
Clinical manifestations:
Timing: develop at any time in the post-transplantation course, mostly in the first 3-6 mo post-transplantation.
Salient features: manifestations are quite variable and can vary from a limited form confined to the kidney to a full blown systemic variant.
systemic form: consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia and acute kidney injury.
Prognosis of de novo TMA:
The prognosis of post-transplant de novo TMA is quite poor for the patient and as well as the allograft. About one-half of the patients lose their graft within the first two years after diagnosis.
Recurrent TMA after transplantation:
Etiology:
aHUS: aHUS is the most common diagnosis in TMA associated with recurrence. CFH and CFI have a robust impact in the evolution of aHUS recurrence. The reported rate of aHUS recurrence approached 70%-90%. Membrane co-factor protein keeps aHUS recurrence lower unless other mutational gene defects have been associated.
TTP: P is the second recognized etiology in TMA. Genetic or acquired lack of ADAMTS13 has been recognized. complete distinction between TTP & HUS is not always possible because of overlap in manifestations. It is reasonable to expect TTP recurrence as long as the underlying defect is present after transplantation.
Current classification of TMA:
Primary hereditary TMA: Includes mutations in ADAMTS13, MMACHC (cb1c deficiency), or in genes encoding complement components.
Primary acquired TMA: Autoantibodies to ADAMTS13 or to CFH, which occurs with homozygous CFHR3/1 deletion.
Infection-associated TMA: Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) and pneumococcal HUS have distinct mechanisms that result in TMA.
Secondary TMA: Presents in a variety of conditions.
Extrarenal manifestation:
digital gangrene.
cerebral artery thrombosis.
myocardial infarction.
ocular, GIT, pulmonary and neurologic involvement.
Drusen formation is not common in aHUS.
Laboratory investigations:
Complement assessment in aHUS:
C3 is low in 30% of aHUS patients and, therefore cannot be used as a screening criteria for aHUS.
CD46 surface expression should be assessed by flow cytometry.
Panel of genetic testing:
CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE.
CFH-H3 and MCP ggaac haplotypes.
Diagnosis of aHUS recurrence:
history
tissue diagnosis with light microscopy, immunofluorescence and electron microscopy.
Estimation of the anti-CFH AB, MCP screening on the peripheral blood WBCs, Examination of the recombination in CFHR region, and Screening of the genetic mutations related to CFH, CFI, CFB, C3, and MCP.
Treatment:
Treatment of de novo TMA:
therapeutic manoeuvres should be individualized for each patient due to the heterogenicity of the disease.
Immunosuppressive medication management: switching from one CNI member to another or to a mTORi.
Plasmapheresis and intravenous immunoglobulins.
Belatacept.
Eculizumab
Treatment of recurrent TMA:
Prevention of aHUS:
Complement activity incited by an injury to endothelium such as ischemia-reperfusion injury, viral infection and immunosuppressive medications, should be avoided.
Certain relations have been reported between CNI use and aHUS recurrence[160], which is not confirmed by other authors.
cannot depend solely on PE therapy in the management of aHUS recurrence.
eculizumab has been reported to be used successfully to prevent aHUS recurrence in patients with CFH, CFH/CFHR1 hybrid genes as well as with C3 gene mutations.
Therapeutic protocols for aHUS recurrence:
Once the diagnosis of primary aHUS has been established, complement blockade therapy should be instituted with a goal of a minimal dosage to establish complement blockade; and a dose withdrawal scheme with close monitoring of the antibody titer.
Duration of therapy:
There is not enough data supporting life-long therapy.
Enough time should be permitted to optimize renal recovery and satisfy TMA resolution.
Renal Transplantation:
Timing:
Renal transplantation should be postponed six months after the institution of dialysis, as limited kidney recovery can occur several months after commencing eculizumab therapy.
The disappearance of the extrarenal manifestations, as well as the resolution of TMA hematological parameters, are the prerequisite for kidney transplantation.
Risk of kidney donation:
Recurrent disease in the recipient.
De novo disease in the donor, if he/she is a genetic mutation carrier.
Future therapy:
Purified products of the deficient genes.
C3 convertase inhibitors.
Level of Evidence:
Level 5 ( review article ).
Reem Younis
2 years ago
Please summarise this article
-Thrombotic microangiopathy (TMA) is a debilitating complication of kidney transplantation that is associated with poor patient and graft outcomes.
-The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis.
– TMA after transplantation can be classified into either: (1) De novo TMA.(2) Recurrent TMA.
–DE NOVO TMA
– Precipitating factors include the following: (1) Antibody mediated rejection (AMR); (2) Immunosuppressive-associated TMA: Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi), single or combined; (3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI); (4) Viral infection: e.g., HCV, CMV, BK and parvovirus; (5) Genetic abnormalities in the complement cascade; (6)
Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation; and (7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA). Etiopathogenesis of de novo TMA
-AMR and medications are the two main causes of de novo TMA.
-Calcineurin-induced TMA: Three underlying mechanisms could explain the role of CNI in TMA development: (1) Loss of the normal balance between the vasodilator peptides and the vasoconstrictor peptides results in arteriolar vasoconstriction[8,9], renal ischemia and establishment of endothelial injury(2) CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity.
(3) Microparticle production from endothelial cells . mTOR inhibitor-associated TMA
-Both sirolimus and everolimus have been reported to be implicated in the pathogenesis of de novo TMA.
-The following explanations have been given: (1) mTORi has antiangiogenic properties, and can decrease renal expression of vascular endothelial growth factor (VEGF) with death of the endothelial progenitor cells. (2) The VEGF inhibition has been recently proven to be associated with reduced renal levels of complement factor H (CFH). (3) Repair of endothelial injury could be hampered by mTORi use; and (4)The procoagulant and the antifibrinolytic activity of mTORi might play additional roles in de novo TMA development. AMR-associated de novo TMA:
-Endothelial cells are a well-known target of allo-immune response.
The peritubular capillary (PTC) C4d staining has been reported to be present in 16.2% of biopsied recipients with TMA. Complement gene mutations. Clinical manifestations:
– TMA could develop at any time in the post transplantation course, however this syndrome is mostly encountered in the first 3-6 mo post transplantation.
– The systemic form of TMA consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI). Prognosis of de novo TMA:
– The prognosis of posttransplant de novo TMA is quite poor for the patient and as well as the allograft. About one half of the patients loses their graft within the first two years after diagnosis. RECURRENT TMA AFTER RENAL TRANSPLANTATION Etiology of recurrent TMA
-aHUS; thrombotic thrombocytopenic purpura (TTP); and autoimmune disease. Current classification of TMA includes the following
Primary hereditary TMA .
Primary acquired TMA .
Infection-associated TMA .
Secondary TMA. THERAPY OF POST-TRANSPLANT TMA Treatment of de novo TMA
– The following approaches have been suggested: (1) Immunosuppressive medication management. (2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG). (3) Belatacept. (4) Complement inhibition: Eculizumab, an anti-C5
agent, blocks the lytic C5b-9 membrane attack complex
generation. Treatment of recurrent TMA
Recommendations for recurrent TMA: (1) The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3(2) All patients with primary or
suspected aHUS, should be surveyed for all complement components and its related proteins; (3) Patients with isolated MCP associated mutations may be safe for kidney donation; (4) Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy[ ; and (5) Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation. -Risk of kidney donation
Two risks have been reported to be associated with living-related kidney donation: (1) Recurrent disease in the recipient; and (2) De novo disease in the donor, if he/she is a genetic mutation carrier
-Any potential donor proved to exhibit alternative pathway
dysregulation should be excluded. What is the level of evidence provided by this article?
Level 5
abosaeed mohamed
2 years ago
· Introduction :
– TMA is a debilitating complication of kidney transplantation which affect outcome. The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis. It can be de novo or recurrent TMA . >>DE NOVO TMA : – Can be associated with:
(1) Antibody mediated rejection (AMR)
(2) Immunosuppressive-associated TMA: Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi), single or combined
(3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI)
(4) Viral infection: e.g., HCV, CMV, BK and parvovirus
(5) Genetic abnormalities in the complement cascade
(6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation
(7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA)
· C/P :
Timing : TMA could develop at any time in the post transplantation course, however this syndrome is mostly encountered in the first 3-6 mo post transplantation. This is probably when the CNI immunosuppressive trough levels are relatively higher
– can vary from a limited form confined to the kidney to a full blown systemic variant
– The systemic form of TMA consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI). Features of MAHA include raised lactic acid dehydrogenase (LDH), drop in hemoglobin (HB) and decreased haptoglobin with schistocytes on peripheral blood smear
– When a renal transplant recipient has significant renal dysfunction and the biopsy does not show any acute rejection, one must suspect two possibilities: (1) TMA or (2) Renal artery stenosis.
– The Limited form can present only with u explained renal dysfunction , The histopathologic changes are usually non-specific but vary in the acute status to the chronic angiopathic changes. In the active stage, there is evidence of endothelial cell injury with platelet aggregation (thrombosis), fibrinoid necrosis and glomerular ischemia. In the chronic stage, the basement membranes undergo duplication and multilayering with increased matrix layers and vessel wall cells, which ultimately ends in the unique onion skin formation
– Prognosis of de novo TMA: The prognosis of posttransplant de novo TMA is quite poor for the patient and as well as the allograft. About one half of the patients loses their graft within the first two years after diagnosis >>RECURRENT TMA AFTER RENAL TRANSPLANTATION :
– Etiology of recurrent TMA : aHUS , thrombotic thrombocytopenic purpura (TTP) , and autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus, with or without anti-phospholipid antibody syndrome >>”Spectrum of TMA”
– Primary hereditary:
1. aHUS with complement gene mutations. 2. TTP with ADAMTS13 mutations. 3. cblC deficiency mediated TMA. 4. DGKE-associated TMA.
– Primary acquired:
1. TTP with ADAMTS13 autoantibodies. 2. aHUS with FH autoantibodies.
– Infection associated:
1. STEC- HUS. 2. Pneumococcal HUS (distinct mechanisms result in TMA). 3. HIV-associated TMA. 4. Other infections (ill defined, infection may trigger manifestation of a primary TMA). – Secondary TMA: 1. Drug-induced TMA. 2. De novo TMA after SOT. 3. Pregnancy-associated TMA (HELLP). 4. Malignancy-associated TMA. 5. TMA with severe HT. 6. TMA with glomerular diseases (MN, MPGN, FSGS, IgAN, AAV). 7. TMA with autoimmune diseases (e.g. SLE, CAPS, SRC). 8. TMA after bone marrow transplant
– Extrarenal manifestation of aHUS : Twenty percent of aHUS patients can express extrarenal manifestations in the form of digital gangrene, cerebral artery thrombosis, myocardial infarction, in addition to ocular, GIT, pulmonary and neurologic involvement .Drusen formation is not common in aHUS
– once diagnosis of aHUS is suspected , screening of ADAMTS13 level & activity is mandatory , in children can start eculizumab immediately without witing the results based on that incidence of TTP in children is less common .also sending for complement assessment & genetic testing for diagnosis.
· Treatment of de novo TMA :
– Should be individualized for each patient .
– (1) Immunosuppressive medication management : can shift from one CNI member to another or to an mTORi although some debates on this but Whatever the situation would be, the withdrawal of the offending agent should be the first line in treating de novo TMA .
– (2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG): Two benefits have been postulated for this type of therapy: Removal of the platelet aggregation factors, e.g., thromboxane A2 and the simultaneous replenishment of the deficient factors, e.g., PGI2-stimulating factor , In AMR-associated TMA, an improved outcome has been reported, which was attributed to removal of the anti-HLA antibodies. A 100% response has been reported to be associated with PE/IVIG therapy in five solid organ transplantation with systemic TMA with no evidence of relapse after withdrawal of the culprit agent (e.g., tacrolimus) in a recent study
– (3) Belatacept: Belatacept is an immunosuppressive co-stimulatory blocker against CD80 and CD86 surface ligands and CD28 on T cells. The first case report in 2009 documented TMA resolution after belatacept therapy used for immunosuppression in post-transplantation TMA due to CNI-induced endothelial toxicity[138]. Two case series have followed, thereafter documenting fair graft outcome due to resolution of the CNI-induced TM. Of note, belatacept has nothing to do with the underlying endothelial derangement, its role is only to replace/displace the culprit drug
– (4) Complement inhibition: Eculizumab, an anti-C5 agent, blocks the lytic C5b-9 membrane attack complex generation. it was proven to be effective in treatment as well as in prevention of recurrent aHUS after renal transplantation. A large percentage of patients with diagnosed TMA express complement activation, including those patients with unrecognized complement genes. This efficacy has been also documented in patients with refractory AMR with TMA
· Treatment of recurrent TMA :
– Prevention of aHUS: The following strategies are suggested to decrease/prevent aHUS:
(1) Complement activity incited by an injury to endothelium, e.g., ischemia-reperfusion injury, viral infection and immunosuppressive medications, should be avoided.
(2) Certain relations have been reported between CNI use and aHUS recurrence, which is not confirmed by other authors, even the usual substitute in such a case (an mTOR) is not innocent and can induce recurrence.
(3) We cannot depend solely on PE therapy in management of aHUS recurrence for several reasons: PE failed to prevent aHUS recurrence in many cases, PE cannot guarantee prevention of aHUS recurrence after cessation of therapy; Many cases under PE therapy were proved to develop “subclinical” aHUS recurrence, which means that PE therapy cannot influence complement activity; Prophylactic use of rituximab proved to be efficacious as anti-CFH-antibodies, the beneficial effect of rituximab can be enhanced by adding PE therapy.
(4) The anti-C5 monoclonal antibiotic eculizumab has been reported to be used successfully to prevent aHUS recurrence in patients with CFH, CFH/CFHR1 hybrid genes as well as with C3 gene mutations.
Prophylaxis against atypical hemolytic uremic syndrome recurrence in allograft based on a risk-assessment strategy :
– High risk (50-100%): Previous early recurrence,Pathogenic mutations or Gain-of-function mutations >> Prophylactic eculizumab Start on the day of transplantation due to potential for severe recurrence and limited
– Moderate risk : no mutation identified, Isolated CFI mutations or Insignificant complement gene mutation>>>prophylactic eculizumab or plasma exchange.
– Low risk : Isolated MCP( membrane cofactor protein) mutations or Persistently negative FH autoantibodies>> No prophylaxis
– Eculizumab dose & monitoring : Minimal dose Desire to continue dosing with the minimal dose required to achieve a pre-identified level of complement blockade .Dose reduction or interval extension Goal CH50 < 10% (recommended) Goal AH50 < 10% (recommended) Goal eculizumab trough > 100 μg/mL Discontinuation Desire to discontinue complement blockade: No consensus exists regarding tapering of dose
· RENAL TRANSPLANTATION
· Timing >> should be postponed six months after institution of dialysis, as limited kidney recovery can occur several months after commencing eculizumab therapy. Disappearance of the extrarenal manifestations as well as resolution of TMA hematological parameters are the prerequisite for kidney transplantation. The magnitude of risk of recurrence can be utilized to guide the necessity of anti-complement blockade
· Risk of kidney donation >>Two risks have been reported to be associated with living-related kidney donation: (1) Recurrent disease in the recipient; and (2) De novo disease in the donor, if he/she is a genetic mutation carrier. Any potential donor proved to exhibit alternative pathway dysregulation should be excluded. On the other hand, any potential living-related donor devoid of complement gene abnormalities can be permitted. “Liver transplantation” may be reserved for patients with liver derived complement protein aberrations, particularly in patients poorly responding to complement blockade.
· The following future therapeutic agents have been addressed: (1) Purified products of the deficient genes; and (2) C3 convertase inhibitors
level of evidence >>>level 5 , article review
Hussein Bagha baghahussein@yahoo.com
2 years ago
Introduction
Thrombotic microangiopathy (TMA) is a significant complication of kidney transplant recipients, associated with poor graft prognosis. It can be classified into either de novo TMA or recurrent TMA. De novo TMA is more prevalent than recurrent TMA and even more prevalent after kidney transplantation.
De novo TMA
It can be triggered by many factors, such as antibody mediated rejection (AMR), immunosuppressive-associated TMA: calcineurin inhibitors (CNI), mTOR inhibitors (mTORi), anti-vascular endothelial growth factor inhibitors, viral infections (HCV, CMV, BK and parvovirus), genetic abnormalities in the complement cascade, phenotypical shift of C3 glomerulopathy and a missed diagnosis of TMA in the native kidney. These factors usually occur in a background of acquired or genetic dysfunction of the alternative complement pathway.
CNI can induce TMA by three possible mechanisms. It could be because of the loss of the normal balance between the vasodilator peptides (for example prostaglandin and prostacyclin) and the vasoconstrictor peptides (thromboxane A2 and endothelin) which results in arterial vasoconstriction, renal ischemia and endothelial injury. CNI induces activation of platelets, pro-coagulant and anti-fibrinolytic activity which may cause the evolution of TMA. Microparticle production from endothelial cells can also induce TMA evolution. mTORi have antiangiogenic properties and these effects have been implicated in TMA pathogenesis, but the exact role is still unknown. Endothelial cells are a well-known target of allo-immune response and hence the role of AMR in post transplantation is well known.
TMA could develop at any time post transplantation, but it most commonly occurs in the first 3 to 6 months post the transplantation. It usually manifests as the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (seen as increased LDH, a decrease in hemoglobin) and acute kidney injury. A renal biopsy will not show acute rejection, the histopathologic changes are usually non-specific. In the active stage, we see evidence of endothelial cell injury with thrombosis, fibrinoid necrosis and glomerular ischemia. In the chronic stage, the basement membranes undergo duplication and layering that leads to a unique onion skin formation.
Once TMA has been diagnosed, prompt treatment of the possible etiology should be initiated. Unfortunately, the prognosis is quite poor for the patient and the graft. It may also lead to the requirement of dialysis, and may also lead to patient mortality.
Recurrent TMA
It may be caused by atypical hemolytic uremic syndrome (aHUS), thrombotic thrombocytopenic purpura (TTP) and autoimmune diseases (such as scleroderma and systemic lupus erythematous).
Recurrence of TMA in the allograft depends on the type involving the native kidney. Overactivation of the AP is known to be the underlying cause of aHUS. It is the most common cause of TMA. TTP is the second most common cause of recurrent TMA. It has been recognized that the cause is a lack of ADAMTS13. It could be either genetic or acquired. Histopathology shows ongoing endothelial injury. The AP is usually active and has stringent regulatory components. Any disturbance involving any of the protective mechanisms will lead to complement activation with subsequent endothelial cell derangement. This is recognized as complement dysregulation. It can occur at any time, it is not easy to predict and therefore the patients are at a constant risk of recurrence. It may also manifest in other forms such as digital gangrene, cerebral artery thrombosis and myocardial infarction.
Once the diagnosis of aHUS is suspected, TTP diagnosis has to be excluded by the exclusion of ADAMTS13 activity. CD46 surface expression should be assessed by flow cytometry. The diagnostic list of genes in aHUS should include CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DKGE. Determining the actual cause of the disease by genetic testing allows for correct genetic counselling, planning for disease management, evaluation of the expected response to treatment and defining the prognostic course of the allograft and the patient survival. For the diagnosis of aHUS recurrence, a detailed clinical history is warranted. A proven tissue diagnosis with light microscopy, immunofluorescence and electron microscopy studies should be available.
The current classification of TMA includes the following:
Primary hereditary TMA
Mutations in ADAMTS13, MMACHC
Primary acquired TMA
Autoantibodies to ADAMTS13
Infection-associated TMA
Shiga toxin-producing Escherichia coli-HUS, pneumococcal HUS
Secondary TMA
Multifactorial
Drug induced TMA
Malignancy-associated TMA
De novo TMA after solid organ transplantation
TMA with autoimmune diseases
TMA with glomerular diseases
Treatment of de novo TMA involves individualizing the therapeutic maneuvers for each patient, as the manifestations and response to treatment are variable. Treatment involves adjusting the immunosuppressant medications, plasmapheresis, intravenous immunoglobulins, belatacept (an immunosuppressive co-stimulatory blocker against CD80 and CD86 surface ligands), eculizumab (an anti-C5 agent that blocks the complement pathway).
Prevention of recurrent TMA is important and the following strategies can be used:
1. Complement activity incited by an injury to the endothelium should be avoided (e.g. viral infections, immunosuppressive medications)
2. Substitution of CNIs
3. Plasmapheresis cannot suffice as the sole treatment
4. Use of eclizumab.
Therapeutic protocols for aHUS recurrence include complement blockade therapy with minimal dosage to establish complement blockade and a dose withdrawal scheme.
The duration of therapy should be enough time for renal recovery and TMA resolution.
Renal transplantation should be delayed for 6 months after starting dialysis and eclizumab therapy. Recurrent disease in the recipient and de novo disease have been recognized as risks for living related kidney donation.
Conclusion:
TMA, either de novo or recurrent can lead to graft loss and has been associated with increased mortality as well. Recurrent TMA has treatment options available unlike de novo TMA. It is important to diagnose TMA promptly and institute the management immediately including removing the offending drug like CNIs or mTORIs, or treatment of the viral infections.
club 5, TMA after KT (denovo or recurrent disease)
Summary:
· TMA post transplantation has deleterious effects on both the graft and patient outcome. it accounts for 5.6 cases per 1000
· Denovo is more common and has worse prognosis than recurrent TMA.
· Recurrent TMA has genetic background. as in case of atypical HUS with mutation in regulatory proteins in alternative complement pathway. proper choice of the donor and exclusion of carrier state in living related donor is essential to minimize the risk of recurrence.
· Treatment includes PEX, stoppage of offending drugs as CNI, or need for ecluizimab (c5A blockage).
· Denovo TMA:
triggers:
· Genetic mutation in regulatory factors of complement pathway (factor H, I loss of function mutations, while factor B, C3 have gain of function mutation).
· CFH is the most common detected mutation with recurrence in 70-90%, CFB has the highest recurrence (100%), MCP has lowest recurrence 15-20%.
· Use of CNI or or anti VEGF by Loss of normal balance between the vasodilator (PG) E2 and prostacyclin (PG12)) and the vasoconstrictor thromboxane A2 and endothelin eventually leading to renal ischemia and endothelial injury.In addition, CNI-has platelet activation, pro-coagulation and anti-fibrinolytic activity.
· Use of m TORi as they have antiangiogenic properties, and can decrease renal expression of vascular endothelial growth factor (VEGF) that leads to decreased level of regulatory factor H, in addition, it inhibits repair of endothelial injury.
· The effect of drug induced TMA, is accentuated by combined use of CNI and mTORi.
· ABMR as endothelial injury is a target site of damage in ABMR.
· Missed diagnosis of TMA as a cause of ESKD in native kidney (did not do biopsy
· viral infection as HCV, CMV or BK. clinical presentation: More common and has Worse (50% graft loss after 2 years) and (50% mortality after 3 years).
· Can be presented at any time, but mostly at 3-6 months post transplantation.
· Either full blown systemic features with triad of decreased platelet count, microangiopathic hemolytic anemia and AKI.
· local or renal confined, presented with acute graft dysfunction and diagnosed by allograft biopsy (presence of thrombosis and fibrinoid necrosis)_
· Revision of original kidney disease is essential, as diagnosis can be missed as misdiagnosed as hypertensive nephrosclerosis. hence, genetic testing is essential to diagnose missed a HUS. Recurrent TMA: · Etiology:
· recurrence of original kidney disease as a HUS, TTP , SLE and antiphospholipid syndrome.
· aHUS is most common recurrent form of TMA, with recurrence approached 70%-90% in factor H and I mutation. while MCP has lower rate of recurrence.
· The most common complement mutation in aHUS is CFH, with 40% of cases inherited and 25% sporadic
· TTP was discriminated from a HUS by presence of neurological manifestations however, nowadays its diagnosis based on detection of low level of ADMATS 13.
· SLE with TMA has 10 % risk of recurrence after KT.
· Triggers;
· either single or multiple factors as viral infections, ABMR and CNI use.
Less common and has Better prognosis than Denovo TMA.
Recurrence of HUS after transplantation and presented with classic triad (decreased platelet count, microangiopathic hemolytic anemia and AKI).
NB:
· Recent trends in genetic mutations of complement regulatory factors includes copy number variation (CNV), hybrid genes, and the complex genomic rearrangements of CFH/CFHRs genomic region.
Management of denovo TMA:
· for DENOVO drug induced: shift from CNI to mTORI and vice versa, or dose modification. promising data about use of beltacept to allow CNI withdrawal in cases of CNI induced TMA.
· PEX and IVIG used early in denovo TMA.
· Ecluizimab can be used in denovo TMA in the following conditions:
o AMR-associated TMA
o Patients who became PE-dependent
o Refractory hemolysis persists despite maximum doses of PE therapy
Management of recurrent TMA:
prophylaxis to prevent recurrence;
· a HUS
o PEX not prevent a HUS recurrence, but can decrease its severity.
o Rituximab proved to be efficacious as anti-CFH-antibodies
o prophylactic ecluizimab can be considered to decrease risk of recurrence.
· cases with +ve anti factor H antibodies:
o use either ecluizimab or PEX either for life.
o or use PEX or ecluizimab (plus anti cellular therapy as cyclophosphamide, rituximab or MMF) and monitor antibody titer.
o Discontinue anti cellular therapy if antibody titer falls below a pathogenic titer for at least 6 months.
· Transplantation without ecluizimab:
o Decreasing the risk of rejection with induction therapy.
o Tac based triple maintenance therapy.
o Minimizing cold ischemic time
o aspirin prophylaxis to provide endothelial protection
· Precaution in renal transplantation:
o Delay renal transplantation for six months after institution of dialysis to allow for hematological remission, to see remission of renal problems with start of ecluizimab.
o Screening for genetic mutations especially in living related donor: as 2 risks are present (1) Recurrent disease in the recipient; and (2) De novo disease in the donor, if he/she is carrier for genetic mutation.
o Permit only donors without genetic mutations.
o Combined liver-kidney transplantation should be preserved only in case of unavailability or none responsive to ecluizimab.
· Future therapy under research:
o Purified products of the deficient genes; and (2) C3 convertase inhibitors
Introduction: Thrombotic microangiopathy (TMA) is a serious, unwanted sequalae post kidney transplant it is either de novo, or recurrent disease. De novo TMA : either acquired or genetic dysregulation of the alternative complement pathway as follow: (1) Antibody mediated rejection (AMR), (2) medication and Immunosuppressive-associated TMA: Calcineurin inhibitors or mTOR inhibitors, and anti-vascular endothelial growth factor inhibitors. (4) Viral infection: e.g., HCV, CMV, BK and parvovirus. (5) Genetic abnormalities in the complement cascade; (6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation.(7) Missed diagnosis of TMA in the native kidney as a cause of ESRD. De novo is more frequent and serious than recurrent disease. Clinical manifestations: usually occur 3-6 months post-transplant, silent (kidney limited proved by biopsy) or clinically overt presentations (thrombocytopenia,AKI, hemolytic anemia+schistocytes on blood film , neurological deficit and fever) are observed. RECURRENT TMA AFTER RENAL TRANSPLANTATION: Atypical HUS- alternative complement mutations defects (CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE…etc), thrombotic thrombocytopenic purpura (TTP)- ADAMTS-13 level; cblC deficiency mediated TMA, DGKE-associated TMA, and autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus, with or without anti-phospholipid antibody syndrome. Laboratory investigations: Complement assessment in aHUS and genetic testing panel.
Treatment of post transplantation TMA : It is a difficult to treat disease, but for whom had history of TMA, should be on HD at least 6 months before transplantation done, genetic testing is required for those living related donors for a TMA induced ESRD recipient.( prevention!). High risk (50-100%): Previous early recurrence, Pathogenic mutations1, Gain-of-function mutations. Prophylactic Eculizumab start at the day of transplantation is recommended. Moderate risk: No mutation identified, Isolated CFI mutations, Insignificant complement gene mutation. Eculizumab, or plasma exchange prophylaxis is recommended. Low risk: isolated MCP mutations, Persistently negative FH autoantibodies. No prophylaxix recommended. For complement factor H mediated HUS = Plasma exchange or eculizumab indefinitely or use of anticellular therapy ( Rituximab, cyclophosphamide or MMF) with monitoring of FH antibodies titer if controlled then stop PE/Eculizumab.. Future therapy: (1) Purified products of the deficient genes; (2) C3 convertase inhibitors; and anti-C3 convertase monoclonal antibodies.
Conclusion: TMA, either de novo or recurrent, on allograft longevity is underestimated. Despite the landmark breakthrough of immense efficacy of complement blockade therapy, the outlook of this devastating syndrome remains poor if the diagnosis is delayed. Recurrent TMA is much more optimistic if there is timely intervention by complement blockade before permanent damage ensue. Knowing early predictors of TMA recurrence improves patient and graft outcomes.
What is the level of evidence provided by this article? Level of evidence V
Introduction;
————————
Post-transplant TMA can occur as a recurrence of the disease involving the native kidney or as denovo disease with no evidence of previous involvement
before transplant.
atypical hemolytic uremic syndrome is a rare disease that results from complement dysregulation with alternative pathway overactivity, denovo TMA is a heterogenous set of various etiologies and constitutes the vast majority of post-transplant TMA cases.
The incidence ;
————————–
The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis.
De novo TMA is more prevalent after kidney transplantation and presumably underestimated. Graft loss rate of 40% is reported in de novo TMA within a couple of years of diagnosis .
DENOVO TMA;
—————————–
A number of precipitating factors have been identified in the context of renal transplantation that trigger the development of de novo TMA, which include;
1- Antibody mediated rejection (AMR)
2- Immunosuppressive-associated TMA: Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi), single or combined.
3- Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI).
4- Viral infection: e.g., HCV, CMV, BK and parvovirus.
5- Genetic abnormalities in the complement cascade.
AMR and medications are the two main causes of de novo TMA.
Clinical manifestations;
——————————————–
1-The systemic form of TMA;
Consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI). Features of MAHA include raised lactic acid dehydrogenase (LDH), drop in hemoglobin (HB) and decreased haptoglobin with schistocytes on peripheral blood smear.
2-Localized (limited) TMA;
Is usually presented later in TMA course, as compared to the systemic form, which can be explained by the urgency of the systemic type, necessitating the diagnostic allograft biopsy .
The histopathologic changes are;
————————————————
A- usually non-specific but vary in the acute status to the chronic angiopathic changes.
B- In the active stage, there is evidence of endothelial cell injury with platelet aggregation (thrombosis), fibrinoid necrosis and glomerular ischemia.
C- In the chronic stage, the basement membranes undergo duplication and multilayering with increased matrix layers and vessel wall cells, which ultimately ends in the unique onion skin formation.
Prognosis of de novo TMA:
—————————————–
The prognosis of post- transplant de novo TMA is quite poor for the patient and as well as the allograft. About one half of the patients loses their graft within the first two years after diagnosis .
RECURRENT TMA AFTER RENAL TRANSPLANTATION;
————————————————————————————————
.
Etiology of recurrent TMA;
1-aHUS; thrombotic thrombocytopenic purpura (TTP).
2- autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus, with or without anti-phospholipid antibody syndrome .
Current classification of TMA includes the following;
———————————————————————————————–
1-Primary hereditary TMA:
Includes mutations in ADAMTS13, MMACHC (cb1c deficiency), or in genes encoding complement components.
2-Primary acquired TMA:
Autoantibodies to ADAMTS13 or to CFH, which occurs with homozygous CFHR3/1 deletion.
3-Infection-associated TMA:
Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) and pneumococcal HUS have distinct mechanisms that result in TMA
4-Secondary TMA:
Presents in a variety of conditions, and in many conditions the culprit mechanisms are usually multi factorial or unknown. In some secondary forms of TMA, e.g., pregnancy-associated TMA or de novo TMA after transplantation, a significant percentage of cases may be associated with genetic predisposition .
The most common complement mutation in aHUS is CFH, with 40% of cases inherited and 25% sporadic . The risk of aHUS recurrence could be four times higher with CFH mutations or with the carriers of CFH/ CFHR1 hybrid genes.
Environmental triggers:
————————————–
The process of aHUS recurrence can be triggered by ;
A-anti-HLA antibodies .
B-viral infection .
C-ischemia-reperfusion injury and im- munosuppressive medications.
Clinical assessment of aHUS:
—————————————————-
1-. Acute vs chronic lesion?
Timing of an aHUS episode is not easily predictable. Dissociation between the pathological entities and the clinical presentation have been reported. For example, TMA can be diagnosed in tissue biopsy without simultaneous decline in platelet count.
2-Extrarenal manifestation:
20%of aHUS patients can express extra renal manifestations in the form of ;
A- Digital gangrene.
B-Cerebral artery thrombosis.
C-Myocardial infarction .
D- Ocular, GIT, Pulmonary and Neurologic involvement .
3- Laboratory investigations and differentialdiagnosis:
Once the diagnosis of aHUS is suspected exclusion of ADAMTS13 activity is urgently mandated to exclude TTP diagnosis.
4- Complement assessment in aHUS:
Before commencing plasma therapy, serum complement component should be thoroughly evaluated. C3 is low in 30% of aHUS patients and, therefore cannot be used as a screening criteria for aHUS. CD46 surface expression should be assessed by flow cytometry.
5- Panel of genetic testing:
The diagnostic list of genes of aHUS should include at least CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE. Genotyping workup should also include CFH-H3 and MCP ggaac haplotypes.
Interpretation of the genetic variants:
————————————————————-
Genetic mutations can be interpreted as:
(1) Benign.
(2) Likely benign.
(3) Variant of uncertain significance.
(4) Likely pathogenic .
(5) Pathogenic, according to the international guidelines.
.
Diagnosis of aHUS recurrence:
————————————————-
1-A full detailed clinical history is usually warranted.
2-A proven tissue diagnosis with (LM), (IF) and (EM) studies supporting the diagnosis of aHUS in the native kidney should be available.
3-Once diagnosis of aHUS is suspected, a full battery of biochemical, genetic as well as pathological investigations of the AP should be accomplished .
Treatment of de novo TMA;
———————————————–
The following approaches have been suggested:
(1) Immunosuppressive medication managemen;
The withdrawal of the offending agent should be the first line in treating de novo TMA, a fundamental step that ultimately results in correction of the hematological profile.
There is a reported better response after switching from one CNI member to another or to an mTORi).
(2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG):
PE can be beneficial for two reasons:Removal of the abnormal mutant complement proteins and supplying normally functioning complement components.
3) Belatacept:
A promising alternate option that allows withdrawal of the offending drug incriminated in TMA evolution.
(4) Complement inhibition:
Efficacy of eculizumab has been documented in several case reports and case series in management of resistant cases of medication-associated TMA, including cases with unrecognized genetic defects. This efficacy has been also documented in patients with refractory AMR with TMA .
On the other hand, Cornell et al reported no difference in death-censored graft survival or biopsy finding at one year when they compared the outcome of eculizumab-treated patients with positive cross matching with controls, even though the incidence of acute AMR was less in the eculizumab group.
So, in view of these conflicting results as well as considering the high cost of the drug, the use of this vital biological agent should be confined to a specified subset of de novo TMA patients, presumably:
(1) AMR-associated TMA .
(2) Patients who became PE-dependent .
(3) Refractory hemolysis persists despite maximum doses of PE therapy.
Recommendations for recurrent TMA:
—————————————————————–
(1) The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3 .
2) All patients with primary or suspected aHUS, should be surveyed for all complement components and its related proteins.
(3) Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation .
(4) Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy .
(5) Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation.
Prevention of aHUS:
————————————–
The following strategies are suggested to decrease/prevent aHUS:
(1) Complement activity incited by an injury to endothelium, e.g., ischemia-reperfusion injury, viral infection and immunosuppressive medications, should be avoided.
2) Certain relations have been reported between CNI use and aHUS recurrence, which is not confirmed by other authors , even the usual substitute in such a case (an mTOR) is not innocent and can induce recurrence .
(3) Prophylactic use of rituximab proved to be efficacious as anti-CFH-antibodies , the beneficial effect of rituximab can be enhanced by adding PE therapy .
(4) The anti-C5 monoclonal antibiotic eculizumab has been reported to be used successfully to prevent aHUS recurrence in patients with CFH, CFH/CFHR1 hybrid genes as well as with C3 gene mutations .
Evidence of increased complement activity during aHUS episodes after exposure to a trigger, e.g., surgery or infection, clinical indication of complement blockade is suggested
RENAL TRANSPLANTATION;
———————————————————-
A-Timing;
1-Renal transplantation should be postponed six months after institution of dialysis, as limited kidney recovery can occur several months after commencing eculizumab therapy.
2- Disappearance of the extrarenal manifestations as well as resolution of TMA hematological parameters are the prerequisite for kidney transplantation.
B-Risk of kidney donation;
1-Two risks have been reported to be associated with living-related kidney donation:
(a) Recurrent disease in the recipient .
(b) De novo disease in the donor, if he/she is a genetic mutation carrier.
2-Any potential donor proved to exhibit alternative pathway dysregulation should be excluded.
3-On the other hand, any potential living-related donor devoid of complement gene abnormalities can be permitted.
4- “Liver transplantation” may be reserved for patients with liver derived complement protein aberrations, particularly in patients poorly responding to complement blockade .
What is the level of evidence provided by this article?
———————————————————————-
Level V
Introduction
De novo TMA: detected for the first time without
any previous occurrence of the disease before transplant
Recurrent TMA : recurrence of TMA in the graft after being the cause of failure of the native kidney before .
TMA diagnosis can be usually missed as biopsy is not regularly done for the native kidneys before transplantation.
Eculizumab is effective in prevention and treatment of a HUS that is why identification and differentiation of both denovo and recurrent have significant therapeutic implications. De novo TMA
Occurs due to certain defect of alternative pathway that could be acquired or genetic , superadded to it precipitating factors including
· Antibody mediated rejection (AMR)
· Immunosuppressive-associated TMA as CNI ,mTORi, either separately or together
· Other medications as anti-VGFI
· Viral infection
· Genetic abnormalities in the complement pathways
· Phenotypical shift of C3 glomerulopathy to an aHUS post transplantation
· Missed diagnosis of TMA in the native kidney as recurrence of TMA . Ø Incidence of denovo TMA
USRDS-based study published that denovo is more common than recurrent ,with 40% graft loss rate in the former type ,on the other hand the recurrence rate was 36.5 times higher for recipients with ESRD due to a HUS.
Ø Pathogenesis of denovo
The main etiology involves AMR ,medications and complement abnormalities. CNI induced TMA mechanism included
-Loss of the normal balance between the vasoconstrictor and the vasodilator peptides leading to arteriolar vasoconstriction and renal ischemia
-CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity
-cyclosporine can lead to macroparticle production from endothelial cells.
Meanwhile a USRDS based study demonstrated that KTR on CNI were less likely to develop TMA and stopping CNI therapy did not resolve the TMA so there could be another predisposing factor other than CNI. mTOR inhibitor-associated TMA
-due to it’s antiangiogenic effects, and the decrease of renal expression of VEGF leading to death of the endothelial progenitor cells.
– decreased VEGF lowers the renal levels of complement factor H (CFH) and cases with CFH genetic mutations are more liable to have de novo TMA specially with mTORi use.
-mTORi can prevent endothelial injury repair.
– m TORi procoagulant and the antifibrinolytic activity can have a role in denovo TMA developpement.
Studies declared that the effect of CNI combined with m TOR I to develop denovo TMA is much more than mTOR I alone. AMR-associated de novo TMA:
Alloimmune response targets endothelial cells .The peritubular capillary (PTC) C4d staining was present in 16% of renal biopsies of TMA cases.
Satoskar et al mentioned an incidence of 55% of de novo TMA patients who had diffuse PTC C4d positivity.
Humoral rejection was involved in the evolution of post-transplant TMA.
Studies declared that the association of both AMR and
TMA can indicate worse graft outcome. Complement gene mutations
Chua et al demonstrated C4d deposits in > 88% and C4d with localized C5b-9 in 60% of 42 biopsies of confirmed TMA cases.
Another study stated genetic mutations in CFH, Complement FactorⅠ(CFI) or both in 29% of their de novo TMA patients. TMA evolution
Is related to AP uncontrolled activity due to dysregulation of CFH or CFI resulting in endothelial injury and thereby TMA. Clinical picture
-It usually occurs in the first 3-6 months after transplantation when CNI reaches high trough levels ,in fact it can occur any time.
-It could be either localised to the kidney or systemic with the classic triad of thrombocytopenia,
microangiopathic hemolytic anemia and AKI.
TMA or RAS can be suspected if a recipient experienced renal dysfunction with negative biopsy to acute rejection.
In the active stage, thrombosis, fibrinoid necrosis and
glomerular ischemia are seen in the biopsy.
In the chronic stage, the basement membranes duplicate giving the unique onion skin formation pattern. Denovo TMA prognosis
Half of the cases loose their graft in the first 2 years after the diagnosis with mortality rate reaching 50% within3 years after the diagnosis. Recurrent TMA after transplantation
· For aHUS: TMA recurrence depends on the type affecting the native kidney, a HUS is common to recur and AP overactivation is the underlying pathology.
CFH and CFI have a great effect on aHUS recurrence after transplantation.
Membrane co-factor protein (MCP) decreases aHUS recurrence unless genetic mutation happens.
· For TTP: caused by genetic or acquired lack of ADAMTS13. To differentiate TTP and HUS , TTP is associated with neurological symptoms and HUS is associated with AKI but overlapping manifestations can occur rendering differentiation difficult.
· Pathology includes thrombotic ,non thrombotic and arterial and arteriolar intraluminal fibrin, myxoid intimal thickening. Pathophysiology of recurrence of TMA
CFH is the main inhibitor of the AP ,it can act in fluid phase and on cell surface and it is a cofactor for CFI.
Other membrane regulators which inhibit MAC formation include MCP/CD46, CR1/CD35, DAF/CD55 and Protectin (CD59) ,any disruption in them can lead to complement activation. TMA classification vPrimary hereditary TMA: with mutations in ADAMTS13, MMACHC (cb1c deficiency), complement encoding genes.
vPrimary acquired TMA: autoantibodies to ADAMTS13 Or CFH
vInfection-associated TMA As Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) and pneumococcal HUS.
vSecondary TMA Involving Drug-induced TMA, De novo TMA after SOT. Pregnancy-associated TMA (HELLP). Malignancy-associated TMA. TMA with severe HT. TMA with glomerular diseases TMA with autoimmune diseases TMA after bone marrow transplantation
The mechanism is mostly multifactorial or unknown. Role of diacylglycerol kinase-ε (DGKE) mutations Those cases unlike other aHUS cases they donot reveal complement overactivity. Homozygous mutations in the gene encoding for DGKε and DGKεassociated nephropathy have been detected. It is associated with AKI, thrombocytopenia and hemolytic anemia. Anti-HLA antibodies, viral infection, ischemia-reperfusion injury and immunosuppressive medications either each one solely or together can predispose to aHUS recurrence. Cases with underlying complement abnormality needs a predisposing factor so that aHUS can manifest. There is dissociation between the pathological entities and the clinical picture. aHUS have extrarenal manifestations as digital gangrene and cerebral artery thrombosis, MI and others. Laboratory diagnosis ADAMTS13 activity assessment is needed to exclude TTP . TTP is less common in children so Eculizumab can be initiated before ADAMTS results are released. STEC-HUS and complement-mediated aHUS symptoms can overlap. Complement need to be evaluated in a HUS C3 is low in 30% of aHUS patients,CD46 surface Expression need to be evaluated by flow cytometry. Genetic testing panel CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE should be at least included . Genetic mapping enables proper diagnosis and therapeutic plans, and helps in genetic counselling specially in living related-donors as donor need to be free from these factors. Genetic screening rationale – Disease actual cause that enables correct genetic counselling – Disease management plan – Evaluation of the therapy response -Defining the prognostic course Genetic variants interpretation Include either benign, likely benign, variant of uncertain significance, likely pathogenic,pathogenic. Acquired drivers of aHUS In pediatrics, CFH autoantibodies assessment need to be confirmed, if positive, on a regular basis. ¼ of patients with anti-CFH-associated HUS are susceptible to relapse. Diagnosing a HUS recurrence Clinical history along with tissue biopsy examined by LM, EM, and IF as well as biochemical ,genetic and pathological investigations involving § anti-CFH AB estimation § MCP screening on the peripheral blood WBCs § Recombination in CFHR region assessment § Screening of the genetic mutations related to CFH, CFI, CFB, C3, and MCP Treatment of denovo TMA It has to be individualised for each patient. Involving -immunosuppressive therapy which did not reveal any variation after shifting or dose modulation or stopping or continuation of immunosuppressive therapy. In fact stopping the accused drug must be a mandatory step. -PE and IVIG Are used in early denovo TMA treatment. A study stated 80% graft salvage with PE ,it works by removal of platelet aggregation factors and replenishment of the deficient factors. Also in systemic TMA PE acts by removing the mutant complement proteins and supplying normally functioning complement components. PE removed anti HLA Ab in AMR mediated TMA . – Belatacept: CNI-induced TMA can be treated with Belatacept. -Complement inhibition : Eculizumab, it inhibits the C5b-9 membrane attack complex . It is effective in the treatment and prevention of a HUS. Chua et al detected C4d renal deposition in all histologically registered cases with post-transplantation TMA. Eculizumab proved efficiency in treatment of resistant medication-associated TMA, and those with unrecognized genetic defects as well as cases with refractory AMR with TMA. Due to variable results and cost wise eculizumab is used for AMR cases with TMA , PE dependent TMA and those with persistent of haemolysis inspite of PE sessions. Treatment of recurrent TMA -Minimal list of genetic screening should be done. -Complement components must be surveyed. – Donors with isolated MCP associated mutations can be included -Cases of a HUS without definite genetic mutations can undergo transplantation undercover of PE therapy. – The polygeneicpattern for aHUS patients need to be carefully manged for living donation . Prevention of a HUS –Avoiding Complement activation due to endothelial injury as during ischemia reperfusion injury. -CNI and m TOR impacts on a HUS is debatable. -PE cannot be the only treatment for a HUS recurrence because it failed to prevent the recurrence. The prophylactic use of rituximab in addition to PE lead to acceptable outcomes. –Eculizumab was used to prevent aHUS recurrence in patients with CFH, CFH/CFHR1 hybrid genes as well as with C3 gene mutations . Complement blockade usage as prophylactic agent has no sufficient evidence. Treatment protocols for a HUS recurrence Include using the lowest dose of complement blockade and having a dose withdrawal scheme ,meanwhile evidence is also lacking for such protocols. -Anti-cellular therapy is adviced for FH autoantibody-driven aHUS with close Ab monitoring. -There are no enough data on a HUS duration of therapy. Kidney transplantation without eculizumab prophylaxis was reported to be successful in 4 high risk cases of a HUS ,indicating the possibility of transplantation for those cases with minimizing cold ischemic time, decreasing the risk of rejection and, thereby, providing endothelial protection. Treatment of DGKE mutation associated TMA A study reported the possibility of transplantation for 5 of such cases without recurrence. Renal transplantation Should be delayed for 6 months after starting dialysis because recovery can take several months after eculizumab initiation. Absence of extrarenal mainfestations can be a sign for suitability for transplant and recurrence risk decides for the use of anticomplement blockade . Recurrent disease in the recipient; and de novo disease in the donor if he/she is a genetic mutation carrier are the 2 risk factors for donation from a living related. –Purified products of the deficient genes, and C3 convertase inhibitors are future therapies. –Anti-C3b blocker, compstatin analog Cp40 and The anti-C3 convertase monoclonal antibodies are under investigations. Conclusion De novo or recurrent TMA effect on allograft longevity is underestimated.
Introduction
Thrombotic microangiopathy is one of the severe post kidney transplant complications with an attendant outcome on patient and graft if prompt diagnosis and treatment is not deployed early. It can be broadly classified into De novo or recurrent TMA with the later been more common having a rate of graft loss of 40% within a year, but they both have different etiopathogenesis.
Precipitating factors for De novo TMA
Antibody mediated rejection
Immunosuppression association (CNIs inhibitors, mTORS inhibitors)
Viral infections, CMV, HCV, BK virus, and parvovirus
Genetic abnormality in complement
Phenotypic shift from C3 glomerulonephritis
Etiology of recurrent TMA
aHUS (mutation of CFH, CHI, MCP)
TTP (genetic or acquired lack of ADAMTS13)
Connective tissue disease (scleroderma, SLE)
Current Classification of TMA
A) primary hereditary TMA
mutation in ADAMTS13, cb1c deficiency
B) primary acquired TMA
autoantibodies to ADAMTS13, CFH
C) Infectious associated TMA
STEC -HUS, pneumococcal HUS
D) secondary TMA
drug induced, malignant associated, pregnancy induced,
TMA after bone marrow, glomerular disease, autoimmune, TMA with severe hypertension
Clinical Manifestation
TMA is usually seen within 3-6 weeks post kidney transplant; however, it can be seen at any time also. The symptoms could be localized to the kidney or systemic
Thrombocytopenia
MAHA
AKI
extra-renal manifestation for HUS; digital gangrene, cerebral arteria thrombosis, MI, ocular and GIT, pulmonary manifestation
Histologic features
thrombosis
fibrinoid necrosis
multilayering of membrane with onion skin appearance in chronic stage
Treatment of TMA
A) De novo
withdrawal of offending agent
Plasmapheresis
IVIG
use of Belatacept as CNI inhibitor free immunosuppression
Eculizumab
B) Recurrent TMA (recommendation for treatment)
genetic screening
survey for compliment component
patient with isolated MCP may be safe for KTP
patient with documented aHUS without genetic documentation can do transplant
Patient with TMA should only be considered for kidney transplantation following disappearance of extrarenal manifestation and resolution of TMA hematological parameters
Conclusion
The negative effect of different types of TMAs on the allograft longevity is huge even despite the discovery of complement inhibitor drug except quick intervention is done before the commencement of tissue damage the outcome will be poor. Although the outcome is better with recurrent TMA if Eculizumab is started on time
INTRODUCTION
*Thrombotic microangiopathy (TMA) is a debilitating
complication of kidney transplantation that is associated
with poor patient and graft outcomes.
*The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis
can be classified into either: A) De novo TMA :
precipitating factors are:
(1) Antibody mediated rejection (AMR)
(2)Immunosuppressive-associated TMA: Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi), single or
combined;
(3) Other medications: e.g., anti-vascular
endothelial growth factor inhibitors (anti-VGFI)
(4) Viral infection: e.g., HCV, CMV, BK and parvovirus;
(5) Genetic abnormalities in the complement cascade
(6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation;
(7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA)
Clinical manifestations
*Timing: TMA could developed at any time in the post
transplantation course
*classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI).
Prognosis of de novo TMA:
*is quite poor for the patient and as well as the allograft
*About one half of the patients loses their graft within the first two years after diagnosis
*patient mortality rate of 50% after three years of diagnosis.
B) RECURRENT TMA AFTER RENAL TRANSPLANTATION
Etiology:
aHUS; thrombotic thrombocytopenic purpura (TTP); and
autoimmune diseases: e.g., scleroderma and systemic
lupus erythematosus, with or without anti-phospholipid
antibody syndrome
Current classification of TMA includes the following
Primary hereditary TMA
*The most common complement mutation in
aHUS is CFH, with 40% of cases inherited and 25% sporadic
*Environmental triggers: by anti-HLA antibodies,
viral infection, ischemia-reperfusion injury and immunosuppressive medications.
*Once the diagnosis of aHUS is suspected,
-A full detailed clinical history is usually warranted. A proven tissue diagnosis with light microscopy (LM), immunofluorescence (IF) and electron microscopy (EM)
-exclusion of ADAMTS13 activity is urgently mandated to
exclude TTP diagnosis.
In children, TTP is less common; therefore, eculizumab therapy should be instituted early without waiting for the results of ADAMTS13 activity.
-Complement assessment in aHUS
-Panel of genetic testing
-Rationale for genetic screening
-Interpretation of the genetic variants
-Acquired drivers of aHUS
Treatment of de novo TMA
(1) Immunosuppressive medication management
(2) Plasmapheresis
(3) Belatacept
(4) Complement inhibition: Eculizumab Treatment of recurrent TMA
1) The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3
2) All patients with primary or suspected aHUS, should be surveyed for all complement components and its related proteins
3) Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation;
4) Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy
5) Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation
Prophylaxis against atypical hemolytic uremic syndrome recurrence in allograft based on a risk-assessment strategy
High risk (50-100%):( Previous early recurrence,
Pathogenic mutations1, Gain-of-function mutations)
>>Prophylactic eculizumab Start on the day of transplantation due to potential for severe recurrence and limited
Thrombotic microangiopathy (TMA) is a debilitating complication of kidney transplantation that is associated with poor patient and graft outcomes. The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis,
TMA classification :
(1) De novo TMA, developed for the first time without any evidence of the disease before transplant
(2) Recurrent TMA, native kidneys failed as a result of TMA and it came back in renal transplantation.
(CNI) or mTOR inhibitors (mTORi), single or combined;
(3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI) (4) Viral infection: e.g., HCV, CMV, BK and parvovirus
(5) Genetic abnormalities in the complement cascade
(6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation;
(7) Missed diagnosis of TMA in the native kidney as a cause of ESRD .
Which is more prevalent, de novo or recurrent TMA?:
Graft loss rate of 40% is reported in de novo TMA within a couple of years of diagnosis Etiopathogenesis of de novo TMA:
AMR and medications Calcineurin-induced TMA
(1) Loss of the normal balance between the vasodilator peptides (e.g., prostaglandin (PG) E2 and prostacyclin (PG12)) and the vasoconstrictor peptides (e.g., thromboxane A2 and endothelin), results in arteriolar vasoconstriction.
(2) CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity
(3) Microparticle production from endothelial cells,
Clinical manifestations: Timing: TMA could develop at any time in the post transplantation course
The prognosis of posttransplant de novo TMA is quite poor.
Etiology of recurrent TMA
aHUS; thrombotic thrombocytopenic purpura (TTP); and autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus, with or without anti-phospholipid
antibody syndrome[
PATHOPHYSIOLOGY OF TMA RECURRENCE:
(1) Membrane cofactor protein (MCP/CD46);
(2) Complement receptor 1 (CR1/ CD35)
(3) Decay accelerating factor (DAF/CD55).
(4) Protectin (CD59), which prohibits MAC formation
Current classification of TMA includes the following
Primary hereditary TMA: Includes mutations ADAMTS13, MMACHC
Primary acquired TMA: Autoantibodies to ADAMTS13 or to CFH, which occurs with homozygous CFHR3/1 deletion.
Infection-associated TMA: Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) and pneumococcal
Secondary TMA: Presents in a variety of conditions RECURRENT TMA AFTER RENAL TRANSPLANTATION: Etiology of recurrent TMA
aHUS; thrombotic thrombocytopenic purpura (TTP); and autoimmune diseases: e.g., scleroderma
Pathology: aHUS is a variety of TMA that represents the tissue response to an ongoing endothelial injury.
PATHOPHYSIOLOGY OF TMA RECURRENCE:
(1) Membrane cofactor protein (MCP/CD46)
(2) Complement receptor 1 (CR1/ CD35)
(3) Decay accelerating factor (DAF/CD55).
(4) Protectin (CD59), which prohibits MAC formation
Current classification of TMA includes the following
Primary hereditary TMA: Includes mutations in ADAMTS13, MMACHC (cb1c deficiency), or in genes encoding complement components.
Primary acquired TMA: Autoantibodies to ADAMTS13 or to CFH, which occurs with homozygous CFHR3/1 deletion.
Infection-associated TMA: Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) and pneumococcal HUS have distinct mechanisms that result in TMA
Secondary TMA: Presents in a variety of conditions, andin many conditions the culprit
mechanisms are usually multifactorial or unknown.
Role of diacylglycerol kinase-ε (DGKE) mutations::
most patients with DGKE mutations exhibit no evidence of complement overactivity.
Environmental triggers:
The process of aHUS recurrence can be triggered by:
1- anti-HLA antibodies
2-viral infection,
3-ischemia-reperfusion injury
4- immunosuppressive medications
Treatment of de novo TMA:
(1) Immunosuppressive medication (CNI.MTOR ).
(2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG): Treatment of recurrent TMA Recommendations for recurrent TMA:
(1) The minimal list of genetic screening should include: CFH, CFI, CFHR,
CFB, MCP and C3.
(2) All patients with primary or suspected aHUS, should be surveyed for all complement
components and its related proteins.
(3) Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation.
(4) Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy[
(5) Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation.
RENAL TRANSPLANTATION
Timing
Renal transplantation should be postponed six months after institution of dialysis, as limited kidney recovery can occur several months after commencing eculizumab
therapy
Risk of kidney donation
Two risks have been reported to be associated with living-related kidney donation:
(1) Recurrent diseasein the recipient;
(2) De novo disease in the donor, if he/she is a genetic mutation carrier.
Future therapy
(1) Purified products of the deficient genes;
(2) C3 convertase inhibitors CONCLUSION
The impact of TMA, either de novo or recurrent, on allograft longevity is underestimated. The spectrum of the culprit genes implicated in the evolution of TMA is currently expanding.In contrast, the recurrent TMA is much more optimistic if there is timely intervention by complement blockade before permanent damage sets in
Thrombotic microangiopathy (TMA) is a debilitating complication of kidney transplantation that is associated with poor patient and graft outcomes.
The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis.
TMA can be classified into either: (1)
1- De novo TMA, i.e., developed for the first time without any evidence of the disease before transplant.
2-Recurrent TMA, i.e., native kidneys failed as a result of TMA and it came back in renal transplantation.
De novo TMA is more common and its prognosis is poorer than recurrent TMA.
-Causes of de novo TMA:-
Antibody mediated rejection (AMR).
Immunosuppressive-associated TMA.
Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi), single or combined.
Other medications: e.g.anti-vascular endothelial growth factor inhibitors (anti-VGFI).
Viral infection: e.g., HCV, CMV, BK and parvovirus.
Genetic abnormalities in the complement cascade.
Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation.
Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA)
Timing: TMA the posttransplantation is mostly encountered in the first 3-6 mo post transplantation. This is probably when the CNI immunosuppressive trough levels are relatively higher.
The systemic form of TMA consists of the classic triad of:
Thrombocytopenia,
microangiopathic hemolytic anemia (MAHA)
Acute kidney injury (AKI).
Features of MAHA include raised lactic acid dehydrogenase (LDH),
Drop in hemoglobin (HB) and decreased haptoglobin with schistocytes on peripheral blood smear.
Localized (limited) TMA is usually presented later in TMA course, as compared to the systemic form, which can be explained by the urgency of the systemic type, necessitating the diagnostic allograft biopsy.
When a renal transplant recipient has significant renal dysfunction and the biopsy does not show any acute rejection, one must suspect two possibilities: -(1) TMA or (2) Renal artery stenosis.
In the active stage, is evidence of endothelial cell injury with platelet aggregation (thrombosis), fibrinoid necrosis and glomerular ischemia.
In the chronic stage, the basement membranes undergo duplication and multilayering with increased matrix layers and vessel wall cells, which ultimately ends in the unique onion skin formation .
====================================================================
Prognosis of de novo TMA:
The prognosis of postransplant de novo TMA is quite poor for the patient and as well as the allograft.
About one half of the patients loses their graft within the first two years after diagnosis.
Mortality rate of 50% after three years of diagnosis.
To compare systemic versus localized TMA, Schwimmer et al] reported that 54% of systemic TMA develops dialysis-requiring AKI and 38% lost their grafts.
On the other hand, none of the patients with localized TMA developed TMA-related early graft loss or required dialysis.
A full detailed clinical history is usually warranted.
A proven tissue diagnosis with light microscopy (LM)
Immunofluorescence (IF) and electron microscopy (EM).
studies supporting
The diagnosis of aHUS in the native kidney should be available. However, once diagnosis of aHUS is suspected, a full battery of biochemical, genetic as well, including the following:
1- Estimation of the anti-CFH AB;
2- MCP screening on the peripheral blood WBCs;
3 -Examination of the recombination in CFHR region.
4- Screening of the genetic mutations related to CFH, CFI, CFB, C3, and MCP.
==================================================================== HERAPY OF POST-TRANSPLANT TMA
Treatment of de novo TMA
1- Immunosuppressive medication management: the role of immunosuppressive medications (e.g., CNI or mTORi) has been reported in the literature, with a documented better response after switching from one CNI member to another or to an mTORi).
131 September 10, 2018|Volume 8|Issue 5|WJT|http://www.wjgnet.com agement of de novo TMA. The withdrawal of the offending agent should be the first line in treating de novo TMA, a fundamental step that ultimately results in correction of the hematological profile
2- Plasmapheresis (PE) and intravenous immunoglobulins (IVIG).
3- Belatacept: A promising alternate option that allows withdrawal of the offending drug incriminated in TMA evolution.
Belatacept is an immunosuppressive co-stimulatory blocker against CD80 and CD86 surface ligands and CD28 on T cells.
4-Complement inhibition: Eculizumab, an anti-C5 agent, blocks the lytic C5b-9 membrane attack complex generation.
This recombinant monoclonal antibody addressed a breakthrough in the management of aHUS, as it was proven to be effective in treatment as well as in prevention of recurrent aHUS after renal transplantation.
Efficacy of eculizumab has been documented in several case reports and case series in management of resistant cases of medication-associated TMA, including cases with unrecognized genetic defects.
This efficacy has been also documented in patients with refractory AMR with TMA.
1- The genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3.
2- All patients with primary or suspected aHUS, should be surveyed for all complement components and its related proteins.
3- Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation.
4- Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy
5- Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation.
. Prevention of aHUS: The following strategies are suggested to decrease/prevent aHUS:
Complement activity incited by an injury to endothelium, e.g., ischemia-reperfusion injury, viral infection and immunosuppressive medications should be avoided.
Certain relations have been reported between CNI use and aHUS recurrence which is not confirmed by other authors even the usual substitute in such a case (an mTOR) is not innocent and can induce recurrence.
We cannot depend solely on PE therapy in ma agement of aHUS recurrence for several reasons:( PE failed to prevent aHUS recurrence in many cases; PE cannot guarantee prevention of aHUS recurrence after cessation of therapy; Many cases under PE therapy wereproved to develop “subclinical” aHUS recurrence, which means that PE therapy cannot influence complement activity; Prophylactic use of rituximab proved to be efficacious as anti-CFH-antibodies the beneficial effect of rituximab can be enhanced by adding PE therapy.
The anti-C5 monoclonal antibiotic eculizumab has been reported to be used successfully to prevent aHUS recurrence in patients with CFH, CFH/CFHR1 hybrid genes as well as with C3 gene mutations
Renal transplantation should be postponed six months after institution of dialysis, as limited kidney recovery can occur several months after commencing eculizu- mab therapy.
Disappearance of the extrarenal manifestations as well as resolution of TMA hematological parameters are the prerequisite for kidney transplantation. The magnitude of risk of recurrence can
Risk of kidney donation
Recurrent disease in the recipient.
De novo disease in the donor,if he/she is a genetic mutation carrier.
Any potential donor proved to exhibit alternative pathwaydysregulation should be excluded.
On the other hand,any potential living-related donor devoid of complementgene abnormalities can be permitted
. “Liver transplantation” may be reserved for patients with liver- derived complement protein aberrations, particularly in patients poorly responding to complement blockade.
The impact of TMA, either de novo or recurrent, on allograft longevity is underestimated.
The spectrum of the culprit genes implicated in the evolution of TMA is currently expanding.
Despite the landmark breakthrough of immense efficacy of complement blockade therapy, the outlook of this devastating syndrome remains poor if the diagnosis is delayed.
In contrast, the recurrent TMA is much more optimistic if there is timely intervention by complement blockade before permanent damage sets in.
More efforts targeting genetic mutation management as well as the advent of early predictors of TMA recurrence are warranted for better disease control and, thereby, better patient and allograft outcome.
====================================================================
What is the level of evidence provided by this article
Thrombotic microangiopathy (TMA) in a renal transplant is seen in 5.6 cases per 1000 transplants per year and is associated with poor graft and patient outcomes (50% mortality at 3 years after diagnosis). TMA post-transplant can be either de novo, or recurrent TMA.
De novo TMA: Alternative complement pathway dysregulation can occur due to factors like ABMR, immunosuppressants like CNIs (due to imbalance between vasoconstrictors and vasodilators as well as platelet activation) and mTOR inhibitors (due to antiangiogenc properties), anti-VEGFI, ribavirin, interferon, viral infections like CMV, BKV, HCV, Parvovirus, genetic abnormalities in complement cascade (mutations in CFH, CFI etc.), C3 glomerulopathy phenotypically shifting to atypical HUS, or sometimes due to missed primary etiology of TMA as a cause of ESRD requiring transplant. Prevalence of de novo TMA post-transplant is 3-14% with 40% graft loss at 2 years post-diagnosis.
Timing of TMA development: It can develop anytime post-transplant, although mostly seen in first 3-6 months.
Features: TMA includes localized form (presenting later) or systemic form (including triad of thrombocytopenia, AKI and microangiopathic hemolytic anemia with elevated LDH, reduced hemoglobin and haptoglobin and schistocytes on peripheral blood film. Kidney biopsy will show thrombi in glomeruli, arterioles and arteries with subendothelial flocculent material, mesangiolysis and myocyte necrosis in active lesions. Chronic lesions will show double contours of peripheral capillary walls and onion skin appearance of arteries.
Prognosis of de novo TMA: It is poor with 50% graft loss within 2 years and 50% death at 3 years post-diagnosis.
Recurrent TMA: Causes of recurrent TMA include atypical HUS (due to mutation of CFH, CFI, MCP etc.), TTP (lack of ADAMTS13), autoimmune disease like scleroderma, SLE with or without antiphospholipid antibody (APLA) syndrome.
Classification of TMA: Primary hereditary TMA (mutations in ADAMTS13, cb1c deficiency, genes encoding complement components), Primary acquired TMA (autoantibodies to ADAMTS13 or CFH), Infection-associated TMA (STEC-HUS, pneumococcal HUS, HIV etc.), and Secondary TMA (drug-induced, pregnancy-associated, de novo post-transplant, malignancy associated, with severe hypertension, with glomerular diseases like MPGN, FSGS, IgA nephropathy etc., with autoimmune diseases like SLE, and after bone marrow transplant).
20% of atypical HUS patients have extrarenal manifestations like MI, cerebral artery thrombosis, digital gangrene etc.
Lab investigation: Once a diagnosis is suspected, ADAMTS13 levels should be checked to exclude TTP, complement levels should be done (although inly 30% have reduced C3) and genetic testing panel including CFH, CFI, C3 CFB, THBD, CFHR1, CFHR5 and DGKE should be sent.
Treatment of de novo TMA: It includes
1) Immunosuppression management: withdrawal of offending drug
2) Plasmapheresis and IVIG: helpful in salvaging graft.
3) Belatacept: used in place of the offending agent
4) Complement inhibition – Eculizumab: First line of therapy for atypical HUS. Useful in ABMR associated TMA, patients who are plasmapheresis dependent and in whom hemolysis persist despite maximum dose of plasmapheresis therapy.
Prevention of recurrent TMA: Genetic screening should be done and complement components and related proteins should be assessed.
Low risk: Isolated MCP mutations and persistently negative FH autoantibodies: No prophylaxis required.
Moderate risk: Isolated CFI mutations or insignificant complement gene mutations: Prophylactic eculizumab or plasma exchange.
High risk: Previous early recurrence, pathogenic mutations and gain of function mutations: Prophylactic eculizumab to be started on the day of transplant.
In a scenario with atypical HUS diagnosis, Plasmapheresis alone is not successful. Eculizumab has been useful in patients with CFH, CFH/CFHR1 hybrid genes as well as C3 gene mutation. Rituximab has been as useful as anti-CFH-antibodies. Simultaneous start of anticellular therapy in form of cyclophosphamide, MMF or rituximab is required and eculizumab will continue indefinitely with monthly or quarterly monitoring of FH autoantibody levels. The anticellular therapy can be discontinued once antibody titres fall below pathogenic threshold for 6 months at least.
Cessation of complement inhibitors depends on case-by-case basis: After at least 3 months of stabilization of renal function, at 3 months in children with pathogenic variants in MCP and having rapid remission, and after 4-6 months in patients on dialysis.
Kidney transplant in recurrent atypical HUS without eculizumab has been done by minimizing cold ischemia time.
Timing of renal transplant: Wait for minimum 6 months after dialysis initiation, and only in absence of extrarenal manifestations including hematological abnormalities.
Risk of kidney donation is in form of recurrence in the recipient and de novo disease in the donor. Donor with alternative pathway dysregulation should be excluded. Liver transplantation can be performed in patients with liver-derived complement protein abnormalities.
C3 invertase inhibitors, purified products of deficient genes, anti-C3b blockers compstatin analog Cp40, and anti-C3 convertase monoclonal antibodies are being investigated for future use.
2. What is the level of evidence provided by this article?
This study is about thrombotic microangiopathy post kidney transplant, both de novo and recurrent disease.
De novo TMA is developed for the first time without any evidence of the disease before transplant. On the other hand, recurrent TMA is related to genetics with mutation errors having different impact on how the disease progresses
De novo TMA is more common with worse prognosis compared to recurrent disease. Recurrent disease is usually related with genetic makeup.
Causes include AMR and medications.
There is a link between CNI drugs such as cyclosporine and tacrolimus with de novo TMA. This can result in renal ischemia, arteriolar vasoconstriction, and endothelial injury.
mTORi can inhibit cell cycle and proliferation. Examples of these drugs include sirolimus and everolimus. Both are implicated in the development of de novo TMA. One important factor is that mTORi block repair of endothelial cell injury.
AMR can lead to the development of denovo TMA. This can be assessed by doing a C4d staining test. It is a marker for AMR. Diffuse PTC C4d positivity can be taken as a good indicator of denovo TMA.
Other causes include chronic infection such as CMV, BK virus, parvovirus, hepatitis C infection. Ischemia perfusion injury can also be another cause. ADAMTS13 deficiency is a rare risk factor for post transplant TMA.
Live donation does not give any protection from graft dysfunction.
C3 glomerulopathy in native kidney can shift phenotypically and present as denovo TMA post kidney transplant.
Complement gene mutations are seen in patients with de novo TMA.
Clinical features include a triad of thrombocytopenia. microangiopathic hemolytic anemia, and acute kidney injury.
Recurrent TMA has etiologies such as aHUS, TTP, scleroderma and SLE with or without anti-phospholipid antibody syndrome.
Management involves
plasmapheresis
drug withdrawal or dose modification
lifelong complement blockade
Recommended approach pre transplant :
careful donor selection
proper recipient preparation
complete genetic screening
Level of evidence
This is a narrative review and hence level of evidence is 5.
Abhijit Patil
2 years ago
Incidence: 5.6 cases per 1000 renal transplant recipients per year
with a 50% mortality rate three years after diagnosis.
TMA after transplantation can be classified into either:
(1) De novo TMA— developed for the first time without any evidence of the disease
before transplant; and
(2) Recurrent TMA– native kidneys failed as a result of TMA and it came back in
renal transplantation. de novo TMA is more prevalent after kidney transplantation
Graft loss rate of 40% is reported in de novo TMA within a couple of years of diagnosis
DE NOVO TMA Causes:
Antibody mediated rejection (AMR);
Immunosuppressive-associated TMA: Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi)
Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI)
Viral infection: e.g., HCV, CMV, BK and parvovirus
Genetic abnormalities in the complement cascade
Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation
Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA)
Clinical manifestations
Timing: is mostly encountered in the first 3-6 mo post transplantation.
This is probably when the CNI immunosuppressive trough levels are relatively higher
The systemic form of TMA
thrombocytopenia,
microangiopathic hemolytic anemia (MAHA)
acute kidney injury (AKI).
raised lactic acid dehydrogenase (LDH),
drop in hemoglobin (HB)
decreased haptoglobin with schistocytes on peripheral blood smear.
Localized (limited) TMA is usually presented later in TMA course.
When a renal transplant recipient has significant renal dysfunction and the biopsy does not show any acute rejection, one must suspect two possibilities: (1) TMA or (2) Renal artery stenosis.
In the active stage, there is evidence of endothelial cell injury with platelet aggregation (thrombosis), fibrinoid necrosis and glomerular ischemia.
In the chronic stage, the basement membranes undergo duplication and multilayering with increased matrix layers and vessel wall cells, which ultimately ends in the unique onion skin formation
Prognosis:
patient mortality rate of 50% after three years of diagnosis.
54% of systemic TMA — dialysis-requiring AKI and 38% lost their grafts.
none of the patients with localized TMA developed TMA-related early graft loss or required dialysis.
RECURRENT TMA Causes:
aHUS; thrombotic thrombocytopenic purpura (TTP);
autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus, with or without anti-phospholipid antibody syndrome
aHUS:
Incidence of recurrence: as high as 60%. Untreated patients– graft loss at a rate of 90%, 80% of them occurring in the first year Genetic or acquired lack of ADAMTS13 has been recognized. Diagnosis:
The diagnostic list of genes of aHUS should include at least CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE. Genotyping workup should also include CFH-H3 and MCP ggaac haplotypes
Diagnosis of aHUS recurrence:
A full detailed clinical history
proven tissue diagnosis with light microscopy (LM), immunofluorescence (IF) and electron microscopy (EM)
full battery of biochemical, genetic as well as pathological investigations of the AP should be accomplished including the following:
Estimation of the anti-CFH AB;
MCP screening on the peripheral blood WBCs;
Examination of the recombination in CFHR region; and
Screening of the genetic mutations related to CFH, CFI, CFB, C3, and MCP.
Management De novo TMA
Withdrawal of the offending agent
Plasmapheresis (PE) and intravenous immunoglobulins (IVIG)
Belatacept: A promising alternate option that allows withdrawal of the offending drug incriminated in TMA evolution.
Belatacept is an immunosuppressive co-stimulatory blocker against CD80 and CD86 surface ligands and CD28 on T cells
Complement inhibition: Eculizumab, an anti-C5 agent, blocks the lytic C5b-9 membrane attack complex generation.
effective in treatment as well as in prevention of recurrent aHUS after renal transplantation
Re current TMA
Genetic screening for CFH, CFI, CFHR, CFB, MCP and C3
Surveyed for all complement components and its related proteins
Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation
Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy
Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation
Prophylaxis against atypical hemolytic uremic syndrome recurrence in allograft based on a risk-assessment strategy
High risk (50-100%):
Previous early recurrence.
Pathogenic mutations
Gain-of-function mutations Prophylactic eculizumab Start on the day of transplantation due to potential for severe recurrence and limited
Moderate risk:
No mutation identified
Isolated CFI mutations
Insignificant complement gene mutation Prophylactic eculizumab or plasma exchange
Low risk:
Isolated MCP mutations
Persistently negative FH autoantibodies. No prophylaxis
RENAL TRANSPLANTATION
Timing
Postponed six months after institution of dialysis– as limited kidney recovery can occur several months after commencing eculizumab therapy Disappearance of the extrarenal manifestations as well as resolution of TMA hematological parameters are the prerequisite for kidney transplantation.
Risk of kidney donation
(1) Recurrent disease in the recipient
(2) De novo disease in the donor, if he/she is a genetic mutation carrier
Any potential donor proved to exhibit alternative pathway dysregulation should be excluded.
any potential living-related donor devoid of complement gene abnormalities can be permitted
Dear Dr Patil,
I like your detailed summary and analysis.
Ajay
Sherif Yusuf
2 years ago
Thrombotic microangiopathy (TMA) is characterized by
Microangiopathic hemolytic anemia = non immune hemolytic anemia with reticulocytosis, indirect hyperbilirubinemia, high LDH with shistocytes in peripheral smear
Thrombocytopenia
Renal dysfunction
May be renal limited or associated with other systemic manifestations (20%) including digital gangrene, cerebral artery thrombosis, MI, ocular, GIT, pulmonary and neurologic involvement
May be recurrent or denovo
Incidence
Around 5.6 per 1000 renal transplant recipients per year develop TMA
Can occur at any time after transplantation but most commonly in the first 3-6 months after transplantation
The incidence of denovo TMA is around 1.5%, while some reported higher incidence (3-14%)
Recurrent TMA occurs 10 times less than denovo TMA
Causes of TMA occurring in adult including renal transplant recipient
Primary TTP which is associated with severe ADAMTS13 deficiency (activity <10%)
Complement meditated TMA and usually it accounts for the majority of recurrent cases after transplantation
Drug induced as CNI and sirolimus
Immune as SLE, antiphospholipid syndrome
Malignancy related
Infection related most commonly CMV infection, BK and parvovirus and HCV
ABMR may cause TMA
Shift of C3 glomerulopathy to complement mediated TMA as they share the same pathogenesis
DIC can mimic the clinical picture of TMA
Complement medicated TMA
Complement medicated TMA occur due to abnormal regulation of alternative pathway of complement due to mutation in either regulators (factor H, I) in the form of loss of function or activators (C3, factor B) in the form of gaining of functions leading to uncontrolled activation of complement system
It is highly recurrent; the risk recurrence was estimated to be 36.5 times higher than the risk wth other etiologies
Genetic variants are interpreted as benign, likely benign, variant of uncertain significance, likely pathogenic, pathogenic.
Drug -induced TMA (CNI,mTOR inhibitor)
CNI can cause arteriolar vasoconstriction due to the increase in vasoconstrictor peptides (thromboxane A2 and endothelin) and the decrease in vasodilator peptides (PG) with subsequent renal ischemia and endothelial injury, with production of microparticles form endothelial cells
CNI can induce platelet activation, release of procoagulants and can exert anti-fibrinolytic activity especially if there is an injury to the endothelium by ABMR or ischemia reperfusion injury
Antiangiogenic property of mTORi can decrease renal expression of VEGF that leads to death of the endothelial progenitor cells.
Inhibition VEGF is associated with the decrease in renal level of CFH, and it was found that patients with CFH mutation has higher risk f denovo TMA if taken mTORi
mTORi use may prevent repair of endothelial injury
mTORi can induce platelet activation, release of procoagulants and can exert anti-fibrinolytic activity
The combination of CNI and mTORi is associated with higher risk of TMA than when using either drug alone. Thus caution should be implemented when using these combination
AMR-associated TMA
The incidence of C4d positive TMA is variable, it is 16.2% in one study and 50 % in other
Types of TMA
1- Recurrent disease
The primary disease of the native kidney is complement mediated TMA
It is less common when compared to denovo TMA
Nearly all patients have complement medicated TMA
The best timing of transplantation is after 6 months of dialysis after resolution of extra renal and hematological manifestations of TMA
There is high risk of recurrence of complement mediated TMA when transplanted from living related donor together with the donor risk of developing denovo TMA later on . Thus it is recommended that all patients with complement mediated TMA to use living- unrelated or deceased donor kidney
Patients with isolated MCP mutation can be transplanted safely, while donors with pyogenic pattern of HUS are at increased risk of recurrence with living donation
Patients with aHUS who have no evidence of genetic mutation can be transplanted under cover of intensive plasma exchange therapy
2- Denovo TMA
The primary disease of the kidney is known (non complement mediated TMA)
It is more common than recurrent
Mostly occur due to immunosuppressive drugs, ABMR, viral infections, phenotypical shift of C3 glomerulopathy to complement mediated TMA
3- Recurrent TMA misdiagnosed as denovo
At this situation complement mediated TMA is the cause of ESRD, and was not diagnosed and the cause if ESRD was postulated to be unknown
Management
A- In patient of recurrent TMA
The most probable diagnosis in recurrent TMA is complement mediated TMA so it is recommended to start eculizumab
B- In patients with denovo TMA
CNI level, genetic testing (CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5, DGKE, genotyping of CFH-H3 and MCP), ADAMTS13 assay CMV, renal biopsy with C4d and DSA status should be evaluated
Start urgently plasmapheresis 1.5 volume exchange every 48 hour (with or without IVIG) and methylprednisolone at dose of 500 mg daily for 3 days till investigation results
If CNI level is above the target we should reduce the dose, switching between CNI or relplace CNI bu mTORI is another option, although all these stratigies
If ADAMTS13 < 10% continue plasmapharesis till improvement of platelets and LDH
If CMV positive treat first CMV
If ABMR detected, start its treatment
If genetic mutation detected treat with eculizumab
In all patients after treating reversible cause if not responding consider the start of eculizumab, if not available start plasmapharesis
So … All patients with denovo TMA should be evaluated for genetic mutations, and all possible reversible causes should be treated till having the result of genetic testing, if genetic mutation found or if patient has progressive disease despite correcting suspected etiology, eculizumab should be started
Cessation of eculizumab therapy
Eculizumab can be discontinued after at least 6-12 months of treatment and at least 3 months of stabilization of kidney functions
Eculizumab can be stopped earlier (at 3 months) in children with pathogenic variants in MCP if renal functions normalized rapidly
Eculizumab should be continued for 4-6 months in patient who become on dialysis with assessment of fibrosis by renal biopsy
Eculizumab should be continued for life in transplant patients with history of loss of the graft before before
Prevention of recurrent TMA:
High risk (50-100%): including those with history of early recurrence or pathogenic or gain of function mutations should receive Eculizumab prophylaxis
Moderate risk: including those no identified mutation, isolated CFI mutations or Insignificant complement gene mutation should receive eculizumab or plasmapheresis prophylaxis
Low risk: including those with isolated MCP mutations or persistently negative FH autoantibodies should not receive prophylaxis
Prognosis
The development of TMA is associated with 50 % mortality after 3 years of diagnosis
TMA is associated with 40% risk of graft loss after 2 years of diagnosis
In another word half of the grafts will be lost at 2 years and half of the patients will be lost at 3 years after transplantation
What is the level of evidence provided by this article?
Dear Dr Yusuf,
I like your summary and analysis.
Ajay
Mohammed Abdallah
2 years ago
Please summarise this article
INTRODUCTION
The incidence of post-transplant TMA is 5.6 cases per recipients per year with a 50% mortality rate three years after diagnosis
It is classified to de novo and recurrent TMA. To differentiate between the two, we must know the cause of ESRD
The aim of the study: discuss the pathophysiology, clinical course and available approaches of prevention and treatment in the two groups
DE NOVO TMA
Acquired or genetic dysregulation of the alternative complement pathway:
1. AMR
2. Immunosuppressive-associated (CNI or mTORi, single or combined
3. Other medications (anti-VGFI)
4. Viral infection (HCV, CMV, BK and parvovirus)
5. Genetic abnormalities in the complement cascade
6. Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation
7. Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA)
De novo TMA is more prevalent than the recurrent (graft loss rate of 40%)
Calcineurin-induced TMA mechanisms:
1. Loss of the normal balance between the vasodilator peptides and the vasoconstrictor peptides results in arteriolar vasoconstriction, renal ischemia and endothelial injury
2. CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity
3. Microparticle production from endothelial cells
AMR-associated de novo TMA the peritubular capillary C4d staining is present in 16.2% of biopsied recipients with TMA
Complement gene mutations C4d deposits in more than 88% and C4d with localized C5b-9 in about 60% of 42 biopsy samples from patients with histologically confirmed diagnosis of TMA
Clinical manifestations any time posttransplant but mostly in the first 3-6 months (relatively high trough levels of CNI). Localized (limited) or systemic TMA. Triad of thrombocytopenia, MAHA and AKI
Consider TMA or RAS when there is significant renal dysfunction and the biopsy does not show any acute rejection
Prognosis of de novo TMA quite poor (patient and graft). 50% of loses their graft within the first two years after diagnosis
RECURRENT TMA AFTER RENAL TRANSPLANTATION
Etiology of recurrent TMA
aHUS, TTP, and autoimmune diseases( e.g., scleroderma SLE, with or without anti-phospholipid antibody syndrome)
aHUS
The most common diagnosis in TMA associated with recurrence. Overactivation of the AP
Risk of recurrence is dependent on the underlying associated abnormality (mutational abnormality)
Diacylglycerol kinase-ε (DGKE) mutations may play a role in the pathophysiology of aHUS
Extrarenal manifestations (20%) includes digital gangrene, cerebral artery thrombosis, myocardial infarction, and ocular, GIT, pulmonary and neurologic involvement
Diagnosis of recurrence: detailed history and tissue diagnosis (LM, IF, and EM). Then estimation of the anti-CFH AB, MCP screening on the peripheral blood WBCs, examination of the recombination in CFHR region, and screening of the genetic mutations related to CFH, CFI, CFB, C3, and MCP.
TTP
Genetic or acquired lack of ADAMTS13. Serology of ADAMTS13 activity is now feasible
THERAPY OF POST-TRANSPLANT TMA
Treatment of de novo TMA
1. Immuno- suppressive medication management
2. Plasmapheresis and IVIG
3. Belatacept
4. Complement inhibition: Eculizumab, an anti-C5 agent, blocks the lytic C5b-9 membrane attack complex generation
Treatment of recurrent TMA
1. genetic screening (CFH, CFI, CFHR, CFB, MCP and C3)
2. survey for all complement components and its related proteins
3. Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation
4. aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy
5. Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation
RENAL TRANSPLANTATION
Timing6 months after institution of dialysis
Risk of kidney donationrisks associated with living-related kidney donation are recurrent disease in the recipient and de novo disease in the donor (if genetic mutation carrier)
Future therapy purified products of the deficient genes and C3 convertase inhibitors
Research targetsanti-C3b blocker (compstatin analog and anti-C3 convertase monoclonal antibodies
CONCLUSION
The impact of both de novo and recurrent TMA is underestimated
Timely intervention by complement blockade before permanent damage in recurrent TMA is much more optimistic
Targeting genetic mutation management and the advent of early predictors of TMA recurrence are warranted
What is the level of evidence provided by this article?
Level 5 (narrative study)
Dear Dr Muhamed,
I like your summary and analysis.
Ajay
Mohamed Mohamed
2 years ago
1. Please summarise this article Introduction
Incidence of PKTX TMA: 5.6 cases/ 1000 KTX recipients/year
Mortality rate 3 years after diagnosis: 50% Classification: De novo TMA
Recurrent TMA
Differentiating these types has clinical implications.
Eculizumab (anti C5 monoclonal Ab) is highly effective in prevention & treatment of aHUS. De novo TMA more prevalent after KTX.
Graft loss rate (2-years) in de novo TMA 40%. DE NOVO TMA Precipitating factors:
1. AMR
2. IS-associated TMA: CNI or mTORi
3. Medications: e.g., anti-VGFI
4. Viral infection: e.g., HCV, CMV, BK & parvovirus
5. Genetic complement system abnormalities
6. Phenotypical shift of C3 glomerulopathy (ESRD), to aHUS post-TX
7. Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e.,recurrent TMA) CNI-induced TMA: Mechanisms:
1. Imbalance between the vasodilator & vaso-constrictor peptides.
2. CNI-induced platelet activation, pro-coagulant & anti-fibrinolytic activity
3. Micro-particle produced by endothelial cells (an effect of CyA).
Arguments against the role of CNI: 1. Although >90% of KTX patients take CNI only
a small % develop. 2. CNI withdrawal in de novo TMA does not guarantee a favorable graft outcome 3. Higher incidence of TMA in KTX recipients not under CNI versus those on CNI maintenance (USRDS based study).
Clinical manifestations Timing: mostly occur in the 1st3-6 mo post-TX. Features:
A triad of thrombocytopenia, MAHA (raised LDH, drop in Hb, low haptoglobin, & schistocytes on PBP) & AKI.
Localized (limited) TMA: presents later compared to the systemic form.
In the context of significant graft dysfunction with biopsy showing no AR, one should consider RAS or TMA.
In the absence of renal biopsy, many cases can be misdiagnosed as hypertensive nephrosclerosis.
Genetic mutations should be done to avoid missing the diagnosis of a recurrent aHUS. Prognosis:
Quite poor for both the patient & the allograft.
A 50% graft loss in 1st2 years (USRDS-based report). Recurrent TMA after renal transplantation Etiology:
1. aHUS
2. TTP
3. Autoimmune diseases: e.g., scleroderma & SLE (+/-anti-phospholipid antibody syndrome). aHUS:
It is the most common cause of recurrent TMA. Higher recurrence rate (70%-90%) with mutations involving CFH & CFI.
Lower recurrence rate associated with Membrane co-factor protein (MCP) mutations.
Without treatment patients with aHUS lose their grafts. TTP:
Is the 2ndknown cause of TMA.
There is genetic or acquired lack of ADAMTS13.
Differentiation between TTP & HUS:
Presence of neurologic features TTP & renal dysfunction in HUS.
Serology of ADAMTS13 activity.
Overlap between both exists. Pathology:
aHUS is a variety of TMA that represents the tissue response to endothelial injury.
Thrombotic features (fibrin/platelet plugging) are not always seen in graft biopsy.
Non-thrombotic features: denuded & swollen endothelium, mesangiolysis, GBM double contour, & electro-lucent material deposit in the sub-endothelium. Pathophysiology of TMA recurrence
CFH is the main inhibitor of the AP.
CFH works in both fluid phase & on cell surfaces.
CFH act as a co-factor to CFI.
Regulatory factors on cell surfaces (“membrane regulators”) include:
1. MCP/CD46
2. Complement receptor 1 (CR1/ CD35)
3. Decay accelerating factor (DAF/CD55)
4. Protectin (CD59). Current classification of TMA: Primary hereditary TMA: mutations in ADAMTS13
, MMACHC (cb1c deficiency), or in genes encoding complement components. Primary acquired TMA: Auto-antibodies to ADAMTS13 or to CFH. Infection-associated TMA: STEC-HUS & pneumococcal HUS. Secondary TMA: e.g., pregnancy-associated TMA or de novo TMA after transplantation. Clinical assessment of aHUS:
aHUS refers to any HUS that is not due to STEC-HUS. “primary HUS” is used when there is underlying abnormality in the AP; however, a trigger factor (infection, surgery, medications, pregnancy) is usually needed. Extra-renal manifestation (in 20%):
Digital gangrene
Cerebral artery thrombosis
Myocardial infarction
Ocular, GIT, pulmonary & neurologic involvement Acute versus chronic lesion?
Penetrance in aHUS is age-related; 64% by age 70.
This late presentation of reflects the effect of the
environmental triggers. Laboratory investigations: 1. Complement assessment in aHUS:
C3 is low in only 30% of aHUS.
CD46 surface expression assessed by flow cytometry. 2. Panel of genetic testing:
CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 & DGKE. 3. Rationale for genetic screening:
-Determination of the actual cause of the disease that allows for correct genetic counseling
-Planning for disease management
-Prediction of response for therapy
-Defining prognosis Interpretation of the genetic variants
1. Benign
2. Likely benign
3. Variant of uncertain significance
4. Likely pathogenic
5. Pathogenic, according to the international guidelines.
Genetic classification affects therapeutic plans, response to therapy, & chance for aHUS recurrence. Diagnosis of aHUS recurrence:
1. Tissue diagnosis with LM), IF, & EM is required.
2. Estimation of the anti-CFH AB
3. MCP screening on the peripheral blood WBCs
4. Examination of the recombination in CFHR region
5. Screening of the genetic mutations related to CFH, CFI, CFB, C3, & MCP. Treatment of de novo TMA
1. IS medication management: e.g., switching from one CNI to another or to an mTORi.
2. PE & IVIG: used early in treating de novo TMA patients.
3. Belatacept: an immunosuppressive co-stimulatory blocker against CD80 & CD86 surface ligands & CD28 on T cells.
4. Complement inhibition: Eculizumab (anti-C5 agent), blocks the lytic C5b-9 MAC generation. Its use should be confined to:
-AMR-associated TMA
-Patients who became PE-dependent
-Refractory hemolysis persists despite maximum doses of PE therapy. Treatment of recurrent TMA
1. The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3
2. All patients with primary or suspected aHUS, should be surveyed for all complement components
3. Patients with isolated MCP associated mutations may be safe for kidney donation
4. Patients with documented aHUS & with lack of definite genetic mutations can proceed in KTX under intensive PE therapy
5. Polygenic pattern for aHUS patients should be handled with extreme caution in LKD. Prevention of aHUS:
1. Avoidance of inciting events ( e.g., IRI, viral infection & IS medications)
2. Substitution of CNI by mTOR is not innocent & can induce recurrence.
3. PE failed to prevent aHUS recurrence in many cases; it cannot guarantee prevention of aHUS recurrence after cessation of therapy.
4. Eculizumab has been used successfully to prevent aHUS recurrence in patients with CFH, CFH/CFHR1 hybrid genes as well as with C3 gene mutations. Renal transplantation Timing
1. Should be delayed 6 months after start of dialysis ( limited kidney recovery may can occur months after eculizumab therapy).
2. Extrarenal & hematological disease should disappear before TX. Risk of kidney donation 1. Recurrent disease in the recipient 2. De novo disease in the donor (in genetic mutation carriers). 3. Those exhibiting alternative pathway dysregulation should be excluded. Future therapy
1. Purified products of the deficient genes
2. C3 convertase inhibitors.
3. Research targets:
-The anti-C3b blocker, compstatin analog Cp40
-The anti-C3 convertase monoclonal antibodies. CONCLUSION
The effect of TMA on graft survival is under-estimated.
Despite the advent of complement blockade therapy, the prognosis remains poor if the diagnosis is delayed.
The recurrent TMA is much more better with timely use of complement blockade before permanent damage occurs. //////////////////////////// What is the level of evidence provided by this article? Level V
INTRODUCTION Thrombotic microangiopathy (TMA)
The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis
TMA after transplantation can be classified into either:
(1) De novo TMA,
(2) Recurrent TMA,
In this review, the author shall try to discuss the main differences between the two categories in the pathophysiology, clinical course and available approaches of prevention and treatment.
DE NOVO TMA
Factors triggers De novo TMA after renal transplant:
(1) Antibody mediated rejection (AMR);
(2) Immunosuppressive-associated TMA: (CNI) or (mTORi), single or combined;
(3) Other medications: e.g., (anti-VGFI);
(4) Viral infection: e.g., HCV, CMV, BK and parvovirus;
(5) Genetic abnormalities in the complement cascade;
(6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation;
(7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA).
Which is more prevalent, de novo or recurrent TMA?
Etiopathogenesis of de novo TMA AMR and medications are the two main causes of de novo TMA.
In addition, the role of complement abnormalities is becoming more apparent with one study
. Calcineurin-induced TMA:
Three underlying mechanisms
(1) Loss of the normal balance between the vasodilator peptides (e.g., (PG) E2 and (PG12)) and the vasoconstrictor peptides (e.g., thromboxane A2 and endothelin)
(2) CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity
(3) Microparticle production from endothelial cells, a known effect of CyA that can result in activation of the AP
three trap points have been speculated to oppose the role of CNI:
(1) Patients utilizing CNI to maintain immunosuppression represent more than 95% of kidney transplant recipients (KTR), and only a small percentage can develop TMA, which suggests the presence of another underlying predisposing factor
(2) CNI withdrawal in de novo TMA does not always guarantee a favorable graft outcome
(3) A USRDSbased study demonstrates a significantly higher incidence of TMA in the group of KTR that was not under CNI maintenance therapy (11.9/1000/year), as compared to those on CNI maintenance (5.0/1000/year).
mTOR inhibitor-associated TMA:
The following explanations have been given:
(1) mTORi has antiangiogenic properties, and can decrease renal expression of (VEGF) with death of the endothelial progenitor cells.
(2) The VEGF inhibition has been recently proven to be associated with reduced renal levels of complement factor H (CFH)
(3) Repair of endothelial injury could be hampered by mTORi use
(4) the procoagulant and the antifibrinolytic activity of mTORi might play additional roles in de novo TMA development
interpretation of these data may be limited by the fact that mTORi itself, e.g., sirolimus, may be used as a rescue medication in the case of diagnosis of CNI-induced TMA
Fortin et al reported that the highest risk of de novo TMA was in the group using CNI and mTORi,
Nava et al studied 396 KTR, 36 (7.3%) developed TMA and 17 of them were drug-related. Not only were the drug levels of CNI and mTORi higher in the TMA group, but the sum of both drug levels in the TMA group was also higher.
AMR-associated de novo TMA:
1. Viral infection, e.g., CMV, BK virus, parvovirus, HCV virus,
2. antiviral medications, e.g., ribavirin and interferon and disseminated histoplasmosis.
3. Ischemia-reperfusion injury
4. (ADAMTS13) deficiency another rare risk factor
Complement gene mutations:
Clinical manifestations :
RECURRENT TMA AFTER RENAL TRANSPLANTATION
Etiology of recurrent TMA aHUS;
Recurrence of TMA in the allograft depends on the underlying type involving the native kidney.
TTP:
SLE
can develop TMA in 5%-10% with documented recurrence after kidney transplantation
PATHOPHYSIOLOGY OF TMA RECURRENCE
Current classification of TMA includes the following
1. Primary hereditary TMA: Includes mutations in ADAMTS13, MMACHC (cb1c deficiency), or in genes encoding complement components.
Primary acquired TMA: Autoantibodies to ADAMTS13 or to CFH.
2. Infection-associated TMA:
(STEC-HUS) and pneumococcal HUS
3. Secondary TMA:
e.g., pregnancy-associated TMA
or de novo TMA after transplantation,
The most common complement mutation in aHUS is CFH, with 40% of cases inherited and 25% sporadic
THERAPY OF POST-TRANSPLANT TMA Treatment of de novo TMA
is highly dependent on diagnosis as well as the patient’s response.
The following approaches have been suggested:
(1) Immunosuppressive medication management:
Satoskar et al, denied any difference in outcomes between temporary discontinuation, dose modulation, withdrawal or continuation of CyA
Whatever the situation would be, the withdrawal of the offending agent should be the first line in treating de novo TMA,
(2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG):
In 2003, Karthikeyan et al reported a graft salvage rate with PE approaching 80%.
Two benefits have been postulated for this type of therapy:
• Removal of the platelet aggregation factors, e.g., thromboxane A2
• the simultaneous replenishment of the deficient factors, e.g., PGI2-stimulating factor
In AMR-associated TMA, 100% response has been reported to be associated with PE/IVIG therapy in five solid organ transplantation with systemic TMA with no evidence of relapse after withdrawal of the culprit agent (e.g., tacrolimus) in a recent study;
(3) Belatacept:
A promising alternate option that allows withdrawal of the offending drug incriminated in TMA evolution.
The first case report in 2009 documented TMA resolution after belatacept therapy used for immunosuppression in post-transplantation TMA due to CNI-induced endothelial toxicity
belatacept has nothing to do with the underlying endothelial derangement, its role is only to replace/displace the culprit drug
(4) Complement inhibition:
Eculizumab was proven to be effective in treatment as well as in prevention of recurrent aHUS after renal transplantation
anti-complement therapy has been suggested to have a fundamental role in the management of de novo post-transplantation TMA.
This efficacy has been also documented in patients with refractory AMR with TMA
Cornell et al reported no difference in death-censored graft survival or biopsy finding at one year when they compared the outcome of eculizumab-treated patients with controls
the use of this vital biological agent should be confined to a specified subset of de novo TMA patients, presumably:
(1) AMR-associated TMA;
(2) Patients who became PE-dependent;
(3) Refractory hemolysis persists despite maximum doses of PE therapy.
Treatment of recurrent TMA Recommendations for recurrent TMA:
most of the recommendations about recurrence and therapeutic advices relied primarily on case reports (level 4 evidence) as well as experts’ opinions (level 5 evidence) .
(1) The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3
(2) All patients with primary or suspected aHUS, should be surveyed for all complement components and its related proteins
(3) Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation
(4) Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy
(5) Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation
Prevention of aHUS:
(1) ischemia-reperfusion injury, viral infection and immunosuppressive medications, should be avoided;
(2) Certain relations have been reported between CNI use and aHUS recurrence, which is not confirmed by other authors, even the usual substitute in such a case (an mTOR) is not innocent and can induce recurrence;
(3) We cannot depend solely on PE therapy in management of aHUS recurrence
Prophylactic use of rituximab proved to be efficacious as anti-CFH-antibodies, the beneficial effect of rituximab can be enhanced by adding PE therapy
(5) The anti-C5 monoclonal antibiotic eculizumab has been reported to be used successfully to prevent aHUS recurrence in patients with CFH, CFH/CFHR1 hybrid genes as well as with C3 gene mutations
Therapeutic protocols for aHUS recurrence:
Once the diagnosis of primary aHUS has been established, complement blockade therapy should be instituted.
Duration of therapy:
There is not enough data supporting life-long therapy for aHUS.
should be permitted to optimize renal recovery and satisfy TMA resolution.
Kidney transplantation without eculizumab prophylaxis:
Verhave et al described therapeutic protocol consisted of:
No recurrence or rejection has been observed after 16-21 mo.
Treatment of DGKE mutation associated TMA:
Azukaitis and colleagues reported the feasibility of kidney transplantation in five patients with no recurrence after transplantation.
RENAL TRANSPLANTATION Timing
Risk of kidney donation
Two risks have been reported to be associated with living-related kidney donation:
(1) Recurrent disease in the recipient;
(2) De novo disease in the donor, if he/she is a genetic mutation carrier
Research targets
The following agents are under investigation:
(1) The anti-C3b blocker,
(2) The anti-C3 convertase monoclonal antibodies
Level 5
Types of TMA after transplantation :
(1) De novo TMA,
(2)Recurrent TMA,
De novo TMA is more prevalent than recurrent TMA.
Causes of De novo TMA:
1- Calcineurin-induced TMA.
2- mTOR inhibitor-associated TMA
3- AMR-associated de novo TMA
4- Viral infection, e.g., CMV infection
5- antiviral medications, e.g., ribavirin and interferon
Clinical manifestations:
Timing: TMA could develop at any time in the post
transplantation course, but is mostly occurred in the first 3-6 mo post transplantation.
Salient features:
TMA manifestations are quite variable. The systemic form
of TMA consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI).
Features of MAHA include raised lactic acid dehydrogenase (LDH), drop in hemoglobin
(HB) and decreased haptoglobin with schistocytes on peripheral blood smear.
Localized (limited) TMA is usually presented later in TMA course, as compared to the
systemic form.
Causes of recurrent TMA :
1- aHUS
2- TTP
Current classification of TMA :
1- Primary hereditary TMA: Includes mutations in
ADAMTS13, MMACHC (cb1c deficiency), or in genes encoding complement components.
2- Primary acquired TMA: Autoantibodies to ADAMTS13
or to CFH, which occurs with homozygous CFHR3/1 deletion.
3- Infection-associated TMA: Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) and pneumococcal HUS have distinct mechanisms that result in TMA; in other infections, the processes are ill-defined and sometimes can trigger manifestations of the primary
TMA.
4- Secondary TMA
Treatment :
This mainly depends on the cause.
-Immunosuppressive medication management: the role of immunosuppressive
medications (e.g., CNI or mTORi) has been reported in the literature, with a documented
better response after switching from one CNI member to another or to an mTORi.
-Plasmapheresis (PE) and intravenous immunoglobulins (IVIG)
-Belatacept
-Complement inhibition: Eculizumab
Ø Post-transplant TMA can occur as a recurrence of the disease involving the native kidney or as de novo disease with no evidence of previous involvement before transplant.
Ø Management of both diseases varies from simple maneuvers, e.g., plasmapheresis, drug withdrawal or dose modification, to lifelong complement blockade, which is rather costly.
De novo TMA:
Ø the incidence of de novo TMA is mentioned to be as high as 3%-14% , precipitating factors have been identified in the context of renal transplantation that trigger the development of de novo TMA:
(1) Antibody mediated rejection (AMR)
(2) Immunosuppressive-associated TMA: Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi), single or combined;
(3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI)
(4) Viral infection: e.g., HCV, CMV, BK and parvovirus
(5) Genetic abnormalities in the complement cascade
(6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation; and
(7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA)
Ø Clinical manifestations:
1) Timing: TMA could develop at any time ,mostly encountered in the first 3-6 mo post transplantation.
2) Manifestations: are quite variable and can vary from a limited form confined to the kidney to a full blown systemic variant. The systemic form of TMA consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI). Features of MAHA include raised lactic acid dehydrogenase (LDH), drop in hemoglobin (HB) and decreased haptoglobin with schistocytes on peripheral blood smear. Localized (limited) necessitating the diagnostic allograft biopsy,
Ø The prognosis of post-transplant de novo TMA is quite poor for the patient and as well as the allograft. About one half of the patients loses their graft within the first two years after diagnosis
Recurrent TMA after renal transplantation:
Ø Etiology of recurrent TMA : aHUS; thrombotic thrombocytopenic purpura (TTP); and autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus, with or without anti-phospholipid antibody syndrome
Ø Current classification of TMA includes the following
1) Primary hereditary TMA: Includes mutations in ADAMTS13, MMACHC (cb1c deficiency), or in genes encoding complement components.
2) Primary acquired TMA: Autoantibodies to ADAMTS13 or to CFH, which occurs with homozygous CFHR3/1 deletion.
3) Infection-associated TMA: Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) and pneumococcal HUS have distinct mechanisms that result in TMA; in other infections, the processes are ill-defined and sometimes can trigger manifestations of the primary TMA.
4) Secondary TMA: Presents in a variety of conditions, and
Therapy of post-transplant TMA
Institution of therapeutic options is highly dependent on diagnosis as well as the patient’s response. therapeutic maneuvers should be individualized for each patient. The following approaches have been suggested:
(1) Immunosuppressive medication management
(2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG)
(3) Belatacept: A promising alternate option that allows withdrawal of the offending drug incriminated in TMA evolution
(4) Complement inhibition: Eculizumab, an anti-C5 agent, blocks the lytic C5b-9 membrane attack complex generation.
Level 5
TMA post transplant is either denovo or recurrent
Denovo TMA could be 2ry to :
1- Immunosuppression (CNI and Mtor inhibitors)
2- Acute rejection (AMR)
3- Viral anfection (CMV)
4- phenotypical changes in case of C3 glomerulopathy
5- genetic abnormality ADAMS 13,or deficiency of Factor H in complement pathway
Recurrent:
TTP or atypical HUS
In som cases it is not known before transplantation that TMA is the original cause of ESRD
Diag:
Cl manifestation: either limited or systemic (AKI ,MAHA and thrombocytopenia)
Biopsy :could come with acute rejection with positive C4D staining
In case of graft dysfunction >no rejection ,and no cause You should suspect TMA or Rena artery stenosis.
prevention:
in case of recurrent TMA :ECulizumab
treatment:
plasmapheresis
Belatacept
Eculizumab
Please summarize this article
TMA post-transplant incidence is 5.6 cases/1000 renal transplants with 50% mortality within 3 years.
Types of TMA: De-novo TMA and Recurrent TMA.
De-novo TMA is more common post-transplant than recurrent TMA which has better prognosis.
Definition and causes: acquired or genetic disorder in the alternate pathway that can be caused by: AMR, CNI, m-TOR inhibitors, CMV, BKV, Parvo-virus, HCV, shift from C3GN to a-HUS post-transplant and missed diagnosis of TMA in native kidney.
Clinical presentation: within first 3-6 months, classical triad: renal dysfunction without acute rejection, TMA, renal artery stenosis. It can present with limited manifestations.
Recurrent TMA causes: a-HUS, TTP, SLE, Scleroderma.
Extra-renal manifestations of TMA: digital gangrene, cerebral artery thrombosis, MI, GIT, Pulmonary thrombosis.
Treatment of TMA:
de novo TMA:
1- Change IS medications.
2- Plasma exchange and IVIG.
3- Eculizumab.
4- Belatacept.
Recurrent TMA:
1- Avoid IRI, viral infection, IS triggered TMA.
2- Rituximab.
3- Eculizumab
What is the level of evidence provided by this article?
level 5
TMA can occur in the form of recurrence TMA of the disease involving the native kidney or in the form of de novo disease with no evidence of previous involvement before transplant.
De novo TMA is more common compared with recurrent TMA
Atypical hemolytic uremic syndrome is a sporadic disease that results from complement dysregulation with alternative pathway increased activity.
Several factors trigger the recurrence of TMA , or de novo TMA:
Drug induced like CNI induced TMA , m Tor inhibitors like sirolimus AMR and acute TMA viral infections eg CMV, genetic mutation variants &C3 nephropathy overlapping with TMA
Recurrent TMA can occur as early as first 3-6 months following transplantation either as a HUS , TTP , autoimmune disease with renal limited or as part of systemic manifestation essentially hematological; like typical MAHA with thrombocytopenia and uremia , both de novo or recurrent TMA following transplantation correlated with poor graft outcome.
Treatment of TMA depends on the underlying cause: if drug induced to stop the offending IS.
Plasmaphereses , IVIG if TMA is associated with AMR.
Eculizumab is the drug of choice for recurrence TMA including a HUS
level of evidence 5 ;narrative review article.
Thrombotic microangiopathy (TMA) is a debilitating complication of kidney transplantation that is associated with poor patient and graft outcomes. The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis[1]. TMA after transplantation can be classified into either:De novo TMA, i.e., developed for the first time without any evidence of the disease before transplant; and Recurrent TMA, i.e., native kidneys failed as a result of TMA and it came back in renal transplantation.
DE NOVO TMA
In the presence of acquired or genetic dysregulation of the alternative complement pathway (AP), a number of precipitating factors have been identified in the context of renal transplantation that trigger the devel- opment of de novo TMA. These factors include the following: (1) Antibody mediated rejection (AMR); (2) Immunosuppressive-associated TMA: Calcineurin in- hibitors (CNI) or mTOR inhibitors (mTORi), single or combined; (3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI); (4) Viral infection: e.g., HCV, CMV, BK and parvovirus; (5) Genetic abnormalities in the complement cascade; (6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation; and( 7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA)
Etiopathogenesis of de novo TMA
AMR and medications are the two main causes of de novo TMA.
Calcineurin-induced TMA: The link between CNI (CyA and tacrolimus) administration and the evolution of de novo TMA is not a new concept.
mTOR inhibitor-associated TMA: mTORi can inhibit cell cycle progression and proliferation. Both sirolimus and everolimus have been reported to be implicated in the pathogenesis of de novo TMA.
AMR-associated de novo TMA: The role of AMR in the development of post-transplant TMA is commonly reported and well-recognized. Endothelial cells are a well-known target of allo-immune response.
Complement gene mutations: Chua et al reported that renal complement activation is the common de- nominator in such a heterogeneous condition. They observed C4d deposits in more than 88% and C4d with localized C5b-9 in about 60% of 42 biopsy samples from patients with histologically confirmed diagnosis of TMA from a heterogenous group of patients
Relation to TMA evolution: The AP depends on two main regulators: CFH and CFI. CFH has the ability to inhibit the C3 cleaving enzyme C3bBb. Moreover, it can serve as co-factor for FI, and the latter has the ability to inactivate C3b.
Clinical manifestations
Timing: TMA could develop at any time in the post transplantation course[5,43], however this syndrome is mostly encountered in the first 3-6 mo post trans- plantation. This is probably when the CNI immuno- suppressive trough levels are relatively higher
Salient features:
TMA manifestations are quite variable and can vary from a limited form confined to the kidney to a full blown systemic variant[4,6,44]. The systemic form of TMA consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI). Features of MAHA include raised lactic acid dehydrogenase (LDH), drop in hemoglobin (HB) and decreased haptoglobin with schistocytes on peripheral blood smear.
Prognosis of de novo TMA:
The prognosis of post- transplant de novo TMA is quite poor for the patient and as well as the allograft. About one half of the patients loses their graft within the first two years after diagnosis
RECURRENT TMA AFTER RENAL
TRANSPLANTATION
Etiology of recurrent TMA
aHUS; thrombotic thrombocytopenic purpura (TTP); and autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus, with or without anti-phospholipid antibody syndrome
aHUS: Recurrence of TMA in the allograft depends on the underlying type involving the native kidney. Overactivation of the AP is known to be the underlying etiology of aHUS. By far, aHUS is the most common diagnosis in TMA associated with recurrence. Risk of recurrence is greatly dependent on the underlying associ- ated abnormality
TTP: TTP is the second recognized etiology in TMA.
Genetic or acquired lack of ADAMTS13 has been recognized. For a long period, differentiation between TTP and HUS relied primarily on the presence of neurologic manifestation in TTP and renal dysfunction in HUS to settle the diagnosis. Serological evaluation of ADAMTS13 activity is now feasible.
PATHOPHYSIOLOGY OF TMA RECURRENCE
The AP is constitutively active and is, therefore, fine- tuned. The regulatory components exist either in the serum (fluid phase) or attached onto cell membranes. CFH is the main inhibitor of the AP. CFH has the ability to work in fluid phase as well as on cell surfaces. Furthermore, CFH can act as a co-factor to CFI[59,60]. Regulatory components on cell surfaces, or “membrane regulators” include the following: (1) Membrane cofactor protein (MCP/CD46); (2) Complement receptor 1 (CR1/ CD35); (3) Decay accelerating factor (DAF/CD55); and (4) Protectin (CD59), which prohibits MAC formation
Current classification of TMA includes the following
Primary hereditary TMA:
Includes mutations in ADAMTS13, MMACHC (cb1c deficiency), or in genes encoding complement components.
Primary acquired TMA:
Autoantibodies to ADAMTS13 or to CFH, which occurs with homozygous CFHR3/1 deletion.
Infection-associated TMA:
Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) and pneumococcal HUS have distinct mechanisms that result in TMA; in other infections, the processes are ill-defined and sometimes can trigger manifestations of the primary TMA.
Secondary TMA:
Presents in a variety of conditions, and in many conditions the culprit mechanisms are usually multifactorial or unknown.
The most common complement mutation
in aHUS is CFH, with 40% of cases inherited and 25% sporadic . Furthermore, not only CFH has its impact on TMA evolution, but the CFH-related genes (CFHR1-5) have additional roles. Through deletion, hybrid protein formation and duplication of these genes, the endothelial cell surface becomes denuded from its protective shield, and consequently aHUS may supervene
The risk of aHUS recurrence could be four times higher with CFH mutations or with the carriers of CFH/ CFHR1 hybrid genes.On the other hand, the impact of CFI mutations is controversial. While early reports about CFI mutations documented a high rate of recurrence and graft loss
Clinical assessment of aHUS: Any HUS that is not due to STEC-HUS has been called aHUS. The recent progress in understanding the pathophysiology and the underlying genetic factors led to the current classification of aHUS
Acute vs chronic lesion?
Timing of an aHUS episode is not easily predictable. Many patients are at persistent risk of recurrence. In medical genetics, penetrance of any disease-causing mutation means the percentage of subjects with genetic mutations who can express clinical symptoms
Extrarenal manifestation: Twenty percent of aHUS patients can express extrarenal manifestations in the form of digital gangrene, cerebral artery thrombosis, myocardial infarction, in addition to ocular, GIT, pul- monary and neurologic involvement. Drusen formation is not common in aHUS
Laboratory investigations and differential diagnosis: Once the diagnosis of aHUS is suspected, exclusion of ADAMTS13 activity is urgently mandated to exclude TTP diagnosis. In children, TTP is less common; therefore, eculizumab therapy should be instituted early without waiting for the results of ADAMTS13 activity.
Complement assessment in aHUS: Before com- mencing plasma therapy, serum complement com- ponent should be thoroughly evaluated. C3 is low in 30% of aHUS patients and, therefore cannot be used as a screening criteria for aHUS
Panel of genetic testing: The diagnostic list of genes of aHUS should include at least CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE
Rationale for genetic screening: The current progress in understanding the underlying genetic background of aHUS and its molecular basis makes it paramount to
provide a full detailed genetic map before transplant, and the following explanations have been given: (1) Determination of the actual cause of the disease that allows for correct genetic counseling; (2) Drawing the plan of disease management; (3) Evaluating the expected response for therapy; and (4) Defining the prognostic course as well as patient and allograft survival.
Interpretation of the genetic variants: Genetic mutations can be interpreted as: (1) Benign; (2) Likely benign; (3) Variant of uncertain significance; (4) Likely pathogenic; or (5) Pathogenic, according to the international guidelines
Acquired drivers of aHUS: The FH autoantibodies are the best reported example. It is typically characterized by homozygosity for delCFHR3-CFHR1
Diagnosis of aHUS recurrence: A full detailed clinical history is usually warranted. A proven tissue diagnosis with light microscopy (LM), immunofluorescence (IF) and electron microscopy (EM) studies supporting the diagnosis of aHUS in the native kidney should be available.
THERAPY OF POST-TRANSPLANT TMA
Treatment of de novo TMA
In view of the extreme heterogenicity of the mechanisms related to variable etiologies of TMA, therapeutic ma- neuvers should be individualized for each patient. Institution of therapeutic options is highly dependent on diagnosis as well as the patient’s response. The following approaches have been suggested: (1) Immuno- suppressive medication management: the role of im- munosuppressive medications (e.g., CNI or mTORi) has been reported in the literature, with a documented better response after switching from one CNI member to another or to an mTORi) dose modulation, withdrawal or continuation of CyA in man- agement of de novo TMA.
(2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG): The following rationales have been addressed in favor of PE/IVIG therapy
(3) Belatacept: A promising alternate option that allows withdrawal of the offending drug incriminated in TMA evolution.
(4) Complement inhibition: Eculizumab, an anti-C5 agent, blocks the lytic C5b-9 membrane attack complex generation.
On the other hand, Cornell et al reported no difference in death-censored graft survival or biopsy finding at one year when they compared the outcome of eculizumab-treated patients with positive cross matching with controls, even though the incidence of acute AMR was less in the eculizumab group. So, in view of these conflicting results as well as considering the high cost of the drug, the use of this vital biological agent should be confined to a specified subset of de novo TMA patients, presumably: (1) AMR-associated TMA; (2) Patients who became PE-dependent; and (3) Refractory hemolysis persists despite maximum doses of PE therapy. However, more efforts are still warranted to declare the best way to utilize this unique agent and which subset of TMA patients are the best candidates for this costly drug. An urgent need for new biomarkers is also warranted for early detection of complement overactivity
Treatment of recurrent TMA
Recommendations for recurrent TMA: First of all, it is worthy to remember that most of the recommendations about recurrence and therapeutic advices relied primarily on case reports (level 4 evidence) as well as experts’ opinions (level 5 evidence) rather than on randomized controlled trials (level 1b evidence). (1) The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3 (2) All patients with primary or suspected aHUS, should be surveyed for all complement components and its related proteins; (3) Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation; (4) Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange the- rapy and (5) Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation
Prevention of aHUS: The following strategies are suggested to decrease/prevent aHUS: (1) Complement activity incited by an injury to endothelium, e.g., ischemia-reperfusion injury, viral infection and immuno- suppressive medications should be avoided; (2) Certain relations have been reported between CNI use and aHUS recurrence which is not confirmed by other authors even the usual substitute in such a case (an mTOR) is not innocent and can induce recurrence (3) We cannot depend solely on PE therapy in man- agement of aHUS recurrence for several reasons: PE failed to prevent aHUS recurrence in many cases
Prophylactic complement blockade: Gene abnor- malities have been reported to be associated with aHUS recurrence in 80% of patients
Therapeutic protocols for aHUS recurrence: Once the diagnosis of primary aHUS has been established, complement blockade therapy should be instituted. The available data points to two strategies: (1) Minimal dosage to establish complement blockade; and (2) Dose withdrawal scheme
FH autoantibody-driven aHUS: Anti-cellular therapy is recommended, with close monitoring of the antibody titer
Duration of therapy: There is not enough data sup- porting life-long therapy for aHUS. Cessation of therapy appears to be plausible in certain situations
Unanswered questions: There is paucity of information about this biological agent, e.g., what is the most optimal dose? What are the ideal dose-intervals? For how long should this kind of costly therapy be continued
What impact does this agent have on the spectrum of renal transplantation
Kidney transplantation without eculizumab pro- phylaxis:
They received living donor kidney with therapeutic protocol consisted of: Basiliximab for induction, tacrolimus in low dose, and prednisone and mycophenolate mofetil as immunosuppressive in addition to a statin. Additional precautions include lowering the blood pressure and minimizing the cold ischemic time.
Treatment of DGKE mutation associated TMA:
The role of complement blockade here is questionable.
RENAL TRANSPLANTATION
Timing
Renal transplantation should be postponed six months after institution of dialysis, as limited kidney recovery can occur several months after commencing eculizu- mab therapy
Risk of kidney donation
Two risks have been reported to be associated with living-related kidney donation: (1) Recurrent disease in the recipient; and (2) De novo disease in the donor, if he/she is a genetic mutation carrier[169]. Any po- tential donor proved to exhibit alternative pathway dysregulation should be excluded. On the other hand, any potential living-related donor devoid of complement gene abnormalities can be permitted
CONCLUSION
The impact of TMA, either de novo or recurrent, on allograft longevity is underestimated. The spectrum of the culprit genes implicated in the evolution of TMA is currently expanding. Despite the landmark breakthrough of immense efficacy of complement blockade therapy, the outlook of this devastating syndrome remains poor if the diagnosis is delayed. In contrast, the recurrent TMA is much more optimistic if there is timely intervention by complement blockade before permanent damage sets in. More efforts targeting genetic mutation management as well as the advent of early predictors of TMA recurrence are warranted for better disease control and, thereby, better patient and allograft outcome
Level 5
Introduction
Thrombotic microangiopathy (TMA) is a debilitating complication of kidney transplantation that is associated with poor patient and graft outcomes. with incidence of 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis
TMA after transplantation can be classified into either:
(1) De novo TMA, i.e., developed for the first time without any evidence of the disease before transplant;
(2) Recurrent TMA, i.e., native kidneys failed as a result of TMA and it came back in renal transplantation
Precipitating factors for De novo TMA development
(1) Antibody mediated rejection (AMR);
(2) Immunosuppressive-associated TMA: (CNI) or mTOR inhibitors (mTORi),
(3) Other medications: e.g.,(anti-VGFI);
(4) Viral infection: e.g., HCV, CMV, BK and parvovirus;
(5) Genetic abnormalities in the complement cascade;
(6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation;
(7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA
Clinical manifestations
2.. Localized (limited) TMA , suspected when there is significant renal dysfunction
and the biopsy does not show any acute rejection,
The prognosis of post transplant de novo TMA is quite poor for the patient and as well as the allograft
Recurrent TMA causes :
The current classification of TMA includes the following:
• Primary hereditary TMA
• Mutations in ADAMTS13, MMACHC
• Primary acquired TMA
• Autoantibodies to ADAMTS13
• Infection-associated TMA
• Shiga toxin-producing Escherichia coli-HUS, pneumococcal HUS
• Secondary TMA
Multifactorial
• Drug induced TMA
• Malignancy-associated TMA
• De novo TMA after solid organ transplantation
• TMA with autoimmune diseases
• TMA with glomerular diseases
Treatment of de novo TMA involves adjusting the immunosuppressant medications, plasmapheresis, intravenous immunoglobulins, belatacept (an immunosuppressive co-stimulatory blocker against CD80 and CD86 surface ligands), eculizumab (an anti-C5 agent that blocks the complement pathway).
Prevention of recurrent TMA is important, and the following strategies can be used:
1. Complement activity incited by an injury to the endothelium should be avoided (e.g. viral infections, immunosuppressive medications)
2. Substitution of CNIs
3. Plasmapheresis cannot suffice as the sole treatment
4. Use of eclizumab.
Therapeutic protocols for aHUS recurrence include complement blockade therapy with minimal dosage to establish complement blockade and a dose withdrawal scheme.
The duration of therapy should be enough time for renal recovery and TMA resolution.
Renal transplantation should be delayed for 6 months after starting dialysis and eclizumab therapy. Recurrent disease in the recipient and de novo disease have been recognized as risks for living related kidney donation.
Level of evidence: V
TMA can occur as a recurrence TMA of the disease involving the native kidney or as
de novo disease with no evidence of earlier involvement before transplant.
De novo TMA is more common than recurrence TMA
Atypical hemolytic uremic syndrome is a sporadic disease that results from complement dysregulation with alternative pathway overactivity,
many factors can triggers the recurrence of TMA , or denovo TMA
recurrence of TMA can occur as early as first 3-6 months post transplantation either as a HUS , TTP , autoimmune disease with renal limited or as part of systemic manifestation mainly hematological; like typical MAHA with thrombocytopenia and uremia , both denovo or recurrence TMA after transplantation associated with poor graft outcome
treatment of TMA
depends on the underlying cause if drug induced need to stop the offending IS
plasmaphereses , IVIG in case of TMA with AMR
Eculizumab is the drug of choice for recurrence TMA including a HUS
level of evidence 5 ( narrative review )
TMA
Incidence of post-transplant TMA is 5.6 cases per 1000 KT recipients per year .
Classified either De Novo TMA or Recurrent TMA.
De Novo is more prevalent than recurrent TMA.
There are many factors that trigger the occurrence of De Novo TMA including:
1-AMR
2-CNIs induced TMA or mTOR inhibitors
3- Drugs
4- viral infection
5-Genetic abnormalities
6-shift of C3 Glomerulopathy to TMA post transplantation
7- missed diagnosis of TMA as a cause of primary GN disease .
Clinical manifestations:
TMA developed at any time but mostly in the first 3-6 months post transplantation.
It can be limited form or systemic form.
The systemic form consists of the triad of thrombocytopenia, microangiopathic hemolytic anemia , and AKI.
MAHA features include raised LDH , drop in Hb , and decrease in haptoglobin with schistocytes on peripheral blood smear.
The localized form occurs later in TMA course.
The prognosis of De Novo TMA is poor for the patients as well as allograft.
Recurrent TMA after KT :
It’s either due to aHUS ,TTP, autoimmune diseases .
The spectrum of TMA :
1- primary hereditary: aHUS with complement gene mutation, TTP with ADAMTS13 mutation.
2- primary acquired: TTP with ADAMTS13 autoantibodies, aHUS with FH autoantibodies.
3-infection associated: STEC-HUS, pneumococcal HUS , HIV- associated TMA and other infections.
4- secondary TMA : drug induced, De Novo TMA , pregnancy induced, malignancy-associated, TMA with severe HT , TMA with GN diseases , TMA with autoimmune diseases and TMA after bone marrow transplantation .
5- TMA due to unknown causes.
Therapy of post KT TMA :
Treatment of De Novo TMA
1- withdrawal of the offending agents.
2- PEX and IVIG
3- Belatacept which is an immunosuppressive co-stimulatory blocker against CD80 and CD86 surface ligands and CD80 on T cells.
4- complements inhibitors: Eculizumab an anti-C5 agent.
Treatment of recurrent TMA
1-genetic screening include CFH, CFI, CFHR, CFB, MCP and C3.
2-surveyed all patients with primary or suspected aHUS for all complements .
3- MCP associated mutations patients may be safe for kidney donation.
4-patients with aHUS with no genetic mutation can proceed for kidney transplantation.
5-patients with polygenic pattern aHUS should be handle with caution in case of living donation.
Level of evidence: V
Thrombotic microangiopathy TMA post transplantation is often encountered with significant consequences on the allograft and recipient in survival.
Classically presented with ideopathic impaired allograft function, however systemic manifestation triad of thrombocytopenia TCP, microangiopathic hemolytic anemia MAHA, and allograft dysfunction.
It might be recurrent and or de novo TMA.
De novo TMA is more common and linked to several etiologies and predisposing factors
as follows:
Acute antibody mediated rejection ABMR:
as its affecting endothelial cells, promoting microangiopathic thrombosis.
It was found related to C4d deposition in peritubular capillaries.
Iatrogenic:
1-owing to the dependence on Calcineurin inhibitors Cyclosporin and Tacrolimus:
with several putative mechanisims linked to platelets stimulation and endothelial cell dysfunction.
2-Sirulimus:
3-Sirulimus and CNI combination.
Summary of Thrombotic microangiopathy after renal transplantation- Current insights in de novo and recurrent diseaseIntroduction:
TMA is one of the causes of poor patient and graft outcomes post-renal transplantation. It could be :
1. De novo TMA
2. Recurrent TMA
In this review, we will try to discuss the main difference between the two categories in the pathophysiology, clinical cause, and available approach of prevention and treatment.
De Novo TMA:
Acquired genetic dysregulation of the alternative complement pathway
Trigger factors include:
1. Antibody-mediated rejection
2. Immunosuppression associated TMA, CNI, or mTUR inhibition 3-anti-VGFI
3. Viral infection HCV, CMV, BK, and parvovirus
4. Genetic abnormalities in the complement cascade
5. C3 glomerulopathy with ESRD
6. Missed changes of TMA
CNI-induced TMA:
We== explain the role of CNI in TMA dependent:
1. Loss of the normal balance between the vasodilator peptide
2. CNI-induced platelet activation
3. Microparticle production from endothelial cells
mTOR inhibitor-associated TMA explanation:
1. mTOR has angiogenic properties and can decrease renal expression of vascular endothelial growth factor
2. the VEGF inhibition has been recently proven to be associated with reduced renal levels of complement factor H
3. repair of endothelial injury could be happened by mTOR use
4. the procoagulant and antifibrinolytic activity of mTOR
AMR-associated de novo TMA:
Endothelial cells is the target of all-immune response. The peritubular capillary(PTC) c4d staining
Other causes less common:
1. viral infection e.g CMV infection, BK virus, parvovirus, chronic hepatic virus
2. ischemic reperfusion injury
3. ADAMTSII3 deficiency
4. C3 glomerulopathy
Complement gene mutation:
Genetic mutation mCFH, complement factor cFI or both in 29% de novo TMA patients 25% for complement factor B( FB)
Relation to TMA evolution:
The AP depends on two regulators CFH and CFI
Clinical features:
Common in the first 3-6 month post-transplantation
Systemic form:
1. Thrombocytopenia
2. MAHA
3. AKI
Features of MAHA:
1. High LDH
2. Low drop Hb
3. Decrease haptoglobin
4. Schistocytes on peripheral blood smear
If the renal transplant biopsy does not show any acute rejection suspect two possibilities:
1. TMA OR
2. Renal artery stenosis
Active thrombosis and glomerular ischemia
Chronic stage:
Basement membranes undergo duplication
Prognosis of de novo TMA:
Relapse 54% of systemic TMA develop dialysis requiring AKI and 38% lost their graft
Recurrent TMA after renal transplantation:
Etiology of recurrent TMA:
TTP, aHUS, autoimmune disease(SLE and Scleroderma with or without APLs
aHus is most cause of recurrent TMA is about 70-90% rate
TTP is second cause of TMA cause of lack of ADAM TSI is ==recurrence after transplantation
Pathology:
Endothelial injury present with fibrin/platelet plugging and intraluminal fibrin are not always seen in renal allograft biopsy
Non-thrombotic features:
1. Denuded and swelling endothelium
2. Mesangiolysis
3. GBM double contour
4. Electrolucent matrial in the subendothelial
Pathophysiology of TMA recurrence:
CFH is the main in== of the AP and co factor CRI and disturbance of regularly complement lead to complement activation
Classification of TMA:
1. Primary hereditary TMA: mutation in AD AMTSIB, MMACHC or in gene encoding complement component
2. Primary acquired TMA: autoantibodies to AbAMB or to CFI which occurs with homozygous (FHR3) 1 deletion
3. Infection associated TMA shiga toxin produce Ecoli-HUS and pneumococcal HUS
4. Secondary TMA: mechanism multifactorial or unknown
Role of DGKE mutation:
Most of a HUS is CFH with 40% of cases inherited and 25% sporadic
The risk of a HUS recurrence could be four time higher with CFH mutation
Role of diacylglycerol kinase( DGKE) mutation:
DGKE associated acute renal failure, thrombocytopenia, and haemolytic anaemia
Environmental triggers:
aHus triggers factors:
· Anti HLA antibodies
· Viral infection
· Ischemic-reperfusion injury
· Immunosuppression medications
Clinical associated of a Hus:
Acute vs chronic lesion:
Timing of an a Hus episode is not easily predictable
Many patients at risk of recurrence
Late presentation of aHus reflect the impact of the environmental triggers
TMA can be diagnosed by tissue biopsy without thrombocytopenia
Compliment inhibition can improve glomerular perfusion and maintain kidney function
Extrarenal manifestation:
aHus 20% of patients have:
1. Digital gangrene
2. Cerebral artery thrombosis
3. Myocardial infarction
4. Ocular, GIT, pulmonary, and neurologic involvement
Laboratory investigations and differential diagnosis:
Exclusion of ADAMB13 (TTP1) once a Hus suspected
Complement assessment in a Hus:
C3 is low in 80% of a Hus patients
CD46 surface expression as functional parameters.
Genetic testing:
Gene of a Hus : CFH, CFI,C3,CFB, THBD
Rationale for genetic screening:
Full genetic map before transplantation because of the following factors:
1. Know the actual cause of the disease that allows for genetic counselling
2. Put plan of management
3. Evaluating the expected response for therapy
4. affecting the prognostic course as well as patient and allograft survival
Genetic variants:
Genetic mutation can be as:
1. Benign
2. Likely benign
3. Variant of uncertain significance
4. Likely pathogenic
5. Pathogenic according to the international guidelines
Genetic designation also has its impact on therapeutic plans, response to therapy as well as the chance for a Hus recurrence
Diagnosis of a Hus recurrence:
History is crucial to be elaborated
Tissue diagnosis:
1. Light microscopy
2. Immunofluorescence
3. Electron microscopy
Biochemical and genetic investigations if a Hus suspected should be any on include:
1. Anti-CFH-AB
2. MCP screening on the peripheral blood WBCs
3. Examination of the recombination in CFHR region
4. Screening of the genetic mutations related to CFH, CFI, CFB, C3, and MCP
Therapy of posttransplant TMA:
Treatment of de novo TMA:
Therapeutic options:
1. Immunosuppressive medication management( switch for CNI to other agents)
2. Plasmapheresis (PE) and intravenous immunoglobulin IVIG now replaced by eculizumab
3. Belatacept promising option therapy
4. Complement inhibition
Eculizumab an anti-C5b-9 membrane attack complex generation
Use for treatment and prevention of recurrent a Hus after renal transplantation
Biological agent use ( eculizumab) should be to specific subset of De Novo
TMA patients:
1. AMR-associated TMA
2. Patient who became PE-dependent and
3. Refractory haemolysis
Treatment of recurrent TMA:
Recommendation for recurrent TMA:
1. The minimal list of genetic screening should be included CFH, CFI,CFHR,CFB, MCP, and C3
2. All patients with primary or suspected a Hus should be survey for all complement component and its related proteins
3. Isolated MCP-associated mutation safe for kidney donation
4. Patient with a Hus and no definite genetic mutation can proceed for kidney transplantation under the umbrella of plasma exchange therapy
5. Polygenetic pattern for a Hus patients should be handled with extreme caution in case of living donation
Prevention of a Hus:
This steps suggest to prevent a Hus:
1. Avoid complement activation by viral infection, immunosuppression medication and ischemic-reperfusion injury
2. A CNI use although uncertain
3. PE failed to prevent a Hus recurrence
4. Use eculizumab to prevent a Hus recurrence in patients with CFH, CFHRI by genes as well as with C3 gene mutation
Prophylactic:
Complement blockage in a Hus after exposure to triggers such as infection although lack enough evidence
Therapeutic protocols:
For a Hus recurrence:
If diagnosis is confirm primary a Hus complement blockage therapy should be initiated:
1. Minimal dosage to complement blockage
2. Dose withdrawal scheme
Although both are lack of evidence
FH autoantibody-driven-a Hus:
Anti-cellular therapy is recommended
No enough data supporting life long therapy for a Hus
There is case series herald the possibility of successful kidney transplantation in recent a Hus without the need for prophylactic eculizumab through decrease cold ischemic time decreasing the risk of rejection
Treatment of DGKE mutation associated TMA:
The role of complement blockage here is questionable
evidence level5
Thrombotic microangiopathy (TMA) is one of the most devastating sequalae of kidney transplantation. Post-transplant TMA can occur as a recurrence of the disease involving the native kidney or as de novo disease with no evidence of previous involvement before transplant. De novo TMA is more common and its prognosis is poorer than recurrent TMA; the latter has a genetic background, with mutations that impact disease behavior and, consequently, allograft and patient survival. When a renal transplant recipient has significant renal dysfunction and the biopsy does not show any acute rejection, one must suspect two possibilities: (1) TMA or (2) Renal artery stenosis.
DE NOVO TMA
In the presence of acquired or genetic dysregulation of the alternative complement pathway (AP), a number of precipitating factors have been identified in the context of renal transplantation that trigger the development of de novo TMA. These factors include the following: (1) Antibody mediated rejection (AMR); (2) Immunosuppressive-associated TMA: Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi), single or combined; (3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI); (4) Viral infection: HCV, CMV, BK and parvovirus; (5) Genetic abnormalities in the complement cascade; (6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation; and (7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA).
Features:
– Occurs at any time post-transplantation, but is most common between 3-6 months.
– The systemic form of TAM consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (increase in lactic acid dehydrogenase (LDH), decrease in hemoglobin (HB) and decrease in haptoglobin with schistocytes in the peripheral blood smear), and acute kidney injury .
– Post-transplant de novo TMA prognosis is quite poor for the patient and also for the allograft., about half of the patients lose the graft in the first two years after.
RECORRENTE TMA
aHUS; thrombotic thrombocytopenic purpura (TTP); and autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus, with or without anti-phospholipid antibody syndrome.
Current classification of TMA includes the following:
– Primary hereditary TMA: Includes mutations in ADAMTS13, MMACHC (cb1c deficiency), or in genes encoding complement components.
-Primary acquired TMA: Autoantibodies to ADAMTS13 or to CFH, which occurs with homozygous CFHR3/1 deletion.
– Infection-associated TMA: Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) and pneumococcal HUS have distinct mechanisms that result in TMA; in other infections, the processes are ill-defined and sometimes can trigger manifestations of the primary TMA.
– Secondary TMA: Presents in a variety of conditions, and in many conditions the culprit mechanisms are usually multifactorial or unknown.
Diagnosis of aHUS recurrence:
A full detailed clinical history is usually warranted. A proven tissue diagnosis with light microscopy (LM), immunofluorescence (IF) and electron microscopy (EM) studies supporting the diagnosis of aHUS in the native kidney should be available. However, once diagnosis of aHUS is suspected, a full battery of biochemical, genetic as well as pathological investigations of the AP should be accomplished, including the following: (1) Estimation of the anti-CFH AB; (2) MCP screening on the peripheral blood WBCs; (3) Examination of the recombination in CFHR region; and (4) Screening of the genetic mutations related to CFH, CFI, CFB, C3, and MCP.
Treatment of de novo TMA
In view of the extreme heterogenicity of the mechanisms related to variable etiologies of TMA, therapeutic maneuvers should be individualized for each patient. The following approaches have been suggested:
– 1- Immunosuppressive medication management: the role of immunosuppressive medications (e.g., CNI or mTORi) has been reported in the literature, with a documented better response after switching from one CNI member to another or to an mTORi)
– 2 – Plasmapheresis (PE) and intravenous immunoglobulins (IVIG)
– 3 – Belatacept: A promising alternate option that allows withdrawal of the offending drug incriminated in TMA evolution. Belatacept is an immunosuppressive co-stimulatory blocker against CD80 and CD86 surface ligands and CD28 on T cells
– 4 – Complement inhibition: Eculizumab, an anti-C5 agent, blocks the lytic C5b-9 membrane attack complex generation.
Treatment of recurrent TMA
Recommendations for recurrent TMA: First of all, it is worthy to remember that most of the recommendations about recurrence and therapeutic advices relied primarily on case reports as well as experts’ opinions rather than on randomized controlled trials. Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy.
Level 5 – because this a narrative review
Thrombotic microangiopathy post-transplantation has a poor prognosis up to 50% will end up with graft loss with in two years.
It could be recurrent or de novo. To confirm the recurrent need genetic testing like CFHR, MCP, CFH and CFI with C3 level. There could be multiple factor of triggering for de novo, usually they present with low platelets, raising creatinine, and features of MAHA.
Treatment is accordingly if by complement cascade blockade, immunosuppression dose modification, PLEX, high dose IVIG, eculizumab and newer agents like belatacept.
Level V.
1. Please summarise this article
Thrombotic microangiopathy might occur in the kidney allograft in 2 forms: either de novo or recurrent TMA. De novo are more common than recurrent TMA.
De novo TMA
It can occur at any time post kidney transplantion but mostly occur in the first 3-6 months.
Triggering factors are : AMR, drug associated(CNI, mTORi, ribavirin, interferon and anti-VGFI associated), viral associated(HCV,CMV,BK and parvovirus), complement gene mutation and native kidney diseases (C3 glomerulopathy and missed TMA diagnosis).
Clinical features may vary from classical triad (low platelets, AKI and MAHA) or localized. Renal biopsy will reveal endothelial cell injury in the active stage with thrombosis ,fibrinoid necrosis and glomerular ischaemia. While the finding in the chronic stage are dublication of the basement membrane.. once diagnosed, the primary cause of renal disease need to be established as aHUS can be treated with eculizumab.
It has poor prognosis as 50% of patients will lose the graft within the first 2 years.
Recurrent TMA
The causes could be aHUS ,TTP, SLE or scleroderma. The most common one is aHUS followed by TTP. The renal biopsy will show thrombotic and non thrombotic features.. recurrence occur due to alterastion in the protective regulatory components of the complement system.
The current classification of TMA:
· Primary heiditory:
1. aHUS with complement gene mutations.
2. TTP with ADAMTS13 mutations.
3. cblC deficiency mediated TMA.
4. DGKE-associated TMA.
· Primary acquired
1. TTP with ADAMTS13 autoantibodies.
2. aHUS with FH autoantibodies.
· infection associated
1. STEC- HUS.
2. Pneumococcal HUS ( distinct mechanisms result in TMA ).
3. HIV-associated TMA.
4. Other infections ( ill defined, infection may trigger manifestation of a primary TMA ).
· Secondary
1. Drug-induced TMA.
2. De novo TMA after SOT.
3. Pregnancy-associated TMA (HELLP).
4. Malignancy-associated TMA.
5. TMA with severe HT.
6. TMA with glomerular diseases (MN, MPGN, FSGS, IgAN, AAV).
7. TMA with autoimmune diseases ( e.g. SLE, CAPS, SRC). 8. TMA after bone marrow transplant
Treatment of de novo TMA:
1- Immunosuppressive medication management ( switching from one CNI member to another or to an mTORi)
2- Plasmapheresis (PE) and intravenous immunoglobulins
3- Belatacept
4- Complement inhibition: Eculizumab
Treatment of recurrent TMA:
· The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3
· All patients with primary or suspected aHUS, should be surveyed for all complement components and its related proteins
· Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation
· Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy
· Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation
Prevention of aHUS is through avoiding complement activation, elicited by ischemia-reperfusion injury, viral infection and immunosuppressive medications, and prophylactic use of rituximab , anti-CFH-antibodies and eculizumab
Therapeutic protocol is use of complement blockade therapy and dose withdrawal scheme
What is the level of evidence provided by this article?
Level V
What is the level of evidence provided by this article?
Level V; review article
INTRODUCTION
Thrombotic microangiopathy (TMA) is a debilitating complication of kidney transplantation that is associated with poor patient and graft outcomes.
TMA after transplantation can be classified into either:
(1) De novo TMA, i.e., developed for the first time without any evidence of the disease before transplant; and (2) Recurrent TMA, i.e., native kidneys failed as a result of TMA and it came back in renal transplantation.
Factors that trigger the development of de novo TMA
(1) Antibody mediated rejection (AMR); (2) Immunosuppressive-associated TMA: Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi), single or combined; (3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI); (4) Viral infection: e.g., HCV, CMV, BK and parvovirus; (5) Genetic abnormalities in the complement cascade; (6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation; and (7) Missed diagnosis
of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA)
Graft loss rate of 40% is reported in de novo TMA within a couple of years of diagnosis.
Clinical features of TMA
TMA is mostly encountered in the first 3-6 months post transplantation. This is probably when the CNI immunosuppressive trough levels are relatively higher; however, it can happen at any time post-transplant
TMA manifestations are quite variable and can vary from a limited form confined to the kidney
to a full blown systemic variant. The systemic form of TMA consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI)
Prognosis of de novo TMA: The prognosis of posttransplant de novo TMA is quite poor for the patient and as well as the allograft
THERAPY OF POST-TRANSPLANT TMA
Treatment of de novo TMA
– (1) The withdrawal of the offending agent should be the first line in treating de novo TMA, a fundamental step that ultimately results in correction of the hematological profile.
– (2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG)
– (3) Belatacept: A promising alternate option that allows withdrawal of the offending drug incriminated in TMA evolution
– (4) Complement inhibition: Eculizumab, an anti-C5 agent.
Treatment of recurrent TMA
(1) Minimal dosage to establish complement blockade; and (2) Dose withdrawal scheme
The following strategies are suggested to decrease/prevent aHUS:
(1) Complement activity incited by an injury to endothelium, e.g., ischemia-reperfusion injury, viral infection and immunosuppressive medications[127], should be avoided;
(2) Certain relations have been reported between CNI use and aHUS recurrence[
(3) PE therapy with rituximab
(4) The anti-C5 monoclonal antibiotic eculizumab
Introduction
Thrombotic microangiopathy (TMA) is a debilitating complication of kidney transplantation that is associated with poor patient and graft outcomes.
TMA after transplantation can be classified into either:
1) De novo TMA, i.e., developed for the first time without any evidence of the disease before transplant
2) Recurrent TMA, i.e., native kidneys failed as a result of TMA and it came back in renal transplantation.
Contrary to what was believed in the past, de novo TMA is more common and its prognosis is poorer. On the other hand, recurrent TMA relies on a wide base of genetic backgrounds, with mutation errors differing in their impact on disease behavior and consequently on allograft and patient survival.
In this review, we shall try to discuss the main differences between the two categories in the pathophysiology, clinical course and available approaches of prevention and treatment.
DE NOVO TMA
a number of precipitating factors have been identified in the context of renal transplantation that trigger the development of de novo TMA.
These factors include the following:
1) Antibody mediated rejection (AMR)
2) Immunosuppressive-associated TMA: Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi), single or combined
3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI)
4) Viral infection: e.g., HCV, CMV, BK and parvovirus
5) Genetic abnormalities in the complement cascade
6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation
7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA)
the incidence of de novo TMA to be 1.5%. However, the incidence of de novo TMA is mentioned to be as high as 3%-14%. It is clear that de novo TMA is more prevalent after kidney transplantation and presumably underestimated.
Graft loss rate of 40% is reported in de novo TMA within a couple of years of diagnosis.
Etiopathogenesis of de novo TMA
AMR and medications are the two main causes of de novo TMA.
The risk of development of TMA with combined CNI and mTORi protocols is higher than using mTORi alone, an effect that has been documented in several studies.
The role of AMR in the development of post-transplant TMA is commonly reported and well-recognized
Several less common etiologies have been reported to be involved in TMA pathogenesis and include:
Viral infection, e.g., CMV infection, BK virus, parvovirus, chronic hepatitis C virus (with or without anti-cardiolipin seropositivity)
antiviral medications, e.g., ribavirin and interferon
disseminated histoplasmosis.
Ischemia-reperfusion injury can augment complement-associated injury through complement activation.
An acquired disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiencyanother rare risk factor- has been shown in one case to represent post-transplant TMA
The systemic form of TMA consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI).
Features of MAHA include raised lactic acid dehydrogenase (LDH), drop in hemoglobin (HB) and decreased haptoglobin with schistocytes on peripheral blood smear.
In the absence of renal biopsy, many cases can be misdiagnosed as hypertensive nephrosclerosis.
Consequently, a prompt testing for genetic mutations should be accomplished to unmask an underlying complement dysregulation and avoid missing the diagnosis of a recurrent aHUS.
This approach has key therapeutic implications, since de novo TMA has limited therapeutic options, in contrast to recurrent aHUS after transplantation, which has a better chance of C-5 blockade through the monoclonal antibody eculizumab, an effective therapeutic agent not only for treatment, but also for prevention of recurrence.
To compare systemic versus localized TMA, Schwimmer et al reported that 54% of systemic TMA develops dialysis-requiring AKI and 38% lost their grafts.
RECURRENT TMA AFTER RENAL TRANSPLANTATION
Etiology of recurrent TMA
aHUS; thrombotic thrombocytopenic purpura (TTP); and autoimmune diseases
Therapeutic protocols for aHUS recurrence:
Once the diagnosis of primary aHUS has been established, complement blockade therapy should be instituted.
The available data points to two strategies:
1) Minimal dosage to establish complement blockade
2) Dose withdrawal scheme[142] . Both options, however, lack enough evidence and require precise monitoring of complement blockade
Level V
Thrombotic microangiopathy (TMA) is serious complications post transplant leading to poor graft survival and outcome.
It’s account 5.6 cases per 1000 patients annually and mortality rate is around 50% of cases diagnostic with Thrombotic microangiopathy (TMA). There’s tow types of Thrombotic microangiopathy (TMA); de novo and recurrence of original renal disease. Since advantage of eculuzmab anti C5 monoclonal in preventing of Thrombotic microangiopathy (TMA) and role of renal biopsy prior to transplant help to diagnosis and treated. However not all transplanted cases underwent biopsy. This article focus on differentiate between de novo and recurrence of Thrombotic microangiopathy (TMA) in clinical courses and prognosis between tow types and role of renal biopsy to differentiate between them.
aDe novo TMA:
It’s due to dysregulation of alternative complement pathways.
It’s may be genetic or due to precipitating factors like (1) Antibody mediated rejection. (2) Immunosuppressive-associated TMA: Calcineurin inhibitors or mTOR inhibitors (mTORi), single or combined; (3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI); (4) Viral infection: e.g., HCV, CMV, BK and parvovirus (5) Genetic abnormalities in the complement cascade; (6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation; and (7) Missed diagnosis of TMA in the native kidney as a cause of ESRD ( recurrence of TMA).
This study shows the risk if de novo TMA is more prevalent post transplant in comparison to recurrence of TMA in recipient with previous aHUS.
Pathophysiology is mainly due to abnormal compelement pathways and the risk factors associated with AMR and immunosuppressive medication.
Drug induced TMA:
calcinurine inhibitors may contribute to abnormal balance between vasodilator peptide ( prostaglandin and prostacyclin) and vasoconstrictor peptide ( thromboxane A and endothelin. leading to renal vasoconstriction and renal ischemic and endothelial injury.
another factor is platelets activation and pro coagulant and anti-fibrinolytic activity contribute to ischemic reperfusion injury.
Microparticle production from endothelial cells results from cyclosporine leading to TMA.
MTori drug associated with TMA especially sirolimus and everolimus because mTori lead to inhibition of vascular endothelial growth factors which are provoke TMA ; also this factors associated with reduced renal levels of complement factor H which carry risk of TMA.
procoagulant and the antifibrinolytic activity of mTORi might play important roles in de novo TMA development. mTori has procoagulant and the antifibrinolytic effects lead to TMA.
AMR recognized by presence of peritubular capillary Cd4 stanning which is strongly associated with TMA.
Other cases are viral infection and antiviral drug and C3 glomerular disease associated with TMA also acquired member 13 (ADAMTS13) deficiency also contribute for development of TMA .
This study shows there’s overlap between aHUS and TMA with deference mechanism and genetic mutations and complement and the coagulation-fibrinolysis cascades activation are associated with TMA.
Clinical presentation may appear at any time post transplant but mainly between 3 to 6 months post transplant.
Clinical classic triad’s presented with thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI). high LDH and low hemoglobin and haptoglobin. Sometimes there’s acute kidney dysfunction with vague symptoms and biopsy but the most possible diagnosis is TMA and renal artery stenosis.
In the active chronic
stage, there is evidence of endothelial cell injury with
platelet aggregation (thrombosis), fibrinoid necrosis and
glomerular ischemia. In the chronic stage, the basement
membranes undergo duplication and multilayering with
increased matrix layers and vessel wall cells.
The best treatment in de novo TMA is C5 monoclonal blocker’s.
Prognosis of de novo TMA is poor to graft and patients.
Recurrence of TMA:
Overactivation of the alternative pathways is recognized cause of aHUS. The risk of recurrence is greatly dependent on the underlying associated abnormality.
aHUS recurrence approached 70%-90%.
Thrombotic thrombocytopenia:
It’s associated with TMA. it’s mainly genetic or acquired due to deficiency of ADAMTS13.
differentiation between TTP and HUS relied primarily on the presence of neurologic manifestation in TTP and renal dysfunction in HUS. The study shows the presence of AKI in more than half of TTP patients (with low ADAMTS13 activity) and 50% progression of CKD and even ESRD is highly suspect TMA. it’s due to recurrent of autoimmune disease like lupus nephritis which associated with TMA.
Spectrum of TMA:
Primary hereditary:
1. aHUS with complement gene mutations.
2. TTP with ADAMTS13 mutations.
3. cblC deficiency mediated TMA.
4. DGKE-associated TMA.
Primary acquired:
1. TTP with ADAMTS13 autoantibodies.
2. aHUS with FH autoantibodies
Infection causes:
C-staphylococcus HUS.
2. Pneumococcal HUS
3. HIV-associated TMA.
Secondary TMA:
Drug-induced TMA.
2. De novo TMA after SOT.
3. Pregnancy-associated TMA (HELLP).
4. Malignancy associated TMA.
5. TMA with severe HT.
6. TMA with glomerular diseases (MN, MPGN, FSGS, IgAN, AAV)
TMA with autoimmune diseases (e.g. SLE, CAPS, SRC).
8. TMA after bone marrow transplant
Extra renal manifestations of HUS is digital gangrene, cerebral artery thrombosis, myocardial infarction, ocular, GIT, pul- monary and neurologic involvement.
Laboratory studies:
Complement assessment in aHUS: C3 is low and CD46 surface activity should be assessed because it’s a marker help in therapy guide.
Panel of genetic testing:
The diagnostic list of genes of aHUS should include at least CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE.
Genotyping workup should also include CFH-H3 and MCP ggaac haplotypes. to differentiate between acquired and genetic.
Treatment of post transplant TMA:
Treatment of de novo TMA:
Shift of calcinurine inhibitors ( cyclosporine); to mTOR temporary and 2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG)
Low risk:
Isolated MCP mutations
Persistently negative FH autoantibodies. those patients no need for prophylaxis
It is level 5
# Please summarise this article
# INTRODUCTION
*Thrombotic microangiopathy (TMA) is a disable complication of renal transplantation that is associated with poor patient and graft survival.
*The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis.
*TMA after transplantation can be classified into either:
(1)De novo TMA
(2)Recurrent TMA
# DE NOVO TMA
The factors that trigger the development of de novo TMA. Include the following:
*AMR
*Immunosuppressive-associated TMA:
(CNI) or mTOR inhibitors (mTORi), single or combined
*Other medications: e.g.(anti-VGFI)
*Viral infection: e.g., HCV, CMV, BK and parvovirus
*Genetic abnormalities in the complement cascade
*Phenotypical shift of C3 glomerulopathy (with ESRD), to
an aHUS post transplantation
*Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA).
# Etiopathogenesis of de novo TMA
*AMR and medications are the two main causes of de novo TMA.
*The role of complement abnormalities is becoming more apparent
# Calcineurin-induced TMA:
(1) Loss of the normal balance between the vasodilator peptides.
(2) CNI-induced platelet activation, pro-coagulant and anti fibrinolytic activity.
(3) Microparticle production from endothelial cells, a known effect of CyA that can result in activation of the AP.
*The trap points have been speculated to oppose the role of CNI:
(1) Patients utilizing CNI to maintain immunosuppression represent more than 95% of (KTR), and only a small percentage can develop TMA.
(2) CNI withdrawal in de novo TMA does not always
guarantee a favorable graft outcome.
(3) A USRDS based study demonstrates higher incidence of TMA in the KTR that was not under CNI compared to those on CNI maintenance.
# mTOR inhibitor-associated TMA:
* Both sirolimus and everolimus have been reported to be implicated in the pathogenesis of de novo TMA.
*The following explanations have been given:
(1) mTORi has antiangiogenic properties decrease renal expression of (VEGF) with death of the endothelial progenitor cells.
(2) The VEGF inhibition associated with reduced renal levels of (CFH).
(3) Repair of endothelial injury could be hampered by mTORi use
(4) The procoagulant and the antifibrinolytic activity of mTORi might play additional roles in de novo TMA development.
*The risk of development of TMA with combined CNI and mTORi protocols is higher than using mTORi alone
#AMR-associated de novo TMA:
*The role of AMR in the development of post-transplant TMA is by:
Endothelial cells are a well-known target of allo-immune response.
*The (PTC) C4d staining has been reported to be present in 16.2% of biopsied recipients with TMA.
* Satoskar et al reported an incidence of 55% of de novo TMA patients who express diffuse PTC C4d positivity.
*The clustering of both AMR and TMA would predict much worse graft outcome.
Other causes involved in TMA pathogenesis (Viral infection and antiviral medications).
# Clinical manifestations
Timing:
*In the first 3-6 mo post transplantation.
*The systemic form of TMA consists of the classic triad of thrombocytopenia, (MAHA) and (AKI). Features of MAHA include raised (LDH), drop in (HB) and decreased haptoglobin with schistocytes on peripheral blood smear.
*Localized (limited) TMA is usually presented later in TMA course.
* When a KTR has significant renal dysfunction and the biopsy does not show any AR, one must suspect two possibilities:
(1) status to the chronic angiopathic changes
(2) Renal artery stenosis.
*The patient mortality rate of 50% after three years of diagnosis.
*To compare systemic versus localized TMA, Schwimmer
et al reported that 54% of systemic TMA develops dialysis-requiring AKI and 38% lost their grafts.
#RECURRENT TMA AFTER RENAL TRANSPLANTATION
Etiology of recurrent TMA
*aHUS
*(TTP)
*Aautoimmune diseases
# aHUS:
*It is depends on the underlying type involving the native kidney.
*aHUS is the most common diagnosis in TMA associated with recurrence, the reported rate of aHUS recurrence approached 70%-90%.
*(MCP), a transmembrane complement regulatory component that is produced by kidney endothelial cells even in post-transplant period, keeps aHUS recurrence lower unless other mutational gene defects have been associated.
*Untreated patients develop graft loss at a rate of 90%, with 80% of them occurring in the first year.
# TTP:
*TTP is the second recognized etiology in TMA.
*Genetic or acquired lack of ADAMTS13 has been recognized.
*The differentiation between TTP and HUS relied primarily on the presence of neurologic manifestation in TTP and renal dysfunction in HUS to settle the diagnosis.
#Pathology:
* aHUS is a variety of TMA that represents the tissue response to an ongoing endothelial injury.
*Thrombotic features, e.g., fibrin/platelet plugging and intraluminal fibrin are not always seen in renal allograft biopsy.
*Non-thrombotic features can appear as denuded and swollen endothelium, mesangiolysis, glomerular basement membrane double contour, as well as accumulation of electrolucent material in the subendothelium.
*Arterial and arteriolar intraluminal fibrin, myxoid intimal thickening as well as concentric myointimal proliferation have also been described.
#PATHOPHYSIOLOGY OF TMA RECURRENCE
The CFH is the main inhibitor of the AP, has the ability to work in fluid phase as well as on cell surfaces and act as a co-factor to CFI.
*Regulatory components on cell surfaces, or “membrane regulators” include the following:
(1) Membrane cofactor protein
(2) Complement receptor 1
(3) Decay accelerating factor
(4) Protectin, which prohibits MAC formation.
# Current classification of TMA
*Primary hereditary TMA
*Primary acquired TMA
*Secondary TMA
# Clinical assessment of aHUS:
*Any HUS that is not due to STEC-HUS has been called aHUS.
*The term “primary HUS” used when there is underlying abnormality in the AP, underlying complement abnormality need a trigger factor(infection, surgery, medications, pregnancy, so that aHUS can clinically manifest.
#Acute vs chronic lesion?
*Penetrance in aHUS is age-related, by age 70, penetrance reaches
64%
* Certain patients may express more than one genetic determines the magnitude of disease penetrance.
*The late presentation of aHUS reflects the impact of the environmental triggers.
# Extrarenal manifestation:
*Twenty percent of Ahus patients can express extrarenal manifestations in the form of digital gangrene, cerebral artery thrombosis, myocardial infarction, in addition to ocular, GIT, pulmonary and neurologic involvement
# Laboratory investigations and differential diagnosis:
*Complement assessment in aHUS
*Panel of genetic testing
*Rationale for genetic screening
#Interpretation of the genetic variants:
Genetic mutations can be interpreted as:
(1) Benign
(2)Likely benign
(3) Variant of uncertain significance
(4)Likely pathogenic
(5) Pathogenic, according to the international guidelines.
# Diagnosis of aHUS recurrence:
* A full detailed clinical history is usually warranted.
*A proven tissue diagnosis with (LM), (IF) and (EM).
*Once diagnosis of aHUS is suspected, a full battery of biochemical, genetic as well
as pathological investigations of the AP, including the following:
(1) Estimation of the anti-CFH AB
(2) MCP screening on the peripheral blood WBCs
(3) Examination of the recombination in CFHR region
(4) Screening of the genetic mutations related to CFH, CFI, CFB, C3, and MCP.
# THERAPY OF POST-TRANSPLANT TMA
Treatment of de novo TMA
(1) Immunosuppressive medication management
(2) Plasmapheresis and intravenous immunoglobulins
(3) Belatacept
(4) Complement inhibition
# Treatment of recurrent TMA
(1) The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3.
(2) All patients with primary or suspected aHUS, should be surveyed for all complement components and its related proteins.
(3) Patients with isolated MCP associated mutations may be safe for kidney donation.
(4) Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy.
(5) Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation.
# Prevention of aHUS:
(1) Complement activity incited by an injury to endothelium should be avoided.
(2) Certain relations have been reported between CNI use and aHUS recurrence in such a case (an mTOR) is not innocent and can induce recurrence.
(3) Not depend solely on PE therapy in management of aHUS recurrence because PE failed to prevent aHUS recurrence in many cases.
(4) The anti-C5 monoclonal antibiotic (eculizumab).
# What is the level of evidence provided by this article?
*Level 5
Thrombotic microangiopathy :
TMA posttransplant either de novo or recurrent TMA in an isolated manner.
Associated with poor patient and graft outcomes.
The incidence is 5.6 cases per 1000 renal transplant recipients per year with a 50%
mortality rate three years after diagnosis.
DE NOVO TMA:
Risk factors:
Genetic or acquired dysregulation of the alternative complement pathway.
(1) AMR.
(2) Immunosuppressive-associated TMA: CNI or mTOR.
(3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-
VGFI).
(4) Viral infection: e.g., HCV, CMV, BK and parvovirus; antiviral medications, e.g.,
ribavirin and interferon and disseminated histoplasmosis.
(5) Genetic abnormalities in the complement cascade.
(6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post
transplantation.
(7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent
TMA).
De novo TMA is more prevalent after kidney transplantation and presumably
underestimated. Graft loss rate of 40%.
Etiopathogenesis of de novo TMA:
AMR and medications are the two main causes of de novo TMA.
Complement mutational abnormality in one third.
Calcineurin-induced TMA:
Suggested mechanism:
1-Due to imbalance between vasodilatation and constriction peptides, results in
arteriolar vasoconstriction, renal ischemia and establishment of endothelial injury.
2- CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity.
3- 3) Microparticle production from endothelial cells.
mTOR:
Has antiangiogenic properties, and can decrease renal expression of VEGF with death
of the endothelial progenitor cells.
(2) The VEGF inhibition has been recently proven associated with reduced renal levels
of complement factor H (CFH).
(3) Repair of endothelial injury could be hampered by mTOR.
(4) The procoagulant and the ant fibrinolytic activity of mTOR might play additional
roles.
AMR-associated de novo TMA:
A role of humoral rejection in the evolution of post-transplant TMA is suggested.
Complement gene mutations:
renal complement activation is the common denominator in such a heterogeneous
condition.
Multiple mutational gene varieties related to complement and the coagulation-fibrinolysis
cascades have been recently recognized in TMA patients
They observed C4d deposits in more than 88% and C4d with localized C5b-9 in about
60% .
reported the presence of genetic mutations in CFH, Complement Factor(CFI) or both in
29% of their studied de novo TMA patients, 25% showed low Complement Factor B
(CFB) and/or low C3, suggesting an AP complement activation.
Clinical manifestations :
Timing:
Any time in the post transplantation course.
Mostly encountered in the first 3-6 month post transplantation.
Salient features:
TMA :
A limited form confined to the kidney.
Systemic variant, MAHA, ARF and thrombocytopenia.
The histopathologic:
Changes are usually non-specific but vary in the acute from chronic.
In the active stage, there is evidence of endothelial cell injury with platelet aggregation
(thrombosis), fibrinoid necrosis and glomerular ischemia.
In the chronic stage, the basement membranes undergo duplication and Multilayering
with increased matrix layers and vessel wall cells, which ultimately ends in the unique
onionskin formation.
Prognosis of de novo TMA:
The prognosis of posttransplant de novo TMA is quite poor for the patient and as well as
the allograft. About one-half of the patients loses their graft within the first two years
after diagnosis.
RECURRENT TMA AFTER RENAL TRANSPLANTATION:
Etiology of recurrent TMA:
AHUS.
Thrombotic thrombocytopenic purpura.
Autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus, with or
without anti-phospholipid antibody syndrome.
AHUS:
Recurrence approached 70%-90%.
Over activation of the AP is known to be the underlying etiology of aHUS.
Mutational abnormality involving CFH and CFI, regulatory complement components
produced by the liver, results in aberrant CFH and CFI.
Additional MCP mutations (> 22percentage), is reported.
Untreated patients, however, ultimately develop graft loss at a rate of 90%, with 80% of
them occurring in the first year.
TTP:
Genetic or acquired lack of ADAMTS13 has been recognized.
Pathology:
aHUS is a variety of TMA .
PATHOPHYSIOLOGY OF TMA RECURRENCE:
The AP is constantly regulated, disturbance of this regulatory leads to complement
activation with subsequent endothelial cell derangement.
Both genetic aberrations as well as autoantibodies can be involved in this process.
There is Role of diacylglycerol kinase-ε (DGKE) mutations.
Current classification of TMA includes:
Primary hereditary TMA: Includes mutations in ADAMTS13, MMACHC (cb1c
deficiency), or in genes encoding complement components.
Primary acquired TMA: Autoantibodies to ADAMTS13 or to CFH, which occurs with
homozygous CFHR3/1 deletion.
Infection-associated TMA: Shiga toxin-producing Escherichia coli-HUS (STEC-HUS)
and pneumococcal
Environmental triggers:
Anti-HLA antibodies can trigger the process of aHUS recurrence
, viral infection, ischemia-reperfusion injury and immunosuppressive medications.
Extra renal manifestation:
Digital gangrene, cerebral artery thrombosis, myocardial infarction, in addition to ocular,
GIT, pulmonary and neurologic involvement
Diagnosis:
Investigation:
ADMTS role out TTP.
Complement assessment.
C3 is low in 30% of aHUS.
Flow cytometry for CD46.
Panel of genetic testing: CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE.
Genotyping workup should also include CFH-H3 and MCP ggaac haplotypes.
Interpretation of the genetic variants:
Genetic mutations is either
: (1) Benign; (2) Likely benign; (3) Variant of uncertain significance; (4) Likely
pathogenic; or (5) Pathogenic, according to the international guideline.
Acquired drivers of aHUS:
The FH autoantibodies. It is typically characterized by homozygosity for delCFHR3-
CFHR1.
Test results need to be confirmed after two weeks if positive.
Diagnosis of aHUS recurrence:
A full detailed clinical history .
Histopathology.
Test of alternative pathway:
(1) Estimation of the anti-CFH AB; (2) MCP screening on the peripheral blood WBCs.
(3) Examination of the recombination in CFHR region; and (4) Screening of the genetic
mutations related to CFH,
CFI, CFB, C3, and MCP.
Treating de novo TMA:
1-withdrawal of the offending agent should be the first line in treating de novo TMA.
(2) Plasmapheresis and intravenous immunoglobulins.
3) Belatacept.
(4) Complement inhibition: Eculizumab
In special subset of de novo TMA patients, presumably:
(1) AMR-associated TMA; (2) Patients who became PE-dependent; and (3) Refractory
hemolysis persists despite maximum doses of PE therapy.
Treatment of recurrent TMA Recommendations for recurrent TMA:
Prevention of aHUS:
Ischemia-reperfusion injury, viral infection and immunosuppressive medications, should
be avoided.
Prophylactic use of rituximab proved to be efficacious as anti-CFH-antibodies
, the beneficial effect of rituximab can be enhanced by adding PE therapy.
The anti-C5 monoclonal antibiotic Eculizumab has been reported to be used
successfully to prevent aHUS recurrence in patients with CFH, CFH/CFHR1 hybrid
genes as well as with C3 gene mutation.
Therapeutic protocols for aHUS recurrence:
Complement blockade therapy should be instituted.
Two strategies: (1) Minimal dosage to establish complement blockade.
(2) Dose withdrawal scheme.
FH autoantibody-driven aHUS:
Anti-cellular therapy is recommended.
Duration of Therapy:
Enough time, should be permitted to optimize renal recovery and satisfy TMA resolution
.
Treatment of DGKE mutation associated TMA:
Many cases experienced disease remission with no specific therapy.
Timing renal transplantation:
Should be postponed six months after institution of dialysis, as limited kidney recovery
can occur several months after commencing Eculizumab therapy.
Level of evidence V
Thrombotic microangiopathy (TMA)
De novo TMA
CNI can induce TMA by three possible mechanisms
mTORi have antiangiogenic properties and these effects have been implicated in TMA pathogenesis, but the exact role is still unknown. Endothelial cells are a well-known target of allo-immune response and hence the role of AMR in post transplantation is well known.
TMA could develop at commonly occurs in the first 3 to 6 months post the transplantation. It usually manifests as the classic triad of thrombocytopenia, microangiopathic haemolytic anaemia and acute kidney injury.
A renal biopsy will not show acute rejection, the histopathologic changes are usually non-specific.
Recurrent TMA
The current classification of TMA includes the following:
• Primary hereditary TMA
• Mutations in ADAMTS13, MMACHC
• Primary acquired TMA
• Autoantibodies to ADAMTS13
• Infection-associated TMA
• Shiga toxin-producing Escherichia coli-HUS, pneumococcal HUS
• Secondary TMA
Multifactorial
• Drug induced TMA
• Malignancy-associated TMA
• De novo TMA after solid organ transplantation
• TMA with autoimmune diseases
• TMA with glomerular diseases
Treatment of de novo TMA involves adjusting the immunosuppressant medications, plasmapheresis, intravenous immunoglobulins, belatacept (an immunosuppressive co-stimulatory blocker against CD80 and CD86 surface ligands), eculizumab (an anti-C5 agent that blocks the complement pathway).
Prevention of recurrent TMA is important, and the following strategies can be used:
1. Complement activity incited by an injury to the endothelium should be avoided (e.g. viral infections, immunosuppressive medications)
2. Substitution of CNIs
3. Plasmapheresis cannot suffice as the sole treatment
4. Use of eclizumab.
Therapeutic protocols for aHUS recurrence include complement blockade therapy with minimal dosage to establish complement blockade and a dose withdrawal scheme.
The duration of therapy should be enough time for renal recovery and TMA resolution.
Renal transplantation should be delayed for 6 months after starting dialysis and eclizumab therapy. Recurrent disease in the recipient and de novo disease have been recognized as risks for living related kidney donation.
Level of evidence: V
Thrombotic microangiopathy after renal transplantation: Current insights in de novo and recurrent disease
________________________
Summary
◇INTRODUCTION ▪︎Thrombotic microangiopathy (TMA) is a debilitating complication of kidney transplantation that is associated with poor patient and graft outcomes. It can be classified into categories:
(1) De novo TMA
(2) Recurrent TMA
Since renal biopsy of native kidney is not performed in many patients with ESRD, missed diagnosis of TMA prior to kidney transplant
is likely.
▪︎The aim of this review is to discuss the main differences between the
two categories in the pathophysiology, clinical course & available approaches of prevention and treatment.
DE NOVO TMA
▪︎In the presence of acquired or genetic dysregulation of the alternative complement pathway, a number of precipitating factors have been identified in the context of renal transplantat that trigger the development of de novo TMA.
(1) Antibody mediated rejection (AMR).
(2) Immunosuppressive-associated TMA: (CNI) or (mTORi), single or
combined.
(3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI).
(4)Viral infection: e.g., HCV, CMV, BK and parvovirus.
(5) Genetic abnormalities in the complement cascade.
(6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation.
(7) Missed diagnosis
of TMA in the native kidney as a cause of ESRD (i.e.,
recurrent TMA).
◇ Clinical manifestations
Timing:
TMA could develop at any time (mostly in the first 3-6 mo post transplantation).
Salient features: TMA manifestations varies from limited form (confined to the kidney and presented later in TMA course) to a full blown systemic variant (classical triad of thrombocytopenia, MAHA and AKI).
▪︎Features of MAHA include raised LDH, drop in HB and decreased haptoglobin with schistocytes on peripheral blood smear.
▪︎Localized (limited) TMA is usually presented later in TMA course
◇ DD of TMA:
(1)AR or (2) Renal artery stenosis.
Histopathologic changes:
▪︎Active stage: evidence of endothelial cell injury with
platelet aggregation, fibrinoid necrosis and glomerular ischemia.
▪︎Chronic stage: the basement membranes undergo duplication and multilayering with increased matrix layers and vessel wall cells, which
ultimately ends in the unique onion skin formation
Prognosis of de novo TMA: is quite poor for the patient
◇ Etiology of recurrent TMA
HUS; TTP; andautoimmune diseases: e.g., scleroderma & SLE, with or without APS.
◇ THERAPY OF POST-TRANSPLANT TMA
Treatment of de novo TMA
▪︎Therapeutic maneuvers must be individualized for each patient.
▪︎Institution of therapeutic options is highly dependent on diagnosis as well as the patient’s response.
▪︎The following approaches have been suggested:
(1) Immunosuppressive medication management:
better response after switching from one CNI member to another or to an mTORi). Withdrawal of the offending agent should be the first line in treating de novo TMA.
(2) PE/IVIG therapy
(3) Belatacept: a promising alternate option
(4) Complement inhibition: Eculizumab, in the management of aHUS,
Treatment of recurrent TMA
Recommendations for recurrent TMA:
(1) The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3;
(2) All patients with primary or suspected a HUS, should be surveyed for all complement components and its related proteins;
(3) Patients with isolated MCP associated mutations may be safe for kidney donation;
(4) Patients with documented a HUS and with lack of definite
genetic mutations can proceed in renal transplant
under the umbrella of intensive PE therapy; and
(5) Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation[80].
CONCLUSION
▪︎Post-transplant TMA can occur as a recurrence of the disease involving the native kidney or as
de novo disease with no evidence of previous involvement
before transplant.
▪︎While atypical hemolytic uremic syndrome
is a rare disease that results from complement
dysregulation with alternative pathway overactivity, de
novo TMA is a heterogenous set of various etiologies
and constitutes the vast majority of post-transplant TMA cases.
▪︎Management of both diseases varies from simple maneuvers, e.g. , plasmapheresis, drug withdrawal or dose
modification, to lifelong complement blockade, which israther costly. ▪︎Careful donor selection and proper recipient
preparation, including complete genetic screening, would
be a pragmatic approach. ▪︎Novel therapies, e.g. , purified products of the deficient genes, though promising in theory, are not yet of proven value.
_______
♧ Level of evidence: V
Summary of the article:
The article dealt with Thrombotic microangiopathy (TMA) after renal transplantation. This pathology has severe complication of the transplant kidney that is associated with poor patient and graft outcomes. It has been noted that the incidence of TMA is about 5.6 cases per 1000 renal per year. It is estimated that there is a 50 % mortality rate about 3 years post-diagnosis.
Classification of TMA
1) De novo TMA. There was no evidence of the disease before the transplant.
2) Recurrent TMA. Before transplantation, the patient had the same and return after transplantation.
The Novo TMA is more prevalent.
Possible causes of TMA:
1) AMR
2) IS-associated TMA with medications like CNI, mTORi
3) Possible viral infections like CMV, BK HCV
4) Possible genetic abnormalities.
5) TMA not diagnosed pre-transplant
The physiopathology of TMA:
Medications:
A) CNI-INDUCED TMA
1) CNI-induced TMA: it causes arteriolar vasoconstriction and renal ischemic that result in causing endothelial lesions.
2) CNI can cause platelet activation and anti-fibrinolytic activity
3) There may be microparticle production from endothelial cells that can result in the activation of the AP.
B) MTORi-induced TMA
1) It causes antiangiogenic properties that reduce kidney expression for VEGF
2) It decreases kidney CFH levels
3) It affected endothelial repair
C) AMR associated with de novo TMA
1) The endothelial cell is being targeted by the alloimmune response
2) The presence of PTC C4d
D) Complement gene mutation. It has shown that mutation of a specific gene for CFH, and CFI has caused TMA and low C3 also.
How does TMA manifest itself:
T can occur at any time but mostly at around 3-6 months after transplantation.
It can present with the triad of thrombocytopenia, MAHA, and AKI.
Will need an allograft biopsy.
It should be noted that the TMA prognosis is poor and about 50% of the recipient can lose their graft after a period of two years.
In the case of recurrent TMA what can be the causes?
a) aHUS are the most common cause.
It has a recurrence of about 60 %
The possible graft loss is 90%
b) TTP
It has a recurrent rate of 5-10% and it can be presented in two forms genetic or acquired due to the lack of ADAMTS13.
c) Autoimmune diseases: scleroderma and SLE
The most recent classification of TMA:
1) Primary hereditary TMA
2) Primary acquired TMA
3) Infection-associated TMA
4) Secondary TMA
The treatment of post-transplant de novo TMA:
1) Discontinue the agent that may be the cause
2) Immunosuppressive medications can be switched from one to a different one.
3) The use of plasmapheresis
4) Belatacept use
5) Eculizumab
Treatment of recurrent TMA:
1) The use of prophylactic complement blockade.
2) Treatment of aHUSs
Renal Transplantation:
Kidney transplantation should be postponed for about 6 months after the institution of dialysis because kidney recovery can occur several months after commencing the eculizumab treatment.
The prerequisite of renal transplant is the disappearance of extra-renal manifestation and hematological resolution of TMA.
The risk of kidney donation has been grouped into two different risks.
1) De novo disease in the donor
2) Recipient may have recurrent disease.
In conclusion: TMA can present itself either de novo or recurrent and can have a negative effect on the graft which is graft loss. This is the reason why it must be identified soon and treated.
The level of the article is V
summary:
Thrombotic microangiopathy (TMA) is a serious complication of transplantation. it is associated with poor outcomes. It occurs in 5.6 cases per 1000 cases with 50% mortality. Graft loss rate in de novo TMA reaches 40%.
TMA types:
a- De novo TMA i.e TMA developed for the first time
b- Recurrent TMA i.e., native kidney failed as a result of TMA and it comes back in renal transplantation, and because biopsy of the native kidney is not performed in many patients with ESRD, TMA diagnosis is likely missed prior to transplantation.
The distinction between these two entities has clear clinical and therapeutic implications, especially with the advance of the drug eculizumab, an anti-C5 monoclonal antibody which is highly effective in the treatment and prevention of atypical HUS.
De novo TMA
A number of factors trigger the development of de novo TMA in the presence of acquired or genetic dysregulation of the alternative complement pathway (AP). These factors include:
1- AMR
2- Immunosuppressive-associated TMA: CNI or mTORi, single or combined
3- Other medications: e.g, anti-vascular endothelial growth factor inhibitors (anti-VGFI).
4- Viral infection: HCV, CMV, BK and parvovirus
5- Genetic abnormalities in the complement cascade
6- Phenotypical shift of C3 GN (with ESRD) to an aHUS post-transplantation.
7- Missed diagnosis of TMA in the native kidney (recurrent TMA).
Which is more prevalent, de novo or recurrent TMA?
De novo TMA is more prevalent after kidney transplantation and it seems to be underestimated. Although; recurrent TMA has 36.5 times risk of recurrence in recipients with ESRD due to hemolytic
uremic syndrome (HUS) as compared to other etiologies.
Etiopathogenesis of de novo TMA
AMR and medications are main causes of de novo TMA. Underlying complement abnormalities determined in one third of patients in one study.
i- Immunosuppression medications
1- Calcineurin-induced TMA:
mechanism is:
a- Loss of equilibrium between the vasodilators (PG E2 , PG12) and vasoconstrictors (thromboxane A2, endothelin), which results in arteriolar vasoconstriction, renal ischemia and establishment of endothelial injury.
b- CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity especially with the presence of endothelial injury due to AMR, ischemia-reperfusion injury or any etiology.
c- Microparticle production from endothelial cells, as effect of CyA that can result in activation of AP.
The role of CNI in TMA has been speculated to be opposed by many points:
1- 95% of recipients use CNI as maintenance therapy and only a small number can develop TMA which suggests presence of another underlying factor.
2- CNI withdrawal in de novo TMA does not always results in good graft outcome.
3- USRDS based study shows a significantly higher incidence of TMA in the group of KTR that was not under CNI maintenance therapy (11.9/1000/year), as compared to those on CNI maintenance (5.0/1000/year).
2- .mTOR inhibitor-associated TMA:
Mechanisms:
1- mTORi has antiangiogenic properties, and decrease renal expression of vascular endothelial progenitor cells.
2- The VEGF inhibition has been recently proven to be associated with reduced renal level of complement factor H (CFH), patients with CFH genetic mutations are susceptible to develop de novo TMA with mTORi.
3- mTORi can obstruct repair of endothelial injury.
4- The procoagulant and the antifibrinolytic activity of mTORi might play roles in de novo TMA.
ii- AMR-associated de novo TMA:
Endothelial cells are a well-known target of allo-immune response. Peritubular capillary (PTC) C4d staining (which is a marker of AMR) has been reported to be present in 16.2% of biopsied patients with TMA. The incidence of TMA is 55% in those express diffuse PTC C4d positivity.
v- Viral infections:
BK, CMV, HCV, parvovirus
iv- antiviral medications
Ribavirin and interferon
V- Disseminated histoplasmosis
Vi- Ischemia-reperfusion injury.
vii- acquired disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency.
viii- recipient with C3 GN as a cause of ESRD can undergo phenotypic shift to de novo TMA post-transpamtation.
ix- Complement gene mutations:
Renal complement activation is the common denominator in TMA development. Genetic mutations in CFH, Complement FactorⅠ (CFI) or both occurs in de novo TMA patients, low Complement Factor B (CFB) and/or low C3, suggesting an AP complement activation.
Relation to TMA evolution:
CFH and CFI are main regulators for AP. CFH inhibit the C3 cleaving enzyme C3bBb. And it acts as co-factor for FI.
CFI has the ability to inactivate C3b.
Inactivation of these proteins either due to genetic mutations or development of neutralizing antibodies, can trigger an uncontrolled AP activity, leading to endothelial injury which is the pathogenic base of TMA.
Clinical manifestation
Timing: TMA can develop at any time post-transplantation. However; it is more common in the first 3-6 months, when the CNI trough levels are relatively high.
Salient feature:
a- Systemic form of TAM:
Consists of a classical triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI).
b- Localized (limited) TMA:
Usually presented late with graft dysfunction, necessitating graft biopsy. When graft biopsy shows no evidence of rejection, TMA or renal artery stenosis should be excluded.
The histopathologic changes
In the active stage, there is evidence of endothelial cell injury with platelet aggregation (thrombosis), fibrinoid necrosis and glomerular ischemia.
In the chronic stage, the basement membranes undergo duplication and multilayering with increased matrix layers and vessel wall cells, which ultimately ends in the unique onion skin formation.
Once TMA diagnosed underlying cause of ESRD in the native kidney should be searched for, with prompt testing for genetic test mutations to discover any complement dysregulation and avoid missing the diagnosis of recurrent aHUS. As eculizumab; monoclonal, C5 blockade antibodies is effective treatment, and can be used also in prevention of recurrent TMA.
Prognosis of de novo TMA:
50% of the recipients loss their graft within 2 years from the diagnosis. A patient mortality rate of 50% after three years of diagnosis.
Recurent TMA after renal transplantation:
Etiology:
Atypical HUS, thrombotic thrombocytopenic purpura (TTP), and autoimmune diseases.
A HUS:
Overactivation of the AP is known to be the underlying etiology of aHUS. By far, aHUS is the most common diagnosis in TMA associated with recurrence.
The reported rate of aHUS recurrence approached 70%-90%.
Etiology: mutational abnormality involving CFH and CFI. Untreated patients,
however, ultimately develop graft loss at a rate of 90%, with 80% of them occurring in the first year.
TTP is the second recognized etiology in TMA. Genetic or acquired lack of ADAMTS13 has been recognized. In the past the differentiation between the TTP and aHUS was depending on the presence of neurological involvement in TTP and renal dysfunction in aHUS. Serology test for ADAMTS13 activity is now feasible. Overlap between the both condition exist.
PATHOPHYSIOLOGY OF TMA RECURRENCE
It is increasingly recognized that complement dysregulation is the fundamental etiology involved in TMA evolution. Both genetic aberrations as well as autoantibodies can be involved in this process. Usually, there is (are) an inciting environmental trigger factor(s).
Classification of TMA
1- primary:
1. aHUS with complement gene mutations.
2. TTP with ADAMTS13 mutations.
3. cblC deficiency mediated TMA.
4. DGKE-associated TMA.
2- primary acquired:
1.TTP with ADAMTS13 autoantibodies.
2. aHUS with FH autoantibodies.
3- Infection associated:
1. STEC- HUS.
2. Pneumococcal HUS (distinct mechanisms result in TMA).
3. HIV-associated TMA.
4. Other infections (ill defined, infection may trigger a primary TMA).
4- Secondary TMA
1. Drug-induced TMA.
2. De novo TMA after SOT.
3. Pregnancy-associated TMA (HELLP).
4. Malignancy-associated TMA.
5. TMA with severe HT.
6. TMA with glomerular diseases (MN, MPGN, FSGS, IgAN, AAV).
7. TMA with autoimmune diseases (e.g. SLE, CAPS, SRC).
8. TMA after bone marrow transplant
CFH, CFI, CFB, C3, MCP, THBD, and CFHR1 del mutation all play role in aHUS. DGKE mutation may play a fundamental role in regulating thrombosis in renal tissues.
Environmental triggers:
Anti-HLA antibodies, viral infection, ischemia-reperfusion injury and immunosuppressive medications.
Acute vs chronic lesion?
Timing of an aHUS episode is not easily predictable. Many patients are at persistent risk of recurrence. Penetrance in aHUS is age-related, by age 70, penetrance reaches 64%. The late presentation of aHUS reflects the impact of the environmental triggers. Current use of eculizumab has an impact on the natural history of aHUS. Complement inhibition improves glomerular perfusion. Withdrawal of this agent, cause complement reaction with endothelium.
Extrarenal manifestation:
20% of patients have extrarenal manifestations:
digital gangrene, cerebral artery thrombosis, myocardial infarction, in addition to ocular, GIT, pulmonary and neurologic involvement.
Laboratory investigations and differential diagnosis:
ADAMTS13 activity is urgently mandated to exclude TTP diagnosis.
Eculizumab therapy should be instituted early without waiting for the results of ADAMTS13 activity.
Complement assessment in aHUS: serum complement should be thoroughly evaluated before any therapy. C3 level cannot be used as a screening criteria for aHUS. Because its low in 30% of cases. CD46 expression assessed by flow cytometry. Functional parameters and activation markers should be also determined. Their role in treatment guide needs further study.
Panel of genetic testing: The diagnostic list of genes of aHUS should include at least CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE.
Full-detailed genetic mapping, allows proper diagnosis and therapeutic plans, and helps in genetic counseling, particularly in living related-donation.
Rationale for genetic screening:
Full genetic map before transplantation is important as it helps:
1- Determine the actual cause of the disease, so allows for correct genetic counseling.
2- Planning disease management.
3- Expecting response for therapy.
4- Define prognosis.
Interpretation of the genetic variants:
according to the international guidelines: genetic mutation typed as:
(1) Benign; (2) Likely benign; (3) Variant of uncertain significance;
(4) Likely pathogenic; or (5) Pathogenic.
Acquired drivers of aHUS: The FH autoantibodies are the best reported example. If anti-CHF autoantibody is positive, confirmation test should be repeated 2 weeks later, and on regular base.
Diagnosis of aHUS recurrence:
Once diagnosis of aHUS is suspected, a detailed clinical history is needed. As well, full biochemical, genetic and pathological investigations of the AP should bedone, including:
(1) Estimation of the anti-CFH AB;
(2) MCP screening on the peripheral blood WBCs;
(3) Examination of the recombination in CFHR region; and
(4) Screening of the genetic mutations related to CFH, CFI, CFB, C3, and MCP.
Although; genetic screen is difficult and complex, it is so important to determine the outcome.
Therapy of TMA post-transplantation:
Treatment should be individualized.
The following approaches have been suggested:
(1) Immunosuppressive medication management: the role of immunosuppressive medications (e.g., CNI or mTORi) has been reported in the literature, with a documented better response after switching from one CNI member to another or to an mTORi). But this approach is not universal. The withdrawal of the offending agent should be the first line in treating de novo TMA, as it corrects the hematological abnormalities.
(2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG)
(3) Belatacept: A promising agent, allows withdrawal of the offending drug contributes in TMA evolution.
(4) Complement inhibition: Eculizumab, the use of this vital biological agent should be confined to a specified subset of de novo TMA patients, presumably: (1) AMR-associated TMA; (2) Patients who
became PE-dependent; and (3) Refractory hemolysis persists despite maximum doses of PE therapy. More efforts are needed to clarify the best way to utilize this costly drug.
Treatment of recurrent TMA
Recommendations for recurrent TMA based on case report and expertise opinion are:
1- Genetic screen includes: CFH, CFI, CFHR, CFB, MCP and C3 at least.
2- All patients with primary or suspected aHUS, should be surveyed for all complement components and its related proteins.
3- Patients with isolated MCP associated mutations (not combined with
other mutations) may be safe for kidney donation.
4- Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy.
5- Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation.
Prevention of aHUS:
1. Endothelial injury caused by ischemia-reperfusion injury, viral infection and immunosuppression should be avoided.
2. a reported relation between aHUS and CNI has been recognized, although, the usual substitute in such case (mTORi) is nor free of this and can induce recurrent aHUS.
3. PE failed to prevent aHUS recurrence in many cases, so it is not the sole therapy. Beneficial effect of rituximab can be enhanced by adding PE therapy.
4. The anti-C5 monoclonal antibiotic eculizumab has been reported to be used successfully.
Duration of therapy: There is not enough data supporting life-long therapy for aHUS.
Renal transplant
Timing
six months after initiation of dialysis, as limited kidney recovery can occur months after given eculizumab. Disappearance of the extrarenal manifestations as well as resolution of TMA hematological parameters are the prerequisite for kidney transplantation.
Risk of donation:
Any potential donor proved to exhibit alternative pathway dysregulation should be excluded.
level 4
● TMA after transplantation can be classified into either:
(1) De novo TMA
(2) Recurrent TMA
DE NOVO TMA
● factors trigger de novo TMA include:
(1) Antibody mediated rejection (AMR)
(2) Immunosuppressive-associated TMA (CNI) or (mTORi)
(3) Others e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI)
(4) Viral infection: e.g., HCV, CMV, BK and parvovirus
(5) Genetic abnormalities in the complement cascade
(6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation
(7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA)
● the risk of posttransplant TMA recurrence was 36.5 times higher in kidney transplant recipients
● the incidence of de novo TMA to be 1.5%.
● de novo TMA is more prevalent than recurrent TMA after kidney transplantation
● Graft loss rate of 40% is reported in de novo TMA within a couple of years of diagnosis
● AMR and medications are the two main causes of de novo TMA.
● highest risk of de novo TMA was in the group using CNi and mTORi
● TMA is mostly encountered in the first 3-6 mo post transplantation.
● Prognosis of de novo TMA: quite poor for the patient and as well as the allograft. ● Recurrence rate in aHUS patients is as high as 60%.
● graft loss in 90%, with 80% of them occurring in the first year
● TTP recurrence after transplantation
● lupus nephritis, wherein patients can develop TMA in 5%-10% with documented recurrence after kidney transplantation
● complement dysregulation is the fundamental etiology involved in TMA evolution.
● Primary hereditary TMA: Includes mutations in complement components.
● Primary acquired TMA: Autoantibodies
● Infection-associated TMA: STEC-HUS and pneumococcal HUS
● Secondary TMA: pregnancy-associated TMA or de novo TMA after transplantation, may associated with genetic predisposition
● The process of aHUS recurrence can be triggered by anti-HLA antibodies , viral infection, ischemia-reperfusion injury and immunosuppressive medications
● Penetrance in aHUS is age-related, by age 70, penetrance reaches 64%
● Laboratory investigations
ADAMTS13 activity
Complement assessment in aHUS: C3 , CD46 ,CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE , CFH-H3 and MCP
● Treatment of de novo TMA :
** withdrawal of the offending agent
** Plasmapheresis (PE)
** intravenous immunoglobulins (IVIG)
** Belatacept: its role is only to replace the culprit drug
** Eculizumab, an anti-C5 agent use in :
(1) AMR-associated TMA
(2) Patients who became PE-dependent
(3) Refractory hemolysis persists despite maximum doses of PE therapy
● Prevention of aHUS:
** avoid injury to endothelium, e.g., ischemia-reperfusion injury, viral infection and immunosuppressive medications
** Certain relations have been reported between CNI use and aHUS recurrence in such a case (an mTOR) is not innocent and can induce recurrenc
** Adding rituximab ti PE therapy
** Anti-C5 monoclonal eculizumab
● Treatment of DGKE mutation associated TMA: feasibility of kidney transplantation with no recurrence after transplantation.
● RENAL TRANSPLANTATION
** Renal transplantation should be six months after institution of dialysis
** Disappearance of the extrarenal manifestations
** resolution of TMA hematological parameters are the prerequisite for kidney transplantation.
● Two risks to be associated with living-related kidney donation:
(1) Recurrent disease in the recipient
(2) De novo disease in the donor, if he/she is a genetic mutation carrier
● “Liver transplantation” may be reserved for patients with liverderived complement protein aberrations, particularly in patients poorly responding to complement blockade
● Future therapy
(1) Purified products of the deficient genes
(2) C3 convertase inhibitors
● Research targets
(1) The anti-C3b blocker, compstatin analog Cp40
(2) The anti-C3 convertase monoclonal antibodies
● Level : 5
Summary of the article
“Thrombotic microangiopathy after renal transplantation- Current insights in de novo and recurrent disease”
This is a narrative review article, addressing de novo and recurrent TMA in the post-transplant period.
De novo TMA
Precipitating factors in the context of renal transplantation:
· Antibody mediated rejection (AMR).
· Immunosuppressive-associated TMA: CNI or mTOR inhibitors (mTORi), single or combined.
· Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI).
· Viral infection: e.g., HCV, CMV, BK and parvovirus.
· Genetic abnormalities in the complement cascade.
· Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation.
· Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA).
· An acquired disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency another rare risk factor, has been shown in one case to represent post-transplant TMA.
· Complement gene mutations: CFH, Complement FactorI(CFI), low Complement Factor B (CFB) and/or low C3, suggesting an AP complement activation.
De novo TMA; Prevalence
· According to USRDS-based study, the risk of post- transplant TMA recurrence was 36.5 times higher in kidney transplant recipients with ESRD due to hemolytic uremic syndrome (HUS) as compared to other etiologies (29.2% vs 0.8%).
De novo TMA; Clinical manifestations
1. TMA could develop at any time in the post transplantation course, and is mostly encountered in the first 3-6 mo post-transplantation.
2. Salient features:
· TMA manifestations are quite variable and can vary from a limited form confined to the kidney to a full blown systemic variant.
The systemic form of TMA consists of the classic triad of:
a) Thrombocytopenia
b) Microangiopathic Hemolytic Anemia (MAHA)
c) Acute kidney injury (AKI)
Localized (limited) TMA is usually presented later in TMA course, as compared to the systemic form, necessitating the diagnostic allograft biopsy.
De novo TMA; Prognosis
· The prognosis of post- transplant de novo TMA is quite poor for the patient and as well as the allograft.
· About one half of the patients loses their graft within the first two years after diagnosis.
· The USRDS-based report presented by Reynolds et al, reported a patient mortality rate of 50% after three years of diagnosis.
· Schwimmer et al reported that 54% of systemic TMA develops dialysis-requiring AKI and 38% lost their grafts.
· None of the patients with localized TMA developed TMA-related early graft loss or required dialysis.
De novo TMA; treatment
Therapeutic maneuvers should be individualized for each patient. The following approaches have been suggested:
· Immuno- suppressive medication management.
· Plasmapheresis (PE) and intravenous immunoglobulins (IVIG).
· Belatacept: A promising alternate option that allows withdrawal of the offending drug incriminated in TMA evolution.
· Complement inhibition: Eculizumab, an anti-C5 agent, blocks the lytic C5b-9 membrane attack complex generation.
Recurrent TMA after renal transplantation
Recurrent TMA; Etiology
1. aHUS; The global rate of recurrence in aHUS patients is reported to be as high as 60%. Untreated patients, however, ultimately develop graft loss at a rate of 90%, with 80% of them occurring in the first year. Recurrence of TMA in the allograft depends on:
a) The underlying type involving the native kidney.
b) Overactivation of the AP is known to be the underlying etiology of aHUS.
c) Mutational gene defects;
· involving CFH and CFI, regulatory complement components produced by the liver, results in aberrant CFH and CFI.
· Membrane co-factor protein (MCP), a transmembrane complement regulatory component that is produced by kidney endothelial cells even in post-transplant period, keeps aHUS recurrence lower unless other mutational gene defects have been associated.
2. Thrombotic Thrombocytopenic Purpura (TTP);
· Either due to genetic or acquired lack of ADAMTS13.
· Zafrani et al documented the presence of AKI in more than half of TTP patients (with low ADAMTS13 activity) and 50% progression of CKD and even ESRD.
3. Autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus, with or without anti-phospholipid antibody syndrome.
· e.g.; lupus nephritis,wherein patients can develop TMA in 5%-10% with documented recurrence after kidney transplantation.
TMA; Current classification: includes the following:
1. Primary hereditary TMA: Includes mutations in ADAMTS13, MMACHC (cb1c deficiency), or in genes encoding complement components.
2. Primary acquired TMA: Autoantibodies to ADAMTS13 or to CFH, which occurs with homozygous CFHR3/1 deletion.
3. Infection-associated TMA: Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) and pneumococcal HUS have distinct mechanisms that result in TMA; in other infections, the processes are ill-defined and sometimes can trigger manifestations of the primary TMA.
4. Secondary TMA: Presents in a variety of conditions.
· Drug-induced TMA.
· De novo TMA after SOT.
· Pregnancy-associated TMA (HELLP).
· Malignancy-associated TMA.
· TMA with severe HT.
· TMA with glomerular diseases (MN, MPGN, FSGS, IgAN, AAV).
· TMA with autoimmune diseases (e.g. SLE, CAPS, SRC).
· TMA after bone marrow transplant.
Recurrent TMA; treatment
Recommendations for recurrent TMA(level 4 evidence):
· The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3.
· All patients with primary or suspected aHUS, should be surveyed for all complement components and its related proteins.
· Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation.
· Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy.
· Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation.
Prevention of aHUS:
The following strategies are suggested to decrease/prevent aHUS:
· Complement activity incited by an injury to endothelium, e.g., ischemia-reperfusion injury, viral infection and immuno- suppressive medications, should be avoided.
· Certain relations have been reported between CNI use and aHUS recurrence, which is not confirmed by other authors, even the usual substitute in such a case (an mTOR) is not innocent and can induce recurrence.
· We cannot depend solely on PE therapy in management of aHUS recurrence for several reasons:
a) PE failed to prevent aHUS recurrence in many cases.
b) PE cannot guarantee prevention of aHUS recurrence after cessation of therapy.
c) Many cases under PE therapy were proved to develop “subclinical” aHUS recurrence, which means that PE therapy cannot influence complement activity.
d) Prophylactic use of rituximab proved to be efficacious as anti-CFH-antibodies, the beneficial effect of rituximab can be enhanced by adding PE therapy.
· The anti-C5 monoclonal antibiotic eculizumab has been reported to be used successfully to prevent aHUS recurrence in patients with CFH, CFH/CFHR1 hybrid genes as well as with C3 gene mu- tations.
TMA and renal transplantation:
1. Timing
· Renal transplantation should be postponed six months after institution of dialysis., as limited kidney recovery can occur several months after commencing eculizu- mab therapy.
· Disappearance of the extrarenal manifestations as well as resolution of TMA hematological parameters are the prerequisite for kidney transplantation.
· The magnitude of risk of recurrence can be utilized to guide the necessity of anti-complement blockade.
2. Risk of kidney donation
Two risks have been reported to be associated with living-related kidney donation:
1. Recurrent disease in the recipient.
2. De novo disease in the donor, if he/she is a genetic mutation carrier.
3. Any potential donor proved to exhibit alternative pathway dysregulation should be excluded.
4. Any potential living-related donor devoid of complement gene abnormalities can be permitted.
5. “Liver transplantation” may be reserved for patients with liver- derived complement protein aberrations, particularly in patients poorly responding to complement blockade .
3. Future therapy ;
· Purified products of the deficient genes.
· C3 convertase inhibitors.
What is the level of evidence provided by this article?
This is a narrative review article
Level of evidence grade 5.
Please summarise this article
Thrombotic microangiopathy is a devastating complication after renal transplant.
Types-
Denovo
Recurrent
Denovo TMA is more common than recurrent. It has poor prognosis that recurrent. Typical Haemolytic uremic syndrome is rare. Denovo TMA is a heterogenous set of various etiologies and constitutes the vast majority of post-transplant TMA cases.
Denovo TMA
Common aetiological factors include-
Antibody mediated rejection
Immunosuppressive-associated TMA: Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi
Medications: e.g., anti-vascular endothelial growth factor inhibitors
Viral infection: e.g., HCV, CMV, BK and parvovirus
Genetic abnormalities in the complement cascade-Phenotypical shift of C3 glomerulopathy HUS post transplantation
Missed diagnosis of TMA in the native kidney as a cause of ESRD
Etiopathogenesis.
Calcineurin-induced TMA-
Underlying mechanisms include-
Loss of the normal balance between the vasodilator peptides and prostacyclin and the vasoconstrictor peptides
CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity
Microparticle production from endothelial cells.
mTOR inhibitor-associated TMA
mTORi has antiangiogenic properties
The VEGF inhibition has been recently proven to be associated with reduced renal levels of complement factor H
Repair of endothelial injury could be hampered by mTORi use.
AMR associated De Novo TMA.
Presentation.
Can present anytime but usually 3-6 months.
Systemic form may have thrombocytopenia, hemolytic anemia and AKI
In case of graft dysfunction when biopsy does not show rejection then suspect TRAS or TMA.
Treatment of Denovo TMA
Immunosuppressive medication- CNI or mTORi
Plasmapheresis (PE) and intravenous immunoglobulins (IVIG
Belatacept
Complement inhibition: Eculizumab, an anti-C5 agent
Treatment of recurrent TMA
The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3
All patients with primary or suspected aHUS, should be surveyed for all complement components
Patients with isolated MCP associated mutations may be safe for kidney donation
Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange
Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation
What is the level of evidence provided by this article?
Level V
INTRODUCTION
· Thrombotic microangiopathy (TMA) after transplantation can be classified into either: De novo TMA and Recurrent TMA
· Missed diagnosis of TMA pre-transplant may happen as biopsy not done in ESKD patients
· As anti C5 monoclonal antibody(eculizumab), is highly effective in prevention and treatment of atypical hemolytic uremic syndrome (aHUS), it worth while to diagnose TMA pre-transplantation
· This review will discuss the main differences between the two categories in the pathophysiology, clinical course and available approaches of prevention and treatment.
DE NOVO TMA
· precipitating factors: (1) Antibody mediated rejection (AMR); (2) CNI or mTORi, single or combined; (3) anti-VGFI (4) HCV, CMV, BK and parvovirus infection (5) Genetic abnormalities in the complement cascade; (6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation; and (7) Recurrence of missed TMA
· The incidence of de novo TMA may reach 3%-14% and more prevalent than recurrent TMA, however the risk of posttransplant TMA recurrence was 36.5 times higher in kidney transplant recipients with ESRD due to HUS as compared to other etiologies
Calcineurin-induced TMA: suggested mechnisms:
1. Loss of the normal balance between the vasodilator peptides and the
vasoconstrictor peptides
2. CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity
3. Microparticle production from endothelial cells
Points against CNI involvement in TMA:
1. 95% of transplant patients on CNI, while small percentage develop TMA
2. CNI withdrawal does not improve graft outcome all the time
3. A USRDSbased study demonstrates a significantly higher incidence of TMA in the group of KTR that was not under CNI maintenance therapy, as compared to those on CNI maintenance
mTOR inhibitor-associated TMA: suggested explanation:
1. mTORi has antiangiogenic properties, and can decrease renal expression of VEGF with death of the endothelial progenitor cells
2. The VEGF inhibition may be associated with reduced renal levels of complement factor H, and those with CFH genetic mutations are more susceptible to develop de novo TMA, particularly with mTORi exposure
3. Repair of endothelial injury could be inhibited by mTORi use
4. The procoagulant and the antifibrinolytic activity of mTORi
AMR-associated de novo TMA:
· The peritubular capillary C4d staining has been reported to be present in 16.2% of biopsied recipients with TMA
Clinical manifestations
· Timing: it could occur at any time, but mostly in the first 3-6 mo post transplantation
· Salient features: classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI)
-MAHA: raised LDH, drop in Hb, decreased haptoglobin with schistocytes on peripheral blood smear
· TMA should be suspected in recipient with impaired graft function with no rejection in biopsy
· Histopathology:
-In active stage of TMA: endothelial cell injury with platelet aggregation (thrombosis), fibrinoid necrosis and glomerular ischemia
– In the chronic stage: the basement membranes undergo duplication and multilayering with increased matrix layers and vessel wall cells ( ends with onion skin formation)
Prognosis of de novo TMA:
· About one half of the patients loses their graft within the first two years after diagnosis
· patient mortality is about 50% after three years of diagnosis
RECURRENT TMA AFTER RENAL TRANSPLANTATION
Etiology of recurrent TMA: aHUS; TTP; and autoimmune diseases: e.g., scleroderma and SLE, with or without anti-phospholipid antibody syndrome
aHUS:
· aHUS is the most common diagnosis in TMA associated with recurrence
· recurrence rate 70%-90% in CFH and CFI mutations
· Membrane co-factor protein (MCP), lower aHUS recurrence
· 90% of untreated patients loose their gtrafts
TTP:
· TTP is the second recognized etiology in TMA
· Genetic or acquired lack of ADAMTS13 has been recognized
· complete distinction between TTP and HUS is not always possible because of overlap in manifestations and 50 % of TTP patients may have low ADAMTS13 activity
PATHOPHYSIOLOGY OF TMA RECURRENCE
· “membrane regulators” are: (1) Membrane cofactor protein (2) Complement receptor 1 (3) Decay accelerating factor and (4) Protectin (CD59), which prohibits MAC formation
· Any disturbance in one of those will lead to complement activation with subsequent endothelial cell derangement
Current classification of TMA:
1. Primary hereditary TMA: Includes mutations in ADAMTS13, MMACHC (cb1c deficiency), or in genes encoding complement components.
2. Primary acquired TMA: Autoantibodies to ADAMTS13 or to CFH, which occurs with homozygous CFHR3/1 deletion.
3. Infection-associated TMA: STEC-HUS, pneumococcal, and other infections
4. Secondary TMA: e.g., pregnancy-associated TMA or de novo TMA after transplantation
· The most common complement mutation in aHUS is CFH, with 40% of cases inherited and 25% sporadic
· The risk of aHUS recurrence could be four times higher with CFH mutations or with the carriers of CFH/ CFHR1 hybrid genes
· Any HUS that is not due to STEC-HUS has been called aHUS
Acute vs chronic lesion?
· Penetrance in aHUS is age-related, by age 70, penetrance reaches 64%
· The late presentation of aHUS reflects the impact of the environmental triggers
Extrarenal manifestation: digital gangrene, cerebral artery thrombosis, myocardial infarction, in addition ocular, GIT, pulmonary and neurologic involvement
Laboratory investigations and differential diagnosis:
· Urgent ADAMTS13 activity
· 5% of STEC-HUS patients have no prodromal diarrhea and 30% of complement-mediated aHUS patients can present with a diarrheal prodrome
· C3 is low in 30% of aHUS patients and, therefore cannot be used as a screening criteria for aHUS
· CD46 surface expression should be assessed by flow cytometry
· The diagnostic list of genes of aHUS should include at least CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE
· Rationale for genetic screening: a full detailed genetic map before transplant should be done as may help in diagnosis, plan, treatment, and prognosis
· Interpretation of the genetic variants: (1) Benign (2) Likely benign (3) Variant of uncertain significance (4) Likely pathogenic (5) Pathogenic
Diagnosis of aHUS recurrence:
· tissue diagnosis with LM, IF and electron microscopy
· Estimation of the anti-CFH AB
· MCP screening on the peripheral blood WBCs
· Examination of the recombination in CFHR region
· Screening of the genetic mutations related to CFH, CFI, CFB, C3, and MCP
THERAPY OF POST-TRANSPLANT TMA
Treatment of de novo TMA
· switching from one CNI member to another or to an mTORi
· Plasmapheresis and IVIG. Effictive in treating patients with TTP and previously was first line therapy for aHUS
· Belatacept: its role is only to replace/displace the offending drug
· Eculizumab, an anti-C5 agent, effective in treatment and in prevention of recurrent aHUS after renal transplantation, but it has high cost and should be confined to a specified patient:
(1) AMR-associated TMA; (2) Patients who became PE-dependent; and (3) Refractory hemolysis persists despite maximum doses of PE therapy
Treatment of recurrent TMA
Recommendations for recurrent TMA:
(1) The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3
(2) All patients with primary or suspected aHUS, should be surveyed for all complement components and its related proteins;
(3) Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation;
(4) Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy
(5) Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation
Prevention of aHUS:
1) Avoid complement activity (ischemia-reperfusion injury, viral infection and immunosuppressive medications
2) Trial with substitution of CNI with mTORi, but may recures
3) PE failed to prevent aHUS recurrence in many cases, and even “subclinical” aHUS recurrence in patients under PE therapy
4) The anti-C5 monoclonal antibiotic eculizumab has been used successfully to prevent aHUS recurrence
Kidney transplantation without eculizumab prophylaxis:
Can be successful through minimizing cold ischemic time, decreasing the risk of rejection and, thereby, providing endothelial protection
RENAL TRANSPLANTATION
Timing
· Renal transplantation should be postponed six months after institution of dialysis
· We should wait for disappearance of the extrarenal manifestations and resolution of TMA hematological parameters
Risk of living kidney donation:
1. Recurrent disease in the recipient
2. De novo disease in the donor, if he/she is a genetic mutation carrier
Future therapy
1. Purified products of the deficient genes
2. C3 convertase inhibitors
Research targets
1. The anti-C3b blocker, compstatin analog Cp40
2. The anti-C3 convertase monoclonal antibodies
CONCLUSION
· TMA, either de novo or recurrent, effect on allograft is underestimated
· Genes involved in TMA etiology is currently expanding
· complement blockade therapy effective in early stages
· The recurrent TMA have better prognosis if complement blockade drugs given before permanent damage
Evidence 5
TMA is a debilitating complication of kidney transplantation that is associated with poor patient and graft outcomes.
The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year, with a 50% mortality rate three years after diagnosis.
Post-transplant TMA classification:
– De novo TMA, no evidence of the disease before transplant more prevalent
– Recurrent TMA came back in renal transplantation.
Differentiation is crucial as it will have clear clinical and therapeutic implications.
DE NOVO TMA
Trigger the development of de novo TMA:
– AMR.
-IS-associated TMA: CNI or mTORi, single or combined
-Other medications: anti-VGFI
-Viral infection: e.g., HCV, CMV, BK and parvovirus
-Genetic abnormalities in the complement cascade.
-Phenotypical shift of C3 glomerulopathy (with ESRD) to an aHUS post-transplantation.
-Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA).
Pathogenesis of de novo TMA
Calcineurin-induced TMA
– Arteriolar vasoconstriction and renal ischemia that results in endothelial injury
– CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity
– Microparticle production (CyA) from endothelial cells that can result in activation of the AP.
mTOR inhibitor-associated TMA
-Antiangiogenic properties decrease renal expression of VEGF with the death of the endothelial progenitor cells.
-Reduce renal levels of CFH
-Repair of endothelial injury could be hampered
-Procoagulant and the antifibrinolytic activity
AMR-associated de novo TMA
– Endothelial cells are the target of alloimmune response.
– PTC C4d staining has been reported in 16.2% of biopsied recipients with TMA.
– Both AMR and TMA would predict much worse graft outcomes.
Complement gene mutations
The presence of genetic mutations in CFH, CFI or both in 29% of de novo TMA patients, 25% showed low CFB and/or low C3,
suggesting an AP complement activation.
Clinical manifestations
Timing: can occur at any time, mostly encountered in the first 3-6 m post-transplantation.
Salient features:
– variable and can vary from a limited form confined to the kidney to a full-blown systemic variant.
– The systemic form consists of the classic triad of thrombocytopenia, MAHA and AKI.
– Localized (limited) usually presented later, necessitating the diagnostic allograft biopsy.
Prognosis of de novo TMA
De novo TMA is relatively poor for the patient and the allograft. About 50 % of the patients lose their graft within the first two years after diagnosis.
RECURRENT TMA AFTER RENAL TRANSPLANTATION
Etiology of recurrent TMA
aHUS:
-The most common diagnosis in TMA associated with recurrence
-Risk of recurrence depends on the underlying type involving the native kidney
– Global rate of recurrence as high as 60%, graft loss at a rate of 90%,
Thrombotic thrombocytopenic purpura (TTP)
– Genetic or acquired lack of ADAMTS13
– Recurrence risk 5%-10%
Autoimmune diseases: scleroderma and SLE, with or without APLA
PATHOPHYSIOLOGY OF TMA RECURRENCE
Complement dysregulation is the fundamental etiology involved in TMA evolution. Both genetic aberrations, as well as autoantibodies can be involved in this process. Usually, there is (are) an inciting environmental trigger factor(s).
The current classification of TMA includes the following
Primary hereditary TMA
Primary acquired TMA
Infection-associated TMA
Secondary TMA
THERAPY OF POST-TRANSPLANT TMA
Treatment of de novo TMA
-IS management: documented better response after switching from one CNI to another or mTORi
– The withdrawal of the offending agent should be the first line in treating de novo TMA.
– Plasmapheresis (PE) and IVIG.
– Belatacept: an alternate option that allows withdrawal of the offending drug
– Complement inhibition: Eculizumab.
Treatment of recurrent TMA
Prophylactic complement blockade: Gene abnormalities have been reported to be associated with aHUS recurrence in 80% of patients
Therapeutic protocols for aHUS recurrence
The available data points to two strategies:
-Minimal dosage to establish complement blockade
– Dose withdrawal scheme
Duration of therapy: There is not enough data supporting life-long therapy for aHUS. Cessation of therapy appears to be plausible in certain situations
RENAL TRANSPLANTATION
Timing:
Should be postponed six months after the institution of dialysis, as limited kidney recovery can occur several months after commencing eculizumab
Prerequisite for transplantation
The disappearance of the extrarenal manifestations
Resolution of TMA hematological parameter.
Risk of kidney donation
Any potential donor proven to exhibit AP dysregulation should be excluded.
Future therapy
-Purified products of the deficient genes;
-C3 convertase inhibitors
Level of evidence 5 narrative review.
Summary of the Article;
Thrombotic Microangiopathy is a very risky complication post donation that is associated with poor patient and graft survival.
Incidence rate is about 5.6 cases /1000 KT/year, with 50% mortality rate after 3 years post donation.
Classification;
De novo TMA;
Factors cause development of De novo TMA;
The most prevalent;
CNI induce TMA;
Mechanism of explanation;
Points which against CNI induce TMA;
mTOR inhibitor-ass TMA;
Both sirolimus and everolimus had TMA incidence reports, explained as follow;
AMR-ass de novo TMA;
Commonly reported and well noticed, as endothelial cell are the target site of allo-immune response, C4d staining present in 16.2% of biopsies with TMA.
Clinical manifestation;
Timing;
Ocurr at any time, but commonly reported at 3-6 month post Tx.
Features.
Prognosis of de novo TMA;
Recurrent TMA;
Causes;
Current classification include the following;
Treatment of de novo TMA;
Treatment of Recurrent TMA;
Renal transplantation;
Timing;
Should be postpended 6 month after initiation of dialysis because of renal failure due to TMA, Conduct transplantation after disappearance of systemic manifestation and TMA hematological parameters.
Conclusion;
The impact or whether type of TMA on grafted kidney outcome is underestimated.
Delayed diagnosis is rather fatal and can lead to graft loss.
Early starting management with complement blockade before permanent endothelial damage is much hoping in recurrent TMA.
Level of evidence;
level ((V)) article review
It is very aggressive disease which tends to occurs post RTX as De novo TMA
we have two type Denovo and recurrent TMA
De novo TMA, post RTX can be triggered by AMR OR immunosuppression medications like CNI,viral infection like CMV,BKV,HCV.
CNI can produce TMA via three potential pathways. Loss of the normal equilibrium between vasodilator peptides (such as prostaglandin and prostacyclin) and vasoconstrictor peptides (thromboxane A2 and endothelin) may be the cause of arterial vasoconstriction, renal ischemia, and endothelial damage. CNI causes platelet activation, procoagulant and antifibrinolytic action, which may contribute to the development of TMA
It typically appears as the traditional triad of thrombocytopenia, microangiopathic hemolytic anemia (characterized by an increase in LDH and a reduction in hemoglobin), and acute kidney damage.
Recurrent TMA
What is the level of evidence provided by this article?
Level 5
Introduction
Thrombotic microangiopathy is a severe post-kidney transplantation complication linked with a poor allograft prognosis. It can be divided into de novo TMA and recurrent TMA. De novo TMA is more common than recurrent TMA, and it is considerably more common following a kidney transplant.
TMA is categorized into De novo TMA and recurrent TMA
De novo TMA
It can be triggered by a variety of factors, including AMR, immunosuppressive-associated TMA, CNI, mTORi, anti-vascular endothelial growth factor inhibitors, viral infections (HCV, CMV, BK, and parvovirus), genetic abnormalities in the complement cascade, phenotypical shift of C3 glomerulopathy, and a missed diagnosis of TMA in the native cell. These variables are typically accompanied by acquired or inherited impairment of the alternative complement pathway.
CNI can produce TMA via three potential pathways. Loss of the normal equilibrium between vasodilator peptides (such as prostaglandin and prostacyclin) and vasoconstrictor peptides (thromboxane A2 and endothelin) may be the cause of arterial vasoconstriction, renal ischemia, and endothelial damage. CNI causes platelet activation, procoagulant and antifibrinolytic action, which may contribute to the development of TMA. TMA evolution can also be induced by endothelial cell microparticle generation. mTORi have antiangiogenic capabilities, and these actions have been linked to the pathophysiology of TMA, although their precise involvement is still understood. Endothelial cells are a well-known target of allo-immune response, and the involvement of AMR in post-transplantation is also well-established.
TMA could develop at any time after a transplant, although it is more prevalent in the first 3 to 6 months after the transplant. It typically appears as the traditional triad of thrombocytopenia, microangiopathic hemolytic anemia (characterized by an increase in LDH and a reduction in hemoglobin), and acute kidney damage. A kidney biopsy will not reveal acute rejection, as histopathologic alterations are typically non-specific. Thrombosis, fibrinoid necrosis, and glomerular ischemia are signs of endothelial cell damage during the active phase. In the chronic phase, basement membranes undergo replication and stacking, resulting in the creation of a characteristic onion peel.
After a diagnosis of TMA has been made, immediate treatment of the potential cause should be undertaken. Unfortunately, both the patient and the graft have a bad prognosis. It may also necessitate dialysis and has the potential to cause patient death.
Recurrent TMA
It may result from atypical hemolytic uremic syndrome, thrombotic thrombocytopenic purpura , or autoimmune illnesses.The recurrence of TMA after the transplant depends on the subtype affecting the original kidney. It is known that the fundamental cause of aHUS is the overactivation of the AP. The most prevalent cause of TMA TTP is the second most prevalent cause of repeated TMA. A deficiency in ADAMTS13 has been identified as the reason. It could be bought or inherited. Histopathology demonstrates persistent endothelial damage. Typically, the AP is active and includes strict regulatory components. Any perturbation involving any of the defensive processes will result in complement activation and endothelial cell derangement. This condition is referred to as complement dysregulation. It can occur at any time, is difficult to predict, and so patients are at risk of recurrence at all times. Additionally, it may appear as digital gangrene, cerebral artery thrombosis, or myocardial infarction.
Once the diagnosis of aHUS is suspected, the diagnosis of TTP must be ruled out by excluding ADAMTS13 activity. Flow cytometry should be used to determine the surface expression of CD46. Include CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5, and DKGE on the diagnostic list of genes for aHUS. Genetic testing enables accurate genetic counseling, planning for disease management, evaluation of the anticipated response to treatment, and determination of the prognosis for the allograft and patient survival. A comprehensive clinical history is required for the diagnosis of recurrent aHUS. Studies involving light microscopy, immunofluorescence, and electron microscopy should be able to provide a conclusive tissue diagnosis.
Interpretation of genetic variants
Genetic mutations may be perceived as
– benign
– Likely benign.
-Variant with unknown significance.
– Probably pathogenic
– pathogenic.
Diagnosis of aHUS recurrence:
1- A comprehensive clinical history is generally required.
2-An established tissue diagnosis with (LM), (IF), and (EM) investigations to support the diagnosis of aHUS in the native kidney should be provided.
3-Once aHUS is detected, a comprehensive battery of biochemical, genetic, and histological examinations of the AP should be performed.
Prophylaxis against the recurrence of atypical hemolytic uremic syndrome in allografts based on a risk assessment strategy
High risk (50-100%): a history of early recurrence, pathogenic mutations, or gain-of-function mutations. Prophylactic eculizumab start on the day of transplantatioecause of the risk of severe recurrence and restricted time for treatment.
Moderate risk: no detected mutations, isolated CFI mutations, or insignificant complement gene mutations. suggested prophylaxis with eculizumab or plasma exchange.
Low risk: isolated MCP mutations or persistently negative FH autoantibodies. No need for prophylaxis
De novo TMA:
Precipitating factors:
De novo TMA is more prevalent after kidney transplantation and is presumably underestimated. A graft loss rate of 40% is reported in de novo TMA within a couple of years of diagnosis.
Etiopathogenesis of de novo TMA
Calcineurin-induced TMA:
Three underlying mechanisms could explain the role of CNI in TMA development:
mTOR inhibitor-associated TMA:
Mechanism:
AMR-associated de novo TMA:
Other causes:
Complement gene mutations:
A study reported the presence of genetic mutations in CFH, CFI or both in 29% of their studied de novo TMA patients; 25% showed low CFB and/or low C3, suggesting an AP complement activation.
Clinical manifestations:
Timing: develop at any time in the post-transplantation course, mostly in the first 3-6 mo post-transplantation.
Salient features: manifestations are quite variable and can vary from a limited form confined to the kidney to a full blown systemic variant.
systemic form: consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia and acute kidney injury.
Prognosis of de novo TMA:
The prognosis of post-transplant de novo TMA is quite poor for the patient and as well as the allograft. About one-half of the patients lose their graft within the first two years after diagnosis.
Recurrent TMA after transplantation:
Etiology:
Current classification of TMA:
Extrarenal manifestation:
Laboratory investigations:
Complement assessment in aHUS:
C3 is low in 30% of aHUS patients and, therefore cannot be used as a screening criteria for aHUS.
CD46 surface expression should be assessed by flow cytometry.
Panel of genetic testing:
CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE.
CFH-H3 and MCP ggaac haplotypes.
Diagnosis of aHUS recurrence:
Treatment:
Treatment of de novo TMA:
therapeutic manoeuvres should be individualized for each patient due to the heterogenicity of the disease.
Treatment of recurrent TMA:
Prevention of aHUS:
Therapeutic protocols for aHUS recurrence:
Once the diagnosis of primary aHUS has been established, complement blockade therapy should be instituted with a goal of a minimal dosage to establish complement blockade; and a dose withdrawal scheme with close monitoring of the antibody titer.
Duration of therapy:
There is not enough data supporting life-long therapy.
Enough time should be permitted to optimize renal recovery and satisfy TMA resolution.
Renal Transplantation:
Timing:
Renal transplantation should be postponed six months after the institution of dialysis, as limited kidney recovery can occur several months after commencing eculizumab therapy.
The disappearance of the extrarenal manifestations, as well as the resolution of TMA hematological parameters, are the prerequisite for kidney transplantation.
Risk of kidney donation:
Future therapy:
Level of Evidence:
Level 5 ( review article ).
Please summarise this article
-Thrombotic microangiopathy (TMA) is a debilitating complication of kidney transplantation that is associated with poor patient and graft outcomes.
-The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis.
– TMA after transplantation can be classified into either: (1) De novo TMA.(2) Recurrent TMA.
–DE NOVO TMA
– Precipitating factors include the following: (1) Antibody mediated rejection (AMR); (2) Immunosuppressive-associated TMA: Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi), single or combined; (3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI); (4) Viral infection: e.g., HCV, CMV, BK and parvovirus; (5) Genetic abnormalities in the complement cascade; (6)
Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation; and (7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA).
Etiopathogenesis of de novo TMA
-AMR and medications are the two main causes of de novo TMA.
-Calcineurin-induced TMA: Three underlying mechanisms could explain the role of CNI in TMA development: (1) Loss of the normal balance between the vasodilator peptides and the vasoconstrictor peptides results in arteriolar vasoconstriction[8,9], renal ischemia and establishment of endothelial injury(2) CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity.
(3) Microparticle production from endothelial cells .
mTOR inhibitor-associated TMA
-Both sirolimus and everolimus have been reported to be implicated in the pathogenesis of de novo TMA.
-The following explanations have been given: (1) mTORi has antiangiogenic properties, and can decrease renal expression of vascular endothelial growth factor (VEGF) with death of the endothelial progenitor cells. (2) The VEGF inhibition has been recently proven to be associated with reduced renal levels of complement factor H (CFH). (3) Repair of endothelial injury could be hampered by mTORi use; and (4)The procoagulant and the antifibrinolytic activity of mTORi might play additional roles in de novo TMA development.
AMR-associated de novo TMA:
-Endothelial cells are a well-known target of allo-immune response.
The peritubular capillary (PTC) C4d staining has been reported to be present in 16.2% of biopsied recipients with TMA.
Complement gene mutations.
Clinical manifestations:
– TMA could develop at any time in the post transplantation course, however this syndrome is mostly encountered in the first 3-6 mo post transplantation.
– The systemic form of TMA consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI).
Prognosis of de novo TMA:
– The prognosis of posttransplant de novo TMA is quite poor for the patient and as well as the allograft. About one half of the patients loses their graft within the first two years after diagnosis.
RECURRENT TMA AFTER RENAL TRANSPLANTATION
Etiology of recurrent TMA
-aHUS; thrombotic thrombocytopenic purpura (TTP); and autoimmune disease.
Current classification of TMA includes the following
Primary hereditary TMA .
Primary acquired TMA .
Infection-associated TMA .
Secondary TMA.
THERAPY OF POST-TRANSPLANT TMA
Treatment of de novo TMA
– The following approaches have been suggested: (1) Immunosuppressive medication management. (2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG). (3) Belatacept. (4) Complement inhibition: Eculizumab, an anti-C5
agent, blocks the lytic C5b-9 membrane attack complex
generation.
Treatment of recurrent TMA
Recommendations for recurrent TMA: (1) The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3(2) All patients with primary or
suspected aHUS, should be surveyed for all complement components and its related proteins; (3) Patients with isolated MCP associated mutations may be safe for kidney donation; (4) Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy[ ; and (5) Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation.
-Risk of kidney donation
Two risks have been reported to be associated with living-related kidney donation: (1) Recurrent disease in the recipient; and (2) De novo disease in the donor, if he/she is a genetic mutation carrier
-Any potential donor proved to exhibit alternative pathway
dysregulation should be excluded.
What is the level of evidence provided by this article?
Level 5
· Introduction :
– TMA is a debilitating complication of kidney transplantation which affect outcome. The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis. It can be de novo or recurrent TMA .
>>DE NOVO TMA :
– Can be associated with:
(1) Antibody mediated rejection (AMR)
(2) Immunosuppressive-associated TMA: Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi), single or combined
(3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI)
(4) Viral infection: e.g., HCV, CMV, BK and parvovirus
(5) Genetic abnormalities in the complement cascade
(6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation
(7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA)
· C/P :
Timing : TMA could develop at any time in the post transplantation course, however this syndrome is mostly encountered in the first 3-6 mo post transplantation. This is probably when the CNI immunosuppressive trough levels are relatively higher
– can vary from a limited form confined to the kidney to a full blown systemic variant
– The systemic form of TMA consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI). Features of MAHA include raised lactic acid dehydrogenase (LDH), drop in hemoglobin (HB) and decreased haptoglobin with schistocytes on peripheral blood smear
– When a renal transplant recipient has significant renal dysfunction and the biopsy does not show any acute rejection, one must suspect two possibilities: (1) TMA or (2) Renal artery stenosis.
– The Limited form can present only with u explained renal dysfunction , The histopathologic changes are usually non-specific but vary in the acute status to the chronic angiopathic changes. In the active stage, there is evidence of endothelial cell injury with platelet aggregation (thrombosis), fibrinoid necrosis and glomerular ischemia. In the chronic stage, the basement membranes undergo duplication and multilayering with increased matrix layers and vessel wall cells, which ultimately ends in the unique onion skin formation
– Prognosis of de novo TMA: The prognosis of posttransplant de novo TMA is quite poor for the patient and as well as the allograft. About one half of the patients loses their graft within the first two years after diagnosis
>>RECURRENT TMA AFTER RENAL TRANSPLANTATION :
– Etiology of recurrent TMA : aHUS , thrombotic thrombocytopenic purpura (TTP) , and autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus, with or without anti-phospholipid antibody syndrome
>>”Spectrum of TMA”
– Primary hereditary:
1. aHUS with complement gene mutations. 2. TTP with ADAMTS13 mutations. 3. cblC deficiency mediated TMA. 4. DGKE-associated TMA.
– Primary acquired:
1. TTP with ADAMTS13 autoantibodies. 2. aHUS with FH autoantibodies.
– Infection associated:
1. STEC- HUS. 2. Pneumococcal HUS (distinct mechanisms result in TMA). 3. HIV-associated TMA. 4. Other infections (ill defined, infection may trigger manifestation of a primary TMA).
– Secondary TMA: 1. Drug-induced TMA. 2. De novo TMA after SOT. 3. Pregnancy-associated TMA (HELLP). 4. Malignancy-associated TMA. 5. TMA with severe HT. 6. TMA with glomerular diseases (MN, MPGN, FSGS, IgAN, AAV). 7. TMA with autoimmune diseases (e.g. SLE, CAPS, SRC). 8. TMA after bone marrow transplant
– Extrarenal manifestation of aHUS : Twenty percent of aHUS patients can express extrarenal manifestations in the form of digital gangrene, cerebral artery thrombosis, myocardial infarction, in addition to ocular, GIT, pulmonary and neurologic involvement .Drusen formation is not common in aHUS
– once diagnosis of aHUS is suspected , screening of ADAMTS13 level & activity is mandatory , in children can start eculizumab immediately without witing the results based on that incidence of TTP in children is less common .also sending for complement assessment & genetic testing for diagnosis.
· Treatment of de novo TMA :
– Should be individualized for each patient .
– (1) Immunosuppressive medication management : can shift from one CNI member to another or to an mTORi although some debates on this but Whatever the situation would be, the withdrawal of the offending agent should be the first line in treating de novo TMA .
– (2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG): Two benefits have been postulated for this type of therapy: Removal of the platelet aggregation factors, e.g., thromboxane A2 and the simultaneous replenishment of the deficient factors, e.g., PGI2-stimulating factor , In AMR-associated TMA, an improved outcome has been reported, which was attributed to removal of the anti-HLA antibodies. A 100% response has been reported to be associated with PE/IVIG therapy in five solid organ transplantation with systemic TMA with no evidence of relapse after withdrawal of the culprit agent (e.g., tacrolimus) in a recent study
– (3) Belatacept: Belatacept is an immunosuppressive co-stimulatory blocker against CD80 and CD86 surface ligands and CD28 on T cells. The first case report in 2009 documented TMA resolution after belatacept therapy used for immunosuppression in post-transplantation TMA due to CNI-induced endothelial toxicity[138]. Two case series have followed, thereafter documenting fair graft outcome due to resolution of the CNI-induced TM. Of note, belatacept has nothing to do with the underlying endothelial derangement, its role is only to replace/displace the culprit drug
– (4) Complement inhibition: Eculizumab, an anti-C5 agent, blocks the lytic C5b-9 membrane attack complex generation. it was proven to be effective in treatment as well as in prevention of recurrent aHUS after renal transplantation. A large percentage of patients with diagnosed TMA express complement activation, including those patients with unrecognized complement genes. This efficacy has been also documented in patients with refractory AMR with TMA
· Treatment of recurrent TMA :
– Prevention of aHUS: The following strategies are suggested to decrease/prevent aHUS:
(1) Complement activity incited by an injury to endothelium, e.g., ischemia-reperfusion injury, viral infection and immunosuppressive medications, should be avoided.
(2) Certain relations have been reported between CNI use and aHUS recurrence, which is not confirmed by other authors, even the usual substitute in such a case (an mTOR) is not innocent and can induce recurrence.
(3) We cannot depend solely on PE therapy in management of aHUS recurrence for several reasons: PE failed to prevent aHUS recurrence in many cases, PE cannot guarantee prevention of aHUS recurrence after cessation of therapy; Many cases under PE therapy were proved to develop “subclinical” aHUS recurrence, which means that PE therapy cannot influence complement activity; Prophylactic use of rituximab proved to be efficacious as anti-CFH-antibodies, the beneficial effect of rituximab can be enhanced by adding PE therapy.
(4) The anti-C5 monoclonal antibiotic eculizumab has been reported to be used successfully to prevent aHUS recurrence in patients with CFH, CFH/CFHR1 hybrid genes as well as with C3 gene mutations.
Prophylaxis against atypical hemolytic uremic syndrome recurrence in allograft based on a risk-assessment strategy :
– High risk (50-100%): Previous early recurrence,Pathogenic mutations or Gain-of-function mutations >> Prophylactic eculizumab Start on the day of transplantation due to potential for severe recurrence and limited
– Moderate risk : no mutation identified, Isolated CFI mutations or Insignificant complement gene mutation>>>prophylactic eculizumab or plasma exchange.
– Low risk : Isolated MCP( membrane cofactor protein) mutations or Persistently negative FH autoantibodies>> No prophylaxis
– Eculizumab dose & monitoring : Minimal dose Desire to continue dosing with the minimal dose required to achieve a pre-identified level of complement blockade .Dose reduction or interval extension Goal CH50 < 10% (recommended) Goal AH50 < 10% (recommended) Goal eculizumab trough > 100 μg/mL Discontinuation Desire to discontinue complement blockade: No consensus exists regarding tapering of dose
· RENAL TRANSPLANTATION
· Timing >> should be postponed six months after institution of dialysis, as limited kidney recovery can occur several months after commencing eculizumab therapy. Disappearance of the extrarenal manifestations as well as resolution of TMA hematological parameters are the prerequisite for kidney transplantation. The magnitude of risk of recurrence can be utilized to guide the necessity of anti-complement blockade
· Risk of kidney donation >>Two risks have been reported to be associated with living-related kidney donation: (1) Recurrent disease in the recipient; and (2) De novo disease in the donor, if he/she is a genetic mutation carrier. Any potential donor proved to exhibit alternative pathway dysregulation should be excluded. On the other hand, any potential living-related donor devoid of complement gene abnormalities can be permitted. “Liver transplantation” may be reserved for patients with liver derived complement protein aberrations, particularly in patients poorly responding to complement blockade.
· The following future therapeutic agents have been addressed: (1) Purified products of the deficient genes; and (2) C3 convertase inhibitors
Introduction
Thrombotic microangiopathy (TMA) is a significant complication of kidney transplant recipients, associated with poor graft prognosis. It can be classified into either de novo TMA or recurrent TMA. De novo TMA is more prevalent than recurrent TMA and even more prevalent after kidney transplantation.
De novo TMA
It can be triggered by many factors, such as antibody mediated rejection (AMR), immunosuppressive-associated TMA: calcineurin inhibitors (CNI), mTOR inhibitors (mTORi), anti-vascular endothelial growth factor inhibitors, viral infections (HCV, CMV, BK and parvovirus), genetic abnormalities in the complement cascade, phenotypical shift of C3 glomerulopathy and a missed diagnosis of TMA in the native kidney. These factors usually occur in a background of acquired or genetic dysfunction of the alternative complement pathway.
CNI can induce TMA by three possible mechanisms. It could be because of the loss of the normal balance between the vasodilator peptides (for example prostaglandin and prostacyclin) and the vasoconstrictor peptides (thromboxane A2 and endothelin) which results in arterial vasoconstriction, renal ischemia and endothelial injury. CNI induces activation of platelets, pro-coagulant and anti-fibrinolytic activity which may cause the evolution of TMA. Microparticle production from endothelial cells can also induce TMA evolution. mTORi have antiangiogenic properties and these effects have been implicated in TMA pathogenesis, but the exact role is still unknown. Endothelial cells are a well-known target of allo-immune response and hence the role of AMR in post transplantation is well known.
TMA could develop at any time post transplantation, but it most commonly occurs in the first 3 to 6 months post the transplantation. It usually manifests as the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (seen as increased LDH, a decrease in hemoglobin) and acute kidney injury. A renal biopsy will not show acute rejection, the histopathologic changes are usually non-specific. In the active stage, we see evidence of endothelial cell injury with thrombosis, fibrinoid necrosis and glomerular ischemia. In the chronic stage, the basement membranes undergo duplication and layering that leads to a unique onion skin formation.
Once TMA has been diagnosed, prompt treatment of the possible etiology should be initiated. Unfortunately, the prognosis is quite poor for the patient and the graft. It may also lead to the requirement of dialysis, and may also lead to patient mortality.
Recurrent TMA
It may be caused by atypical hemolytic uremic syndrome (aHUS), thrombotic thrombocytopenic purpura (TTP) and autoimmune diseases (such as scleroderma and systemic lupus erythematous).
Recurrence of TMA in the allograft depends on the type involving the native kidney. Overactivation of the AP is known to be the underlying cause of aHUS. It is the most common cause of TMA. TTP is the second most common cause of recurrent TMA. It has been recognized that the cause is a lack of ADAMTS13. It could be either genetic or acquired. Histopathology shows ongoing endothelial injury. The AP is usually active and has stringent regulatory components. Any disturbance involving any of the protective mechanisms will lead to complement activation with subsequent endothelial cell derangement. This is recognized as complement dysregulation. It can occur at any time, it is not easy to predict and therefore the patients are at a constant risk of recurrence. It may also manifest in other forms such as digital gangrene, cerebral artery thrombosis and myocardial infarction.
Once the diagnosis of aHUS is suspected, TTP diagnosis has to be excluded by the exclusion of ADAMTS13 activity. CD46 surface expression should be assessed by flow cytometry. The diagnostic list of genes in aHUS should include CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DKGE. Determining the actual cause of the disease by genetic testing allows for correct genetic counselling, planning for disease management, evaluation of the expected response to treatment and defining the prognostic course of the allograft and the patient survival. For the diagnosis of aHUS recurrence, a detailed clinical history is warranted. A proven tissue diagnosis with light microscopy, immunofluorescence and electron microscopy studies should be available.
The current classification of TMA includes the following:
Primary hereditary TMA
Mutations in ADAMTS13, MMACHC
Primary acquired TMA
Autoantibodies to ADAMTS13
Infection-associated TMA
Shiga toxin-producing Escherichia coli-HUS, pneumococcal HUS
Secondary TMA
Treatment of de novo TMA involves individualizing the therapeutic maneuvers for each patient, as the manifestations and response to treatment are variable. Treatment involves adjusting the immunosuppressant medications, plasmapheresis, intravenous immunoglobulins, belatacept (an immunosuppressive co-stimulatory blocker against CD80 and CD86 surface ligands), eculizumab (an anti-C5 agent that blocks the complement pathway).
Prevention of recurrent TMA is important and the following strategies can be used:
1. Complement activity incited by an injury to the endothelium should be avoided (e.g. viral infections, immunosuppressive medications)
2. Substitution of CNIs
3. Plasmapheresis cannot suffice as the sole treatment
4. Use of eclizumab.
Therapeutic protocols for aHUS recurrence include complement blockade therapy with minimal dosage to establish complement blockade and a dose withdrawal scheme.
The duration of therapy should be enough time for renal recovery and TMA resolution.
Renal transplantation should be delayed for 6 months after starting dialysis and eclizumab therapy. Recurrent disease in the recipient and de novo disease have been recognized as risks for living related kidney donation.
Conclusion:
TMA, either de novo or recurrent can lead to graft loss and has been associated with increased mortality as well. Recurrent TMA has treatment options available unlike de novo TMA. It is important to diagnose TMA promptly and institute the management immediately including removing the offending drug like CNIs or mTORIs, or treatment of the viral infections.
I like your summary and analysis.
Ajay
club 5, TMA after KT (denovo or recurrent disease)
Summary:
· TMA post transplantation has deleterious effects on both the graft and patient outcome. it accounts for 5.6 cases per 1000
· Denovo is more common and has worse prognosis than recurrent TMA.
· Recurrent TMA has genetic background. as in case of atypical HUS with mutation in regulatory proteins in alternative complement pathway. proper choice of the donor and exclusion of carrier state in living related donor is essential to minimize the risk of recurrence.
· Treatment includes PEX, stoppage of offending drugs as CNI, or need for ecluizimab (c5A blockage).
· Denovo TMA:
· Genetic mutation in regulatory factors of complement pathway (factor H, I loss of function mutations, while factor B, C3 have gain of function mutation).
· CFH is the most common detected mutation with recurrence in 70-90%, CFB has the highest recurrence (100%), MCP has lowest recurrence 15-20%.
· Use of CNI or or anti VEGF by Loss of normal balance between the vasodilator (PG) E2 and prostacyclin (PG12)) and the vasoconstrictor thromboxane A2 and endothelin eventually leading to renal ischemia and endothelial injury. In addition, CNI-has platelet activation, pro-coagulation and anti-fibrinolytic activity.
· Use of m TORi as they have antiangiogenic properties, and can decrease renal expression of vascular endothelial growth factor (VEGF) that leads to decreased level of regulatory factor H, in addition, it inhibits repair of endothelial injury.
· The effect of drug induced TMA, is accentuated by combined use of CNI and mTORi.
· ABMR as endothelial injury is a target site of damage in ABMR.
· Missed diagnosis of TMA as a cause of ESKD in native kidney (did not do biopsy
· viral infection as HCV, CMV or BK.
clinical presentation: More common and has Worse (50% graft loss after 2 years) and (50% mortality after 3 years).
· Can be presented at any time, but mostly at 3-6 months post transplantation.
· Either full blown systemic features with triad of decreased platelet count, microangiopathic hemolytic anemia and AKI.
· local or renal confined, presented with acute graft dysfunction and diagnosed by allograft biopsy (presence of thrombosis and fibrinoid necrosis)_
· Revision of original kidney disease is essential, as diagnosis can be missed as misdiagnosed as hypertensive nephrosclerosis. hence, genetic testing is essential to diagnose missed a HUS.
Recurrent TMA: · Etiology:
· recurrence of original kidney disease as a HUS, TTP , SLE and antiphospholipid syndrome.
· aHUS is most common recurrent form of TMA, with recurrence approached 70%-90% in factor H and I mutation. while MCP has lower rate of recurrence.
· The most common complement mutation in aHUS is CFH, with 40% of cases inherited and 25% sporadic
· TTP was discriminated from a HUS by presence of neurological manifestations however, nowadays its diagnosis based on detection of low level of ADMATS 13.
· SLE with TMA has 10 % risk of recurrence after KT.
· Triggers;
· either single or multiple factors as viral infections, ABMR and CNI use.
Less common and has Better prognosis than Denovo TMA.
Recurrence of HUS after transplantation and presented with classic triad (decreased platelet count, microangiopathic hemolytic anemia and AKI).
NB:
· Recent trends in genetic mutations of complement regulatory factors includes copy number variation (CNV), hybrid genes, and the complex genomic rearrangements of CFH/CFHRs genomic region.
Management of denovo TMA:
· for DENOVO drug induced: shift from CNI to mTORI and vice versa, or dose modification. promising data about use of beltacept to allow CNI withdrawal in cases of CNI induced TMA.
· PEX and IVIG used early in denovo TMA.
· Ecluizimab can be used in denovo TMA in the following conditions:
o AMR-associated TMA
o Patients who became PE-dependent
o Refractory hemolysis persists despite maximum doses of PE therapy
Management of recurrent TMA:
prophylaxis to prevent recurrence;
· a HUS
o PEX not prevent a HUS recurrence, but can decrease its severity.
o Rituximab proved to be efficacious as anti-CFH-antibodies
o prophylactic ecluizimab can be considered to decrease risk of recurrence.
· cases with +ve anti factor H antibodies:
o use either ecluizimab or PEX either for life.
o or use PEX or ecluizimab (plus anti cellular therapy as cyclophosphamide, rituximab or MMF) and monitor antibody titer.
o Discontinue anti cellular therapy if antibody titer falls below a pathogenic titer for at least 6 months.
· Transplantation without ecluizimab:
o Decreasing the risk of rejection with induction therapy.
o Tac based triple maintenance therapy.
o Minimizing cold ischemic time
o aspirin prophylaxis to provide endothelial protection
· Precaution in renal transplantation:
o Delay renal transplantation for six months after institution of dialysis to allow for hematological remission, to see remission of renal problems with start of ecluizimab.
o Screening for genetic mutations especially in living related donor: as 2 risks are present (1) Recurrent disease in the recipient; and (2) De novo disease in the donor, if he/she is carrier for genetic mutation.
o Permit only donors without genetic mutations.
o Combined liver-kidney transplantation should be preserved only in case of unavailability or none responsive to ecluizimab.
· Future therapy under research:
o Purified products of the deficient genes; and (2) C3 convertase inhibitors
· Level of evidence: narrative review (level V).
I like your summary and analysis.
Ajay
Please summarise this article
Introduction:
Thrombotic microangiopathy (TMA) is a serious, unwanted sequalae post kidney transplant it is either de novo, or recurrent disease.
De novo TMA : either acquired or genetic dysregulation of the alternative complement pathway as follow:
(1) Antibody mediated rejection (AMR), (2) medication and Immunosuppressive-associated TMA: Calcineurin inhibitors or mTOR inhibitors, and anti-vascular endothelial growth factor inhibitors. (4) Viral infection: e.g., HCV, CMV, BK and parvovirus. (5) Genetic abnormalities in the complement cascade; (6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation.(7) Missed diagnosis of TMA in the native kidney as a cause of ESRD.
De novo is more frequent and serious than recurrent disease.
Clinical manifestations:
usually occur 3-6 months post-transplant, silent (kidney limited proved by biopsy) or clinically overt presentations (thrombocytopenia,AKI, hemolytic anemia+schistocytes on blood film , neurological deficit and fever) are observed.
RECURRENT TMA AFTER RENAL TRANSPLANTATION:
Atypical HUS- alternative complement mutations defects (CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE…etc), thrombotic thrombocytopenic purpura (TTP)- ADAMTS-13 level; cblC deficiency mediated TMA, DGKE-associated TMA, and autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus, with or without anti-phospholipid antibody syndrome.
Laboratory investigations:
Complement assessment in aHUS and genetic testing panel.
Treatment of post transplantation TMA :
It is a difficult to treat disease, but for whom had history of TMA, should be on HD at least 6 months before transplantation done, genetic testing is required for those living related donors for a TMA induced ESRD recipient.( prevention!).
High risk (50-100%): Previous early recurrence, Pathogenic mutations1, Gain-of-function mutations.
Prophylactic Eculizumab start at the day of transplantation is recommended.
Moderate risk: No mutation identified, Isolated CFI mutations, Insignificant complement gene mutation.
Eculizumab, or plasma exchange prophylaxis is recommended.
Low risk: isolated MCP mutations, Persistently negative FH autoantibodies. No prophylaxix recommended.
For complement factor H mediated HUS = Plasma exchange or eculizumab indefinitely or use of anticellular therapy ( Rituximab, cyclophosphamide or MMF) with monitoring of FH antibodies titer if controlled then stop PE/Eculizumab..
Future therapy: (1) Purified products of the deficient genes; (2) C3 convertase inhibitors; and anti-C3 convertase monoclonal antibodies.
Conclusion:
TMA, either de novo or recurrent, on allograft longevity is underestimated.
Despite the landmark breakthrough of immense efficacy of complement blockade therapy, the outlook of this devastating syndrome remains poor if the diagnosis is delayed.
Recurrent TMA is much more optimistic if there is timely intervention by complement blockade before permanent damage ensue.
Knowing early predictors of TMA recurrence improves patient and graft outcomes.
What is the level of evidence provided by this article?
Level of evidence V
I like your summary and analysis.
Ajay
Introduction;
————————
Post-transplant TMA can occur as a recurrence of the disease involving the native kidney or as denovo disease with no evidence of previous involvement
before transplant.
atypical hemolytic uremic syndrome is a rare disease that results from complement dysregulation with alternative pathway overactivity, denovo TMA is a heterogenous set of various etiologies and constitutes the vast majority of post-transplant TMA cases.
The incidence ;
————————–
The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis.
De novo TMA is more prevalent after kidney transplantation and presumably underestimated. Graft loss rate of 40% is reported in de novo TMA within a couple of years of diagnosis .
DENOVO TMA;
—————————–
A number of precipitating factors have been identified in the context of renal transplantation that trigger the development of de novo TMA, which include;
1- Antibody mediated rejection (AMR)
2- Immunosuppressive-associated TMA: Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi), single or combined.
3- Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI).
4- Viral infection: e.g., HCV, CMV, BK and parvovirus.
5- Genetic abnormalities in the complement cascade.
AMR and medications are the two main causes of de novo TMA.
Clinical manifestations;
——————————————–
1-The systemic form of TMA;
Consists of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI). Features of MAHA include raised lactic acid dehydrogenase (LDH), drop in hemoglobin (HB) and decreased haptoglobin with schistocytes on peripheral blood smear.
2-Localized (limited) TMA;
Is usually presented later in TMA course, as compared to the systemic form, which can be explained by the urgency of the systemic type, necessitating the diagnostic allograft biopsy .
The histopathologic changes are;
————————————————
A- usually non-specific but vary in the acute status to the chronic angiopathic changes.
B- In the active stage, there is evidence of endothelial cell injury with platelet aggregation (thrombosis), fibrinoid necrosis and glomerular ischemia.
C- In the chronic stage, the basement membranes undergo duplication and multilayering with increased matrix layers and vessel wall cells, which ultimately ends in the unique onion skin formation.
Prognosis of de novo TMA:
—————————————–
The prognosis of post- transplant de novo TMA is quite poor for the patient and as well as the allograft. About one half of the patients loses their graft within the first two years after diagnosis .
RECURRENT TMA AFTER RENAL TRANSPLANTATION;
————————————————————————————————
.
Etiology of recurrent TMA;
1-aHUS; thrombotic thrombocytopenic purpura (TTP).
2- autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus, with or without anti-phospholipid antibody syndrome .
Current classification of TMA includes the following;
———————————————————————————————–
1-Primary hereditary TMA:
Includes mutations in ADAMTS13, MMACHC (cb1c deficiency), or in genes encoding complement components.
2-Primary acquired TMA:
Autoantibodies to ADAMTS13 or to CFH, which occurs with homozygous CFHR3/1 deletion.
3-Infection-associated TMA:
Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) and pneumococcal HUS have distinct mechanisms that result in TMA
4-Secondary TMA:
Presents in a variety of conditions, and in many conditions the culprit mechanisms are usually multi factorial or unknown. In some secondary forms of TMA, e.g., pregnancy-associated TMA or de novo TMA after transplantation, a significant percentage of cases may be associated with genetic predisposition .
The most common complement mutation in aHUS is CFH, with 40% of cases inherited and 25% sporadic . The risk of aHUS recurrence could be four times higher with CFH mutations or with the carriers of CFH/ CFHR1 hybrid genes.
Environmental triggers:
————————————–
The process of aHUS recurrence can be triggered by ;
A-anti-HLA antibodies .
B-viral infection .
C-ischemia-reperfusion injury and im- munosuppressive medications.
Clinical assessment of aHUS:
—————————————————-
1-. Acute vs chronic lesion?
Timing of an aHUS episode is not easily predictable. Dissociation between the pathological entities and the clinical presentation have been reported. For example, TMA can be diagnosed in tissue biopsy without simultaneous decline in platelet count.
2-Extrarenal manifestation:
20%of aHUS patients can express extra renal manifestations in the form of ;
A- Digital gangrene.
B-Cerebral artery thrombosis.
C-Myocardial infarction .
D- Ocular, GIT, Pulmonary and Neurologic involvement .
3- Laboratory investigations and differentialdiagnosis:
Once the diagnosis of aHUS is suspected exclusion of ADAMTS13 activity is urgently mandated to exclude TTP diagnosis.
4- Complement assessment in aHUS:
Before commencing plasma therapy, serum complement component should be thoroughly evaluated. C3 is low in 30% of aHUS patients and, therefore cannot be used as a screening criteria for aHUS. CD46 surface expression should be assessed by flow cytometry.
5- Panel of genetic testing:
The diagnostic list of genes of aHUS should include at least CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE. Genotyping workup should also include CFH-H3 and MCP ggaac haplotypes.
Interpretation of the genetic variants:
————————————————————-
Genetic mutations can be interpreted as:
(1) Benign.
(2) Likely benign.
(3) Variant of uncertain significance.
(4) Likely pathogenic .
(5) Pathogenic, according to the international guidelines.
.
Diagnosis of aHUS recurrence:
————————————————-
1-A full detailed clinical history is usually warranted.
2-A proven tissue diagnosis with (LM), (IF) and (EM) studies supporting the diagnosis of aHUS in the native kidney should be available.
3-Once diagnosis of aHUS is suspected, a full battery of biochemical, genetic as well as pathological investigations of the AP should be accomplished .
Treatment of de novo TMA;
———————————————–
The following approaches have been suggested:
(1) Immunosuppressive medication managemen;
The withdrawal of the offending agent should be the first line in treating de novo TMA, a fundamental step that ultimately results in correction of the hematological profile.
There is a reported better response after switching from one CNI member to another or to an mTORi).
(2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG):
PE can be beneficial for two reasons:Removal of the abnormal mutant complement proteins and supplying normally functioning complement components.
3) Belatacept:
A promising alternate option that allows withdrawal of the offending drug incriminated in TMA evolution.
(4) Complement inhibition:
Efficacy of eculizumab has been documented in several case reports and case series in management of resistant cases of medication-associated TMA, including cases with unrecognized genetic defects. This efficacy has been also documented in patients with refractory AMR with TMA .
On the other hand, Cornell et al reported no difference in death-censored graft survival or biopsy finding at one year when they compared the outcome of eculizumab-treated patients with positive cross matching with controls, even though the incidence of acute AMR was less in the eculizumab group.
So, in view of these conflicting results as well as considering the high cost of the drug, the use of this vital biological agent should be confined to a specified subset of de novo TMA patients, presumably:
(1) AMR-associated TMA .
(2) Patients who became PE-dependent .
(3) Refractory hemolysis persists despite maximum doses of PE therapy.
Recommendations for recurrent TMA:
—————————————————————–
(1) The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3 .
2) All patients with primary or suspected aHUS, should be surveyed for all complement components and its related proteins.
(3) Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation .
(4) Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy .
(5) Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation.
Prevention of aHUS:
————————————–
The following strategies are suggested to decrease/prevent aHUS:
(1) Complement activity incited by an injury to endothelium, e.g., ischemia-reperfusion injury, viral infection and immunosuppressive medications, should be avoided.
2) Certain relations have been reported between CNI use and aHUS recurrence, which is not confirmed by other authors , even the usual substitute in such a case (an mTOR) is not innocent and can induce recurrence .
(3) Prophylactic use of rituximab proved to be efficacious as anti-CFH-antibodies , the beneficial effect of rituximab can be enhanced by adding PE therapy .
(4) The anti-C5 monoclonal antibiotic eculizumab has been reported to be used successfully to prevent aHUS recurrence in patients with CFH, CFH/CFHR1 hybrid genes as well as with C3 gene mutations .
Prophylactic complement blockade:
—————————————————-
Evidence of increased complement activity during aHUS episodes after exposure to a trigger, e.g., surgery or infection, clinical indication of complement blockade is suggested
RENAL TRANSPLANTATION;
———————————————————-
A-Timing;
1-Renal transplantation should be postponed six months after institution of dialysis, as limited kidney recovery can occur several months after commencing eculizumab therapy.
2- Disappearance of the extrarenal manifestations as well as resolution of TMA hematological parameters are the prerequisite for kidney transplantation.
B-Risk of kidney donation;
1-Two risks have been reported to be associated with living-related kidney donation:
(a) Recurrent disease in the recipient .
(b) De novo disease in the donor, if he/she is a genetic mutation carrier.
2-Any potential donor proved to exhibit alternative pathway dysregulation should be excluded.
3-On the other hand, any potential living-related donor devoid of complement gene abnormalities can be permitted.
4- “Liver transplantation” may be reserved for patients with liver derived complement protein aberrations, particularly in patients poorly responding to complement blockade .
What is the level of evidence provided by this article?
———————————————————————-
Level V
Thank you
Introduction
De novo TMA: detected for the first time without
any previous occurrence of the disease before transplant
Recurrent TMA : recurrence of TMA in the graft after being the cause of failure of the native kidney before .
TMA diagnosis can be usually missed as biopsy is not regularly done for the native kidneys before transplantation.
Eculizumab is effective in prevention and treatment of a HUS that is why identification and differentiation of both denovo and recurrent have significant therapeutic implications.
De novo TMA
Occurs due to certain defect of alternative pathway that could be acquired or genetic , superadded to it precipitating factors including
· Antibody mediated rejection (AMR)
· Immunosuppressive-associated TMA as CNI ,mTORi, either separately or together
· Other medications as anti-VGFI
· Viral infection
· Genetic abnormalities in the complement pathways
· Phenotypical shift of C3 glomerulopathy to an aHUS post transplantation
· Missed diagnosis of TMA in the native kidney as recurrence of TMA .
Ø Incidence of denovo TMA
USRDS-based study published that denovo is more common than recurrent ,with 40% graft loss rate in the former type ,on the other hand the recurrence rate was 36.5 times higher for recipients with ESRD due to a HUS.
Ø Pathogenesis of denovo
The main etiology involves AMR ,medications and complement abnormalities.
CNI induced TMA mechanism included
-Loss of the normal balance between the vasoconstrictor and the vasodilator peptides leading to arteriolar vasoconstriction and renal ischemia
-CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity
-cyclosporine can lead to macroparticle production from endothelial cells.
Meanwhile a USRDS based study demonstrated that KTR on CNI were less likely to develop TMA and stopping CNI therapy did not resolve the TMA so there could be another predisposing factor other than CNI.
mTOR inhibitor-associated TMA
-due to it’s antiangiogenic effects, and the decrease of renal expression of VEGF leading to death of the endothelial progenitor cells.
– decreased VEGF lowers the renal levels of complement factor H (CFH) and cases with CFH genetic mutations are more liable to have de novo TMA specially with mTORi use.
-mTORi can prevent endothelial injury repair.
– m TORi procoagulant and the antifibrinolytic activity can have a role in denovo TMA developpement.
Studies declared that the effect of CNI combined with m TOR I to develop denovo TMA is much more than mTOR I alone.
AMR-associated de novo TMA:
Alloimmune response targets endothelial cells .The peritubular capillary (PTC) C4d staining was present in 16% of renal biopsies of TMA cases.
Satoskar et al mentioned an incidence of 55% of de novo TMA patients who had diffuse PTC C4d positivity.
Humoral rejection was involved in the evolution of post-transplant TMA.
Studies declared that the association of both AMR and
TMA can indicate worse graft outcome.
Complement gene mutations
Chua et al demonstrated C4d deposits in > 88% and C4d with localized C5b-9 in 60% of 42 biopsies of confirmed TMA cases.
Another study stated genetic mutations in CFH, Complement FactorⅠ(CFI) or both in 29% of their de novo TMA patients.
TMA evolution
Is related to AP uncontrolled activity due to dysregulation of CFH or CFI resulting in endothelial injury and thereby TMA.
Clinical picture
-It usually occurs in the first 3-6 months after transplantation when CNI reaches high trough levels ,in fact it can occur any time.
-It could be either localised to the kidney or systemic with the classic triad of thrombocytopenia,
microangiopathic hemolytic anemia and AKI.
TMA or RAS can be suspected if a recipient experienced renal dysfunction with negative biopsy to acute rejection.
In the active stage, thrombosis, fibrinoid necrosis and
glomerular ischemia are seen in the biopsy.
In the chronic stage, the basement membranes duplicate giving the unique onion skin formation pattern.
Denovo TMA prognosis
Half of the cases loose their graft in the first 2 years after the diagnosis with mortality rate reaching 50% within3 years after the diagnosis.
Recurrent TMA after transplantation
· For aHUS: TMA recurrence depends on the type affecting the native kidney, a HUS is common to recur and AP overactivation is the underlying pathology.
CFH and CFI have a great effect on aHUS recurrence after transplantation.
Membrane co-factor protein (MCP) decreases aHUS recurrence unless genetic mutation happens.
· For TTP: caused by genetic or acquired lack of ADAMTS13. To differentiate TTP and HUS , TTP is associated with neurological symptoms and HUS is associated with AKI but overlapping manifestations can occur rendering differentiation difficult.
· Pathology includes thrombotic ,non thrombotic and arterial and arteriolar intraluminal fibrin, myxoid intimal thickening.
Pathophysiology of recurrence of TMA
CFH is the main inhibitor of the AP ,it can act in fluid phase and on cell surface and it is a cofactor for CFI.
Other membrane regulators which inhibit MAC formation include MCP/CD46, CR1/CD35, DAF/CD55 and Protectin (CD59) ,any disruption in them can lead to complement activation.
TMA classification
vPrimary hereditary TMA:
with mutations in
ADAMTS13,
MMACHC (cb1c deficiency),
complement encoding genes.
vPrimary acquired TMA:
autoantibodies to
ADAMTS13
Or CFH
vInfection-associated TMA
As Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) and pneumococcal HUS.
vSecondary TMA
Involving
Drug-induced TMA,
De novo TMA after SOT.
Pregnancy-associated TMA (HELLP).
Malignancy-associated TMA.
TMA with severe HT.
TMA with glomerular diseases
TMA with autoimmune diseases
TMA after bone marrow transplantation
The mechanism is mostly multifactorial or unknown.
Role of diacylglycerol kinase-ε (DGKE) mutations
Those cases unlike other aHUS cases they donot reveal complement overactivity.
Homozygous mutations in the gene encoding for DGKε and DGKεassociated nephropathy have been detected.
It is associated with AKI, thrombocytopenia and hemolytic anemia.
Anti-HLA antibodies, viral infection, ischemia-reperfusion injury and immunosuppressive medications either each one solely or together can predispose to aHUS recurrence.
Cases with underlying complement abnormality needs a predisposing factor so that aHUS can manifest.
There is dissociation between the pathological entities and the clinical picture.
aHUS have extrarenal manifestations as digital gangrene and cerebral artery thrombosis, MI and others.
Laboratory diagnosis
ADAMTS13 activity assessment is needed to exclude TTP .
TTP is less common in children so Eculizumab can be initiated before ADAMTS results are released.
STEC-HUS and complement-mediated aHUS symptoms can overlap.
Complement need to be evaluated in a HUS
C3 is low in 30% of aHUS patients, CD46 surface
Expression need to be evaluated by flow cytometry.
Genetic testing panel
CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE should be at least included .
Genetic mapping enables proper diagnosis
and therapeutic plans, and helps in genetic counselling specially in living related-donors as donor need to be free from these factors.
Genetic screening rationale
– Disease actual cause that enables correct genetic counselling
– Disease management plan
– Evaluation of the therapy response
-Defining the prognostic course
Genetic variants interpretation
Include either benign, likely benign, variant of uncertain significance, likely pathogenic,pathogenic.
Acquired drivers of aHUS
In pediatrics, CFH autoantibodies assessment need to be confirmed, if positive, on a regular basis. ¼ of patients with anti-CFH-associated HUS are susceptible to relapse.
Diagnosing a HUS recurrence
Clinical history along with tissue biopsy examined by LM, EM, and IF as well as biochemical ,genetic and pathological investigations involving
§ anti-CFH AB estimation
§ MCP screening on the peripheral blood WBCs
§ Recombination in CFHR region assessment
§ Screening of the genetic mutations related to CFH, CFI, CFB, C3, and MCP
Treatment of denovo TMA
It has to be individualised for each patient.
Involving
-immunosuppressive therapy which did not reveal any variation after shifting or dose modulation or stopping or continuation of immunosuppressive therapy. In fact stopping the accused drug must be a mandatory step.
-PE and IVIG
Are used in early denovo TMA treatment.
A study stated 80% graft salvage with PE ,it works by removal of platelet aggregation factors and
replenishment of the deficient factors.
Also in systemic TMA PE acts by removing the mutant complement proteins and supplying normally functioning complement components.
PE removed anti HLA Ab in AMR mediated TMA .
– Belatacept:
CNI-induced TMA can be treated with Belatacept.
-Complement inhibition : Eculizumab, it inhibits the C5b-9 membrane attack complex .
It is effective in the treatment and prevention of a HUS.
Chua et al detected C4d renal deposition in all histologically registered cases with post-transplantation TMA.
Eculizumab proved efficiency in treatment of resistant medication-associated TMA, and those with unrecognized genetic defects as well as cases with refractory AMR with TMA.
Due to variable results and cost wise eculizumab is used for AMR cases with TMA , PE dependent TMA and those with persistent of haemolysis inspite of PE sessions.
Treatment of recurrent TMA
-Minimal list of genetic screening should be done.
-Complement components must be surveyed.
– Donors with isolated MCP associated mutations can be included
-Cases of a HUS without definite genetic mutations can undergo transplantation undercover of PE therapy.
– The polygeneic pattern for aHUS patients need to be carefully manged for living donation .
Prevention of a HUS
–Avoiding Complement activation due to endothelial injury as during ischemia reperfusion injury.
-CNI and m TOR impacts on a HUS is debatable.
-PE cannot be the only treatment for a HUS recurrence because it failed to prevent the recurrence.
The prophylactic use of rituximab in addition to PE lead to acceptable outcomes.
– Eculizumab was used to prevent aHUS recurrence in patients with CFH, CFH/CFHR1 hybrid genes as well as with C3 gene mutations .
Complement blockade usage as prophylactic agent has no sufficient evidence.
Treatment protocols for a HUS recurrence
Include using the lowest dose of complement blockade and having a dose withdrawal scheme ,meanwhile evidence is also lacking for such protocols.
-Anti-cellular therapy is adviced for FH autoantibody-driven aHUS with close Ab monitoring.
-There are no enough data on a HUS duration of therapy.
Kidney transplantation without eculizumab prophylaxis was reported to be successful in 4 high risk cases of a HUS ,indicating the possibility of transplantation for those cases with minimizing cold
ischemic time, decreasing the risk of rejection and,
thereby, providing endothelial protection.
Treatment of DGKE mutation associated TMA
A study reported the possibility of transplantation for 5 of such cases without recurrence.
Renal transplantation
Should be delayed for 6 months after starting dialysis because recovery can take several months after eculizumab initiation.
Absence of extrarenal mainfestations can be a sign for suitability for transplant and recurrence risk decides for the use of anticomplement blockade .
Recurrent disease in the recipient; and de novo disease in the donor if he/she is a genetic mutation carrier are the 2 risk factors for donation from a living related.
– Purified products of the deficient genes, and C3 convertase inhibitors are future therapies.
– Anti-C3b blocker, compstatin analog Cp40 and
The anti-C3 convertase monoclonal antibodies are under investigations.
Conclusion
De novo or recurrent TMA effect on allograft longevity is underestimated.
-level of evidence is 5
I like your detailed summary and analysis.
Ajay
SUMMARY
Introduction
Thrombotic microangiopathy is one of the severe post kidney transplant complications with an attendant outcome on patient and graft if prompt diagnosis and treatment is not deployed early. It can be broadly classified into De novo or recurrent TMA with the later been more common having a rate of graft loss of 40% within a year, but they both have different etiopathogenesis.
Precipitating factors for De novo TMA
Etiology of recurrent TMA
Current Classification of TMA
A) primary hereditary TMA
B) primary acquired TMA
C) Infectious associated TMA
D) secondary TMA
Clinical Manifestation
TMA is usually seen within 3-6 weeks post kidney transplant; however, it can be seen at any time also. The symptoms could be localized to the kidney or systemic
Histologic features
Treatment of TMA
A) De novo
B) Recurrent TMA (recommendation for treatment)
Patient with TMA should only be considered for kidney transplantation following disappearance of extrarenal manifestation and resolution of TMA hematological parameters
Conclusion
The negative effect of different types of TMAs on the allograft longevity is huge even despite the discovery of complement inhibitor drug except quick intervention is done before the commencement of tissue damage the outcome will be poor. Although the outcome is better with recurrent TMA if Eculizumab is started on time
Level of evidence is 5
Yes
I like your detailed summary and analysis.
Ajay
INTRODUCTION
*Thrombotic microangiopathy (TMA) is a debilitating
complication of kidney transplantation that is associated
with poor patient and graft outcomes.
*The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis
can be classified into either:
A) De novo TMA :
precipitating factors are:
(1) Antibody mediated rejection (AMR)
(2)Immunosuppressive-associated TMA: Calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi), single or
combined;
(3) Other medications: e.g., anti-vascular
endothelial growth factor inhibitors (anti-VGFI)
(4) Viral infection: e.g., HCV, CMV, BK and parvovirus;
(5) Genetic abnormalities in the complement cascade
(6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation;
(7) Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA)
Clinical manifestations
*Timing: TMA could developed at any time in the post
transplantation course
*classic triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute kidney injury (AKI).
Prognosis of de novo TMA:
*is quite poor for the patient and as well as the allograft
*About one half of the patients loses their graft within the first two years after diagnosis
*patient mortality rate of 50% after three years of diagnosis.
B) RECURRENT TMA AFTER RENAL TRANSPLANTATION
Etiology:
aHUS; thrombotic thrombocytopenic purpura (TTP); and
autoimmune diseases: e.g., scleroderma and systemic
lupus erythematosus, with or without anti-phospholipid
antibody syndrome
Current classification of TMA includes the following
Primary hereditary TMA
Primary acquired TMA
Infection-associated TMA
Secondary TMA
*The most common complement mutation in
aHUS is CFH, with 40% of cases inherited and 25% sporadic
*Environmental triggers: by anti-HLA antibodies,
viral infection, ischemia-reperfusion injury and immunosuppressive medications.
*Once the diagnosis of aHUS is suspected,
-A full detailed clinical history is usually warranted. A proven tissue diagnosis with light microscopy (LM), immunofluorescence (IF) and electron microscopy (EM)
-exclusion of ADAMTS13 activity is urgently mandated to
exclude TTP diagnosis.
In children, TTP is less common; therefore, eculizumab therapy should be instituted early without waiting for the results of ADAMTS13 activity.
-Complement assessment in aHUS
-Panel of genetic testing
-Rationale for genetic screening
-Interpretation of the genetic variants
-Acquired drivers of aHUS
Treatment of de novo TMA
(1) Immunosuppressive medication management
(2) Plasmapheresis
(3) Belatacept
(4) Complement inhibition: Eculizumab
Treatment of recurrent TMA
1) The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3
2) All patients with primary or suspected aHUS, should be surveyed for all complement components and its related proteins
3) Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation;
4) Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy
5) Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation
Prophylaxis against atypical hemolytic uremic syndrome recurrence in allograft based on a risk-assessment strategy
High risk (50-100%):( Previous early recurrence,
Pathogenic mutations1, Gain-of-function mutations)
>>Prophylactic eculizumab Start on the day of transplantation due to potential for severe recurrence and limited
Moderate risk:(No mutation identified, Isolated CFI mutations,Insignificant complement gene mutation)
>>Prophylactic eculizumab or plasma exchange
Low risk(Isolated MCP mutations,Persistently negative FH autoantibodies.)
>> No prophylaxis
Thank you
Thrombotic microangiopathy (TMA) is a debilitating complication of kidney transplantation that is associated with poor patient and graft outcomes. The incidence of post-transplant TMA has been reported to be 5.6 cases per 1000 renal transplant recipients per year with a 50% mortality rate three years after diagnosis,
TMA classification :
(1) De novo TMA, developed for the first time without any evidence of the disease before transplant
(2) Recurrent TMA, native kidneys failed as a result of TMA and it came back in renal transplantation.
DE NOVO TMA: precipitating factors:
(1) Antibody mediated rejection (AMR)
(2) Immunosuppressive-associated TMA: Calcineurin inhibitors
(CNI) or mTOR inhibitors (mTORi), single or combined;
(3) Other medications: e.g., anti-vascular endothelial growth factor inhibitors (anti-VGFI) (4) Viral infection: e.g., HCV, CMV, BK and parvovirus
(5) Genetic abnormalities in the complement cascade
(6) Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation;
(7) Missed diagnosis of TMA in the native kidney as a cause of ESRD .
Which is more prevalent, de novo or recurrent TMA?:
Graft loss rate of 40% is reported in de novo TMA within a couple of years of diagnosis
Etiopathogenesis of de novo TMA:
AMR and medications
Calcineurin-induced TMA
(1) Loss of the normal balance between the vasodilator peptides (e.g., prostaglandin (PG) E2 and prostacyclin (PG12)) and the vasoconstrictor peptides (e.g., thromboxane A2 and endothelin), results in arteriolar vasoconstriction.
(2) CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity
(3) Microparticle production from endothelial cells,
Clinical manifestations:
Timing: TMA could develop at any time in the post transplantation course
The prognosis of posttransplant de novo TMA is quite poor.
Etiology of recurrent TMA
aHUS; thrombotic thrombocytopenic purpura (TTP); and autoimmune diseases: e.g., scleroderma and systemic lupus erythematosus, with or without anti-phospholipid
antibody syndrome[
PATHOPHYSIOLOGY OF TMA RECURRENCE:
(1) Membrane cofactor protein (MCP/CD46);
(2) Complement receptor 1 (CR1/ CD35)
(3) Decay accelerating factor (DAF/CD55).
(4) Protectin (CD59), which prohibits MAC formation
Current classification of TMA includes the following
Primary hereditary TMA: Includes mutations ADAMTS13, MMACHC
Primary acquired TMA: Autoantibodies to ADAMTS13 or to CFH, which occurs with homozygous CFHR3/1 deletion.
Infection-associated TMA: Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) and pneumococcal
Secondary TMA: Presents in a variety of conditions
RECURRENT TMA AFTER RENAL TRANSPLANTATION:
Etiology of recurrent TMA
aHUS; thrombotic thrombocytopenic purpura (TTP); and autoimmune diseases: e.g., scleroderma
Pathology: aHUS is a variety of TMA that represents the tissue response to an ongoing endothelial injury.
PATHOPHYSIOLOGY OF TMA RECURRENCE:
(1) Membrane cofactor protein (MCP/CD46)
(2) Complement receptor 1 (CR1/ CD35)
(3) Decay accelerating factor (DAF/CD55).
(4) Protectin (CD59), which prohibits MAC formation
Current classification of TMA includes the following
Primary hereditary TMA: Includes mutations in ADAMTS13, MMACHC (cb1c deficiency), or in genes encoding complement components.
Primary acquired TMA: Autoantibodies to ADAMTS13 or to CFH, which occurs with homozygous CFHR3/1 deletion.
Infection-associated TMA: Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) and pneumococcal HUS have distinct mechanisms that result in TMA
Secondary TMA: Presents in a variety of conditions, andin many conditions the culprit
mechanisms are usually multifactorial or unknown.
Role of diacylglycerol kinase-ε (DGKE) mutations::
most patients with DGKE mutations exhibit no evidence of complement overactivity.
Environmental triggers:
The process of aHUS recurrence can be triggered by:
1- anti-HLA antibodies
2-viral infection,
3-ischemia-reperfusion injury
4- immunosuppressive medications
Treatment of de novo TMA:
(1) Immunosuppressive medication (CNI.MTOR ).
(2) Plasmapheresis (PE) and intravenous immunoglobulins (IVIG):
Treatment of recurrent TMA
Recommendations for recurrent TMA:
(1) The minimal list of genetic screening should include: CFH, CFI, CFHR,
CFB, MCP and C3.
(2) All patients with primary or suspected aHUS, should be surveyed for all complement
components and its related proteins.
(3) Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation.
(4) Patients with documented aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy[
(5) Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation.
RENAL TRANSPLANTATION
Timing
Renal transplantation should be postponed six months after institution of dialysis, as limited kidney recovery can occur several months after commencing eculizumab
therapy
Risk of kidney donation
Two risks have been reported to be associated with living-related kidney donation:
(1) Recurrent diseasein the recipient;
(2) De novo disease in the donor, if he/she is a genetic mutation carrier.
Future therapy
(1) Purified products of the deficient genes;
(2) C3 convertase inhibitors
CONCLUSION
The impact of TMA, either de novo or recurrent, on allograft longevity is underestimated. The spectrum of the culprit genes implicated in the evolution of TMA is currently expanding.In contrast, the recurrent TMA is much more optimistic if there is timely intervention by complement blockade before permanent damage sets in
LEVEL 5
I like your detailed summary and analysis.
Ajay
V. Thrombotic microangiopathy after renal transplantation- Current insights in de novo and recurrent disease
==================================================================
1- De novo TMA, i.e., developed for the first time without any evidence of the disease before transplant.
2-Recurrent TMA, i.e., native kidneys failed as a result of TMA and it came back in renal transplantation.
-Causes of de novo TMA:-
====================================================================
Clinical manifestations
The systemic form of TMA consists of the classic triad of:
In the active stage, is evidence of endothelial cell injury with platelet aggregation (thrombosis), fibrinoid necrosis and glomerular ischemia.
In the chronic stage, the basement membranes undergo duplication and multilayering with increased matrix layers and vessel wall cells, which ultimately ends in the unique onion skin formation .
====================================================================
Prognosis of de novo TMA:
====================================================================
RECURRENT TMA AFTER RENAL TRANSPLANTATION
Etiology of recurrent TMA
.
.===================================================================
Diagnosis of aHUS recurrence:
====================================================================
HERAPY OF POST-TRANSPLANT TMA
Treatment of de novo TMA
1- Immunosuppressive medication management: the role of immunosuppressive medications (e.g., CNI or mTORi) has been reported in the literature, with a documented better response after switching from one CNI member to another or to an mTORi).
131 September 10, 2018|Volume 8|Issue 5|WJT|http://www.wjgnet.com
agement of de novo TMA. The withdrawal of the offending agent should be the first line in treating de novo TMA, a fundamental step that ultimately results in correction of the hematological profile
2- Plasmapheresis (PE) and intravenous immunoglobulins (IVIG).
3- Belatacept: A promising alternate option that allows withdrawal of the offending drug incriminated in TMA evolution.
4-Complement inhibition: Eculizumab, an anti-C5 agent, blocks the lytic C5b-9 membrane attack complex generation.
====================================================================
Treatment of recurrent TMA
Recommendations for recurrent TMA:
====================================================================
.
Prevention of aHUS: The following strategies are suggested to decrease/prevent aHUS:
====================================================================
Prophylactic complement blockade:
Gene abnor- malities have beenassociated with aHUS recurrence in 80% of patients.
Prophylaxis against atypical hemolytic uremic syndrome recurrence in allograft based on a risk-assessment strategy
1- High risk (50-100%):
=================================================================
Modreate risk
===================================================================
low risk
Isolated MCP mutations
Persistently negative FH autoantibodies
No prophylaxis
====================================================================
RENAL TRANSPLANTATION
Timing
Risk of kidney donation
====================================================================
CONCLUSION
====================================================================
What is the level of evidence provided by this article
the level of evidence is V
I like your detailed summary and analysis.
Ajay
Thrombotic microangiopathy (TMA) in a renal transplant is seen in 5.6 cases per 1000 transplants per year and is associated with poor graft and patient outcomes (50% mortality at 3 years after diagnosis). TMA post-transplant can be either de novo, or recurrent TMA.
De novo TMA: Alternative complement pathway dysregulation can occur due to factors like ABMR, immunosuppressants like CNIs (due to imbalance between vasoconstrictors and vasodilators as well as platelet activation) and mTOR inhibitors (due to antiangiogenc properties), anti-VEGFI, ribavirin, interferon, viral infections like CMV, BKV, HCV, Parvovirus, genetic abnormalities in complement cascade (mutations in CFH, CFI etc.), C3 glomerulopathy phenotypically shifting to atypical HUS, or sometimes due to missed primary etiology of TMA as a cause of ESRD requiring transplant. Prevalence of de novo TMA post-transplant is 3-14% with 40% graft loss at 2 years post-diagnosis.
Timing of TMA development: It can develop anytime post-transplant, although mostly seen in first 3-6 months.
Features: TMA includes localized form (presenting later) or systemic form (including triad of thrombocytopenia, AKI and microangiopathic hemolytic anemia with elevated LDH, reduced hemoglobin and haptoglobin and schistocytes on peripheral blood film. Kidney biopsy will show thrombi in glomeruli, arterioles and arteries with subendothelial flocculent material, mesangiolysis and myocyte necrosis in active lesions. Chronic lesions will show double contours of peripheral capillary walls and onion skin appearance of arteries.
Prognosis of de novo TMA: It is poor with 50% graft loss within 2 years and 50% death at 3 years post-diagnosis.
Recurrent TMA: Causes of recurrent TMA include atypical HUS (due to mutation of CFH, CFI, MCP etc.), TTP (lack of ADAMTS13), autoimmune disease like scleroderma, SLE with or without antiphospholipid antibody (APLA) syndrome.
Classification of TMA: Primary hereditary TMA (mutations in ADAMTS13, cb1c deficiency, genes encoding complement components), Primary acquired TMA (autoantibodies to ADAMTS13 or CFH), Infection-associated TMA (STEC-HUS, pneumococcal HUS, HIV etc.), and Secondary TMA (drug-induced, pregnancy-associated, de novo post-transplant, malignancy associated, with severe hypertension, with glomerular diseases like MPGN, FSGS, IgA nephropathy etc., with autoimmune diseases like SLE, and after bone marrow transplant).
20% of atypical HUS patients have extrarenal manifestations like MI, cerebral artery thrombosis, digital gangrene etc.
Lab investigation: Once a diagnosis is suspected, ADAMTS13 levels should be checked to exclude TTP, complement levels should be done (although inly 30% have reduced C3) and genetic testing panel including CFH, CFI, C3 CFB, THBD, CFHR1, CFHR5 and DGKE should be sent.
Treatment of de novo TMA: It includes
1) Immunosuppression management: withdrawal of offending drug
2) Plasmapheresis and IVIG: helpful in salvaging graft.
3) Belatacept: used in place of the offending agent
4) Complement inhibition – Eculizumab: First line of therapy for atypical HUS. Useful in ABMR associated TMA, patients who are plasmapheresis dependent and in whom hemolysis persist despite maximum dose of plasmapheresis therapy.
Prevention of recurrent TMA: Genetic screening should be done and complement components and related proteins should be assessed.
Low risk: Isolated MCP mutations and persistently negative FH autoantibodies: No prophylaxis required.
Moderate risk: Isolated CFI mutations or insignificant complement gene mutations: Prophylactic eculizumab or plasma exchange.
High risk: Previous early recurrence, pathogenic mutations and gain of function mutations: Prophylactic eculizumab to be started on the day of transplant.
In a scenario with atypical HUS diagnosis, Plasmapheresis alone is not successful. Eculizumab has been useful in patients with CFH, CFH/CFHR1 hybrid genes as well as C3 gene mutation. Rituximab has been as useful as anti-CFH-antibodies. Simultaneous start of anticellular therapy in form of cyclophosphamide, MMF or rituximab is required and eculizumab will continue indefinitely with monthly or quarterly monitoring of FH autoantibody levels. The anticellular therapy can be discontinued once antibody titres fall below pathogenic threshold for 6 months at least.
Cessation of complement inhibitors depends on case-by-case basis: After at least 3 months of stabilization of renal function, at 3 months in children with pathogenic variants in MCP and having rapid remission, and after 4-6 months in patients on dialysis.
Kidney transplant in recurrent atypical HUS without eculizumab has been done by minimizing cold ischemia time.
Timing of renal transplant: Wait for minimum 6 months after dialysis initiation, and only in absence of extrarenal manifestations including hematological abnormalities.
Risk of kidney donation is in form of recurrence in the recipient and de novo disease in the donor. Donor with alternative pathway dysregulation should be excluded. Liver transplantation can be performed in patients with liver-derived complement protein abnormalities.
C3 invertase inhibitors, purified products of deficient genes, anti-C3b blockers compstatin analog Cp40, and anti-C3 convertase monoclonal antibodies are being investigated for future use.
2. What is the level of evidence provided by this article?
Level of evidence: level 5 – Narrative review
I like your detailed summary and analysis.
Ajay
Summary
This study is about thrombotic microangiopathy post kidney transplant, both de novo and recurrent disease.
De novo TMA is developed for the first time without any evidence of the disease before transplant. On the other hand, recurrent TMA is related to genetics with mutation errors having different impact on how the disease progresses
De novo TMA is more common with worse prognosis compared to recurrent disease. Recurrent disease is usually related with genetic makeup.
Causes include AMR and medications.
Clinical features include a triad of thrombocytopenia. microangiopathic hemolytic anemia, and acute kidney injury.
Recurrent TMA has etiologies such as aHUS, TTP, scleroderma and SLE with or without anti-phospholipid antibody syndrome.
Management involves
Recommended approach pre transplant :
Level of evidence
This is a narrative review and hence level of evidence is 5.
Incidence: 5.6 cases per 1000 renal transplant recipients per year
with a 50% mortality rate three years after diagnosis.
TMA after transplantation can be classified into either:
(1) De novo TMA— developed for the first time without any evidence of the disease
before transplant; and
(2) Recurrent TMA– native kidneys failed as a result of TMA and it came back in
renal transplantation.
de novo TMA is more prevalent after kidney transplantation
Graft loss rate of 40% is reported in de novo TMA within a couple of years of diagnosis
DE NOVO TMA
Causes:
Clinical manifestations
Prognosis:
RECURRENT TMA
Causes:
aHUS:
Incidence of recurrence: as high as 60%.
Untreated patients– graft loss at a rate of 90%,
80% of them occurring in the first year
Genetic or acquired lack of ADAMTS13 has been recognized.
Diagnosis:
Diagnosis of aHUS recurrence:
Management
De novo TMA
Re current TMA
Prophylaxis against atypical hemolytic uremic syndrome recurrence in allograft based on a risk-assessment strategy
Previous early recurrence.
Pathogenic mutations
Gain-of-function mutations
Prophylactic eculizumab
Start on the day of transplantation due to potential for severe recurrence and limited
No mutation identified
Isolated CFI mutations
Insignificant complement gene mutation
Prophylactic eculizumab or plasma exchange
Isolated MCP mutations
Persistently negative FH autoantibodies.
No prophylaxis
RENAL TRANSPLANTATION
Postponed six months after institution of dialysis– as limited kidney recovery can occur several months after commencing eculizumab therapy
Disappearance of the extrarenal manifestations as well as resolution of TMA hematological parameters are the prerequisite for kidney transplantation.
(1) Recurrent disease in the recipient
(2) De novo disease in the donor, if he/she is a genetic mutation carrier
Dear Dr Patil,
I like your detailed summary and analysis.
Ajay
Thrombotic microangiopathy (TMA) is characterized by
May be renal limited or associated with other systemic manifestations (20%) including digital gangrene, cerebral artery thrombosis, MI, ocular, GIT, pulmonary and neurologic involvement
May be recurrent or denovo
Incidence
Causes of TMA occurring in adult including renal transplant recipient
Complement medicated TMA
Drug -induced TMA (CNI, mTOR inhibitor)
AMR-associated TMA
Types of TMA
1- Recurrent disease
2- Denovo TMA
3- Recurrent TMA misdiagnosed as denovo
Management
A- In patient of recurrent TMA
B- In patients with denovo TMA
So … All patients with denovo TMA should be evaluated for genetic mutations, and all possible reversible causes should be treated till having the result of genetic testing, if genetic mutation found or if patient has progressive disease despite correcting suspected etiology, eculizumab should be started
Cessation of eculizumab therapy
Prevention of recurrent TMA:
Prognosis
What is the level of evidence provided by this article?
Dear Dr Yusuf,
I like your summary and analysis.
Ajay
Please summarise this article
INTRODUCTION
The incidence of post-transplant TMA is 5.6 cases per recipients per year with a 50% mortality rate three years after diagnosis
It is classified to de novo and recurrent TMA. To differentiate between the two, we must know the cause of ESRD
The aim of the study: discuss the pathophysiology, clinical course and available approaches of prevention and treatment in the two groups
DE NOVO TMA
Acquired or genetic dysregulation of the alternative complement pathway:
1. AMR
2. Immunosuppressive-associated (CNI or mTORi, single or combined
3. Other medications (anti-VGFI)
4. Viral infection (HCV, CMV, BK and parvovirus)
5. Genetic abnormalities in the complement cascade
6. Phenotypical shift of C3 glomerulopathy (with ESRD), to an aHUS post transplantation
7. Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e., recurrent TMA)
De novo TMA is more prevalent than the recurrent (graft loss rate of 40%)
Calcineurin-induced TMA mechanisms:
1. Loss of the normal balance between the vasodilator peptides and the vasoconstrictor peptides results in arteriolar vasoconstriction, renal ischemia and endothelial injury
2. CNI-induced platelet activation, pro-coagulant and anti-fibrinolytic activity
3. Microparticle production from endothelial cells
AMR-associated de novo TMA the peritubular capillary C4d staining is present in 16.2% of biopsied recipients with TMA
Complement gene mutations C4d deposits in more than 88% and C4d with localized C5b-9 in about 60% of 42 biopsy samples from patients with histologically confirmed diagnosis of TMA
Clinical manifestations any time posttransplant but mostly in the first 3-6 months (relatively high trough levels of CNI). Localized (limited) or systemic TMA. Triad of thrombocytopenia, MAHA and AKI
Consider TMA or RAS when there is significant renal dysfunction and the biopsy does not show any acute rejection
Prognosis of de novo TMA quite poor (patient and graft). 50% of loses their graft within the first two years after diagnosis
RECURRENT TMA AFTER RENAL TRANSPLANTATION
Etiology of recurrent TMA
aHUS, TTP, and autoimmune diseases( e.g., scleroderma SLE, with or without anti-phospholipid antibody syndrome)
aHUS
The most common diagnosis in TMA associated with recurrence. Overactivation of the AP
Risk of recurrence is dependent on the underlying associated abnormality (mutational abnormality)
Diacylglycerol kinase-ε (DGKE) mutations may play a role in the pathophysiology of aHUS
Extrarenal manifestations (20%) includes digital gangrene, cerebral artery thrombosis, myocardial infarction, and ocular, GIT, pulmonary and neurologic involvement
Diagnosis of recurrence: detailed history and tissue diagnosis (LM, IF, and EM). Then estimation of the anti-CFH AB, MCP screening on the peripheral blood WBCs, examination of the recombination in CFHR region, and screening of the genetic mutations related to CFH, CFI, CFB, C3, and MCP.
TTP
Genetic or acquired lack of ADAMTS13. Serology of ADAMTS13 activity is now feasible
THERAPY OF POST-TRANSPLANT TMA
Treatment of de novo TMA
1. Immuno- suppressive medication management
2. Plasmapheresis and IVIG
3. Belatacept
4. Complement inhibition: Eculizumab, an anti-C5 agent, blocks the lytic C5b-9 membrane attack complex generation
Treatment of recurrent TMA
1. genetic screening (CFH, CFI, CFHR, CFB, MCP and C3)
2. survey for all complement components and its related proteins
3. Patients with isolated MCP associated mutations (not combined with other mutations) may be safe for kidney donation
4. aHUS and with lack of definite genetic mutations can proceed in renal transplantation under the umbrella of intensive plasma exchange therapy
5. Polygenic pattern for aHUS patients should be handled with extreme caution in case of living donation
RENAL TRANSPLANTATION
Timing 6 months after institution of dialysis
Risk of kidney donation risks associated with living-related kidney donation are recurrent disease in the recipient and de novo disease in the donor (if genetic mutation carrier)
Future therapy purified products of the deficient genes and C3 convertase inhibitors
Research targets anti-C3b blocker (compstatin analog and anti-C3 convertase monoclonal antibodies
CONCLUSION
The impact of both de novo and recurrent TMA is underestimated
Timely intervention by complement blockade before permanent damage in recurrent TMA is much more optimistic
Targeting genetic mutation management and the advent of early predictors of TMA recurrence are warranted
What is the level of evidence provided by this article?
Level 5 (narrative study)
Dear Dr Muhamed,
I like your summary and analysis.
Ajay
1. Please summarise this article
Introduction
Incidence of PKTX TMA: 5.6 cases/ 1000 KTX recipients/year
Mortality rate 3 years after diagnosis: 50%
Classification:
De novo TMA
Recurrent TMA
Differentiating these types has clinical implications.
Eculizumab (anti C5 monoclonal Ab) is highly effective in prevention & treatment of aHUS.
De novo TMA more prevalent after KTX.
Graft loss rate (2-years) in de novo TMA 40%.
DE NOVO TMA
Precipitating factors:
1. AMR
2. IS-associated TMA: CNI or mTORi
3. Medications: e.g., anti-VGFI
4. Viral infection: e.g., HCV, CMV, BK & parvovirus
5. Genetic complement system abnormalities
6. Phenotypical shift of C3 glomerulopathy (ESRD), to aHUS post-TX
7. Missed diagnosis of TMA in the native kidney as a cause of ESRD (i.e.,recurrent TMA)
CNI-induced TMA:
Mechanisms:
1. Imbalance between the vasodilator & vaso-constrictor peptides.
2. CNI-induced platelet activation, pro-coagulant & anti-fibrinolytic activity
3. Micro-particle produced by endothelial cells (an effect of CyA).
Arguments against the role of CNI:
1. Although >90% of KTX patients take CNI only
a small % develop.
2. CNI withdrawal in de novo TMA does not guarantee a favorable graft outcome
3. Higher incidence of TMA in KTX recipients not under CNI versus those on CNI maintenance (USRDS based study).
Clinical manifestations
Timing: mostly occur in the 1st3-6 mo post-TX.
Features:
A triad of thrombocytopenia, MAHA (raised LDH, drop in Hb, low haptoglobin, & schistocytes on PBP) & AKI.
Localized (limited) TMA: presents later compared to the systemic form.
In the context of significant graft dysfunction with biopsy showing no AR, one should consider RAS or TMA.
In the absence of renal biopsy, many cases can be misdiagnosed as hypertensive nephrosclerosis.
Genetic mutations should be done to avoid missing the diagnosis of a recurrent aHUS.
Prognosis:
Quite poor for both the patient & the allograft.
A 50% graft loss in 1st2 years (USRDS-based report).
Recurrent TMA after renal transplantation
Etiology:
1. aHUS
2. TTP
3. Autoimmune diseases: e.g., scleroderma & SLE (+/-anti-phospholipid antibody syndrome).
aHUS:
It is the most common cause of recurrent TMA. Higher recurrence rate (70%-90%) with mutations involving CFH & CFI.
Lower recurrence rate associated with Membrane co-factor protein (MCP) mutations.
Without treatment patients with aHUS lose their grafts.
TTP:
Is the 2ndknown cause of TMA.
There is genetic or acquired lack of ADAMTS13.
Differentiation between TTP & HUS:
Presence of neurologic features TTP & renal dysfunction in HUS.
Serology of ADAMTS13 activity.
Overlap between both exists.
Pathology:
aHUS is a variety of TMA that represents the tissue response to endothelial injury.
Thrombotic features (fibrin/platelet plugging) are not always seen in graft biopsy.
Non-thrombotic features: denuded & swollen endothelium, mesangiolysis, GBM double contour, & electro-lucent material deposit in the sub-endothelium.
Pathophysiology of TMA recurrence
CFH is the main inhibitor of the AP.
CFH works in both fluid phase & on cell surfaces.
CFH act as a co-factor to CFI.
Regulatory factors on cell surfaces (“membrane regulators”) include:
1. MCP/CD46
2. Complement receptor 1 (CR1/ CD35)
3. Decay accelerating factor (DAF/CD55)
4. Protectin (CD59).
Current classification of TMA:
Primary hereditary TMA: mutations in ADAMTS13
, MMACHC (cb1c deficiency), or in genes encoding complement components.
Primary acquired TMA: Auto-antibodies to ADAMTS13 or to CFH.
Infection-associated TMA: STEC-HUS & pneumococcal HUS.
Secondary TMA: e.g., pregnancy-associated TMA or de novo TMA after transplantation.
Clinical assessment of aHUS:
aHUS refers to any HUS that is not due to STEC-HUS. “primary HUS” is used when there is underlying abnormality in the AP; however, a trigger factor (infection, surgery, medications, pregnancy) is usually needed.
Extra-renal manifestation (in 20%):
Digital gangrene
Cerebral artery thrombosis
Myocardial infarction
Ocular, GIT, pulmonary & neurologic involvement
Acute versus chronic lesion?
Penetrance in aHUS is age-related; 64% by age 70.
This late presentation of reflects the effect of the
environmental triggers.
Laboratory investigations:
1. Complement assessment in aHUS:
C3 is low in only 30% of aHUS.
CD46 surface expression assessed by flow cytometry.
2. Panel of genetic testing:
CFH, CFI, C3, CFB, THBD, CFHR1, CFHR5 & DGKE.
3. Rationale for genetic screening:
-Determination of the actual cause of the disease that allows for correct genetic counseling
-Planning for disease management
-Prediction of response for therapy
-Defining prognosis
Interpretation of the genetic variants
1. Benign
2. Likely benign
3. Variant of uncertain significance
4. Likely pathogenic
5. Pathogenic, according to the international guidelines.
Genetic classification affects therapeutic plans, response to therapy, & chance for aHUS recurrence.
Diagnosis of aHUS recurrence:
1. Tissue diagnosis with LM), IF, & EM is required.
2. Estimation of the anti-CFH AB
3. MCP screening on the peripheral blood WBCs
4. Examination of the recombination in CFHR region
5. Screening of the genetic mutations related to CFH, CFI, CFB, C3, & MCP.
Treatment of de novo TMA
1. IS medication management: e.g., switching from one CNI to another or to an mTORi.
2. PE & IVIG: used early in treating de novo TMA patients.
3. Belatacept: an immunosuppressive co-stimulatory blocker against CD80 & CD86 surface ligands & CD28 on T cells.
4. Complement inhibition: Eculizumab (anti-C5 agent), blocks the lytic C5b-9 MAC generation. Its use should be confined to:
-AMR-associated TMA
-Patients who became PE-dependent
-Refractory hemolysis persists despite maximum doses of PE therapy.
Treatment of recurrent TMA
1. The minimal list of genetic screening should include: CFH, CFI, CFHR, CFB, MCP and C3
2. All patients with primary or suspected aHUS, should be surveyed for all complement components
3. Patients with isolated MCP associated mutations may be safe for kidney donation
4. Patients with documented aHUS & with lack of definite genetic mutations can proceed in KTX under intensive PE therapy
5. Polygenic pattern for aHUS patients should be handled with extreme caution in LKD.
Prevention of aHUS:
1. Avoidance of inciting events ( e.g., IRI, viral infection & IS medications)
2. Substitution of CNI by mTOR is not innocent & can induce recurrence.
3. PE failed to prevent aHUS recurrence in many cases; it cannot guarantee prevention of aHUS recurrence after cessation of therapy.
4. Eculizumab has been used successfully to prevent aHUS recurrence in patients with CFH, CFH/CFHR1 hybrid genes as well as with C3 gene mutations.
Renal transplantation
Timing
1. Should be delayed 6 months after start of dialysis ( limited kidney recovery may can occur months after eculizumab therapy).
2. Extrarenal & hematological disease should disappear before TX.
Risk of kidney donation
1. Recurrent disease in the recipient
2. De novo disease in the donor (in genetic mutation carriers).
3. Those exhibiting alternative pathway dysregulation should be excluded.
Future therapy
1. Purified products of the deficient genes
2. C3 convertase inhibitors.
3. Research targets:
-The anti-C3b blocker, compstatin analog Cp40
-The anti-C3 convertase monoclonal antibodies.
CONCLUSION
The effect of TMA on graft survival is under-estimated.
Despite the advent of complement blockade therapy, the prognosis remains poor if the diagnosis is delayed.
The recurrent TMA is much more better with timely use of complement blockade before permanent damage occurs.
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What is the level of evidence provided by this article?
Level V
Dear Dr Muhamed,
I like your summary and analysis.
Ajay