5. A 66-year-old CKD 5 received a kidney transplant from his wife, 202 mismatch on tacrolimus based triple immunosuppression. His S Cr went down to 121 µmol/L, started to go up during the same hospital admission to 231 µmol/L. His blood picture showed anaemia and thrombocytopenia. His liver function test showed raised bilirubin. Urgent blood film and kidney biopsy are shown below:
- What is your diagnosis
- What is your management plan?
the blood film shows shistocytes which present with microangipathic haemlytic anaemia
renal biopsy suggesting TMA
TMA may occur de novo , often triggered by immunosupressive drugs (Tacrolimus)
and acute antibody-mediated rejection
or recur in patients with previous history of haemolytic uraemic syndrome
De novo TMA management
Recurrent HUS
by complement blockade therapy ( Eculizumab)
1What is your diagnosis?
TMA.
2)What is your management plan?
Admit isolation ward.
Investigation : Hemolytic markers. Check for CNI level, C4d stain in allograft biopsy, plasma ADAMTS 13 level, DSA, Complement c3 c4, plasma CMV BKV PCR. Urine culture and microscopy.
Dose reduction of tacrolimus.
Antimicrobial treatment if evidence of infection.
IV steroid if evidence of graft rejection and infection has been rule out.
HUS consider plasma exchange
peripheral blood smear shows fragmented RBCs & helmet cells suggestive for microangiopathic hemolytic anemia. Kidney biopsy show fibrin thrombi, indicating thrombotic microangiopathy and these two together show some kind of HUS/TTP.
differential diagnosis :
So, monitor Tac level, DSA, C4d staining of biopsy, C3,C4, CH50, ANA, anti ds-DNA, Factor H, I, ADAMTs-13 level and activity
Manage it according to cause:
this patient mostly has TMA
the first image shows fragmented red blood clells.
the biopsy on the other image shows fibrin thrombosis,
full labs including : drug levels, complement, C4d staining, DSA
start plasma pharesis sessions + IV immunoglobulin
use ATG, MMF till lab results obtained.
diagnosis:
blood film shows shizocytes (fragmented RBCs)
kidney biopsy shows: glomeruli with microthrombi and tubulitis? vacuolation
systemic involvement with high bilirubin,,,, cr increased
all point to TMA
most likely systemic which can be due to genetic mutation or antibodies against the complement, but before this, we need to exclude secondary causes such as:
1- CNI toxicity
2- AMR
2- infection CMV, BK
3- malignant hypertension
so, we need to request CNI trough level, PCR for viral infection, DSA Titre, C4d staining,
4- Good history about the cause of ESRD
according to the cause, but while investigation results bending,
we can decrease the Tac if its level is high or change to CsA. may even hold it for while.
treat the infection
treat AMR if provide
Start plasma exchange
Eculizumab if no improvement after direct therapy
What is your diagnosis?
A case of TMA.
What’s your management plan?
What is your Diagnosis?
In this clinical scenario we can see clearly a picture of TMA.
Anemia+low platelets+high bilirubin
Blood film: fragmented RBCs, schistocytes.
Renal Biopsy: Fibrin thrombi in the glomerulus.
DD of TMA post renal transplantation: Recurrent and Denovo
Recurrent: Complement mediated diseases as in a-HUS
Denovo: Drug related as with CNI and m-TOR inhibitors, ischaemia reperfusion injury, ABMR, infections (CMV, BK, HIV), anti-phospholipid syndrome.
Management plan:
Investigations: CNI trough level, C3, C4, CH 50, ADAMTS-13, blood film, DSA
C4d staining of kidney biopsy
ABMR—à Plasma-exchange, IVIG, ATG, +/- rituximab, heavy immunosuppression.
a-HUS—à Plasma exchange, Eculizumab
TTP–à Plasma exchange+
CNI induced TMA: reduce the dose and adjust it therapeutic level, monitor for other drugs interaction, another strategy is to switch to another CNI (Tacrolimus-à Cyclosporin) or switch to m-TOR inhitors (Sirolimus).
Infections: treat accordingly
Q1- Post transplant thrombotic microangiopathy.
Q2- treatment of the cause, consider infection, immunosupressive drugs, AMR or recurrence.
Plasma exchange should be done
What is your diagnosis?
TMA ( thrombotic microangiopathy) due to full picture which includes, anemia , low platelet , high bilirubin in the blood indicates hemolysis , peripheral blood smear showed shistocytes cells , biopsy showed microthrombi .
1- What is your diagnosis
Post transplant thrombotic micrangiopathy .
– R B- shows microthrombi
– Blood film – fragmented RBC .
– Elevated liver enzyme ,thrombocytopenia , anemia (microangiopathic hemolytic anemia )
All these pictures goes whith the diagnosis of TMA.
What is your management plan?
1ST to keep in mind the causes of TMA .
PRIMARY CAUSES
A- TTP due to deficiency of ADAMTS 13 enzyme > 10% .
B- HUS due to shiga toxin producing E coli .
C- Atypical HUS due to hereditary complement factor deficiency .
SECONDARY CAUSES
A- DRUGS ( CNI , MTOR , ANTI MALIGNANCY – GEGF inhibitor ,….)
B- ABMR
C- Infection ( CMV ,BK ,HIV …)
D- MALIGNANCY
E- TRANSPLANTATION ( KIDNEY — ISCHEMIA REPERFUSION )
F- SLE
G- VASCULTIS
PLAN
1- Adequate history and family history . hereditary complement deficiency .
If suggestive to send for genetic study for complement componenet .
Eucluzomzb may be good treatment choice .
2- Exclude drug induced TMA
If this patient receiving ATG as induction , I can stop tacrolimus temporarily depending on ATG and MMF and steroid for immune suppression .
If it is not possible to stop CNI I can convert tarolimus to cyclosporine ( although this approach may be beneficial ,keep in mind that cyclosporine by itself can cause TMA .
3- Exclude ABMR
Especially in highly sensitized patient ( high risk patient ). This may need biopsy details about signs of ABMR plus DSA status.
4- Searching for other causes and treating accordingly .
5- TTP can be treated with plasma exchange with FFP.
GENERALLY TMA has poor graft prognosis .
The peripheral blood film reveals schistocytes along with anemia and thrombocytopenia. The bilirubin and liver enzymes are also high, all suggesting hemolysis.
This picture is highly suggestive of thrombotic microangiopathy
The cause may be de novo or recurrent.
De novo TMA due to:
– AMR.
-Immunosuppression ( CNI or mTOR).
-Viral infections: HCV , CMV , BK or Parovirus.
-Genetic abnormalities.
Recurrent TMA :
HUS or TTP.
Management plan :
Hospital admission .
full history and examination
history of primary diseases .
trying to avoid blood transfusion , platelet transfusion except of severe anemia and in case of bleeding
Hemodialysis if indicated
-Lab : drugs level , DSA level , Screening for ADAMAT 13 and C4d stain and viral serology .
-Immunological and genetic screening.
Then treatment:
-in case of drug toxicity (stop drug and then shift to cyclosporine).
In case of AMR (plasma exchange with IVIG and Rituximab ).
In case of aHUS and TTP (plasma exchange and Eculizumab ).
In case of infections like CMV (Valgancyclovir).
Most probably a case of posttransplant thrombotic microangiopathy(PT-TMA) with hemolytic anemia, thrombocytopenia, and renal failure; systemic form.
PT-TMA could be caused by recurrence of atypical hemolytic uremic syndrome or de novo thrombotic microangiopathy (more common), Complement overactivity is essential in all post-transplant thrombotic microangiopathies.
*Causes of de novo TMA include ischemia-reperfusion injury, immunosuppressive drugs like CNIs, mTOR inhibitors, of acute antibody mediated rejection, viral infections, and post-transplant relapse of antiphospholipid antibody syndrome
Lab work up include among othsers,:C4d staining DSA level, viral serology, complement levels ..
Treatment of underlying cause: plasma exchange to correct hematologic abnormalities . Eculizumab is effective in treatment of post-transplant TMA.
Dose reduction or stopping the offending medicine, switching to another CNI or to an m TORi.
Plasmapheresis with IV IG and intensification of immunosuppression for ABMR.
Diagnosis:
In view of presence of Micro Angiopathic Haemolytic Anaemia picture in the peripheral smear ( Crenated RBC, Schistocytes and Nucleated RBC), Microthrombi in the glomerular capillary loops in conjunction with Thrombocytopenia and elevated Bilirubin, Haemolytic Uremic Syndrome (HUS) is the most probable Diagnosis.
Rationale for Workup & Probable causes of HUS:
Management Plan:
1. Fragmented RBCs (shistocytes) with anemia and thrombocytopenia with high bilirubin a picture suggestive of Thrombotic microangiopathy
Causes may be
AMR , drug induced , infections , atypical HUS , TTP
2 . Proper supportive management with managment of TMA
If the causd is high CNI level modify the dose
If AMR plasma exchange or IVIG
IF ttp plasma exchange
Atypical HUS Eculizumab if available
And treatment of infections if present
fragmented RBCs are compatible with TMA. also thrombi in the glomerulus is presented. here we need to stop the offending agent (Tacrolimus). this may be enough in this case, plus hydration and conservative treatment. Eculizumab is used in the case of aHUS.
My diagnosis : Thrombotic microangiopathy :
Denovo / recurrent atypical HUS
denovo :
DITMA
INFECTIONS -CMV BKV HCV HIV H1N1
ABMR
management plan :
denovo : discontinue or reduction of offending agent
CNI switch or to MTORi
Belatacept
Plasmapharesis
IVIG
Eculizumab
My diagnosis is TMA.
It is either denovo tma-1.abmr
2.cmv,bkv,hcv infection
3.drug induced cni/mtori
Or Recurrent TMA.
Treatment-therapeutic plasma exchange and eculizumab
diagnosis going with thrombotic microangiopathy ( TMA ) as peripheral blood film shows schistocytes patient has picture of anemia thrombocytopenia high bilirubin level all suggest hemolysis.
management plan?
good hydration electrolyte imbalance ttt
treatment according to the cause:
early post transx TMA mostly to cni toxicity so drug level should be done plus reduction or stoppage of the drug and change to cyclosporine
ABMR TREATED WITH PLASMAPHARESIS PLUS IVIG .
HUS : Eculizumab
Findings of MAHA +thrombocytopenia +AKI + capillary clots in kidney biopsy makes the Dx of TMA which is either a recurring event (aHUS) or a de novo one .
de novo type can occur due to :
Management : besides supportive measures, RRT – hemodialysis might be considered. , if ABMR is proved then Plasma exchange + IVIG and eventually eculizumab might be considered in resistant cases or who become plasma exchange dependant .
switch Cyc A to Tac or change to mTor inhibitor
1.Diagnosis: The diagnosis in this case Thrombotic microangiopathy
There is anemia with thrombocytopenia, peripheral smear shows schistocytes and other fragmented RBC. Renal biopsy shows fibrin thrombi in the capillary loops making this diagnosis very clear. The reason for TMA has to be elucidated
History of native kidney disease – important to know the basic kidney disease if it is an atypical HUS due to alternate complement pathway deficiency.
We need to know the sensitizing events in the recipient like any blood transfusion during HD or plasma infusions, any previous surgeries as these could elicit Donor specific antibodies which could cause AMR and present as TMA
Tacrolimus level are needed to know if there is toxicity. As CNI toxicity is the most common cause of TMA in the post transplant period. CNI toxicity is reported with isolated TMA involving the graft with no signs of systemic TMA. It has also been reported with normal levels of TMA. TMA is known to get precipitated with concomitant use of mTOR inhibitors and Tacrolimus.
I would also like to know if there is delayed graft function, cold ischemia time and total ischemia time as complement activation can happen with episodes of IRI.
Management:
Supportive treatment: Correct IV hydration, correct severe anemia with transfusion; avoid platelet transfusion unless patient is bleeding. I would like to ask for C3 level, c4d staining on kidney biopsy, Complement Factor H and Factor D level, ADAMST13 level if feasible. I would repeat DSA to make sure that we are not missing an AMR that is lingering around. Although CMV and parvo virus, EBV are rare in the immediate post transplant setting I would keep them at the back of my mind and investigate them if needed.
I would like to hold tacrolimus. Escalate the dose of antimetabolite and steroid in this patient. I would do 3 to 4 sessions for plasma exchange if the diagnosis is due to CNI toxicity and wait for response. If the DSA or the C4d is positive I would treat him as acute AMR with plasmapheresis , IVIG and Rituximab. He needs close monitoring of renal functions and the prognosis of TMA post transplant is poor and is associated with worsening graft function.
The peripheral blood film reveals schistocytes along with anemia and thrombocytopenia. The bilirubin and liver enzymes are also high, all suggesting hemolysis.
This picture is highly suggestive of thrombotic microangiopathy
The cause of TMA in early post-transplant period may be due to: Antibody mediated rejection, Ischemia-reperfusion injury, CNI, mTOR inhibitors, TTP, SLE, CMV.
Drug levels, CMV PCR quantitative, C4d on the biopsy and DSA’S .
Treatment of the cause:
In case of high CNI levels, reduce or stop the drug and shift to cyclosporine.
In case of AMR, Plasmapheresis and IVIG , Mabthera , CMV prophylaxis will be required and intensification of immunosuppression.
In case of infections like CMV Valgancyclovir.
For TTP: plasma exchange
In addition to supportive management, proper hydration, attaining an acceptable drug level
*** 66 y old patient CKD 5 received a kidney transplant from his wife, 202 mismatch on tacrolimus based triple immunosuppression. His S Cr went down to 121 µmol/L, started to go up during the same hospital admission to 231 µmol/L and had anaemia, thrombocytopenia and elevated bilirubin.
Blood film shows fragments RBCS with renal biopsy stained by H and E stain shows one glomerulus filled with fibrin thrombus all these pushed towards diagnosis of TMA .
*** Post-transplant TMA may be de novo or recurrent.
De novo TMA due to:
– AMR.
-Immunosuppression ( CNI or mTOR).
-Viral infections: HCV , CMV , BK or Parovirus.
-Genetic abnormalities.
Recurrent TMA :
HUS or TTP.
Management plan :
>>>Firstly :
– history of primary diseases , purpuric rash .
-Lab : drugs level , DSA level , C4d stain viral serology .
-Immunological and genetic screening.
Then treatment:
-Hydration by intravenous fluids , electrolytes correction , blood transfusions if needed and haemodialysis if indicated.
– trough level of tacrolimus if high stop drug and then shift to cyclosporine.
– AMR : plasma exchange with IVIG and Rituximab.
– aHUS : Eculizumab .
– Screening for ADAMAT 13.
REFERENCES
Miller RB, Burke BA, Schmidt WJ, et al. Recurrence of haemolytic-uraemic syndrome in renal transplants: a single-centre report. Nephrol Dial Transplant 1997; 12:1425.
Zarifian A, Meleg-Smith S, O’donovan R, et al. Cyclosporine-associated thrombotic microangiopathy in renal allografts. Kidney Int 1999; 55:2457.
Ruggenenti P. Post-transplant hemolytic-uremic syndrome. Kidney Int 2002; 62:1093.
Kwon O, Hong SM, Sutton TA, Temm CJ. Preservation of peritubular capillary endothelial integrity and increasing pericytes may be critical to recovery from postischemic acute kidney injury. Am J Physiol Renal Physiol 2008; 295:F351.
Murer L, Zacchello G, Bianchi D, et al. Thrombotic microangiopathy associated with parvovirus B 19 infection after renal transplantation. J Am Soc Nephrol 2000; 11:1132.
Diagnosis:
This patient received renal transplant with HLA mismatch and he is on CNI based immunosuppression. He has Anaemia, Thrombocytopenia and high bilirubin levels. Blood Film shows Schistocytes and fragmented RBCs. Kidney biopsy shows fibrin thrombi on the capillaries lumen. All of these findings is consistent with Post-transplant TMA. Post-transplant TMA results from complement over activation and could be divided to Recurrent TMA or de novo TMA.
De novo TMA can be caused by: (most common)
Recurrent TMA can be caused by:
Management Plan:
Treatment according to underline cause:
The management of TMA
According to the history of the patient of AKI, microangiopathic hemolytic anaemia( fragmented RBC on blood film) & renal biopsy that show endocapillary fibrin thrombi he had systemic TMA.
TMA is a serious disease can threaten the life. It can be classified into primary ( TTP, HUS,& aHUS) or secondary TMA due to infection, malignancy, organ transplantation, pregnancy or autoimmune disease. The differentiation between primary & secondary form is difficult & sometimes it is can’t done.
PT-TMA can be a recurrence of primary disease or de novo which may be caused by:
PT-TMA can be limited to the kidney or systemic form ( AKI+ thrombocytopenia+ microangipathic hemolytic anemia) which can occur in 18-62% of recipients with PT-TMA. Affected recipient had both poor graft outcome( graft loss in 33-40% in 1st 2 years) & poor patient survival.
ABMR should be investigated by DSA & C4d staining of graft biopsy, as well as exclusion of infection is very important in management plan.
Drug induced PT-TMA also can be suspected when there is sudden onset of AKI occur in 1st few days after transplant when the drug level is very high.
The treatment directed according to the underlying cause as explained in the figure below
What is your diagnosis
Thrombotic microangiopathy
causes
primary
compliment mediated
drug induced like CNI
immune related like SLE
infective aetiology like CMV.
What is your management Plan.
Check the tacrolimus levels and tailor accordingly. Those on cyclosporins can be switched to Tacrolimus as TMA is more common with Cyclosporin as compared to tacrolimus.
Perform PCR to rule out any viral infection and if positive will require treatment accordingly.
If CD4 and DSA positive and confirmed ABMR then start plasmaphresis and use IVIG after each session at 100 mg/kg.
If no improvement after correction of a reversible cause then start eculizumab(very expensive)
Anemia + thrombocytopenia + impaired liver function, associated with glomerular deposit kidney injury suggest vascular phenomenon that for this period of transplantation suggests Thrombotic Microangiopathy (TMA)
Need to evaluate etiology:
– acute antibody-mediated rejection: review pre-transplant crossmatch. And if it fails for found option for treatment for acute acute. Plasma cell depletion with the proteasome inhibitor bortezomib and complement inhibition with Eculizumab have been proposed as novel therapeutic strategies.
– TMA again because Tacrolimus is possible. It is necessary to discontinue treatment, replacing it with Sirolimus and associating plasma therapy.
– History of Hemolytic Uremic Syndrome (HUS). Recurrence of the disease is possible and is related to CFH and MCP mutation. Eculizumab was used to treat aHUS recurrence in patients with complement gene abnormality because it blocked hemolysis and improved transplant function.
TMA.
Review history if any family history or personal history of renal failure ,proteinuria.
Assessment of IS trough level.
Screening for virology ,i.e. HCV ,HIV,CMV And parvovirus 19.
DSA
Biopsy rule out AMR.
Complements study.
Doppler USS .
Supportive measures.
FFP infusion. Plus minus plasma exchange if no response or severe.
Belatacept if result negative and drug induced HUS is suspected.
Eculizumab effective in genetic and resistant HUS.
Post-transplant TMA is most probably due to recurrent atypical HUS support by the presence of schistocytes in peripheral blood film & lab evidence of hemolytic anemia & intraluminal capillary thrombosis in renal biopsy on the other hand CNI toxicity, ABMR, &infection need to be ruled out.
1)viral screening – CMV PCR, HIV screening.
2- for C4d, C1q staining of the renal biopsy to rule out ABMR
3- DSA level- ABMR
4- ANA, dsDNA, serum complement levels (Evaluate the possibility of HUS )
5- tacrolimus level.
6)genetic test for complement factor H&I
All patients with complement-mediated TMA due to genetic deficiency or dysfunction of complement factor H or I suggest prophylactic with Eculizumab
Post transplant TMA, most probably de novo related to Tacrolimus
Rising s.creatinine, with new onset/ worsening anemia with thrombocytopenia , peripheral smear examination showing fragmented RBC, Kidney biopsy having evidence of fibrin rich thrombus inside glomerular capillaries. In present picture, interstitium appears to be normal with out any leukocytic infiltration, with some tubular epithelial degenerative changes, doesn,t show evidence of AMR.
-Past history of TMA pre transplant or history of primary kidney disease- to exclude recurrence of TMA, history of LUPUS, APLA has to be excluded
investigation- 1) Tac level
2) PCR for CMV,B.K. VIRUS, parvo virus, HIV,HCV, Covid 19 RT PCR
3) ADAMTS 13 level
4) DSA- LUMINAX
5) COMPLEMENT LEVEL
6) ANA, APLA TITRE, Anti cardiolipin antibody titre
In this patient with suspected Tacrolimus induced de novo TMA, if the tac level is > 15 ng/ml, i would stop tacrolimus now otherwise its dose should be reduced and patient should be monitored with daily urine output, s. creatinine, BUN, haemoglobin, platelet count. If he is improving, to continue same treatment with good hydration. If deterioration ocuurs, need to stop tacrolimus and switch to mTor inhibitor can be considered.
What is your diagnosis
Thrombotic microangiopathy is a significant complication post transplant which can lead to graft failure. This can be do novo often precipitated by immunosuppressive drugs or antibody mediated AMR. It can recur in patients who have history of haemolytic uremic syndrome- HUS. It is characterized by microangiopathic Haemolytic anaemia, thrombocytopenia and renal dysfunction. It can be primary, compliment mediated, drug induced like CNI, immune related like SLE, infective aetiology like CMV.
Here peripheral blood smear shows fragmented RBCs and histology shows Thrombotic microangiopathy.
What is your management Plan.
Check the tacrolimus levels and tailor accordingly. It should not be stopped until there are very high levels. Those on cyclosporins can be switched to Tacrolimus as TMA is more common with Cyclosporin as compared to tacrolimus.
Perform PCR to rule out any viral infection and if positive will require treatment accordingly.
If CD4 and DSA positive and confirmed ABMR then start plasmaphresis and use IVIG after each session at 100 mg/kg.
If DSA and CD4 is negative then stop tacrolimus and start Sirulimus .
If no improvement after correction of a reversible cause then start eculizumab
Recurrent TMA is usually compliment mediated and it is important to check compliment levels. The option here will be eculizumab although it is very costly medication
Rui Zhang et al . Efficacy and Safety of Eculizumab in the Treatment of Transplant-Associated Thrombotic Microangiopathy: A Systematic Review and Meta-Analysis. Front Immunol . 2020; 11: 564647.
Dear All
Also, it is a good practice to check the CNI level in case of any graft dysfunction, but TMA can be caused by CNI at a low level.
Always remember that not only drugs can cause TMA, but also viral infection and rejection.
For recurrent TMA or where the primary disease was TMA, we need to check the complement level.
Ecluzumab is the most expensive drug in transplantation HELPS in this condition, but almost unafforadable.
👍🏽
• What is your diagnosis?
Post-transplant TMA (PT-TMA)
It can occur as de novo disease caused by various pathogenic mechanisms and account for majority of cases or sometimes as recurrence of previous aHUS undiagnosed before transplantation as a consequence of complement system deregulation.
Distinguishing between PT-TMA and aHUS recurrence is difficult clinically and pathologically due to the overlap between them.
Drug induced TMA is suspected when there is sudden onset few days after drug exposure (association between CNI and drug exposure is well documented especially with cyclosporine)
It may occur due to ischemia reperfusion injury which leads to more complement activating events.
• What is your management plan?
Lab. tests done to identify TMA:
Anemia (decreased hematocrit), thrombocytopenia (>25% drop from baseline), Schistocytes in blood film (pathognomonic if present), rising creatinine or absence of improvement post-transplant, proteinuria >300mgdl
To identify the cause:
Drug induced PT-TMA: cyclosporine trough level
Exclude infections: blood PCR for CMV (most commonly involved virus) and BK virus.
Antibody mediated rejection: Luminex for antibodies to HLA class I and II, diagnosis is predominantly confirmed by histological findings
Treatment of de novo PT-TMA:
It depends on correction of potential cause
CMV infection: treatment with IV ganciclovir and plasma exchange to resolve the hemolysis
Drug induced: reduce dose of cyclosporine or switch to Tacrolimus (the effectiveness of this strategy is controversial)
Belatacept allow minimization or discontinuation of CNI, however, a high risk of rejection was observed after conversion to Belatacept
Antibody mediated rejection associated TMA, treatment with plasma exchange with or without IVIG
Plasma exchange has been used but was not associated with improvement of kidney function but improved hematological abnormalities
Eculizumab use is recommended as rescue therapy when hemolysis persist despite maximal management, used in cases resistant to treatment of the cause but very expensive.
Ávila A, Gavela E and Sancho A (2021) Thrombotic Microangiopathy After Kidney Transplantation: An Underdiagnosed and Potentially Reversible Entity. Front. Med. 8:642864.
Bayer G, von Tokarski F, Thoreau B, Bauvois A, Barbet C, Cloarec S, et al. Etiology and outcomes of thrombotic microangiopathies. Clin J Am Soc Nephrol. (2019) 14:557–66.
Avila Bernabeu AI, Cavero Escribano T, Cao Vilarino M. Atypical hemolytic uremic syndrome: new challenges in the complement blockage era. Nephron. (2020) 144:537-49.
Satoskar AA, Pelletier R, Adams P, Nadasdy GM, Brodsky S, Pesavento T, et al. De novo thrombotic microangiopathy in re-nal allograft biopsiesrole of antibody-mediated rejection. Am J Transplant. (2010) 10:1804–11.
Van der Zwan M, Hesselink DA, van den Hoogen MWF, Baan CC. Costimulation blockade in kidney transplant recipients. Drugs. (2020) 80:33–46.
Palma LMP, Sridharan M, Sethi S. Complement in secondarythrombotic microangiopathy. Kidney Int Rep. (2021) 6:11–23.
Al-Nouri ZL, Reese JA, Terrell DR, Vesely SK, George JN. Drug induced thrombotic microangiopathy: a systematic review of published reports. Blood. (2015) 125:616–8.
Loupy A, Lefaucheur C. Antibody-mediated rejection of solid-organ allografts. N Engl J Med. (2018) 379:1150–60.
Portolés J, Huerta A, Arjona E, Gavela E, Agüera M, Jiménez C, et al. Characteristics, management and outcomes of atypical haemolytic uraemic syndrome in kidney transplant patients: a retrospective national study. Clin Kidney J. (2020) 93:1-8.
Cavero T, Rabasco C, López A, Román E, Ávila A, Sevillano A, et al. Eculizumab in secondary atypical haemolytic uraemic syndrome. Nephrol Dial Transplant. (2017) 32:466–74.
Thrombotic Microangiopathy TMA with MAHA and acute kidnet injury, as the blood film is clearly showing schisticytes and fragmented RBC. Post kidney transplant is either recurrent or de novo TMA. Recurrent TMA is usually related to complement mediated disease that produce both pretransplant TMA and the recurrence after transplantation. De novo TMA may be related to any of the etiologies that cause TMA in general population or may be specifically related to transplantation.
Causes of TMA that are soecifically related to transplant recepient s include
1_immunosuppressive drugs CNI(more with Cyclosporin vs Tacrolimus) and mTor inhibitors.
2_Ischemia reperfusion injury.
3_viral infection like CMV, parvovirus B19, Nile fever.Covid 19
4_ABMR.
5_other medication s like valacyclovir.
The diagnosis of TMA should be suspected in any kidney transplant recipient with an elevated serum creatinine especially if its associated with MAHA and thrombocytopenia.
Diagnosis:
Kidney biopsy:
Its not required to diagnose TMA with risk higher risk of bleeding due to thrombocytopenia. However, allograft biopsy is important diagnostic tool to showcase the cause of TMA, importantly ABMR, viral infection and CNI.
Genetic screening :
In recurrent TMA or those suspected to have complement mediated TMA(strong family history of complement mediated TMA) ,genetic testing is indicated Treatment might involve eculizomab to salvage the kidney. Planning the treatment is according to genetic result.
De novo TMA:
Genetic analysis to complement mediated TMA is indicated to rule out this possibility.
If CNI blood level is above the target, then it has to be adjusted. And to stop temporarly if its more than 15 ng/ml for Tacrolimus.
If the patient is on Cyclosporin while developing TMA, then switch to Tacrolimus (as mentioned earlier Cyclosporin is associates with higher risk of TMA then Tacrolimus) and replacement with Tacrolimus would reverse the disease process in significant proportion of patients)
Excluding virology etiology by PCR for CMV, Parvo B19, Covid 19 and HIV, to treat accordingly and to add eculizumab if no improvement reported after treatment of the culprit viruses.
If kidney biopsy eevealed ABMR, then treatment with PE, Rituximab and probably eculizumab to be aggressively implemented.
ADAMTS13 activity testing is usually performed to assess for TTP, and in patients with activity less than 10 percent, then treatment for TTP is indicated( usually with PE).
Lastly in patient with Diarrhoea, Shiga toxin producing organism should be excluded. Like E. Coli serotype 0157.
Treatment include adminstering Eculizumab until diarrhoea resolve and patient genetic status is known.
Eculizumab:
is indicated in the following condition:
1)In patient with genetic mutation
2)Persistant symotoms and signs of TMA
3)progressive disease despite addressing potentially reversible causes.
If Eculizumab is not available then PE is an alternative.
References:
1)Thrombotic Microangiopathy Aftrr Kidney transplantation :An underdiagnosed and pitentially reversible entity.Ana Avila, Ana Gavela and Asuncion Sancho. Front. Med. April 2021.
2)Thrombotic microangiopathy after renal transplantation:Current insight in de novo and recurrent diseade., world J transplant
What is your diagnosis?
Thrombotic microangiopathic anemia(TMA) possibly drug-induced (tacrolimus).
TMA may occur de novo, often caused by immunosuppressive drugs (CNI), infections, and acute antibody-mediated rejection, or recur in patients with a previous history of hemolytic uremic syndrome (HUS).
What is your management plan?
First, we should investigate what is the cause to set the better treatment
1- viral screening – CMV PCR, parvovirus screening, Hepatitis C serology, HIV screening. Treating the underlying disease is paramount for an adequate clinical response.
2- for C4d, C1q staining of the renal biopsy together with features of rejection – ABMR (Plasmapheresis and IVIg could be necessary)
3- DSA level- ABMR
4- ANA, dsDNA, serum complement levels (Evaluate the possibility of HUS and the cost-effectiveness of performing eculizumab – gonorrhea infections and high cost)
5- tacrolimus level (set swap to another class such as mTor)
This patient has thrombotic microangiopathy (TMA)
Based on the following findings
Acute kidney injury
Anaemia
Thrombocytopenia
Blood film showing schistocytes
The kidney biopsy shows fibrin deposits in the glomerular capillary loops and the
Causes of TMA in a transplant patient
– Drugs Calcineurin inhibitor (Tacrolimus)
– Acute antibody mediated rejection
–
The management would include excluding other causes of TMA which include
HUS/TTP
Hypercoagulable state like antiphospholipid syndrome
Malignant hypertension
The ultimate treatment in this case is to stop Tacrolimus and consider an alternative agent like Everolimus or Sirolimus.
– Diagnosis
TMA (thrombotic microangiopathy )
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, as in post transplant
– Management
Treatment 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[1] and modification of immunosuppressants
– 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.
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[2]
– Hemodialysis if indicated
– Hydration with UOP monitoring to avoid volume overload if associated with oliguria
[1] Garg N, Rennke HG, Pavlakis M, Zandi-Nejad K. De novo thrombotic microangiopathy after kidney transplantation. Transplant Rev (Orlando) 2018; 32: 58-68 [PMID: 29157988 DOI: 10.1016/ j.trre.2017.10.001]
[2] Abbas, F., El Kossi, M., Kim, J. J., Sharma, A., & Halawa, A. (2018). Thrombotic microangiopathy after renal transplantation: Current insights in de novo and recurrent disease. World journal of transplantation, 8(5), 122–141. https://doi.org/10.5500/wjt.v8.i5.122
. What is your diagnosis?
-This patient has anemia and thrombocytopenia and his liver function test showed raised bilirubin. His peripheral blood picture showed fragmented RBCs and renal biopsy showed thrombosis inside glomerular capillaries→Thrombotic microangiopathy (TMA).
-Post-transplant TMA may occur de novo, or recurrence TMA.
De novo TMA can be due to :
1. Antibody-mediated rejection (AMR)
2. Immunosuppressive-associated TMA: CNI or mTOR inhibitors.
3. Viral infection: e.g., HCV, CMV, BK, and parvovirus.
4. Genetic abnormalities in the complement cascade.
5. Missed diagnosis of TMA in the native kidney as a cause of ESRD.
Recurrent TMA after renal transplantation can be due to :
1 -Hemolytic uraemic syndrome or Thrombotic thrombocytopenic purpura.
2. Malignant hypertension.
3. Autoimmune disorders like SLE.
– What is your management plan?
– Take a careful history of an original disease that causes ESRD, and examine for petechiae and purpura.
– Investigations: TAC level, DSA, C4d staining, viral serology, complement levels, immunological and genetic screening.
–There are no treatment guidelines for de novo or recurrent post-transplant TMA.
-Aggressive supportive care includes minimizing transfusions, aggressive hypertension management, and treatment of any underlying infection
-Treatment according to underline cause: e.g, gradual change of immunosuppression or reduce the dose. Reduction or withdrawal of CNI or switching to sirolimus have been attempted to limit drug-related nephrotoxic insult. However, 60–100% graft loss has been reported with these procedures alone.
-In the case of AMR: plasmapheresis and IV IG.
-TMA associated with antibody-mediated rejection is often refractory to treatment and most patients eventually loose the graft. Depletion of plasma cells with the proteasome inhibitor bortezomib and complement inhibition with Eculizumab, have been proposed as new therapeutic strategies.
– Plasma-exchange combined with belatacept, in a patient with recurrent TMA allowed CNI discontinuation and reversed TMA while preventing acute rejection.
-Eculizumab is an effective therapy in post-transplant TMA.
References:
-Fedaey Abbas, Mohsen El Kossi, Jon Jin Kim, Ajay Sharma, and Ahmed Halawa. Thrombotic microangiopathy after renal transplantation: Current insights in de novo and recurrent disease. World J Transplant. 2018 Sep 10; 8(5): 122–141
.-M. Noris,G. Remuzzi .Thrombotic Microangiopathy After Kidney Transplantation American Journal of transplantation. 25 June 2010
This gentleman has 202 mismatches and presented with aneamia and thrombocytopenia. His creatine has been elevated.
Clinical presentation:
1- anaemia, thrombocytopenia
2-elevated creatinine
3- elevated bilirubin
FBP showed : shistocytes
Renal Biopsy: intraluminal fibrin occlusive thrombi, mesangiolysis
there are cumulative evidences of Thrombotic microangiopathy (TMA)
he is on tacrolimus – although can cause TMA but lesser than CyA and mTORI
Further evaluation
I need to explore the history of any complement over activation prior to transplant , any hypotensive episode during organ procurement and cold ischemic time to elicit any ischemic prefusion injury
I need to know the primary disease for the kidney failure for patient (recipient) – possible SLE, ?APLS that can cause TMA ( secondary) or aHUS that can have recurrence of aHUS
Investigations
1- viral screening – CMV PCR, parvovirus screening, Hepatitis C serology , HIV screening
2- for C4d, C1q staining of the renal biopsy together with features of rejection -ABMR
3-DSA level- ABMR
4-ANA, dsDNA, serum complement levels
5- tacrolimus level
General Management
1- hydration ( provided not oliguric)
2- haemodialysis if indicated
3- stop CNI ( if CNI induec)
4- blood transfusion if Hb low
TMA treatment
AMR- Plasmapheresis with or without IVIG intensify immunosuppression.
aHUS- Eculizumab shown to be beneficial
TTP- PLEX
Ana Ávila et al 2021-Thrombotic Microangiopathy After Kidney Transplantation: An Underdiagnosed and Potentially Reversible Entity
This is a scenario with graft dysfunction in early post-transplant period of a 202 mismatch living donor transplant.
The peripheral blood film reveals fragmented red blood cells (schistocytes) in association with anemia and low platelet counts. The bilirubin is also high, pointing towards hemolysis.
The kidney biopsy shows fibrin deposition in the glomerulus.
This picture is consistent with thrombotic microangiopathy (TMA).
The cause of TMA in early post-transplant period may be either de-novo or recurrent TMA. (1,2)
Etiology for de-novo TMA include:
1) Antibody mediated rejection (AMR).
2) In deceased donor transplant: due to associated complement activation
3) Ischemia-reperfusion injury
4) Drug induced: CNI, mTOR inhibitors
5) Infections: CMV, Parvovirus, Fungal infection
6) Atypical HUS
Recurrent TMA causes include:
1) atypical HUS
2) TTP (will have neurological manifestations additionally)
3) Autoimmune disease: Scleroderma, SLE with or without Antiphospholipid syndrome.
Management includes:
1) supportive management
2) Specific management
1) Supportive management includes
a) fluid and electrolyte management,
b) blood transfusion,platelet transfusion as per requirement
c) hemodialysis as per requirement
2) Specific management: Depends on etiology of the TMA.
Hence investigations including DSA, CMV PCR, Hepatitis C virus PCR, CNI drug levels, C4d stain for the graft biopsy, ANA, dsDNA, serum complement levels need to be done.
In case of high CNI levels, reduce or stop the drug.
In case of AMR, Plasmapheresis and IVIG will be required in addition to increasing the immunosuppression.
In case of infections like CMV, HCV, they need to be treated.
For TTP, treatment would be plasma exchange
For atypical HUS, genetic testing will be needed and Eculizumab might be needed in refractory cases.
References:
1) Abbas F, El Kossi M, Kim JJ, Sharma A, Halawa A. Thrombotic microangiopathy after renal transplantation: Current insights in de novo and recurrent disease. World J Transplant. 2018 Sep 10;8(5):122-141. doi: 10.5500/wjt.v8.i5.122. PMID: 30211021; PMCID: PMC6134269.
2) Ávila A, Gavela E, Sancho A. Thrombotic Microangiopathy After Kidney Transplantation: An Underdiagnosed and Potentially Reversible Entity. Front Med (Lausanne). 2021 Apr 8;8:642864. doi: 10.3389/fmed.2021.642864. PMID: 33898482; PMCID: PMC8063690.
Renal biopsy reveal intra vascular thrombi
blood film fragmented RBC with shistocyte
Anemia ,thrombocytopenia, hyperbilirubinemia
LDH expect to be high ?
Diagnosis TMA:
could be acquired or denovo ?
since primary disease unknown or not mention so possibility of recurrence of primary disease (ex ,atypical HUS ).so need to send patient to genetic study if no ovious cause found .
Acquired causes:
Ab mediated rejection should be first to think since acute presentation with rapid rise in his serum Cr with HLA mismatch so need to know pretransplant immunological risk ,
send for DSA and compare with pre transplant(base line),look for histopathological finding of rejection, and peritubular capillary C4d.
Other cause
Drug related CNI, mTOR
Infection .
Treatment toward underlying cause :
drug related minimized or stop.
Ab mediated rejection
plasma exchange
IVIg
+-rituximab
TTP
plasma exchange if no response
or refractory Eculizumab (anti C5)
Karthikeyan V, Parasuraman R, Shah V, Vera E, Venkat KK. Outcome of plasma exchange therapy in thrombotic microangiopathy after renal transplantation. Am J Transplant. (2003) 3:1289–1294. doi: 10.1046/j.1600-6143.2003.00222.x
PubMed Abstract | CrossRef Full Text | Google Scholar
renal biopsy reveal intra vascular thrombi
blood film show fragmented RBC with shistocyte
Anemia,, thrombocytopenia ,hyperbilirubinemia
LDH expect to be high ?
Diagnosis :THROMBOTIC MICRO ANGIOPATHY
Could be recurrence or denovo thrombotic microangiopathy
Primary disease not mention in this case so if it is undetermined or thrombotic microangiopathy so think about recurrence and need to send for genetic study .
denovo thrombotic microangiopathy :
most common cause and first to think antibody mediated rejection especially our patient
acute rise in serum Cr, low PLT, and HLA mismatch
so we should to look for pre transplant full immunological risk and DSA titer and
peritubular capillary C4d and read for histopathological finding of rejection .
Other causes for acquired TMA
drug related CNI ,mTOR inhibitor, infection .
treatment according to underlying cause
drug related minimize or omit
Ab mediated rejection
Plasm exchange
Iv Ig +
Karthikeyan V, Parasuraman R, Shah V, Vera E, Venkat KK. Outcome of plasma exchange therapy in thrombotic microangiopathy after renal transplantation. Am J Transplant. (2003) 3:1289–1294. doi: 10.1046/j.1600-6143.2003.00222.x
PubMed Abstract | CrossRef Full Text | Google Scholar
1- 1st picture show several fragmented RBCs, 2 nd one show intraglomerular thrombus. Diagnosis is posttransplant TMA (systemic form) either
a- Recurrent TMA
b- De no vo TMA
· Malignant HPN
· Drug SE specially CNI, m TOR
· AMR
· Genetic mutation in complement pathway
2- Management plan
· Stop the offending drug ( that is mostly CNI , can try shift to m TOR inhibitors
· Plasma exchange
· Eculizumab : may be beneficial
* What is your diagnosis
* Post transplant thrombotic microangiopathy which confirmed by presence of anemia/ thrombocytopenia/ haemolytic anemia. peripheral blood film shows schistocytes (fragmented RBC), renal biopsy shows intraluminal fibrin thrombi.
* it’s may underlying cause drug induce like Calcinurine inhibitors / activation of complement system/ viral infection / Autoimmune disease e.g. Vasculitis / SLE /
* What is your management plan?
1- identify underlying factors and treated
2- Plasma Exchange
3- Eculizumab monoclonal antibody to reduce activation of complement and prevent recurrence of disease
What is your diagnosis ?
What is your management plan?
What is your diagnosis?
Thrombtic microangiopathy for differential diagnosis
What is your management plan?
Depends on the underlying cause
TMA its pathological pattern can be caused by multiple causes like
1-recurrence of the original kidney disease which may be atypical HUS or TTP
2-CNI toxicity
3- ABMR
so
-Trough level should be send and if it was high i will stop CNI till improvement of kidney function
And then may start by very small dose tac or shift to cyclosporine
-send DSA and c4d in the biopsy if positive I’ll augment my immunosuppressant medications and give the patient cumulative dose IVIG 0.5-1mg /kg divided after 3-5sessions of plasmapheresis follwed by rutiximab
-finally if there’s no other explaination
Screen for the cause like ADAMAT13 , GENETIC mutation or antibodies screening for Atypical HUS will be send and plasmapheresis will be started with different prognosis according to table in the picture
*What is your diagnosis?
This patient with HLA 2-0-2 ,on tacrolimus based triple immunosuppression ,s.cr increased ,blood picture showed anaemia ,thrombocytopenia and there is fragmented RBCs , schistocytes in the blood film ,LFT showed rised bilirubn and biopsy showed intravascular fibrin thrombi
*This patient developed post transplant systemic thrombotic microangiopathy
*Thrombotic microangiopathy (TMA) is a condition characterized by
thrombocytopenia and microangiopathic hemolytic anemia (MAHA) with varying degrees of organ damage in the setting of normal international normalized ratio and activated partial thromboplastin time. Complement has been implicated in the
etiology of TMA, which are classified as primary TMA when genetic and acquired defects in complement proteins are the primary drivers of TMA (complement-mediated TMA or atypical hemolytic uremic syndrome, aHUS) or secondary TMA, when complement activation occurs in the context of other disease processes, such as infection, malignant hypertension, autoimmune disease, malignancy, transplantation, pregnancy, and drugs. It is important to recognize that this classification is not absolute because genetic variants in complement genes have been identified in patients with secondary TMA, and distinguishing complement/genetic-mediated TMA from secondary causes of TMA can be challenging and lead to potentially harmful delays in treatment. In this review, we focus on data supporting the involvement of complement in aHUS and in secondary forms of TMA associated with malignant hypertension, drugs, autoimmune diseases, pregnancy, and infections. In aHUS, genetic variants in complement genes are found in up to 60% of patients, whereas in the secondary forms, the finding of genetic defects is variable, ranging from almost 60% in TMA associated with malignant hypertension to less than 10% in drug-induced TMA. On the basis of these findings, a new approach to management of TMA is proposed.
(Complement in Secondary Thrombotic Microangiopathy
Lilian Monteiro Pereira Palma, Meera Sridharan, and Sanjeev Sethi)
*What is your management plan?
Treat the cause of TMA for example ,infection with antibiotics and supportive care,rejection plasma exchange ,immunosuppression Eculizumab
complement blocking therapies may be used
in sever kidney injury may require dialysis
(Eculizumab improves posttransplant thrombotic microangiopathy due to antiphospholipid syndrome recurrence but fails to prevent chronic vascular changes
(G Canaud, N Kamar, D Anglicheau, L Esposito, M Rabant, L‐H Noël, C Guilbeau‐Frugier, R Sberro‐Soussan, A Del Bello, F Martinez, J Zuber, L Rostaing, )
thankyou for the comprehensive reply ,so to reach a decision wether it is
aHUS with reccurance or
de novo or secondary HUS
THE following are more with primary: family or personal history, systemic and other organ features as in our case offcourse genetic mutations in complement system ,early occurance.
While in secondary onset depends on the cause of the insult to the complement system as you mentioned but special emphasis is directed to the DONOR as IRI, DBD,DCD cold ischemia time.needless to mention is that complement removal is needed in both but the responseis different.
Thanks prof Belal
Denovo TMA post kidney transplant is one of rare causes of graft loss with complex pathogenesis , usuallu happened early post transplant , months to less than 1 years , can be triggered by factors related to the recpients including the duration of dialysis , high PRA , and mismatches , prolong cold ischemia time , drugs likeCNI , rapamycin inhibitirs , induction with depleting agents,but most important trigger factors is due to humoral alloimmune response in sensitized kidney transplant recipients therefore, patients with de novo TMA and AMR should be considered to be at the highest risk and to likely require more aggressive antirejection treatment and
monitoring. In the cases of those not associated with rejection,
the elimination of complement aggravating factors and CNI withdrawal or minimization may be considered.
reference:
Transplantation Direct 2021;7: e779; doi: 10.1097/TXD.0000000000001239. Published online 22 October, 2021.)
Thankyou Saja an important point in de Nova aHUS is that we try to look for a reason among whichis :viral infections CMVas it is treatable,PARVOVIRUS,HCV and its treatment,native kidney desease asanti PLS.
WHY the hastle : because they are correctable situations
Diagnosis?
schistocytes in the blood film and intra-capillary thrombi in the renal biopsy
The diagnosis of TMA is made on the basis of the laboratory results (anaemia, thrombocytopenia, increased liver enzymes) and the histology findings (schistocytes on the blood film and fibrin thrombi on the renal biopsies).
management?
In the case of de-novo TMA, the fundamental reasons were first addressed.
-In patients with a tacrolimus or cyclosporine concentration in their blood that is higher than the therapeutic range, the calcineurin inhibitor should be reduced in dosage.
-shifting the patient from cyclosporine to tacrolimus and vice versa.
-Confirm the absence of infection by using polymerase chain reaction (PCR), such as CMV, BK, parvovirus.
-Perform the ADAMTS13 test to rule out the possibility of thrombotic thrombocytopenic purpura (TTP).
-Exclude the presence of AMR using a DSA titer and c4d staining of biopsy samples, and treat the patient appropriately.
the treatment will depend on the cause:
but until the result of the lab appear, start plasma exchange with IVIG g as soon as possible.
up-to date
Your causes for de novo TMA are correct
TTP is usually with positive history and allways a neurological lesion is presant.
offcourse overlap in diagnosis is there but decision to treat and prognosis are different.
B.film show fragmentsed RBC
Biopsy show intraglomerlar thrombosis
Thrombotic microangiopathic anemia (TMA) is characterized by
mechanical hemolytic anemia, thrombocytopenia, and kidney function impairment.
TMA divided in to type:-
1- de novo TMA
Occoure after transplantion when the native cause of ESRD not related to TMA
Causes of TMA include:-
1-immune suppressive drugs (CNI)
2-AMR
3-infection like CMV, BK ,parvovirus and HIV.
4- ischemia reperfusion injury
2- recurrent TMA
patients with recurrent TMA have a complement-mediated disease that produced both the pretransplant TMA and the recurrence after transplantation
complement-mediated disease either genetic defect in complement or autoantibodies aggnist complement
TREATMENT
*In denovo TMA first of all treated the underlying causes
1-In patients with a blood tacrolimus or cyclosporine concentration above the therapeutic range reduce the dose of the calcineurin inhibitor.
do not discontinue the calcineurin inhibitor unless the blood concentration is elevated ( tacrolimus trough level >15 ng/mL or cyclosporine trough level >400 ng/mL
Among patients who develop de novo TMA while on cyclosporine, switching to tacrolimus (or vice versa) is an alternative option once the acute episode of TMA resolves.
If the patient is taking a(mTOR) inhibitor discontinue this agent.
2-exclude infection by polymerase chain reaction (PCR)like CMV, BK ,parvovirus and HIV.
And treated accordingly
3- perform ADAMTS13
exclude a diagnosis of thrombotic thrombocytopenic purpura (TTP)
3- Exclude the AMR by DSA titer and c4d staining of biopsy and treated accordingly
*In recurrent TMA
1-In patients with ESKD due to TMA related to mutations of complement factors that are produced by the liver (eg, factor H), combined kidney-liver transplant has been used to correct the ESKD along with the underlying etiology of TMA
2-Using eculizumab (an antibody that targets the complement component C5) prior to transplantation in all patients with complement-mediated TMA due to a genetic deficiency or dysfunction of CFH or CFI as prophylactic therapy and also used after recurrence of TMA post transplant
*Prognosis
Overall graft outcomes are worse in patients with recurrent TMA
Reference
Up to date 2022
You are right prognosis is bad specially in recurrent TMA ,positive systemic manifestations as in our case is a clue that it is not de novo.
Keeping in mind that both have a triggered complement stimulation that will need management.