Primary GN is one of leading cause of ESKD worldwide (about 10-15 % of ESKD). Glomerulonephritis (primary or secondary) are heterogenous in respect to recurrence after kidney transplantation. The prevalence of GN recurrence after kidney transplantation is between 3-15%, particularly in patients with high-risk subtypes of IgA nephropathy, idiopathic membranous GN, FSGS, and MPGN). Most of the GN recurrences occur 3-5 years post transplantation with the exception of FSGS and MPGN which can occur early post transplantation.
Among ESKD patients due to primary GN the risk of recurrence is high, particularly in FSGS and MPGN.
IgA nephropathy:
Recurrence of IgA nephropathy occurs late post-transplantation, and it is correlated with better prognosis than other glomerulonephritis. Allograft survival after MPGN recurrence is poorer than other glomerulonephritis.
Risk factors for post-transplant IgA nephropathy recurrence consist of younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy (ATG may be associated with a lower risk of recurrence), HLA allelic subtypes, crescentic (and rapidly progressive) IgA nephropathy in the native kidneys and shorter total ischemic time.
The suggested treatment for IgA nephropathy includes CNIs and corticosteroids, and for crescentic rapidly progressive form cyclophosphamide or rituximab can be considered.
Recurrent primary FSGS:
Up to 1 in 3 patients with primary FSGS will experience post-transplant recurrence with five times higher risk of graft loss. Differentiation between secondary and primary FSGS may be difficult late post transplantation. On the other hand, familial FSGS is associated with no or low risk of recurrence. It is practical to consider screening genetic testing for recipients with family history of FSGS or who has a relative living donor candidate for kidney transplantation. Risk factors for recurrence of primary FSGS include younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESKD, and prior allograft failure from disease recurrence. A pathologic role for suPAR is proposed for primary FSGS. Serum suPAR is non-specific and can increase in other conditions such as infection and inflammation. Anti CD40 autoantibody and anti AT1R antibody are promising as prognostic factors. Close monitoring of high-risk patients is suggested in the first three months post transplantation.
Plasmapheresis or rituximab or CNIs are therapeutic options for primary FSGS. It seems that Rituximab function on podocyte is essential factor rather than its effect on B cells. The function of CNIs on T cells and actin cytoskeleton in podocytes are important in inducing remission in primary FSGS. Switch to CNIs in patients who are on mTOR inhibitors is recommended.
Recurrent primary MPGN:
Recurrence of post-transplant MPGN is common and occurs early after transplantation with high risk of graft loss.
MPGN is classified to immune-mediated (monoclonal or polyclonal), complement mediated (C3 glomerulopathy including C3 glomerulonephritis and DDD). Dysregulation of alternative pathway of complement with manifestation of intense C3 staining is seen in C3 glomerulopathy. Although DDD occurs later than C3 glomerulonephritis, its consequence is only graft loss. Monoclonal related MPGN is associated with activation of complement classical pathway. Presence of monoclonal immunoglobulin +/- positive C4d is associated with poor prognosis. Treatment of recurrent disease comprises of plasmapheresis, cyclophosphamide, eculizumab, or rituximab. Eculizumab has a potential benefit in C3 glomerulopathy treatment. Plasmapheresis and anti B-cell therapy can be considered for Ig-mediated MPGN.
Recurrent idiopathic membranous GN:
Anti PLA2R antibody is important for differentiate primary and secondary MN, furthermore prediction the risk of recurrence and prognosis after kidney transplantation. THSD7A is another autoantibody detected 5% in primary MN, typically in PLA2R seronegative patients. Nevertheless, up to 20% of Idiopathic MN are negative for both autoantibodies. The rate of idiopathic MN recurrence is 30-50% and it is correlated with higher titers of pre- and post-transplant anti PLA2R antibodies. It should be monitored after transplantation in patients with high pre-transplant titer or early recurrence post transplantation. The treatment disease recurrence consists of antiproteinuric agents in addition to CNI based therapy and rituximab (that is superior to alkylating agents). Bortezomib can be considered for rituximab-resistant recurrent idiopathic MN. Pre-emptive use of rituximab is an option in patients with high titer of anti PLA2R antibody with previous history of graft loss due to recurrence or with persistent and progressive increase in post-transplant anti PLA2R antibody titers.
Secondary GN:
Post-transplant recurrence after secondary GN occurs late and less frequently is associate with graft loss. For example, the rate of recurrence of ANCA associated vasculitis and anti GBM is low.
De novo GN:
The most common forms of de novo GN post transplantation are FSGS (the most common form), IgA nephropathy, idiopathic MN and MPGN, and they are associated with significantly reduced graft survival.
Development of de novo FSGS is related to reduction in nephron number in different conditions such as BKV nephropathy and DM. treatment consists of antiproteinuric agent and removing offending factors. De novo IgA nephropathy is usually benign except for crescentic form, and therapy consist of antiproteinuric and antihypertensive agents. De novo MN and MPGN are less common, usually secondary to viral infection, autoimmune, and occur late post transplantation. The pattern of IgG staining can help to differentiate between de novo and recurrent MN (Recurrent is IgG1 dominant with more frequent anti PLA2R antibody, and de novo is IgG4 dominant).
In the presence of de novo GN, awareness of the need to exclude secondary causes is essential.
MICHAEL Farag
2 years ago
Please give a summary of this article
Recurrent and de novo Glomerulonephritis After Kidney Transplantation
This review focuses on the incidence, genetics, characteristics, clinical course, and risk of allograft failure of patients with recurrent or de novo GN after kidney transplantation, ascertaining potential disparities between “high risk” disease subtypes of IgA nephropathy, idiopathic membranous glomerulonephritis, focal segmental glomerulosclerosis, and membranoproliferative glomerulonephritis. We will examine in detail the management of patients with high risk GN, including the pre-transplant assessment, post-transplant monitoring, and the available treatment options for disease recurrence. INTRODUCTION All GN subtypes can potentially recur after transplantation, with the prevalence of GN recurrence between 3 and 15%, particularly in patients with high risk subtypes of IgA nephropathy, idiopathic membranous GN, focal segmental glomerulosclerosis (FSGS), and membranoproliferative GN (MPGN). the incidence of de novo or recurrent GN after kidney transplantation is likely to be under-estimated because of the likelihood of selection bias (i.e., systematic differences in the selection and listing of ESKD patients with different GN subtypes), varying biopsy practices, ascertainment of the primary cause of ESKD, differing follow-up period, disparate clinical presentations ranging from asymptomatic urinary abnormalities to rapidly progressive GN, misclassification, and indication bias (where kidney biopsy may be carried out only for specific clinical indication and therefore may fail to identify asymptomatic incidental cases of early disease recurrence) and the competing risk of other causes of allograft failures. Epidemiology, Pathogenesis, and Outcomes of GN Recurrence After Kidney Transplantation The incidence of GN recurrence posttransplant varies according to GN subtypes and time post-transplantation. Recurrent IgA Nephropathy Recurrent IgA nephropathy is relatively common, but typically occurs late post-transplant with cumulative incidence of disease recurrence at 15 years of 15%. Following disease recurrence, up to 40% of patients with recurrent IgA nephropathy have been reported to lose their allografts, predominantly from disease recurrence (up to 60%). Compared with other GN subtypes, the long-term allograft and patient outcomes of patients with IgA nephropathy are substantially better. Several risk factors for disease recurrence have been described including younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy (whereas anti-thymocyte globulin [ATG] may be associated with a lower risk of recurrence), HLA allelic subtypes, crescentic (and rapidly progressive) IgA nephropathy in the native kidneys and shorter total ischemic time, but given these findings were identified in population cohort studies, it is difficult to ascertain the true causality of these risk factors for disease recurrence. The optimal treatment of recurrent IgA nephropathy remains unknown and there are no current studies to suggest that alterations in immunosuppression will improve allograft outcome. The current practice is to maintain (or change to) a calcineruin-inhibitor (CNI) and corticosteroids-based immunosuppressive regimen in addition to anti-proteinuric treatments, although the optimal dosing/target therapeutic CNI level or specific CNI type in the treatment of those with recurrent disease remains unknown. In cases of crescentic rapidly progressive IgA nephropathy, more aggressive immunosuppression (e.g., cyclophosphamide or rituximab) may be considered but this is largely unproven and unlikely to successfully reverse the disease process. Recurrent Primary FSGS Up to 1 in 3 patients with primary FSGS will experience disease recurrence after kidney transplantation, with the risk of allograft failure (predominantly from GN recurrence) 5-times the risk compared to those without disease recurrence. In contrast to patients with primary FSGS, familial FSGS in adults,have low to no risk (<3%) of disease recurrence post-transplant suggesting the relative importance of genetic testing in the evaluation of a subset of patients with adult-onset FSGS for transplantation. file:///C:/Users/micha/AppData/Local/Temp/msohtmlclip1/01/clip_image002.jpg Many of the genetic mutations associated with adult-onset FSGS have an incomplete penetrance and therefore, the identification of patients with familial FSGS remains challenging. file:///C:/Users/micha/AppData/Local/Temp/msohtmlclip1/01/clip_image004.jpg The management of patients with recurrent primary FSGS remains challenging. Plasmapheresis is often preferred and recommended (in the American Society for Apheresis guidelines) in the treatment of primary FSGS recurrence in the allograft of both pediatric and adult patients. The efficacy of adjunctive therapy including rituximab and CNI such as cyclosporine remains uncertain. However, a switch to CNI if patients were on mammalian target of rapamycin [mTOR]-inhibitor is advocated, given that mTOR-inhibitor, especially at higher doses have been associated with the development of de novo FSGS. The roles of pre-emptive plasmapheresis (pre and/or posttransplantation), immunoadsorption therapy, and other novel
options such as ofatumumab or B7-1 blockers (abatacept and belatacept) to prevent disease recurrence or to treat recurrence appear promising but the efficacy of these treatments remain debatable and not always consistent or supported in subsequent studies. Recurrent Primary MPGN Disease recurrence post-transplant from primary MPGN is relatively common, with over 50% of recurrence occurring within the first 24 months post-transplant. Immune-complex mediated MPGN is characterized by the glomerular deposition of polyclonal or monoclonal immunoglobulins (Ig), whereas C3 glomerulopathy [comprising of C3GN and dense deposit disease (DDD)] is characterized by the glomerular deposition of C3 in the absence of Ig deposition. There is a high rate of post-transplant recurrence for both C3GN and DDD, with over 50% of patients with disease recurrence reported to experience allograft failure, although the number of patients in these studies was relatively small. The timing and clinical presentations of patients with C3GN and DDD may be dissimilar, with DDD more likely to recur later post-transplant and often associated with no clinical manifestations other than allograft dysfunction. C3GN and DDD are characterized by the presence of strong glomerular staining for C3 and electron deposits on electron microscopy, but these diseases are potentially morphologically distinguishable by the nature and ultrastructural characteristics of these electron dense deposits For immune-mediated MPGN, the patterns and types of Ig deposits may have diagnostic and prognostic significance. The presence of serum monoclonal proteins, with and without low complement levels (±glomerular C4d deposition), implying activation of the complement cascade was associated with a less favorable clinical course post-transplant, with higher risk of recurrence and disease progression following recurrence. Recurrent Idiopathic Membranous GN The ability to test for the presence of anti-PLA2R autoantibody has resulted in improved recognition and differentiating primary vs. secondary membranous GN, as well as assisting clinicians in the management of patients pre and post-transplantation, identifying those patients at high risk of post-transplant disease recurrence that may benefit from more intensive monitoring post-transplant as well as monitoring response to treatment. The rate of disease recurrence in patients with idiopathic membranous GN following kidney transplantation is between 30 and 50%, with the disparate detection rates reported in the studies influenced by the characteristics of the cohort The treatment of disease recurrence is largely extrapolated from treatment in the general population and typically includes a combination of anti-proteinuric agents, corticosteroids, alkylating agents, CNI, and rituximab. Secondary GN In contrast to ESKD attributed to primary GN, patients with secondary GN subtypes attributed to systemic diseases [such as atypical hemolytic uremic syndrome (aHUS), systemic lupus erythematosus (SLE), anti-glomerular basement membrane (GBM) disease, and crescentic GN (e.g., from
systemic vasculitis)] may experience GN recurrence after kidney transplantation, but these relapses often occur later post-transplant and infrequently lead to allograft failure.
Mohammed Sobair
2 years ago
According to the 2018 Australia and New Zealand Dialysis and Transplant (ANZDATA)
registry report, GN as cause of ESKD accounted for 17% of incident treated ESKD
patients.
In the US, GN as cause of ESKD, Recurrent Glomerulonephritis in Kidney
Transplantation of 7 and 13% of incident ESKD initiated on dialysis and have received
kidney transplants, respectively; with similar proportion reported in the United Kingdom.
Recurrent or de novo GN in the renal allograft is an important cause of premature
allograft failure.
All GN subtypes can potentially recur after transplantation, with the prevalence of GN
recurrence between 3 and 15%, particularly in patients with high risk subtypes of IgA
T maintain (or change to) a Calcineurin-inhibitor (CNI) and corticosteroids-based
immunosuppressive regimen in addition to anti-proteinuric treatments,
In cases of crescentic rapidly progressive IgA nephropathy, more aggressive
immunosuppression (e.g., cyclophosphamide or rituximab).
Recurrent Primary FSGS:
10% of patients experienced disease recurrence Poorer 5-year allograft survival of 54%.
Less to zero risk with familial.
Screening for familial:
A clear family history of FSGS or those with a potential live-related donor for
transplantation, including undertaking genetic screening of the donors for the same
genetic mutations (if present in the potential recipients).
Risk factors for disease recurrence:
Younger age at presentation.
Recipients of live-donor kidneys,
Non-white ethnicity.
Severe manifestations of disease at presentation, rapid progression to ESKD, and prior
allograft failure from disease recurrence.
Treatment:
Plasmapheresis.
The efficacy of adjunctive therapy including rituximab and CNI such as cyclosporine
remains uncertain.
Recurrent Primary MPGN:
Common, with over 50% of recurrence occurring within the first 24 months post-
transplant.
, the risk of allograft failure is relatively high with 5-year allograft survival post-disease
recurrence of only 30%.
Risk factors for disease recurrence:
Monoclonal gammopathy.
Presence of serum monoclonal proteins with and without low complement levels
Glomerular monoclonal Ig deposits (typically IgG3κ and IgG3λ).
Treatment:
Plasmapheresis and other immunosuppressive agents including cyclophosphamide,
Eculizumab, and rituximab.
Recurrent Idiopathic Membranous GN:
Disease recurrence in patients with idiopathic membranous GN following kidney
transplantation is between 30 and 50%.
Relative risk of allograft failure, up to 50% at 10-years.
Those with high titters of circulating anti-PLA2R autoantibody have a greater risk of
recurrent.
Treatment:
Combination of anti-proteinuric agents, corticosteroids, alkylating agents, CNI, and
rituximab.
Rituximab is an effective treatment for native and recurrent membranous GN in the
allograft, with up to 80% achieving complete or partial remission with the use of
rituximab for early disease recurrence post-transplant.
Secondary GN:
Relapses often occur later post-transplant and infrequently lead to allograft failure.
ANCA)-associated vasculitis, the relapse rate has been reported at 0.02 per patient-
years.
Incidence of recurrent lupus nephritis varies between 0 and 44%.
AntiGBM disease, disease recurrence after kidney transplant is less than5%, with a rare
graft loss.
De novo GN :
The incidence of de novo GN after kidney transplant varies between 4 and 20%, with
FSGS, IgA nephropathy, membranous GN, and MPGN being the most common de novo
GN subtypes.
Is associated with significantly reduced allograft survival. IF non-GN causes ESRD had
developed de novo GN, over 95% of cases were FSGS.
Presentation:
Ranging from asymptomatic urinary or biochemical abnormalities to overt symptoms and
signs of GN with nephrotic syndrome and renal dysfunction.
The treatment of de novo FSGS predominantly revolves around adequate anti-
proteinuric treatment and the removal of the offending agents/factors where possible, but
more aggressive therapy may be considered.
De novo IgA nephropathy is likely to be underestimated, with asymptomatic IgA
deposition not infrequently found.
Prognosis of those with de novo IgA nephropathy is usually relatively benign with
treatment predominantly focuses on antiproteinuric and/or anti-hypertensive therapy.
Crescentic de novo IgA nephropathy tend to have a poorer prognosis.
De novo membranous GN and MPGN are much less common, and the reported cases
primarily related to secondary causes including viral infections, rejection, autoimmune
disease, CNI and thrombotic microangiopathy.
. The onset of de novo membranous GN or MPGN tend to occur later post-transplant
(compared to recurrent disease).
With symptoms ranging from asymptomatic detection of mild proteinuria and incidental
biopsy findings to nephrotic range proteinuria and rapidly progressive GN.
IgG1 staining in capillary loop deposits was dominant/co-dominant IN RECURRENT
DISEASE .whereas, IgG4 staining in capillary loop deposits was dominant/codominant
in de novo disease. AntiPLAR is more with recurrent disease.
Conclusion:
More research is needed. Post-Transplant Glomerular Disease (TANGO) study, an
observational, multicenter cohort study was initiated to undertake collaborative studies
and clinical intervention trials to improve the management and clinical outcomes of these
patients.
mai shawky
2 years ago
• Summary:
• Some glomerular diseases have high risk of recurrence post-transplantation as IgA nephropathy, idiopathic membranous glomerulonephritis, focal segmental glomerulosclerosis (FSGS), and membranoproliferative glomerulonephritis(MPGN).
• Glomerulonephritis represent immune mediated spectrum of diseases either 1ry or 2ry.
• Recurrence of glomerular diseases occurs in 3-15%, and is a leading cause of allograft loss. it mostly occurs years post-transplant, except FSGS and MPGN which can occur early post transplant.
• presentation varies between asymptomatic urinary abnormalities to rapidly progressive glomerulonephritis.
• Recurrent IgA Nephropathy:
Common, usually late onset.
Benign presentation as microscopic hematuria or evidence of IGA deposition in allograft biopsies
40 % reported to have graft loss.
However, better patient and graft outcomes than recurrent FSGS, MPGN and membranous nephropathy.
Risk factors and predictors of disease recurrence are: young age, zero-HLA-mismatched, live-related donor kidneys (LDKT), non-use of induction therapy, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, , HLA allelic subtypes, crescentic and RPGN presentation of IgA nephropathy in the native kidneys and shorter total ischemic time, but these factors were identified in population cohort studies, it is difficult to ascertain the true causality for IgA nephropathy recurrence. certain molecules as galactose-deficient IgA1 (Gd-IgA1), IgG anti-Gd-IgA1 antibodies, glycan-specific IgG antibodies, and soluble CD89 were linked to disease recurrence and progression as predictors.
prevention: induction with ATG and avoidance of steroid free maintenance protocols.
ttt : No available RCT. standard is optimization of maintenance therapy, shift to CNI (if not maintained on it), keeping steroid based maintenance therapy and supportive measures as anti-protinuric therapy.
Aggressive therapy as cyclophosphamide or rituximab can be used in crescentic form, but of little evidence. tonsillectomy was reported in case reports and series (but cannot be generally recommended).
• Recurrent 1ry FSGS:
• 30 % risk of recurrence.
• 2ry FSGS can occur de novo in the graft and is difficult to be differentiated from recurrent FSGS.
• Familial FSGS has very low rate of recurrence (up to 3%), so genetic study is essential to determine the prognosis of the disease. its diagnosis clinically based on positive family history , incomplete penetrance can lead to adult onset FSGS.
Indications of genetic testing:
In adults, uncertainty regarding the likelihood of primary disease as (atypical clinical/pathological features or poor response to immunosuppressive treatment) and secondary (no obvious causes identified) FSGS or when there is a clear family history of FSGS.
Screening of related donor in LDKT may be beneficial, but costly, so preserved only to those with genetic mutations identified in the recipients.
In children, it is indicated in idiopathic steroid-resistant nephrotic syndrome (SRNS) with FSGS pathology.
N.B: There is a low risk of FSGS recurrence in pediatric patients with genetic FSGS post-transplant (3%), as those with mutation in podocin (NPHS2).
Risk factors of recurrence include younger age at presentation, recipients of LDKT, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESKD, and prior allograft failure from disease recurrence.
Early recurrence post-transplant may be mediated by circulating permeability factors as SUPAR.
↑ Pre-transplant Serum suPAR, predicts post-transplant recurrence. Urine suPAR ↑ Post-transplant.
Early detection of recurrence by urine analysis and A/C ratio, is essential for early and prompt diagnosis of disease recurrence. early graft biopsy with E/M examination (for early detection of effacement of podocytes foot processes is mandatory).
ttt: plasmapheresis and optimization of CNI plus anti-protinuric therapy are the proposed treatment. Rituximab can be an adjuvant and additional belatacept can be used.
There is no evidence that shift from one CNI to another can improve FSGS. However, shift from mTORi to CNI is suggested to decrease rate of recurrence.
Rituximab is suggested as B cell may play a role in 1ry FSGS, CNI has inhibitory effect on T cells and mechanical effect on podocyte cytoskeleton.
Pre-emptive PEX and rituximab may be beneficial, but still not standard of care, need validation from larger RCT.
Ofatumumab, an anti-CD20 monoclonal antibody and belatacept (used in cases with positive podocyte B7-1) need further studies to prove their efficacy in prevention of FSGS recurrence and are preserved for refractory cases to steroids and plasmapheresis.
• Recurrent idiopathic membranous nephropathy:
• Anti PLA2R antibodies is acceptable test to differentiate between 1ry and 2ry forms of membranous nephropathy with sensitivity of 65% (63–67%) and 97–98% specificity. so, the absence of PLA2R autoantibody does not definitively exclude cases of idiopathic membranous GN.
• Although the circulating levels of anti-PLA2R autoantibody tend to decline post-transplant (adsorption into the allograft or the effect of immunosuppression), there is a direct relationship between the titer level and risk of disease recurrence post-transplant.
• Prevention: pre-emptive use of rituximab for patients with idiopathic membranous GN and high pre-transplant levels of anti-PLA2R antibody has insuffient evidence, but this (or early initiation post-transplant) can be considered in those with detectable high levels of anti-PLA2R antibody with prior allograft failure from recurrent membranous GN or have persistent high or increasing levels of circulating anti-PLA2R antibody post-transplant with early histological recurrence.
• Post transplant follow up of recurrence with the anti PLA2R antibodies, proteinuria
• ttt: is generally the same as native disease in general population, Rituximab is promising in those with anti PLA2R antibody positive, plus use of antiprotinuric treatment as ACEi and ARBs. Boretezomib can be an adjuvant.
• If anti PLA2R antibody are negative, trial of rituximab can be used.
• Recurrent MPGN:
• 50% risk of recurrence, mostly during 1 st year post transplant, high risk of graft loss.
• 2 subcategories: immune complex mediated or complement mediated. C3 glomerulopthy includes (C3GN and dense deposit disease (DDD)).
• C3GN and DDD are characterized by the presence of strong glomerular staining for C3 and electron deposits on E/M, but these diseases are potentially morphologically distinguishable by the nature and ultrastructural characteristics of these electron dense deposits.
• C3 glomerulopthy recurrence occurs early post transplant.
• ttt: Eculizumab if C3 glomerulopathy.
• Plasmapheresis (PEX) and Immunosuppression (IA) (alkylating agent, rituximab) if immune complex MPGN
• Secondary GN:
• systemic diseases as aHUS, SLE, anti- GBM disease, and crescentic GN (e.g., from systemic vasculitis)] may experience GN recurrence after kidney transplantation, but these relapses often occur later post-transplant and infrequently lead to allograft failure.
• Recurrent lupus nephritis range from 0-44% with a high risk of graft failure and death.
• Recurrent anti GBM is rare with modern immunosuppressive therapy.
• a HUS has 80 % of recurrence (without prophylactic Ecluizimab). Combined liver and kidney transplantation can be used.
• Presumed or Advanced GN
• In cases with ESKD, and the biopsy revealed non specific glomerulo-sclerosis, tubular atrophy and interstitial fibrosis.
• De novo GN after transplantation;
• When original kidney disease is uncertain (biopsies were often not undertaken or were non-diagnostic), the presence of GN in the donor kidney may not be known.
• Presentation varies from asymptomatic urine sediment to overt nephrotic or nephritis.
• Risk factors include: diseases with hyperfilteration injury, as diabetes, hypertension, BK viral infection, CNI therapy, and rejection) or the introduction of sirolimus (through the effects on podocyte integrity).
• de novo FSGS occurs late than the recurrence of 1ry FSGS.
• ttt: mostly similar to 1ry disease and supportive anti protinuric.
Alyaa Ali
2 years ago
primary glomerulonephritis is a common cause of ESRD , account for 7% ESRD patients on dialysis and 13% of transplanted patient
recurrent or denovo s an important cause GN of allograft failure
prevalence of GN recurrence is between 3 to15% Recurrent IgA nephropathy
is common, occurs late post-transplant with cumulative incidence of disease recurrence at 15 years of 15%
after disease recurrence, up to 40% of patients develop allograft failure
Compared with other GN subtypes, the long-term allograft and patient outcomes of patients with IgA nephropathy are relatively better.
risk factors include younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy
no optimal treatment,
The practice is to maintain (or change to) a calcineruin-inhibitor (CNI) and corticosteroids-based
immunosuppressive regimen in addition to anti-proteinuric treatments, but the optimal doses remains unknown. Recurrent primary FSGS
Up to 1 in 3 patients with primary FSGS will develop disease recurrence after kidney transplantation, with the risk of allograft failure 5-times the risk compared to those without disease recurrence
In contrast to patients with primary FSGS, familial FSGS in adults, comprising of those with mutations of podocin or structural podocyte proteins have low to no risk (<3%) of disease recurrence post-transplant
risk factors for disease recurrence in patient with primary FSGS include younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESKD, and prior allograft failure from disease recurrence
A pathogenic role of the circulating serum soluble urokinase receptor (suPAR) has
been proposed in the pathogenesis , by activating podocyte b(3) integrin resulting
in effacement of foot processes and proteinuria
Close monitoring for proteinuria in high risk patients, and proceeding to a kidney biopsy
Plasmapheresis is often preferred and recommended in the treatment of primary FSGS recurrence in the allograft of both pediatric and adult patients. The efficacy of adjunctive therapy including rituximab and CNI such as cyclosporine remains uncertain. Recurrent primary MPGN
is common, with over 50% of recurrence occurring within the first 24 months post-transplant In patients who had experienced diseaser ecurrence, the risk of allograft failure is relatively high with 5-year allograft survival post-disease recurrence of only 30%
have two subtypes immune complex-mediated MPGN and complement-mediated MPGN
The approach to treatment for recurrent disease is not well established,limited to case series of successful treatment with the use of plasmapheresis and other immunosuppressive agents including cyclophosphamide, eculizumab, and rituximab
The use of Eculizumab showed benefit in reduction of proteinuria and stabilization of kidney function post transplant. Recurrent Idiopathic Membranous GN
The rate of disease recurrence in patients with idiopathic membranous GN following kidney transplantation is between 30 and 50% ,those with high titres of circulating anti-PLA2R autoantibody have a greater risk of recurrent disease.
The treatment of disease recurrence includes a combination of anti-proteinuric agents, corticosteroids, alkylating agents, CNI, and rituximab. Secondary GN patients with secondary GN subtypes attributed to systemic diseases [such as atypical hemolytic uremic syndrome (aHUS), systemic lupus erythematosus (SLE), anti-glomerular basement membrane (GBM) disease, and crescentic GN may experience GN recurrence after kidney transplantation, but these relapses often occur later post-transplant and infrequently lead to allograft failure De novo GN
The prevalence of de novo GN is unknown, but is associated with significantly reduced
allograft survival compared to those without de novo glomerular disease. The incidence of de novo GN after kidney transplant varies between 4 and 20%, with FSGS, IgA nephropathy, membranous GN, and MPGN being the most common de novo
GN subtypes. There are difficulties in diagnosis because the cause of native ESKD is often uncertain (kidney biopsies were often not undertaken or were non-diagnostic), the presence of GN in the donor kidney may not be known (particularly in the absence of pre-implantation biopsy), variations histopathological evaluation of allograft biopsies where immunofluorescence and electron microscopy of biopsies may be not done
Alyaa Ali
2 years ago
primary glomerulonephritis is a common cause of ESRD , account for 7% ESRD patients on dialysis and 13% of transplanted patient
recurrent or denovo s an important cause GN of allograft failure
prevalence of GN recurrence is between 3 to15%
Recurrent IgA nephropathy
is common, occurs late post-transplant with cumulative incidence of disease recurrence at 15 years of 15%
after disease recurrence, up to 40% of patients develop allograft failure
Compared with other GN subtypes, the long-term allograft and patient outcomes of patients with IgA nephropathy are relatively better.
risk factors include younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy
no optimal treatment,
The practice is to maintain (or change to) a calcineruin-inhibitor (CNI) and corticosteroids-based
immunosuppressive regimen in addition to anti-proteinuric treatments, but the optimal doses remains unknown.
Recurrent primary FSGS
Up to 1 in 3 patients with primary FSGS will develop disease recurrence after kidney transplantation, with the risk of allograft failure 5-times the risk compared to those without disease recurrence
In contrast to patients with primary FSGS, familial FSGS in adults, comprising of those with mutations of podocin or structural podocyte proteins have low to no risk (<3%) of disease recurrence post-transplant
risk factors for disease recurrence in patient with primary FSGS include younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESKD, and prior allograft failure from disease recurrence
A pathogenic role of the circulating serum soluble urokinase receptor (suPAR) has
been proposed in the pathogenesis , by activating podocyte b(3) integrin resulting
in effacement of foot processes and proteinuria
Close monitoring for proteinuria in high risk patients, and proceeding to a kidney biopsy
Safi Annour
2 years ago
Recurrent and de novo Glomerulonephritis after Renal Transplantation
Please give a summary of this article
Primary GN are considered to be one of the major causes of ESKD in native kidneys, while recurrent or de novo GN post transplant is an important cause of premature graft failure. All GN subtypes can potentially recur post transplant at a rate between 3 and 15% particularly IgAN, idiopathic membranous GN, FSGS and MPGN. 5 year graft survival is similar between GN subtypes, apart from MPGN which is substantially poorer. Recurrent IgA Nephropathy
Recurrence is relatively common, occurs late post transplantation with recurrence at 15 years of 15%.
Up to 40% of recurrent IgAN patients tend to loose their graft and predominantly because of recurrence. The proportion of allograft failure secondary to disease recurrence was 1.6% for those with IgA nephropathy.
risk factors for disease recurrence; younger age, zero-mismatch LRD, steroid avoidance or early withdrawal, non-use of induction, crescentic IgAN in native kidneys and shorter total ischemia time.
No optimal treatment is known for recurrence, the practice to continue CNI, steroids and antiproteinuric. In crescentic and RPGN more aggressive therapy is needed (cyclophosphamide or rituximab) although not having a proven outcome. Tonsillectomy has limited potential benefit.
Recurrent Primary FSGS
Recurrence occur in third of patients with the risk of graft failure 5 times the risk compared to those without disease recurrence.
According to ANZDATA registry analysis, recurrence rate of FSGS among first KTRs is 10% with 5 years graft survival of 52% compared to 83% graft survival in those without disease recurrence.
The proportion of allograft failure secondary to disease recurrence is 2.7%.
Familial FSGS has low to no risk of recurrence(<3%) similar to pediatric genetic FSGS, making genetic testing of great importance in pre-transplant work up for patients with FSGS. Genetic screening may be more practical for patients with a clear family history of FSGS or those with a potential live-related donor for transplantation.
Risk factors for disease recurrence ; younger age at presentation, non-white ethnicity, severe disease at presentation, rapid deterioration to ESKD and previous graft failure.
management of FSGS recurrence include plasmapheresis, maximizing anti-proteinuric therapy, and converting to a CNI- based immunosuppressive regimen. Rituximab is considered as adjunctive therapy in resistant cases. Data is insufficient regarding the benefit of plasmapheresis and rituximab in reducing the risk of disease recurrence post Transplant.
Recurrent Primary MPGN
Disease recurrence is relatively common, with 50% of recurrence occur I the first 2 years. 5 year graft survival is 30% in disease recurrence.
The use of Eculizumab showed benefit in reduction of proteinuria and stabilization of kidney function post transplant.
The proportion of allograft failure secondary to disease recurrence is 5.6%.
Recurrent Idiopathic Membranous GN
The rate of disease recurrence is between 30 and 50%.
The reported incidence of recurrent lupus nephritis varies between 0 and 44%
The proportion of allograft failure secondary to disease recurrence is 3.3%.
The treatment of disease recurrence includes a combination of anti-proteinuric agents, corticosteroids, alkylating agents, CNI, and rituximab.
De novo GN
The true prevalence of de novo GN in kidney transplant recipients remains unknown and the incidence rate varies between 4 and 20%.
The risk of allograft failure is 7 times and more in those with de novo GN.
The commonest de novo subtypes are; FSGS, IgA nephropathy, membranous GN and MPGN.
Manal Malik
2 years ago
Summary of Recurrent and de novo
Glomerulonephritis After Kidney
Transplantation Introduction:
Primary glomerulonephritis is well known cause of end-stage renal disease and account about 17% of them. For post renal transplantation recipient or de novo glomerulonephritis. In the renal allograft is important cause of premature allograft failure. In the most common subtype of new glomerulonephritis are: IgA nephropathy, Idiopathic medullary glomerulonephritis, Focal segmental glomerulosclerosis, and membranoproliferative glomerulonephritis. The majority of glomerulonephritis recurrence resulting in allograft failure after 3-5 years post transplantation, although recurrence can occur early in patients with glomerulonephritis subtypes of membranoproliferative glomerulonephritis and focal segmental glomerulosclerosis. Recurrent IgA:
Usually occurs late and is common. It has begun presentation of the majority of patients such as microscopic hematourea or evidence of IgA deposition in allograft biopsies. 40% of patients with IgAN recurrence have been noted to lose their allograft (up to 60%). Data from the ANDATA registers showed that 5-year allograft survival following disease recurrence was similar between IgAN, Idiopathic membranous glomerulonephritis, and FSGS with the allograft survival of patients with membranous glomerulonephritis = compared to the glomerulonephritis subtypes.
Several risk factors for disease recurrence include young age recipient, zero-HLA mismatch live related donor, steroid free regimen immunosuppression medication, non-use of induction therapy, HLA-allele subtypes, crescentic IgAN, presence of galactose-deficient IgAI, and presence of antibodies glycan-specific IgG antibodies and soluble CD89(an Fc receptor for IgA). Still there are no biomarker with clinical relevance that can predicting disease recurrence post renal transplantation. For IgAN no guideline for management of recurrent IgAN post kidney transplantation but the current practice is to: maintain or change to CNIb and steroid based immunosuppression regimen, and anti-proteinuria treatment. Crescentic IgAN: use cyclophosphamide or rituximab although unlikely to reverse the disease process. Recurrent primary FSGS:
Risk of allograft failure from recurrence glomerulonephritis is 5 times the risk compared to those without disease recurrence. In spite of many reports mention high incidence of recurrence of primary FSGS but the time incidence recurrence unknown as secondary forms of FSGS can occur late post-transplant make difficulties in differentiating primary from secondary forms. Familial FSGS recurrence such as NPHSZ emphasized the importance of genetic testing in evaluation of patients with FSGS for transplantation especially in this group of patients:1) primary FSGS with atypical clinical or pathological feature or poor response to immunosuppression treatment, 2) family history of FSGS. The pathogenesis of disease recurrence in patients with primary FSGS remain unclear, with no studies confirming the presence of circulating permeability factors causing podocyte injury. Pathogenic role of the circulating serum soluble urokinase receptor (su PAR) by activating podocyte B (3) antigen resulting in effacement of foot processes and proteinuria, but its evaluation in inflammation and infection makes it independeted prognostic biomarker in precluding further risk of cardiovascular and mortality in general population, so the clinical utility of routine maintaining su PAR level post-transplant to predict disease recurrence remains poorly defined. Post renal transplantation recommendations are close maintain for proteinuria in high-risk patients, with regular checks of urine protein/creatinine ratio in the first 3 months of transplantation and proceeding to a kidney biopsy (electron microscopy detect early effacement of foot process). If there is persisting or increasing proteinuria, lack of random control trails and data about management of patients with resistance primary FSGS . A practical approach in the management of FSGS recurrence post transplantation: 1) initially plasmapheresis 2) maximizing anti-proteinuria therapy 3) converting to a CNI based immunosuppression regimen 4) B-cell depletion (rituximab) considered as adjunctive treatment or in resistant cases. There is insufficient data to suggest the pre-emptive use of plasmapheresis ± rituximab will reduce the risk of disease recurrence post transplantation. Recurrent primary membranoproliferative glomerulonephritis:
recurrence of primary MPGN is 50% in the first 2 years in the past 2 years post-transplant and 5 years allograft survival post disease recurrence of early 30% with highest rate for both C3GN and DDD are 50% of the patients. DDD usually recur late post renal transplant and often associated with no clinical manifestation other than allograft dysfunction. Presence of glomerular monoclonal Ig deposits has been associated with poorer prognosis. Up to 70% of patients with immune-mediated GN and monoclonal deposits have no evidence of plasma cell dysfunction. Its crucial pre-transplant screening for monoclonal gammopathy ± hematology review. In patients with MPGN. Treatment for recurrent disease of MPGN is not well established. The new classification and current knowledge of MPGN may assist clean to adapt a personalized treatment strategy according to the most likely pathogenesis and anti-B cell therapy for immune complex-mediated GN or monoclonal gammopathy or to consider eculizumab for C3 glomerulopathy. More cases and studies with large to low up data needed to determining the most appropriate treatment option for most renal transplantation recurrent disease. Recurrent idiopathic membranous GN:
The diagnostic test accuracy of circulating anti-PLAZR auto antibody in differentiating primary from secondary MN is acceptable with test sensitivity 65% and 97% specificity. 30 to 50% is the rate of primary MN recurrence. There is a direct relationship between the titer level and risk of disease recurrence post-transplantation. Circulating levels of anti-PLAZR maintain remain unclear but should be considered in those with: 1) high pre-transplant circulating levels of anti-PLAZR antibody 2) early disease recurrence (to predict disease progression. 3) to determine response to treatment. 4) to differentiate disease recurrence from de novo membranous GN or other cause of proteinuria. Practical approach to pre and post kidney transplantation risk assessment management of idiopathic membranous GN recurrence. Pre-transplant assessment: high risk characterized: 1) high titer anti-PAZR antibody 2) rapid progression of native ESRD 3) prior allograft failure secondary to recurrent IMN (less 5 years) Transplant period: 1) anti-PLAZR antibody titer 2) CNI-based immunosuppression Post renal transplant: maintain (frequency). Anti-PLAZR antibody titer, proteinuria, early allograft biopsy. If there is recurrence: 1) CNI+ steroid+ rituximab 2) alkylating agents De novo GN:
Time prevalence of de novo GN in kidney transplantation recipient remains unknown. With incidence 4 to 20% with FSGS, IgAN, MN, and MPGN being the most common de novo GN subtypes. The presentation of these with de novo GN are similar to those with primary G N subtype remaining from a symptomatic = or biochemical abnormalities to event symptoms and signs of GN with nephrotic syndrome and renal dysfunction. Factors cause de novo FSGS: 1) reduction in nephron mass 2) induction of sirolimus and is difficult to differentiate secondary forms of FSGS from de novo GN. Treatment of de novo FSGS: 1) can be resolved by adequate ant-proteinuria treatment 2) treat the cause ( agents or factor) 3) in some cases aggressive therapy may be needed. de novo IgAN:
Is usually benign and response to anti-proteinuria or antihypertensive therapy, but crescentic de novo IgAN tend to have a poor prognosis even with aggressive treatment with steroid and alkylating agents. de novo membranous GN and MPGN:
Are less common. secondary causes in recipient who develop de novo GN. Should be role out before commence treatment options and re-transplant potential. Conclusion:
Approach and treatment of post-transplant GN recurrence remain uncertain. More researches needed for understanding and treatment of recurrence GN post-transplant
Ramy Elshahat
2 years ago
Recurrent and de novo Glomerulonephritis After Kidney Transplantation
INTRODUCTION
Primary glomerulonephritis (GN) in the native kidneys is one of the leading causes of end-stage kidney disease (ESKD) worldwide. GN is a group of immunological kidney diseases with different histological subtypes, causes (primary vs. secondary), and clinical phenotypes and is also associated with different prognoses after kidney transplantation. All GN subtypes can potentially recur after transplantation, with different prevalence of GN recurrence generally around 15%. there is a group considered at high risk of recurrence this include (IgA nephropathy, idiopathic membranous GN, focal segmental glomerulosclerosis (FSGS), and membranoproliferative GN (MPGN).
the incidence of de novo or recurrent GN after kidney transplantation is under-estimated mostly related to the unknown primary causes of ESKD, misclassification, and indication bias. The risk of GN recurrence is directly related to time post-transplant some diseases recurrence is early like MPGN and 1ry FSGS and some others recurrence is late like SLE and 1ry MGN but the majority of GN recurrence occurs after 3–5 years post-transplant. 1. Recurrent IgA Nephropathy
Recurrent IgA nephropathy is relatively common around 15% and usually occurs late but the Risk of graft loss after recurrence is around 40%.
This disease usually presents with microscopic hematuria or evidence of IgA deposition in allograft biopsies.
There are multiple risk factors for disease recurrence including younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy (whereas anti-thymocyte globulin [ATG] may be associated with a lower risk of recurrence), HLA allelic subtypes, crescentic (and rapidly progressive) IgA nephropathy in the native kidneys and shorter total ischemic time.
There are multiple urine and serum biomarkers like serum level of IgG anti-Gd-IgA1 antibodies, glycan-specific IgG antibodies, and soluble CD89 (an Fc receptor for IgA) which are involved in the pathogenesis of IgA nephropathy used to predict the risk of disease progression and recurrence post-transplant but the prognostic value of these biomarkers have not been truly established.
The optimal treatment of recurrent IgA nephropathy remains unknown and the current practice is to maintain (or change to) a calcineurin-inhibitor (CNI) and corticosteroids-based immunosuppressive regimen in addition to anti-proteinuric treatments+SGLT2 inhibitors after rising of its effectiveness in DAPA CKD study. In cases of crescentic rapidly progressive IgA nephropathy, more aggressive immunosuppression (e.g., cyclophosphamide or rituximab) may be considered 2. Recurrent Primary FSGS
the true incidence of recurrent disease remains unknown as secondary forms of FSGS can occur late post-transplant, resulting in difficulties in differentiating primary from secondary forms but usually rate of recurrence is up to 1 in 3 (33%) patients with primary FSGS with the risk of allograft failure (predominantly from GN recurrence) 5-times the risk compared to those without disease recurrence. poorer 5-year allograft survival of 52%. with disease recurrence, compared with 83% in those without recurrent disease.
To differentiate 1ry from 2ry is sometimes very difficult and some recommend doing a genetic study to rule our familial FSGS which has a very low risk of recurrence and may provide important information regarding prognosis and best immunosuppression regimens pre-and post-transplant or those with a potential live-related donor for transplantation, including undertaking genetic screening of the donors for the same genetic mutations (if present in the potential recipients). Some serum marker was evaluated for both diagnostic and prognostic value like suPAR but serum suPAR level was higher in patients with familial FSGS compared to those with non-genetic primary FSGS, also be nonspecifically elevated in other pathological processes including inflammation and infection and has been shown to be an independent prognostic biomarker in predicting future risk of CVD and mortality in the general population. Other potential biomarkers including urine suPAR, Anti-CD40 autoantibody, and angiotensin receptor II type 1 (AT1R) antibody appear promising but further studies are required to determine the accuracy of these prognostic biomarkers in predicting disease recurrence.
Usual clinical presentation is a nephrotic syndrome which may occur early post-transplant so, Close monitoring for proteinuria in high-risk patients, with regular checks of urine protein/creatinine ratio or self-check urine dip-stick in the first 3 months post-transplant are recommended, and proceeding to a kidney biopsy with electron microscopy to detect early effacement of foot processes)
The management of patients with recurrent primary FSGS remains challenging Plasmapheresis is often preferred and recommended for the removal of unknown offending circulating factors. The roles of pre-emptive plasmapheresis (pre and/or post-transplantation), immunoadsorption therapy, and other novel options such as ofatumumab or B7-1 blockers (abatacept and belatacept) to prevent disease recurrence or to treat recurrence appear promising but the efficacy of these treatments remains debatable.
Using of adjunctive therapy including rituximab and CNI such as cyclosporine remains uncertain However, a switch to CNI if patients were on mammalian target of rapamycin [mTOR]-inhibitor is recommended. and not always consistent or supported in subsequent studies. 3. Recurrent Primary MPGN
Disease recurrence post-transplant from primary MPGN is common and early within the first 24 months post-transplant and the risk of allograft failure within 5-year 70%. The new classification of MPGN is more convenient as its more related to disease pathogenesis and histological findings (i.e., immune complex-mediated MPGN and complement-mediated MPGN
Immune-complex mediated MPGN is characterized by the glomerular deposition of polyclonal or monoclonal immunoglobulins (Ig), whereas C3 glomerulopathy [comprising of C3GN and dense deposit disease (DDD)] is characterized by the glomerular deposition of C3 in the absence of Ig deposition. high rate of post-transplant recurrence for both C3GN and DDD, with over 50% of patients with disease recurrence reported experiencing allograft failure. DDD is more likely to recur later post-transplant and often associated with no clinical manifestations other than allograft dysfunction. For immune-mediated MPGN, the patterns and types of Ig deposits may have diagnostic and prognostic significance. The presence of serum monoclonal proteins is associated with a poorer prognosis, characterized by early disease recurrence and substantially greater risk of premature allograft failure following disease recurrence. Up to 70% of patients with immune-mediated GN and monoclonal deposits have no evidence of plasma cell dyscrasia (i.e., absence of serum and urine monoclonal Ig proteins or evidence of plasma cell dyscrasia in the bone marrow), whereas in the remaining 30% of patients, patients often have detectable elevated monoclonal proteins without fulfilling the criteria for multiple myeloma (often termed “monoclonal gammopathies of renal significance”).
It is important to note that monoclonal gammopathy may be present in both immune complex-mediated and complement-mediated MPGN) so, pre-transplant screening for monoclonal gammopathy ± hematology review in patients with MPGN, while ensuring close monitoring post-transplant for signs of disease recurrence.
the optimal treatment strategy remains unknown but plasmapheresis and other immunosuppressive agents including cyclophosphamide, eculizumab, and rituximab can be used. The new classification and current knowledge of MPGN may assist clinicians to adopt a personalized treatment strategy according to the most likely pathogenesis of the disease process (e.g., consideration of plasmapheresis and anti-B cell therapy for immune complex-mediated GN or those with monoclonal gammopathy or to consider eculizumab for C3 glomerulopathy). 4. Recurrent Idiopathic Membranous GN
The discoveries of the pathogenic antiphospholipase A2 receptor (PLA2R) have led to breakthroughs in the understanding, management, and treatment of patients with idiopathic membranous GN which improved recognition and differentiating primary vs. secondary membranous GN, as well as assisting clinicians in the management of patients pre and post-transplantation. Serum test sensitivity of 65%, specificity of 97%.
The rate of disease recurrence in patients with idiopathic membranous GN following kidney transplantation is between 30 and 50%. there is a direct relationship between the titer level and risk of disease recurrence post-transplant and the positive predictive value of pre-transplant anti-PLA2R antibodies for disease recurrence is 83%, the diagnostic threshold of anti-PLA2R antibody in defining the risk of disease recurrence remains poorly defined (some recent publications showed it could be more than 40ng/l.
The treatment of disease recurrence includes a combination of anti-proteinuric agents, corticosteroids, alkylating agents, CNI, and rituximab. Rituximab is an effective treatment for native and recurrent membranous GN in the allograft, with up to 80% achieving complete or partial remission with the use of rituximab for early disease recurrence post-transplant.
Secondary GN: relapses often occur later post-transplant and infrequently lead to allograft failure.
patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, the relapse rate 2% per year, with no association between ANCA subtypes or disease severity prior to transplantation and disease recurrence occurring post-transplant.
Recurrence of lupus nephritis post-kidney transplantation is unclear and varies between 0 and 44%, with patients who had experienced recurrent lupus nephritis at a greater risk of allograft failure and mortality. However, this association remains inconsistent.
In patients with anti-GBM disease, disease recurrence after kidney transplant is <5% in the era of modern immunosuppression, and allograft failure from disease recurrence exceedingly rare.
the risk of disease recurrence following transplantation of patients with aHUS was up to 80%, with a substantial proportion of patients losing their allografts from the recurrent disease within the first-year post-transplant but these results improved after the availability of the C5-inhibitor eculizumab and make it appeared to be safe with excellent allograft outcome, even in those with pathogenic mutations known to be associated with a high risk of disease recurrence. kidney transplantation without the use of prophylactic eculizumab but this is generally not recommended or undertaken with extreme caution in patients with certain genetic mutations (membrane-associated complement regulator membrane cofactor protein mutation). Presumed or Advanced GN
Patients with unknown 1ry kidney disease because a biopsy was not undertaken or done but too late. fortunately, the incidence of allograft failure attributed to GN is extremely low. De novo GN
The true prevalence of de novo GN in kidney transplant recipients remains unknown, the incidence of de novo GN after kidney transplant varies between 4 and 20%, with FSGS, IgA nephropathy, and membranous GN, and MPGN being the most common de novo GN subtypes.
There are difficulties in identifying and confirming the presence of de novo GN post-transplant because the cause of native ESKD is often uncertain, and the presence of GN in the donor’s kidney may not be known (particularly in the absence of pre-implantation biopsy).In patients whose ESKD was attributed to non-GN causes and had developed de novo GN, over 95% of cases were FSGS [42%], IgA nephropathy[27%], membranous GN [15%], and MPGN [12%]. The presentations of those with de novo GN are similar to those with primary GN subtypes De novo FSGS
it is often difficult to differentiate secondary forms of FSGS from “actual” de novo 1ry FSGS GN and may to some extent explain why most cases of de novo FSGS tend to occur later post-transplant (compared to the recurrence of primary FSGS). the treatment of de novo FSGS predominantly revolves around adequate anti-proteinuric treatment and the removal of the offending agents/factors where possible. Re-transplantation following allograft failure from de novo FSGS can be considered, but clinicians should attempt to establish and exclude or avoid potential causative factors that had resulted in the development of de novo FSGS. de novo IgA nephropathy
The incidence of de novo IgA nephropathyis likely to be underestimated, with asymptomatic IgA deposition not infrequently found (detected incidentally in protocol or indication biopsies or potentially donor-derived asymptomatic disease detected on pre-implantation biopsies). However, presentation with macroscopic hematuria is unusual.
The prognosis of those with de novo IgA nephropathy is usually relatively benign with treatment predominantly focusing on anti proteinuric and/or anti-hypertensive therapy but crescentic de novo IgA nephropathy tends to have a poorer prognosis De novo membranous GN and MPGN The incidence is much less common and mostly related to secondary causes including viral infections, rejection, autoimmune disease, CNI, and thrombotic microangiopathy.
The onset of de novo membranous GN or MPGN tends to occur later post-transplant (compared to recurrent disease),
For membranous GN, glomerular staining for PLA2R may help to differentiate as glomerular staining for PLA2R was more common in those with recurrent disease (83%) compared to de novo disease (17%).
2ry causes need to exclude in any de novo GN, which is critical when considering treatment options and re-transplant potential following allograft failure.
Mohamad Habli
2 years ago
(ANZDATA) registry report, GN as cause of ESKD accounted for 17% of incident treated ESKD patients. In the US, GN as cause of ESKD comprised of 7 and 13% of incident ESKD initiated on dialysis and have received kidney transplants.
When considering the medical suitability of potential kidney transplant candidates with GN for kidney transplantation, clinicians must provide sufficient information with regards to the risk of disease recurrence post-transplant.
All GN subtypes can potentially recur after transplantation, with the prevalence of GN recurrence between 3 and 15%.
Recurrent IgA Nephropathy
Recurrent IgA nephropathy is relatively common, but typically occurs late post-transplant with cumulative incidence of disease recurrence at 15 years of 15%.
Following disease recurrence, up to 40% of patients with recurrent IgA nephropathy have been reported to lose their allografts, predominantly from disease recurrence.
Several risk factors for disease recurrence have been described including younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy (whereas anti-thymocyte globulin [ATG] may be associated with a lower risk of recurrence), HLA allelic subtypes, crescentic (and rapidly progressive) IgA nephropathy in the native kidneys and shorter total ischemic time.
The current practice is to maintain (or change to) a calcineruin-inhibitor (CNI) and corticosteroids-based immunosuppressive regimen in addition to anti-proteinuric treatments, although the optimal dosing/target therapeutic CNI level or specific CNI type in the treatment of those with recurrent disease remains unknown.
Recurrent Primary FSGS
Up to 1 in 3 patients with primary FSGS will experience disease recurrence after kidney transplantation, with the risk of allograft failure (predominantly from GN recurrence) 5-times the risk compared to those without disease recurrence.
Close monitoring for proteinuria in high risk patients, with regular checks of urine protein/creatinine ratio or self-check urine dip-stick in the first 3 months post-transplant are recommended, and proceeding to a kidney biopsy. CNI such as cyclosporine, through the inhibitory effect on T cell function and stabilization effect on actin cytoskeleton in kidney podocytes, has been shown to induce clinical remission in patients with recurrent FSGS.
The roles of pre-emptive plasmapheresis (pre and/or posttransplantation), immunoadsorption therapy, and other novel options such as ofatumumab or B7-1 blockers (abatacept and belatacept) to prevent disease recurrence or to treat recurrence appear promising but the efficacy of these treatments remain debatable and not always consistent or supported in subsequent studies .
Recurrent primary MPGN
Disease is classified into IC-mediated and complement-mediated ( C3GN & DDD). There is up to 50% risk of recurrence in the post-transplant period for both C3GN and DDD, with over 50% of patients with disease recurrence reported will have allograft failure. DDD is more likely to recur later post-transplant and often associated with no clinical manifestations other than allograft dysfunction.
The approach to treatment for recurrent disease is not wellestablished, limited to case series of successful treatment with the use of plasmapheresis and other immunosuppressive agents including cyclophosphamide, eculizumab, and rituximab.
De novo GN
FSGS, IgA nephropathy, MN, & MPGN are the most common de novo GN subtypes. De novo GN occurred in 3.4% of those with primary ESRD from GN & 3.6% of those with ESRD from non-GN causes.In those with primary non-GN causes, FSGS was the commonest cause of de novo GN (over 95%);IgA nephropathy, MN, & MPGN were less common.
The risk of graft loss was 7-times greater in patients with de novo GN, compared to those
without disease.
It is difficult to differentiate secondary FSGS from“actual” de novo non-collapsing GN & may explain why de novo FSGS tend to occur later post-transplant (compared to primary FSGS).
The long-term outcome of de novo FSGS is relatively poor (5-year allograft survival of <50%).
In conclusion,despite the advances in the understanding of the epidemiology, pathogenesis, and classification of primary and recurrent GN after kidney transplantation, considerable uncertainty remains in the approach and treatment of post-transplant GN recurrence
Amit Sharma
2 years ago
Please give a summary of this article
Glomerulonephritis (GN) is an important cause of end stage renal disease requiring kidney transplant. Post-transplant recurrent or de-novo primary GN especially IgA nephropathy, idiopathic membranous nephropathy, focal segmental glomerulosclerosis (FSGS) and membranoproliferative GN (MPGN) has a major role in graft loss. Most of the recurrent GN occur 3-5 years post-transplant but can present earlier with FSGS and MPGN.
1) Recurrent IgA Nephropathy: It occurs late with 15% at 15 years post-transplant, with recurrence rates of 30-40%, losing graft in 40% cases with 60% due to the disease recurrence.
Risk factors for recurrence include younger age, zero HLA mismatched kidney recipient, steroid avoidance or withdrawal regime use, non-use of induction therapy, HLA allelic subtypes, increased galactose deficient IgA1 and IgA-IgG immune complex, decreased levels of circulating complexes of IgA soluble CD89, shorter ischemic time and crescentic and rapidly progressive IgA nephropathy in the native kidneys.
The optimal treatment is unknown. The patient is maintained on calcineurin inhibitors (CNI) with steroids and anti-proteinuric treatment. Crescentic IgA nephropathy may be treated with cyclophosphamide or rituximab although they are unlikely to be helpful.
2) Recurrent primary FSGS: One third of primary FSGS patients develop recurrence post-transplant with 5 times increased risk of graft loss upto 65% at 5 year post-transplant.
Risk factors for recurrence include younger age, living donor, severe disease (decreased serum albumin and increased proteinuria), non-white race, rapidly progressive disease in the native kidneys, second transplant due to prior recurrence. Biomarkers for recurrence include serum and urine suPAR, anti-CD40 autoantibody and angiotensin receptor II type 1 (AT1R) antibody have shown promise. It is important to monitor proteinuria closely post-transplant and an early kidney biopsy in case of increasing or persisting proteinuria.
The patient is managed with plasmapheresis with or without rituximab, use of CNI and anti-proteinuric treatment. Efficacy of pre-emptive plasmapheresis with or without rituximab, and drugs like abatacept and ofatumumab has not been proved in prevention of recurrence.
3) Recurrent Primary MPGN: 50% of primary MPGN patients develop recurrence post-transplant within first 2 years with 5-year graft failure in 66% patients.
MPGN can be either C3 glomerulopathy including C3 glomerulonephritis (C3GN) and dense deposit disease (DDD) or immune-mediated MPGN including polyclonal immunoglobulin and monoclonal immunoglobulins deposition disease. All the types recur early except the polyclonal immunoglobulin deposit disease. Amongst the C3 glomerulopathy, DDD occur later than C3GN.
Risk factors for recurrence include C3 glomerulopathy subtypes, presence of monoclonal gammopathy, poor response to treatment and rapidly progressive disease in the native kidneys.
The patient is managed with anti-proteinuric treatment and treatment of monoclonal gammopathy if present. Eculizumab us is helpful in C3 glomerulopathy while plasmapheresis with immunosuppression like alkylating agents and rituximab are helpful in treating immune complex MPGN.
4) Recurrent idiopathic Membranous GN: It occurs late with 30-50% recurrence rates post-transplant, with recurrence rates of 30-40%, losing graft in 44% cases at 5-year post-transplant.
Risk factors for recurrence include presence (and high titre) of antiPLA2R autoantibody prior to transplant (having 60-75% recurrence rate as compared to 28-30% recurrence in absence of these antibodies), rapid progression of native disease and prior graft failure due to recurrence of membranous nephropathy, especially in first 5 years post-transplant. Patients with high titres prior to transplant should be monitored for titres as well as proteinuria.
The treatment should be started early, when proteinuria is >1gram per day and includes anti-proteinurics, calcineurin inhibitors (CNI) with steroids and rituximab achieving 80-90% remission, having better results than alkylating agents.
5) Secondary GN: These include atypical hemolytic uremic syndrome (aHUS), SLE, anti-GBM disease and crescentic GN. Relapses in these cases occur late and graft loss is infrequent. SLE relapse rates are 0-44% while aHUS has relapse rates of upto 80% which has now reduced due to pre-emptive use of eculizumab.
6) Presumed or Advanced GN: Recurrence in patients with uncertain etiology of renal failure is very low (5%), 90% of which is due to FSGS, membranous nephropathy and IgA nephropathy.
7) De novo GN: It is usually seen later in post-transplant period (compared to recurrent GN) and occurs in 4-20% of transplant recipients with FSGS (most common), IgA nephropathy, MPGN and membranous nephropathy as the predominant forms and increases the risk of graft loss by 7 times. De novo FSGS has less than 50% graft survival at 5 years post-transplant. De novo MPGN with graft failure has high risk of graft failure after re-transplantation. Prognosis of de novo IgA nephropathy is favourable except in presence of crescents.
Hence it is important to remain vigilant about recurrence of GN in a kidney transplant patient
Ahmed Abd El Razek
2 years ago
INTRODUCTION
Primary glomerulonephritis is one of the leading causes of end-stage renal disease worldwide. GN is a heterogeneous group of immunological kidney diseases differ in histological subtypes, causes (primary vs. secondary) and clinical phenotypes resulting in variable prognoses post renal transplantation with dissimilar GN subtypes and their risk of recurrence after. Recurrent or de novo GN in the renal allograft is an important cause of premature allograft failure. All GN subtypes can potentially recur particularly IgA nephropathy, idiopathic membranous GN, focal segmental glomerulosclerosis (FSGS), and membranoproliferative GN (MPGN). Recurrent IgA Nephropathy
It is common, but typically occurs late post-transplant. Demonstrated by the relative benign presentations of the majority of patients (presenting with microscopic hematuria or evidence of IgA deposition in allograft biopsies). About 40% of patients with recurrent IgA nephropathy have reported graft loss, predominantly from disease recurrence (up to 60%).Compared to other GN subtypes, the long-term allograft and patient outcomes of patients are substantially better.
In this study, the proportion of allograft failure secondary to disease recurrence was 1.6% for those with IgA nephropathy, compared with 5.6, 2.7, and 3.3% for those with MPGN, FSGS, and idiopathic membranous GN, respectively.
Risk factors for disease recurrence (younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy).
Anti-thymocyte globulin [ATG] and shorter total ischemic time may be associated with a lower risk of recurrence.
The presence of some molecules, as galactose-deficient IgA1 (Gd-IgA1), IgG anti-Gd-IgA1 antibodies, glycan-specific IgG antibodies, and soluble CD89 (an Fc receptor for IgA) which may be involved in the pathogenesis of IgA nephropathy predicts a greater risk of disease progression and disease recurrence posttransplant.
The current practice regarding recurrence is to use calcineruin-inhibitor (CNI) and corticosteroids-based immunosuppressive regimen in addition to anti-proteinuric measures.
Recurrent Primary FSGS
Up to 1 in 3 patients with primary FSGS will experience disease recurrence after kidney transplantation, with the risk of allograft failure (predominantly from GN recurrence) 5-times the risk compared to those without disease recurrence.
Familial FSGS in adults, have low to no risk (<3%) of disease recurrence post-transplant suggesting the relative importance of genetic testing in the evaluation of patients with adult-onset FSGS for transplantation.
Risk factors for disease recurrence in patient with primary FSGS (younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESKD, and prior allograft failure from disease recurrence ).
The pathogenesis of disease recurrence may be suggested by the pathogenic role of circulating serum soluble urokinase receptor (suPAR) by activating podocyte beta (3) integrin resulting in effacement of foot processes and proteinuria.
Serum suPAR level was found elevated in patients with FSGS, also, reduction of serum suPAR level with immunosuppressive treatment was associated with a greater probability of achieving clinical remission.
However, this patho-physiological link remains debatable.
Other potential biomarkers may include urine suPAR, Anti-CD40 autoantibody, and angiotensin receptor II type 1 (AT1R) antibody seem to be promising.
Close monitoring of proteinuria in high risk patients in the first 3 months post-transplant are recommended, and proceeding to a kidney biopsy (tissues should be sent for electron microscopy to detect early effacement of foot processes) if there is persistent or increasing proteinuria.
The management of patients with recurrent primary FSGS: Plasmapheresis combined with adjunctive therapy including rituximab and CNI. Recent research showed that rituximab binds sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) protein, resulting in preservation of podocyte SMPDL-3b expression, preventing podocyte apoptosis. CNI exhibit inhibitory effect on T cell function and stabilization effect on actin cytoskeleton of podocytes, inducing clinical remission in patients with recurrent FSGS.
Ofatumumab, an anti-CD20 monoclonal antibody that induces B cell depletion appears promising in the prevention and treatment of recurrent FSGS post-renal transplant.
A practical approach in the management of FSGS recurrence post-transplantation should initially include plasmapheresis, maximizing anti-proteinuric therapy, and converting to a CNI based immunosuppressive regimen with B cell depletion (rituximab) considered as adjunctive treatment in resistant cases. Recurrent Primary MPGN
It is relatively common, with over 50% of recurrence occurring within the first year post-transplantation. The high risk of allograft failure with 5-year allograft survival post-disease recurrence is about 30%.
Immune-complex mediated MPGN is characterized by the glomerular deposition of polyclonal or monoclonal immunoglobulins (Ig), whereas C3 glomerulopathy [comprising of C3GN and dense deposit disease (DDD)] is characterized by the glomerular deposition of C3 in the absence of Ig deposition.
DDD recurs later post-transplant associated with no clinical manifestations other than allograft dysfunction.
C3GN and DDD are identified by the presence of strong glomerular staining for C3 and electron deposits on electron microscopy.
The pathogenesis of this disease regarding complement dysregulation remains uncertain. Genetic mutations (e.g., presence of H402,V62 alleles of Factor H, mutations of Factor H, and I genes) or autoantibodies (e.g., C3 or C4 nephritic factor directed against C3 convertase or Factor H autoantibodies) are being suggested.
Immune-mediated MPGN patterns and types of Ig deposits may have diagnostic and prognostic significance.
The presence of glomerular monoclonal Ig deposits (typically IgG3k and IgG3l) was associated with poorer prognosis, characterized by early disease recurrence and substantially greater risk of premature allograft failure following disease recurrence.
The approach to treatment for recurrent disease relies on the use of plasmapheresis and other immunosuppressive agents as cyclophosphamide, eculizumab, and rituximab. The benefit of eculizumab in reducing proteinuria and stabilization of kidney function is being studied.
Consideration of plasmapheresis and anti-B cell therapy for immune complex-mediated GN or those with monoclonal gammopathy or to consider eculizumab for C3 glomerulopathy would be a wise approach in such cases. Recurrent Idiopathic Membranous GN
Recognition and differentiating primary vs. secondary membranous GN improved by the presence of anti-PLA2R autoantibody. The absence of PLA2R autoantibody does not definitively exclude cases of idiopathic membranous GN. The test’s diagnostic accuracy in differentiating primary from secondary membranous GN is acceptable, with sensitivity 65% (63–67%) and specificity 97% (97–98%).
The test’s performance accuracy is similar to the positive glomerular staining of PLA2R antigen. Another antibody specific for the autoantigen thrombospondin type 1 domain–containing 7A (THSD7A) has been detected in up to 5% of patients with idiopathic membranous GN.
The rate of disease recurrence in patients ranges between 30 and 50%post renal transplant. Patients with high titres of anti-PLA2R autoantibody have a greater risk of disease recurrence. The positive predictive value of pre-transplant anti-PLA2R antibodies for disease recurrence is 83%. However, the diagnostic threshold of anti-PLA2R antibody in defining the risk of disease recurrence is still undefined.
The need for monitoring anti-PLA2R antibody post-transplant should be considered in patients with high pretransplant levels of anti-PLA2R antibody and those showing early disease recurrence (to predict disease progression, determine response to treatment and to differentiate disease recurrence from de novo membranous GN or other causes of proteinuria).
The treatment of disease recurrence is mainly by anti-proteinuric agents, corticosteroids, alkylating agents, CNI, and rituximab. Rituximab is an effective treatment for native and recurrent membranous GN in the allograft, with up to 80% achieving complete or partial remission for early disease recurrence post-transplant. Secondary GN
Patients with secondary GN post renal transplant experience relapses later post-transplant and infrequently cause allograft failure.The incidence of recurrent lupus nephritis varies between 0 and 44% and it is associated with high risk of allograft failure and mortality. While patients with anti-GBM disease, disease recurrence after kidney transplant is <5%. Patients with aHUS show recurrence up to 80%, with the prophylactic use of eculizumab renal transplantation became safer with excellent allograft outcome. Presumed or Advanced GN
In this study, 90% of the allograft failures from GN were due to FSGS, membranous GN and IgA nephropathy, but it is unknown whether these GNs represent recurrent or de novo GN. De novo GN
It is associated with significantly reduced allograft survival compared to those without de novo glomerular disease. The incidence of de novo GN post renal transplant varies between 4 and 20%. FSGS, IgA nephropathy, membranous GN, and MPGN are the most common de novo GN subtypes.
In this study, the risk of allograft failure was over 7-times greater among recipients who have developed de novo GN, compared to those without disease. The presentations of those with de novo GN are similar to those with primary GN subtypes, ranging from asymptomatic urinary or biochemical abnormalities to overt symptoms and signs of GN with nephrotic syndrome and renal dysfunction.
Risk factors predisposing to the development of de novo FSGS are associated with a reduction in nephron mass (leading to compensatory hyperfiltration as diabetes, hypertension, BK viral infection,CNI and rejection).
Irrespective of the nature of de novo FSGS, the long-term allograft outcome is relatively poor, particularly in the presence of interstitial fibrosis/tubular atrophy with 5-year allograft survival of <50% after diagnosis. Treatment of de novo FSGS mainly is anti-proteinuric measures.
The incidence of de novo IgA nephropathy is underestimated, with asymptomatic IgA deposition detected incidentally in biopsies and presentation with macroscopic hematuria is unusual. The prognosis is relatively benign with treatment mainly directed to antiproteinuric and anti-hypertensive therapy if existed. With special regards to crescentic de novo IgA nephropathy being of poor prognosis later on.
De novo membranous GN and MPGN are much less common. They also occur later post-transplant with symptoms ranging from asymptomatic mild proteinuria and incidental biopsy findings to nephrotic range proteinuria and rapidly progressive GN. Regarding membranous GN, the pattern of staining for PLA2R may help to differentiate de novo from recurrent disease. Injury to the podocytes occurring post-transplantation triggers the release of podocyte antigens inducing the formation of auto-antibodies and deposition of subepithelial immune complexes. All patients with de novo membranous GN and MPGN, careful histological examination for potential secondary causes must be sought. CONCLUSION
The clinical care of patients with recurrent or de novo GN remains challenging with tailoring of specific treatment strategies of different types of recurrent or de novo GN should be achieved.
Hinda Hassan
2 years ago
The optimal treatment strategy remains unknown Recurrent IgA Nephropathy Epidemiology: the cumulative incidence of recurrence at 15 years is 15% and the rate of graft loss is 40% up to 60. Risk factors for disease recurrence: younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy (whereas anti-thymocyte globulin may be associated with a lower risk of recurrence), HLA allelic subtypes, crescentic (and rapidly progressive) IgA nephropathy in the native kidneys , shorter total ischemic time, several molecules( galactose-deficient IgA1 (Gd-IgA1), IgG anti-Gd-IgA1 antibodies, glycan-specific IgG antibodies, and soluble CD89 (an Fc receptor for IgA)) and other non-specific serum and urine biomarkers. The treatment: Maintain/change to a calcineruin-inhibitor, corticosteroids-based immunosuppressive regimen and anti-proteinuric treatments. Tonsillectomy has been suggested. In crescentic rapidly progressive IgA nephropathy use more aggressive approach like cyclophosphamide or rituximab. Recurrent Primary FSGS Epidemiology: Up to 1 in 3 patients with primary FSGS and the risk of allograft failure is 5-times the risk compared to those without disease recurrence. Familial FSGS have low to no risk (<3%) of disease recurrence Risk factors for disease recurrence younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESKD, prior allograft failure from disease recurrence and serum suPAR level ,urine suPAR, Anti-CD40 autoantibody and angiotensin receptor II type 1 (AT1R) antibody. Treatment: Close monitoring for proteinuria in high risk patients. Regular checks of urine protein/creatinine ratio or self check urine dip stick in the first 3 months post-transplant proceeding to a kidney biopsy and EM if there is persistent or increasing proteinuria. Plasmapheresis, maximizing anti-proteinuric therapy, CNI based immunosuppressive regimen and rituximab. Use of the following is promising; pre-emptive plasmapheresis (pre and/or posttransplantation), immunoadsorption therapy, atumumab or B7-1 blockers (abatacept and belatacept). Genetic screening , after a discussion between clinicians and patients, of patients with a clear family history of FSGS or those with a potential live related donor (screening of the donors for the same genetic mutations of the potential recipients). Recurrent Primary MPGN Epidemiology > 50% of recurrence occurs within the first 24 months post transplant. The 5-year allograft survival after recurrence is 30%. DDD tends more likely to recur later when compared to C3GN and is often associated with no clinical manifestations other than allograft dysfunction. Risk factors: For immune-mediated MPGN, the activation of the complement cascade, the presence of glomerular monoclonal deposits of IgG3k and IgG3l (IgG2l has been reported) Treatment Plasmapheresis , cyclophosphamide, eculizumab, and rituximab . Recurrent Idiopathic Membranous GN Epidemiology The rate of disease recurrence is 30 – 50%.The relative risk of allograft failure is 50% at 10-years. Risk factors High titers of circulating anti-PLA2R autoantibody Management: Monitoring anti-PLA2R antibody post-transplant for: Those with high pre-transplant circulating levels of anti-PLA2R antibody Those with early disease recurrence (to predict disease progression) To determine the response to treatment To differentiate disease recurrence from de novo membranous GN or other causes of proteinuria Treatment include: anti-proteinuric agents, corticosteroids, alkylating agents, CNI or changing from mTOR inhibitor-based regimen to CNI and addition of anti-CD20 antibodies rather than introducing alkylating agents (Rituximab can be considered in those with detectable high levels of anti-PLA2R antibody with prior allograft failure from recurrent membranous GN or have persistent high or increasing levels of circulating anti-PLA2R antibody post-transplant with early histological recurrence. Bortezomib in rituximab resistant recurrent). Secondary GN Secondary GN were associated with a late recurrence post-transplant and infrequently lead to allograft failure. ANCA associated vasculitis: the relapse rate (often extra-renal complications) has been reported at 0.02 per patient-years, with no association betweenrecurrence and ANCA subtypes or disease severity prior to transplantation . Lupus nephritis: incidence of recurrent lupus nephritis varies between 0 and 44%. Anti- GBM disease: disease recurrence after kidney transplant is <5%. Allograft failure is rare. Atypical hemolytic uremic syndrome aHUS: before eculizumab use, the risk was up to 80%. Presumed or Advanced GN These are cases in which a biopsy was not undertaken or were non-diagnostic with non-specific histological features. The incidence of allograft failure attributed to them is extremely low. De novo GN The incidence of de novo GN after kidney transplant varies between 4 and 20%. The common subtypes are FSGS, IgA nephropathy, membranous GN, and MPGN. It is difficult to identify and confirm the presence of de novo GN post-transplant because the cause of native ESKD is often uncertain. The de novo FSGS: occur due to a reduction in nephron mass (resulting in compensatory hyperfiltration of remaining nephrons such as diabetes, hypertension, BK viral infection, CNI therapy, and rejection) or the introduction of sirolimus (through the effects on podocyte integrity). Most cases of de novo FSGS tend to appear later post transplant (compared to the recurrence of primary FSGS). The long-term allograft outcome is relatively poor, particularly in the presence of interstitial fibrosis/tubular atrophy with 5-year allograft survival of <50% after diagnosis. Treatment include adequate anti-proteinuric treatment and the removal of the offending agents/factors where possible, but more aggressive therapy (similar to disease recurrence) may be considered. Re-transplantation following allograft failure from de novo FSGS can be considered. The de novo IgA nephropathy: prognosis is usually relatively benign with treatment predominantly focuses on anti-proteinuric and/or anti-hypertensive therapy. Crescentic de novo IgA nephropathy have a poorer prognosis and the efficacy of more aggressive treatment with steroids and alkylating agent remains unknown. Re-transplantation of patients with either disease is possible. De novo membranous GN and MPGN: are much less common, and the reported cases primarily related to secondary causes including viral infections, rejection, autoimmune disease, CNI and thrombotic microangiopathy. The onset of de novo membranous GN or MPGN tend to occur later post-transplant compared to recurrent disease. For membranous GN, the pattern of Ig staining or glomerular staining for PLA2R may help to differentiate de novo from recurrent disease ( recurrent disease have IgG1 staining in capillary loop while IgG4 staining in capillary loop is present in de novo disease).
Riham Marzouk
2 years ago
Recurrent GN is an important cause of graft failure in young patients, and responsible for 18-22 % of graft loss, it is an important cause of death either censored or uncensored graft failure.
Post-transplant GN can be either de novo or recurrent or donor derived.
De novo GN can be happened earlier post-transplant than recurrent one.
Risk factors for GN recurrence post-transplant: 1- age at the time of transplantation; more in younger
2- Longer ischemic time
3- Steroid use
1- Recurrent FSGS
30-70% of the primary cases can recur early or late post transplant, genetic type has low rate of recurrence, FSGS recur mostly late secondary to reduced renal mass.
Risk factors for recurrence of FSGS :
1- Young age
2- High BMI
3- White race
4- Rapid progression to ESRD in native kidney
5- Pre transplant severe proteinuria
6- Low serum albumin at the time of diagnosis
7- 80% risk of recurrence in second transplant
Prevention and treatment of recurrent FSGS:
1- Pre transplant plasmapheresis and rituximab is of benefit to prevent recurrence and also used in treatment of recurrence
2- Protocol biopsy is important in early detection.
2- Recurrent MGN (membranous GN)
40-50% of primary idiopathic MGN recur post transplant, 70-80% of them have anti-PLA2R antibodies with high risk of recurrence in contrast to 30% of cases whom have no detected antibodies have low risk of recurrence.
Recurrence can be detected early 1-2 weeks post transplant by protocol biopsy, if recurrence happens late 5 years or more due to new production of antibodies.
De novo MGN is not associated with antibodies.
Management of recurrent MGN:
1- Pre transplant detection of high risk patients; rapid progression to ESRD in native kidney, high titer of antibodies, history of graft failure due to recurrent idiopathic membranous GN in the graft in less than 5 years post transplant.
2- Anti-PLA2R antibodies titer, immunosuppression should be CNI based
3- Titer of antibodies should be monitored post transplant , also proteinuria, and protocol biopsy should be done
4- CNI, steroid and rituximab should be a treatment of choice if recurrence happened.
3- Recurrent MPGN
MPGN can be classified based on IF as the following:
a- Immune mediated immunoglobulin and complement which may be mono or polyclonal
b- C3 dominant either C3 or DDD
c- Null complement and null immunoglobulin TMA
Recurrence is high in DDD and C3 glomerulopathy which are 25% and 50% respectively.
Rituximab prevent and treat MPGN with monoclonal immunoglobulin deposits.
Eculizumzb is monoclonal antibody inhibits C5 activation so prevent and treat C3 GN.
4- Recurrent IgA nephropathy
In 30-40% of the cases, histological recurrence is common than the clinical one, late presentation is common
Risk factors for recurrence:
a- HLA-B8-DR3
b- Steroid free regimen
c- Crescentic type
d- High level of circulating galactose deficient A1 and IgA Ig immune complex
e- Low level of circulating soluble complex of IgA CD89
No more therapeutic options to treat or prevent recurrence like ACEI, ARBS, cyclophosphamide, increase MMF dose, induction with ATG.
5- Secondary GN LN lupus nephritis
Recurrence can be early or late post transplant , protocol biopsy is important which can detect histological changes as it remains subclinical as class II is more common one.
amiri elaf
2 years ago
# Please give a summary of this article
*One of the most important causes of
(ESKD) is Primary glomerulonephritis (GN).
* GN is a heterogeneous group of immunological kidney diseases with different pattern that result in differences in the prognosis after kidney transplantation
*Recurrent or de novo GN following allograft transplantation is an important cause of premature kidney failure
* All GN subtypes can potentially recur after KT (3 & 15%) with high risk subtypes of IgA nephropathy, idiopathic membranous GN, (FSGS), and (MPGN)
* The risk of GN recurrence is typically related to the post transplant time, majority occurring after 3–5 years PKT, while MPGN and FSGS recurrences early.
# Epidemiology, Pathogenesis, and Outcomes of GN Recurrence After Kidney Transplantion
Recurrent IgA Nephropathy
*Relatively common, occurs late PKT with incidence of recurrence at 15 years of 15% and may be reducing over time, more than 40% of patients lose their grafts.
* Compared with other GN subtypes, the outcomes is better.
*Data from the ANDATA registry showed that 5-year allograft survival following disease recurrence was similar between IgA
nephropathy, idiopathic membranous GN, and FSGS, with the poor allograft survival in MPGN compared to other GN .
*Risk factors for disease recurrence including younger age, recipients of zero HLA mismatched, live related donor kidneys, steroid avoidance or early withdrawal immunosuppressive regimens, the non use of induction therapy, HLA allelic
subtypes, crescentic, shorter total ischemic time, several molecules (Gd-IgA1), IgG anti-Gd-IgA1 antibodies, glycan-specific IgG antibodies, and soluble CD89
*The treatment of recurrent IgA nephropathy remains unknown
# Recurrent Primary FSGS
*1 in 3 patients with primary FSGS has recurrence after KT with the risk of allograft failure 5-times compared to without disease recurrence
*Secondary forms of FSGS can occur late after KT resulting in difficulties to differentiate between primary and secondary forms.
*In comparison to primary FSGS, familial FSGS in adults, comprising of those with mutations of podocin or structural podocyte proteins have low to no risk (<3%) of disease recurrence suggesting the importance of genetic testing for patients with adult onset FSGS when uncertain primary and secondary FSGS sub types present or in case of clear family history of FSGS .
*There are several risk factors for disease recurrence in patient with primary FSGS including:
Younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESKD, and prior allograft failure from disease recurrence.
*The pathogenesis of disease recurrence is unclear, but could be due to presence of circulating permeability factor(s) causing podocyte injury instigating early disease recurrence.
*The role of urokinase receptor by activating podocyte b(3) integrin resulting
in effacement of foot processes and proteinuria and development of primary FSGS.
* Close monitoring for proteinuria in high risk patients, protein/creatinine ratio are recommended in the first 3 months post-transplant.
*kidney biopsy in persistent or increasing proteinuria .
*The management is by plasmapheresis, rituximab and CNI remains uncertain.
# Recurrent Primary MPGN
*Common, more than 50% of recurrence rate within the first 2 years post-transplant
*Immune-complex mediated MPGN is characterized by the glomerular deposition of polyclonal or monoclonal immunoglobulins.
*C3 glomerulopathy (C3GN and dense deposit disease (DDD)) is characterized by the glomerular deposition of C3 in the absence of Ig deposition .
* The pattern of glomerular Ig and complement product deposition may differentiate
between the MPGN subtypes and give information on the pathogenesis of the disease processes.
*The timing and clinical presentations of C3GN and DDD may be dissimilar, with DDD recur later post-transplant
and associated with allograft dysfunction.
* C3GN and DDD are characterized by the presence of strong glomerular staining for C3 and electron deposits on electron microscopy, but these diseases are morphologically different.
*The treatment for recurrent disease is not well clear but the use of plasmapheresis, cyclophosphamide, eculizumab, and rituximab may be successful.
# Recurrent Idiopathic Membranous GN
* The ability to test for the presence of anti-PLA2R autoantibody has resulted
in improved recognition and differentiating primary vs. secondary membranous GN and managing the patients
*The absence of PLA2R autoantibody does not exclude cases of idiopathic membranous GN.
*The recurrence rate between 30 and 50%, and those with high titres of circulating anti-PLA2R autoantibody have a greater risk of recurrence that tend to decline
post-transplant.
*The treatment includes a combination of anti-proteinuric agents, corticosteroids,
alkylating agents, CNI, and rituximab.
*Rituximab is an effective treatment for native and recurrent membranous with 80% complete or partial remission
*Bortezomib has been used for rituximab resistant casese.
# Secondary GN
*It may occurs secondary to systemic diseases (aHUS), (SLE), anti- (GBM), and crescentic GN.
*(ANCA)-associated vasculitis, the relapse rate 0.02 per patient-years, with no association between subtypes & disease severity.
*The incidence of recurrent lupus nephritis between 0 and 44%, while anti- GBM disease is <5%.
# Presumed or Advanced GN
*In patients with ESKD where the underlying etiology of the cause of ESKD is uncertain
*This study conducted that 90% of the allograft failures from GN may be due to FSGS, membranous GN and IgA nephropathy.
# De novo GN
* The incidence between 4 and 20%, with FSGS, IgA nephropathy,
membranous GN, and MPGN are the most common de novo GN subtypes.
*Some study showed, the incidence of de novo GN occurred in 3.4 and 3.6% of those with primary ESKD from GN and those with ESKD from non-GN causes respectively.
*In patients with non-GN causes and developed de novo GN, more than 95% of cases were FSGS, while IgA nephropathy, membranous GN and MPGN were less incidence.
*The risk of graft failure was 7-times more in recipients who developed de novo GN, compared to those without disease.
*The long-term graft survival is relatively poor, especially in the presence of interstitial fibrosis/tubular atrophy with 5-year of <50% after diagnosis.
*Treatment of de novo FSGS with anti-proteinuric and removal of the causative agents, but more aggressive therapy and re-transplantation may be inculcated.
*De novo IgA nephropathy is underestimated, with asymptomatic IgA deposition not infrequently found in biopsies, prognosis is relatively benign and the treatment with antiproteinuric and/or anti-hypertensive therapy.
*Crescentic de novo IgA nephropathy has poorer prognosis, aggressive treatment with steroids and alkylating agent may be considered.
* De novo membranous GN and MPGN are less common, and primarily related to secondary causes (viral infections, rejection, autoimmune disease, CNI and thrombotic microangiopathy), it is occur later, symptoms ranging from asymptomatic mild proteinuria and incidental biopsy findings to nephrotic
range proteinuria and rapidly progressive GN.
saja Mohammed
2 years ago
Introduction:
Glomerulonephritis primary vs secondary’s still considered one of the common causes to ESKF and the prevalence vary according to the different registry data in the range of 7-17 %. Recurrence or denovo GN is one of important risk of graft failure. Aim of the study:
This review article emphasis on the incidence, genetics, clinical characteristics and course of glomerular disease with attention to the risk of early graft loss. Post-transplant recurrence or denovo GN.
In attention to subtypes of high-risk glomerular disease like IgA nephropathy, primary FSGS, Idiopathic membranous and MPGN and their management plan pre and post transplantation assessments follow up and monitoring, treatment options in case of recurrence.
the rate of GN recurrence post-transplant increased over time in the range of 3-5 years post transplantation and its underestimated due to selection bias, misclassification and biopsies indication bias all these factors can affect the true incidence of post-transplant denovo or glomerular disease recurrence with diver results from different registry data from US , Canada , Australia , Korea but overall FSGS And MPGN shows higher rate of recurrence and higher rate of graft loss post transplantation followed by IgA and idiopathic membranous nephropathy as shown in table1. IgA nephropathy recurrence Usually common and late after 10-15 years, factors associated increase rate of recurrence including aggressive type of IgA in native kidney with crescentic IgA nephropathy, younger age, high IgA level. Recurrent Primary MPGN
Recurrence rate common Up to 50% in first 24 months post-transplant with lower 5-year graft survival only 30%. according to the new classification of MPGN, both IC mediated MPGN (glomerular deposition of polyclonal or monoclonal IG with risk of overlap and all patients with IC mediated MPGN should have screen for monoclonal disease with serum electrophoresis for plasma cell dyscrasia + bone marrow trephine biopsy , c3/c4 level and hematology review with close monitoring for disease recurrence post TX recurrence early and late with characteristic glomerular IG deposits +/-c4d , or Complement mediated like C3 nephropathy (c3 deposition without IG, Both C3 GN and DDD have > 50% risk of recurrence post-transplant with poor graft survival
C3 GN due to alternative pathway dysregulation with amplification of c3 complement proteins, some have genetic mutation alleles of factor H and I or factor H autoantibodies Treatment options varies between plasmapheresis, rituximab, eculizumab, , MMF based IS with diverse response and weak evidence from pilot studies and case series .however the new classification of MPGN with understanding the pathogenesis this help to personalized the treatment protocol with targeting IC mediated MPGN with plasmapheresis and rituximab , MMF based IS while limited the use of eculizumab for c3 GN . Idiopathic membranous:
Recurrence rate range 30-50%
Markers for idiopathic MGD
Anti -PLA2R autoantibody sensitivity 68 but high specificity 98%, and have direct relation with higher PLA2 auto-AB titer have higher chance for recurrence post-transplant
THSD7A only in 5% of idiopathic cases
20% OF idiopathic MGD are seronegative for both markers
Treatment almost similar to the treatment option of idiopathic MG for general population with focus on CNI based IS, ACEI, ARBS for proteinuria control and rituximab shows good response > 80% of cases, alkylating agents preferred to be avoided due to high risk of infection with intense IS, avoid m TOR as maintenance IS therapy. Some centers use rituximab prophylaxis pre transplant or immediately post-transplant in those with high APLA2 Titer to avoid recurrence. Secondary GN:
Like SLE, AAV, AHUS, anti GMB, Crescentic GN, those secondary GN associated with lower rate of recurrence and usually late post transplantation SlE incidence 0-44% and inconsistent but in case of recurrence associated with poor graft survival. Anti GBM < 5% and rarely impact the graft survival.
AHUS before the era of eculizumab associated with higher rate of recurrence > 80% with early graft loss and transplantation was contraindication for AHUS but nowadays its safe even from LD with the use of eculizumab prophylaxis even with rare genetic mutations and in certain gene mutation in MCP the transplantation is consider safe even without eculizumab prophylaxis but frequent monitoring needed for recurrence risk. De novo GN:
Common subtypes
Denovo IgA nephropathy, symptomatic hematuria unless RPGN crescentic Ig A with graft loss. Denovo FSGS (Non -Collapsing variant) up to 20% usually late compared to idiopathic FSGS, denovo FSGS Need to rule out secondary causes like DM, Drugs ( m TOR , Pamidronates , CNI ) , infection parvovirus , cmv , BKV ,associated with poor graft survival and 40% risk graft loss in 5 year, treatment focus on the control of underlying cause. Denovo MPGN, in < 3% secondary to Ig mediated MPGN, TMA, hepatitis C viral infection, Rejection, other systemic disease associated with higher rate of graft loss Denovo MGN IN 2% may be secondary to viral infection, HCV, HBV, ABMR, histologically in IF its IgG1 predominate and positive staining for PLA2 auto-antibodies. Less common and rare subtypes of denovo GN:
Minimal change GN
Immunotectoid GN
Fibrillary GN
FSGS collapsing variant rare < 1% could be viral or alloantibodies to angiotensin 11.
Conclusion: till date the management and care of patients with recurrence or denovo glomerular disease is challenging and underpowered by limited studies and we need more integrated researches to improve and personalized specific therapeutic options to specific types of recurrent or denovo GN .
Theepa Mariamutu
2 years ago
7-17 % of all causes of ESRD comprised glomerulonephritis which can be classified either primary or secondary and occurring as denovo or recurrence.
Recurrent IgA nephropathy
Occurs about 10% at 10 years and 15% at 15 years
Usually late in occurrence
About 50% who had recurrence will lose their grafts
Risk factors for recurrence:
younger age
living related kidney transplantation,
0 HLA mismatch,
use of no induction immunosuppression,
steroid avoidance or minimization strategies (use of ATG is associated with favorable outcome)
Treatment mainly conservative adjusting or maintaining immunosuppressive used in transplantation without any additional measures
Recurrent primary FSGS
commonly present in the early post-transplant period usually at first 3 months
recur in one-third of the patient with primary FSGS
recurrence associated with graft loss in nearly half of the patients after 5 years
secondary FSGS recur rarely recur
Recurrence rate in genetic FSGS is < 3%
In real world it will be difficult to determine the actual risk of recurrence and difficult to determine the type of FSGS
Genetic screening can be used to detect genetically determined FSGS
Risk factors for recurrence of primary FSGS
Age: Patients with disease onset at a younger age
Race: non-white is at increased risk
LRKT is associated with a higher risk than DDKT
Recurrence of FSGS in the previous transplant
aggressive FSGS leading to renal failure within a short time after onset is associated with a higher recurrence rate.
A family history of FSGS is considered a lower risk factor
Aggressive monitoring of proteinuria should be done in the early post-transplant period especially at first 3 months, if proteinuria is > 1 gram, renal biopsy should be done
Recurrent FSGS is treated mainly with plasmapheresis with or without rituximab
Recurrent idiopathic MPGN
MPGN is classified according to IF into three types :
Immune complex MPGN which is characterized by immune complex deposition (polyclonal or monoclonal), it may be idiopathic or secondary to infection, malignancy, immune disease, or toxins
C3GN which is characterized by glomerular deposition of C3 and
Pauci immune MPGN which is characterized by neither deposition of Ig nor complement
More than half reoccur within 2 years
1/3 immune complex MPGN and 1/2 C3 glomerulopathy who had recurrence will lose graft within the first 5 years
Monoclonal Ig deposition can occur in both immune complex MPGN and C3 glomerulopathy and only around one-third of immune complex MPGN cases are diagnosed as plasma cell dyscrasia, its presence is associated with a higher rate of recurrence, early recurrence, and poorer prognosis
Treatment of recurrent C3 glomerulopathy include supportive treatment (ACEI, or ARBS) in mild disease, corticosteroids, cyclophosphamide, and PLEX
Eculizumab treatment used in refractory cases, and Rituximab for poor response
Recurrent idiopathic MN
Disease process involves autoantibody against PLA2R
PLA2R helps to distinguish between primary and secondary MN
If patient is negative for PLA2R, THSD7A should be checked
Levels of PLA2R decline after transplant and possible reason are
adsorption into allograft
effect of immunosuppression
Treatment includes combination of anti-proteinuria agents, rituximab, corticosteroids, CNI, and alkylating agents.
Prophylactic rituximab can be given for high-risk patients who had previous allograft failure due to disease recurrence, persistent high levels of circulating PLA2R
Secondary GN
aHUS, SLE, ANCA vasculitis, and anti-GBM Ab disease
Recurrence is up to 80% in aHUS (the use of prophylactic Eculizumab decrease the incidence of recurrence significantly), 0-44% in SLE and rare < 5% in anti-GBM Ab
Usually, recurrence occurs late
Lower likelihood of graft loss after recurrence however aHUS and SLE have higher graft loss rate
De novo GN
Denovo GN – occur in the recipient or may be present in the donor kidney
4-20 % of cases
associated with increase in the graft loss rate and poor outcome
Most common forms include IgAN , FSGS, MPGN and MN.
Risk factors for denovo GN;
reduction of nephron mass due to DM
HTN
rejection
infection
CNI
podocyte injury induced by sirolimus use
Treatment includes conservative treatment and treatment of the cause
Last edited 2 years ago by Theepa Mariamutu
Wael Jebur
2 years ago
Recurrent and de novo glomerular disease post transplantation is an important factor in determining the outcome of the allograft.Developing particular criteria to identify the risk of recurrence of various glomerular diseases post transplantation is the key to ascertain favourable long term outcome.Risk of recurrence of GN post transplant is 3.-15%. All types of GN can recur especially the risk glomerular diseases of IgA, FSGS ,MN and MPGN.Incidence is underestimated due to variable biopsy protocol in different centers.The risk of GN recurrence is directly related to incremental time post transplant and the GN subtype. The majority of recurrent GN is resulting in allograft failure in 3-5 years post transplant. There are particular features concerning each subtypes of GN recurrence ,that would be discussed as follows:
1- IgA nephropathy:
Its recurrence is common , at 15% incidence. Some studies showed reduced risk over time. Up to 40 % of recurrent IgA nephropathy have been reported to have allograft failure secondary to disease recurrence.
in general the outcome of recurrence of IgA nephropathy is largely better than the recurrence of other GN subtypes.
Risk factors for recurrence of IgA nephropathy:
Clinical ;
1] Younger age.
2] Zero HLA-mismatched life related kidney donor.
3] steroid avoidance or early steroid withdrawal immunosuppressive protocol.
4] Non use of induction therapy .
5] ATG is associated with lower risk of recurrence
6]crescentic and Rapidly progressive IgA nephropathy in native kidney.
7]Short total ischemia time.
Molecular:
1]Galactose deficient IgA 1 Gd-IgA1
2]IgG anti Gd-IgA1
3]Glycan specific IgG antibody.
4]Soluble CD 89, which is FC receptor for IgA1.
presence of these markers at time of transplantation portend higher risk of recurrence.
The optimal treatment of recurrence is unknown , but advisable to have CNi, prerdnisolon and MMF in the maintenance .
FSGS:
1 in 3 patients with primary FSGS will be having recurrence of disease after transplantation with 5 times risk of having allograft loss from disease recurrence in comparison to those with non recurrent disease.
The genetic FSGS is not associated with recurrence in post transplant.The indications for genetic analysis in patients with FSGS are:
1-Steroid resistant
2-life related donor.
3-strong family history.
predictors of FSGS recurrence:
1]Rapid progression of disease towards renal failure.
2]young age .
3]Severe manifestation of disease at presentation.
4]prior allograft failure.
5]recipient of life donor.
Etiology of Recurrence:
The presence of circulating factor like Serum Soluble urokinase receptors was strongly speculated as a marker of FSGS familial type. Nevertheless, its credibility in diagnosing FSGS and predicting potential recurrence is debatable.
Treatment:
PP is the standard therapy of choice to remove the circulating factor.
Rituximab is of unproven efficacy in treating recurrent FSGS. With a substantial debate concerning the involvement of B lymphocytes in the pathogenesis of recurrence. It might be having an effect on the podocyte cytoskeleton enhancing the recovery of glomerular disease.
CNI is helpful in improving the the proteinuria and recurrent FSGS, by stabilizing the Podocyte cells.
mTori is linked to higher incidence of FSGS, and its recommended to be switched to CNI.
Membranoproliferative GN:
Its a heterogenous group of disease presented in an unanimous clinical and histological pattern of glomerular disease. Progression potential risk and allograft out come depend on the discernible underlying etiology.Generally classified according to immunofluorescent study into immune-complex mediated and complement mediated MPGN with different underlying etiologies.
commonly recurring with 50% recurrence rate over the first 2 years post transplantation. 5 years graft survival is 30% for those with recurrent disease.
The immunoglobulines deposition and complement deposition are characteristically shaping the progression of the disease and the potential risk of recurrence.
in patients with monoclonal immunoglobulin with complement activation is usually having high recurrence risk.
In 70% of immune mediated MPGN and monoclonal deposits there os no evidence of plasma cell dyscrasia[no evidence of serum or urine monoclonal Ig protein or evidence of plasma cell dyscrasia in bone marrow.Where as in 30% its associated with serum and urine monoclonal ig without fulfilling the criteria for MM.{Monoclonal Gammopathy of renal significance MGRS.}.
Importantly,MGRS can present with immune-complex mediated MPGN or complement mediated MPGN.MPGN always calls for thorough investigation and hematology review to to preclude plasma cell disease associated GN.
Treatment :
Eculizumab to treat the complement mediated MPGN.
PP.
Rituximab to deplete the involved B lymphocytes and Bortezomib for the monoclonal Plasma cell clone .
Membranous Nephropathy:
The discovery of an antibody specific against a Podocyte antigen phospholipase A2 receptor antigen PLA2R as the main culprit associated with MN has changed the management strategy of the disease, as the titer of PLA2R antibodies is diagnostic and reflecting activity of the disease. PLA2R negative MN might be be positive for another antibody against Podocytes THSD7A antigen in 5% of the MN patients. Following up of those antibodies post transplantation is substantially predictive of recurrence of the disease. Recurrence rate is 30-50%. High pre transplant antibodies titer is associated with 80% risk of recurrence.
Treatment is largely copied from non transplant MN patients. with CNi , corticosteroid and Rituximab.
mTori is advocated to be changed to CNi.
Lupus Nephritis:
Risk of recurrence is 0-40% with poor allograft outcome .
Anti-GBM disease :
Risk is less than 5 %, with extremely rare allograft failure.
aHUS:
Risk of recurrence is 80%.It was contraindicated before the introduction of Eculizumab, which is prophylactically indicated for safer kidney transplantation.
Huda Al-Taee
2 years ago
Summary:
Following kidney transplantation, recurrent or de novo GN in the renal allograft is an important cause of premature allograft failure. All GN subtypes can potentially recur after transplantation, with the prevalence of GN recurrence between 3 and 15%.
the incidence of de novo or recurrent GN after kidney transplantation is likely to be underestimated due to many factors.
The risk of GN recurrence is typically directly related to incremental time post-transplant, with the majority of GN recurrence resulting in allograft failure occurring after 3–5 years post-transplant, although early recurrences can occur in patients with MPGN and FSGS.
Recurrent IgA Nephropathy
relatively common
occurs late post-transplant
recurrence rate is 15% and reduces over time.
40% of patients lose their allograft due to recurrence, but in general the long-term allograft and patient outcomes of patients with IgA nephropathy are substantially better when compared to other causes of GN.
risk factors for disease recurrence: younger age, recipients of zero HLA-MM LRD kidneys, steroid-avoidance or early steroid-withdrawal IS regimens, the non-use of induction therapy, HLA allelic subtypes, crescentic (and rapidly progressive) IgA nephropathy in the native kidneys, and shorter total ischemic time.
several molecules, including galactose-deficient IgA1, IgG anti-Gd-IgA1 antibodies, glycan-specific IgG antibodies, and soluble CD89 are implicated in the pathogenesis of IgA nephropathy.
The optimal treatment is unknown.
The potential benefit of tonsillectomy in disease recurrence has been limited to case reports and therefore cannot be recommended as a treatment option for patients with recurrent IgA nephropathy.
Recurrent primary FSGS:
high risk of recurrence and allograft loss.
In genetic FSGS, patients with podocin mutation have the highest risk of disease recurrence post-transplant.
secondary causes of FSGS can happen post-transplant leading to difficulties in differentiation between primary and secondary FSGS.
risk factors for disease recurrence are: younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESRD, and prior allograft failure from disease recurrence.
the pathogenesis of recurrence is unclear, a role for the circulating permeability factor SuPAR has been suggested, but still debated.
management of recurrent primary FSGS is challenging, the most commonly used protocols are PLEX, rituximab, CNI.
roles of pre-emptive plasmapheresis (pre and/or post-transplantation), immunoadsorption therapy, and other novel options such as ofatumumab or B7-1 blockers (abatacept and belatacept) to prevent disease recurrence or to treat recurrence appear promising.
Recurrent primary MPGN:
recurrence rate is over 50% with a high risk of allograft failure.
the disease is now classified into IC-mediated and complement-mediated ( C3GN & DDD).
There is a high rate of post-transplant recurrence for both C3GN and DDD, with over 50% of patients with disease recurrence reported will have allograft failure.
DDD is more likely to recur later post-transplant and often associated with no clinical manifestations other than allograft dysfunction.
approach to treatment for recurrent disease is not well established, limited to case series of successful treatment with the use of plasmapheresis and other immunosuppressive agents including cyclophosphamide, eculizumab, and rituximab.
Recurrent idiopathic MN:
Testing for PLA2R ab helps in diagnosing and treating primary MN and monitoring the risk of recurrence post-transplant.
A second antibody specific for the autoantigen thrombospondin type 1 domain-containing 7A (THSD7A) has been detected in up to 5% of patients with idiopathic membranous GN, typically in those who were seronegative for the PLA2R autoantibody.
up to 20% of patients with idiopathic membranous GN do not have detectable autoantibodies to PLA2R or THSD7A.
the rate of recurrence is between 30-50% and those with high titres of circulating anti-PLA2R autoantibody have a greater risk of recurrent disease.
treatment y includes a combination of anti-proteinuric agents, corticosteroids, alkylating agents, CNI, and rituximab.
Secondary GN:
recurrence occurs later post-transplant and rarely leads to graft failure.
recurrence rate in ANCA vasculitis is 0.02% per patient /year and no association was demonstrated between ANCA subtypes or disease severity prior to transplantation and disease recurrence.
The incidence and outcome of patients with recurrent lupus nephritis post-kidney transplantation are unclear.
n patients with anti-GBM disease, recurrence after kidney transplant is <5% and allograft failure is rare.
With prophylactic use of eculizumab, kidney transplantation in aHUS appeared safe with excellent allograft outcome, even in those with pathogenic mutations known to be associated with a high risk of disease recurrence.
De Novo GN:
the true prevalence is unknown.
associated with reduced allograft survival.
MPGN is the most common de novo GN subtype.
many factors limiting the diagnosis of de novo GN post-transplant such as the absence of kidney biopsy pre-transplant, the presence of glomerular disease in the donor’s kidney may not be known, variations in allograft biopsy practices and differences in the histopathological evaluation of allograft biopsies where immunofluorescence and electron microscopy of biopsies may not be routinely performed.
presentations of de novo GN is similar to primary GN.
several risk factors that may predispose to the development of de novo FSGS, such as reduction in nephron mass or the introduction of sirolimus. the long-term allograft outcome is relatively poor, treatment consists of antiproteinuric agents, removal of the cause and more aggressive IS medications may be considered. re-transplantation can be considered.
the incidence of de novo IgA nephropathy is likely to be underestimated, and presentation with macroscopic hematuria is unusual. The prognosis of de novo IgA nephropathy is usually relatively benign, treatment predominantly focusing on antiproteinuric and/or antihypertensive therapy. re-transplantation is possible.
de novo MN, and MPGN tend to occur later post-transplantation and they are uncommon. for MN, the pattern of Ig staining or glomerular staining for PLA2R may help to differentiate de novo from recurrent disease( in de novo MGN IgG4 and negative PLA2R).
Recurrent and de novo Glomerulonephritis After Kidney Transplantation. INTRODUCTION.
Glomerulonephritis is one of the most common cause of ESRD worldwide. It is considered to be an immunological kidney disease with heterogeneous abnormality which have many structural characteristic features under microscopy due to different pathological process and may be secondary to systemic diseases.
Glomerulonephritis is one of the common cause of recurrent disease post kidney transplant and affect graft survival whether recurrent or De novo with the prevalence 3- 15 % particularly in patients with high risk subtypes of IgA nephropathy, idiopathic membranous GN, focal segmental glomerulosclerosis (FSGS), and membranoproliferative (MPGN) . Recurrent IgA Nephropathy.
Mainly it occur late post-transplant with rate incidence of disease recurrence at 15 years of 15%, around 40 % of patients with recurrent disease lost their graft.
Some risk factors mentioned in some studies such as younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy but still need more ascertainment.
Recurrent IgA has no specific protocol of treatment till now but depend on CNI based protocol and with crescentic IgA mainly depends on cyclophosphamide or rituximab. Recurrent Primary FSGS.
Primary FSGS has high risk of recurrence around 10 to 30 % with high risk of graft failure but familial FSGS has low or no risk of recurrence.
Better to do genetic testing for adult patients with FSGS specially there are no obvious cause of secondary FSGS or presentation not correlated with primary FSGS.
Genetic testing also should be considered in pediatric with FSGS resistant to steroid.
younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESKD, and prior allograft failure from disease recurrence all are risk factors or FSGS recurrence.
There are many biomarkers has a role in pathogenesis of recurrence of FSGS e.g.( circulating permeability factor(s), serum soluble urokinase receptor (suPAR) ) but still most of them are under studies also used as biomarkers for recurrence but still sub-optimal e.g.( suPAR, Anti-CD40 autoantibody, and angiotensin receptor II type 1 (AT1R) antibody).
Treatment of recurrent FSGS is still challenging but some studies showed efficacy of PEX with or without Rituximab .
CNI has some effect on podocytes specially when shifting the patients from m-TOR to CNI.
Ofatumumab Abatecept/belatacept have promising effect but still need more studies.
Some centers use Anti-CD20 + PP as clinical protocol to prevent and treat recurrence in high-risk patients. (Overall remission rate 73%). Recurrent Primary MPGN.
New classifications of MPGN depends on immunofluorescence classified to immune-mediated GN and C3 Glomerulopathy.
Recurrence of MPGN more than 50% with high recurrence of DDD 80-90% WITH graft failure 25% and C3GN 70% recurrence.
Immune-mediated GN 30-60% with graft failure 50%.
Monoclonal antibodies that inhibit activation of the C5 component of complement (eculizumab) have been used in prevention and treatment of C3GN.
plasmapheresis and anti-B cell therapy for immune complex-mediated GN but still need studies . Recurrent Idiopathic Membranous GN.
40% -50% of primary/idiopathic MN cases recur in the allograft and 70-80% have anti-PLA2R antibodies.
Patients with anti-PLA2R antibodies pre-transplantation have a 60% to 76% risk of histologic recurrence and Antibody negative patients have a significantly lower risk (28%–30%).
Higher relative risk of allograft failure (up to 50% at 10-years of follow-up).
Treatment of recurrence (CNI+ steroids +Rituximab).
Rituximab therapy for early MN recurrence leads to 80% complete or partial remission with resolution of sub-epithelial deposits has been documented in 40% of patients. Secondary GN.
Recurrence rate (early/late) of LN has varied from 2% to 54%.
Anti-GBM disease, disease recurrence after kidney transplant is <5%.
De novo GN.
The incidence of de novo GN after kidney transplant varies between 4 and 20%.
FSGS, IgA nephropathy, membranous GN, and MPGN being the most common de novo GN subtypes.
Reduction in nephron mass as diabetes, hypertension, BK viral infection, CNI therapy, and rejection) or the introduction of sirolimus all are risk factors for De novo GN . CONCLUSION.
Recurrent and De novo Glomerulonephritis are common causes of graft failure.
Treatment of each one still need more studies to give strong evident guidelines.
Follow up by clinical and biochemical markers is so important for early detection and treatment.
Please give a summary of this article Recurrent IgA Nephropathy Relatively common Occurs late after transplant (15% at 15 years). Better long term allograft & patient outcomes compared to other types of GN (graft failure: 1.6% for IgAN, 5.6% MPGN, 2.7% FSGS, & 3.3% for idiopathic MN). Risk factors for disease recurrence include: – Younger age – Recipients of 0-HLA-mm LRD kidneys – Steroid-avoidance or early withdrawal – IS regimens – Non-induction (ATG may lower recurrence risk) – HLA allelic subtypes – Crescentic IgAN in the native kidneys – Shorter total ischemic time. Molecules implicated in pathogenesis include: – Galactose-deficient IgA1 – IgG anti-Gd-IgA1 antibodies – Glycan-specific IgG antibodies – Soluble CD89 (an Fc receptor for IgA Treatment of recurrent IgAN: Maintain CNI & corticosteroids-based IS. Anti-proteinuric treatments. Cyclophosphamide or rituximab (In crescentic RPGN) ——————————————————– Recurrent Primary FSGS 1 in 3 recurrence rate. 5-times increased risk of allograft failure. Secondary & familial FSGS have low to no risk (<3%) of recurrence. Genetic test may be indicated only if there is uncertainty of primary & secondary FSGS or when there is a clear FH of FSGS. Risk factors for disease recurrence in primary FSGS: – Younger age at presentation – Recipients of live-donor kidneys – Non-white ethnicity – Severe disease at presentation – Rapid progression to ESRD – Prior allograft failure from disease recurrence. Pathogenesis of FSGS recurrence: – Remains unclear. – A pathogenic role of the circulating suPAR has been proposed; serum suPAR level was high in >50% of cases versus 6% of controls. – Reduction of suPAR level with IS treatment was associated with a greater remission rates. – Close monitoring for proteinuria in high risk patients is recommended. – Kidney biopsy if persistent or increasing proteinuria. Treament of recurrent primary FSGS: PP is often recommended (AS for Apheresis guidelines). CNI induce remission in recurrent FSGS. Switch to CNI if on mTOR-i is advised (mTOR-i associated with de novo FSGS). A practical treatment approach of include PP, anti-proteinuric therapy, & conversion to a CNI based IS. Rituximab used as adjunctive or in resistant cases. ——————————————————- Recurrent Primary MPGN >50% recurrence rate within the 1st2 years. Risk of allograft failure; 5-year graft survival is only 30%. The recurrence rate is high for both C3GN & DDD. DDD tends to recur later post-transplant & allograft dysfunction is usually the sole feature of recurrence. Treatment approach for recurrent MPGN is not well established. Case series reported successful treatment with PP & agents, e.g. cyclophosphamide, eculizumab, & rituximab. The knowledge of pathogenesis & new classification of MPGN will help nephrologists to individualize treatment strategies, e.g. PP & anti-B cell therapy for immune complex-mediated GN or eculizumab for C3 glomerulo-pathy. ——————————————————— Recurrent Idiopathic Membranous GN Anti-PLA2R autoantibody test differentiate primary from secondary MN, & help clinicians to arrange management policies. Absence of PLA2R autoantibody, however, does not exclude idiopathic MN. The sensitivity of test is 65%, specificity is 97%, positive LHR of 15.65, & negative LHR of 0.37. Positive glomerular staining of PLA2R antigen shows similar test performance accuracy. Anti-THSD7A antibody occurs in 5% of patients with idiopathic MN, typically in those negative for PLA2R autoantibody. Up to 20% of patients with idiopathic MN are negative for both PLA2R & THSD7A. The recurrence rate in idiopathic MN is 30-50%. There is a direct relationship between anti-PLA2R titer level & risk of recurrence; positive predictive value of pre-transplant anti-PLA2R for disease recurrence is 83%. Treatment of recurrent MN: Includes a combination of anti-proteinuric agents, corticosteroids, alkylating agents, CNI, & rituximab. Rituximab achieves up to 80% complete or partial in early recurrence. Bortezomib caused complete remission in single case of rituximab resistant recurrent MN. Pre-emptive rituximab can be considered in those with high levels of anti-PLA2R titer with prior graft loss from recurrent MN or have persistent high or increasing titers post-transplant with early histological recurrence. ———————————————– Secondary GN Caused by systemic diseases including: – aHUS – SLE – anti-GBM disease – crescentic GN (e.g., from systemic vasculitis). Recurrence of secondary GN often occur later post-transplant & graft failure is infrequent. In ANCA-associated vasculitis, the recurrence rate is low & often extra-renal. Recurrent lupus nephritis is variable (0 -44%), those who recurrent have greater risk of graft & mortality. In anti-GBM disease, recurrence is <5% & allograft failure is rare. In aHUS, the recurrence rate was up to 80% before eculizumab era, & kidney transplantation was considered a contraindication. The outcome appears excellent with the prophylactic use of eculizumab. ———————————————— De novo GN FSGS, IgA nephropathy, MN, & MPGN are the most common de novo GN subtypes. In a Canadian cohort, de novo GN occurred in 3.4% of those with primary ESRD from GN & 3.6% of those with ESRD from non-GN causes. In those with primary non-GN causes, FSGS was the commonest cause of de novo GN (over 95%);IgA nephropathy, MN, & MPGN were less common. In this study, the risk of graft loss was over 7-times greater in those who had de novo GN, compared to those without disease. It is difficult to differentiate secondary FSGS from“actual” de novo non-collapsing GN & may explain why de novo FSGS tend to occur later post-transplant (compared to primary FSGS). The long-term outcome of de novo FSGS is relatively poor (5-year allograft survival of <50%). Treatment of de novo FSGS: Adequate anti-proteinuric treatment & the removal of causative factors if possible. More aggressive therapy may be considered. Re-transplantation can be considered. De novo IgA nephropathy: Is under-estimated; IgA deposition not infrequently found in protocol biopsies. The prognosis is usually relatively benign Treatment focuses on antiproteinuric &/or BP control. Crescentic de novo IgA nephropathy carries a poorer prognosis. De novo membranous GN and MPGN: Much less common Later onset compared to recurrent disease. Primarily secondary to viral infections, rejection, autoimmune disease, CNI & TMA. Symptoms range from asymptomatic mild proteinuria & incidental biopsy findings to nephritic range proteinuria & RPGN. —————————————————— CONCLUSION Uncertainty exists regarding approach & treatment of post-transplant GN recurrence. It is important to establish a global GN registry, focusing on clinical data, histological features, treatment, & outcome of post-transplant GN.
-Recurrent or de novo GN in the renal allograft causes early allograft failure after transplantation. All GN subtypes may recur after transplantation, with an incidence of 3 to 15%, especially in high-risk subtypes of IgA nephropathy, idiopathic membranous GN, focal segmental glomerulosclerosis (FSGS), and membranoproliferative GN (MPGN). The incidence of de novo or recurrent GN after kidney transplantation is likely to be underestimated due to selection bias (systematic differences in the selection and listing of ESKD patients with different GN subtypes), varying biopsy practices, ascertaining the primary cause of ESKD, differing follow-up period, disparate clinical presentations ranging from asymptomatic urinary abnormalities to rapidly progressive GN.
Recurrent IgA Nephropathy:
-The cumulative incidence of disease recurrence after 15 years is 15 per cent, however, the risk of disease recurrence may be decreasing with time. Recurrent IgA nephropathy is rather frequent, but it often develops late post-transplant.
-Several risk factors for disease recurrence have been identified, including younger age, recipients of zero-HLA-mismatched live-related donor kidneys, immunosuppressive regimens that avoid steroids or withdraw them early, the non-use of induction therapy (whereas anti-thymocyte globulin [ATG] may be associated with a lower risk of disease recurrence), HLA allelic subtypes, crescentic (and rapidly progressive) IgA nephropathy.
-The optimum therapy for recurrent IgA nephropathy is uncertain, and no research show immunosuppression changes enhance allograft outcomes. The ideal dosing/target therapeutic CNI level or particular CNI type in the treatment of recurring illness is uncertain. In crescentic quickly progressing IgA nephropathy, more severe immunosuppression (e.g., cyclophosphamide or rituximab) may be attempted, however, this is mainly untested and unlikely to alter the disease course.
Recurrent Primary FSGS:
-Up to one-third of patients diagnosed with primary FSGS will experience disease recurrence following kidney transplantation. Patients who do experience disease recurrence have a fivefold increased risk of allograft failure, which is primarily caused by GN recurrence when compared to patients who do not experience disease recurrence.
-The diagnostic test accuracy of suPAR in differentiating primary FSGS from other proteinuric diseases or predicting disease recurrence after transplantation remains suboptimal, and the clinical utility of routinely monitoring suPAR levels post-transplant to predict disease recurrence remains poorly defined.
-Treatment methods for recurrent primary FSGS are based on tiny case studies. Plasmapheresis is typically favoured and recommended in the treatment of primary FSGS recurrence in juvenile and adult allografts. The effectiveness of rituximab with CNIs like cyclosporine is unknown. The case report of rituximab’s effectiveness in ameliorating early primary FSGS recurrence post-transplant in a kid with post-transplant lymphoma drew substantial attention and showed that B cells may play a role in disease recurrence in a subset of patients with primary FSGS.
Recurrent Primary MPGN:
–Over fifty per cent of disease recurrences that occur post-transplant from primary MPGN do so within the first twenty-four months after the transplant. This is considered to be a very typical occurrence. In patients who have had a previous instance of disease recurrence, the probability of allograft failure is quite significant, and there is only a thirty per cent chance of allograft survival five years after disease recurrence.
-.Plasmapheresis and other immunosuppressive drugs, including cyclophosphamide, eculizumab, and rituximab, have been shown in case series to be beneficial in treating recurrent illness, although this does not constitute a well-established method for treating the condition. However, the most effective course of therapy has not been determined.
Recurrent Idiopathic Membranous GN:
-Depending on the study, the risk of illness recurrence in individuals with idiopathic membranous GN after kidney transplantation is 30 to 50%.
–The discovery of key podocyte antigens and the pathogenic autoantibody against phospholipase A2 receptor (PLA2R) led to advancements in the knowledge, management, and therapy of idiopathic membranous GN.
-Recurrence therapy is extrapolated from general population treatment and includes anti-proteinuric drugs, corticosteroids, alkylating agents, CNI, and rituximab. Given that kidney transplant recipients are likely to be on corticosteroids and CNI, most clinicians would recommend continuing CNI and considering the addition of anti-CD20 antibodies rather than alkylating agents to avoid overimmunosuppression resulting in severe infectious complications.
Up to 80% of patients with early disease recurrence post-transplant achieve full or partial remission with rituximab.
Presumed or Advanced GN:
–The incidence of allograft failure that can be attributed to GN is extremely low in patients who have ESKD and where the underlying aetiology of the cause of ESKD is unknown because a biopsy was not undertaken (but with clinical suspicion) or was non-diagnostic with non-specific histological features of interstitial fibrosis and glomerulosclerosis. In these patients, the clinical suspicion may point to GN as the cause of ESKD.
Secondary GN:
–Patients with secondary GN subtypes attributed to systemic diseases [such as aHUS, SLE, anti-glomerular basement membrane (GBM) disease, and crescentic GN (e.g., from systemic vasculitis)] may experience GN recurrence after kidney transplantation, but these relapses often occur later post-transplant and infrequently lead to allograft failure.
-De novo GN:
-De novo GN is linked with considerably lower allograft survival in kidney transplant patients. FSGS, IgA nephropathy, membranous GN, and MPGN are typical de novo GN subtypes following kidney transplants. The incidence of de novo GN after a kidney transplant varies between 4 and 20%. –IgA nephropathy: Generally favourable unless crescentic GN, re-transplantation possible.
-FSGS (non-collapsing): Prognosis poor, 40% 5-year renal allograft survival, re-transplantation possible.
-Membranous GN: possible higher risk of allograft failure. Re-transplantation is possible.
-MPGN: High risk of allograft failure, caution if considering re-transplantation.
CONCLUSION:
Despite progress in understanding the epidemiology, pathophysiology, and categorization of original and recurrent GN following kidney transplantation, management of post-transplant GN recurrence remains unknown.
Recurrent and de novo Glomerulonephritis after Renal Transplantation
Glomerulonephritis is an important cause of graft loss. It can primary or secondary. Post transplant it can be denovo or recurrent. Incidence is variable and type dependent.
Recurrent IgA nephropathy
Relatively common post transplant with rates at 15% at 15vyears
Following recurrence 40 % may lose graft.
Compared to others GN the long term outcome are better
Graft failure in this study due to IgA nephropathy recurrence was 1.6% while in MPGN ( 5.6%) FSGS (3.3%)Idiopathic membranous GN (3.3%)
Predictors of recurrence include -ESRD secondary to GN, male gender, young age, non white.
Standard immunosuppression with CNI and steroids should be maintained
In cresentic type IgA nephropathy more aggressive immune suppression will be required
Recurrent Primary FSGS
1 in3 with primary FSGS will have recurrence.
5 times higher risk of graft failure as compared to those without disease
Genetic testing should be done once adult FSGS is diagnosed
This is an evidence level 5 paper because it is a narrative review on recurrent and de novo glomerulonephritis after kidney transplantation. It is a group of diseases with different causes, clinical phenotypes, histological subtypes, and prognoses, consequently, different types of treatment. Regardless, these are lesions that lead to early graft loss and tend to reappear after transplantation.
IgA nephropathy is relatively common and when it recurs it is late, with a lower risk of graft loss compared to other glomerulopathies. The risk factors for its recurrence are young, living donors with 0 mismatch, steroid-sparing therapies, IgA nephropathy with crescents, and short ischemia times. The treatment is to maintain or optimize the dose of CNI and corticosteroids. In cases of lesions with crescent, the ideal is a pulse of cyclophosphamide or rituximab.
Primary recurrent FSGS has a high risk of recurrence, de novo injury, and graft loss. When familiar, the risk is much lower, but it needs genetic tests to confirm the diagnosis, being quite expensive for common use. The main risk factors are youth, living donors, non-Caucasian ethnicity, severe clinical manifestations, rapid progression to renal failure, and graft failure from recurrent disease. Treatment with rituximab, plasmapheresis, and CNI optimization is the most frequent.
Recurrent primary MPGN is relatively common and usually occurs within the first 24 months after transplantation, and may be mediated by immune complexes (monoclonal or polyclonal) or by complement-induced glomerulopathy (C3GN and DDD). The latter has a very high rate of recurrence and can only be diagnosed if immunofluorescence is performed. Monoclonal diseases can be controlled by rituximab, polyclonal diseases by controlling the underlying disease (infectious or autoimmune), and complement-induced diseases may benefit from eculizumab. DDD recurrence is later when compared to C3GN. There is a risk of a mixed disease (overlap) that is difficult to control.
Recurrent idiopathic membranous GN is closely related to anti-PLA2R antibodies and may recur in the graft at an early stage (proteinuria and protocol biopsy are needed). Treatment is optimizing doses of CNI, corticosteroids, and rituximab.
Secondary GN is related to systemic diseases, such as atypical hemolytic uremic syndrome, SLE, Goodpasture (GBM), and vasculitis which can lead to graft loss. De novo lesions usually occur in the reactivation of underlying diseases and the severity of the two situations is variable for each pathology, its intensity, and the organ recipient. Treatment should be individualized due to the lack of randomized studies and not enough to define an adequate protocol.
GN caused around 17% of ESKD in Australia and New Zealand and 13% in US and UK(1,2,3)
GN represent a group of diseases with different causes ,clinical presentations and prognosis.
High risk recurrent GN are IgA nephropathy, Idiopathic membranous,FSGS ,and MPGN.
Epidemiology, Pathogenesis,and Outcomes of GN Recurrence after Kidney Transplantation
Recurrent IgA Nephropathy
Usually late postTx, 15% at 15 years, allograft loss 40-60%
Risk factors ; Young age, 0-HLA mismatch live related donor,steroid free regimen, no ATG, crescentric IgA in the native kidney,shorter total ischemic time, galactose -deficent IgA1, IgG anti-Gd-IgA1.
Treatment ; anti-proteinuric, CNI , and steroids. Other options includes alkaline agent for crescentric, tonsillectomy.
Recurrent primary FSGS
1 in every 3 patients, 5 times risk of allograft failure
Genetic FSGS rarely recur(< 3%)
Genetic screening is indicated in patients with clear family history of FSGS or those with potential live related donor, resistant nephrotic syndrome in children
Risk factors ; Young age, live-related donor,non-white race,severe disease ,rapid progression to ESKD, previous history of graft failure due to FSGS.
Close monitoring for proteinuria in high risk patient or self checking for proteinuria is recommended in the first 3 month
Treatment ; This is challenging , initial treatment are ; anti-proteinuric, plasmapheresis+/- RTX, CNI. Other options are belatacept/ Abatacept
Recurrent Primary MPGN
Recurrence is common > 50% in the first 2 years
5 year allograft survival ~ 30%
IC-MPGN is defined by IgG or monoclonality+ C3 on IF
C3 GN & DDD ; C3 deposition + no IgG
C3 deposition indicates dysregulation of the alternative complement pathway( genetic or auto-antibodies). This result in amplification and subsequent over production of C3 and related fragments of the terminal pathway.
70% ~ of patients with IC-MPGN + monoclonal deposit do not have features to suggest plasma cell dyscrasia
Treatment ; Anti-proteinuric, treat underlying monoclonal gammopathy if diagnosed, eculizumab for C3GN, and plasmapheresis, immunesuppression(alkalyting agents),RTX in case of IC-MPGN
Idiopathic recurrent membranous GN ;
The diagnosis & treatment and prognosis are based on PLA2R Ab titer which has sensitivity of 65% and specificity of 97%
Absence of PLA2R Ab cannot completely rule out this condition
Another antibody is THSD7A in 5% of cases
Recurrence rate is 30 to 50%
PLA2RAb should monitored closely for those with high level of pre-transplant PLA2RA or those with early disease recurrence
Treatment ; anti-proteinuric, CNI, Rituximab. Other options are alkalyating agents,& bortezomib
Secondary GN ; Generally these can lead to recurrence but usually later after transpant with less frequent loss of allograft loss. Examples are ;
ANCA ; < 0.2% / patient / year
Lupus Nephritis ; 0-44%
Anti-GBM disease ; < 5%
aHUS ; 80%
Presumed or advanced GN ; The etiology of the ESRD is unknown or biopsy is not done or the biopsy was not specific = interstitial fibrosis, tubular atrophy or glomerulosclerosis
The incidence of allograft loss attributed to presumed or advanced GN is very loss ~ < 5%
De novo GN ;
Exact incidence is not known ~4 – 20% but it is not innocent disease
Commonly FSGS, IgA, MPGN, & Membranous
Diagnosis is difficult due to ; a) In many cases the cause of native ESRD is unknown b) May be donor derived in absence of implantation biopsy c) Histology practice e.g. in many places there is no IF or EM
Clinical they present the same as the native kidney primary GN
Risk factors for de novo FSGS ; DM, HTN, BK virus nephropathy, Rejections, & immune-suppression e.g. CNI, mTORi
Conclusion ;
The approach and treatment of recurrent GN is not yet clear, This calls for global GN registry considering clinical, histological features, treatment and outcomes of post-Tx GN
The current TANGO may give some insight on this issues. TANGO is The Post-TrANsplant GLOmerular Disease study
Recurrent and de novo Glomerulonephritis After Kidney Transplantation:
¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤
▪︎Recurrent or de novo GN in the renal allograft is an important cause of premature allograft failure.
▪︎All GN subtypes can potentially recur after transplantation.
▪︎GN recurrence posttransplant depends on: 1) GN subtypes 2) time posttransplant.
☆Recurrent IgA Nephropathy:
________________________________
▪︎Is relatively common and typically occurs late post-transplant
▪︎Compared with other GN subtypes, the long-term allograft and patient outcomes are substantially better.
▪︎Risk factors for disease recurrence: younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal IS regimens, the non-use of induction therapy, HLA allelic
subtypes, crescentic (and rapidly progressive) IgA nephropathy
in the native kidneys and shorter total ischemic time,
▪︎ The optimal treatment of recurrent IgA nephropathy remain unknown. The current practice is to maintain (or change to) CNI and corticosteroids-based IS regimen in addition to anti-proteinuric treatments
▪︎ In crescentic rapidly progressive IgA nephropathy, more aggressive IS may be considered
☆Recurrent Primary FSGS:
________________________________
▪︎Up to 1 in 3 patients with primary FSGS will experience disease recurrence after kidney transplantation.
▪︎ It is important to consider genetic screening for patients with a clear family history of FSGS or those with a potential live-related donor for transplantation, including undertaking genetic screening of the donors.
▪︎When there is no genetic mutation in the potential recipients, genetic screening of live-related donors is not recommended
▪︎Genetic testing may be considered for pediatric patients with FSGS, including those with idiopathic steroid-resistant nephrotic syndrome
▪︎ Risk factors for disease recurrence in patient with primary FSGS includes: younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESKD, and prior allograft failure from disease recurrence.
▪︎The pathogenesis of disease recurrence in patients with primary FSGS remains unclear
▪︎Close monitoring for proteinuria in high risk patients, and proceeding to a
kidney biopsy (electron microscopy to detect early effacement of foot processes) if there is persistent or increasing proteinuria.
▪︎Management of FSGS recurrence post-transplantation must initially include plasmapheresis, maximizing anti-proteinuric therapy, and converting to a CNI based immunosuppressive regimen, with B cell depletion (rituximab) considered as adjunctive treatment or in resistant cases.
☆Recurrent Primary MPGN:
_____________________________
▪︎ High recurrence rate ( >50%) with increased risk of allograft failure
▪︎Classification of MPGN:
1) Immune complex-mediated MPGN
2) Complement-mediated MPGN [comprising of C3GN and dense deposit disease (DDD)].
▪︎ The presence of serum monoclonal proteins and Ig deposits in immune-mediated MPGN, is associated with higher risk of recurrence
▪︎ The approach to treatment for recurrent disease is not well established. But, The new classification and current knowledge of MPGN may assist clinicians to adopt a personalized treatment strategy according to the most likely pathogenesis of the disease process (e.g., consideration of plasmapheresis and anti-B cell therapy
for immune complex-mediated GN or those with monoclonal gammopathy or to consider eculizumab for C3 glomerulopathy)
☆Recurrent Idiopathic Membranous GN:
________________________________________
▪︎There is a pathogenic role of autoantibody against the podocyte antigen phospholipase A2 receptor (PLA2R).
▪︎ The rate of recurrence between 30- 50%.
which is influenced by high titres of circulating anti-PLA2R Abs, follow-up period and dissimilar biopsy practices.
▪︎Monitoring of anti-PLA2R antibody post-transplant must be considered in:
1. High pretransplant circulating levels of
anti-PLA2R antibody
2. Early disease recurrence, to determine
response to treatment.
3. To differentiate disease recurrence
from de novo membranous GN or other
causes of proteinuria.
▪︎The treatment includes a combination of anti-proteinuric agents, corticosteroids, CNI, alkylating agents and change to CNI if in mTOR inhibitor. Rituximab is effective in native and recurrent membranous GN, and bortezomib has been described for rituximab resistant cases.
☆Secondary GN:
__________________
▪︎ Can occur late and infrequently lead to allograft failure
▪︎The reported incidence of recurrent lupus nephritis varies between 0 -44%
▪︎ Recurrence of ant GBM after kidney transplant is <5%
▪︎ In HUS: kidney transplantation
appeared safe with excellent allograft outcome with prophylactic use of eculizumab.
☆De novo GN:
________________
▪︎The incidence of de novo GN after kidney transplant varies between 4 and 20%, with FSGS, IgA nephropathy, membranous GN, and MPGN being the most common ones.
▪︎ Causes of difficulties in identifying and confirming the presence of de novo GN post-transplant:
1- The cause of native ESKD is often
uncertain
2- Presence of GN in the donor kidney may not be known.
3- Variations in allograft biopsy practices
4- Differences in the histopathological evaluation of allograft biopsies.
▪︎ The presentations of those with de novo GN are similar to those with primary GN.
▪︎Risk factors which may predispose to the development of de novo FSGS:
1- Reduction in nephron mass
2- Introduction of sirolimus (through the effects on podocyte integrity).
▪︎Treatment of de novo FSGS: anti proteinuric and the removal of the offending factors where possible, but more aggressive therapy may be considered.
▪︎ Re-transplantation following allograft failure from de novo FSGS can be considered
▪︎de novo IgA nephropathy: the incidence is underestimated, and the presentation with macroscopic hematuria is unusual, the prognosis usually relatively benign with treatment predominantly focuses on antiproteinuric and/or anti-hypertensive therapy.
▪︎Patients who have developed crescentic de novo IgA nephropathy tend to have a poorer prognosis.
▪︎De novo membranous GN and MPGN: are less common, and the reported cases primarily related to secondary causes, the onset tend to occur late, the symptoms are often indistinguishable compared to the timing, presentations, and clinical course of those with recurrent diseases.
▪︎In membranous GN, the pattern of Ig staining or glomerular staining for PLA2R may help to differentiate de novo from recurrent disease.
▪︎It is imp to exclude secondary causes in recipients who have developed de novo GN, which is critical when considering treatment options and re-transplant potential.
☆CONCLUSION: Considerable uncertainty remains in the approach and treatment of post-transplant GN recurrence.
Recurrent and de novo Glomerulonephritis after kidney transplantation
GNs are immunological kidney diseases with different histological subtypes, causes (primary vs secondary), and clinical presentations. Pose different prognoses and recurrence risks post-kidney transplantation. Therefore; clinicians should give enough information regarding the risk of disease recurrence in the transplant graft while evaluating potential kidney transplant candidates with GN for kidney transplantation. Recurrent or de novo GN in the renal allograft is a major cause of graft loss following kidney transplantation. All GN subtypes carry a risk of recurrence in the renal allograft with a prevalence of GN recurrence between 3 and 15% according to subtypes.
GN recurrence is directly related to the time post-transplant, with a majority of them resulting in allograft failure after 3 to 5 years post-transplant. As well, the recurrence risk varies according to GN subtypes with FSGS and MPGN subtypes are of early recurrence.
Epidemiology, pathogenesis, and outcomes of GN recurrence after kidney transplantation
Recurrent IgA nephropathy:
IgA nephropathy recurrence is common, but it occurs late post-transplant. Following disease recurrence, up to 40% of patients lose their allografts. Patients with IgA nephropathy have better allograft long-term outcomes after disease recurrence as compared with other GN subtypes. Risk factors for disease recurrence include young age, recipients of zero HLA-mismatch live related donor kidneys, steroid-free or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy, HLA allelic subtypes, crescentic type and shorter total ischemic time. There are several serum and urine biomarkers that may predict the risk of disease recurrence after kidney transplantation, but their prognostic role has not been truly established.
The ideal treatment of recurrent disease remains unknown. Current practice is to maintain or change to CNI and steroid-based regimen in addition to anti-proteinuria therapy. The dose and target CNI level remain unknown. Rituximab or Cyclophosphamide may be considered in crescentic IgA nephropathy.
Recurrent primary FSGS
FSGS has a high recurrence rate, up to 1 in 3 patients experience recurrent disease after kidney transplantation. The allograft failure risk after disease recurrence is 5 times compared to patients who do not get disease recurrence.
In contrast to patients with primary FSGS, familial FSGS in adults, have low to no risk (< 3%) of disease recurrence post-transplant suggesting the relative importance of genetic testing in the evaluation of a subset of patients with adult-onset FSGS for transplantation. In view of cost; it may be more practical to consider screening for patients with a clear family history of FSGS or those with a potential live-related donor for the same genetic mutations if present in the potential recipients). Similar to the adult population, there is a low risk of FSGS recurrence in pediatric patients with genetic FSGS post-transplant.
Other risk factors for disease recurrence are young age and severe manifestations at presentation, recipients of live-donor kidneys, non-white ethnicity, rapid progression to ESRD and prior allograft failure from disease recurrence.
Genetic screening should be considered in patients with adult-onset FSGS when the distinction between the primary and secondary form is uncertain or when there is a clear family history of FSGS.
The pathogenesis of disease recurrence in patients with primary FSGS is still unclear. Some studies proposed the role of serum soluble urokinase receptor (suPAR) in the insult that cause podocyte foot process effacement.
Nevertheless, the use of suPAR as a diagnostic test to differentiate primary FSGS from other proteinuric diseases or to predict disease recurrence remains suboptimal. Other biomarkers like anti-CD40 antibody, urine suPAR, and angiotensin receptor II type 1 (AT1R) antibody appear promising.
Regular checks of urine protein/creatinine ratio or self-check urine dip-stick in the first 3 months post-transplant are recommended. Kidney biopsy is done if there is persistent or increasing proteinuria. Electron microscope examination is needed to detect early effacement of the podocyte foot processes.
The treatment of recurrent primary FSGS remains challenging. Plasmapheresis is often preferred and recommended in the treatment of primary FSGS recurrence in the allograft. Adjunctive therapy with CNI and rituximab remain uncertain. There is no data to support that changing from one CNI to another will be effective. While switching to CNI if patients were on mTOR inhibitor is advocated, as mTOR
Inhibitor, especially in at higher doses has been associated with the development of de novo FSGS.
Novel therapy such as ofatumumab which is an anti-CD20 monoclonal antibody or B7-1 blockers (abatacept and belatacept) to prevent or treat recurrence appears promising but the efficacy of these therapies remains to be evaluated.
Recurrent primary MPGN
MPGN has an early and high recurrence rate post-transplant. The 5-year graft survival post-disease recurrence is only 30%. New MPGN classification has enabled a more understanding of the nature course, and risk of its recurrence post-transplant.
MPGN subtypes are:
1- immune complex-mediated MPGN characterized by glomerular deposition of polyclonal or monoclonal immunoglobulin (Ig). The pattern of deposition has both diagnostic and prognostic significance. The presence of serum monoclonal proteins with or without low complement levels (C4d deposition), or the presence of glomerular monoclonal Ig deposits both were associated with early disease recurrence and premature allograft failure. 70% of immune-mediated GN have no plasma cell dyscrasia while 30% have detectable elevated monoclonal proteins that do not fulfilling the criteria for multiple myeloma this is termed monoclonal gammopathies of renal significance.
2- complement-mediated MPGN or C3 glomerulopathy which includes C3GN and dense deposit disease DDD, these are characterized by glomerular deposition of C3 in the absence of Ig. Although, they have similar courses, the timing and clinical presentations of patients with C3GN and DDD. DDD more likely to recur later post-transplant. Genetic mutation or autoantibodies play role in the pathogenesis.
Monoclonal gammopathy can be associated with C3GN which is associated with the rapid rate of disease recurrence and allograft failure compared with those without monoclonal gammopathy.
The pattern of glomerular deposition may help to differentiate between the MPGN subtypes.
Clinicians should be aware of the need to undertake pre-transplant screening for monoclonal gammopathy and possible haematology review in patients with MPGN, as well as the importance of close monitoring post-transplant for signs of recurrence.
The optimum treatment strategy remains unknown. The use of plasmapheresis, and immunosuppressive agents including cyclophosphamide, eculizumab and rituximab has been to be of beneficial effect.
Recurrent Idiopathic Membranous GN:
Test for Anti-PLA2R autoantibody which is an antibody against podocyte antigen phospholipase A2 receptor can differentiate primary vs. secondary membranous GN, as well as help the clinicians in the management of these patients and in predicting the recurrence post-transplant. Antibody against autoantigen thrombospondin type 1 domain-containing 7A (THSD7A) has been detected in up to 55 of the idiopathic membranous GN. Nevertheless, about 20% of patients with idiopathic membranous GN do not have detectable autoantibodies to PLA2R OR THSD7A. the rate of disease recurrence in patients with idiopathic membranous GN post-transplant is between 30 – 50% and there is a direct relationship between the PLA2R titer level and the risk of recurrence. The role PLA2R antibody monitoring post-transplant is still unclear. But it should be considered if there is high pre-transplant circulating levels of PLA2R antibody, in patients with early disease recurrence to predict progression, determine response to therapy and differentiate disease recurrence from de novo membranous GN or other causes of proteinuria.
The treatment of the recurrence includes a combination of antiproteinuric agents, steroids, CNI, and rituximab.
Secondary GN
Patients with secondary GN that is attributed to systemic diseases such as SLE, Crescentic GN from vasculitis, anti-GBM disease, aHUS may experience GN recurrence after kidney transplantation but these are often late. The recurrence rates vary according to the aetiology with the highest rate among aHUS reaching 80%, therefore, it had been a contraindication to transplantation, but with the discovery of eculizumab, the kidney transplantation appeared safe with excellent allograft outcome in these patients.
Presumed or Advanced GN
Where the underlying aetiology of the ESRD is uncertain because the biopsy was not taken or it was not diagnostic with non-specific histological features. The incidence of allograft failure attributed to GN is extremely low as compared with primary GN subtypes. FSGS and IgA nephropathy is attributed to most of the recurrence.
De novo GN
The incidence of de novo GN after kidney transplant varies between 4 and 20%, and the most common subtypes are FSGS, IgA nephropathy, membranous GN, and MPGN. De novo GN post-transplant is difficult to confirm because the cause of native ESRD is often uncertain. Several risk factors are associated with the development of FSGS like DM, hypertension, BK, CNI therapy, and rejection. De novo FSGS recurrence tends to be later post-transplant compared to the primary form. Irrespective of the nature of de novo FSGS, the long-term allograft outcome is relatively poor. No specific therapy is approved.
De novo IgA nephropathy incidence seems to e underestimated. Macroscopic hematuria is unusual. The prognosis is relatively benign with treatment mainly focused on antiproteinuric and antihypertensive therapy. De novo membranous and de novo MPGN are of less recurrence rate.
Clinicians should be aware of the need to exclude secondary causes in recipients who have developed de novo GN. Conclusion:
The recurrent GN after kidney transplantation still carries considerable uncertainty in their approach and treatment.
. – post-transplantation, recurrent or de novo GN in the renal allograft is an important cause of premature allograft failure .
-All GN subtypes can potentially recur aftertransplantation, with the prevalence of GN recurrence between 3 and 15%, particularly in patients with high risk subtypes of IgA nephropathy, idiopathic membranous GN, focal segmental glomerulosclerosis (FSGS) , and membranoproliferative GN (MPGN) .
-The majority of GN recurrence resulting in allograft failure occurring after 3–5 years post-transplant, although early recurrences can occur in patients with GN subtypes of MPGN and FSGS. Recurrent IgA Nephropathy
-Recurrent IgA nephropathy is relatively common .
– 40% of patients with recurrent IgA nephropathy havebeen reported to lose their allografts, predominantly fromdisease recurrence (up to 60%) .
– Compared with other GN subtypes, the long-term allograft and patient outcomes of patients with IgA nephropathy are substantially better.
-Risk factors for disease recurrence: younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroidwithdrawal immunosuppressive regimens, the non-use of
induction therapy , HLA allelic subtypes, crescentic IgA nephropathy in the native kidneys and shorter total ischemic time.
-There are several molecules, including galactose-deficient IgA1 (Gd-IgA1), IgG anti-Gd-IgA1 antibodies, glycan-specific IgG antibodies, and soluble CD that may be implicated in the pathogenesis of IgA nephropathy, the presence of which may portend a greater risk of disease progression and possibly disease recurrence posttransplant
-The optimal treatment of recurrent IgA nephropathy remains unknown . Recurrent Primary FSGS
-1 in 3 patients with primary FSGS will experience disease recurrence after kidney transplantation, with the risk of allograft failure 5-times and poorer 5-year allograft survival .
-Risk factors for disease recurrence : younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease
at presentation, rapid progression to ESKD, and prior allograft failure from disease recurrence .
-The pathogenesis of disease recurrence due to presence of circulating permeability factor(s) causing podocyte injury instigating early disease recurrence.
– Close monitoring for proteinuria in high risk patients, in the first 3 months post-transplant are recommended, and proceeding to a kidney biopsy if there is persistent or increasing proteinuria .
-A practical approach in the management of FSGS recurrence post-transplantation should initially include plasmapheresis, maximizing anti-proteinuric therapy, and converting to a CNIbased immunosuppressive regimen , with B cell depletion (rituximab) considered as adjunctive treatment or in resistant cases . Recurrent Primary MPGN
-50% of recurrence occurring within the first 24 months post-transplant and 5-year allograft survival post-disease recurrence of only 30%.
-There is a high rate of post-transplant recurrence for both C3GN and DDD subtypes, withover 50% of patients experience allograft failure .
-The presence of glomerular monoclonal Ig deposits was associated with poorer prognosis, characterizedby early disease recurrence and substantially greater risk ofpremature allograft failure following disease recurrence .
-The approach to treatment for recurrent disease is not wellestablished,
limited to case series of successful treatment with the use of plasmapheresis and other immunosuppressive agents including cyclophosphamide, eculizumab, and rituximab . Recurrent Idiopathic Membranous GN
-The diagnostic test accuracy of circulating anti- PLA2R autoantibody in differentiating primary from secondary membranous GN is acceptable( sensitivity of 65% , specificity of 97% ).
-20% of patients with idiopathic membranous GN do not have detectable autoantibodies to PLA2R .
-The rate of disease recurrence in patients with idiopathic membranous GN following kidney transplantation is between 30 and 50% .
– The circulating levels of anti-PLA2R autoantibody tend to decline post-transplant .
-The treatment of disease recurrence includes a combination of anti-proteinuric agents, corticosteroids, alkylating agents, CNI, and rituximab. Secondary GN
-The incidence and outcome of patients with recurrent lupus nephritis post-kidney transplantation are unclear.
-In patients with anti- GBM disease, disease recurrence after kidney transplant is <5%in the era of modern immunosuppression, and allograft failure from disease recurrence exceedingly rare .
-Disease recurrence following transplantation of patients with aHUS was up to 80%, with a substantial proportion of patients losing their allografts from recurrent disease within the first year post-transplant and therefore, kidney transplantation was considered a contraindication for patients with aHUS . De novo GN
– The incidence of de novo GN after kidney transplant varies between 4 and 20%, with FSGS, IgA nephropathy, membranous GN, and MPGN being the most common de novoGN subtypes.
-The incidence of de novo IgA nephropathy is likely to be underestimated, presentation with macroscopic hematuria is unusual.The prognosis of those with de novo IgA nephropathy is usually relatively benign with treatment predominantly focuses on antiproteinuric and/or anti-hypertensive therapy
-Crescentic de novo IgA nephropathy tend to have a poorer prognosis.
-De novo membranous GN and MPGN are much less common, and the reported cases primarily related to secondary causes including viral infections, rejection,
autoimmune disease, CNI and thrombotic microangiopathy.
-The onset of de novo membranous GN or MPGN tend to occur later post-transplant .
Nice effort. What is the level of evidence of this paper
Sherif Yusuf
2 years ago
Glomerulonephritis is considered an important cause of ESRD constituting 7-17 % of all causes of ESRD
Glomerulonephritis is either primary or secondary, and glomerulonephritis occurring after transplantation is either denovo or recurrent
Recurrence of glomerulonephritis is common, incidence differs according to the type and is associated with an increase in the incidence of graft loss within the first 2-3 years post-transplantation
Recurrent IgA nephropathy
Common incidence ranges from 10% at 10 years and 15% at 15 years
Usually occurs late
Around half of the patients who develop recurrence will lose their grafts,
Risk factors for recurrence include younger age, living related kidney transplantation, 0 HLA mismatch, use of no induction immunosuppression, steroid avoidance or minimization strategies (use of ATG is associated with favorable outcome)
Treatment is conservative with no known specific therapy other than the immunosuppressive used in transplantation
Recurrent primary FSGS:
Patients commonly present in the early post-transplant period (first 3 months)
FSGS recur in one-third of the patient with primary FSGS and once recur it can cause graft loss in nearly half of the patients 5 years after recurrence, secondary FSGS recur less and the recurrence rate in genetic FSGS is estimated to be < 3%
In practice it may be difficult to determine the actual risk of recurrence since sometimes it is difficult to differentiate between types of FSGS. Genetis screening may be a good option to detect genetic FSGS before transplantation
Risk factors for recurrence of primary FSGS
1- Age: Patients with disease onset at a younger age are more prone to
recurrence
2- Race: non-white are at increased risk of recurrence
3- Living donor kidney is associated with a higher risk of recurrence than
deceased donor kidney transplantation
4- Recurrence of FSGS in the previous transplant increases the risk of
recurrence in subsequent graft
5- aggressive FSGS leading to renal failure within a short time after onset is
associated with a higher recurrence rate.
6- A family history of FSGS is considered a lower risk factor for recurrence a
it indicates autosomal dominance
Aggressive monitoring of proteinuria should be done in the early post-transplant period (first 3 months) and if proteinuria is > 1 gram, renal biopsy is indicated.
Recurrent FSGS is treated mainly with plasmapheresis with or without rituximab
Recurrent idiopathic MPGN:
MPGN ( LM finding) is classified according to IF into three types : (1) Immune complex MPGN which is characterized by immune complex deposition (polyclonal or monoclonal), it may be idiopathic or secondary to infection, malignancy, immune disease or toxins (2) C3 glomerulopathy which is characterized by glomerular deposition of C3 and (3) Pauci immune MPGN which is characterized by neither deposition of Ig nor complement
Common, occur in more than half of cases in the first 2 years.
Around one-third of the patients (with immune complex MPGN ) and half of the patients (with C3 glomerulopathy) who develop recurrence will lose their grafts within the first 5 years post-transplantation
Monoclonal Ig deposition can occur in both immune complex MPGN and C3 glomerulopathy and only around one-third of immune complex MPGN cases are diagnosed as plasma cell dyscrasia, its presence is associated with a higher rate of recurrence, early recurrence, and more poor prognosis
Options in the treatment of recurrent C3 glomerulopathy include supportive treatment (ACEI, or ARBS) in mild disease, corticosteroids cyclophosphamide , plasma exchange, Eculizumab treatment can be used in refractory cases, and Rituximab (poor response)
Recurrent idiopathic MGN:
Anti-PLA2R Ab has diagnostic value :
Used in differentiating idiopathic from secondary MN, but it has good positive predictive value this means positive results indicating primary MN but negative results does not necessarily means secondary (sensitivity 65%, while specificity 97%)
Used in differentiating between recurrent idiopathic MN and other denovo GN following transplantation
Also anti PLA2R has prognostic value as it predict recurrence after renal transplantation, recurrence rate of idiopathic MN is ranging between 30-50% of cases with higher rate detected in patients with high anti PLA2R antibodies detected before transplantation
Options in the treatment of recurrent MN include: supportive treatment (ACEI, or ARBS), corticosteroids, CNI, cyclophosphamide, Rituximab (preferd TTT, good response, in both anti PLA2R positive and negative cases, remission occurs in 80% of cases) and Bortezumib ( can be tried in cases resisitant to Rituximab)
Secondary GN:
Occurs secondary to systemic diseases such as aHUS, SLE, ANCA vasculitis, and anti-GBM Ab disease
Recurrence is variable which is up to 80% in aHUS (the use of prophylactic Eculizumab decrease the incidence of recurrence significantly), 0-44% in SLE and rare < 5% in anti-GBM Ab
Usually recurrence occurs late
Lower likelihood of graft loss after recurrence but aHUS and SLE has higher graft loss rate after recurrence
De novo GN:
Denovo GN either develop in the recipient or may be present in the donor kidney
Occurs in 4-20 % of cases
associated with increase in the graft loss rate and poor outcome
Most common forms include IgAN , FSGS, MPGN and MN.
Sometimes It is difficult to distinguish denovo from recurrent disease especially if the primary disease of ESRD is not known
Risk factors for denovo GN include the reduction of nephron mass due to DM, HTN, rejection, infection, and CNI use or due to podocyte injury induced by sirolimus use
Treatment includes conservative treatment and treatment of the cause
Recurrent and de novo glomerulonephritis after renal transplant Summary
This article is about the possible causes of GN post kidney transplant, as well as the consequences of it. This includes recurrence of GN and de novo GN.
The main consequence of GN recurrence after renal transplant is failure of allograft prematurely.
Any subtype of GN can recur.
Gn recurrence leading to failure of graft generally is higher around 3-5 years post transplant.
FSGS and MPGN are associated with higher risk of recurrence
IgA nephropathy subtype
The best graft and patient outcomes are seen with subtype IgA nephropathy.
Risk factors for disease recurrence include
younger age
recipients of related donor kidneys (O HLA mismatch)
steroid avoidance
early withdrawal of steroids
Not using induction therapy
HLA allele subtypes
crescentic rapidly progressive IgA nephropathy in native kidney
shorter total ischemia time
ATG is associated with lower rates of recurrence of this subtype
Pathogenesis involves Gd IgA1, IgG anti Gd IgA1 antibodies, glycan specific IgG antibodies, soluble CD89.
Treatment unknown
CNI and steroid IS to be given, rituximab for aggressive cases.
Anti – proteinuria treatment
Recurrent primary FSGS
High rate of recurrence following kidney transplant.
High risk of allograft failure
Secondary form can occur late post transplant
Genetic testing for familial FSGS can help in assessing recurrence incidence risk. Test for mutations in podocin or podocyte proteins.
Genetic testing to be done also for pediatric patients especially with steroid resistant nephrotic syndrome and known NPHS2 mutation.
Pathogenesis : unclear. Possible role of serum soluble urokinase receptor activating podocyte beta Integrieren leading to effacement of foot processes and proteinuria, resulting ultimately in FSGS.
Treatment : plasmapheresis is recommended. CNI plus rituximab.
Possible Prophylaxis : Pre-emptive plasmapheresis, immunoadsorption therapy, ofatumumab.
Recurrent primary MPGN
Common
Occurs within first 2 years post transplant (mostly)
Prophylactic rituximab can be given for high risk patients such as those with previous allograft failure due to disease recurrence, persistent high levels of circulating PLA2R.
Recurrent or de novo GN in the renal allograft is a cause of premature allograft failure
High risk subtypes of GN as IgA nephropathy, idiopathic membranous GN,
focal segmental glomerulosclerosis (FSGS), and membranoproliferative GN (MPGN) are more likely to recur after transplantation.
The risk of GN recurrence is related to time post-transplant, most cases recurring 3–5 years post-transplant, but with MPGN and FSGS recurrence can occur earlier. Recurrent IgA Nephropathy
It is common, occurring late post-transplant with 40% of cases losing their allografts but outcome is better in comparison to other GN subtypes.
There are multiple risk factors for disease recurrence as younger age, zero-HLA-mismatched live-related donors, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy crescentic Ig A nephropathy, and shorter total ischemic time.
There are multiple molecules as galactose-deficient IgA1, as well as serum and urinary biomarkers that could have prognostic importance and could be indicative of recurrence.
There isn’t a specific therapy for Ig A nephropathy recurrence but a CNI and steroids-based regimen with anti-proteinuric measures are the used therapy
In crescentic IgA nephropathy more intensive immunosuppression can be needed Recurrent Primary FSGS
Cases with primary FSGS has high rate of recurrence risk and poor allograft long term outcome
For secondary FSGS the recurrence risk is unknown
Genetic testing is essential in the assessment of FSGS cases before transplantation particularly in cases with uncertainty for primary , secondary or familial FSGS because Familial FSGS with mutations of podocin and apolipoprotein L-1 genotype have low risk of recurrence in the graft.
Circulating serum soluble urokinase receptor is supposed to be implicated in the development of primary FSGS specially familial subtype,meanwhile it is not specific.
Other prognostic markers for disease recurrence as Anti-CD40 autoantibody, and AT1R antibody are under study.
Treatment regimen usually used is plasmapheresis ,Rituximab , CNI and optimizing antiprotienuric tretament
New therapies are ofatumumab or B7-1 blockers (abatacept and belatacept) are investigated for prevention and treatment Recurrent Primary MPGN
Is common with more than 50% risk of occurring within the first 24 months post-transplant.
The pattern of glomerular Ig and complement deposition can differentiate between the MPGN subtypes and the pathogenesis of the different diseases
DDD usually recur later post-transplant and often associated with only allograft dysfunction. C3GN and DDD are characterized by heavy glomerular staining for C3 and electron deposits on electron microscopy, but both of them differ morphologically .
Genetic mutations or autoantibodies were involved in disease pathogenesis
Transplant recipients due to C3glomerulopathy with monoclonal gammopathy experienced rapid disease recurrence.
Serum monoclonal proteins with and without low complement levels are associated with higher recurrence risk .
Glomerular monoclonal Ig deposits as IgG3κ , IgG3λ, and IgG2λ were associated with worst outcomes.
Screening for monoclonal gammopathy with or without hematology consultation before transplantation in patients with MPGN, meanwhile close monitoring post-transplant for signs of disease recurrence is essential.
The best treatment strategy remains unknown, plasmapheresis and other immunosuppressive agents including cyclophosphamide, eculizumab, and rituximab were used Recurrent Idiopathic Membranous GN
Anti-PLA2R autoantibody detection improved the recognition and differentiation of primary vs. secondary membranous GN as well as detecting those at high risk of post-transplant disease recurrence .
Thrombospondin type 1 domain–containing 7A (THSD7A) was detected in 5% of patients with idiopathic membranous GN, whom were seronegative for the PLA2R autoantibody while other primary membranous GN were negative for both autoantibodies.
Recurrence of idiopathic membranous GN posttransplantation is between 30 and 50%.
Patients with high titers of anti-PLA2R autoantibody detection have a greater risk of disease recurrence.
Treatment includes combination of anti-proteinuric agents, corticosteroids, alkylating agents, CNI, and rituximab.
Complete clinical remission with bortezomib occurred in a single case with rituximab resistant recurrent membranous GN Secondary GN
secondary to systemic diseases as atypical hemolytic uremic syndrome (aHUS), systemic lupus erythematosus (SLE), anti-glomerular basement membrane (GBM) disease, and crescentic GN can have GN recurrence post transplantation, but occur later and not common to cause allograft failure. Presumed or Advanced GN
In cases of unknown cause of ESKD because biopsy was not done allograft failure due to GN is extremely low. De novo GN De novo GN recurrence postkidney transplant is 4 – 20%, with FSGS, IgA nephropathy, membranous GN, and MPGN being the most common de novo GN subtypes.
Confirming de novo GN post-transplant is difficult due to uncertainity about the ESKD etiology in the cases
The presentations for de novo GN are similar to primary GN subtypes. Conclusion
The approach and treatment of post-transplant GN recurrence is uncertain till now
Recurrent and de novo glomerulonephritis (GN) are important causes of allograft loss, however, it is likely to be underestimated.
The incidence of GN recurrence differ according to the subtype of GN and time posttransplant. Epidemiology, pathogenesis and outcomes of GN recurrence after kidney transplant: Recurrent IgA nephropathy:
Relatively common, occurs late posttransplant and leads to graft loss in 40% of patients due to recurrence.
Associated with better long-term patient and graft survival compared to other subtypes.
Risk factors for recurrence include young age, zero HLA mismatch live related donor kidneys, steroid avoidance or withdrawal and crescentic form, however, it is difficult to determine the true causes of recurrence.
Several biomarkers are investigated to predict the risk of disease recurrence but are still not validated.
The optimal therapy is unknown, but current practice includes CNI, steroids and antiproteinuric drugs. Recurrent primary FSGS:
Associated with 5-times higher risk of graft loss.
Familial FSGS have low to no risk of recurrence post transplant so genetic testing may be considered in patients with adult onset FSGS.
Risk factors for recurrence of primary FSGS include younger age at presentation, live donor kidney, severe disease at presentation, rapid progression to ESKD and previous graft failure due to recurrence.
The pathogenesis of recurrence is unclear, it is suggested that circulating permeability factors as suPAR may be involved in pathogenesis but its clinical utility is not yet determined.
Management is difficult, Plasmapheresis (PP) is recommended in primary FSGS, the benefit of adjunctive therapy with rituximab and CNI is still uncertain.
Preemptive PP, immunoadsorption, belatacept and ofatumumab are promising agents but still need further studies. Recurrent primary MPGN:
Relatively common, 50% of recurrence occur within first year post transplant.
New classification:
Immune complex mediated (depend on monoclonal or polyclonal immunoglobulins)
C3 glomerulopathy (C3 glomerulonephritis and dense deposit disease)
The 2 types have overlapping clinical and histological features.
Pre transplant screening for monoclonal gammopathy should be considered.
Balancing between the risk premature graft failure due to disease recurrence post transplant and the risk of remaining on dialysis.
Optimal treatment is unknown, PP, cyclophosphamide, eculizumab and rituximab are treatment options but need fiurther studies to determine the most appropriate treatment. Recurrent idiopathic membranous GN:
Rate of recurrence of primary membranous GN ranges from 30-50%, patients with high titers of anti-PLA2R autoantibodies are at greater risk of recurrence.
Monitoring of theses antibodies should be considered in patients with high levels pre transplant, early disease recurrence, to determine response to treatment and to differentiate recurrence from de novo membranous GN
Treatment is similar to that in general population including, antiproteinuric agents, steroids, alkylating agents, CNI and rituximab
Rituximab is efficient when used early after recurrence, however the timing of starting specific treatment is not well determined. Secondary GN:
May recur later post transplant and infrequently lead to graft loss. ANCA associated vasculitis, relapse rate reported at 0.02 per patient-years, no association with ANCA type or disease severity pre transplant. Recurrent lupus nephritis, incidence and outcome are unclear. Anti GBM disease, Recurrence <5% and graft loss is rare. aHUS, was considered a contraindication for transplantation as the risk of recurrence was 80% with graft loss in the first year but availability of eculizumab resulted in excellent patient and graft outcome. Presumed or advanced GN:
Patients with presumed or advanced GN as cause of ESKD have low incidence of graft failure due to GN De novo GN:
The prevalence is unknown, associated with significant lower graft survival.
Secondary causes should be excluded before determining treatment choice and before arranging for re-transplantation.
Management is similar to that in patients with GN without transplantation. FSGS:
long-term outcome is poor, it is difficult to differentiate 2ry FSGS from actual de novo FSGS, treatment include antiproteinuric agents and removing the offending cause if possible with no data about efficacy of using more aggressive therapy. IgA nephropathy:
prognosis is relatively good, treated with antiproteinuric and antihypertensive therapy. membranous GN and MPGN are less common and tend to be late post transplant
Primary GN is an important cause of ESRD worldwide. It It constitute ~17% 0f ESRD patient( ANZDATA). GN is an immune disease with different histological subtypes & clinical phenotypes & differ in recurrence rate after transplantation. Both recurrent & de novo GN associated with premature graft loss. The incidence of post transplant ( recur or de novo) GN is under estimated due to:
Post transplant recurrence usually occur 2-3 years, but can occur earliar in FSGS & MPGN.
Recurrent IgAN:
It is common, later in post transplant period & can be reduced overtime. Comparing to other types of GN, IgAN had better patient & graft long term outcome. Risk factors associated with increased risk of recurrence include:
young age
recipient of 0-HLA mismatch live related donor kidney
steroid avoidance or early withdrawal.
no induction therapy pre-transplant.
molecular factors e.g. Gd-IgA1, IgG anti Gd-IgA1 Ab
The optimal treatment is unknown.
Recurrent primary FSGS:
One third of patients had recurrence with 5 folds increased risk of graft loss compared to patients without recurrence. Patients with familial type had low risk of recurrence <3%( NPHS2). But identification of familial subtype is difficult due to incomplete penetrance. Genetic screening done for:
adult onset FSGS with uncertain subtypes ( primary or secondary)
positive family history
Due to high cost of genetic study, it is better to screen patients with clear family history of FSGS or potential live donor for transplantation. Risk factors for recurrence include:
young age at presentation
recipient with live donor kidney
non white ethnicity
severe manifestation at presentation.
rapid progression to ESRD
previous transplantation with recurrence.
The exact cause of recurrence is unclear, but presence of circulatory serum suPAR proposed to be a cause. Reduction of serum suPAR can predict remission but it can’t differentiate between primary or secondary types or prediction of recurrence. Urin suPAR, anti-CD40 Ab & AT1R AB are other markers of FSGS but need more studies to confirm its validity.
Post transplant (first 3 mon) monitoring of proteinuria in high risk patient is important for early detection of recurrence in addition to graft biopsy in case of increasing proteinuria. Optimal treatment is uncertain, but PP, rituximab & CNI can be used with anti-proteinuric measures.
Recurrent MPGN:
Post transplant recurrence is common >50% in first 2 years with high risk of graft loss ( 5 years graft survival 30%). It classifies into:
immune complex-mediated GN: polyclonal or monoclonal Ig glomerular deposition. High recurrence rate among patients with Ig deposition & complement activation. Appropriate treatment for recurrence it is not established, but PP, cyclophosphamide, eculizumab & rituximab were successful in case series.
Complemented mediated MPGN: e.g. C3GN & DDD.
Recurrent idiopathic MGN:
Identification of anti-PLA2R Ab was important in treatment of idiopathic & differentiation between primary & secondary MGN in addition to prediction of disease recurrence post transplantation. Anti-PLA2R sensitivity ~65% & specificity ~97%. THSD7A Ab found in %% of idiopathic MGN patients ( negative PLA2R).
Recurrence occur in 30-50%. Pre transplant high level of PLA2R Ab associated with prediction of recurrence.
Treatment include optimizing anti-proteinuria drugs, CS, CNI, alkalizing agent & rituximab( associated with 80% remission). Bortezumib shown to be effective in cases of rituximab resistance.
Secondary GN:
It attributed to systemic diseases e.g. aHUS, SLE, anti-GBM & systemic vasculitis. Recurrence usually occur late with infrequent graft loss.
De novo GN:
Exact prevalence is unknown, but it associated with reduced graft survival when compared to patients without de novo GN. Incidence 4-20% with FSGS, IgAN, MGN & MPGN as most common subtypes.
It is difficult to confirm diagnosis of de novo GN because the primary cause of ESRD unknown & GN disease may present in donor kidney. Risk factors that predisposed to de novo GN include:
introduction of sirolimus ( affect podocytes integrity)
It associated with poor long term outcome & treatment depends mainly on anti-proteinuria drugs & treatment of offending factor, Immunosuppression may be considered.
IgAN recurrence course is benign & treatment only anti-proteinuria drugs, but patients with crescentic IgAN have poor outcome.
De novo MGN & MPGN less common & it related to secondary causes e.g. viral infection, rejection, autoimmune diseases, CNI & TMA. Secondary causes should be excluded in recipient who develop de novo GN because it important for treatment option & re transplant potential.
Primary GN is one of leading cause of ESKD worldwide (about 10-15 % of ESKD).
Glomerulonephritis (primary or secondary) are heterogenous in respect to recurrence after kidney transplantation. The prevalence of GN recurrence after kidney transplantation is between 3-15%, particularly in patients with high-risk subtypes of IgA nephropathy, idiopathic membranous GN, FSGS, and MPGN). Most of the GN recurrences occur 3-5 years post transplantation with the exception of FSGS and MPGN which can occur early post transplantation.
Among ESKD patients due to primary GN the risk of recurrence is high, particularly in FSGS and MPGN.
IgA nephropathy:
Recurrence of IgA nephropathy occurs late post-transplantation, and it is correlated with better prognosis than other glomerulonephritis. Allograft survival after MPGN recurrence is poorer than other glomerulonephritis.
Risk factors for post-transplant IgA nephropathy recurrence consist of younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy (ATG may be associated with a lower risk of recurrence), HLA allelic subtypes, crescentic (and rapidly progressive) IgA nephropathy in the native kidneys and shorter total ischemic time.
The suggested treatment for IgA nephropathy includes CNIs and corticosteroids, and for crescentic rapidly progressive form cyclophosphamide or rituximab can be considered.
Recurrent primary FSGS:
Up to 1 in 3 patients with primary FSGS will experience post-transplant recurrence with five times higher risk of graft loss. Differentiation between secondary and primary FSGS may be difficult late post transplantation. On the other hand, familial FSGS is associated with no or low risk of recurrence. It is practical to consider screening genetic testing for recipients with family history of FSGS or who has a relative living donor candidate for kidney transplantation. Risk factors for recurrence of primary FSGS include younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESKD, and prior allograft failure from disease recurrence. A pathologic role for suPAR is proposed for primary FSGS. Serum suPAR is non-specific and can increase in other conditions such as infection and inflammation. Anti CD40 autoantibody and anti AT1R antibody are promising as prognostic factors. Close monitoring of high-risk patients is suggested in the first three months post transplantation.
Plasmapheresis or rituximab or CNIs are therapeutic options for primary FSGS. It seems that Rituximab function on podocyte is essential factor rather than its effect on B cells. The function of CNIs on T cells and actin cytoskeleton in podocytes are important in inducing remission in primary FSGS. Switch to CNIs in patients who are on mTOR inhibitors is recommended.
Recurrent primary MPGN:
Recurrence of post-transplant MPGN is common and occurs early after transplantation with high risk of graft loss.
MPGN is classified to immune-mediated (monoclonal or polyclonal), complement mediated (C3 glomerulopathy including C3 glomerulonephritis and DDD). Dysregulation of alternative pathway of complement with manifestation of intense C3 staining is seen in C3 glomerulopathy. Although DDD occurs later than C3 glomerulonephritis, its consequence is only graft loss. Monoclonal related MPGN is associated with activation of complement classical pathway. Presence of monoclonal immunoglobulin +/- positive C4d is associated with poor prognosis. Treatment of recurrent disease comprises of plasmapheresis, cyclophosphamide, eculizumab, or rituximab. Eculizumab has a potential benefit in C3 glomerulopathy treatment. Plasmapheresis and anti B-cell therapy can be considered for Ig-mediated MPGN.
Recurrent idiopathic membranous GN:
Anti PLA2R antibody is important for differentiate primary and secondary MN, furthermore prediction the risk of recurrence and prognosis after kidney transplantation. THSD7A is another autoantibody detected 5% in primary MN, typically in PLA2R seronegative patients. Nevertheless, up to 20% of Idiopathic MN are negative for both autoantibodies. The rate of idiopathic MN recurrence is 30-50% and it is correlated with higher titers of pre- and post-transplant anti PLA2R antibodies. It should be monitored after transplantation in patients with high pre-transplant titer or early recurrence post transplantation. The treatment disease recurrence consists of antiproteinuric agents in addition to CNI based therapy and rituximab (that is superior to alkylating agents). Bortezomib can be considered for rituximab-resistant recurrent idiopathic MN. Pre-emptive use of rituximab is an option in patients with high titer of anti PLA2R antibody with previous history of graft loss due to recurrence or with persistent and progressive increase in post-transplant anti PLA2R antibody titers.
Secondary GN:
Post-transplant recurrence after secondary GN occurs late and less frequently is associate with graft loss. For example, the rate of recurrence of ANCA associated vasculitis and anti GBM is low.
De novo GN:
The most common forms of de novo GN post transplantation are FSGS (the most common form), IgA nephropathy, idiopathic MN and MPGN, and they are associated with significantly reduced graft survival.
Development of de novo FSGS is related to reduction in nephron number in different conditions such as BKV nephropathy and DM. treatment consists of antiproteinuric agent and removing offending factors. De novo IgA nephropathy is usually benign except for crescentic form, and therapy consist of antiproteinuric and antihypertensive agents. De novo MN and MPGN are less common, usually secondary to viral infection, autoimmune, and occur late post transplantation. The pattern of IgG staining can help to differentiate between de novo and recurrent MN (Recurrent is IgG1 dominant with more frequent anti PLA2R antibody, and de novo is IgG4 dominant).
In the presence of de novo GN, awareness of the need to exclude secondary causes is essential.
Recurrent and de novo Glomerulonephritis After Kidney Transplantation
This review focuses on the incidence, genetics, characteristics, clinical course, and risk of allograft failure of patients with recurrent or de novo GN after kidney transplantation, ascertaining potential disparities between “high risk” disease subtypes of IgA nephropathy, idiopathic membranous glomerulonephritis, focal segmental glomerulosclerosis, and membranoproliferative glomerulonephritis. We will examine in detail the management of patients with high risk GN, including the pre-transplant assessment, post-transplant monitoring, and the available treatment options for disease recurrence.
INTRODUCTION
All GN subtypes can potentially recur after transplantation, with the prevalence of GN recurrence between 3 and 15%, particularly in patients with high risk subtypes of IgA nephropathy, idiopathic membranous GN, focal segmental glomerulosclerosis (FSGS), and membranoproliferative GN
(MPGN).
the incidence of de novo or recurrent GN after kidney transplantation is likely to be under-estimated because of the likelihood of selection bias (i.e., systematic differences in the selection and listing of ESKD patients with different GN subtypes), varying biopsy practices, ascertainment of the primary cause of ESKD, differing follow-up period, disparate clinical presentations ranging from asymptomatic urinary abnormalities to rapidly progressive GN, misclassification, and indication bias (where kidney biopsy may be carried out only for specific clinical indication and therefore may fail to identify asymptomatic incidental cases of early disease recurrence) and the competing risk of other causes of allograft failures.
Epidemiology, Pathogenesis, and Outcomes of GN Recurrence After Kidney Transplantation
The incidence of GN recurrence posttransplant varies according to GN subtypes and time post-transplantation.
Recurrent IgA Nephropathy
Recurrent IgA nephropathy is relatively common, but typically occurs late post-transplant with cumulative incidence of disease recurrence at 15 years of 15%.
Following disease recurrence, up to 40% of patients with recurrent IgA nephropathy have been reported to lose their allografts, predominantly from disease recurrence (up to 60%).
Compared with other GN subtypes, the long-term allograft and patient outcomes of patients with IgA nephropathy are substantially better.
Several risk factors for disease recurrence have been described including younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy (whereas anti-thymocyte globulin [ATG] may be associated with a lower risk of recurrence), HLA allelic subtypes, crescentic (and rapidly progressive) IgA nephropathy in the native kidneys and shorter total ischemic time, but given these findings were identified in population cohort studies, it is difficult to ascertain the true causality of these risk factors for disease recurrence.
The optimal treatment of recurrent IgA nephropathy remains unknown and there are no current studies to suggest that alterations in immunosuppression will improve allograft outcome. The current practice is to maintain (or change to) a calcineruin-inhibitor (CNI) and corticosteroids-based
immunosuppressive regimen in addition to anti-proteinuric treatments, although the optimal dosing/target therapeutic CNI level or specific CNI type in the treatment of those with recurrent disease remains unknown. In cases of crescentic rapidly progressive IgA nephropathy, more aggressive
immunosuppression (e.g., cyclophosphamide or rituximab) may be considered but this is largely unproven and unlikely to successfully reverse the disease process.
Recurrent Primary FSGS
Up to 1 in 3 patients with primary FSGS will experience disease recurrence after kidney transplantation, with the risk of allograft failure (predominantly from GN recurrence) 5-times the risk compared to those without disease recurrence.
In contrast to patients with primary FSGS, familial FSGS in adults, have low to no risk (<3%) of disease recurrence post-transplant suggesting the relative importance of genetic testing in the evaluation of a subset of patients with adult-onset FSGS for transplantation.
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Many of the genetic mutations associated with adult-onset FSGS have
an incomplete penetrance and therefore, the identification of
patients with familial FSGS remains challenging.
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The management of patients with recurrent primary FSGS remains challenging. Plasmapheresis is often preferred and recommended (in the American Society for Apheresis guidelines) in the treatment of primary FSGS recurrence in the allograft of both pediatric and adult patients. The efficacy of adjunctive therapy including rituximab and CNI such as cyclosporine remains uncertain. However, a switch to CNI if patients were on mammalian target of rapamycin [mTOR]-inhibitor is advocated, given that mTOR-inhibitor, especially at higher doses have been associated with the development of de novo FSGS. The roles of pre-emptive plasmapheresis (pre and/or posttransplantation), immunoadsorption therapy, and other novel
options such as ofatumumab or B7-1 blockers (abatacept and belatacept) to prevent disease recurrence or to treat recurrence appear promising but the efficacy of these treatments remain debatable and not always consistent or supported in subsequent studies.
Recurrent Primary MPGN
Disease recurrence post-transplant from primary MPGN is relatively common, with over 50% of recurrence occurring within the first 24 months post-transplant. Immune-complex mediated MPGN is characterized by the glomerular deposition of polyclonal or monoclonal immunoglobulins (Ig), whereas C3 glomerulopathy [comprising of C3GN and dense deposit disease (DDD)] is characterized by the glomerular deposition of C3 in the absence
of Ig deposition.
There is a high rate of post-transplant recurrence for both C3GN and DDD, with over 50% of patients with disease recurrence reported to experience allograft failure, although the number of patients in these studies was relatively small.
The timing and clinical presentations of patients with C3GN and DDD may be dissimilar, with DDD more likely to recur later post-transplant and often associated with no clinical manifestations other than allograft dysfunction. C3GN and DDD are characterized by the presence of strong glomerular staining for C3 and electron deposits on electron microscopy, but these diseases are potentially morphologically distinguishable by the nature and
ultrastructural characteristics of these electron dense deposits
For immune-mediated MPGN, the patterns and types of Ig deposits may have diagnostic and prognostic significance.
The presence of serum monoclonal proteins, with and without low complement levels (±glomerular C4d deposition), implying activation of the complement cascade was associated with a less favorable clinical course post-transplant, with higher risk of recurrence and disease progression following recurrence.
Recurrent Idiopathic Membranous GN
The ability to test for the presence of anti-PLA2R autoantibody has resulted in improved recognition and differentiating primary vs. secondary membranous GN, as well as assisting clinicians in the management of patients pre and post-transplantation, identifying those patients at high risk of post-transplant disease recurrence that may benefit from more intensive monitoring post-transplant as well as monitoring response to treatment.
The rate of disease recurrence in patients with idiopathic membranous GN following kidney transplantation is between 30 and 50%, with the disparate detection rates reported in the studies influenced by the characteristics of the cohort
The treatment of disease recurrence is largely extrapolated from treatment in the general population and typically includes a combination of anti-proteinuric agents, corticosteroids, alkylating agents, CNI, and rituximab.
Secondary GN
In contrast to ESKD attributed to primary GN, patients with secondary GN subtypes attributed to systemic diseases [such as atypical hemolytic uremic syndrome (aHUS), systemic lupus erythematosus (SLE), anti-glomerular basement membrane (GBM) disease, and crescentic GN (e.g., from
systemic vasculitis)] may experience GN recurrence after kidney transplantation, but these relapses often occur later post-transplant and infrequently lead to allograft failure.
According to the 2018 Australia and New Zealand Dialysis and Transplant (ANZDATA)
registry report, GN as cause of ESKD accounted for 17% of incident treated ESKD
patients.
In the US, GN as cause of ESKD, Recurrent Glomerulonephritis in Kidney
Transplantation of 7 and 13% of incident ESKD initiated on dialysis and have received
kidney transplants, respectively; with similar proportion reported in the United Kingdom.
Recurrent or de novo GN in the renal allograft is an important cause of premature
allograft failure.
All GN subtypes can potentially recur after transplantation, with the prevalence of GN
recurrence between 3 and 15%, particularly in patients with high risk subtypes of IgA
nephropathy, idiopathic membranous GN, focal segmental glomerulosclerosis (FSGS),
and membranoproliferative GN (MPGN).
His majority of GN recurrence resulting in allograft failure occurring after 3–5 years post-
transplant, although early recurrences can occur in patients with GN subtypes of MPGN
and FSGS.
Epidemiology, Pathogenesis, and Outcomes of GN Recurrence after Kidney
Transplantation:
The incidence of GN recurrence posttransplant varies according to GN subtypes and
time posttransplantation.
Recurrent IgA Nephropathy:
Common.
Late post-transplant.
Incidence at 15 years of 15%.
40% of patients lose their allografts.
The long-term allograft and patient outcomes of patients with IgA nephropathy are
substantially better compared with other GN subtypes.
risk factors for disease recurrence:
Younger age.
Recipients of zero-HLA-mismatched live-related donor kidneys.
Steroid-avoidance or early steroid withdrawal immunosuppressive regimens,
The non-use of induction therapy (whereas anti-thymocyte globulin [ATG] may be
associated with a lower risk of recurrence),HLA allelic subtypes,
Crescentic (and rapidly progressive) IgA nephropathy in the native kidneys.
Shorter total ischemic time.
Galactose-deficient IgA1 (Gd-IgA1), IgG anti-Gd-IgA1 antibodies, glycan-specific IgG
antibodies, and soluble CD89.
Treatment:
T maintain (or change to) a Calcineurin-inhibitor (CNI) and corticosteroids-based
immunosuppressive regimen in addition to anti-proteinuric treatments,
In cases of crescentic rapidly progressive IgA nephropathy, more aggressive
immunosuppression (e.g., cyclophosphamide or rituximab).
Recurrent Primary FSGS:
10% of patients experienced disease recurrence Poorer 5-year allograft survival of 54%.
Less to zero risk with familial.
Screening for familial:
A clear family history of FSGS or those with a potential live-related donor for
transplantation, including undertaking genetic screening of the donors for the same
genetic mutations (if present in the potential recipients).
Risk factors for disease recurrence:
Younger age at presentation.
Recipients of live-donor kidneys,
Non-white ethnicity.
Severe manifestations of disease at presentation, rapid progression to ESKD, and prior
allograft failure from disease recurrence.
Treatment:
Plasmapheresis.
The efficacy of adjunctive therapy including rituximab and CNI such as cyclosporine
remains uncertain.
Recurrent Primary MPGN:
Common, with over 50% of recurrence occurring within the first 24 months post-
transplant.
, the risk of allograft failure is relatively high with 5-year allograft survival post-disease
recurrence of only 30%.
Risk factors for disease recurrence:
Monoclonal gammopathy.
Presence of serum monoclonal proteins with and without low complement levels
Glomerular monoclonal Ig deposits (typically IgG3κ and IgG3λ).
Treatment:
Plasmapheresis and other immunosuppressive agents including cyclophosphamide,
Eculizumab, and rituximab.
Recurrent Idiopathic Membranous GN:
Disease recurrence in patients with idiopathic membranous GN following kidney
transplantation is between 30 and 50%.
Relative risk of allograft failure, up to 50% at 10-years.
Those with high titters of circulating anti-PLA2R autoantibody have a greater risk of
recurrent.
Treatment:
Combination of anti-proteinuric agents, corticosteroids, alkylating agents, CNI, and
rituximab.
Rituximab is an effective treatment for native and recurrent membranous GN in the
allograft, with up to 80% achieving complete or partial remission with the use of
rituximab for early disease recurrence post-transplant.
Secondary GN:
Relapses often occur later post-transplant and infrequently lead to allograft failure.
ANCA)-associated vasculitis, the relapse rate has been reported at 0.02 per patient-
years.
Incidence of recurrent lupus nephritis varies between 0 and 44%.
AntiGBM disease, disease recurrence after kidney transplant is less than5%, with a rare
graft loss.
De novo GN :
The incidence of de novo GN after kidney transplant varies between 4 and 20%, with
FSGS, IgA nephropathy, membranous GN, and MPGN being the most common de novo
GN subtypes.
Is associated with significantly reduced allograft survival. IF non-GN causes ESRD had
developed de novo GN, over 95% of cases were FSGS.
Presentation:
Ranging from asymptomatic urinary or biochemical abnormalities to overt symptoms and
signs of GN with nephrotic syndrome and renal dysfunction.
The treatment of de novo FSGS predominantly revolves around adequate anti-
proteinuric treatment and the removal of the offending agents/factors where possible, but
more aggressive therapy may be considered.
De novo IgA nephropathy is likely to be underestimated, with asymptomatic IgA
deposition not infrequently found.
Prognosis of those with de novo IgA nephropathy is usually relatively benign with
treatment predominantly focuses on antiproteinuric and/or anti-hypertensive therapy.
Crescentic de novo IgA nephropathy tend to have a poorer prognosis.
De novo membranous GN and MPGN are much less common, and the reported cases
primarily related to secondary causes including viral infections, rejection, autoimmune
disease, CNI and thrombotic microangiopathy.
. The onset of de novo membranous GN or MPGN tend to occur later post-transplant
(compared to recurrent disease).
With symptoms ranging from asymptomatic detection of mild proteinuria and incidental
biopsy findings to nephrotic range proteinuria and rapidly progressive GN.
IgG1 staining in capillary loop deposits was dominant/co-dominant IN RECURRENT
DISEASE .whereas, IgG4 staining in capillary loop deposits was dominant/codominant
in de novo disease. AntiPLAR is more with recurrent disease.
Conclusion:
More research is needed. Post-Transplant Glomerular Disease (TANGO) study, an
observational, multicenter cohort study was initiated to undertake collaborative studies
and clinical intervention trials to improve the management and clinical outcomes of these
patients.
• Summary:
• Some glomerular diseases have high risk of recurrence post-transplantation as IgA nephropathy, idiopathic membranous glomerulonephritis, focal segmental glomerulosclerosis (FSGS), and membranoproliferative glomerulonephritis(MPGN).
• Glomerulonephritis represent immune mediated spectrum of diseases either 1ry or 2ry.
• Recurrence of glomerular diseases occurs in 3-15%, and is a leading cause of allograft loss. it mostly occurs years post-transplant, except FSGS and MPGN which can occur early post transplant.
• presentation varies between asymptomatic urinary abnormalities to rapidly progressive glomerulonephritis.
• Recurrent IgA Nephropathy:
Common, usually late onset.
Benign presentation as microscopic hematuria or evidence of IGA deposition in allograft biopsies
40 % reported to have graft loss.
However, better patient and graft outcomes than recurrent FSGS, MPGN and membranous nephropathy.
Risk factors and predictors of disease recurrence are: young age, zero-HLA-mismatched, live-related donor kidneys (LDKT), non-use of induction therapy, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, , HLA allelic subtypes, crescentic and RPGN presentation of IgA nephropathy in the native kidneys and shorter total ischemic time, but these factors were identified in population cohort studies, it is difficult to ascertain the true causality for IgA nephropathy recurrence. certain molecules as galactose-deficient IgA1 (Gd-IgA1), IgG anti-Gd-IgA1 antibodies, glycan-specific IgG antibodies, and soluble CD89 were linked to disease recurrence and progression as predictors.
prevention: induction with ATG and avoidance of steroid free maintenance protocols.
ttt : No available RCT. standard is optimization of maintenance therapy, shift to CNI (if not maintained on it), keeping steroid based maintenance therapy and supportive measures as anti-protinuric therapy.
Aggressive therapy as cyclophosphamide or rituximab can be used in crescentic form, but of little evidence. tonsillectomy was reported in case reports and series (but cannot be generally recommended).
• Recurrent 1ry FSGS:
• 30 % risk of recurrence.
• 2ry FSGS can occur de novo in the graft and is difficult to be differentiated from recurrent FSGS.
• Familial FSGS has very low rate of recurrence (up to 3%), so genetic study is essential to determine the prognosis of the disease. its diagnosis clinically based on positive family history , incomplete penetrance can lead to adult onset FSGS.
Indications of genetic testing:
In adults, uncertainty regarding the likelihood of primary disease as (atypical clinical/pathological features or poor response to immunosuppressive treatment) and secondary (no obvious causes identified) FSGS or when there is a clear family history of FSGS.
Screening of related donor in LDKT may be beneficial, but costly, so preserved only to those with genetic mutations identified in the recipients.
In children, it is indicated in idiopathic steroid-resistant nephrotic syndrome (SRNS) with FSGS pathology.
N.B: There is a low risk of FSGS recurrence in pediatric patients with genetic FSGS post-transplant (3%), as those with mutation in podocin (NPHS2).
Risk factors of recurrence include younger age at presentation, recipients of LDKT, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESKD, and prior allograft failure from disease recurrence.
Early recurrence post-transplant may be mediated by circulating permeability factors as SUPAR.
↑ Pre-transplant Serum suPAR, predicts post-transplant recurrence. Urine suPAR ↑ Post-transplant.
Early detection of recurrence by urine analysis and A/C ratio, is essential for early and prompt diagnosis of disease recurrence. early graft biopsy with E/M examination (for early detection of effacement of podocytes foot processes is mandatory).
ttt: plasmapheresis and optimization of CNI plus anti-protinuric therapy are the proposed treatment. Rituximab can be an adjuvant and additional belatacept can be used.
There is no evidence that shift from one CNI to another can improve FSGS. However, shift from mTORi to CNI is suggested to decrease rate of recurrence.
Rituximab is suggested as B cell may play a role in 1ry FSGS, CNI has inhibitory effect on T cells and mechanical effect on podocyte cytoskeleton.
Pre-emptive PEX and rituximab may be beneficial, but still not standard of care, need validation from larger RCT.
Ofatumumab, an anti-CD20 monoclonal antibody and belatacept (used in cases with positive podocyte B7-1) need further studies to prove their efficacy in prevention of FSGS recurrence and are preserved for refractory cases to steroids and plasmapheresis.
• Recurrent idiopathic membranous nephropathy:
• Anti PLA2R antibodies is acceptable test to differentiate between 1ry and 2ry forms of membranous nephropathy with sensitivity of 65% (63–67%) and 97–98% specificity. so, the absence of PLA2R autoantibody does not definitively exclude cases of idiopathic membranous GN.
• Although the circulating levels of anti-PLA2R autoantibody tend to decline post-transplant (adsorption into the allograft or the effect of immunosuppression), there is a direct relationship between the titer level and risk of disease recurrence post-transplant.
• Prevention: pre-emptive use of rituximab for patients with idiopathic membranous GN and high pre-transplant levels of anti-PLA2R antibody has insuffient evidence, but this (or early initiation post-transplant) can be considered in those with detectable high levels of anti-PLA2R antibody with prior allograft failure from recurrent membranous GN or have persistent high or increasing levels of circulating anti-PLA2R antibody post-transplant with early histological recurrence.
• Post transplant follow up of recurrence with the anti PLA2R antibodies, proteinuria
• ttt: is generally the same as native disease in general population, Rituximab is promising in those with anti PLA2R antibody positive, plus use of antiprotinuric treatment as ACEi and ARBs. Boretezomib can be an adjuvant.
• If anti PLA2R antibody are negative, trial of rituximab can be used.
• Recurrent MPGN:
• 50% risk of recurrence, mostly during 1 st year post transplant, high risk of graft loss.
• 2 subcategories: immune complex mediated or complement mediated. C3 glomerulopthy includes (C3GN and dense deposit disease (DDD)).
• C3GN and DDD are characterized by the presence of strong glomerular staining for C3 and electron deposits on E/M, but these diseases are potentially morphologically distinguishable by the nature and ultrastructural characteristics of these electron dense deposits.
• C3 glomerulopthy recurrence occurs early post transplant.
• ttt: Eculizumab if C3 glomerulopathy.
• Plasmapheresis (PEX) and Immunosuppression (IA) (alkylating agent, rituximab) if immune complex MPGN
• Secondary GN:
• systemic diseases as aHUS, SLE, anti- GBM disease, and crescentic GN (e.g., from systemic vasculitis)] may experience GN recurrence after kidney transplantation, but these relapses often occur later post-transplant and infrequently lead to allograft failure.
• Recurrent lupus nephritis range from 0-44% with a high risk of graft failure and death.
• Recurrent anti GBM is rare with modern immunosuppressive therapy.
• a HUS has 80 % of recurrence (without prophylactic Ecluizimab). Combined liver and kidney transplantation can be used.
• Presumed or Advanced GN
• In cases with ESKD, and the biopsy revealed non specific glomerulo-sclerosis, tubular atrophy and interstitial fibrosis.
• De novo GN after transplantation;
• When original kidney disease is uncertain (biopsies were often not undertaken or were non-diagnostic), the presence of GN in the donor kidney may not be known.
• Presentation varies from asymptomatic urine sediment to overt nephrotic or nephritis.
• Risk factors include: diseases with hyperfilteration injury, as diabetes, hypertension, BK viral infection, CNI therapy, and rejection) or the introduction of sirolimus (through the effects on podocyte integrity).
• de novo FSGS occurs late than the recurrence of 1ry FSGS.
• ttt: mostly similar to 1ry disease and supportive anti protinuric.
primary glomerulonephritis is a common cause of ESRD , account for 7% ESRD patients on dialysis and 13% of transplanted patient
recurrent or denovo s an important cause GN of allograft failure
prevalence of GN recurrence is between 3 to15%
Recurrent IgA nephropathy
is common, occurs late post-transplant with cumulative incidence of disease recurrence at 15 years of 15%
after disease recurrence, up to 40% of patients develop allograft failure
Compared with other GN subtypes, the long-term allograft and patient outcomes of patients with IgA nephropathy are relatively better.
risk factors include younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy
no optimal treatment,
The practice is to maintain (or change to) a calcineruin-inhibitor (CNI) and corticosteroids-based
immunosuppressive regimen in addition to anti-proteinuric treatments, but the optimal doses remains unknown.
Recurrent primary FSGS
Up to 1 in 3 patients with primary FSGS will develop disease recurrence after kidney transplantation, with the risk of allograft failure 5-times the risk compared to those without disease recurrence
In contrast to patients with primary FSGS, familial FSGS in adults, comprising of those with mutations of podocin or structural podocyte proteins have low to no risk (<3%) of disease recurrence post-transplant
risk factors for disease recurrence in patient with primary FSGS include younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESKD, and prior allograft failure from disease recurrence
A pathogenic role of the circulating serum soluble urokinase receptor (suPAR) has
been proposed in the pathogenesis , by activating podocyte b(3) integrin resulting
in effacement of foot processes and proteinuria
Close monitoring for proteinuria in high risk patients, and proceeding to a kidney biopsy
Plasmapheresis is often preferred and recommended in the treatment of primary FSGS recurrence in the allograft of both pediatric and adult patients. The efficacy of adjunctive therapy including rituximab and CNI such as cyclosporine remains uncertain.
Recurrent primary MPGN
is common, with over 50% of recurrence occurring within the first 24 months post-transplant In patients who had experienced diseaser ecurrence, the risk of allograft failure is relatively high with 5-year allograft survival post-disease recurrence of only 30%
have two subtypes immune complex-mediated MPGN and complement-mediated MPGN
The approach to treatment for recurrent disease is not well established,limited to case series of successful treatment with the use of plasmapheresis and other immunosuppressive agents including cyclophosphamide, eculizumab, and rituximab
The use of Eculizumab showed benefit in reduction of proteinuria and stabilization of kidney function post transplant.
Recurrent Idiopathic Membranous GN
The rate of disease recurrence in patients with idiopathic membranous GN following kidney transplantation is between 30 and 50% ,those with high titres of circulating anti-PLA2R autoantibody have a greater risk of recurrent disease.
The treatment of disease recurrence includes a combination of anti-proteinuric agents, corticosteroids, alkylating agents, CNI, and rituximab.
Secondary GN
patients with secondary GN subtypes attributed to systemic diseases [such as atypical hemolytic uremic syndrome (aHUS), systemic lupus erythematosus (SLE), anti-glomerular basement membrane (GBM) disease, and crescentic GN may experience GN recurrence after kidney transplantation, but these relapses often occur later post-transplant and infrequently lead to allograft failure
De novo GN
The prevalence of de novo GN is unknown, but is associated with significantly reduced
allograft survival compared to those without de novo glomerular disease. The incidence of de novo GN after kidney transplant varies between 4 and 20%, with FSGS, IgA nephropathy, membranous GN, and MPGN being the most common de novo
GN subtypes.
There are difficulties in diagnosis because the cause of native ESKD is often uncertain (kidney biopsies were often not undertaken or were non-diagnostic), the presence of GN in the donor kidney may not be known (particularly in the absence of pre-implantation biopsy), variations histopathological evaluation of allograft biopsies where immunofluorescence and electron microscopy of biopsies may be not done
primary glomerulonephritis is a common cause of ESRD , account for 7% ESRD patients on dialysis and 13% of transplanted patient
recurrent or denovo s an important cause GN of allograft failure
prevalence of GN recurrence is between 3 to15%
Recurrent IgA nephropathy
is common, occurs late post-transplant with cumulative incidence of disease recurrence at 15 years of 15%
after disease recurrence, up to 40% of patients develop allograft failure
Compared with other GN subtypes, the long-term allograft and patient outcomes of patients with IgA nephropathy are relatively better.
risk factors include younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy
no optimal treatment,
The practice is to maintain (or change to) a calcineruin-inhibitor (CNI) and corticosteroids-based
immunosuppressive regimen in addition to anti-proteinuric treatments, but the optimal doses remains unknown.
Recurrent primary FSGS
Up to 1 in 3 patients with primary FSGS will develop disease recurrence after kidney transplantation, with the risk of allograft failure 5-times the risk compared to those without disease recurrence
In contrast to patients with primary FSGS, familial FSGS in adults, comprising of those with mutations of podocin or structural podocyte proteins have low to no risk (<3%) of disease recurrence post-transplant
risk factors for disease recurrence in patient with primary FSGS include younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESKD, and prior allograft failure from disease recurrence
A pathogenic role of the circulating serum soluble urokinase receptor (suPAR) has
been proposed in the pathogenesis , by activating podocyte b(3) integrin resulting
in effacement of foot processes and proteinuria
Close monitoring for proteinuria in high risk patients, and proceeding to a kidney biopsy
Recurrent and de novo Glomerulonephritis after Renal Transplantation
Primary GN are considered to be one of the major causes of ESKD in native kidneys, while recurrent or de novo GN post transplant is an important cause of premature graft failure. All GN subtypes can potentially recur post transplant at a rate between 3 and 15% particularly IgAN, idiopathic membranous GN, FSGS and MPGN. 5 year graft survival is similar between GN subtypes, apart from MPGN which is substantially poorer.
Recurrent IgA Nephropathy
Recurrent Primary FSGS
Recurrent Primary MPGN
Recurrent Idiopathic Membranous GN
De novo GN
Summary of Recurrent and de novo
Glomerulonephritis After Kidney
Transplantation
Introduction:
Primary glomerulonephritis is well known cause of end-stage renal disease and account about 17% of them. For post renal transplantation recipient or de novo glomerulonephritis. In the renal allograft is important cause of premature allograft failure. In the most common subtype of new glomerulonephritis are: IgA nephropathy, Idiopathic medullary glomerulonephritis, Focal segmental glomerulosclerosis, and membranoproliferative glomerulonephritis. The majority of glomerulonephritis recurrence resulting in allograft failure after 3-5 years post transplantation, although recurrence can occur early in patients with glomerulonephritis subtypes of membranoproliferative glomerulonephritis and focal segmental glomerulosclerosis.
Recurrent IgA:
Usually occurs late and is common. It has begun presentation of the majority of patients such as microscopic hematourea or evidence of IgA deposition in allograft biopsies. 40% of patients with IgAN recurrence have been noted to lose their allograft (up to 60%). Data from the ANDATA registers showed that 5-year allograft survival following disease recurrence was similar between IgAN, Idiopathic membranous glomerulonephritis, and FSGS with the allograft survival of patients with membranous glomerulonephritis = compared to the glomerulonephritis subtypes.
Several risk factors for disease recurrence include young age recipient, zero-HLA mismatch live related donor, steroid free regimen immunosuppression medication, non-use of induction therapy, HLA-allele subtypes, crescentic IgAN, presence of galactose-deficient IgAI, and presence of antibodies glycan-specific IgG antibodies and soluble CD89(an Fc receptor for IgA). Still there are no biomarker with clinical relevance that can predicting disease recurrence post renal transplantation. For IgAN no guideline for management of recurrent IgAN post kidney transplantation but the current practice is to: maintain or change to CNIb and steroid based immunosuppression regimen, and anti-proteinuria treatment. Crescentic IgAN: use cyclophosphamide or rituximab although unlikely to reverse the disease process.
Recurrent primary FSGS:
Risk of allograft failure from recurrence glomerulonephritis is 5 times the risk compared to those without disease recurrence. In spite of many reports mention high incidence of recurrence of primary FSGS but the time incidence recurrence unknown as secondary forms of FSGS can occur late post-transplant make difficulties in differentiating primary from secondary forms. Familial FSGS recurrence such as NPHSZ emphasized the importance of genetic testing in evaluation of patients with FSGS for transplantation especially in this group of patients:1) primary FSGS with atypical clinical or pathological feature or poor response to immunosuppression treatment, 2) family history of FSGS. The pathogenesis of disease recurrence in patients with primary FSGS remain unclear, with no studies confirming the presence of circulating permeability factors causing podocyte injury. Pathogenic role of the circulating serum soluble urokinase receptor (su PAR) by activating podocyte B (3) antigen resulting in effacement of foot processes and proteinuria, but its evaluation in inflammation and infection makes it independeted prognostic biomarker in precluding further risk of cardiovascular and mortality in general population, so the clinical utility of routine maintaining su PAR level post-transplant to predict disease recurrence remains poorly defined. Post renal transplantation recommendations are close maintain for proteinuria in high-risk patients, with regular checks of urine protein/creatinine ratio in the first 3 months of transplantation and proceeding to a kidney biopsy (electron microscopy detect early effacement of foot process). If there is persisting or increasing proteinuria, lack of random control trails and data about management of patients with resistance primary FSGS . A practical approach in the management of FSGS recurrence post transplantation: 1) initially plasmapheresis 2) maximizing anti-proteinuria therapy 3) converting to a CNI based immunosuppression regimen 4) B-cell depletion (rituximab) considered as adjunctive treatment or in resistant cases. There is insufficient data to suggest the pre-emptive use of plasmapheresis ± rituximab will reduce the risk of disease recurrence post transplantation.
Recurrent primary membranoproliferative
glomerulonephritis:
recurrence of primary MPGN is 50% in the first 2 years in the past 2 years post-transplant and 5 years allograft survival post disease recurrence of early 30% with highest rate for both C3GN and DDD are 50% of the patients. DDD usually recur late post renal transplant and often associated with no clinical manifestation other than allograft dysfunction. Presence of glomerular monoclonal Ig deposits has been associated with poorer prognosis. Up to 70% of patients with immune-mediated GN and monoclonal deposits have no evidence of plasma cell dysfunction. Its crucial pre-transplant screening for monoclonal gammopathy ± hematology review. In patients with MPGN. Treatment for recurrent disease of MPGN is not well established. The new classification and current knowledge of MPGN may assist clean to adapt a personalized treatment strategy according to the most likely pathogenesis and anti-B cell therapy for immune complex-mediated GN or monoclonal gammopathy or to consider eculizumab for C3 glomerulopathy. More cases and studies with large to low up data needed to determining the most appropriate treatment option for most renal transplantation recurrent disease.
Recurrent idiopathic membranous GN:
The diagnostic test accuracy of circulating anti-PLAZR auto antibody in differentiating primary from secondary MN is acceptable with test sensitivity 65% and 97% specificity. 30 to 50% is the rate of primary MN recurrence. There is a direct relationship between the titer level and risk of disease recurrence post-transplantation. Circulating levels of anti-PLAZR maintain remain unclear but should be considered in those with: 1) high pre-transplant circulating levels of anti-PLAZR antibody 2) early disease recurrence (to predict disease progression. 3) to determine response to treatment. 4) to differentiate disease recurrence from de novo membranous GN or other cause of proteinuria. Practical approach to pre and post kidney transplantation risk assessment management of idiopathic membranous GN recurrence.
Pre-transplant assessment: high risk characterized: 1) high titer anti-PAZR antibody 2) rapid progression of native ESRD 3) prior allograft failure secondary to recurrent IMN (less 5 years)
Transplant period: 1) anti-PLAZR antibody titer 2) CNI-based immunosuppression
Post renal transplant: maintain (frequency). Anti-PLAZR antibody titer, proteinuria, early allograft biopsy. If there is recurrence: 1) CNI+ steroid+ rituximab 2) alkylating agents
De novo GN:
Time prevalence of de novo GN in kidney transplantation recipient remains unknown. With incidence 4 to 20% with FSGS, IgAN, MN, and MPGN being the most common de novo GN subtypes. The presentation of these with de novo GN are similar to those with primary G N subtype remaining from a symptomatic = or biochemical abnormalities to event symptoms and signs of GN with nephrotic syndrome and renal dysfunction. Factors cause de novo FSGS: 1) reduction in nephron mass 2) induction of sirolimus and is difficult to differentiate secondary forms of FSGS from de novo GN. Treatment of de novo FSGS: 1) can be resolved by adequate ant-proteinuria treatment 2) treat the cause ( agents or factor) 3) in some cases aggressive therapy may be needed.
de novo IgAN:
Is usually benign and response to anti-proteinuria or antihypertensive therapy, but crescentic de novo IgAN tend to have a poor prognosis even with aggressive treatment with steroid and alkylating agents.
de novo membranous GN and MPGN:
Are less common. secondary causes in recipient who develop de novo GN. Should be role out before commence treatment options and re-transplant potential.
Conclusion:
Approach and treatment of post-transplant GN recurrence remain uncertain. More researches needed for understanding and treatment of recurrence GN post-transplant
Recurrent and de novo Glomerulonephritis After Kidney Transplantation
INTRODUCTION
Primary glomerulonephritis (GN) in the native kidneys is one of the leading causes of end-stage kidney disease (ESKD) worldwide. GN is a group of immunological kidney diseases with different histological subtypes, causes (primary vs. secondary), and clinical phenotypes and is also associated with different prognoses after kidney transplantation. All GN subtypes can potentially recur after transplantation, with different prevalence of GN recurrence generally around 15%. there is a group considered at high risk of recurrence this include (IgA nephropathy, idiopathic membranous GN, focal segmental glomerulosclerosis (FSGS), and membranoproliferative GN (MPGN).
the incidence of de novo or recurrent GN after kidney transplantation is under-estimated mostly related to the unknown primary causes of ESKD, misclassification, and indication bias. The risk of GN recurrence is directly related to time post-transplant some diseases recurrence is early like MPGN and 1ry FSGS and some others recurrence is late like SLE and 1ry MGN but the majority of GN recurrence occurs after 3–5 years post-transplant.
1. Recurrent IgA Nephropathy
Recurrent IgA nephropathy is relatively common around 15% and usually occurs late but the Risk of graft loss after recurrence is around 40%.
This disease usually presents with microscopic hematuria or evidence of IgA deposition in allograft biopsies.
There are multiple risk factors for disease recurrence including younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy (whereas anti-thymocyte globulin [ATG] may be associated with a lower risk of recurrence), HLA allelic subtypes, crescentic (and rapidly progressive) IgA nephropathy in the native kidneys and shorter total ischemic time.
There are multiple urine and serum biomarkers like serum level of IgG anti-Gd-IgA1 antibodies, glycan-specific IgG antibodies, and soluble CD89 (an Fc receptor for IgA) which are involved in the pathogenesis of IgA nephropathy used to predict the risk of disease progression and recurrence post-transplant but the prognostic value of these biomarkers have not been truly established.
The optimal treatment of recurrent IgA nephropathy remains unknown and the current practice is to maintain (or change to) a calcineurin-inhibitor (CNI) and corticosteroids-based immunosuppressive regimen in addition to anti-proteinuric treatments+SGLT2 inhibitors after rising of its effectiveness in DAPA CKD study. In cases of crescentic rapidly progressive IgA nephropathy, more aggressive immunosuppression (e.g., cyclophosphamide or rituximab) may be considered
2. Recurrent Primary FSGS
the true incidence of recurrent disease remains unknown as secondary forms of FSGS can occur late post-transplant, resulting in difficulties in differentiating primary from secondary forms but usually rate of recurrence is up to 1 in 3 (33%) patients with primary FSGS with the risk of allograft failure (predominantly from GN recurrence) 5-times the risk compared to those without disease recurrence. poorer 5-year allograft survival of 52%. with disease recurrence, compared with 83% in those without recurrent disease.
To differentiate 1ry from 2ry is sometimes very difficult and some recommend doing a genetic study to rule our familial FSGS which has a very low risk of recurrence and may provide important information regarding prognosis and best immunosuppression regimens pre-and post-transplant or those with a potential live-related donor for transplantation, including undertaking genetic screening of the donors for the same genetic mutations (if present in the potential recipients).
Some serum marker was evaluated for both diagnostic and prognostic value like suPAR but serum suPAR level was higher in patients with familial FSGS compared to those with non-genetic primary FSGS, also be nonspecifically elevated in other pathological processes including inflammation and infection and has been shown to be an independent prognostic biomarker in predicting future risk of CVD and mortality in the general population. Other potential biomarkers including urine suPAR, Anti-CD40 autoantibody, and angiotensin receptor II type 1 (AT1R) antibody appear promising but further studies are required to determine the accuracy of these prognostic biomarkers in predicting disease recurrence.
Usual clinical presentation is a nephrotic syndrome which may occur early post-transplant so, Close monitoring for proteinuria in high-risk patients, with regular checks of urine protein/creatinine ratio or self-check urine dip-stick in the first 3 months post-transplant are recommended, and proceeding to a kidney biopsy with electron microscopy to detect early effacement of foot processes)
The management of patients with recurrent primary FSGS remains challenging Plasmapheresis is often preferred and recommended for the removal of unknown offending circulating factors. The roles of pre-emptive plasmapheresis (pre and/or post-transplantation), immunoadsorption therapy, and other novel options such as ofatumumab or B7-1 blockers (abatacept and belatacept) to prevent disease recurrence or to treat recurrence appear promising but the efficacy of these treatments remains debatable.
Using of adjunctive therapy including rituximab and CNI such as cyclosporine remains uncertain However, a switch to CNI if patients were on mammalian target of rapamycin [mTOR]-inhibitor is recommended. and not always consistent or supported in subsequent studies.
3. Recurrent Primary MPGN
Disease recurrence post-transplant from primary MPGN is common and early within the first 24 months post-transplant and the risk of allograft failure within 5-year 70%. The new classification of MPGN is more convenient as its more related to disease pathogenesis and histological findings (i.e., immune complex-mediated MPGN and complement-mediated MPGN
Immune-complex mediated MPGN is characterized by the glomerular deposition of polyclonal or monoclonal immunoglobulins (Ig), whereas C3 glomerulopathy [comprising of C3GN and dense deposit disease (DDD)] is characterized by the glomerular deposition of C3 in the absence of Ig deposition. high rate of post-transplant recurrence for both C3GN and DDD, with over 50% of patients with disease recurrence reported experiencing allograft failure. DDD is more likely to recur later post-transplant and often associated with no clinical manifestations other than allograft dysfunction.
For immune-mediated MPGN, the patterns and types of Ig deposits may have diagnostic and prognostic significance. The presence of serum monoclonal proteins is associated with a poorer prognosis, characterized by early disease recurrence and substantially greater risk of premature allograft failure following disease recurrence. Up to 70% of patients with immune-mediated GN and monoclonal deposits have no evidence of plasma cell dyscrasia (i.e., absence of serum and urine monoclonal Ig proteins or evidence of plasma cell dyscrasia in the bone marrow), whereas in the remaining 30% of patients, patients often have detectable elevated monoclonal proteins without fulfilling the criteria for multiple myeloma (often termed “monoclonal gammopathies of renal significance”).
It is important to note that monoclonal gammopathy may be present in both immune complex-mediated and complement-mediated MPGN) so, pre-transplant screening for monoclonal gammopathy ± hematology review in patients with MPGN, while ensuring close monitoring post-transplant for signs of disease recurrence.
the optimal treatment strategy remains unknown but plasmapheresis and other immunosuppressive agents including cyclophosphamide, eculizumab, and rituximab can be used. The new classification and current knowledge of MPGN may assist clinicians to adopt a personalized treatment strategy according to the most likely pathogenesis of the disease process (e.g., consideration of plasmapheresis and anti-B cell therapy for immune complex-mediated GN or those with monoclonal gammopathy or to consider eculizumab for C3 glomerulopathy).
4. Recurrent Idiopathic Membranous GN
The discoveries of the pathogenic antiphospholipase A2 receptor (PLA2R) have led to breakthroughs in the understanding, management, and treatment of patients with idiopathic membranous GN which improved recognition and differentiating primary vs. secondary membranous GN, as well as assisting clinicians in the management of patients pre and post-transplantation. Serum test sensitivity of 65%, specificity of 97%.
The rate of disease recurrence in patients with idiopathic membranous GN following kidney transplantation is between 30 and 50%. there is a direct relationship between the titer level and risk of disease recurrence post-transplant and the positive predictive value of pre-transplant anti-PLA2R antibodies for disease recurrence is 83%, the diagnostic threshold of anti-PLA2R antibody in defining the risk of disease recurrence remains poorly defined (some recent publications showed it could be more than 40ng/l.
The treatment of disease recurrence includes a combination of anti-proteinuric agents, corticosteroids, alkylating agents, CNI, and rituximab. Rituximab is an effective treatment for native and recurrent membranous GN in the allograft, with up to 80% achieving complete or partial remission with the use of rituximab for early disease recurrence post-transplant.
Secondary GN: relapses often occur later post-transplant and infrequently lead to allograft failure.
patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, the relapse rate 2% per year, with no association between ANCA subtypes or disease severity prior to transplantation and disease recurrence occurring post-transplant.
Recurrence of lupus nephritis post-kidney transplantation is unclear and varies between 0 and 44%, with patients who had experienced recurrent lupus nephritis at a greater risk of allograft failure and mortality. However, this association remains inconsistent.
In patients with anti-GBM disease, disease recurrence after kidney transplant is <5% in the era of modern immunosuppression, and allograft failure from disease recurrence exceedingly rare.
the risk of disease recurrence following transplantation of patients with aHUS was up to 80%, with a substantial proportion of patients losing their allografts from the recurrent disease within the first-year post-transplant but these results improved after the availability of the C5-inhibitor eculizumab and make it appeared to be safe with excellent allograft outcome, even in those with pathogenic mutations known to be associated with a high risk of disease recurrence. kidney transplantation without the use of prophylactic eculizumab but this is generally not recommended or undertaken with extreme caution in patients with certain genetic mutations (membrane-associated complement regulator membrane cofactor protein mutation).
Presumed or Advanced GN
Patients with unknown 1ry kidney disease because a biopsy was not undertaken or done but too late. fortunately, the incidence of allograft failure attributed to GN is extremely low.
De novo GN
The true prevalence of de novo GN in kidney transplant recipients remains unknown, the incidence of de novo GN after kidney transplant varies between 4 and 20%, with FSGS, IgA nephropathy, and membranous GN, and MPGN being the most common de novo GN subtypes.
There are difficulties in identifying and confirming the presence of de novo GN post-transplant because the cause of native ESKD is often uncertain, and the presence of GN in the donor’s kidney may not be known (particularly in the absence of pre-implantation biopsy).In patients whose ESKD was attributed to non-GN causes and had developed de novo GN, over 95% of cases were FSGS [42%], IgA nephropathy[27%], membranous GN [15%], and MPGN [12%]. The presentations of those with de novo GN are similar to those with primary GN subtypes
De novo FSGS
it is often difficult to differentiate secondary forms of FSGS from “actual” de novo 1ry FSGS GN and may to some extent explain why most cases of de novo FSGS tend to occur later post-transplant (compared to the recurrence of primary FSGS). the treatment of de novo FSGS predominantly revolves around adequate anti-proteinuric treatment and the removal of the offending agents/factors where possible. Re-transplantation following allograft failure from de novo FSGS can be considered, but clinicians should attempt to establish and exclude or avoid potential causative factors that had resulted in the development of de novo FSGS.
de novo IgA nephropathy
The incidence of de novo IgA nephropathy is likely to be underestimated, with asymptomatic IgA deposition not infrequently found (detected incidentally in protocol or indication biopsies or potentially donor-derived asymptomatic disease detected on pre-implantation biopsies). However, presentation with macroscopic hematuria is unusual.
The prognosis of those with de novo IgA nephropathy is usually relatively benign with treatment predominantly focusing on anti proteinuric and/or anti-hypertensive therapy but crescentic de novo IgA nephropathy tends to have a poorer prognosis
De novo membranous GN and MPGN
The incidence is much less common and mostly related to secondary causes including viral infections, rejection, autoimmune disease, CNI, and thrombotic microangiopathy.
The onset of de novo membranous GN or MPGN tends to occur later post-transplant (compared to recurrent disease),
For membranous GN, glomerular staining for PLA2R may help to differentiate as glomerular staining for PLA2R was more common in those with recurrent disease (83%) compared to de novo disease (17%).
2ry causes need to exclude in any de novo GN, which is critical when considering treatment options and re-transplant potential following allograft failure.
(ANZDATA) registry report, GN as cause of ESKD accounted for 17% of incident treated ESKD patients. In the US, GN as cause of ESKD comprised of 7 and 13% of incident ESKD initiated on dialysis and have received kidney transplants.
When considering the medical suitability of potential kidney transplant candidates with GN for kidney transplantation, clinicians must provide sufficient information with regards to the risk of disease recurrence post-transplant.
All GN subtypes can potentially recur after transplantation, with the prevalence of GN recurrence between 3 and 15%.
Recurrent IgA Nephropathy
Recurrent IgA nephropathy is relatively common, but typically occurs late post-transplant with cumulative incidence of disease recurrence at 15 years of 15%.
Following disease recurrence, up to 40% of patients with recurrent IgA nephropathy have been reported to lose their allografts, predominantly from disease recurrence.
Several risk factors for disease recurrence have been described including younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy (whereas anti-thymocyte globulin [ATG] may be associated with a lower risk of recurrence), HLA allelic subtypes, crescentic (and rapidly progressive) IgA nephropathy in the native kidneys and shorter total ischemic time.
The current practice is to maintain (or change to) a calcineruin-inhibitor (CNI) and corticosteroids-based immunosuppressive regimen in addition to anti-proteinuric treatments, although the optimal dosing/target therapeutic CNI level or specific CNI type in the treatment of those with recurrent disease remains unknown.
Recurrent Primary FSGS
Up to 1 in 3 patients with primary FSGS will experience disease recurrence after kidney transplantation, with the risk of allograft failure (predominantly from GN recurrence) 5-times the risk compared to those without disease recurrence.
Close monitoring for proteinuria in high risk patients, with regular checks of urine protein/creatinine ratio or self-check urine dip-stick in the first 3 months post-transplant are recommended, and proceeding to a kidney biopsy. CNI such as cyclosporine, through the inhibitory effect on T cell function and stabilization effect on actin cytoskeleton in kidney podocytes, has been shown to induce clinical remission in patients with recurrent FSGS.
The roles of pre-emptive plasmapheresis (pre and/or posttransplantation), immunoadsorption therapy, and other novel options such as ofatumumab or B7-1 blockers (abatacept and belatacept) to prevent disease recurrence or to treat recurrence appear promising but the efficacy of these treatments remain debatable and not always consistent or supported in subsequent studies .
Recurrent primary MPGN
Disease is classified into IC-mediated and complement-mediated ( C3GN & DDD). There is up to 50% risk of recurrence in the post-transplant period for both C3GN and DDD, with over 50% of patients with disease recurrence reported will have allograft failure. DDD is more likely to recur later post-transplant and often associated with no clinical manifestations other than allograft dysfunction.
The approach to treatment for recurrent disease is not wellestablished, limited to case series of successful treatment with the use of plasmapheresis and other immunosuppressive agents including cyclophosphamide, eculizumab, and rituximab.
De novo GN
FSGS, IgA nephropathy, MN, & MPGN are the most common de novo GN subtypes. De novo GN occurred in 3.4% of those with primary ESRD from GN & 3.6% of those with ESRD from non-GN causes.In those with primary non-GN causes, FSGS was the commonest cause of de novo GN (over 95%);IgA nephropathy, MN, & MPGN were less common.
The risk of graft loss was 7-times greater in patients with de novo GN, compared to those
without disease.
It is difficult to differentiate secondary FSGS from“actual” de novo non-collapsing GN & may explain why de novo FSGS tend to occur later post-transplant (compared to primary FSGS).
The long-term outcome of de novo FSGS is relatively poor (5-year allograft survival of <50%).
In conclusion,despite the advances in the understanding of the epidemiology, pathogenesis, and classification of primary and recurrent GN after kidney transplantation, considerable uncertainty remains in the approach and treatment of post-transplant GN recurrence
Glomerulonephritis (GN) is an important cause of end stage renal disease requiring kidney transplant. Post-transplant recurrent or de-novo primary GN especially IgA nephropathy, idiopathic membranous nephropathy, focal segmental glomerulosclerosis (FSGS) and membranoproliferative GN (MPGN) has a major role in graft loss. Most of the recurrent GN occur 3-5 years post-transplant but can present earlier with FSGS and MPGN.
1) Recurrent IgA Nephropathy: It occurs late with 15% at 15 years post-transplant, with recurrence rates of 30-40%, losing graft in 40% cases with 60% due to the disease recurrence.
Risk factors for recurrence include younger age, zero HLA mismatched kidney recipient, steroid avoidance or withdrawal regime use, non-use of induction therapy, HLA allelic subtypes, increased galactose deficient IgA1 and IgA-IgG immune complex, decreased levels of circulating complexes of IgA soluble CD89, shorter ischemic time and crescentic and rapidly progressive IgA nephropathy in the native kidneys.
The optimal treatment is unknown. The patient is maintained on calcineurin inhibitors (CNI) with steroids and anti-proteinuric treatment. Crescentic IgA nephropathy may be treated with cyclophosphamide or rituximab although they are unlikely to be helpful.
2) Recurrent primary FSGS: One third of primary FSGS patients develop recurrence post-transplant with 5 times increased risk of graft loss upto 65% at 5 year post-transplant.
Risk factors for recurrence include younger age, living donor, severe disease (decreased serum albumin and increased proteinuria), non-white race, rapidly progressive disease in the native kidneys, second transplant due to prior recurrence. Biomarkers for recurrence include serum and urine suPAR, anti-CD40 autoantibody and angiotensin receptor II type 1 (AT1R) antibody have shown promise. It is important to monitor proteinuria closely post-transplant and an early kidney biopsy in case of increasing or persisting proteinuria.
The patient is managed with plasmapheresis with or without rituximab, use of CNI and anti-proteinuric treatment. Efficacy of pre-emptive plasmapheresis with or without rituximab, and drugs like abatacept and ofatumumab has not been proved in prevention of recurrence.
3) Recurrent Primary MPGN: 50% of primary MPGN patients develop recurrence post-transplant within first 2 years with 5-year graft failure in 66% patients.
MPGN can be either C3 glomerulopathy including C3 glomerulonephritis (C3GN) and dense deposit disease (DDD) or immune-mediated MPGN including polyclonal immunoglobulin and monoclonal immunoglobulins deposition disease. All the types recur early except the polyclonal immunoglobulin deposit disease. Amongst the C3 glomerulopathy, DDD occur later than C3GN.
Risk factors for recurrence include C3 glomerulopathy subtypes, presence of monoclonal gammopathy, poor response to treatment and rapidly progressive disease in the native kidneys.
The patient is managed with anti-proteinuric treatment and treatment of monoclonal gammopathy if present. Eculizumab us is helpful in C3 glomerulopathy while plasmapheresis with immunosuppression like alkylating agents and rituximab are helpful in treating immune complex MPGN.
4) Recurrent idiopathic Membranous GN: It occurs late with 30-50% recurrence rates post-transplant, with recurrence rates of 30-40%, losing graft in 44% cases at 5-year post-transplant.
Risk factors for recurrence include presence (and high titre) of antiPLA2R autoantibody prior to transplant (having 60-75% recurrence rate as compared to 28-30% recurrence in absence of these antibodies), rapid progression of native disease and prior graft failure due to recurrence of membranous nephropathy, especially in first 5 years post-transplant. Patients with high titres prior to transplant should be monitored for titres as well as proteinuria.
The treatment should be started early, when proteinuria is >1gram per day and includes anti-proteinurics, calcineurin inhibitors (CNI) with steroids and rituximab achieving 80-90% remission, having better results than alkylating agents.
5) Secondary GN: These include atypical hemolytic uremic syndrome (aHUS), SLE, anti-GBM disease and crescentic GN. Relapses in these cases occur late and graft loss is infrequent. SLE relapse rates are 0-44% while aHUS has relapse rates of upto 80% which has now reduced due to pre-emptive use of eculizumab.
6) Presumed or Advanced GN: Recurrence in patients with uncertain etiology of renal failure is very low (5%), 90% of which is due to FSGS, membranous nephropathy and IgA nephropathy.
7) De novo GN: It is usually seen later in post-transplant period (compared to recurrent GN) and occurs in 4-20% of transplant recipients with FSGS (most common), IgA nephropathy, MPGN and membranous nephropathy as the predominant forms and increases the risk of graft loss by 7 times. De novo FSGS has less than 50% graft survival at 5 years post-transplant. De novo MPGN with graft failure has high risk of graft failure after re-transplantation. Prognosis of de novo IgA nephropathy is favourable except in presence of crescents.
Hence it is important to remain vigilant about recurrence of GN in a kidney transplant patient
INTRODUCTION
Primary glomerulonephritis is one of the leading causes of end-stage renal disease worldwide. GN is a heterogeneous group of immunological kidney diseases differ in histological subtypes, causes (primary vs. secondary) and clinical phenotypes resulting in variable prognoses post renal transplantation with dissimilar GN subtypes and their risk of recurrence after. Recurrent or de novo GN in the renal allograft is an important cause of premature allograft failure. All GN subtypes can potentially recur particularly IgA nephropathy, idiopathic membranous GN, focal segmental glomerulosclerosis (FSGS), and membranoproliferative GN (MPGN).
Recurrent IgA Nephropathy
It is common, but typically occurs late post-transplant. Demonstrated by the relative benign presentations of the majority of patients (presenting with microscopic hematuria or evidence of IgA deposition in allograft biopsies). About 40% of patients with recurrent IgA nephropathy have reported graft loss, predominantly from disease recurrence (up to 60%).Compared to other GN subtypes, the long-term allograft and patient outcomes of patients are substantially better.
In this study, the proportion of allograft failure secondary to disease recurrence was 1.6% for those with IgA nephropathy, compared with 5.6, 2.7, and 3.3% for those with MPGN, FSGS, and idiopathic membranous GN, respectively.
Risk factors for disease recurrence (younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy).
Anti-thymocyte globulin [ATG] and shorter total ischemic time may be associated with a lower risk of recurrence.
The presence of some molecules, as galactose-deficient IgA1 (Gd-IgA1), IgG anti-Gd-IgA1 antibodies, glycan-specific IgG antibodies, and soluble CD89 (an Fc receptor for IgA) which may be involved in the pathogenesis of IgA nephropathy predicts a greater risk of disease progression and disease recurrence posttransplant.
The current practice regarding recurrence is to use calcineruin-inhibitor (CNI) and corticosteroids-based immunosuppressive regimen in addition to anti-proteinuric measures.
Recurrent Primary FSGS
Up to 1 in 3 patients with primary FSGS will experience disease recurrence after kidney transplantation, with the risk of allograft failure (predominantly from GN recurrence) 5-times the risk compared to those without disease recurrence.
Familial FSGS in adults, have low to no risk (<3%) of disease recurrence post-transplant suggesting the relative importance of genetic testing in the evaluation of patients with adult-onset FSGS for transplantation.
Risk factors for disease recurrence in patient with primary FSGS (younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESKD, and prior allograft failure from disease recurrence ).
The pathogenesis of disease recurrence may be suggested by the pathogenic role of circulating serum soluble urokinase receptor (suPAR) by activating podocyte beta (3) integrin resulting in effacement of foot processes and proteinuria.
Serum suPAR level was found elevated in patients with FSGS, also, reduction of serum suPAR level with immunosuppressive treatment was associated with a greater probability of achieving clinical remission.
However, this patho-physiological link remains debatable.
Other potential biomarkers may include urine suPAR, Anti-CD40 autoantibody, and angiotensin receptor II type 1 (AT1R) antibody seem to be promising.
Close monitoring of proteinuria in high risk patients in the first 3 months post-transplant are recommended, and proceeding to a kidney biopsy (tissues should be sent for electron microscopy to detect early effacement of foot processes) if there is persistent or increasing proteinuria.
The management of patients with recurrent primary FSGS: Plasmapheresis combined with adjunctive therapy including rituximab and CNI. Recent research showed that rituximab binds sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) protein, resulting in preservation of podocyte SMPDL-3b expression, preventing podocyte apoptosis. CNI exhibit inhibitory effect on T cell function and stabilization effect on actin cytoskeleton of podocytes, inducing clinical remission in patients with recurrent FSGS.
Ofatumumab, an anti-CD20 monoclonal antibody that induces B cell depletion appears promising in the prevention and treatment of recurrent FSGS post-renal transplant.
A practical approach in the management of FSGS recurrence post-transplantation should initially include plasmapheresis, maximizing anti-proteinuric therapy, and converting to a CNI based immunosuppressive regimen with B cell depletion (rituximab) considered as adjunctive treatment in resistant cases.
Recurrent Primary MPGN
It is relatively common, with over 50% of recurrence occurring within the first year post-transplantation. The high risk of allograft failure with 5-year allograft survival post-disease recurrence is about 30%.
Immune-complex mediated MPGN is characterized by the glomerular deposition of polyclonal or monoclonal immunoglobulins (Ig), whereas C3 glomerulopathy [comprising of C3GN and dense deposit disease (DDD)] is characterized by the glomerular deposition of C3 in the absence of Ig deposition.
DDD recurs later post-transplant associated with no clinical manifestations other than allograft dysfunction.
C3GN and DDD are identified by the presence of strong glomerular staining for C3 and electron deposits on electron microscopy.
The pathogenesis of this disease regarding complement dysregulation remains uncertain. Genetic mutations (e.g., presence of H402,V62 alleles of Factor H, mutations of Factor H, and I genes) or autoantibodies (e.g., C3 or C4 nephritic factor directed against C3 convertase or Factor H autoantibodies) are being suggested.
Immune-mediated MPGN patterns and types of Ig deposits may have diagnostic and prognostic significance.
The presence of glomerular monoclonal Ig deposits (typically IgG3k and IgG3l) was associated with poorer prognosis, characterized by early disease recurrence and substantially greater risk of premature allograft failure following disease recurrence.
The approach to treatment for recurrent disease relies on the use of plasmapheresis and other immunosuppressive agents as cyclophosphamide, eculizumab, and rituximab. The benefit of eculizumab in reducing proteinuria and stabilization of kidney function is being studied.
Consideration of plasmapheresis and anti-B cell therapy for immune complex-mediated GN or those with monoclonal gammopathy or to consider eculizumab for C3 glomerulopathy would be a wise approach in such cases.
Recurrent Idiopathic Membranous GN
Recognition and differentiating primary vs. secondary membranous GN improved by the presence of anti-PLA2R autoantibody. The absence of PLA2R autoantibody does not definitively exclude cases of idiopathic membranous GN. The test’s diagnostic accuracy in differentiating primary from secondary membranous GN is acceptable, with sensitivity 65% (63–67%) and specificity 97% (97–98%).
The test’s performance accuracy is similar to the positive glomerular staining of PLA2R antigen. Another antibody specific for the autoantigen thrombospondin type 1 domain–containing 7A (THSD7A) has been detected in up to 5% of patients with idiopathic membranous GN.
The rate of disease recurrence in patients ranges between 30 and 50%post renal transplant. Patients with high titres of anti-PLA2R autoantibody have a greater risk of disease recurrence. The positive predictive value of pre-transplant anti-PLA2R antibodies for disease recurrence is 83%. However, the diagnostic threshold of anti-PLA2R antibody in defining the risk of disease recurrence is still undefined.
The need for monitoring anti-PLA2R antibody post-transplant should be considered in patients with high pretransplant levels of anti-PLA2R antibody and those showing early disease recurrence (to predict disease progression, determine response to treatment and to differentiate disease recurrence from de novo membranous GN or other causes of proteinuria).
The treatment of disease recurrence is mainly by anti-proteinuric agents, corticosteroids, alkylating agents, CNI, and rituximab. Rituximab is an effective treatment for native and recurrent membranous GN in the allograft, with up to 80% achieving complete or partial remission for early disease recurrence post-transplant.
Secondary GN
Patients with secondary GN post renal transplant experience relapses later post-transplant and infrequently cause allograft failure. The incidence of recurrent lupus nephritis varies between 0 and 44% and it is associated with high risk of allograft failure and mortality. While patients with anti-GBM disease, disease recurrence after kidney transplant is <5%. Patients with aHUS show recurrence up to 80%, with the prophylactic use of eculizumab renal transplantation became safer with excellent allograft outcome.
Presumed or Advanced GN
In this study, 90% of the allograft failures from GN were due to FSGS, membranous GN and IgA nephropathy, but it is unknown whether these GNs represent recurrent or de novo GN.
De novo GN
It is associated with significantly reduced allograft survival compared to those without de novo glomerular disease. The incidence of de novo GN post renal transplant varies between 4 and 20%. FSGS, IgA nephropathy, membranous GN, and MPGN are the most common de novo GN subtypes.
In this study, the risk of allograft failure was over 7-times greater among recipients who have developed de novo GN, compared to those without disease. The presentations of those with de novo GN are similar to those with primary GN subtypes, ranging from asymptomatic urinary or biochemical abnormalities to overt symptoms and signs of GN with nephrotic syndrome and renal dysfunction.
Risk factors predisposing to the development of de novo FSGS are associated with a reduction in nephron mass (leading to compensatory hyperfiltration as diabetes, hypertension, BK viral infection,CNI and rejection).
Irrespective of the nature of de novo FSGS, the long-term allograft outcome is relatively poor, particularly in the presence of interstitial fibrosis/tubular atrophy with 5-year allograft survival of <50% after diagnosis. Treatment of de novo FSGS mainly is anti-proteinuric measures.
The incidence of de novo IgA nephropathy is underestimated, with asymptomatic IgA deposition detected incidentally in biopsies and presentation with macroscopic hematuria is unusual. The prognosis is relatively benign with treatment mainly directed to antiproteinuric and anti-hypertensive therapy if existed. With special regards to crescentic de novo IgA nephropathy being of poor prognosis later on.
De novo membranous GN and MPGN are much less common. They also occur later post-transplant with symptoms ranging from asymptomatic mild proteinuria and incidental biopsy findings to nephrotic range proteinuria and rapidly progressive GN. Regarding membranous GN, the pattern of staining for PLA2R may help to differentiate de novo from recurrent disease. Injury to the podocytes occurring post-transplantation triggers the release of podocyte antigens inducing the formation of auto-antibodies and deposition of subepithelial immune complexes. All patients with de novo membranous GN and MPGN, careful histological examination for potential secondary causes must be sought.
CONCLUSION
The clinical care of patients with recurrent or de novo GN remains challenging with tailoring of specific treatment strategies of different types of recurrent or de novo GN should be achieved.
The optimal treatment strategy remains unknown
Recurrent IgA Nephropathy
Epidemiology:
the cumulative incidence of recurrence at 15 years is 15% and the rate of graft loss is 40% up to 60.
Risk factors for disease recurrence:
younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy (whereas anti-thymocyte globulin may be associated with a lower risk of recurrence), HLA allelic subtypes, crescentic (and rapidly progressive) IgA nephropathy in the native kidneys , shorter total ischemic time, several molecules( galactose-deficient IgA1 (Gd-IgA1), IgG anti-Gd-IgA1 antibodies, glycan-specific IgG antibodies, and soluble CD89 (an Fc receptor for IgA)) and other non-specific serum and urine biomarkers.
The treatment:
Maintain/change to a calcineruin-inhibitor, corticosteroids-based immunosuppressive regimen and anti-proteinuric treatments. Tonsillectomy has been suggested.
In crescentic rapidly progressive IgA nephropathy use more aggressive approach like cyclophosphamide or rituximab.
Recurrent Primary FSGS
Epidemiology:
Up to 1 in 3 patients with primary FSGS and the risk of allograft failure is 5-times the risk compared to those without disease recurrence. Familial FSGS have low to no risk (<3%) of disease recurrence
Risk factors for disease recurrence
younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESKD, prior allograft failure from disease recurrence and serum suPAR level ,urine suPAR, Anti-CD40 autoantibody and angiotensin receptor II type 1 (AT1R) antibody.
Treatment:
Close monitoring for proteinuria in high risk patients.
Regular checks of urine protein/creatinine ratio or self check urine dip stick in the first 3 months post-transplant proceeding to a kidney biopsy and EM if there is persistent or increasing proteinuria.
Plasmapheresis, maximizing anti-proteinuric therapy, CNI based immunosuppressive regimen and rituximab.
Use of the following is promising; pre-emptive plasmapheresis (pre and/or posttransplantation), immunoadsorption therapy, atumumab or B7-1 blockers (abatacept and belatacept).
Genetic screening , after a discussion between clinicians and patients, of patients with a clear family history of FSGS or those with a potential live related donor (screening of the donors for the same genetic mutations of the potential recipients).
Recurrent Primary MPGN
Epidemiology
> 50% of recurrence occurs within the first 24 months post transplant. The 5-year allograft survival after recurrence is 30%. DDD tends more likely to recur later when compared to C3GN and is often associated with no clinical manifestations other than allograft dysfunction.
Risk factors:
For immune-mediated MPGN, the activation of the complement cascade, the presence of glomerular monoclonal deposits of IgG3k and IgG3l (IgG2l has been reported)
Treatment
Plasmapheresis , cyclophosphamide, eculizumab, and rituximab .
Recurrent Idiopathic Membranous GN
Epidemiology
The rate of disease recurrence is 30 – 50%.The relative risk of allograft failure is 50% at 10-years.
Risk factors
High titers of circulating anti-PLA2R autoantibody
Management:
Monitoring anti-PLA2R antibody post-transplant for:
Those with high pre-transplant circulating levels of anti-PLA2R antibody
Those with early disease recurrence (to predict disease progression)
To determine the response to treatment
To differentiate disease recurrence from de novo membranous GN or other causes of proteinuria
Treatment include: anti-proteinuric agents, corticosteroids, alkylating agents, CNI or changing from mTOR inhibitor-based regimen to CNI and addition of anti-CD20 antibodies rather than introducing alkylating agents (Rituximab can be considered in those with detectable high levels of anti-PLA2R antibody with prior allograft failure from recurrent membranous GN or have persistent high or increasing levels of circulating anti-PLA2R antibody post-transplant with early histological recurrence. Bortezomib in rituximab resistant recurrent).
Secondary GN
Secondary GN were associated with a late recurrence post-transplant and infrequently lead to allograft failure.
ANCA associated vasculitis: the relapse rate (often extra-renal complications) has been reported at 0.02 per patient-years, with no association betweenrecurrence and ANCA subtypes or disease severity prior to transplantation .
Lupus nephritis: incidence of recurrent lupus nephritis varies between 0 and 44%.
Anti- GBM disease: disease recurrence after kidney transplant is <5%. Allograft failure is rare.
Atypical hemolytic uremic syndrome aHUS: before eculizumab use, the risk was up to 80%.
Presumed or Advanced GN
These are cases in which a biopsy was not undertaken or were non-diagnostic with non-specific histological features. The incidence of allograft failure attributed to them is extremely low.
De novo GN
The incidence of de novo GN after kidney transplant varies between 4 and 20%. The common subtypes are FSGS, IgA nephropathy, membranous GN, and MPGN. It is difficult to identify and confirm the presence of de novo GN post-transplant because the cause of native ESKD is often uncertain.
The de novo FSGS: occur due to a reduction in nephron mass (resulting in compensatory hyperfiltration of remaining nephrons such as diabetes, hypertension, BK viral infection, CNI therapy, and rejection) or the introduction of sirolimus (through the effects on podocyte integrity).
Most cases of de novo FSGS tend to appear later post transplant (compared to the recurrence of primary FSGS). The long-term allograft outcome is relatively poor, particularly in the presence of interstitial fibrosis/tubular atrophy with 5-year allograft survival of <50% after diagnosis.
Treatment include adequate anti-proteinuric treatment and the removal of the offending agents/factors where possible, but more aggressive therapy (similar to disease recurrence) may be considered. Re-transplantation following allograft failure from de novo FSGS can be considered.
The de novo IgA nephropathy: prognosis is usually relatively benign with treatment predominantly focuses on anti-proteinuric and/or anti-hypertensive therapy. Crescentic de novo IgA nephropathy have a poorer prognosis and the efficacy of more aggressive treatment with steroids and alkylating agent remains unknown. Re-transplantation of patients with either disease is possible.
De novo membranous GN and MPGN: are much less common, and the reported cases primarily related to secondary causes including viral infections, rejection, autoimmune disease, CNI and thrombotic microangiopathy. The onset of de novo membranous GN or MPGN tend to occur later post-transplant compared to recurrent disease. For membranous GN, the pattern of Ig staining or glomerular staining for PLA2R
may help to differentiate de novo from recurrent disease ( recurrent disease have IgG1 staining in capillary loop while IgG4 staining in capillary loop is present in de novo disease).
Recurrent GN is an important cause of graft failure in young patients, and responsible for 18-22 % of graft loss, it is an important cause of death either censored or uncensored graft failure.
Post-transplant GN can be either de novo or recurrent or donor derived.
De novo GN can be happened earlier post-transplant than recurrent one.
Risk factors for GN recurrence post-transplant: 1- age at the time of transplantation; more in younger
2- Longer ischemic time
3- Steroid use
1- Recurrent FSGS
30-70% of the primary cases can recur early or late post transplant, genetic type has low rate of recurrence, FSGS recur mostly late secondary to reduced renal mass.
Risk factors for recurrence of FSGS :
1- Young age
2- High BMI
3- White race
4- Rapid progression to ESRD in native kidney
5- Pre transplant severe proteinuria
6- Low serum albumin at the time of diagnosis
7- 80% risk of recurrence in second transplant
Prevention and treatment of recurrent FSGS:
1- Pre transplant plasmapheresis and rituximab is of benefit to prevent recurrence and also used in treatment of recurrence
2- Protocol biopsy is important in early detection.
2- Recurrent MGN (membranous GN)
40-50% of primary idiopathic MGN recur post transplant, 70-80% of them have anti-PLA2R antibodies with high risk of recurrence in contrast to 30% of cases whom have no detected antibodies have low risk of recurrence.
Recurrence can be detected early 1-2 weeks post transplant by protocol biopsy, if recurrence happens late 5 years or more due to new production of antibodies.
De novo MGN is not associated with antibodies.
Management of recurrent MGN:
1- Pre transplant detection of high risk patients; rapid progression to ESRD in native kidney, high titer of antibodies, history of graft failure due to recurrent idiopathic membranous GN in the graft in less than 5 years post transplant.
2- Anti-PLA2R antibodies titer, immunosuppression should be CNI based
3- Titer of antibodies should be monitored post transplant , also proteinuria, and protocol biopsy should be done
4- CNI, steroid and rituximab should be a treatment of choice if recurrence happened.
3- Recurrent MPGN
MPGN can be classified based on IF as the following:
a- Immune mediated immunoglobulin and complement which may be mono or polyclonal
b- C3 dominant either C3 or DDD
c- Null complement and null immunoglobulin TMA
Recurrence is high in DDD and C3 glomerulopathy which are 25% and 50% respectively.
Rituximab prevent and treat MPGN with monoclonal immunoglobulin deposits.
Eculizumzb is monoclonal antibody inhibits C5 activation so prevent and treat C3 GN.
4- Recurrent IgA nephropathy
In 30-40% of the cases, histological recurrence is common than the clinical one, late presentation is common
Risk factors for recurrence:
a- HLA-B8-DR3
b- Steroid free regimen
c- Crescentic type
d- High level of circulating galactose deficient A1 and IgA Ig immune complex
e- Low level of circulating soluble complex of IgA CD89
No more therapeutic options to treat or prevent recurrence like ACEI, ARBS, cyclophosphamide, increase MMF dose, induction with ATG.
5- Secondary GN LN lupus nephritis
Recurrence can be early or late post transplant , protocol biopsy is important which can detect histological changes as it remains subclinical as class II is more common one.
# Please give a summary of this article
*One of the most important causes of
(ESKD) is Primary glomerulonephritis (GN).
* GN is a heterogeneous group of immunological kidney diseases with different pattern that result in differences in the prognosis after kidney transplantation
*Recurrent or de novo GN following allograft transplantation is an important cause of premature kidney failure
* All GN subtypes can potentially recur after KT (3 & 15%) with high risk subtypes of IgA nephropathy, idiopathic membranous GN, (FSGS), and (MPGN)
* The risk of GN recurrence is typically related to the post transplant time, majority occurring after 3–5 years PKT, while MPGN and FSGS recurrences early.
# Epidemiology, Pathogenesis, and Outcomes of GN Recurrence After Kidney Transplantion
Recurrent IgA Nephropathy
*Relatively common, occurs late PKT with incidence of recurrence at 15 years of 15% and may be reducing over time, more than 40% of patients lose their grafts.
* Compared with other GN subtypes, the outcomes is better.
*Data from the ANDATA registry showed that 5-year allograft survival following disease recurrence was similar between IgA
nephropathy, idiopathic membranous GN, and FSGS, with the poor allograft survival in MPGN compared to other GN .
*Risk factors for disease recurrence including younger age, recipients of zero HLA mismatched, live related donor kidneys, steroid avoidance or early withdrawal immunosuppressive regimens, the non use of induction therapy, HLA allelic
subtypes, crescentic, shorter total ischemic time, several molecules (Gd-IgA1), IgG anti-Gd-IgA1 antibodies, glycan-specific IgG antibodies, and soluble CD89
*The treatment of recurrent IgA nephropathy remains unknown
# Recurrent Primary FSGS
*1 in 3 patients with primary FSGS has recurrence after KT with the risk of allograft failure 5-times compared to without disease recurrence
*Secondary forms of FSGS can occur late after KT resulting in difficulties to differentiate between primary and secondary forms.
*In comparison to primary FSGS, familial FSGS in adults, comprising of those with mutations of podocin or structural podocyte proteins have low to no risk (<3%) of disease recurrence suggesting the importance of genetic testing for patients with adult onset FSGS when uncertain primary and secondary FSGS sub types present or in case of clear family history of FSGS .
*There are several risk factors for disease recurrence in patient with primary FSGS including:
Younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESKD, and prior allograft failure from disease recurrence.
*The pathogenesis of disease recurrence is unclear, but could be due to presence of circulating permeability factor(s) causing podocyte injury instigating early disease recurrence.
*The role of urokinase receptor by activating podocyte b(3) integrin resulting
in effacement of foot processes and proteinuria and development of primary FSGS.
* Close monitoring for proteinuria in high risk patients, protein/creatinine ratio are recommended in the first 3 months post-transplant.
*kidney biopsy in persistent or increasing proteinuria .
*The management is by plasmapheresis, rituximab and CNI remains uncertain.
# Recurrent Primary MPGN
*Common, more than 50% of recurrence rate within the first 2 years post-transplant
*Immune-complex mediated MPGN is characterized by the glomerular deposition of polyclonal or monoclonal immunoglobulins.
*C3 glomerulopathy (C3GN and dense deposit disease (DDD)) is characterized by the glomerular deposition of C3 in the absence of Ig deposition .
* The pattern of glomerular Ig and complement product deposition may differentiate
between the MPGN subtypes and give information on the pathogenesis of the disease processes.
*The timing and clinical presentations of C3GN and DDD may be dissimilar, with DDD recur later post-transplant
and associated with allograft dysfunction.
* C3GN and DDD are characterized by the presence of strong glomerular staining for C3 and electron deposits on electron microscopy, but these diseases are morphologically different.
*The treatment for recurrent disease is not well clear but the use of plasmapheresis, cyclophosphamide, eculizumab, and rituximab may be successful.
# Recurrent Idiopathic Membranous GN
* The ability to test for the presence of anti-PLA2R autoantibody has resulted
in improved recognition and differentiating primary vs. secondary membranous GN and managing the patients
*The absence of PLA2R autoantibody does not exclude cases of idiopathic membranous GN.
*The recurrence rate between 30 and 50%, and those with high titres of circulating anti-PLA2R autoantibody have a greater risk of recurrence that tend to decline
post-transplant.
*The treatment includes a combination of anti-proteinuric agents, corticosteroids,
alkylating agents, CNI, and rituximab.
*Rituximab is an effective treatment for native and recurrent membranous with 80% complete or partial remission
*Bortezomib has been used for rituximab resistant casese.
# Secondary GN
*It may occurs secondary to systemic diseases (aHUS), (SLE), anti- (GBM), and crescentic GN.
*(ANCA)-associated vasculitis, the relapse rate 0.02 per patient-years, with no association between subtypes & disease severity.
*The incidence of recurrent lupus nephritis between 0 and 44%, while anti- GBM disease is <5%.
# Presumed or Advanced GN
*In patients with ESKD where the underlying etiology of the cause of ESKD is uncertain
*This study conducted that 90% of the allograft failures from GN may be due to FSGS, membranous GN and IgA nephropathy.
# De novo GN
* The incidence between 4 and 20%, with FSGS, IgA nephropathy,
membranous GN, and MPGN are the most common de novo GN subtypes.
*Some study showed, the incidence of de novo GN occurred in 3.4 and 3.6% of those with primary ESKD from GN and those with ESKD from non-GN causes respectively.
*In patients with non-GN causes and developed de novo GN, more than 95% of cases were FSGS, while IgA nephropathy, membranous GN and MPGN were less incidence.
*The risk of graft failure was 7-times more in recipients who developed de novo GN, compared to those without disease.
*The long-term graft survival is relatively poor, especially in the presence of interstitial fibrosis/tubular atrophy with 5-year of <50% after diagnosis.
*Treatment of de novo FSGS with anti-proteinuric and removal of the causative agents, but more aggressive therapy and re-transplantation may be inculcated.
*De novo IgA nephropathy is underestimated, with asymptomatic IgA deposition not infrequently found in biopsies, prognosis is relatively benign and the treatment with antiproteinuric and/or anti-hypertensive therapy.
*Crescentic de novo IgA nephropathy has poorer prognosis, aggressive treatment with steroids and alkylating agent may be considered.
* De novo membranous GN and MPGN are less common, and primarily related to secondary causes (viral infections, rejection, autoimmune disease, CNI and thrombotic microangiopathy), it is occur later, symptoms ranging from asymptomatic mild proteinuria and incidental biopsy findings to nephrotic
range proteinuria and rapidly progressive GN.
Introduction:
Glomerulonephritis primary vs secondary’s still considered one of the common causes to ESKF and the prevalence vary according to the different registry data in the range of 7-17 %. Recurrence or denovo GN is one of important risk of graft failure.
Aim of the study:
This review article emphasis on the incidence, genetics, clinical characteristics and course of glomerular disease with attention to the risk of early graft loss.
Post-transplant recurrence or denovo GN.
In attention to subtypes of high-risk glomerular disease like IgA nephropathy, primary FSGS, Idiopathic membranous and MPGN and their management plan pre and post transplantation assessments follow up and monitoring, treatment options in case of recurrence.
the rate of GN recurrence post-transplant increased over time in the range of 3-5 years post transplantation and its underestimated due to selection bias, misclassification and biopsies indication bias all these factors can affect the true incidence of post-transplant denovo or glomerular disease recurrence with diver results from different registry data from US , Canada , Australia , Korea but overall FSGS And MPGN shows higher rate of recurrence and higher rate of graft loss post transplantation followed by IgA and idiopathic membranous nephropathy as shown in table1.
IgA nephropathy recurrence Usually common and late after 10-15 years, factors associated increase rate of recurrence including aggressive type of IgA in native kidney with crescentic IgA nephropathy, younger age, high IgA level.
Recurrent Primary MPGN
Recurrence rate common Up to 50% in first 24 months post-transplant with lower 5-year graft survival only 30%. according to the new classification of MPGN, both IC mediated MPGN (glomerular deposition of polyclonal or monoclonal IG with risk of overlap and all patients with IC mediated MPGN should have screen for monoclonal disease with serum electrophoresis for plasma cell dyscrasia + bone marrow trephine biopsy , c3/c4 level and hematology review with close monitoring for disease recurrence post TX recurrence early and late with characteristic glomerular IG deposits +/-c4d , or Complement mediated like C3 nephropathy (c3 deposition without IG, Both C3 GN and DDD have > 50% risk of recurrence post-transplant with poor graft survival
C3 GN due to alternative pathway dysregulation with amplification of c3 complement proteins, some have genetic mutation alleles of factor H and I or factor H autoantibodies Treatment options varies between plasmapheresis, rituximab, eculizumab, , MMF based IS with diverse response and weak evidence from pilot studies and case series .however the new classification of MPGN with understanding the pathogenesis this help to personalized the treatment protocol with targeting IC mediated MPGN with plasmapheresis and rituximab , MMF based IS while limited the use of eculizumab for c3 GN .
Idiopathic membranous:
Recurrence rate range 30-50%
Markers for idiopathic MGD
Anti -PLA2R autoantibody sensitivity 68 but high specificity 98%, and have direct relation with higher PLA2 auto-AB titer have higher chance for recurrence post-transplant
THSD7A only in 5% of idiopathic cases
20% OF idiopathic MGD are seronegative for both markers
Treatment almost similar to the treatment option of idiopathic MG for general population with focus on CNI based IS, ACEI, ARBS for proteinuria control and rituximab shows good response > 80% of cases, alkylating agents preferred to be avoided due to high risk of infection with intense IS, avoid m TOR as maintenance IS therapy. Some centers use rituximab prophylaxis pre transplant or immediately post-transplant in those with high APLA2 Titer to avoid recurrence.
Secondary GN:
Like SLE, AAV, AHUS, anti GMB, Crescentic GN, those secondary GN associated with lower rate of recurrence and usually late post transplantation
SlE incidence 0-44% and inconsistent but in case of recurrence associated with poor graft survival.
Anti GBM < 5% and rarely impact the graft survival.
AHUS before the era of eculizumab associated with higher rate of recurrence > 80% with early graft loss and transplantation was contraindication for AHUS but nowadays its safe even from LD with the use of eculizumab prophylaxis even with rare genetic mutations and in certain gene mutation in MCP the transplantation is consider safe even without eculizumab prophylaxis but frequent monitoring needed for recurrence risk.
De novo GN:
Common subtypes
Denovo IgA nephropathy, symptomatic hematuria unless RPGN crescentic Ig A with graft loss.
Denovo FSGS (Non -Collapsing variant) up to 20% usually late compared to idiopathic FSGS, denovo FSGS Need to rule out secondary causes like DM, Drugs ( m TOR , Pamidronates , CNI ) , infection parvovirus , cmv , BKV ,associated with poor graft survival and 40% risk graft loss in 5 year, treatment focus on the control of underlying cause.
Denovo MPGN, in < 3% secondary to Ig mediated MPGN, TMA, hepatitis C viral infection, Rejection, other systemic disease associated with higher rate of graft loss
Denovo MGN IN 2% may be secondary to viral infection, HCV, HBV, ABMR, histologically in IF its IgG1 predominate and positive staining for PLA2 auto-antibodies.
Less common and rare subtypes of denovo GN:
Minimal change GN
Immunotectoid GN
Fibrillary GN
FSGS collapsing variant rare < 1% could be viral or alloantibodies to angiotensin 11.
Conclusion: till date the management and care of patients with recurrence or denovo glomerular disease is challenging and underpowered by limited studies and we need more integrated researches to improve and personalized specific therapeutic options to specific types of recurrent or denovo GN .
7-17 % of all causes of ESRD comprised glomerulonephritis which can be classified either primary or secondary and occurring as denovo or recurrence.
Recurrent IgA nephropathy
Occurs about 10% at 10 years and 15% at 15 years
Usually late in occurrence
About 50% who had recurrence will lose their grafts
Risk factors for recurrence:
Treatment mainly conservative adjusting or maintaining immunosuppressive used in transplantation without any additional measures
Recurrent primary FSGS
commonly present in the early post-transplant period usually at first 3 months
recur in one-third of the patient with primary FSGS
recurrence associated with graft loss in nearly half of the patients after 5 years
secondary FSGS recur rarely recur
Recurrence rate in genetic FSGS is < 3%
In real world it will be difficult to determine the actual risk of recurrence and difficult to determine the type of FSGS
Genetic screening can be used to detect genetically determined FSGS
Risk factors for recurrence of primary FSGS
Aggressive monitoring of proteinuria should be done in the early post-transplant period especially at first 3 months, if proteinuria is > 1 gram, renal biopsy should be done
Recurrent FSGS is treated mainly with plasmapheresis with or without rituximab
Recurrent idiopathic MPGN
MPGN is classified according to IF into three types :
More than half reoccur within 2 years
1/3 immune complex MPGN and 1/2 C3 glomerulopathy who had recurrence will lose graft within the first 5 years
Monoclonal Ig deposition can occur in both immune complex MPGN and C3 glomerulopathy and only around one-third of immune complex MPGN cases are diagnosed as plasma cell dyscrasia, its presence is associated with a higher rate of recurrence, early recurrence, and poorer prognosis
Treatment of recurrent C3 glomerulopathy include supportive treatment (ACEI, or ARBS) in mild disease, corticosteroids, cyclophosphamide, and PLEX
Eculizumab treatment used in refractory cases, and Rituximab for poor response
Recurrent idiopathic MN
Disease process involves autoantibody against PLA2R
PLA2R helps to distinguish between primary and secondary MN
If patient is negative for PLA2R, THSD7A should be checked
Levels of PLA2R decline after transplant and possible reason are
Treatment includes combination of anti-proteinuria agents, rituximab, corticosteroids, CNI, and alkylating agents.
Prophylactic rituximab can be given for high-risk patients who had previous allograft failure due to disease recurrence, persistent high levels of circulating PLA2R
Secondary GN
aHUS, SLE, ANCA vasculitis, and anti-GBM Ab disease
Recurrence is up to 80% in aHUS (the use of prophylactic Eculizumab decrease the incidence of recurrence significantly), 0-44% in SLE and rare < 5% in anti-GBM Ab
Usually, recurrence occurs late
Lower likelihood of graft loss after recurrence however aHUS and SLE have higher graft loss rate
De novo GN
Denovo GN – occur in the recipient or may be present in the donor kidney
4-20 % of cases
associated with increase in the graft loss rate and poor outcome
Most common forms include IgAN , FSGS, MPGN and MN.
Risk factors for denovo GN;
Treatment includes conservative treatment and treatment of the cause
Recurrent and de novo glomerular disease post transplantation is an important factor in determining the outcome of the allograft.Developing particular criteria to identify the risk of recurrence of various glomerular diseases post transplantation is the key to ascertain favourable long term outcome.Risk of recurrence of GN post transplant is 3.-15%. All types of GN can recur especially the risk glomerular diseases of IgA, FSGS ,MN and MPGN.Incidence is underestimated due to variable biopsy protocol in different centers.The risk of GN recurrence is directly related to incremental time post transplant and the GN subtype. The majority of recurrent GN is resulting in allograft failure in 3-5 years post transplant. There are particular features concerning each subtypes of GN recurrence ,that would be discussed as follows:
1- IgA nephropathy:
Its recurrence is common , at 15% incidence. Some studies showed reduced risk over time. Up to 40 % of recurrent IgA nephropathy have been reported to have allograft failure secondary to disease recurrence.
in general the outcome of recurrence of IgA nephropathy is largely better than the recurrence of other GN subtypes.
Risk factors for recurrence of IgA nephropathy:
Clinical ;
1] Younger age.
2] Zero HLA-mismatched life related kidney donor.
3] steroid avoidance or early steroid withdrawal immunosuppressive protocol.
4] Non use of induction therapy .
5] ATG is associated with lower risk of recurrence
6]crescentic and Rapidly progressive IgA nephropathy in native kidney.
7]Short total ischemia time.
Molecular:
1]Galactose deficient IgA 1 Gd-IgA1
2]IgG anti Gd-IgA1
3]Glycan specific IgG antibody.
4]Soluble CD 89, which is FC receptor for IgA1.
presence of these markers at time of transplantation portend higher risk of recurrence.
The optimal treatment of recurrence is unknown , but advisable to have CNi, prerdnisolon and MMF in the maintenance .
FSGS:
1 in 3 patients with primary FSGS will be having recurrence of disease after transplantation with 5 times risk of having allograft loss from disease recurrence in comparison to those with non recurrent disease.
The genetic FSGS is not associated with recurrence in post transplant.The indications for genetic analysis in patients with FSGS are:
1-Steroid resistant
2-life related donor.
3-strong family history.
predictors of FSGS recurrence:
1]Rapid progression of disease towards renal failure.
2]young age .
3]Severe manifestation of disease at presentation.
4]prior allograft failure.
5]recipient of life donor.
Etiology of Recurrence:
The presence of circulating factor like Serum Soluble urokinase receptors was strongly speculated as a marker of FSGS familial type. Nevertheless, its credibility in diagnosing FSGS and predicting potential recurrence is debatable.
Treatment:
PP is the standard therapy of choice to remove the circulating factor.
Rituximab is of unproven efficacy in treating recurrent FSGS. With a substantial debate concerning the involvement of B lymphocytes in the pathogenesis of recurrence. It might be having an effect on the podocyte cytoskeleton enhancing the recovery of glomerular disease.
CNI is helpful in improving the the proteinuria and recurrent FSGS, by stabilizing the Podocyte cells.
mTori is linked to higher incidence of FSGS, and its recommended to be switched to CNI.
Membranoproliferative GN:
Its a heterogenous group of disease presented in an unanimous clinical and histological pattern of glomerular disease. Progression potential risk and allograft out come depend on the discernible underlying etiology.Generally classified according to immunofluorescent study into immune-complex mediated and complement mediated MPGN with different underlying etiologies.
commonly recurring with 50% recurrence rate over the first 2 years post transplantation. 5 years graft survival is 30% for those with recurrent disease.
The immunoglobulines deposition and complement deposition are characteristically shaping the progression of the disease and the potential risk of recurrence.
in patients with monoclonal immunoglobulin with complement activation is usually having high recurrence risk.
In 70% of immune mediated MPGN and monoclonal deposits there os no evidence of plasma cell dyscrasia[no evidence of serum or urine monoclonal Ig protein or evidence of plasma cell dyscrasia in bone marrow.Where as in 30% its associated with serum and urine monoclonal ig without fulfilling the criteria for MM.{Monoclonal Gammopathy of renal significance MGRS.}.
Importantly,MGRS can present with immune-complex mediated MPGN or complement mediated MPGN.MPGN always calls for thorough investigation and hematology review to to preclude plasma cell disease associated GN.
Treatment :
Eculizumab to treat the complement mediated MPGN.
PP.
Rituximab to deplete the involved B lymphocytes and Bortezomib for the monoclonal Plasma cell clone .
Membranous Nephropathy:
The discovery of an antibody specific against a Podocyte antigen phospholipase A2 receptor antigen PLA2R as the main culprit associated with MN has changed the management strategy of the disease, as the titer of PLA2R antibodies is diagnostic and reflecting activity of the disease. PLA2R negative MN might be be positive for another antibody against Podocytes THSD7A antigen in 5% of the MN patients. Following up of those antibodies post transplantation is substantially predictive of recurrence of the disease. Recurrence rate is 30-50%. High pre transplant antibodies titer is associated with 80% risk of recurrence.
Treatment is largely copied from non transplant MN patients. with CNi , corticosteroid and Rituximab.
mTori is advocated to be changed to CNi.
Lupus Nephritis:
Risk of recurrence is 0-40% with poor allograft outcome .
Anti-GBM disease :
Risk is less than 5 %, with extremely rare allograft failure.
aHUS:
Risk of recurrence is 80%.It was contraindicated before the introduction of Eculizumab, which is prophylactically indicated for safer kidney transplantation.
Summary:
Following kidney transplantation, recurrent or de novo GN in the renal allograft is an important cause of premature allograft failure. All GN subtypes can potentially recur after transplantation, with the prevalence of GN recurrence between 3 and 15%.
the incidence of de novo or recurrent GN after kidney transplantation is likely to be underestimated due to many factors.
The risk of GN recurrence is typically directly related to incremental time post-transplant, with the majority of GN recurrence resulting in allograft failure occurring after 3–5 years post-transplant, although early recurrences can occur in patients with MPGN and FSGS.
Recurrent IgA Nephropathy
Recurrent primary FSGS:
Recurrent primary MPGN:
Recurrent idiopathic MN:
Secondary GN:
De Novo GN:
Thanks, Huda
Recurrent and de novo Glomerulonephritis After Kidney Transplantation.
INTRODUCTION.
Glomerulonephritis is one of the most common cause of ESRD worldwide. It is considered to be an immunological kidney disease with heterogeneous abnormality which have many structural characteristic features under microscopy due to different pathological process and may be secondary to systemic diseases.
Glomerulonephritis is one of the common cause of recurrent disease post kidney transplant and affect graft survival whether recurrent or De novo with the prevalence 3- 15 % particularly in patients with high risk subtypes of IgA nephropathy, idiopathic membranous GN, focal segmental glomerulosclerosis (FSGS), and membranoproliferative (MPGN) .
Recurrent IgA Nephropathy.
Mainly it occur late post-transplant with rate incidence of disease recurrence at 15 years of 15%, around 40 % of patients with recurrent disease lost their graft.
Some risk factors mentioned in some studies such as younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy but still need more ascertainment.
Recurrent IgA has no specific protocol of treatment till now but depend on CNI based protocol and with crescentic IgA mainly depends on cyclophosphamide or rituximab.
Recurrent Primary FSGS.
Primary FSGS has high risk of recurrence around 10 to 30 % with high risk of graft failure but familial FSGS has low or no risk of recurrence.
Better to do genetic testing for adult patients with FSGS specially there are no obvious cause of secondary FSGS or presentation not correlated with primary FSGS.
Genetic testing also should be considered in pediatric with FSGS resistant to steroid.
younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESKD, and prior allograft failure from disease recurrence all are risk factors or FSGS recurrence.
There are many biomarkers has a role in pathogenesis of recurrence of FSGS e.g.( circulating permeability factor(s), serum soluble urokinase receptor (suPAR) ) but still most of them are under studies also used as biomarkers for recurrence but still sub-optimal e.g.( suPAR, Anti-CD40 autoantibody, and angiotensin receptor II type 1 (AT1R) antibody).
Treatment of recurrent FSGS is still challenging but some studies showed efficacy of PEX with or without Rituximab .
CNI has some effect on podocytes specially when shifting the patients from m-TOR to CNI.
Ofatumumab Abatecept/belatacept have promising effect but still need more studies.
Some centers use Anti-CD20 + PP as clinical protocol to prevent and treat recurrence in high-risk patients. (Overall remission rate 73%).
Recurrent Primary MPGN.
New classifications of MPGN depends on immunofluorescence classified to immune-mediated GN and C3 Glomerulopathy.
Recurrence of MPGN more than 50% with high recurrence of DDD 80-90% WITH graft failure 25% and C3GN 70% recurrence.
Immune-mediated GN 30-60% with graft failure 50%.
Monoclonal antibodies that inhibit activation of the C5 component of complement (eculizumab) have been used in prevention and treatment of C3GN.
plasmapheresis and anti-B cell therapy for immune complex-mediated GN but still need studies .
Recurrent Idiopathic Membranous GN.
40% -50% of primary/idiopathic MN cases recur in the allograft and 70-80% have anti-PLA2R antibodies.
Patients with anti-PLA2R antibodies pre-transplantation have a 60% to 76% risk of histologic recurrence and Antibody negative patients have a significantly lower risk (28%–30%).
Higher relative risk of allograft failure (up to 50% at 10-years of follow-up).
Treatment of recurrence (CNI+ steroids +Rituximab).
Rituximab therapy for early MN recurrence leads to 80% complete or partial remission with resolution of sub-epithelial deposits has been documented in 40% of patients.
Secondary GN.
Recurrence rate (early/late) of LN has varied from 2% to 54%.
Anti-GBM disease, disease recurrence after kidney transplant is <5%.
De novo GN.
The incidence of de novo GN after kidney transplant varies between 4 and 20%.
FSGS, IgA nephropathy, membranous GN, and MPGN being the most common de novo GN subtypes.
Reduction in nephron mass as diabetes, hypertension, BK viral infection, CNI therapy, and rejection) or the introduction of sirolimus all are risk factors for De novo GN .
CONCLUSION.
Recurrent and De novo Glomerulonephritis are common causes of graft failure.
Treatment of each one still need more studies to give strong evident guidelines.
Follow up by clinical and biochemical markers is so important for early detection and treatment.
Thanks, Mohamed
Please give a summary of this article
Recurrent IgA Nephropathy
Relatively common
Occurs late after transplant (15% at 15 years).
Better long term allograft & patient outcomes compared to other types of GN (graft failure: 1.6% for IgAN, 5.6% MPGN, 2.7% FSGS, & 3.3% for idiopathic MN).
Risk factors for disease recurrence include:
– Younger age
– Recipients of 0-HLA-mm LRD kidneys
– Steroid-avoidance or early withdrawal
– IS regimens
– Non-induction (ATG may lower recurrence risk)
– HLA allelic subtypes
– Crescentic IgAN in the native kidneys
– Shorter total ischemic time.
Molecules implicated in pathogenesis include:
– Galactose-deficient IgA1
– IgG anti-Gd-IgA1 antibodies
– Glycan-specific IgG antibodies
– Soluble CD89 (an Fc receptor for IgA
Treatment of recurrent IgAN:
Maintain CNI & corticosteroids-based IS.
Anti-proteinuric treatments.
Cyclophosphamide or rituximab (In crescentic RPGN)
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Recurrent Primary FSGS
1 in 3 recurrence rate.
5-times increased risk of allograft failure.
Secondary & familial FSGS have low to no risk (<3%) of recurrence.
Genetic test may be indicated only if there is uncertainty of primary & secondary FSGS or when there is a clear FH of FSGS.
Risk factors for disease recurrence in primary FSGS:
– Younger age at presentation
– Recipients of live-donor kidneys
– Non-white ethnicity
– Severe disease at presentation
– Rapid progression to ESRD
– Prior allograft failure from disease recurrence.
Pathogenesis of FSGS recurrence:
– Remains unclear.
– A pathogenic role of the circulating suPAR has been proposed; serum suPAR level was high in >50% of cases versus 6% of controls.
– Reduction of suPAR level with IS treatment was associated with a greater remission rates.
– Close monitoring for proteinuria in high risk patients is recommended.
– Kidney biopsy if persistent or increasing proteinuria.
Treament of recurrent primary FSGS:
PP is often recommended (AS for Apheresis guidelines).
CNI induce remission in recurrent FSGS.
Switch to CNI if on mTOR-i is advised (mTOR-i associated with de novo FSGS).
A practical treatment approach of include PP, anti-proteinuric therapy, & conversion to a CNI based IS. Rituximab used as adjunctive or in resistant cases.
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Recurrent Primary MPGN
>50% recurrence rate within the 1st2 years.
Risk of allograft failure; 5-year graft survival is only 30%.
The recurrence rate is high for both C3GN & DDD.
DDD tends to recur later post-transplant & allograft dysfunction is usually the sole feature of recurrence.
Treatment approach for recurrent MPGN is not well established.
Case series reported successful treatment with PP & agents, e.g. cyclophosphamide, eculizumab, & rituximab.
The knowledge of pathogenesis & new classification of MPGN will help nephrologists to individualize treatment strategies, e.g. PP & anti-B cell therapy for immune complex-mediated GN or eculizumab for C3 glomerulo-pathy.
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Recurrent Idiopathic Membranous GN
Anti-PLA2R autoantibody test differentiate primary from secondary MN, & help clinicians to arrange management policies.
Absence of PLA2R autoantibody, however, does not exclude idiopathic MN. The sensitivity of test is 65%, specificity is 97%, positive LHR of 15.65, & negative LHR of 0.37.
Positive glomerular staining of PLA2R antigen shows similar test performance accuracy.
Anti-THSD7A antibody occurs in 5% of patients with idiopathic MN, typically in those negative for PLA2R autoantibody.
Up to 20% of patients with idiopathic MN are negative for both PLA2R & THSD7A.
The recurrence rate in idiopathic MN is 30-50%.
There is a direct relationship between anti-PLA2R titer level & risk of recurrence; positive predictive value of pre-transplant anti-PLA2R for disease recurrence is 83%.
Treatment of recurrent MN:
Includes a combination of anti-proteinuric agents, corticosteroids, alkylating agents, CNI, & rituximab.
Rituximab achieves up to 80% complete or partial in early recurrence.
Bortezomib caused complete remission in single case of rituximab resistant recurrent MN.
Pre-emptive rituximab can be considered in those with high levels of anti-PLA2R titer with prior graft loss from
recurrent MN or have persistent high or increasing
titers post-transplant with early histological recurrence.
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Secondary GN
Caused by systemic diseases including:
– aHUS
– SLE
– anti-GBM disease
– crescentic GN (e.g., from systemic vasculitis).
Recurrence of secondary GN often occur later post-transplant & graft failure is infrequent.
In ANCA-associated vasculitis, the recurrence rate is low & often extra-renal.
Recurrent lupus nephritis is variable (0 -44%), those who recurrent have greater risk of graft & mortality.
In anti-GBM disease, recurrence is <5% & allograft failure is rare.
In aHUS, the recurrence rate was up to 80% before eculizumab era, & kidney transplantation was considered a contraindication.
The outcome appears excellent with the prophylactic use of eculizumab.
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De novo GN
FSGS, IgA nephropathy, MN, & MPGN are the most common de novo GN subtypes.
In a Canadian cohort, de novo GN occurred in 3.4% of those with primary ESRD from GN & 3.6% of those with ESRD from non-GN causes.
In those with primary non-GN causes, FSGS was the commonest cause of de novo GN (over 95%);IgA nephropathy, MN, & MPGN were less common.
In this study, the risk of graft loss was over 7-times greater in those who had de novo GN, compared to those
without disease.
It is difficult to differentiate secondary FSGS from“actual” de novo non-collapsing GN & may explain why de novo FSGS tend to occur later post-transplant (compared to primary FSGS).
The long-term outcome of de novo FSGS is relatively poor (5-year allograft survival of <50%).
Treatment of de novo FSGS:
Adequate anti-proteinuric treatment & the removal of causative factors if possible.
More aggressive therapy may be considered.
Re-transplantation can be considered.
De novo IgA nephropathy:
Is under-estimated; IgA deposition not infrequently found in protocol biopsies.
The prognosis is usually relatively benign
Treatment focuses on antiproteinuric &/or BP control. Crescentic de novo IgA nephropathy carries a poorer prognosis.
De novo membranous GN and MPGN:
Much less common
Later onset compared to recurrent disease.
Primarily secondary to viral infections, rejection, autoimmune disease, CNI & TMA.
Symptoms range from asymptomatic mild proteinuria & incidental biopsy findings to nephritic range proteinuria & RPGN.
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CONCLUSION
Uncertainty exists regarding approach & treatment of post-transplant GN recurrence.
It is important to establish a global GN registry, focusing on clinical data, histological features, treatment, & outcome of post-transplant GN.
Thanks, Mohamed
Introduction:
-Recurrent or de novo GN in the renal allograft causes early allograft failure after transplantation. All GN subtypes may recur after transplantation, with an incidence of 3 to 15%, especially in high-risk subtypes of IgA nephropathy, idiopathic membranous GN, focal segmental glomerulosclerosis (FSGS), and membranoproliferative GN (MPGN). The incidence of de novo or recurrent GN after kidney transplantation is likely to be underestimated due to selection bias (systematic differences in the selection and listing of ESKD patients with different GN subtypes), varying biopsy practices, ascertaining the primary cause of ESKD, differing follow-up period, disparate clinical presentations ranging from asymptomatic urinary abnormalities to rapidly progressive GN.
Recurrent IgA Nephropathy:
-The cumulative incidence of disease recurrence after 15 years is 15 per cent, however, the risk of disease recurrence may be decreasing with time. Recurrent IgA nephropathy is rather frequent, but it often develops late post-transplant.
-Several risk factors for disease recurrence have been identified, including younger age, recipients of zero-HLA-mismatched live-related donor kidneys, immunosuppressive regimens that avoid steroids or withdraw them early, the non-use of induction therapy (whereas anti-thymocyte globulin [ATG] may be associated with a lower risk of disease recurrence), HLA allelic subtypes, crescentic (and rapidly progressive) IgA nephropathy.
-The optimum therapy for recurrent IgA nephropathy is uncertain, and no research show immunosuppression changes enhance allograft outcomes. The ideal dosing/target therapeutic CNI level or particular CNI type in the treatment of recurring illness is uncertain. In crescentic quickly progressing IgA nephropathy, more severe immunosuppression (e.g., cyclophosphamide or rituximab) may be attempted, however, this is mainly untested and unlikely to alter the disease course.
Recurrent Primary FSGS:
-Up to one-third of patients diagnosed with primary FSGS will experience disease recurrence following kidney transplantation. Patients who do experience disease recurrence have a fivefold increased risk of allograft failure, which is primarily caused by GN recurrence when compared to patients who do not experience disease recurrence.
-The diagnostic test accuracy of suPAR in differentiating primary FSGS from other proteinuric diseases or predicting disease recurrence after transplantation remains suboptimal, and the clinical utility of routinely monitoring suPAR levels post-transplant to predict disease recurrence remains poorly defined.
-Treatment methods for recurrent primary FSGS are based on tiny case studies. Plasmapheresis is typically favoured and recommended in the treatment of primary FSGS recurrence in juvenile and adult allografts. The effectiveness of rituximab with CNIs like cyclosporine is unknown. The case report of rituximab’s effectiveness in ameliorating early primary FSGS recurrence post-transplant in a kid with post-transplant lymphoma drew substantial attention and showed that B cells may play a role in disease recurrence in a subset of patients with primary FSGS.
Recurrent Primary MPGN:
–Over fifty per cent of disease recurrences that occur post-transplant from primary MPGN do so within the first twenty-four months after the transplant. This is considered to be a very typical occurrence. In patients who have had a previous instance of disease recurrence, the probability of allograft failure is quite significant, and there is only a thirty per cent chance of allograft survival five years after disease recurrence.
-.Plasmapheresis and other immunosuppressive drugs, including cyclophosphamide, eculizumab, and rituximab, have been shown in case series to be beneficial in treating recurrent illness, although this does not constitute a well-established method for treating the condition. However, the most effective course of therapy has not been determined.
Recurrent Idiopathic Membranous GN:
-Depending on the study, the risk of illness recurrence in individuals with idiopathic membranous GN after kidney transplantation is 30 to 50%.
–The discovery of key podocyte antigens and the pathogenic autoantibody against phospholipase A2 receptor (PLA2R) led to advancements in the knowledge, management, and therapy of idiopathic membranous GN.
-Recurrence therapy is extrapolated from general population treatment and includes anti-proteinuric drugs, corticosteroids, alkylating agents, CNI, and rituximab. Given that kidney transplant recipients are likely to be on corticosteroids and CNI, most clinicians would recommend continuing CNI and considering the addition of anti-CD20 antibodies rather than alkylating agents to avoid overimmunosuppression resulting in severe infectious complications.
Up to 80% of patients with early disease recurrence post-transplant achieve full or partial remission with rituximab.
Presumed or Advanced GN:
–The incidence of allograft failure that can be attributed to GN is extremely low in patients who have ESKD and where the underlying aetiology of the cause of ESKD is unknown because a biopsy was not undertaken (but with clinical suspicion) or was non-diagnostic with non-specific histological features of interstitial fibrosis and glomerulosclerosis. In these patients, the clinical suspicion may point to GN as the cause of ESKD.
Secondary GN:
–Patients with secondary GN subtypes attributed to systemic diseases [such as aHUS, SLE, anti-glomerular basement membrane (GBM) disease, and crescentic GN (e.g., from systemic vasculitis)] may experience GN recurrence after kidney transplantation, but these relapses often occur later post-transplant and infrequently lead to allograft failure.
-De novo GN:
-De novo GN is linked with considerably lower allograft survival in kidney transplant patients. FSGS, IgA nephropathy, membranous GN, and MPGN are typical de novo GN subtypes following kidney transplants.
The incidence of de novo GN after a kidney transplant varies between 4 and 20%.
–IgA nephropathy: Generally favourable unless crescentic GN, re-transplantation possible.
-FSGS (non-collapsing): Prognosis poor, 40% 5-year renal allograft survival, re-transplantation possible.
-Membranous GN: possible higher risk of allograft failure. Re-transplantation is possible.
-MPGN: High risk of allograft failure, caution if considering re-transplantation.
CONCLUSION:
Despite progress in understanding the epidemiology, pathophysiology, and categorization of original and recurrent GN following kidney transplantation, management of post-transplant GN recurrence remains unknown.
Thanks, Weam
Recurrent and de novo Glomerulonephritis after Renal Transplantation
Glomerulonephritis is an important cause of graft loss. It can primary or secondary. Post transplant it can be denovo or recurrent. Incidence is variable and type dependent.
Recurrent IgA nephropathy
Relatively common post transplant with rates at 15% at 15vyears
Following recurrence 40 % may lose graft.
Compared to others GN the long term outcome are better
Graft failure in this study due to IgA nephropathy recurrence was 1.6% while in MPGN ( 5.6%) FSGS (3.3%)Idiopathic membranous GN (3.3%)
Predictors of recurrence include -ESRD secondary to GN, male gender, young age, non white.
Standard immunosuppression with CNI and steroids should be maintained
In cresentic type IgA nephropathy more aggressive immune suppression will be required
Recurrent Primary FSGS
1 in3 with primary FSGS will have recurrence.
5 times higher risk of graft failure as compared to those without disease
Genetic testing should be done once adult FSGS is diagnosed
Risk factors for recurrent FSGS
These include :
Onset during childhood
Rapid progression of primary FSGS to ESRD
Recurrent FSGC in previous Graft
Diffuse mesangial hypercellularity
Collapsing variant of FSGS in native kidney
White Race
Treatment is only managing immune suppression.
Recurrent Primary MPGN
3 main subtypes — Immune MPGN, C3 Glomerulopathy, Pauci immune MPGN
Recurrence rate from primary MPGN are around 50% at 2 years.
There can be an overlap between immune MPGN and C3 Glomerulopathy.
Treatment of C3 Glomerulopathy can be ACEI, PP, cyclophophamide and Eculuzimab for refractory cases
Recurrent idiopathic Membranous GN
Diagnosis can be made by antibody to podocyte antigen phospholipase A2receptor
Differentiation between primary and secondary disease is possible with sensitivity of 65 and specificity of 95%
Treatment is supportive
Secondary GN
Recurrence rate can as high as 80% and presentation is late
It can be due to HUS, SLE, ANCA vasculitis
Reported incidence of lupus nephritis can be 0-44%
Better outcomes with prophylactic eculizumab
Presumed or advanced GN
Where cause of ESRD was not known as biopsy was not undertaken
Denovo GN
True prevalence not known.
Incidence varies between 4-20%.
Difficulty in identifying the presence of denovo GN post transplant because the cause of native ESRD often not known.
Risk factors include loss of nephrons due to medical conditions due to diabetes , BK virus infection and hypertension.
Conclusion
There is considerable controversy in management of recurrent GN.
Focus should be on establishment to global GN registry
Further research needed to establish novel treatment
Thanks, Dr Khan
This is an evidence level 5 paper because it is a narrative review on recurrent and de novo glomerulonephritis after kidney transplantation. It is a group of diseases with different causes, clinical phenotypes, histological subtypes, and prognoses, consequently, different types of treatment. Regardless, these are lesions that lead to early graft loss and tend to reappear after transplantation.
IgA nephropathy is relatively common and when it recurs it is late, with a lower risk of graft loss compared to other glomerulopathies. The risk factors for its recurrence are young, living donors with 0 mismatch, steroid-sparing therapies, IgA nephropathy with crescents, and short ischemia times. The treatment is to maintain or optimize the dose of CNI and corticosteroids. In cases of lesions with crescent, the ideal is a pulse of cyclophosphamide or rituximab.
Primary recurrent FSGS has a high risk of recurrence, de novo injury, and graft loss. When familiar, the risk is much lower, but it needs genetic tests to confirm the diagnosis, being quite expensive for common use. The main risk factors are youth, living donors, non-Caucasian ethnicity, severe clinical manifestations, rapid progression to renal failure, and graft failure from recurrent disease. Treatment with rituximab, plasmapheresis, and CNI optimization is the most frequent.
Recurrent primary MPGN is relatively common and usually occurs within the first 24 months after transplantation, and may be mediated by immune complexes (monoclonal or polyclonal) or by complement-induced glomerulopathy (C3GN and DDD). The latter has a very high rate of recurrence and can only be diagnosed if immunofluorescence is performed. Monoclonal diseases can be controlled by rituximab, polyclonal diseases by controlling the underlying disease (infectious or autoimmune), and complement-induced diseases may benefit from eculizumab. DDD recurrence is later when compared to C3GN. There is a risk of a mixed disease (overlap) that is difficult to control.
Recurrent idiopathic membranous GN is closely related to anti-PLA2R antibodies and may recur in the graft at an early stage (proteinuria and protocol biopsy are needed). Treatment is optimizing doses of CNI, corticosteroids, and rituximab.
Secondary GN is related to systemic diseases, such as atypical hemolytic uremic syndrome, SLE, Goodpasture (GBM), and vasculitis which can lead to graft loss. De novo lesions usually occur in the reactivation of underlying diseases and the severity of the two situations is variable for each pathology, its intensity, and the organ recipient. Treatment should be individualized due to the lack of randomized studies and not enough to define an adequate protocol.
Thanks, Filipe
Introduction
GN caused around 17% of ESKD in Australia and New Zealand and 13% in US and UK(1,2,3)
GN represent a group of diseases with different causes ,clinical presentations and prognosis.
High risk recurrent GN are IgA nephropathy, Idiopathic membranous,FSGS ,and MPGN.
Epidemiology, Pathogenesis,and Outcomes of GN Recurrence after Kidney Transplantation
Recurrent IgA Nephropathy
Recurrent primary FSGS
Recurrent Primary MPGN
Idiopathic recurrent membranous GN ;
Secondary GN ; Generally these can lead to recurrence but usually later after transpant with less frequent loss of allograft loss. Examples are ;
Presumed or advanced GN ; The etiology of the ESRD is unknown or biopsy is not done or the biopsy was not specific = interstitial fibrosis, tubular atrophy or glomerulosclerosis
De novo GN ;
Conclusion ;
Thanks, Ben
Recurrent and de novo Glomerulonephritis After Kidney Transplantation:
¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤
▪︎Recurrent or de novo GN in the renal allograft is an important cause of premature allograft failure.
▪︎All GN subtypes can potentially recur after transplantation.
▪︎GN recurrence posttransplant depends on: 1) GN subtypes 2) time posttransplant.
☆Recurrent IgA Nephropathy:
________________________________
▪︎Is relatively common and typically occurs late post-transplant
▪︎Compared with other GN subtypes, the long-term allograft and patient outcomes are substantially better.
▪︎Risk factors for disease recurrence: younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroid withdrawal IS regimens, the non-use of induction therapy, HLA allelic
subtypes, crescentic (and rapidly progressive) IgA nephropathy
in the native kidneys and shorter total ischemic time,
▪︎ The optimal treatment of recurrent IgA nephropathy remain unknown. The current practice is to maintain (or change to) CNI and corticosteroids-based IS regimen in addition to anti-proteinuric treatments
▪︎ In crescentic rapidly progressive IgA nephropathy, more aggressive IS may be considered
☆Recurrent Primary FSGS:
________________________________
▪︎Up to 1 in 3 patients with primary FSGS will experience disease recurrence after kidney transplantation.
▪︎ It is important to consider genetic screening for patients with a clear family history of FSGS or those with a potential live-related donor for transplantation, including undertaking genetic screening of the donors.
▪︎When there is no genetic mutation in the potential recipients, genetic screening of live-related donors is not recommended
▪︎Genetic testing may be considered for pediatric patients with FSGS, including those with idiopathic steroid-resistant nephrotic syndrome
▪︎ Risk factors for disease recurrence in patient with primary FSGS includes: younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease at presentation, rapid progression to ESKD, and prior allograft failure from disease recurrence.
▪︎The pathogenesis of disease recurrence in patients with primary FSGS remains unclear
▪︎Close monitoring for proteinuria in high risk patients, and proceeding to a
kidney biopsy (electron microscopy to detect early effacement of foot processes) if there is persistent or increasing proteinuria.
▪︎Management of FSGS recurrence post-transplantation must initially include plasmapheresis, maximizing anti-proteinuric therapy, and converting to a CNI based immunosuppressive regimen, with B cell depletion (rituximab) considered as adjunctive treatment or in resistant cases.
☆Recurrent Primary MPGN:
_____________________________
▪︎ High recurrence rate ( >50%) with increased risk of allograft failure
▪︎Classification of MPGN:
1) Immune complex-mediated MPGN
2) Complement-mediated MPGN [comprising of C3GN and dense deposit disease (DDD)].
▪︎ The presence of serum monoclonal proteins and Ig deposits in immune-mediated MPGN, is associated with higher risk of recurrence
▪︎ The approach to treatment for recurrent disease is not well established. But, The new classification and current knowledge of MPGN may assist clinicians to adopt a personalized treatment strategy according to the most likely pathogenesis of the disease process (e.g., consideration of plasmapheresis and anti-B cell therapy
for immune complex-mediated GN or those with monoclonal gammopathy or to consider eculizumab for C3 glomerulopathy)
☆Recurrent Idiopathic Membranous GN:
________________________________________
▪︎There is a pathogenic role of autoantibody against the podocyte antigen phospholipase A2 receptor (PLA2R).
▪︎ The rate of recurrence between 30- 50%.
which is influenced by high titres of circulating anti-PLA2R Abs, follow-up period and dissimilar biopsy practices.
▪︎Monitoring of anti-PLA2R antibody post-transplant must be considered in:
1. High pretransplant circulating levels of
anti-PLA2R antibody
2. Early disease recurrence, to determine
response to treatment.
3. To differentiate disease recurrence
from de novo membranous GN or other
causes of proteinuria.
▪︎The treatment includes a combination of anti-proteinuric agents, corticosteroids, CNI, alkylating agents and change to CNI if in mTOR inhibitor. Rituximab is effective in native and recurrent membranous GN, and bortezomib has been described for rituximab resistant cases.
☆Secondary GN:
__________________
▪︎ Can occur late and infrequently lead to allograft failure
▪︎The reported incidence of recurrent lupus nephritis varies between 0 -44%
▪︎ Recurrence of ant GBM after kidney transplant is <5%
▪︎ In HUS: kidney transplantation
appeared safe with excellent allograft outcome with prophylactic use of eculizumab.
☆De novo GN:
________________
▪︎The incidence of de novo GN after kidney transplant varies between 4 and 20%, with FSGS, IgA nephropathy, membranous GN, and MPGN being the most common ones.
▪︎ Causes of difficulties in identifying and confirming the presence of de novo GN post-transplant:
1- The cause of native ESKD is often
uncertain
2- Presence of GN in the donor kidney may not be known.
3- Variations in allograft biopsy practices
4- Differences in the histopathological evaluation of allograft biopsies.
▪︎ The presentations of those with de novo GN are similar to those with primary GN.
▪︎Risk factors which may predispose to the development of de novo FSGS:
1- Reduction in nephron mass
2- Introduction of sirolimus (through the effects on podocyte integrity).
▪︎Treatment of de novo FSGS: anti proteinuric and the removal of the offending factors where possible, but more aggressive therapy may be considered.
▪︎ Re-transplantation following allograft failure from de novo FSGS can be considered
▪︎de novo IgA nephropathy: the incidence is underestimated, and the presentation with macroscopic hematuria is unusual, the prognosis usually relatively benign with treatment predominantly focuses on antiproteinuric and/or anti-hypertensive therapy.
▪︎Patients who have developed crescentic de novo IgA nephropathy tend to have a poorer prognosis.
▪︎De novo membranous GN and MPGN: are less common, and the reported cases primarily related to secondary causes, the onset tend to occur late, the symptoms are often indistinguishable compared to the timing, presentations, and clinical course of those with recurrent diseases.
▪︎In membranous GN, the pattern of Ig staining or glomerular staining for PLA2R may help to differentiate de novo from recurrent disease.
▪︎It is imp to exclude secondary causes in recipients who have developed de novo GN, which is critical when considering treatment options and re-transplant potential.
☆CONCLUSION: Considerable uncertainty remains in the approach and treatment of post-transplant GN recurrence.
Thanks, Tahani
Recurrent and de novo Glomerulonephritis after kidney transplantation
GNs are immunological kidney diseases with different histological subtypes, causes (primary vs secondary), and clinical presentations. Pose different prognoses and recurrence risks post-kidney transplantation. Therefore; clinicians should give enough information regarding the risk of disease recurrence in the transplant graft while evaluating potential kidney transplant candidates with GN for kidney transplantation. Recurrent or de novo GN in the renal allograft is a major cause of graft loss following kidney transplantation. All GN subtypes carry a risk of recurrence in the renal allograft with a prevalence of GN recurrence between 3 and 15% according to subtypes.
GN recurrence is directly related to the time post-transplant, with a majority of them resulting in allograft failure after 3 to 5 years post-transplant. As well, the recurrence risk varies according to GN subtypes with FSGS and MPGN subtypes are of early recurrence.
Epidemiology, pathogenesis, and outcomes of GN recurrence after kidney transplantation
Recurrent IgA nephropathy:
IgA nephropathy recurrence is common, but it occurs late post-transplant. Following disease recurrence, up to 40% of patients lose their allografts. Patients with IgA nephropathy have better allograft long-term outcomes after disease recurrence as compared with other GN subtypes. Risk factors for disease recurrence include young age, recipients of zero HLA-mismatch live related donor kidneys, steroid-free or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy, HLA allelic subtypes, crescentic type and shorter total ischemic time. There are several serum and urine biomarkers that may predict the risk of disease recurrence after kidney transplantation, but their prognostic role has not been truly established.
The ideal treatment of recurrent disease remains unknown. Current practice is to maintain or change to CNI and steroid-based regimen in addition to anti-proteinuria therapy. The dose and target CNI level remain unknown. Rituximab or Cyclophosphamide may be considered in crescentic IgA nephropathy.
Recurrent primary FSGS
FSGS has a high recurrence rate, up to 1 in 3 patients experience recurrent disease after kidney transplantation. The allograft failure risk after disease recurrence is 5 times compared to patients who do not get disease recurrence.
In contrast to patients with primary FSGS, familial FSGS in adults, have low to no risk (< 3%) of disease recurrence post-transplant suggesting the relative importance of genetic testing in the evaluation of a subset of patients with adult-onset FSGS for transplantation. In view of cost; it may be more practical to consider screening for patients with a clear family history of FSGS or those with a potential live-related donor for the same genetic mutations if present in the potential recipients). Similar to the adult population, there is a low risk of FSGS recurrence in pediatric patients with genetic FSGS post-transplant.
Other risk factors for disease recurrence are young age and severe manifestations at presentation, recipients of live-donor kidneys, non-white ethnicity, rapid progression to ESRD and prior allograft failure from disease recurrence.
Genetic screening should be considered in patients with adult-onset FSGS when the distinction between the primary and secondary form is uncertain or when there is a clear family history of FSGS.
The pathogenesis of disease recurrence in patients with primary FSGS is still unclear. Some studies proposed the role of serum soluble urokinase receptor (suPAR) in the insult that cause podocyte foot process effacement.
Nevertheless, the use of suPAR as a diagnostic test to differentiate primary FSGS from other proteinuric diseases or to predict disease recurrence remains suboptimal. Other biomarkers like anti-CD40 antibody, urine suPAR, and angiotensin receptor II type 1 (AT1R) antibody appear promising.
Regular checks of urine protein/creatinine ratio or self-check urine dip-stick in the first 3 months post-transplant are recommended. Kidney biopsy is done if there is persistent or increasing proteinuria. Electron microscope examination is needed to detect early effacement of the podocyte foot processes.
The treatment of recurrent primary FSGS remains challenging. Plasmapheresis is often preferred and recommended in the treatment of primary FSGS recurrence in the allograft. Adjunctive therapy with CNI and rituximab remain uncertain. There is no data to support that changing from one CNI to another will be effective. While switching to CNI if patients were on mTOR inhibitor is advocated, as mTOR
Inhibitor, especially in at higher doses has been associated with the development of de novo FSGS.
Novel therapy such as ofatumumab which is an anti-CD20 monoclonal antibody or B7-1 blockers (abatacept and belatacept) to prevent or treat recurrence appears promising but the efficacy of these therapies remains to be evaluated.
Recurrent primary MPGN
MPGN has an early and high recurrence rate post-transplant. The 5-year graft survival post-disease recurrence is only 30%. New MPGN classification has enabled a more understanding of the nature course, and risk of its recurrence post-transplant.
MPGN subtypes are:
1- immune complex-mediated MPGN characterized by glomerular deposition of polyclonal or monoclonal immunoglobulin (Ig). The pattern of deposition has both diagnostic and prognostic significance. The presence of serum monoclonal proteins with or without low complement levels (C4d deposition), or the presence of glomerular monoclonal Ig deposits both were associated with early disease recurrence and premature allograft failure. 70% of immune-mediated GN have no plasma cell dyscrasia while 30% have detectable elevated monoclonal proteins that do not fulfilling the criteria for multiple myeloma this is termed monoclonal gammopathies of renal significance.
2- complement-mediated MPGN or C3 glomerulopathy which includes C3GN and dense deposit disease DDD, these are characterized by glomerular deposition of C3 in the absence of Ig. Although, they have similar courses, the timing and clinical presentations of patients with C3GN and DDD. DDD more likely to recur later post-transplant. Genetic mutation or autoantibodies play role in the pathogenesis.
Monoclonal gammopathy can be associated with C3GN which is associated with the rapid rate of disease recurrence and allograft failure compared with those without monoclonal gammopathy.
The pattern of glomerular deposition may help to differentiate between the MPGN subtypes.
Clinicians should be aware of the need to undertake pre-transplant screening for monoclonal gammopathy and possible haematology review in patients with MPGN, as well as the importance of close monitoring post-transplant for signs of recurrence.
The optimum treatment strategy remains unknown. The use of plasmapheresis, and immunosuppressive agents including cyclophosphamide, eculizumab and rituximab has been to be of beneficial effect.
Recurrent Idiopathic Membranous GN:
Test for Anti-PLA2R autoantibody which is an antibody against podocyte antigen phospholipase A2 receptor can differentiate primary vs. secondary membranous GN, as well as help the clinicians in the management of these patients and in predicting the recurrence post-transplant. Antibody against autoantigen thrombospondin type 1 domain-containing 7A (THSD7A) has been detected in up to 55 of the idiopathic membranous GN. Nevertheless, about 20% of patients with idiopathic membranous GN do not have detectable autoantibodies to PLA2R OR THSD7A. the rate of disease recurrence in patients with idiopathic membranous GN post-transplant is between 30 – 50% and there is a direct relationship between the PLA2R titer level and the risk of recurrence. The role PLA2R antibody monitoring post-transplant is still unclear. But it should be considered if there is high pre-transplant circulating levels of PLA2R antibody, in patients with early disease recurrence to predict progression, determine response to therapy and differentiate disease recurrence from de novo membranous GN or other causes of proteinuria.
The treatment of the recurrence includes a combination of antiproteinuric agents, steroids, CNI, and rituximab.
Secondary GN
Patients with secondary GN that is attributed to systemic diseases such as SLE, Crescentic GN from vasculitis, anti-GBM disease, aHUS may experience GN recurrence after kidney transplantation but these are often late. The recurrence rates vary according to the aetiology with the highest rate among aHUS reaching 80%, therefore, it had been a contraindication to transplantation, but with the discovery of eculizumab, the kidney transplantation appeared safe with excellent allograft outcome in these patients.
Presumed or Advanced GN
Where the underlying aetiology of the ESRD is uncertain because the biopsy was not taken or it was not diagnostic with non-specific histological features. The incidence of allograft failure attributed to GN is extremely low as compared with primary GN subtypes. FSGS and IgA nephropathy is attributed to most of the recurrence.
De novo GN
The incidence of de novo GN after kidney transplant varies between 4 and 20%, and the most common subtypes are FSGS, IgA nephropathy, membranous GN, and MPGN. De novo GN post-transplant is difficult to confirm because the cause of native ESRD is often uncertain. Several risk factors are associated with the development of FSGS like DM, hypertension, BK, CNI therapy, and rejection. De novo FSGS recurrence tends to be later post-transplant compared to the primary form. Irrespective of the nature of de novo FSGS, the long-term allograft outcome is relatively poor. No specific therapy is approved.
De novo IgA nephropathy incidence seems to e underestimated. Macroscopic hematuria is unusual. The prognosis is relatively benign with treatment mainly focused on antiproteinuric and antihypertensive therapy. De novo membranous and de novo MPGN are of less recurrence rate.
Clinicians should be aware of the need to exclude secondary causes in recipients who have developed de novo GN.
Conclusion:
The recurrent GN after kidney transplantation still carries considerable uncertainty in their approach and treatment.
good
. – post-transplantation, recurrent or de novo GN in the renal allograft is an important cause of premature allograft failure .
-All GN subtypes can potentially recur aftertransplantation, with the prevalence of GN recurrence between 3 and 15%, particularly in patients with high risk subtypes of IgA nephropathy, idiopathic membranous GN, focal segmental glomerulosclerosis (FSGS) , and membranoproliferative GN (MPGN) .
-The majority of GN recurrence resulting in allograft failure occurring after 3–5 years post-transplant, although early recurrences can occur in patients with GN subtypes of MPGN and FSGS.
Recurrent IgA Nephropathy
-Recurrent IgA nephropathy is relatively common .
– 40% of patients with recurrent IgA nephropathy havebeen reported to lose their allografts, predominantly fromdisease recurrence (up to 60%) .
– Compared with other GN subtypes, the long-term allograft and patient outcomes of patients with IgA nephropathy are substantially better.
-Risk factors for disease recurrence: younger age, recipients of zero-HLA-mismatched live-related donor kidneys, steroid-avoidance or early steroidwithdrawal immunosuppressive regimens, the non-use of
induction therapy , HLA allelic subtypes, crescentic IgA nephropathy in the native kidneys and shorter total ischemic time.
-There are several molecules, including galactose-deficient IgA1 (Gd-IgA1), IgG anti-Gd-IgA1 antibodies, glycan-specific IgG antibodies, and soluble CD that may be implicated in the pathogenesis of IgA nephropathy, the presence of which may portend a greater risk of disease progression and possibly disease recurrence posttransplant
-The optimal treatment of recurrent IgA nephropathy remains unknown .
Recurrent Primary FSGS
-1 in 3 patients with primary FSGS will experience disease recurrence after kidney transplantation, with the risk of allograft failure 5-times and poorer 5-year allograft survival .
-Risk factors for disease recurrence : younger age at presentation, recipients of live-donor kidneys, non-white ethnicity, severe manifestations of disease
at presentation, rapid progression to ESKD, and prior allograft failure from disease recurrence .
-The pathogenesis of disease recurrence due to presence of circulating permeability factor(s) causing podocyte injury instigating early disease recurrence.
– Close monitoring for proteinuria in high risk patients, in the first 3 months post-transplant are recommended, and proceeding to a kidney biopsy if there is persistent or increasing proteinuria .
-A practical approach in the management of FSGS recurrence post-transplantation should initially include plasmapheresis, maximizing anti-proteinuric therapy, and converting to a CNIbased immunosuppressive regimen , with B cell depletion (rituximab) considered as adjunctive treatment or in resistant cases .
Recurrent Primary MPGN
-50% of recurrence occurring within the first 24 months post-transplant and 5-year allograft survival post-disease recurrence of only 30%.
-There is a high rate of post-transplant recurrence for both C3GN and DDD subtypes, withover 50% of patients experience allograft failure .
-The presence of glomerular monoclonal Ig deposits was associated with poorer prognosis, characterizedby early disease recurrence and substantially greater risk ofpremature allograft failure following disease recurrence .
-The approach to treatment for recurrent disease is not wellestablished,
limited to case series of successful treatment with the use of plasmapheresis and other immunosuppressive agents including cyclophosphamide, eculizumab, and rituximab .
Recurrent Idiopathic Membranous GN
-The diagnostic test accuracy of circulating anti- PLA2R autoantibody in differentiating primary from secondary membranous GN is acceptable( sensitivity of 65% , specificity of 97% ).
-20% of patients with idiopathic membranous GN do not have detectable autoantibodies to PLA2R .
-The rate of disease recurrence in patients with idiopathic membranous GN following kidney transplantation is between 30 and 50% .
– The circulating levels of anti-PLA2R autoantibody tend to decline post-transplant .
-The treatment of disease recurrence includes a combination of anti-proteinuric agents, corticosteroids, alkylating agents, CNI, and rituximab.
Secondary GN
-The incidence and outcome of patients with recurrent lupus nephritis post-kidney transplantation are unclear.
-In patients with anti- GBM disease, disease recurrence after kidney transplant is <5%in the era of modern immunosuppression, and allograft failure from disease recurrence exceedingly rare .
-Disease recurrence following transplantation of patients with aHUS was up to 80%, with a substantial proportion of patients losing their allografts from recurrent disease within the first year post-transplant and therefore, kidney transplantation was considered a contraindication for patients with aHUS .
De novo GN
– The incidence of de novo GN after kidney transplant varies between 4 and 20%, with FSGS, IgA nephropathy, membranous GN, and MPGN being the most common de novoGN subtypes.
-The incidence of de novo IgA nephropathy is likely to be underestimated, presentation with macroscopic hematuria is unusual.The prognosis of those with de novo IgA nephropathy is usually relatively benign with treatment predominantly focuses on antiproteinuric and/or anti-hypertensive therapy
-Crescentic de novo IgA nephropathy tend to have a poorer prognosis.
-De novo membranous GN and MPGN are much less common, and the reported cases primarily related to secondary causes including viral infections, rejection,
autoimmune disease, CNI and thrombotic microangiopathy.
-The onset of de novo membranous GN or MPGN tend to occur later post-transplant .
Nice effort. What is the level of evidence of this paper
Glomerulonephritis is considered an important cause of ESRD constituting 7-17 % of all causes of ESRD
Glomerulonephritis is either primary or secondary, and glomerulonephritis occurring after transplantation is either denovo or recurrent
Recurrence of glomerulonephritis is common, incidence differs according to the type and is associated with an increase in the incidence of graft loss within the first 2-3 years post-transplantation
Recurrent IgA nephropathy
Recurrent primary FSGS:
1- Age: Patients with disease onset at a younger age are more prone to
recurrence
2- Race: non-white are at increased risk of recurrence
3- Living donor kidney is associated with a higher risk of recurrence than
deceased donor kidney transplantation
4- Recurrence of FSGS in the previous transplant increases the risk of
recurrence in subsequent graft
5- aggressive FSGS leading to renal failure within a short time after onset is
associated with a higher recurrence rate.
6- A family history of FSGS is considered a lower risk factor for recurrence a
it indicates autosomal dominance
Recurrent idiopathic MPGN:
Recurrent idiopathic MGN:
Secondary GN:
De novo GN:
Thanks, Sherif
Recurrent and de novo glomerulonephritis after renal transplant
Summary
IgA nephropathy subtype
Recurrent primary FSGS
Recurrent primary MPGN
Recurrent idiopathic membrane GN
Secondary GN
Presumed or advanced GN
De novo GN
Thanks, Nandita
Recurrent or de novo GN in the renal allograft is a cause of premature allograft failure
High risk subtypes of GN as IgA nephropathy, idiopathic membranous GN,
focal segmental glomerulosclerosis (FSGS), and membranoproliferative GN (MPGN) are more likely to recur after transplantation.
The risk of GN recurrence is related to time post-transplant, most cases recurring 3–5 years post-transplant, but with MPGN and FSGS recurrence can occur earlier.
Recurrent IgA Nephropathy
It is common, occurring late post-transplant with 40% of cases losing their allografts but outcome is better in comparison to other GN subtypes.
There are multiple risk factors for disease recurrence as younger age, zero-HLA-mismatched live-related donors, steroid-avoidance or early steroid withdrawal immunosuppressive regimens, the non-use of induction therapy crescentic Ig A nephropathy, and shorter total ischemic time.
There are multiple molecules as galactose-deficient IgA1, as well as serum and urinary biomarkers that could have prognostic importance and could be indicative of recurrence.
There isn’t a specific therapy for Ig A nephropathy recurrence but a CNI and steroids-based regimen with anti-proteinuric measures are the used therapy
In crescentic IgA nephropathy more intensive immunosuppression can be needed
Recurrent Primary FSGS
Cases with primary FSGS has high rate of recurrence risk and poor allograft long term outcome
For secondary FSGS the recurrence risk is unknown
Genetic testing is essential in the assessment of FSGS cases before transplantation particularly in cases with uncertainty for primary , secondary or familial FSGS because Familial FSGS with mutations of podocin and apolipoprotein L-1 genotype have low risk of recurrence in the graft.
Circulating serum soluble urokinase receptor is supposed to be implicated in the development of primary FSGS specially familial subtype,meanwhile it is not specific.
Other prognostic markers for disease recurrence as Anti-CD40 autoantibody, and AT1R antibody are under study.
Treatment regimen usually used is plasmapheresis ,Rituximab , CNI and optimizing antiprotienuric tretament
New therapies are ofatumumab or B7-1 blockers (abatacept and belatacept) are investigated for prevention and treatment
Recurrent Primary MPGN
Is common with more than 50% risk of occurring within the first 24 months post-transplant.
The pattern of glomerular Ig and complement deposition can differentiate between the MPGN subtypes and the pathogenesis of the different diseases
DDD usually recur later post-transplant and often associated with only allograft dysfunction. C3GN and DDD are characterized by heavy glomerular staining for C3 and electron deposits on electron microscopy, but both of them differ morphologically .
Genetic mutations or autoantibodies were involved in disease pathogenesis
Transplant recipients due to C3glomerulopathy with monoclonal gammopathy experienced rapid disease recurrence.
Serum monoclonal proteins with and without low complement levels are associated with higher recurrence risk .
Glomerular monoclonal Ig deposits as IgG3κ , IgG3λ, and IgG2λ were associated with worst outcomes.
Screening for monoclonal gammopathy with or without hematology consultation before transplantation in patients with MPGN, meanwhile close monitoring post-transplant for signs of disease recurrence is essential.
The best treatment strategy remains unknown, plasmapheresis and other immunosuppressive agents including cyclophosphamide, eculizumab, and rituximab were used
Recurrent Idiopathic Membranous GN
Anti-PLA2R autoantibody detection improved the recognition and differentiation of primary vs. secondary membranous GN as well as detecting those at high risk of post-transplant disease recurrence .
Thrombospondin type 1 domain–containing 7A (THSD7A) was detected in 5% of patients with idiopathic membranous GN, whom were seronegative for the PLA2R autoantibody while other primary membranous GN were negative for both autoantibodies.
Recurrence of idiopathic membranous GN posttransplantation is between 30 and 50%.
Patients with high titers of anti-PLA2R autoantibody detection have a greater risk of disease recurrence.
Treatment includes combination of anti-proteinuric agents, corticosteroids, alkylating agents, CNI, and rituximab.
Complete clinical remission with bortezomib occurred in a single case with rituximab resistant recurrent membranous GN
Secondary GN
secondary to systemic diseases as atypical hemolytic uremic syndrome (aHUS), systemic lupus erythematosus (SLE), anti-glomerular basement membrane (GBM) disease, and crescentic GN can have GN recurrence post transplantation, but occur later and not common to cause allograft failure.
Presumed or Advanced GN
In cases of unknown cause of ESKD because biopsy was not done allograft failure due to GN is extremely low.
De novo GN
De novo GN recurrence postkidney transplant is 4 – 20%, with FSGS, IgA nephropathy, membranous GN, and MPGN being the most common de novo GN subtypes.
Confirming de novo GN post-transplant is difficult due to uncertainity about the ESKD etiology in the cases
The presentations for de novo GN are similar to primary GN subtypes.
Conclusion
The approach and treatment of post-transplant GN recurrence is uncertain till now
Thanks, Doaa
Recurrent and de novo glomerulonephritis (GN) are important causes of allograft loss, however, it is likely to be underestimated.
The incidence of GN recurrence differ according to the subtype of GN and time posttransplant.
Epidemiology, pathogenesis and outcomes of GN recurrence after kidney transplant:
Recurrent IgA nephropathy:
Relatively common, occurs late posttransplant and leads to graft loss in 40% of patients due to recurrence.
Associated with better long-term patient and graft survival compared to other subtypes.
Risk factors for recurrence include young age, zero HLA mismatch live related donor kidneys, steroid avoidance or withdrawal and crescentic form, however, it is difficult to determine the true causes of recurrence.
Several biomarkers are investigated to predict the risk of disease recurrence but are still not validated.
The optimal therapy is unknown, but current practice includes CNI, steroids and antiproteinuric drugs.
Recurrent primary FSGS:
Associated with 5-times higher risk of graft loss.
Familial FSGS have low to no risk of recurrence post transplant so genetic testing may be considered in patients with adult onset FSGS.
Risk factors for recurrence of primary FSGS include younger age at presentation, live donor kidney, severe disease at presentation, rapid progression to ESKD and previous graft failure due to recurrence.
The pathogenesis of recurrence is unclear, it is suggested that circulating permeability factors as suPAR may be involved in pathogenesis but its clinical utility is not yet determined.
Management is difficult, Plasmapheresis (PP) is recommended in primary FSGS, the benefit of adjunctive therapy with rituximab and CNI is still uncertain.
Preemptive PP, immunoadsorption, belatacept and ofatumumab are promising agents but still need further studies.
Recurrent primary MPGN:
Relatively common, 50% of recurrence occur within first year post transplant.
New classification:
The 2 types have overlapping clinical and histological features.
Pre transplant screening for monoclonal gammopathy should be considered.
Balancing between the risk premature graft failure due to disease recurrence post transplant and the risk of remaining on dialysis.
Optimal treatment is unknown, PP, cyclophosphamide, eculizumab and rituximab are treatment options but need fiurther studies to determine the most appropriate treatment.
Recurrent idiopathic membranous GN:
Rate of recurrence of primary membranous GN ranges from 30-50%, patients with high titers of anti-PLA2R autoantibodies are at greater risk of recurrence.
Monitoring of theses antibodies should be considered in patients with high levels pre transplant, early disease recurrence, to determine response to treatment and to differentiate recurrence from de novo membranous GN
Treatment is similar to that in general population including, antiproteinuric agents, steroids, alkylating agents, CNI and rituximab
Rituximab is efficient when used early after recurrence, however the timing of starting specific treatment is not well determined.
Secondary GN:
May recur later post transplant and infrequently lead to graft loss.
ANCA associated vasculitis, relapse rate reported at 0.02 per patient-years, no association with ANCA type or disease severity pre transplant.
Recurrent lupus nephritis, incidence and outcome are unclear.
Anti GBM disease, Recurrence <5% and graft loss is rare.
aHUS, was considered a contraindication for transplantation as the risk of recurrence was 80% with graft loss in the first year but availability of eculizumab resulted in excellent patient and graft outcome.
Presumed or advanced GN:
Patients with presumed or advanced GN as cause of ESKD have low incidence of graft failure due to GN
De novo GN:
The prevalence is unknown, associated with significant lower graft survival.
Secondary causes should be excluded before determining treatment choice and before arranging for re-transplantation.
Management is similar to that in patients with GN without transplantation.
FSGS:
long-term outcome is poor, it is difficult to differentiate 2ry FSGS from actual de novo FSGS, treatment include antiproteinuric agents and removing the offending cause if possible with no data about efficacy of using more aggressive therapy.
IgA nephropathy:
prognosis is relatively good, treated with antiproteinuric and antihypertensive therapy.
membranous GN and MPGN are less common and tend to be late post transplant
Thanks, Heba
Primary GN is an important cause of ESRD worldwide. It It constitute ~17% 0f ESRD patient( ANZDATA). GN is an immune disease with different histological subtypes & clinical phenotypes & differ in recurrence rate after transplantation. Both recurrent & de novo GN associated with premature graft loss. The incidence of post transplant ( recur or de novo) GN is under estimated due to:
Post transplant recurrence usually occur 2-3 years, but can occur earliar in FSGS & MPGN.
Recurrent IgAN:
It is common, later in post transplant period & can be reduced overtime. Comparing to other types of GN, IgAN had better patient & graft long term outcome. Risk factors associated with increased risk of recurrence include:
The optimal treatment is unknown.
Recurrent primary FSGS:
One third of patients had recurrence with 5 folds increased risk of graft loss compared to patients without recurrence. Patients with familial type had low risk of recurrence <3%( NPHS2). But identification of familial subtype is difficult due to incomplete penetrance. Genetic screening done for:
Due to high cost of genetic study, it is better to screen patients with clear family history of FSGS or potential live donor for transplantation. Risk factors for recurrence include:
The exact cause of recurrence is unclear, but presence of circulatory serum suPAR proposed to be a cause. Reduction of serum suPAR can predict remission but it can’t differentiate between primary or secondary types or prediction of recurrence. Urin suPAR, anti-CD40 Ab & AT1R AB are other markers of FSGS but need more studies to confirm its validity.
Post transplant (first 3 mon) monitoring of proteinuria in high risk patient is important for early detection of recurrence in addition to graft biopsy in case of increasing proteinuria. Optimal treatment is uncertain, but PP, rituximab & CNI can be used with anti-proteinuric measures.
Recurrent MPGN:
Post transplant recurrence is common >50% in first 2 years with high risk of graft loss ( 5 years graft survival 30%). It classifies into:
Recurrent idiopathic MGN:
Identification of anti-PLA2R Ab was important in treatment of idiopathic & differentiation between primary & secondary MGN in addition to prediction of disease recurrence post transplantation. Anti-PLA2R sensitivity ~65% & specificity ~97%. THSD7A Ab found in %% of idiopathic MGN patients ( negative PLA2R).
Recurrence occur in 30-50%. Pre transplant high level of PLA2R Ab associated with prediction of recurrence.
Treatment include optimizing anti-proteinuria drugs, CS, CNI, alkalizing agent & rituximab( associated with 80% remission). Bortezumib shown to be effective in cases of rituximab resistance.
Secondary GN:
It attributed to systemic diseases e.g. aHUS, SLE, anti-GBM & systemic vasculitis. Recurrence usually occur late with infrequent graft loss.
De novo GN:
Exact prevalence is unknown, but it associated with reduced graft survival when compared to patients without de novo GN. Incidence 4-20% with FSGS, IgAN, MGN & MPGN as most common subtypes.
It is difficult to confirm diagnosis of de novo GN because the primary cause of ESRD unknown & GN disease may present in donor kidney. Risk factors that predisposed to de novo GN include:
It associated with poor long term outcome & treatment depends mainly on anti-proteinuria drugs & treatment of offending factor, Immunosuppression may be considered.
IgAN recurrence course is benign & treatment only anti-proteinuria drugs, but patients with crescentic IgAN have poor outcome.
De novo MGN & MPGN less common & it related to secondary causes e.g. viral infection, rejection, autoimmune diseases, CNI & TMA.
Secondary causes should be excluded in recipient who develop de novo GN because it important for treatment option & re transplant potential.
Thanks, Ban