We aimed to assess the efficacy of different treatments for C3G recurrence after Kidney transplant patient.
C3 glomerulopathy is a rare glomerulonephritis, characterized by the dysregulation of the
alternative complement pathway in the glomeruli.
It leads to prominent complement C3 deposition in the renal biopsy samples with absent
or scanty immunoglobulin deposition
Microscopically, C3G may present as patterns of membranoproliferative GN , crescentic
GN, diffuse endocapillary proliferative GN, or mesangioproliferative GN.
Methods:
Meta-analysis.
Results:
Twelve studies (7 cohort studies and 5 case series) consisting of 122 kidney transplant
patients with C3G (73 C3 glomerulonephritis (C3GN) and 49 dense deposit disease
(DDD)) were included.
The pooled estimated rates of allograft loss among Kidney transplant patients with C3G
were 33% (95% CI: 12–57%) after Eculizumab, 42% (95% CI: 2–89%) after therapeutic
plasma exchange (TPE), and 81% (95% CI: 50–100%) after rituximab.
80% of patients with elevated sMAC before Eculizumab responded to treatment.
In addition, all patients who responded to Eculizumab had normal sMAC levels after
post-Eculizumab.
Conclusions:
the study suggests that the lowest incidence of allograft loss (33%) among kidney
transplant patients with C3G are those treated with Eculizumab.
Among those who received no treatment for C3G due to stable allograft function, there is
a high incidence of allograft loss of 32% in C3GN and 53% in DDD. SMAC level may
help to select good responders to Eculizumab.
Esmat MD
2 years ago
This study is a systematic review with a level 1 of evidence. C3 glomerulopathy is a rare glomerulonephritis that result from dysregulation of the alternative complement pathway. It is associated with poor kidney outcomes (ESRD in approximately 50% of patients) and substantially high recurrence rate after kidney transplantation. It is classified to C3 glomerulonephritis and DDD. The diagnosis of C3 glomerulopathy is made by IF on kidney biopsy with two-fold greater intensity of C3 staining in combination with absence or near absence of immunoglobulins. In EM, C3GN is characterized by deposits in glomerular matrix (subendothelial and few intramembranous) while DDD is distinguished by typical finding of osmiophilic sausage-shaped deposits in the glomerular basement membrane. According to the etiology, C3GN can be classified into genetic causes and acquired causes probably due to triggering factors such as infections, monoclonal gammopathies, and autoimmune diseases. According to high post-transplant recurrence rate, monitoring of the patient and implementation of available therapeutic options is crucial to improve kidney allograft survival. Recurrence commonly occurs early post-transplantation. Based on this study, the impact of different agents on treatment of C3 glomerulopathy in kidney allografts is different and also depend on various subclasses (DDD or C3GN). Management of C3GN is based on severity of disease. For mild disease supportive therapy and for moderate disease supportive therapy along with MMF and steroids is suggested. Rituximab and plasma exchange was associated with mixed results. In severe disease with proteinuria more than 2 gr/day and endocapillary proliferation, limited success with immunosuppressive agents. In kidney transplant recipient, despite triple therapy with MMF, CNI, and prednisolone, the recurrence rate is high. In this setting, the role of anti-complement therapy was proposed. Eculizumab is more effective than plasma exchange and rituximab in the treatment of C3GN. Furthermore, eculizumab is effective in the treatment of DDD but with less graft survival rate compared to C3GN. The allograft survival in DDD is worse than C3GN. Patients with elevated sMAC before treatment with eculizumab have had better response to therapy (about 80%) with normal sMAC after eculizumab. Therefore, sMAC level can guide to select responders to eculizumab.
MICHAEL Farag
2 years ago
A Systematic Review; level I evidence
Reclassification of as immunoglobulin and non-immunoglobulin mediated disease has paved the pathway to the spectrum of diseases named C3G . C3G is characterized by activation of the alternative complement pathways leading to C3 glomerular deposition. With this mechanism, it is suggested that eculizumab may be an effective treatment of C3G . The etiologies of C3G can be classified into genetic causes (mutations/variants resulting in alternative complement pathway abnormalities) and acquired causes (C3Nef/autoantibodies) with possible triggering factors including infections, monoclonal immunoglobulin, and autoimmune diseases.
KTX patients with C3G treated with eculizumab had the lowest incidence of allograft loss (33%) when compared to those treated with TPE and rituximab. Among those who received no treatment for C3G due to stable allograft function, there was an incidence of allograft loss of 32% in C3GN and 53% in DDD
mai shawky
2 years ago
Summary of ttt of C3 glomeulopathy
• C3 gloerulopathy is a rare form of GN, 2ry to alternative complement dysregulation and triggered with infection or autoimmune process, with high risk of recurrence post transplant, ranging from s 1.5 months to 97 months post-KTx. It is either genetic mutation or acquired after infectious or autoimmune triggers.
• It has predominant C3 deposits in IF (more than 2 folds + absent Ig deposits), it either presented with membranoproliferative GN (MPGN), crescentic GN, diffuse endocapillary proliferative GN, or mesangioproliferative GN.
• It includes 2 categories: DDD and C3GN.
o DDD has intra-membranous sausage shaped deposits
o C3 GN has subendothelial deposits.
• ttt of C3 glomerulopathy in native kidney includes: MMF, corticosteroids, eculizumab, rituximab, CNI, cyclophosphamide, and conservative management.
• Although maintenance therapy in kidney transplantation includes 3 of the essential ttt of C3 glomerulopathy (triple therapy, CNI, MMF and steroids), recurrence commonly occurs.
• Ecluizimab has better allograft survival than PEX and rituximab.
• Mild cases are treated with steroids and MMF.
• Severe cases with nephrotic range proteinuria, crescents and graft dysfunction are treated with PEX, rituximab.
• Further longitudinal studies are essential to assess outcomes.
Evidence: systematic review and meta-analysis (evidence level I)
amiri elaf
2 years ago
* C3 glomerulopathy (C3G) is a rare type of
(GN) characterized by the dysregulation
of the alternative complement pathway in the glomeruli and deposition of C3 with absent or scanty immunoglobulin in the renal biopsy.
*C3G comprises of dense deposit disease (DDD), with electron microscopic findings of highly electron-dense, osmiophilic sausage-shaped deposits in the glomerular basement membrane, and C3 glomerulonephritis (C3GN) with deposits in glomerular matrix (subendothelial and few intramembranous).
* Although it is a rare disease, it can lead to (ESKD) in up to 50% of patients, also with higher recurrence rates post kidney transplantation, patients being on a triple-drug regimen, including mycophenolate mofetil, corticosteroid, and calcineurin inhibitor, C3G still commonly recurs after KTx.
*This systematic review and meta-analysis to assess the efficacy of deferent treatments for C3G recurrence after KTx. The protocol for this systematic review is registered with PROSPERO (International Prospective Register of Systematic Reviews).
Result
*A total of 207 articles were identified and screened. Twenty-three articles were assessed in detail, of which 12 studies (7 cohort studies and 5 case series) consisting of 122 KTx patients with C3G (73 C3GN and 49 DDD were included in our systematic review.
*Allograft Loss among KTx Patients with C3G
33% after eculizumab.
42% plasma exchange.
81% after rituximab.
*Allograft Loss among KTx Patients with C3GN and DDD
# Allograft loss in C3GN KTx patients were 22% after eculizumab
56% after TPE
70% after rituximab
# Allograft loss in DDD KTx patients after different treatment modalities
67% after eculizumab
0% after TPE
100% after rituximab
100% allograft loss at 6 months after rituximab followed by eculizumab.
Sixty-six patients (38 C3GN, 28 DDD) receive no treatment (due to stable allograft function at
presentation).
*Thos received treatment for C3G had significant acute kidney injury of kidney allograft and/or proteinuria than those who did not receive treatment (100% vs. 17%).
*Allograft loss among those who did not receive treatment were 32% and 53% for C3GN and DDD, respectively.
*80% patients with elevated soluble membrane attack complex of complement (sMAC) before eculizumab responded to treatment and all patients who responded to eculizumab had normal sMAC levels post-eculizumab.
Conclusions
KTX patients with C3G treated with eculizumab had the lowest incidence of allograft loss (33%)
when compared to those treated with TPE and rituximab. Among those who received no treatment for
C3G due to stable allograft function, there was an incidence of allograft loss of 32% in C3GN and 53%
in DDD.
What is the level of evidence provided by this study?
Level 1 systemic review
Alyaa Ali
2 years ago
level of evidence 1 : A systematic review and meta-analysis
summary of article, this article done for assessment of the efficacy of different
treatments for C3G recurrence after kidney transplant.
C3 glomerulopathy is a rare disease, its incidence in the US about 5 cases per million.
It cause ESRD in 50% of its cases and has a high rate of recurrence .the recurrence occurs early post-transplant account for more than 50% of causes of graft loss
It caused by dys-regulation of the alternative complement pathway in the glomeruli on light microscopy it resembles pattern of MPGN, membranoproliferativeGN, cresentic GN
diagnosed done by electron microscopy which show two fold greater intensity of C3 stain in absence of immunoglobulin and it is divided into two subtypes dense deposite disease with dense deposits in GBM and C3 GN with deposits in glomerular matrix.
outcome of most treatment studies , their evidence is lack
this study is a systemic review and met-analysis study done for assessment the efficacy of different treatments for C3 glomerulopathy after kidney transplantation
207 relevant studies after exclusion of invalid ones , the analysis done on 12 studies included 122 patients . the results showed that KTx patients with C3G who were treated with eculizumab had the lowest rate of allograft loss.the pooled estimated rates of allograft loss among kidney transplant patients with C3 glomerulopathy was 33% after Eculizumab ,42% after therapeutic plasma exchange and 81% after rituximab
up to 80% of C3G treated patients with elevated sMAC responded to eculizumab
therapy. sMAC levels have been suggested as a serum marker for alternative complement pathway activation limitation of the study
all included studies were observational or case series which susceptible to selection bias.
there is no standard treatment for C3G to allow comparison of interventions.
the rates of remissions or relapses were not reported in most of the included studies. Only the rate of graft loss was available for pooled analysis.
Balaji Kirushnan
2 years ago
Level of evidence of this article is level 1 ; As it is a systematic review and meta analysis….
Summary of the article: This article provides the latest update about the treatment options of C3 glomerulopathy after renal transplantation. c3 glomerulopathy is a complement mediated disease of the alternate pathway of the complement system which has predominant (>2+)C3 deposition in the mesangium and less or no immunoglobulin deposition.. Sethi et al re-classified MPGN as Immunoglobulin mediated and non immunoglobulin mediated disease… C3 glomerulopathy comes under the non immunoglobulin mediated disease.. It can occur due to genetic defects in the alternative complement pathway products and acquired causes which can be due to C3 nephritic factor (autoantibodies) which can trigger through infections, vaccines and other autoimmune diseases…. There have been guidelines to treat C3GN based on the severity of the disease, but the detail treatment about the post transplant recurrence is lacking… The role of eculizumab has been explored in all the recent studies…The risk of allograft loss after transplantation in C3 glomerulopathy is around 40% and it can be reduced to 22% after the use of eculizumab…
This systematic review have analyzed 122 kidney transplant recipients in 12 studies (7 cohort studies and 5 case series)…Both living and deceased donor renal transplants have been included in the analysis.. ..The median time of recurrence after transplant in these cases were ranging from 6 months to 190 months…This meta analysis revealed for the first time that the recurrence of C3GN after transplant can be reduced to 22% after eculizumab, 56% with TPE and 70% after rituximab…This data showed the more usage of eculizumab in post transplant C3G associated with improved graft outcomes…More over the usage of sMAC (soluble Membrane attack complex) measurement in the serum guides the responsiveness of the patients to eculizumab therapy in them…
limitations of the meta analysis were small case series and no standard treatment guidelines were used
Safi Annour
2 years ago
Treatment of C3 Glomerulopathy in Adult Kidney Transplant Recipients: A Systematic Review Please give a summary of this article
This is a systematic review article involving a total of 12 studies including 7 cohorts and 5 case series. It reviewed the management’s policies and it’s outcome for patients with C3GN and DDD when being associated with C3 staining.
C3GN is a rare disease with 50% progression to ESKD, due to an abnormal regulation of the complement system in which the alternative pathway is mainly involved in the pathogenesis of the disease. The disease has high recurrence rate after kidney Transplantation and associated with graft loss. Kidney biopsy with IF and electron microscopy are crucial in diagnosing C3GN, the findings tend to be dominant C3 staining and complex deposition in the membrane(intramembranous) in association with DDD. Deposits can be mesangial, sub-epithelial or sub-endothelial.
There is no standard therapy for C3GN, complement inhibitors were considered in the management of C3GN based on the underlying complement dysregulation in the pathogenesis of the disease.
Of used therapeutic agents, Eculizumab was associated with better outcome(33%) regarding post-transplant graft loss in C3GN in comparison to TPE(42%) and Rituximab(80%). In C3GN with DDD,the systematic review showed that Eculizumab is superior to TPE and Rituximab in management of C3GN and reduction of graft loss.
Study limitations:
Selection bias susceptiblity may be referred to study design( observational or case series).
No standard treatment or recommended guidelines for C3GN to compare between modalities of interventions.
Remissions and relapses were not included in most of the studies.
What is the level of evidence provided by this study?
2a(systematic review of cohort studies).
Wael Jebur
2 years ago
This study represent a systemic review and meta-analysis of 12 studies with a total of 122 patients diagnosed with post transplant C3G, focusing particularly on the modality of treatment and the outcome thereof.
C3G:
Its a rare glomerular disease represent membrano-proliferative pattern of glomerulonephritis with a predominant mesangeal complement C3 deposition. 2 Types of C3G:
1}DDD, in which the C3 deposition in mainly linear on the glomerular basement membrane , that appear thick tortuous, ribbon -like on electrone microscopy study
2}diffuse mesangeal deposition of C3 by IF study.
MPGN classification:
Depending on the IF study , 3 types C3 predominant, Immunocomplex and negative IF finding.
C3G is a rare disease that present with variable degrees of renal function impairment and proteinuria.
Alternative pathway of complement is involved as the main trigger to inflict the disease with its 2 pathways , the genetically determined with aberrant factor H and the acquired with systemic nephritic factor.Due the crucial role of complement in initiating the C3G, Eculizumab , (C5 inhibitor) is the drug of choice. Furthermore, MMF, Rituximab and prednisolon are other options used in its management.
There is no consensus on the management of C3G post transplantation, and most of the expertise was extrapolated from the treatment in general population.C3G is a rare disease , but potentially with a high recurrence rate post transplantation despite the triple immunosuppressant protocol including MMF, prednisolone and CNi, which is indicative that its non effective in preventing treating the disease recurrence post transplantation.
Recurrence rate was variable between 1.5 to 97 months.
the follow up period varied between 6 to 197 months . Life and deceased donors were included, and both DDD and C3G were involved. The allograft outcome was best reported with Eculizumab treated group then with therapeutic plasma exchange TPE and Rituximab respectively. Which is inline with the supposed underlying alternative complement pathway activation, this conclusion was further bolstered by the finding of direct correlation between systemic membrane attack complex sMAC blood level and response to eculizumab . On the other hand the allograft outcome of C3G and DDD patients who kept on conservative therapy due to mild proteinuria and normal renal function was better with C3G then with DDD variant.
limitations of this study:
1-All included studies are observational or case series.
2-No standardized therapy pertaining to C3G is agreed upon.
3-The pooled sample size is small.
4-Needs larger studies to verify the findings
The study is meta-analysis and systemic review with level of evidence 1
Manal Malik
2 years ago
1- Summary treatment of C3 glomerulopathy in adult transplant recipient: A systemic review Introduction:
C3 glomerulopathy is a rare GN characterized by complement dysregulation at level of C3 convertase mediated by genetic mutation and or trigger factors including: infection, monoclonal immunoglobulin, or autoimmune disease when C3GN develop worsening kidney function, ESRD occurred up to 50% of patients. Diagnosis of C3GN made by immunofluorescence on kidney biopsy. C3 staining with absence or new absence of immunoglobulin in DDD, there is electron microscopy of highly electron-dense, osmiophilic sausage-shaped deposits in the glomerular basement membrane and C3GN with deposit in glomerular matrix. The treatment option among non-transplant patients for C3G including: mycophenolate mofetil, corticosteroid, eculizumab, rituximab, calcincinurin inhibitors, cyclophosphamide, and conservative management.
The aim of this systemic review and meta-analysis to assess the efficacy of different treatment for C3G recurrence after transplantation. Material and methods:
The data base included OVID MEDLINE, EMBASE, and the Co chrome Data base of systemic reviews.
C3G is diagnosed by kidney biopsy-proven C3G in kidney transplant allograft without prior history of C3G.
Calculation of rate of allograft loss among kidney transplant patients with C3G sub-group analysis bared in the type of C3G and DDD.
A random effects model was used to the expected clinical heterogenicity in the included populations. Publicans bias was evaluated by using Egger-test. Results:
Potentially relevant articles identified from search of MEDLINE and EMBASE and Cochrane data base screened for retrieval and finally 12 studies 7cohat and 5 case series were included consisting of 122 kidney transplant patients with C3G and 49 DDD were included in systemic review. The estimated rats of allograft loss among kidney transplant patients with C3G were 33% after eculizumab, 42% after therapeutic plasma exchange and 81% after rituximab and allograft loss among kidney transplant patients with C3GN and DDD sub-group analysis based on the type of C3G was reformed so estimated rates of allograft loss in C3GN kidney transplant patients were 22% after TPE and 70% after rituximab. Allograft loss in DDD kidney transplant patients after treatment modalities, data were limited allograft loss after eculizumab 1 case series 67%, TYPE 0 % allograft loss case series and rituximab 100% graft loss and 100% graft loss at 6 months after rituximab followed by eculizumab. Sixty-six patients (38 C3GN, 28 DDD receive no treatment due to stable graft function or clinical judejment) so estimated rate of allograft loss those who did not receive treatment were 32% and 53% for C3GN and DDD respectively. Treated C3G patients data on (SMAC) were limited to patients treated with eculizumab 80% patients with elevated SMAC before eculizumab respond to treatment and they had SMAC levels after post eculizumab. Discussion:
Kidney transplant patients with C3G who were treated with eculizumab had the lowest rate of allograft loss 33% for eculizumab, 42% for TPE and 81% for rituximab and 40% for patients who did not receive treatment. C3G is mainly mediated by activation of the alternative complement pathway and for that reason eculizumab may be on effective treatment of C3G
Kidney transplant recipient despite the immune-systemic effects of a triple. Drug regimen C3G still news after kidney transplantation. Data ongoing treatment for recurrent C3G post kidney transplant is lacking so the role of anticomplement therapies is being explained. In this systemic review of 122 kidney transplant patients’ diagnosis post kidney transplant C3GN the estimated rates of graft loss among kidney transplant patients with C3G were lowest with eculizumab therapy as compared to plasma exchange and rituximab subgroup analysis based on the type of C3G reveled similar results. Data on allograft loss in DDD transplant patients who were treated with above therapies was limited. Use of SMAC levels to monitor eculizumab treatment in C3G is limited. Development of C3G after kidney transplantation despite use of a triple-drug regimen this finding the study suggest that the use of eculizumab for the treatment of C3G after kidney transplantation is reasonable.
Limitation of this study:
1) All included studies were observational or case series.
2) Absence of standard treatment of C3G to make comparison of inventions.
3) Data for the patients who did not receive treatment was provided as a reference.
4) Most of included studies were not maintain the rates of remission or relapses.
Although in this study eculizumab suggested to be considered as an additional therapy for C3G in kidney transplant patients, the sample size was small so future studies are required to asses and compare the efficacy and safety of these complement inhibition for the treatment of C3G among kidney transplant patients. There are currently ongoing clinical trials of complement inhibition for the treatment of C3G among non-kidney transplant patients. Conclusion:
Kidney transplant patients with C3G treated with eculizumab had the lowest incidence of allograft loss 33% when compared to those treated with TPE and rituximab.
Patients who did not received treatment for C3G, incidence of allograft loss of 32% in C3G and 53% in DDD.
A systematic review and metanalysis level 1
2- level of evidence is 1
Mohamad Habli
2 years ago
This is a systematic review with level of evidence I. The review included 12 studies consisting of 122 kidney transplant recipients diagnosed as C3 glomerulopathy of whom (73 patients with C3GN and 49 patients with DDD.
The aim of this systemic review is to determine the efficacy of different immunosuppressive strategies in the treatment of C3G recurrence posttransplant. The study evaluated graft outcome following treatment with Plasma exchange , Rituximab, Eculizumab and no therapy.
C3 glomerulopathy is a very rare glomerular disease which occurs in 5 cases per million in USA.
C3 glomerulopathy is characterized by MPGN pattern in LM, deposition of C3 in IF. EM further classify C3 glomerulopathy into DDD (intramembranous ) and C3GN (subendothelial, mesangial and sometimes subepithelial). C3 glomerulopathy is an aggressive disease with most of the patient develop ESRD, C3 glomerulopathy recur in half of the patients after transplantation.
C3 glomerulopathy is caused by dysregulation of the alternative pathway of complement system due to either mutation or acquired defect in complement protein which leads to uncontrolled activation with subsequent deposition of C3 in glomeruli causing renal injury.
The study reported following results:
Recipients with C3G who received Eculizumab had the lowest rate of graft loss of 33% comparing to other therapies, plasma exchange – 42%, rituximab – 81% and no treatment – 40%.
The estimated risk of graft loss for recipients with C3GN when treated with eculizumab was 22%, TPE – 56%, rituximab – 70% and no treatment – 32%.
Patients with elevated sMAC responded better to eculizumab therapy in up to 80% of cases.
In conclusion, Eculizumab is an effective treatment of C3 GN in the post-transplant period and more effective than rituximab or plasma exchange.
Ahmed Abd El Razek
2 years ago
Introduction
C3 glomerulopathy (C3G) is a rare glomerulonephritis. It is caused by the dysregulation of the alternative complement pathway in the renal glomeruli with prominent complement C3 deposition displayed in the renal biopsy.
Diagnosis of C3G is classically by immunofluorescence on renal biopsy. It is evident by the greater intensity of C3 staining in conjunction with absence or near absence of immunoglobulins. Dense deposit disease (DDD) on electron microscopy reveals electron-dense, osmiophilic sausage-shaped deposits in the glomerular basement membrane.
Complement dysregulation is dependent on the level of C3 convertase, which is mediated by genetic mutations and/or triggering factors including infections, monoclonal immunoglobulin, or autoimmune diseases. This disease despite being rare yet it displays a high recurrence rate post renal transplantation and it accounts for overall 50% of allograft loss.
Diverse treatment strategies as mycophenolate mofetil, corticosteroids, eculizumab, rituximab, calcineurin inhibitors, cyclophosphamide, and conservative management were tried.
Materials and Methods
This is a systematic review registered with PROSPERO till 3 May 2019. Renal biopsy with typically dominant C3 staining of at least 2 orders of magnitude above any immunoglobulin deposition with characteristic deposits either intramembranous sausage-shaped or ribbon-shaped electron-dense deposits in DDD or mesangial, subepithelial, or subendothelial electron-dense deposits in C3GN seen by electron microscopy is the term for diagnosis in this study.
Result
122 KTx patients with C3G and 49 DDDwere included in this systematic review.
Allograft Loss among KTx Patients with C3G:
The total estimated rate of allograft loss is 33% after eculizumab, 42% after therapeutic plasma exchange, and 81% after rituximab.
Allograft Loss among KTx Patients with C3GN and DDD:
22% after eculizumab, 56% after TPE, and 70% after rituximab were the estimated rates of graft loss among C3 glomerulopathies.
Data on allograft loss in DDD KTx patients after different treatment modalities were limited. Sixty-six patients (38 C3GN, 28 DDD) received no treatment being of stable allograft function at presentation.
Estimated rates of allograft loss among those who did not receive treatment were 32% for C3GN and 53% for DDD. 80% patients with elevated sMAC before eculizumab responded to treatment. All patients who responded to eculizumab had normal sMAC levels after post-eculizumab.
Discussion
KTx patients with C3G who were treated with eculizumab had the lowest rate of allograft loss. The estimated rates of allograft loss were 33% for eculizumab, 42% for TPE and 81% for rituximab. Patients who received no treatment had an estimated graft loss about 40%.
C3G is characterized by activation of the alternative complement pathways leading to C3 glomerular deposition, so highlighting the role of eculizumab in the future to be used as an effective treatment for cases with C3G.
Mild and moderate disease can be managed by supportive treatment, along with steroids and mycophenolate. Rituximab and plasma-exchange have been tried as well. Data of treatment strategies for recurrent C3G post-KTx are still limited.
This meta-analysis came up for the first time that KTx patients with C3GN had an associated allograft loss of 22% after treatment with eculizumab, 56% with TPE, and 70% with rituximab. Estimated rates of allograft loss were 32% among C3GN and 53% among DDD groups those who had no treatment at all. Recently in this review up to 80% of C3G treated patients with elevated sMAC responded to eculizumab therapy. Also sMAC levels have been suggested as a serum marker for alternative complement pathway activation. The findings of this study recommends the use of eculizumab for the treatment of C3G after KTx. Given that majority of patients with elevated sMAC prior to treatment responded to eculizumab therapy, future validation studies with a larger number of patients are required.
Study limitations are including studies which were observational or case series, the unavailability of standard treatment for C3G to allow comparison of interventions, data from patients who did not receive treatment was provided as a reference, the small sample size and finally the rates of remissions or relapses were not included.
Clinical trials of other complement inhibitors for the treatment of C3G among non-KTx patients is still ongoing. So, future studies are needed to assess and compare the efficacy and safety of these proposed various complement inhibitors for the treatment of C3G among KTx recipients.
Conclusions
KTX patients with C3G treated with eculizumab had the lowest incidence of allograft loss (33%) on comparison to those treated with TPE and rituximab. The estimated allograft loss rates are about 32% in C3GN and 53% in DDD for those renal transplant patients who were not treated.
Level of evidence 1.
Mohamed Fouad
2 years ago
Introduction
C3 glomerulopathy (C3G) is a rare glomerulonephritis (GN) characterized by the dysregulation of the alternative complement pathway in the glomeruli. It leads to complement C3 deposition in the renal biopsy samples with absent or scanty immunoglobulin deposition. Histopathologically, C3G may present as patterns of membranoproliferative GN (MPGN), crescentic GN, diffuse endocapillary proliferative GN, or mesangioproliferative GN. Diagnosis of C3G is done by immunofluorescence on kidney biopsy with predominant C3 staining in addition to absence or near absence of immunoglobulins.
With electron microscopy, C3G comprises of dense deposit disease(DDD), with findings of highly electron-dense deposits in the glomerular basement membrane, and C3 glomerulonephritis (C3GN) with deposits in glomerular matrix (subendothelial and few intramembranous). Although C3G is a rare glomerular disease, there is high recurrence rates are noted post kidney transplantation. Among KTx recipients, despite the immunosuppressive effects of a triple-drug regimen, including mycophenolate, corticosteroid, and calcineurin inhibitor, C3G still recurs after KTx
Materials and Methods
The sources for this systematic review (level of evidence ,level 1) included eligible studies must be clinical trials, observational studies (cohort, case-control, or cross-sectional studies), or case series that reported outcomes of adult (age ≥ 18 years old) KTx recipients with C3G.
Results
Kidney transplant patients with C3G who were treated with eculizumab had the lowest rate of allograft loss. The pooled estimated rates of allograft loss were 33% for eculizumab, 42% for TPE and 81% for rituximab. Patients who received no treatment had an estimated graft loss of approximately 40%.
In this systematic review, twelve studies were analysed consisting of 122 KTx patients, with the majority carrying a diagnosis of post-KTx C3GN. Living and deceased donors were included in most of the included studies, and the median time from transplantation to the recurrence of the disease varied from 1.5 months to 97 months post-KTx. The Median follow-up period was 6 to 197 months. The pooled estimated rates of allograft loss among KTx patients with C3G were lowest with eculizumab therapy as compared to plasma exchange and rituximab.
Study Limitations
1-All included studies were observational or case series in design, making them susceptible to selection bias.
2-There is no standard treatment for C3G to allow comparison of interventions.
3-data from patients who did not receive treatment other than supportive therapy was provided as a reference.
4- The rates of remissions or relapses were not reported in most of the included studies. Only the rate of graft loss was available for pooled analysis.
Conclusions:
The pooled estimated rates of allograft loss among KTx patients with C3G were lowest with eculizumab therapy(33%) as compared to plasma exchange and rituximab.
Amit Sharma
2 years ago
Please give a summary of this article
C3 glomerulopathy, including C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), a glomerular disease involving dysregulated alternative complement pathway, is associated with high rates of end stage renal failure and increased post-transplant recurrence and graft loss. The study was a meta-analysis involving the treatment modalities used and their response in kidney transplant recipients with C3 glomerulopathy.
Databases for C3 glomerulopathy in transplant patients were searched till 3 May 2019. Out of 207 articles, 12 were included in the study, involving 122 patients with 73 having C3GN and 49 having DDD.
The median time to recurrence was between 1.5 months and 97 months.66 patients were treated with either eculizumab, therapeutic plasma exchange or rituximab. 66 patients did not receive any treatment. Among the non-treated C3 glomerulopathy patients, the rates of graft loss were 40% with 32% in C3GN sub-group and 53% in DDD sub-group.
The graft loss rates of C3 glomerulopathy patients were 33%, 42% and 81% with eculizumab, therapeutic plasma exchange and rituximab respectively. In the subgroup analysis, the graft loss rates of C3GN patients were 22%, 56% and 70% with eculizumab, therapeutic plasma exchange and rituximab respectively while the graft loss rate for the DDD patients was 67% for eculizumab use and 0% and 100% for therapeutic plasma exchange and rituximab as well as rituximab followed by eculizumab (although only limited data was available for DDD).
Among the patients treated with eculizumab, the levels of soluble membrane attack complex of complement (sMAC) reduced in 80% patients after treatment.
The limitations of the study included observational nature of the study, non-use of a standard treatment modality, remission and relapse rates were not reported in the studies and a small pooled sample size.
The study concluded that even with treatment, 33% to 80% of patients with C3 glomerulopathy lose their graft, more so in the DDD group patients. The lower rates of graft loss in untreated patients is due to mild nature of the disease in them. Higher sMAC levels prior to treatment may point towards the candidates who will respond to eculizumab.
What is the level of evidence provided by this study?
The level of evidence is Level 1: This is a systematic review and meta-analysis
Riham Marzouk
2 years ago
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 which are related to dysregulated alternative complement system
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 so result in low incidence of graft loss.
saja Mohammed
2 years ago
Introduction:
C3 nephropathy is a rare type of nephritis with diverse incidence and prevalence worldwide, its due to alternative complement pathway dysregulation which lead to C3 deposition by IF staining without immunoglobulin, histological characteristic of c3 nephropathy its MPGN like pattern and associated with high rate of recurrence after kidney transplantation> 50%, so post transplantation monitoring is mandatory with prompt intervention to improve the graft outcome despite those patient on triple immunosuppression including MMF ,CNI steroids which is part of treatment options for C3GN in nontransplant patients still there is a chance of high rate of recurrence and the current treatments’ options and their effect on the C3G in kidney transplantation are missing the evidence therefore this study aims to evaluate the effectiveness of the available treatments of C3GN recurrence PostKTX. Method and selection criteria: systematic review and metanalysis for the available studies from May 2019 from international data source Midline, PubMed and Cochrane database and reviewed undependably by two reviewers .eligibilities must be clinical trials ,observational studies with case control or cross-sectional studies , case series for all adults above the age of 18 , with biopsy proven C3GN including IF , EM , DDD characteristic histological deposits in native kidneys and post KTX biopsies Data analysis:
They used the Random effect module to avoid the clinical heterogenicities with population selection. Also using I2 statistic and the chi-square test to overcome the heterogenicity of effect size among individual studies. Publication bias was assessed by using egger test with P value < 0.05 indicate publication bias. Results:
Only 12 studies included in the systematic review out of 277 studies, 7 cohort studies and 5 case series with total of 122 patients with C3G (73 C3G and another 57/ DDD).
This study shows the lowest rate of graft loss in eculizumab treatment group (33%) compared to 42% in TPE and 80% in rituximab group. while patients whom received no treatment the overall graft loss reached 40%. In subgroup analysis based on C3 GN subtypes shows no difference among the available treatment options. The soluble membrane attack complex level (s MAC) was higher among those c3gn patient whom received eculizumab (80%) of cases with complete normalization of s MAC after eculizumab therapy among responders.
66% of cases received no treatments as they are stable graft function upon FU and as per physician decision, 37 /73 with C3GN and 28/DDD shows 32% and 56 % graft loss respectively.
Limitation:
1-Small sample size and the pool of the studies from small case series and observation cohorts with high risk of selection bias.
2-no homogenous treatment for C3GN to permit comparison with interventions
3-Rate of relapse and remission not recorded.
Conclusion:
lower incidence of graft loss reported in eculizumab cohorts compared to other treatments option, the role of anti c5 complement targeting therapy with eculizumab consider promising therapy for C3GN and the use of sMAC as prognostic indicator for treatment response we need to explore its effect by large clinical studies with homogenous designs and longer follow up.
What is the level of evidence provided by this study?
Level 1C, systematic review but still limited to cohort studies with case series.
Batool Butt
2 years ago
C3 glomerulopathy-a rare disease- is defined by the presence of two-fold greater intensity of C3 deposition without immunoglobulin on immunofluorescence in renal biopsy samples and occurs due to dysregulation of the alternative complement pathway .Two diseases fall under this category which are differentiated on the basis of electron microscopy findings. C3G can be because of genetic causes (mutations/variants )and acquired causes (C3Nef/autoantibodies) with precipitating factors like infections, monoclonal immunoglobulin, and autoimmune diseases .50% patients develop ESRD and also had high recurrence rate comprising about 50% allograft loss.
This systemic review included included 12 studies (7 cohort studies and 5 case series)comprising 122 Kidney transplant patients with C3G (73 C3GN and 49 DDD )with the aim to determine the efficacy of different agents in treatment of C3G recurrence post transplant. RESULTS:
This study showed different response rate with different regimens and eclizumab having better response and lower graft loss (33%) among all others .Rest showing PLEX(42% ), 81% for rituximab and 40% with no treatment.
Data is scarce on the management strategies for C3GN . KDIGO recommendation is to treat the patient according to severity. Steroids and mycophenolate along with supportive treatment is for mild and moderate disease. Pulse solumedrol with other immunosuppressive therapies including Rituximab and plasma-exchange for severe disease . Trials on Eclizimab role for post transplant C3Gn is going on as exact management for recurrent C3GN post transplantation is lacking. C3GN had allograft loss 32% and DDD had 53% allograft loss. sMAC levels has been used in various studies as a marker for alternative complement pathway activation and our study showed eculizumab response in 80% of C3G treated patients with elevated sMAC .
What is the level of evidence provided by this study?
LEVEL OF EVIDENCE:1
Nandita Sugumar
2 years ago
Summary
This article is a meta analysis based on observational or case series design studies.
Aim :
Analyse the different treatment options for C3 glomerulopathy in kidney transplant recipients and their corresponding outcomes with respect to allograft loss.
Disease spectrum :
C3 is a rare glomerular disease caused by disruption to alternate complement pathway.
High rate of recurrence following kidney transplant
Disease recurrence can occur between 1.5 months to 97 months post transplant.
Associated with high risk of graft loss.
Complement dysregulation can be caused by
genetic mutations
Infections
Monoclonal immunoglobulin
Autoimmune disease
Diagnosis
Diagnosed by kidney biopsy.
Biopsy reveals prominent deposition of C3 in glomeruli with absent or scanty deposition of immunoglobulin.
C3 can be categorized as DDD and C3GN.
DDD or dense deposit disease – highly electron dense osmiophilic sausage shaped deposits in the GBM.
C3GN or C3 glomerulonephritis – deposits in the glomerular matrix in the subendothelial and intramembranous area.
Treatment
Multiple treatment options including MMF, corticosteroids, eculizumab, rituximab, CNI, cyclophosphamide, and conservative treatment.
Lowest incidence of allograft loss is seen with eculizumab treatment, which when contrasted with plasma therapy and rituximab is seen to be the better alternative.
KDIGO guidelines recommend management according to disease severity.
Severe disease is characterized by 24 hour urine protein geraten than 2g or severe endocapillary proliferation with or without crescentic formation.
C3G can recur post kidney transplant despite tripe IS – MMF, corticosteroids and CNI.
sMAC level is a serum marker for alternative complement pathway activation.
sMAC level can be used to select patients for eculizumab therapy. Elevated sMAC levels in patients, when treated with eculizumab, yields good results.
Study conclusions
Kidney transplant recipients with C3G have lower incidence of allograft loss when treated with eculizumab in contrast with TPE and rituximab therapy.
Limitations of study
Possible selection bias
Rates of remissions or relapses not reported. Study only included follow up until 197 months post kidney transplant.
Small pooled sample size which could influence outcome or conclusion of study.
Level of evidence :
This article is a meta analysis. Hence level of evidence is 1.
Weam Elnazer
2 years ago
Introduction:
C3 glomerulopathy is uncommon glomerulonephritis caused by alternative complement system dysfunction. Although uncommon, post-kidney transplantation recurrence rates are significant, thus post-transplant monitoring and careful use of medicines are needed to optimize clinical outcomes.
The result:
-C3GN is identified by kidney biopsy with C3 staining with EM deposits. De novo C3GN is freshly diagnosed C3GN following kidney transplantation without a previous history of C3G.
-The meta-analysis intended to investigate the effectiveness of various medications in treating C3G recurrence after transplant.
It includes 12 trials with 122 kidney transplant patients, most with C3GN.
-Eculizumab reduces graft loss in C3G patients.
In C3G patients treated with eculizumab, TPE, or rituximab, graft loss was 33%, 42%, 81%, and 40% in those who received no therapy.
-80% of C3G patients with high sMAC reacted to eculizumab, although sMAC level is not utilized to monitor treatment since it has no association with disease severity. –In C3GN patients, eculizumab had a 22% graft loss rate, TPE 56%, rituximab 70%, and no therapy 32%.
-Study limitations include bias and the absence of recurrence or remission data. limited sample size, lack of standardized therapy.
Conclusions
Ecluzimab reduces allograft loss after C3 GN renal transplant.
Introduction C3G is a rare GN (5 cases/million in US) caused by the alternative complement pathway dysregulation. It consists of 2 subtypes: – DDD (electron-dense deposits in the GBM) – C3GN (subendothelial deposits) Clinical pattern: – 50% develop ESRD. – Highly recurrent post-transplant. Microscopic patterns of C3 G: – MPGN – Crescentic GN – Diffuse endocapillary proliferative GN – Mesangioproliferative GN IF patterns of C3GN: – Prominent C3 deposition – Absent or scanty immunoglobulin deposition ————————————————- Methodology: This is a systemic review of several databases search of the studies of post-transplant outcomes of patients with C3G. The protocol for meta-analysis is registered with PROSPERO. Eligible studies included for analysis:
– Clinical trials
– Observational studies (cohort, case-control, or cross-sectional)
– Case series. Extracted data:
– 1stauthor name
– Publication year
– Number of patients
– Follow-up duration
– Transplant’s type
– Mean age
– Sex
– Recurrence of C3G
– Time transplant to from recurrence
– treatment of G3G. Statistical Analysis Estimate rates of allograft loss were calculated. Subgroup analysis (C3GN & DDD) was done. A random-effects model was used (due to hetero-geneity in the study populations). MetaXL software used for meta-analysis. ——————————————————– Results & Dicussion: A 207 articles were identified;23 articles assessed in detail, of which 12 studies (7 cohort & 5 case series) consisting of 122 transplant patients with C3G (73 C3GN & 49 DDD) were included in the systematic review. Allograft Loss among C3G patients:
– 33% after eculizumab
– 42% after PP
– 81% after rituximab Allograft Loss among subgroups of C3G 1. C3GN:
– 22% after eculizumab
– 56% after PP
– 70% after rituximab 2. DDD: – 4/6 (67%) after eculizumab – 0/2 (0%) after PP – 3/3 (100%) after rituximab – 2/2 (100%) allograft loss at 6 months after rituximab followed by eculizumab. 66 patients (38 C3GN, 28 DDD) received no treatment (stable graft function at presentation). Patients treated for C3G had significant AKI of allograft &/or proteinuria than those not treated (100%vs.17%). Allograft loss among those not treated was 32% for C3GN & 53% for DDD. Soluble membrane attack complex of complement (sMAC): 80% patients with elevated sMAC levels before eculizumab responded to treatment; all responders had normal levels post-eculizumab. Imitations: All included studies were observational or case series, thus susceptible to selection bias. No standard therapy for C3G to compare with interventions. Rates of remissions or relapses were not reported in most of the studies; only the rate of graft loss was available for analysis. Conclusions C3G transplant patients treated with eculizumab had the lowest incidence of allograft loss compared to those treated with PP & rituximab. Among no-treated C3G patients the incidence of allograft loss was 32% in C3GN & 53% in DDD. ============================ What is the level of evidence provided by this study? Level 1: systemic review
C3glomerulopathy is one of the rare glomerular diseases and consists of two entities; C3GN and DDD. It occurs due to dysregulation of the alternative complement pathways( genetic mutation or autoantibodies). C3GN is associated with a high risk of recurrence and allograft loss following transplantation. The objective of this systematic review was to evaluate the efficacy of various treatment modalities for recurrent C3G
Methodology
Extensive search for databases from MEDLINE, EMBASE, and Cochrane was done on 3 May 2019
The study was performed by PRISMA = Prefered Reporting Items for Systematic Review and Meta-analysis
After identification and screening, studies which looked at outcomes of post TX C3GN were included
Random-effects model was considered for assessment of heterogeneity
This protocol was registered under PROSPERO( no.42019125718)
Results
The final protocol involved 12 studies(7cohort and 5 case series) with atotal of 122 recipients of C3G ; 73 cases of C3GN and 49 cases of DDD.
The pooled estimated rates of allograft in those with C3GN were 33% for eculizumab, 42% for therapeutic plasma exchange, and 81% for rituximab.
In subgroup analysis, similar findings were seen in C3GN, while data on graft loss in DDD were limited to one case series and one cohort
Those who didn’t receive treatment (66= 38 C3GN and 28 DDD) due to stable allograft function had an estimated allograft loss of ~ 40%
Data on sMAC= soluble membrane attack complex were limited to patients treated with eculizumab and around 80% of those with high levels of sMAC before eculizumab benefited from the drug.
Those who benefited from eculizumab had normal levels of sMAC after treatment
Discussion
Patients treated with eculizumab had the lowest rate of allograft loss. The difference in the clinical response may be attributed to the mechanism of C3G
At the moment, there is no strong evidence for the treatment options for recurrent C3G, but this study showed for the first time that recurrent had an associated allograft loss of 22% for eculizumab, 56% for TPE, and 70% for rituximab
The problem is that triple immune suppression ( CNI, MPA, Pred) are not effective in preventing or mitigating the risk of recurrent C3G
There is no correlation between sMAC levels and disease severity, although patients in the eculizumab arm had normal levels of sMAC after treatment
Limitation
The studies are observational or case series = risk of selection bias
No standard treatment for C3G to allow for comparison
Support therapy or no treatment group served as a reference
Recurrence rates were not reported in most studies
Small pooled sample size
Conclusions
Recurrent C3G treated with eculizumab had the lowest rate of allograft loss compared to those treated with TPE, and rituximab
No treatment groups due to stable allograft functions had allograft loss of 32% for C3GN, and 53% for DDD
C3 glomerulopathy is rare glomerulonephritis characterized by the dysregulation of the alternative complement pathway in the glomeruli. Although it is rare, substantially high recurrence rates are noted post kidney transplantation, thus, post-transplant monitoring and appropriate implementation of the available therapies are necessary to improve clinical outcomes.
Study design: systematic review and meta-analysis.
Aim: To assess the efficacy of different treatments for C3G recurrence after KTx.
Materials and methods: A comprehensive search of several databases including Ovid Medline, Embase, and Cochrane till May 2019. A systematic literature review was conducted independently by two investigators, using the search strategy that consolidated the terms (kidney transplantation, renal transplantation, kidney graft, kidney graft rejection) and (C3 glomerulopathy, or C3 glomerulonephritis, dense deposit disease).no restrictions on language, sample size, or study duration.
The study was conducted by the PRISMA statement.
C3GN is diagnosed by kidney biopsy with typically dominant C3 staining with characteristic deposits as seen by electron microscopy. Recurrent C3GN is diagnosed by biopsy-proven C3GN in kidney transplant allograft without prior history of C3G, and de novo C3G is defined by newly diagnosed C3GN after kidney transplantation without prior history of C3GN.
Study Selection: clinical trials, observational studies, and case series that reported outcomes of adult (age ≥ 18 years old) KTx recipients with C3GN are the eligible studies for this meta-analysis. Inclusion was not limited by language, sample size, or study duration.
Data Extraction: first author name, year of publication, number of patients, duration of follow-up, type of transplant, mean age, sex, recurrence of C3G after KTx, time from KTx to recurrence, and treatment of G3GN.
The primary outcome was graft failure.
Results: Twelve studies (7 cohort studies and 5 case series) consisting of 122 KTx patients with C3GN (73 C3 glomerulonephritis and 49 DDD) were included.
The rate of allograft loss among KTx patients with C3GN was 33% after eculizumab, 42% after therapeutic plasma exchange, and 81% after rituximab.
Pooled estimated rates of allograft loss in DDD KTx patients were 53% after eculizumab.
Among 66 patients (38 C3GN, 28 DDD) who received no treatment, pooled estimated rates of allograft loss were 32% and 53% for C3GN and DDD, respectively.
80% of patients with elevated soluble membrane attack complex of complements before eculizumab responded to treatment and have normal sMAC levels after eculizumab treatment.
Conclusion: lowest incidence of allograft loss (33%) among KTX patients with C3GN who were treated with eculizumab. Among those who received no treatment for C3GN due to stable allograft function, there is a high incidence of allograft loss of 32% in C3GN and 53% in DDD. sMAC level may help to select good responders to eculizumab.
What is the level of evidence provided by this study?
Ø Summary
-C3 glomerulopathy is associated with Complement deposition in renal biopsy with immunofluorescence in absence of immunoglobulin .
-Being a rare disease ,C3G leads to deterioration of kidney function and leading to end-stage kidney disease (ESKD) in up to 50% of cases with high recurrence risk post transplantation.
-C3G has high recurrence rate inspite of keeping the patients on a triple-drug regimen, including mycophenolate mofetil, corticosteroid, and calcineurin inhibitor in renal transplant recipients .
– 122 KTx patients were included, most of them experiencing post-KTx C3GN with disease recurrence ranging from 1.5 months to 97 months post-KTx.
–Results of this systematic review revealed that estimated rates of allograft loss among KTx recipients with C3G were 33% after eculizumab, 42% after therapeutic plasma exchange (TPE), and 81% after rituximab
-A subgroup analysis was done revealed that the rates of allograft loss in C3GN KTx patients were 22% after ecluzimab ,56% after TPE and 70% after Rituximab while for DDD KTx patients the available studies were limited but showed that ; allograft loss after eculizumab was 67%, after TPE was 0%, after rituximab was 100% , and 100%allograft loss at 6 months after rituximab followed by eculizumab
– Allograft loss rates for patients who did not receive treatment were 32% for C3GN and 53% for DDD.
-80% of C3G treated patients with elevated sMAC responded to eculizumab therapy.
–Discussion
C3 GN post KTx cases treated with Ecluzimab had the lowest rejection rate.
MPGN was reclassified as immunoglobulin and non-immunoglobulin mediated disease .
Etiologies of C3GN are either genetic or acquired
-KDIGO advise for the management of C3G according to disease severity .
For mild to moderate cases , supportive treatment, with steroids and MMF ,Rituximab and plasma-exchange did not lead to definite results .
For severe cases , pulse solumedrol and other immunosuppression therapies results weren’t promising.
-Most cases with elevated sMAC before treatment responded to eculizumab therapy meanwhile MAC level correlation with disease severity need to be investigated
-Study limitations include liability to study bias, small sample size included ,lack of standardised treatment, unavailability of data on relapse or remission of the cases.
Conclusions
Ecluzimab usage for treatment of C3 GN post renal transplant can lower rate of allograft loss
C3 glomerulopathy (C3G) is a rare disease, mediated by dysregulation of alternative complement pathway which lead to C3 glomerular deposition.
It includes C3 glomerulonephritis (C3GN) and dense deposit disease (DDD)
The incidence and prevalence are not well determined.
It leads to ESKD in 50% of patients with high rate of recurrence post transplant and may lead to graft loss.
The systemic review and met-analysis aimed to determine the efficacy of different agents in treatment of C3G recurrence post transplant
It included 12 studies consisting of 122 kidney transplant recipients with the majority having C3GN post transplant.
The study showed that:
Recipients with C3G who received eculizumab had the lowest rate of graft loss.
The estimated rate of graft loss in recipients with C3G treated with eculizumab was 33%, therapeutic plasma exchange (TPE) was 42%, rituximab was 81% and in those who had no treatment was 40%
Recipients with C3GN, the estimated risk of graft loss when treated with eculizumab was 22%, TPE was 56%, rituximab was 70% and no treatment was 32%
80% of patients with C3G who had elevated sMAC responded to eculizumab therapy, however, sMAC level is not used to monitor eculizumab treatment as no correlation was established between sMAC level and disease severity.
The use of eculizumab in treatment of C3G post transplant is reasonable.
Limitations:
Included observational studies and case series which are susceptible to selection bias.
Couldn’t compare between interventions as no standard treatment is available.
Rates of remissions and relapses were not reported in included studies.
C3 Glomerulopathy results from dysregulation of alternate compliment pathway leading to C3 deposition in renal biopsy. It can be membranoproliferative, cresentic, diffuse endocapillary and mesangioproliferative. Diagnosis is made by immunofluorescence on kidney biopsy. There are two types. Dense deposit disease
Eosinophilic sausage shaped deposits in glomerular basement membrane. C3GN-
Deposits in glomerular matrix
C3GN is rare but has high recurrence rate after renal transplant. Current evidence is lacking on outcome post transplant.
Systemic review registered with PROSPERO
The study evaluated the graft outcome after Plasma exchange , Rituximab, Eculizumab and after no therapy.
Results.
The rate of graft loss in renal transplant patient with C3G was-
After Eculizumab-33%
After Therapeutic plasma exchange -42%
After Rituximab 81% and also the rate of graft loss was lower in this group.
Graft loss rates were high in dense deposit group as compared to C3GN. Conclusion.
Eculizumab is more effective than Rituximab and plasma exchange in treatmnet of C3 Glomerulonephritis recurrence post transplant
C3 glomerulopathy is a rare disease occurring in 5 cases per million in USA
Characterized by MPGN pattern in LM, deposition of C3 in IF and they are further classified by EM according to the location of dense deposits into DDD (intramembranous ) and C3GN (subendothelial, mesangial and sometimes subepithelial)
Caused by dysregulation of the alternative pathway of complement system due to either mutation or acquired defect in complement protein (the presence of antibodies that either stabilize C3 convertase or inhibit complement regulatory proteins) leading to uncontrolled activation with subsequent deposition of C3 in glomeruli, thus it share the same pathogenesis of a HUS, but the difference that C3G occurs in the fluid phase not in the solid phase like HUS
C3 glomerulopathy is an aggressive disease with most of the patient develop ESRD, C3 glomerulopathy recur in half of the patients after transplantation
This is a systematic review (level of evidence I) including 12 studies consisting of 122 kidney transplant recipients diagnosed as C3 glomerulopathy of whom (73 patients with C3GN and 49 patients with DDD.
The study evaluated the rate of graft loss after eculizumab, plasmapheresis, Rituximab therapy and after no treatment (only for patients with stable graft function)
Before and after Eculizumab treatment, soluble membrane attack complex of complement was measured
Results
The rate of graft loss was highest in Rituximab group (81%), followed by plasmpahresis (42%) and then Eculizumab group (33%)
Graft loss was higher in patients with DDD when compared to C3GN
Graft loss in patients not receiving treatment because of stable graft function was more common in DDD (53%)than in C3GN (32%)
80% of patients with high sMAC level before Eculizumab responded well and sMAC level normalized in patients responded to Eculizumab. So sMAC level can be used as a marker for anticipation of the response to Eculizumab.
C3G is a rare GN result from dysregulation of alternative complement pathway in glomeruli. It may presented with different histopathological pattern: MPGN, crescent GN, diffuse endocapillary proliferative GN or mesangiproliferative GN.C2G include 2 distinct diseases: C3GN & DDD. 50% of cases end with ESRD with high post transplant recurrence.
Systemic review study with meta-analysis. All included studies were clinical trial or case series with adult outcome renal transplant recipients. The study include 122 patients diagnosed with post transplant recurrence C3G ( live & deceased donor kidneys) with median follow-up period 6-197 months
Result & discussion:
There are difference in clinical response to treatment which may be due to underlying pathogenesis of C3G.
C3G can be classifies into: genetic ( abnormality in alternative complement pathway) & acquired (C3Nef) with triggering factors e.g. infection & auto-immune disease.
Strong evidence studies for post transplant recurrence treatment is absent.
KDIGO recommend treatment according to severity ( mild-moderate severity treated with supportive measures in addition to steroid & MMF)
Severe cases has poor response to pulse MP & other immunosuppression
PE & rituximab using had mixed results.
In this study, graft loss was lower with eculizumab(23%) than PE (56%) & rituximab (70).
Graft loss was lower in C3GN( 32%) than DDD (53%).
80% of patients with C3GN & high level of sMAC show good response to treatment with eculizumab, but correlation of sMAC level & disease severity is not established.
According to this results, the use of eculizumab is reasonable in treatment of post transplant recurrent C3G.
Limitation of the study:
All studies included were observational or case series which make them susceptible to selection bias
No standard treatment for C3G allows comparison of intervention
Studies include patient receive supportive treatment or no treatment were used as a reference
Relapse & remission not reported in most studies.
Due to small size pool, more controlled trails to assess efficacy of eculizumab, TPE & rituximab are needed.
C3 nephropathy is a rare disease and its due to a complement dysregulation.
it’s has a high grade of recurrence post transplant
it’s may related to genetic mutation/ infection/ monoclonal immunoglobulin and autoimmune disease
it’s diagnosis by renal biopsy ( electron microscopy and immunofluorescence ); it’s shows deposits of C3 in basement membrane and it may shows membranoproliferative GN / crescent GN and endocapillary GN
it’s associated with graft loss and ESRD post transplant
It’s need close monitoring and fallow up with close adherence to immunosuppressive agents to avoid recurrence of C3 nephropathy.
This article is systemic literature review and meta analysis done in 2019 focus on efficacy of immunosuppressive therapy to prevent recurrence of disease.
Treatment of non kidney transplant C3 nephropathy are steroid / calcinurine inhibitors and MFF / cyclophosphamide and rituximab and eculizumab.
Post transplant treatment of recurrence are steroid/ MFF and calcinurine inhibitors.
Study selection// this study not limited by language or samples size or study duration.
C3 nephropathy proven by renal biopsy with dominant C3 staining.
Dense deposits disease diagnostic by electron microscopy seen in mesangial/ sub epithelial/ sub endothelial.
Results// this article review cases in detail between cases of C3 nephropathy and dense deposits disease and shows effects of drug on recurrence of these diseases post transplant whether cases live donor or deceased donor.
Date on graft loss in DDD are limited but shows response to eculiumab more than use of rituximab and plasma exchange.
Patients who not receive treatment because stable graft function regardless to personal data and type of kidney transplant shows 40% evidence of graft loss with time.
Those patients with high level of soluble membrane attack complex of complement were limited but shows responded to eculizumab and return of sMAC level to normal post eculizumab.
Discussion//
Patients who receive eculizumab had lower rate of loss graft post eculizumab.
The pooled estimated rate of allograft loss high with rituximab 80% followed by TPE 40% and 33% by eculizumab.
MPGN classified by sethi et to immunological and non immunological mediated disease.
C3 GN is characterised by activation of alternative complement pathway leading to C3 glomerular deposition; So eculizumab is effective treatment of C3G.
KDIGO guidelines recommended C3 G depend on severity of disease.
Mild to moderate needs support treatment by steroid and MFF
In mixed disease treatment by rituximab and plasma exchange.
Severe disease with proteinuria more than 2 g and severe endocapillary proliferation with or without crescent formation need pulse therapy of steroid and immunosuppressive drug.
Among transplant patients still there is evidence of recurrence of C3GN and responded to eculizumab and evidence of graft loss low with eclizumab and high with rituximab and plasma exchange.
Even with limited data on allograft loss in DDD kidney transplant patients but they get benefits from eculizumb.
Conclusion// Eculizumab is effective in treatment of C3 GN recurrence post transplant in comparison to rituximab and plasma exchange
C3 glomerulopathy (C3G) is rare glomerulonephritis (GN) characterized by the dysregulation of the alternative complement pathwayin the glomeruli.
Diagnosed by histopathology only and mainly by Immunohistochemistry microscopy in which there is prominent complement C3 deposition in the renal biopsy samples with absent or scanty immunoglobulin deposition.
L/M is usually present in C3G as patterns of membranoproliferative GN (MPGN), crescentic GN, diffuse endocapillary proliferative GN, or mesangioproliferative GN.
C3G comprises of
· dense deposit disease (DDD), with electron microscopic findings of highly electron-dense, osmiophilic sausage-shaped deposits in the glomerular basement membrane
· C3 glomerulonephritis (C3GN) with deposits in the glomerular matrix (subendothelial and few intramembranous). The prevalencein the United States (US) is estimated at 5 cases per million. patients with C3G can develop worsening kidney function leading to end-stage kidney disease (ESKD) in up to 50% of patients. Pathogenesis is mediated by Complement dysregulation in the fluid phaseat the level of C3 convertase, predominantly mediated by genetic mutations and/or triggering factors including infections, monoclonal immunoglobulin, or autoimmune diseases.
C3G is associated with high recurrence rates are noted post kidney transplantation (KTx). Thus, post-transplant monitoring is necessary to improve clinical outcomes. Histopathological illustration of C3G recurrence can be detected early post-KTx (1.5 months to 97 months post-KTx), with C3G accounting for an overall 50% of allograft loss.
KDIGO recommends the management of C3G based on disease severity.
· For mild and moderate disease, supportive treatment, along with steroids and mycophenolate, is advised.
· Rituximab and plasma exchange have been tried with mixed results.
· In severe disease with 24 h urine protein >2 g or severe endocapillary proliferation with/without crescent formation, limited success has been described with pulse solumedrol and other immunosuppression therapies like cyclophosphamide and rituximab.
However, among KTx recipients, despite the immunosuppressive effects of a triple-drug regimen, including mycophenolate, corticosteroid, and calcineurin inhibitor, C3G still recurs after KTx And there is no sufficient data on guiding treatment. Regarding management post-transplant
Results: Twelve studies (7 cohort studies and 5 case series) consisting of 122 KTx patients with C3G (73 C3 glomerulonephritis (C3GN) and 49 dense deposit disease (DDD)) were included.
The pooled estimated rates of allograft loss among KTx patients with C3G were 33% after eculizumab, 42% after therapeutic plasma exchange (TPE), and 81% after rituximab. Subgroup analysis based on the type of C3G was performed. Pooled estimated rates of allograft loss in C3GN KTx patients were 22% after eculizumab, 56% after TPE, and 70% after rituximab. Pooled estimated rates of allograft loss in DDD KTx patients were 53% after eculizumab. Data on allograft loss in DDD after TPE (1 case series, 0/2 (0%) allograft loss at 6 months) and rituximab (1 cohort, 3/3 (100%) allograft loss) were limited.
Among 66 patients (almost 50% of the total pool which includes 122 patients) (38 C3GN, 28 DDD) who received no treatment(due to stable allograft function at presentation and/or clinical judgment of physicians), pooled estimated rates of allograft loss were 32% and 53%(the same exact number if treated with eculizumab so treatment may be of no value for DDD) for C3GN and DDD, respectively.
Among treated C3G 2 of 15 patients, data on soluble membrane attack complex of complement (sMAC) were limited to patients treated with eculizumab (N = 7). 80% of patients with elevated sMAC before eculizumab responded to treatment. In addition, all patients who responded to eculizumab had normal sMAC levels post-eculizumab.
Limitations
· Patients who didn’t receive treatment almost 50% of the study group so medications efficacy is only evaluated based on almost 60 patients
· all included studies were observational or case series in design, making them susceptible to selection bias.
· there is no standard treatment for C3G to allow comparison of interventions.
· No control groups
· the rates of remissions or relapses were not reported in most of the included studies. Only the rate of graft loss was available for pooled analysis.
· the pooled sample size remains small, and further controlled trials describing the efficacy of eculizumab, TPE, or rituximab are warranted.
Conclusions
KTX patients with C3G treated with eculizumab had the lowest incidence of allograft loss (33%) when compared to those treated with TPE and rituximab. Among those who received no treatment for C3G due to stable allograft function, there was an incidence of allograft loss of 32% in C3GN and 53% in DDD.
What is the level of evidence provided by this study?
level II because it’s based on a case reports and observational studies
Treatment of C3 Glomerulopathy in Adult Kidney Transplant Recipients: A Systematic Review
This is a systematic review and meta-analysis to assess the efficacy of different treatments for C3G recurrence after kidney transplantation.
Data from twelve studies contain ( 7 cohort studies and 5 case series) consisting of 122 Ktx patients with C3G .
A-(73 C3 glomerulonephritis (C3GN) .
B-(49 dense deposit disease (DDD).
Patients received different medication from the following (eculizumab, therapeutic plasma exchange (TPE) , rituximab and conservative treatment ).
Efficacy of treatment assessed by detecting the rate of graft loss after treatment.
Overall , rates of allograft loss among Ktx patients with C3G were 33% after eculizumab, 42% after therapeutic plasma exchange (TPE), and 81% after rituximab.
Also eculizumab showed lowest incidence of graft loss in sub-groups of C3GN and DDD.
A 66 patients who received no treatment has a high incidence of allograft loss of 32% in C3GN and 53% in DDD.
Meta-analysis concluded that patients who developed post kidney transplant C3G and treated by eculizumab had the lowest rate of allograft loss.
Still we need more/large randomized controlled trials for strong evident protocol for treating post kidney transplant C3G. Level of evidence I A systematic review and meta-analysis.
C3 glomerulopathy (C3G) is a rare glomerular disease. it is mediated by dysregulation of the alternative pathway of complement activation. it includes 2 main disorders ; C3 glomerulonephritis (C3GN ) and dense deposit disease (DDD).
C3G has a high rate of recurrence and graft loss after kidney transplantation.
the aim of this review was to assess the efficacy of differrent therapies for C3G.
this review included 12 studies, 7 cohort and 5 case series. 122 patients were included of whom 73 patients have C3GN and 49 patients have DDD.
for all patients ( C3G), graft loss occurred in 33% after Eculozumab, 42% after plasmapharesis and 81% after Rituximab.
for patients with C3GN, graft loss occurred in 22% after Eculozumab, 56% after plasmapharesis and 70% after Rituximab.
lower incidence of graft loss occurred with Eculizumab in all patients.
for those patients who received no ttt owing to stable kidney functions, there was a higher incidence of graft loss.
What is the level of evidence provided by this study?
Introduction
-C3 glomerulopathy is a rare complement dysregulation related glomerulonephritis characterized by prominent C3 deposition with absent or scanty immunoglobulin deposition
-C3G includes dense deposit disease and C3 glomerulonephritis (C3GN)
-It is aggressive diseases weather in the native kidney with an ESRD risk of 50% in cases , and also after transplant with a recurrence rate and graft failure rate of 50%
-It recurs after Tx despite triple immunosuppressive therapy and unfortunately no consensus on treatment for its recurrence till now this is a meta-analysis and systematic review for assessment of treatment efficacy in the literature Results:
-23 Of 207 relevant articles were assessed, 11 were excluded.
122 ktx were included through 12 studies, 73 C3GN, and 49 DDD.
-soluble membrane attack complex of complement (sMAC) were assessed in only patient treated with eculizumab and was elevated in 80% of them before treatment abd was normalized in all successfully treated patients. Discussion:
The patients who responded to treatment with eculizumab were who have complement dysregulation either due to genetic causes or
and acquired causes (C3Nef/autoantibodies) with possible triggering factors including infections,
monoclonal immunoglobulin, and autoimmune diseases
level of evidence 1 (systematic review and meta-analysis study limitation:
1 no comparative studies, all were observational or case series.
2-No standard treatment for C3G to allow comparison of interventions.
3- no detailed data about those who didn’t receive treatment other than supportive
4- remissions or relapses have not been reported in the studies.
5-duration of follow-up and time elapsed till graft failure.
We aimed to assess the efficacy of different treatments for C3G recurrence after Kidney transplant patient.
C3 glomerulopathy is a rare glomerulonephritis, characterized by the dysregulation of the
alternative complement pathway in the glomeruli.
It leads to prominent complement C3 deposition in the renal biopsy samples with absent
or scanty immunoglobulin deposition
Microscopically, C3G may present as patterns of membranoproliferative GN , crescentic
GN, diffuse endocapillary proliferative GN, or mesangioproliferative GN.
Methods:
Meta-analysis.
Results:
Twelve studies (7 cohort studies and 5 case series) consisting of 122 kidney transplant
patients with C3G (73 C3 glomerulonephritis (C3GN) and 49 dense deposit disease
(DDD)) were included.
The pooled estimated rates of allograft loss among Kidney transplant patients with C3G
were 33% (95% CI: 12–57%) after Eculizumab, 42% (95% CI: 2–89%) after therapeutic
plasma exchange (TPE), and 81% (95% CI: 50–100%) after rituximab.
80% of patients with elevated sMAC before Eculizumab responded to treatment.
In addition, all patients who responded to Eculizumab had normal sMAC levels after
post-Eculizumab.
Conclusions:
the study suggests that the lowest incidence of allograft loss (33%) among kidney
transplant patients with C3G are those treated with Eculizumab.
Among those who received no treatment for C3G due to stable allograft function, there is
a high incidence of allograft loss of 32% in C3GN and 53% in DDD. SMAC level may
help to select good responders to Eculizumab.
This study is a systematic review with a level 1 of evidence.
C3 glomerulopathy is a rare glomerulonephritis that result from dysregulation of the alternative complement pathway. It is associated with poor kidney outcomes (ESRD in approximately 50% of patients) and substantially high recurrence rate after kidney transplantation. It is classified to C3 glomerulonephritis and DDD.
The diagnosis of C3 glomerulopathy is made by IF on kidney biopsy with two-fold greater intensity of C3 staining in combination with absence or near absence of immunoglobulins. In EM, C3GN is characterized by deposits in glomerular matrix (subendothelial and few intramembranous) while DDD is distinguished by typical finding of osmiophilic sausage-shaped deposits in the glomerular basement membrane.
According to the etiology, C3GN can be classified into genetic causes and acquired causes probably due to triggering factors such as infections, monoclonal gammopathies, and autoimmune diseases.
According to high post-transplant recurrence rate, monitoring of the patient and implementation of available therapeutic options is crucial to improve kidney allograft survival. Recurrence commonly occurs early post-transplantation.
Based on this study, the impact of different agents on treatment of C3 glomerulopathy in kidney allografts is different and also depend on various subclasses (DDD or C3GN).
Management of C3GN is based on severity of disease. For mild disease supportive therapy and for moderate disease supportive therapy along with MMF and steroids is suggested. Rituximab and plasma exchange was associated with mixed results. In severe disease with proteinuria more than 2 gr/day and endocapillary proliferation, limited success with immunosuppressive agents. In kidney transplant recipient, despite triple therapy with MMF, CNI, and prednisolone, the recurrence rate is high. In this setting, the role of anti-complement therapy was proposed.
Eculizumab is more effective than plasma exchange and rituximab in the treatment of C3GN. Furthermore, eculizumab is effective in the treatment of DDD but with less graft survival rate compared to C3GN. The allograft survival in DDD is worse than C3GN. Patients with elevated sMAC before treatment with eculizumab have had better response to therapy (about 80%) with normal sMAC after eculizumab. Therefore, sMAC level can guide to select responders to eculizumab.
A Systematic Review; level I evidence
Reclassification of as immunoglobulin and non-immunoglobulin mediated disease has paved the pathway to the spectrum of diseases named C3G . C3G is characterized by activation of the alternative complement pathways leading to C3 glomerular deposition. With this mechanism, it is suggested that eculizumab may be an effective treatment of C3G . The etiologies of C3G can be classified into genetic causes (mutations/variants resulting in alternative complement pathway abnormalities) and acquired causes (C3Nef/autoantibodies) with possible triggering factors including infections, monoclonal immunoglobulin, and autoimmune diseases.
KTX patients with C3G treated with eculizumab had the lowest incidence of allograft loss (33%) when compared to those treated with TPE and rituximab. Among those who received no treatment for C3G due to stable allograft function, there was an incidence of allograft loss of 32% in C3GN and 53% in DDD
Summary of ttt of C3 glomeulopathy
• C3 gloerulopathy is a rare form of GN, 2ry to alternative complement dysregulation and triggered with infection or autoimmune process, with high risk of recurrence post transplant, ranging from s 1.5 months to 97 months post-KTx. It is either genetic mutation or acquired after infectious or autoimmune triggers.
• It has predominant C3 deposits in IF (more than 2 folds + absent Ig deposits), it either presented with membranoproliferative GN (MPGN), crescentic GN, diffuse endocapillary proliferative GN, or mesangioproliferative GN.
• It includes 2 categories: DDD and C3GN.
o DDD has intra-membranous sausage shaped deposits
o C3 GN has subendothelial deposits.
• ttt of C3 glomerulopathy in native kidney includes: MMF, corticosteroids, eculizumab, rituximab, CNI, cyclophosphamide, and conservative management.
• Although maintenance therapy in kidney transplantation includes 3 of the essential ttt of C3 glomerulopathy (triple therapy, CNI, MMF and steroids), recurrence commonly occurs.
• Ecluizimab has better allograft survival than PEX and rituximab.
• Mild cases are treated with steroids and MMF.
• Severe cases with nephrotic range proteinuria, crescents and graft dysfunction are treated with PEX, rituximab.
• Further longitudinal studies are essential to assess outcomes.
Evidence: systematic review and meta-analysis (evidence level I)
* C3 glomerulopathy (C3G) is a rare type of
(GN) characterized by the dysregulation
of the alternative complement pathway in the glomeruli and deposition of C3 with absent or scanty immunoglobulin in the renal biopsy.
*C3G comprises of dense deposit disease (DDD), with electron microscopic findings of highly electron-dense, osmiophilic sausage-shaped deposits in the glomerular basement membrane, and C3 glomerulonephritis (C3GN) with deposits in glomerular matrix (subendothelial and few intramembranous).
* Although it is a rare disease, it can lead to (ESKD) in up to 50% of patients, also with higher recurrence rates post kidney transplantation, patients being on a triple-drug regimen, including mycophenolate mofetil, corticosteroid, and calcineurin inhibitor, C3G still commonly recurs after KTx.
*This systematic review and meta-analysis to assess the efficacy of deferent treatments for C3G recurrence after KTx. The protocol for this systematic review is registered with PROSPERO (International Prospective Register of Systematic Reviews).
Result
*A total of 207 articles were identified and screened. Twenty-three articles were assessed in detail, of which 12 studies (7 cohort studies and 5 case series) consisting of 122 KTx patients with C3G (73 C3GN and 49 DDD were included in our systematic review.
*Allograft Loss among KTx Patients with C3G
33% after eculizumab.
42% plasma exchange.
81% after rituximab.
*Allograft Loss among KTx Patients with C3GN and DDD
# Allograft loss in C3GN KTx patients were 22% after eculizumab
56% after TPE
70% after rituximab
# Allograft loss in DDD KTx patients after different treatment modalities
67% after eculizumab
0% after TPE
100% after rituximab
100% allograft loss at 6 months after rituximab followed by eculizumab.
Sixty-six patients (38 C3GN, 28 DDD) receive no treatment (due to stable allograft function at
presentation).
*Thos received treatment for C3G had significant acute kidney injury of kidney allograft and/or proteinuria than those who did not receive treatment (100% vs. 17%).
*Allograft loss among those who did not receive treatment were 32% and 53% for C3GN and DDD, respectively.
*80% patients with elevated soluble membrane attack complex of complement (sMAC) before eculizumab responded to treatment and all patients who responded to eculizumab had normal sMAC levels post-eculizumab.
Conclusions
KTX patients with C3G treated with eculizumab had the lowest incidence of allograft loss (33%)
when compared to those treated with TPE and rituximab. Among those who received no treatment for
C3G due to stable allograft function, there was an incidence of allograft loss of 32% in C3GN and 53%
in DDD.
What is the level of evidence provided by this study?
Level 1 systemic review
level of evidence 1 : A systematic review and meta-analysis
summary of article, this article done for assessment of the efficacy of different
treatments for C3G recurrence after kidney transplant.
C3 glomerulopathy is a rare disease, its incidence in the US about 5 cases per million.
It cause ESRD in 50% of its cases and has a high rate of recurrence .the recurrence occurs early post-transplant account for more than 50% of causes of graft loss
It caused by dys-regulation of the alternative complement pathway in the glomeruli on light microscopy it resembles pattern of MPGN, membranoproliferativeGN, cresentic GN
diagnosed done by electron microscopy which show two fold greater intensity of C3 stain in absence of immunoglobulin and it is divided into two subtypes dense deposite disease with dense deposits in GBM and C3 GN with deposits in glomerular matrix.
outcome of most treatment studies , their evidence is lack
this study is a systemic review and met-analysis study done for assessment the efficacy of different treatments for C3 glomerulopathy after kidney transplantation
207 relevant studies after exclusion of invalid ones , the analysis done on 12 studies included 122 patients . the results showed that KTx patients with C3G who were treated with eculizumab had the lowest rate of allograft loss.the pooled estimated rates of allograft loss among kidney transplant patients with C3 glomerulopathy was 33% after Eculizumab ,42% after therapeutic plasma exchange and 81% after rituximab
up to 80% of C3G treated patients with elevated sMAC responded to eculizumab
therapy. sMAC levels have been suggested as a serum marker for alternative complement pathway activation
limitation of the study
Level of evidence of this article is level 1 ; As it is a systematic review and meta analysis….
Summary of the article: This article provides the latest update about the treatment options of C3 glomerulopathy after renal transplantation. c3 glomerulopathy is a complement mediated disease of the alternate pathway of the complement system which has predominant (>2+)C3 deposition in the mesangium and less or no immunoglobulin deposition.. Sethi et al re-classified MPGN as Immunoglobulin mediated and non immunoglobulin mediated disease… C3 glomerulopathy comes under the non immunoglobulin mediated disease.. It can occur due to genetic defects in the alternative complement pathway products and acquired causes which can be due to C3 nephritic factor (autoantibodies) which can trigger through infections, vaccines and other autoimmune diseases…. There have been guidelines to treat C3GN based on the severity of the disease, but the detail treatment about the post transplant recurrence is lacking… The role of eculizumab has been explored in all the recent studies…The risk of allograft loss after transplantation in C3 glomerulopathy is around 40% and it can be reduced to 22% after the use of eculizumab…
This systematic review have analyzed 122 kidney transplant recipients in 12 studies (7 cohort studies and 5 case series)…Both living and deceased donor renal transplants have been included in the analysis.. ..The median time of recurrence after transplant in these cases were ranging from 6 months to 190 months…This meta analysis revealed for the first time that the recurrence of C3GN after transplant can be reduced to 22% after eculizumab, 56% with TPE and 70% after rituximab…This data showed the more usage of eculizumab in post transplant C3G associated with improved graft outcomes…More over the usage of sMAC (soluble Membrane attack complex) measurement in the serum guides the responsiveness of the patients to eculizumab therapy in them…
limitations of the meta analysis were small case series and no standard treatment guidelines were used
Treatment of C3 Glomerulopathy in Adult Kidney Transplant Recipients: A Systematic Review
Please give a summary of this article
This is a systematic review article involving a total of 12 studies including 7 cohorts and 5 case series. It reviewed the management’s policies and it’s outcome for patients with C3GN and DDD when being associated with C3 staining.
C3GN is a rare disease with 50% progression to ESKD, due to an abnormal regulation of the complement system in which the alternative pathway is mainly involved in the pathogenesis of the disease. The disease has high recurrence rate after kidney Transplantation and associated with graft loss. Kidney biopsy with IF and electron microscopy are crucial in diagnosing C3GN, the findings tend to be dominant C3 staining and complex deposition in the membrane(intramembranous) in association with DDD. Deposits can be mesangial, sub-epithelial or sub-endothelial.
There is no standard therapy for C3GN, complement inhibitors were considered in the management of C3GN based on the underlying complement dysregulation in the pathogenesis of the disease.
Of used therapeutic agents, Eculizumab was associated with better outcome(33%) regarding post-transplant graft loss in C3GN in comparison to TPE(42%) and Rituximab(80%). In C3GN with DDD,the systematic review showed that Eculizumab is superior to TPE and Rituximab in management of C3GN and reduction of graft loss.
Study limitations:
What is the level of evidence provided by this study?
2a(systematic review of cohort studies).
This study represent a systemic review and meta-analysis of 12 studies with a total of 122 patients diagnosed with post transplant C3G, focusing particularly on the modality of treatment and the outcome thereof.
C3G:
Its a rare glomerular disease represent membrano-proliferative pattern of glomerulonephritis with a predominant mesangeal complement C3 deposition. 2 Types of C3G:
1}DDD, in which the C3 deposition in mainly linear on the glomerular basement membrane , that appear thick tortuous, ribbon -like on electrone microscopy study
2}diffuse mesangeal deposition of C3 by IF study.
MPGN classification:
Depending on the IF study , 3 types C3 predominant, Immunocomplex and negative IF finding.
C3G is a rare disease that present with variable degrees of renal function impairment and proteinuria.
Alternative pathway of complement is involved as the main trigger to inflict the disease with its 2 pathways , the genetically determined with aberrant factor H and the acquired with systemic nephritic factor.Due the crucial role of complement in initiating the C3G, Eculizumab , (C5 inhibitor) is the drug of choice. Furthermore, MMF, Rituximab and prednisolon are other options used in its management.
There is no consensus on the management of C3G post transplantation, and most of the expertise was extrapolated from the treatment in general population.C3G is a rare disease , but potentially with a high recurrence rate post transplantation despite the triple immunosuppressant protocol including MMF, prednisolone and CNi, which is indicative that its non effective in preventing treating the disease recurrence post transplantation.
Recurrence rate was variable between 1.5 to 97 months.
the follow up period varied between 6 to 197 months . Life and deceased donors were included, and both DDD and C3G were involved. The allograft outcome was best reported with Eculizumab treated group then with therapeutic plasma exchange TPE and Rituximab respectively. Which is inline with the supposed underlying alternative complement pathway activation, this conclusion was further bolstered by the finding of direct correlation between systemic membrane attack complex sMAC blood level and response to eculizumab . On the other hand the allograft outcome of C3G and DDD patients who kept on conservative therapy due to mild proteinuria and normal renal function was better with C3G then with DDD variant.
limitations of this study:
1-All included studies are observational or case series.
2-No standardized therapy pertaining to C3G is agreed upon.
3-The pooled sample size is small.
4-Needs larger studies to verify the findings
The study is meta-analysis and systemic review with level of evidence 1
1- Summary treatment of C3 glomerulopathy in adult transplant recipient: A systemic review
Introduction:
C3 glomerulopathy is a rare GN characterized by complement dysregulation at level of C3 convertase mediated by genetic mutation and or trigger factors including: infection, monoclonal immunoglobulin, or autoimmune disease when C3GN develop worsening kidney function, ESRD occurred up to 50% of patients. Diagnosis of C3GN made by immunofluorescence on kidney biopsy. C3 staining with absence or new absence of immunoglobulin in DDD, there is electron microscopy of highly electron-dense, osmiophilic sausage-shaped deposits in the glomerular basement membrane and C3GN with deposit in glomerular matrix. The treatment option among non-transplant patients for C3G including: mycophenolate mofetil, corticosteroid, eculizumab, rituximab, calcincinurin inhibitors, cyclophosphamide, and conservative management.
The aim of this systemic review and meta-analysis to assess the efficacy of different treatment for C3G recurrence after transplantation.
Material and methods:
The data base included OVID MEDLINE, EMBASE, and the Co chrome Data base of systemic reviews.
C3G is diagnosed by kidney biopsy-proven C3G in kidney transplant allograft without prior history of C3G.
Calculation of rate of allograft loss among kidney transplant patients with C3G sub-group analysis bared in the type of C3G and DDD.
A random effects model was used to the expected clinical heterogenicity in the included populations. Publicans bias was evaluated by using Egger-test.
Results:
Potentially relevant articles identified from search of MEDLINE and EMBASE and Cochrane data base screened for retrieval and finally 12 studies 7cohat and 5 case series were included consisting of 122 kidney transplant patients with C3G and 49 DDD were included in systemic review. The estimated rats of allograft loss among kidney transplant patients with C3G were 33% after eculizumab, 42% after therapeutic plasma exchange and 81% after rituximab and allograft loss among kidney transplant patients with C3GN and DDD sub-group analysis based on the type of C3G was reformed so estimated rates of allograft loss in C3GN kidney transplant patients were 22% after TPE and 70% after rituximab. Allograft loss in DDD kidney transplant patients after treatment modalities, data were limited allograft loss after eculizumab 1 case series 67%, TYPE 0 % allograft loss case series and rituximab 100% graft loss and 100% graft loss at 6 months after rituximab followed by eculizumab. Sixty-six patients (38 C3GN, 28 DDD receive no treatment due to stable graft function or clinical judejment) so estimated rate of allograft loss those who did not receive treatment were 32% and 53% for C3GN and DDD respectively. Treated C3G patients data on (SMAC) were limited to patients treated with eculizumab 80% patients with elevated SMAC before eculizumab respond to treatment and they had SMAC levels after post eculizumab.
Discussion:
Kidney transplant patients with C3G who were treated with eculizumab had the lowest rate of allograft loss 33% for eculizumab, 42% for TPE and 81% for rituximab and 40% for patients who did not receive treatment. C3G is mainly mediated by activation of the alternative complement pathway and for that reason eculizumab may be on effective treatment of C3G
Kidney transplant recipient despite the immune-systemic effects of a triple. Drug regimen C3G still news after kidney transplantation. Data ongoing treatment for recurrent C3G post kidney transplant is lacking so the role of anticomplement therapies is being explained. In this systemic review of 122 kidney transplant patients’ diagnosis post kidney transplant C3GN the estimated rates of graft loss among kidney transplant patients with C3G were lowest with eculizumab therapy as compared to plasma exchange and rituximab subgroup analysis based on the type of C3G reveled similar results. Data on allograft loss in DDD transplant patients who were treated with above therapies was limited. Use of SMAC levels to monitor eculizumab treatment in C3G is limited. Development of C3G after kidney transplantation despite use of a triple-drug regimen this finding the study suggest that the use of eculizumab for the treatment of C3G after kidney transplantation is reasonable.
Limitation of this study:
1) All included studies were observational or case series.
2) Absence of standard treatment of C3G to make comparison of inventions.
3) Data for the patients who did not receive treatment was provided as a reference.
4) Most of included studies were not maintain the rates of remission or relapses.
Although in this study eculizumab suggested to be considered as an additional therapy for C3G in kidney transplant patients, the sample size was small so future studies are required to asses and compare the efficacy and safety of these complement inhibition for the treatment of C3G among kidney transplant patients. There are currently ongoing clinical trials of complement inhibition for the treatment of C3G among non-kidney transplant patients.
Conclusion:
Kidney transplant patients with C3G treated with eculizumab had the lowest incidence of allograft loss 33% when compared to those treated with TPE and rituximab.
Patients who did not received treatment for C3G, incidence of allograft loss of 32% in C3G and 53% in DDD.
A systematic review and metanalysis level 1
2- level of evidence is 1
This is a systematic review with level of evidence I. The review included 12 studies consisting of 122 kidney transplant recipients diagnosed as C3 glomerulopathy of whom (73 patients with C3GN and 49 patients with DDD.
The aim of this systemic review is to determine the efficacy of different immunosuppressive strategies in the treatment of C3G recurrence posttransplant. The study evaluated graft outcome following treatment with Plasma exchange , Rituximab, Eculizumab and no therapy.
C3 glomerulopathy is a very rare glomerular disease which occurs in 5 cases per million in USA.
C3 glomerulopathy is characterized by MPGN pattern in LM, deposition of C3 in IF. EM further classify C3 glomerulopathy into DDD (intramembranous ) and C3GN (subendothelial, mesangial and sometimes subepithelial). C3 glomerulopathy is an aggressive disease with most of the patient develop ESRD, C3 glomerulopathy recur in half of the patients after transplantation.
C3 glomerulopathy is caused by dysregulation of the alternative pathway of complement system due to either mutation or acquired defect in complement protein which leads to uncontrolled activation with subsequent deposition of C3 in glomeruli causing renal injury.
The study reported following results:
Recipients with C3G who received Eculizumab had the lowest rate of graft loss of 33% comparing to other therapies, plasma exchange – 42%, rituximab – 81% and no treatment – 40%.
The estimated risk of graft loss for recipients with C3GN when treated with eculizumab was 22%, TPE – 56%, rituximab – 70% and no treatment – 32%.
Patients with elevated sMAC responded better to eculizumab therapy in up to 80% of cases.
In conclusion, Eculizumab is an effective treatment of C3 GN in the post-transplant period and more effective than rituximab or plasma exchange.
Introduction
C3 glomerulopathy (C3G) is a rare glomerulonephritis. It is caused by the dysregulation of the alternative complement pathway in the renal glomeruli with prominent complement C3 deposition displayed in the renal biopsy.
Diagnosis of C3G is classically by immunofluorescence on renal biopsy. It is evident by the greater intensity of C3 staining in conjunction with absence or near absence of immunoglobulins. Dense deposit disease (DDD) on electron microscopy reveals electron-dense, osmiophilic sausage-shaped deposits in the glomerular basement membrane.
Complement dysregulation is dependent on the level of C3 convertase, which is mediated by genetic mutations and/or triggering factors including infections, monoclonal immunoglobulin, or autoimmune diseases. This disease despite being rare yet it displays a high recurrence rate post renal transplantation and it accounts for overall 50% of allograft loss.
Diverse treatment strategies as mycophenolate mofetil, corticosteroids, eculizumab, rituximab, calcineurin inhibitors, cyclophosphamide, and conservative management were tried.
Materials and Methods
This is a systematic review registered with PROSPERO till 3 May 2019. Renal biopsy with typically dominant C3 staining of at least 2 orders of magnitude above any immunoglobulin deposition with characteristic deposits either intramembranous sausage-shaped or ribbon-shaped electron-dense deposits in DDD or mesangial, subepithelial, or subendothelial electron-dense deposits in C3GN seen by electron microscopy is the term for diagnosis in this study.
Result
122 KTx patients with C3G and 49 DDD were included in this systematic review.
Allograft Loss among KTx Patients with C3G:
The total estimated rate of allograft loss is 33% after eculizumab, 42% after therapeutic plasma exchange, and 81% after rituximab.
Allograft Loss among KTx Patients with C3GN and DDD:
22% after eculizumab, 56% after TPE, and 70% after rituximab were the estimated rates of graft loss among C3 glomerulopathies.
Data on allograft loss in DDD KTx patients after different treatment modalities were limited. Sixty-six patients (38 C3GN, 28 DDD) received no treatment being of stable allograft function at presentation.
Estimated rates of allograft loss among those who did not receive treatment were 32% for C3GN and 53% for DDD. 80% patients with elevated sMAC before eculizumab responded to treatment. All patients who responded to eculizumab had normal sMAC levels after post-eculizumab.
Discussion
KTx patients with C3G who were treated with eculizumab had the lowest rate of allograft loss. The estimated rates of allograft loss were 33% for eculizumab, 42% for TPE and 81% for rituximab. Patients who received no treatment had an estimated graft loss about 40%.
C3G is characterized by activation of the alternative complement pathways leading to C3 glomerular deposition, so highlighting the role of eculizumab in the future to be used as an effective treatment for cases with C3G.
Mild and moderate disease can be managed by supportive treatment, along with steroids and mycophenolate. Rituximab and plasma-exchange have been tried as well. Data of treatment strategies for recurrent C3G post-KTx are still limited.
This meta-analysis came up for the first time that KTx patients with C3GN had an associated allograft loss of 22% after treatment with eculizumab, 56% with TPE, and 70% with rituximab. Estimated rates of allograft loss were 32% among C3GN and 53% among DDD groups those who had no treatment at all. Recently in this review up to 80% of C3G treated patients with elevated sMAC responded to eculizumab therapy. Also sMAC levels have been suggested as a serum marker for alternative complement pathway activation. The findings of this study recommends the use of eculizumab for the treatment of C3G after KTx. Given that majority of patients with elevated sMAC prior to treatment responded to eculizumab therapy, future validation studies with a larger number of patients are required.
Study limitations are including studies which were observational or case series, the unavailability of standard treatment for C3G to allow comparison of interventions, data from patients who did not receive treatment was provided as a reference, the small sample size and finally the rates of remissions or relapses were not included.
Clinical trials of other complement inhibitors for the treatment of C3G among non-KTx patients is still ongoing. So, future studies are needed to assess and compare the efficacy and safety of these proposed various complement inhibitors for the treatment of C3G among KTx recipients.
Conclusions
KTX patients with C3G treated with eculizumab had the lowest incidence of allograft loss (33%) on comparison to those treated with TPE and rituximab. The estimated allograft loss rates are about 32% in C3GN and 53% in DDD for those renal transplant patients who were not treated.
Level of evidence 1.
Introduction
C3 glomerulopathy (C3G) is a rare glomerulonephritis (GN) characterized by the dysregulation of the alternative complement pathway in the glomeruli. It leads to complement C3 deposition in the renal biopsy samples with absent or scanty immunoglobulin deposition. Histopathologically, C3G may present as patterns of membranoproliferative GN (MPGN), crescentic GN, diffuse endocapillary proliferative GN, or mesangioproliferative GN. Diagnosis of C3G is done by immunofluorescence on kidney biopsy with predominant C3 staining in addition to absence or near absence of immunoglobulins.
With electron microscopy, C3G comprises of dense deposit disease (DDD), with findings of highly electron-dense deposits in the glomerular basement membrane, and C3 glomerulonephritis (C3GN) with deposits in glomerular matrix (subendothelial and few intramembranous). Although C3G is a rare glomerular disease, there is high recurrence rates are noted post kidney transplantation. Among KTx recipients, despite the immunosuppressive effects of a triple-drug regimen, including mycophenolate, corticosteroid, and calcineurin inhibitor, C3G still recurs after KTx
Materials and Methods
The sources for this systematic review (level of evidence ,level 1) included eligible studies must be clinical trials, observational studies (cohort, case-control, or cross-sectional studies), or case series that reported outcomes of adult (age ≥ 18 years old) KTx recipients with C3G.
Results
Kidney transplant patients with C3G who were treated with eculizumab had the lowest rate of allograft loss. The pooled estimated rates of allograft loss were 33% for eculizumab, 42% for TPE and 81% for rituximab. Patients who received no treatment had an estimated graft loss of approximately 40%.
In this systematic review, twelve studies were analysed consisting of 122 KTx patients, with the majority carrying a diagnosis of post-KTx C3GN. Living and deceased donors were included in most of the included studies, and the median time from transplantation to the recurrence of the disease varied from 1.5 months to 97 months post-KTx. The Median follow-up period was 6 to 197 months. The pooled estimated rates of allograft loss among KTx patients with C3G were lowest with eculizumab therapy as compared to plasma exchange and rituximab.
Study Limitations
1-All included studies were observational or case series in design, making them susceptible to selection bias.
2-There is no standard treatment for C3G to allow comparison of interventions.
3-data from patients who did not receive treatment other than supportive therapy was provided as a reference.
4- The rates of remissions or relapses were not reported in most of the included studies. Only the rate of graft loss was available for pooled analysis.
Conclusions:
The pooled estimated rates of allograft loss among KTx patients with C3G were lowest with eculizumab therapy(33%) as compared to plasma exchange and rituximab.
C3 glomerulopathy, including C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), a glomerular disease involving dysregulated alternative complement pathway, is associated with high rates of end stage renal failure and increased post-transplant recurrence and graft loss. The study was a meta-analysis involving the treatment modalities used and their response in kidney transplant recipients with C3 glomerulopathy.
Databases for C3 glomerulopathy in transplant patients were searched till 3 May 2019. Out of 207 articles, 12 were included in the study, involving 122 patients with 73 having C3GN and 49 having DDD.
The median time to recurrence was between 1.5 months and 97 months.66 patients were treated with either eculizumab, therapeutic plasma exchange or rituximab. 66 patients did not receive any treatment. Among the non-treated C3 glomerulopathy patients, the rates of graft loss were 40% with 32% in C3GN sub-group and 53% in DDD sub-group.
The graft loss rates of C3 glomerulopathy patients were 33%, 42% and 81% with eculizumab, therapeutic plasma exchange and rituximab respectively. In the subgroup analysis, the graft loss rates of C3GN patients were 22%, 56% and 70% with eculizumab, therapeutic plasma exchange and rituximab respectively while the graft loss rate for the DDD patients was 67% for eculizumab use and 0% and 100% for therapeutic plasma exchange and rituximab as well as rituximab followed by eculizumab (although only limited data was available for DDD).
Among the patients treated with eculizumab, the levels of soluble membrane attack complex of complement (sMAC) reduced in 80% patients after treatment.
The limitations of the study included observational nature of the study, non-use of a standard treatment modality, remission and relapse rates were not reported in the studies and a small pooled sample size.
The study concluded that even with treatment, 33% to 80% of patients with C3 glomerulopathy lose their graft, more so in the DDD group patients. The lower rates of graft loss in untreated patients is due to mild nature of the disease in them. Higher sMAC levels prior to treatment may point towards the candidates who will respond to eculizumab.
The level of evidence is Level 1: This is a systematic review and meta-analysis
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 which are related to dysregulated alternative complement system
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 so result in low incidence of graft loss.
Introduction:
C3 nephropathy is a rare type of nephritis with diverse incidence and prevalence worldwide, its due to alternative complement pathway dysregulation which lead to C3 deposition by IF staining without immunoglobulin, histological characteristic of c3 nephropathy its MPGN like pattern and associated with high rate of recurrence after kidney transplantation> 50%, so post transplantation monitoring is mandatory with prompt intervention to improve the graft outcome despite those patient on triple immunosuppression including MMF ,CNI steroids which is part of treatment options for C3GN in nontransplant patients still there is a chance of high rate of recurrence and the current treatments’ options and their effect on the C3G in kidney transplantation are missing the evidence therefore this study aims to evaluate the effectiveness of the available treatments of C3GN recurrence PostKTX.
Method and selection criteria: systematic review and metanalysis for the available studies from May 2019 from international data source Midline, PubMed and Cochrane database and reviewed undependably by two reviewers .eligibilities must be clinical trials ,observational studies with case control or cross-sectional studies , case series for all adults above the age of 18 , with biopsy proven C3GN including IF , EM , DDD characteristic histological deposits in native kidneys and post KTX biopsies
Data analysis:
They used the Random effect module to avoid the clinical heterogenicities with population selection. Also using I2 statistic and the chi-square test to overcome the heterogenicity of effect size among individual studies. Publication bias was assessed by using egger test with P value < 0.05 indicate publication bias.
Results:
Only 12 studies included in the systematic review out of 277 studies, 7 cohort studies and 5 case series with total of 122 patients with C3G (73 C3G and another 57/ DDD).
This study shows the lowest rate of graft loss in eculizumab treatment group (33%) compared to 42% in TPE and 80% in rituximab group. while patients whom received no treatment the overall graft loss reached 40%. In subgroup analysis based on C3 GN subtypes shows no difference among the available treatment options. The soluble membrane attack complex level (s MAC) was higher among those c3gn patient whom received eculizumab (80%) of cases with complete normalization of s MAC after eculizumab therapy among responders.
66% of cases received no treatments as they are stable graft function upon FU and as per physician decision, 37 /73 with C3GN and 28/DDD shows 32% and 56 % graft loss respectively.
Limitation:
1-Small sample size and the pool of the studies from small case series and observation cohorts with high risk of selection bias.
2-no homogenous treatment for C3GN to permit comparison with interventions
3-Rate of relapse and remission not recorded.
Conclusion:
lower incidence of graft loss reported in eculizumab cohorts compared to other treatments option, the role of anti c5 complement targeting therapy with eculizumab consider promising therapy for C3GN and the use of sMAC as prognostic indicator for treatment response we need to explore its effect by large clinical studies with homogenous designs and longer follow up.
What is the level of evidence provided by this study?
Level 1C, systematic review but still limited to cohort studies with case series.
C3 glomerulopathy-a rare disease- is defined by the presence of two-fold greater intensity of C3 deposition without immunoglobulin on immunofluorescence in renal biopsy samples and occurs due to dysregulation of the alternative complement pathway .Two diseases fall under this category which are differentiated on the basis of electron microscopy findings. C3G can be because of genetic causes (mutations/variants )and acquired causes (C3Nef/autoantibodies) with precipitating factors like infections, monoclonal immunoglobulin, and autoimmune diseases .50% patients develop ESRD and also had high recurrence rate comprising about 50% allograft loss.
This systemic review included included 12 studies (7 cohort studies and 5 case series)comprising 122 Kidney transplant patients with C3G (73 C3GN and 49 DDD )with the aim to determine the efficacy of different agents in treatment of C3G recurrence post transplant.
RESULTS:
This study showed different response rate with different regimens and eclizumab having better response and lower graft loss (33%) among all others .Rest showing PLEX(42% ), 81% for rituximab and 40% with no treatment.
Data is scarce on the management strategies for C3GN . KDIGO recommendation is to treat the patient according to severity. Steroids and mycophenolate along with supportive treatment is for mild and moderate disease. Pulse solumedrol with other immunosuppressive therapies including Rituximab and plasma-exchange for severe disease . Trials on Eclizimab role for post transplant C3Gn is going on as exact management for recurrent C3GN post transplantation is lacking. C3GN had allograft loss 32% and DDD had 53% allograft loss. sMAC levels has been used in various studies as a marker for alternative complement pathway activation and our study showed eculizumab response in 80% of C3G treated patients with elevated sMAC .
Summary
This article is a meta analysis based on observational or case series design studies.
Aim :
Analyse the different treatment options for C3 glomerulopathy in kidney transplant recipients and their corresponding outcomes with respect to allograft loss.
Disease spectrum :
Diagnosis
Treatment
Study conclusions
Limitations of study
Level of evidence :
This article is a meta analysis. Hence level of evidence is 1.
Introduction:
C3 glomerulopathy is uncommon glomerulonephritis caused by alternative complement system dysfunction. Although uncommon, post-kidney transplantation recurrence rates are significant, thus post-transplant monitoring and careful use of medicines are needed to optimize clinical outcomes.
The result:
-C3GN is identified by kidney biopsy with C3 staining with EM deposits. De novo C3GN is freshly diagnosed C3GN following kidney transplantation without a previous history of C3G.
-The meta-analysis intended to investigate the effectiveness of various medications in treating C3G recurrence after transplant.
It includes 12 trials with 122 kidney transplant patients, most with C3GN.
-Eculizumab reduces graft loss in C3G patients.
In C3G patients treated with eculizumab, TPE, or rituximab, graft loss was 33%, 42%, 81%, and 40% in those who received no therapy.
-80% of C3G patients with high sMAC reacted to eculizumab, although sMAC level is not utilized to monitor treatment since it has no association with disease severity.
–In C3GN patients, eculizumab had a 22% graft loss rate, TPE 56%, rituximab 70%, and no therapy 32%.
-Study limitations include bias and the absence of recurrence or remission data. limited sample size, lack of standardized therapy.
Conclusions
Ecluzimab reduces allograft loss after C3 GN renal transplant.
Level I research evidence(systematic review).
Thanks, Weam
Please give a summary of this article
Introduction
C3G is a rare GN (5 cases/million in US) caused by the alternative complement pathway dysregulation.
It consists of 2 subtypes:
– DDD (electron-dense deposits in the GBM)
– C3GN (subendothelial deposits)
Clinical pattern:
– 50% develop ESRD.
– Highly recurrent post-transplant.
Microscopic patterns of C3 G:
– MPGN
– Crescentic GN
– Diffuse endocapillary proliferative GN
– Mesangioproliferative GN
IF patterns of C3GN:
– Prominent C3 deposition
– Absent or scanty immunoglobulin deposition
————————————————-
Methodology:
This is a systemic review of several databases search of the studies of post-transplant outcomes of patients with C3G.
The protocol for meta-analysis is registered with PROSPERO.
Eligible studies included for analysis:
– Clinical trials
– Observational studies (cohort, case-control, or cross-sectional)
– Case series.
Extracted data:
– 1stauthor name
– Publication year
– Number of patients
– Follow-up duration
– Transplant’s type
– Mean age
– Sex
– Recurrence of C3G
– Time transplant to from recurrence
– treatment of G3G.
Statistical Analysis
Estimate rates of allograft loss were calculated.
Subgroup analysis (C3GN & DDD) was done.
A random-effects model was used (due to hetero-geneity in the study populations).
MetaXL software used for meta-analysis.
——————————————————–
Results & Dicussion:
A 207 articles were identified; 23 articles assessed in detail, of which 12 studies (7 cohort & 5 case series) consisting of 122 transplant patients with C3G (73 C3GN & 49 DDD) were included in the systematic review.
Allograft Loss among C3G patients:
– 33% after eculizumab
– 42% after PP
– 81% after rituximab
Allograft Loss among subgroups of C3G
1. C3GN:
– 22% after eculizumab
– 56% after PP
– 70% after rituximab
2. DDD:
– 4/6 (67%) after eculizumab
– 0/2 (0%) after PP
– 3/3 (100%) after rituximab
– 2/2 (100%) allograft loss at 6 months after
rituximab followed by eculizumab.
66 patients (38 C3GN, 28 DDD) received no treatment (stable graft function at presentation).
Patients treated for C3G had significant AKI of allograft &/or proteinuria than those not treated (100%vs.17%).
Allograft loss among those not treated was 32% for C3GN & 53% for DDD.
Soluble membrane attack complex of complement (sMAC):
80% patients with elevated sMAC levels before eculizumab responded to treatment; all responders had normal levels post-eculizumab.
Imitations:
All included studies were observational or case series, thus susceptible to selection bias.
No standard therapy for C3G to compare with interventions.
Rates of remissions or relapses were not reported in most of the studies; only the rate of graft loss was available for analysis.
Conclusions
C3G transplant patients treated with eculizumab had the lowest incidence of allograft loss compared to those treated with PP & rituximab.
Among no-treated C3G patients the incidence of allograft loss was 32% in C3GN & 53% in DDD.
============================
What is the level of evidence provided by this study?
Level 1: systemic review
Excellent comprehensive summary.Notice the relation between the response to eculizumab and positive sMAC.
Introduction
C3glomerulopathy is one of the rare glomerular diseases and consists of two entities; C3GN and DDD. It occurs due to dysregulation of the alternative complement pathways( genetic mutation or autoantibodies). C3GN is associated with a high risk of recurrence and allograft loss following transplantation. The objective of this systematic review was to evaluate the efficacy of various treatment modalities for recurrent C3G
Methodology
Results
Discussion
Limitation
Conclusions
A systematic review and meta-analysis = Level I
Very good
Thank Prof
Summary:
C3 glomerulopathy is rare glomerulonephritis characterized by the dysregulation of the alternative complement pathway in the glomeruli. Although it is rare, substantially high recurrence rates are noted post kidney transplantation, thus, post-transplant monitoring and appropriate implementation of the available therapies are necessary to improve clinical outcomes.
Study design: systematic review and meta-analysis.
Aim: To assess the efficacy of different treatments for C3G recurrence after KTx.
Materials and methods: A comprehensive search of several databases including Ovid Medline, Embase, and Cochrane till May 2019. A systematic literature review was conducted independently by two investigators, using the search strategy that consolidated the terms (kidney transplantation, renal transplantation, kidney graft, kidney graft rejection) and (C3 glomerulopathy, or C3 glomerulonephritis, dense deposit disease).no restrictions on language, sample size, or study duration.
The study was conducted by the PRISMA statement.
C3GN is diagnosed by kidney biopsy with typically dominant C3 staining with characteristic deposits as seen by electron microscopy. Recurrent C3GN is diagnosed by biopsy-proven C3GN in kidney transplant allograft without prior history of C3G, and de novo C3G is defined by newly diagnosed C3GN after kidney transplantation without prior history of C3GN.
Study Selection: clinical trials, observational studies, and case series that reported outcomes of adult (age ≥ 18 years old) KTx recipients with C3GN are the eligible studies for this meta-analysis. Inclusion was not limited by language, sample size, or study duration.
Data Extraction: first author name, year of publication, number of patients, duration of follow-up, type of transplant, mean age, sex, recurrence of C3G after KTx, time from KTx to recurrence, and treatment of G3GN.
The primary outcome was graft failure.
Results: Twelve studies (7 cohort studies and 5 case series) consisting of 122 KTx patients with C3GN (73 C3 glomerulonephritis and 49 DDD) were included.
The rate of allograft loss among KTx patients with C3GN was 33% after eculizumab, 42% after therapeutic plasma exchange, and 81% after rituximab.
Pooled estimated rates of allograft loss in DDD KTx patients were 53% after eculizumab.
Among 66 patients (38 C3GN, 28 DDD) who received no treatment, pooled estimated rates of allograft loss were 32% and 53% for C3GN and DDD, respectively.
80% of patients with elevated soluble membrane attack complex of complements before eculizumab responded to treatment and have normal sMAC levels after eculizumab treatment.
Conclusion: lowest incidence of allograft loss (33%) among KTX patients with C3GN who were treated with eculizumab. Among those who received no treatment for C3GN due to stable allograft function, there is a high incidence of allograft loss of 32% in C3GN and 53% in DDD. sMAC level may help to select good responders to eculizumab.
Level 1
Very good
Ø Summary
-C3 glomerulopathy is associated with Complement deposition in renal biopsy with immunofluorescence in absence of immunoglobulin .
-Being a rare disease ,C3G leads to deterioration of kidney function and leading to end-stage kidney disease (ESKD) in up to 50% of cases with high recurrence risk post transplantation.
-C3G has high recurrence rate inspite of keeping the patients on a triple-drug regimen, including mycophenolate mofetil, corticosteroid, and calcineurin inhibitor in renal transplant recipients .
– 122 KTx patients were included, most of them experiencing post-KTx C3GN with disease recurrence ranging from 1.5 months to 97 months post-KTx.
–Results of this systematic review revealed that estimated rates of allograft loss among KTx recipients with C3G were 33% after eculizumab, 42% after therapeutic plasma exchange (TPE), and 81% after rituximab
-A subgroup analysis was done revealed that the rates of allograft loss in C3GN KTx patients were 22% after ecluzimab ,56% after TPE and 70% after Rituximab while for DDD KTx patients the available studies were limited but showed that ; allograft loss after eculizumab was 67%, after TPE was 0%, after rituximab was 100% , and 100%allograft loss at 6 months after rituximab followed by eculizumab
– Allograft loss rates for patients who did not receive treatment were 32% for C3GN and 53% for DDD.
-80% of C3G treated patients with elevated sMAC responded to eculizumab therapy.
–Discussion
C3 GN post KTx cases treated with Ecluzimab had the lowest rejection rate.
MPGN was reclassified as immunoglobulin and non-immunoglobulin mediated disease .
Etiologies of C3GN are either genetic or acquired
-KDIGO advise for the management of C3G according to disease severity .
For mild to moderate cases , supportive treatment, with steroids and MMF ,Rituximab and plasma-exchange did not lead to definite results .
For severe cases , pulse solumedrol and other immunosuppression therapies results weren’t promising.
-Most cases with elevated sMAC before treatment responded to eculizumab therapy meanwhile MAC level correlation with disease severity need to be investigated
-Study limitations include liability to study bias, small sample size included ,lack of standardised treatment, unavailability of data on relapse or remission of the cases.
Conclusions
Ecluzimab usage for treatment of C3 GN post renal transplant can lower rate of allograft loss
Level of evidence of the study is level I
Very good
C3 glomerulopathy (C3G) is a rare disease, mediated by dysregulation of alternative complement pathway which lead to C3 glomerular deposition.
It includes C3 glomerulonephritis (C3GN) and dense deposit disease (DDD)
The incidence and prevalence are not well determined.
It leads to ESKD in 50% of patients with high rate of recurrence post transplant and may lead to graft loss.
The systemic review and met-analysis aimed to determine the efficacy of different agents in treatment of C3G recurrence post transplant
It included 12 studies consisting of 122 kidney transplant recipients with the majority having C3GN post transplant.
The study showed that:
Limitations:
Included observational studies and case series which are susceptible to selection bias.
Couldn’t compare between interventions as no standard treatment is available.
Rates of remissions and relapses were not reported in included studies.
Level of evidence: 1
Thanks, Heba
C3 Glomerulopathy results from dysregulation of alternate compliment pathway leading to C3 deposition in renal biopsy. It can be membranoproliferative, cresentic, diffuse endocapillary and mesangioproliferative. Diagnosis is made by immunofluorescence on kidney biopsy. There are two types.
Dense deposit disease
Eosinophilic sausage shaped deposits in glomerular basement membrane.
C3GN-
Deposits in glomerular matrix
C3GN is rare but has high recurrence rate after renal transplant. Current evidence is lacking on outcome post transplant.
Systemic review registered with PROSPERO
The study evaluated the graft outcome after Plasma exchange , Rituximab, Eculizumab and after no therapy.
Results.
The rate of graft loss in renal transplant patient with C3G was-
After Eculizumab-33%
After Therapeutic plasma exchange -42%
After Rituximab 81% and also the rate of graft loss was lower in this group.
Graft loss rates were high in dense deposit group as compared to C3GN.
Conclusion.
Eculizumab is more effective than Rituximab and plasma exchange in treatmnet of C3 Glomerulonephritis recurrence post transplant
Level of Evidence -1
Thanks, Dr Khan
C3 glomerulopathy is a rare disease occurring in 5 cases per million in USA
Characterized by MPGN pattern in LM, deposition of C3 in IF and they are further classified by EM according to the location of dense deposits into DDD (intramembranous ) and C3GN (subendothelial, mesangial and sometimes subepithelial)
Caused by dysregulation of the alternative pathway of complement system due to either mutation or acquired defect in complement protein (the presence of antibodies that either stabilize C3 convertase or inhibit complement regulatory proteins) leading to uncontrolled activation with subsequent deposition of C3 in glomeruli, thus it share the same pathogenesis of a HUS, but the difference that C3G occurs in the fluid phase not in the solid phase like HUS
C3 glomerulopathy is an aggressive disease with most of the patient develop ESRD, C3 glomerulopathy recur in half of the patients after transplantation
This is a systematic review (level of evidence I) including 12 studies consisting of 122 kidney transplant recipients diagnosed as C3 glomerulopathy of whom (73 patients with C3GN and 49 patients with DDD.
The study evaluated the rate of graft loss after eculizumab, plasmapheresis, Rituximab therapy and after no treatment (only for patients with stable graft function)
Before and after Eculizumab treatment, soluble membrane attack complex of complement was measured
Results
Thanks, Sherif
Level 1 study
C3G is a rare GN result from dysregulation of alternative complement pathway in glomeruli. It may presented with different histopathological pattern: MPGN, crescent GN, diffuse endocapillary proliferative GN or mesangiproliferative GN.C2G include 2 distinct diseases: C3GN & DDD. 50% of cases end with ESRD with high post transplant recurrence.
Systemic review study with meta-analysis. All included studies were clinical trial or case series with adult outcome renal transplant recipients. The study include 122 patients diagnosed with post transplant recurrence C3G ( live & deceased donor kidneys) with median follow-up period 6-197 months
Result & discussion:
Limitation of the study:
Due to small size pool, more controlled trails to assess efficacy of eculizumab, TPE & rituximab are needed.
Thanks, Ban
C3 nephropathy is a rare disease and its due to a complement dysregulation.
it’s has a high grade of recurrence post transplant
it’s may related to genetic mutation/ infection/ monoclonal immunoglobulin and autoimmune disease
it’s diagnosis by renal biopsy ( electron microscopy and immunofluorescence ); it’s shows deposits of C3 in basement membrane and it may shows membranoproliferative GN / crescent GN and endocapillary GN
it’s associated with graft loss and ESRD post transplant
It’s need close monitoring and fallow up with close adherence to immunosuppressive agents to avoid recurrence of C3 nephropathy.
This article is systemic literature review and meta analysis done in 2019 focus on efficacy of immunosuppressive therapy to prevent recurrence of disease.
Treatment of non kidney transplant C3 nephropathy are steroid / calcinurine inhibitors and MFF / cyclophosphamide and rituximab and eculizumab.
Post transplant treatment of recurrence are steroid/ MFF and calcinurine inhibitors.
Study selection// this study not limited by language or samples size or study duration.
C3 nephropathy proven by renal biopsy with dominant C3 staining.
Dense deposits disease diagnostic by electron microscopy seen in mesangial/ sub epithelial/ sub endothelial.
Results// this article review cases in detail between cases of C3 nephropathy and dense deposits disease and shows effects of drug on recurrence of these diseases post transplant whether cases live donor or deceased donor.
Date on graft loss in DDD are limited but shows response to eculiumab more than use of rituximab and plasma exchange.
Patients who not receive treatment because stable graft function regardless to personal data and type of kidney transplant shows 40% evidence of graft loss with time.
Those patients with high level of soluble membrane attack complex of complement were limited but shows responded to eculizumab and return of sMAC level to normal post eculizumab.
Discussion//
Patients who receive eculizumab had lower rate of loss graft post eculizumab.
The pooled estimated rate of allograft loss high with rituximab 80% followed by TPE 40% and 33% by eculizumab.
MPGN classified by sethi et to immunological and non immunological mediated disease.
C3 GN is characterised by activation of alternative complement pathway leading to C3 glomerular deposition; So eculizumab is effective treatment of C3G.
KDIGO guidelines recommended C3 G depend on severity of disease.
Mild to moderate needs support treatment by steroid and MFF
In mixed disease treatment by rituximab and plasma exchange.
Severe disease with proteinuria more than 2 g and severe endocapillary proliferation with or without crescent formation need pulse therapy of steroid and immunosuppressive drug.
Among transplant patients still there is evidence of recurrence of C3GN and responded to eculizumab and evidence of graft loss low with eclizumab and high with rituximab and plasma exchange.
Even with limited data on allograft loss in DDD kidney transplant patients but they get benefits from eculizumb.
Conclusion// Eculizumab is effective in treatment of C3 GN recurrence post transplant in comparison to rituximab and plasma exchange
This evidence 1
System review and meta analysis
Thanks, Sahar
C3 glomerulopathy (C3G) is rare glomerulonephritis (GN) characterized by the dysregulation of the alternative complement pathway in the glomeruli.
Diagnosed by histopathology only and mainly by Immunohistochemistry microscopy in which there is prominent complement C3 deposition in the renal biopsy samples with absent or scanty immunoglobulin deposition.
L/M is usually present in C3G as patterns of membranoproliferative GN (MPGN), crescentic GN, diffuse endocapillary proliferative GN, or mesangioproliferative GN.
C3G comprises of
· dense deposit disease (DDD), with electron microscopic findings of highly electron-dense, osmiophilic sausage-shaped deposits in the glomerular basement membrane
· C3 glomerulonephritis (C3GN) with deposits in the glomerular matrix (subendothelial and few intramembranous).
The prevalence in the United States (US) is estimated at 5 cases per million. patients with C3G can develop worsening kidney function leading to end-stage kidney disease (ESKD) in up to 50% of patients.
Pathogenesis is mediated by Complement dysregulation in the fluid phase at the level of C3 convertase, predominantly mediated by genetic mutations and/or triggering factors including infections, monoclonal immunoglobulin, or autoimmune diseases.
C3G is associated with high recurrence rates are noted post kidney transplantation (KTx). Thus, post-transplant monitoring is necessary to improve clinical outcomes. Histopathological illustration of C3G recurrence can be detected early post-KTx (1.5 months to 97 months post-KTx), with C3G accounting for an overall 50% of allograft loss.
KDIGO recommends the management of C3G based on disease severity.
· For mild and moderate disease, supportive treatment, along with steroids and mycophenolate, is advised.
· Rituximab and plasma exchange have been tried with mixed results.
· In severe disease with 24 h urine protein >2 g or severe endocapillary proliferation with/without crescent formation, limited success has been described with pulse solumedrol and other immunosuppression therapies like cyclophosphamide and rituximab.
However, among KTx recipients, despite the immunosuppressive effects of a triple-drug regimen, including mycophenolate, corticosteroid, and calcineurin inhibitor, C3G still recurs after KTx And there is no sufficient data on guiding treatment.
Regarding management post-transplant
Results: Twelve studies (7 cohort studies and 5 case series) consisting of 122 KTx patients with C3G (73 C3 glomerulonephritis (C3GN) and 49 dense deposit disease (DDD)) were included.
The pooled estimated rates of allograft loss among KTx patients with C3G were 33% after eculizumab, 42% after therapeutic plasma exchange (TPE), and 81% after rituximab. Subgroup analysis based on the type of C3G was performed. Pooled estimated rates of allograft loss in C3GN KTx patients were 22% after eculizumab, 56% after TPE, and 70% after rituximab. Pooled estimated rates of allograft loss in DDD KTx patients were 53% after eculizumab. Data on allograft loss in DDD after TPE (1 case series, 0/2 (0%) allograft loss at 6 months) and rituximab (1 cohort, 3/3 (100%) allograft loss) were limited.
Among 66 patients (almost 50% of the total pool which includes 122 patients) (38 C3GN, 28 DDD) who received no treatment (due to stable allograft function at presentation and/or clinical judgment of physicians), pooled estimated rates of allograft loss were 32% and 53%(the same exact number if treated with eculizumab so treatment may be of no value for DDD) for C3GN and DDD, respectively.
Among treated C3G 2 of 15 patients, data on soluble membrane attack complex of complement (sMAC) were limited to patients treated with eculizumab (N = 7). 80% of patients with elevated sMAC before eculizumab responded to treatment. In addition, all patients who responded to eculizumab had normal sMAC levels post-eculizumab.
Limitations
· Patients who didn’t receive treatment almost 50% of the study group so medications efficacy is only evaluated based on almost 60 patients
· all included studies were observational or case series in design, making them susceptible to selection bias.
· there is no standard treatment for C3G to allow comparison of interventions.
· No control groups
· the rates of remissions or relapses were not reported in most of the included studies. Only the rate of graft loss was available for pooled analysis.
· the pooled sample size remains small, and further controlled trials describing the efficacy of eculizumab, TPE, or rituximab are warranted.
Conclusions
KTX patients with C3G treated with eculizumab had the lowest incidence of allograft loss (33%) when compared to those treated with TPE and rituximab. Among those who received no treatment for C3G due to stable allograft function, there was an incidence of allograft loss of 32% in C3GN and 53% in DDD.
level II because it’s based on a case reports and observational studies
Thanks, Ramy
Treatment of C3 Glomerulopathy in Adult Kidney Transplant Recipients: A Systematic Review
This is a systematic review and meta-analysis to assess the efficacy of different treatments for C3G recurrence after kidney transplantation.
Data from twelve studies contain ( 7 cohort studies and 5 case series) consisting of 122 Ktx patients with C3G .
A-(73 C3 glomerulonephritis (C3GN) .
B-(49 dense deposit disease (DDD).
Patients received different medication from the following (eculizumab, therapeutic plasma exchange (TPE) , rituximab and conservative treatment ).
Efficacy of treatment assessed by detecting the rate of graft loss after treatment.
Overall , rates of allograft loss among Ktx patients with C3G were 33% after eculizumab, 42% after therapeutic plasma exchange (TPE), and 81% after rituximab.
Also eculizumab showed lowest incidence of graft loss in sub-groups of C3GN and DDD.
A 66 patients who received no treatment has a high incidence of allograft loss of 32% in C3GN and 53% in DDD.
Meta-analysis concluded that patients who developed post kidney transplant C3G and treated by eculizumab had the lowest rate of allograft loss.
Still we need more/large randomized controlled trials for strong evident protocol for treating post kidney transplant C3G.
Level of evidence I
A systematic review and meta-analysis.
Thanks, Ben
Please give a summary of this article :
What is the level of evidence provided by this study?
Thanks, Ibrahim
This is also short summary
Introduction
-C3 glomerulopathy is a rare complement dysregulation related glomerulonephritis characterized by prominent C3 deposition with absent or scanty immunoglobulin deposition
-C3G includes dense deposit disease and C3 glomerulonephritis (C3GN)
-It is aggressive diseases weather in the native kidney with an ESRD risk of 50% in cases , and also after transplant with a recurrence rate and graft failure rate of 50%
-It recurs after Tx despite triple immunosuppressive therapy and unfortunately no consensus on treatment for its recurrence till now this is a meta-analysis and systematic review for assessment of treatment efficacy in the literature
Results:
-23 Of 207 relevant articles were assessed, 11 were excluded.
122 ktx were included through 12 studies, 73 C3GN, and 49 DDD.
-soluble membrane attack complex of complement (sMAC) were assessed in only patient treated with eculizumab and was elevated in 80% of them before treatment abd was normalized in all successfully treated patients.
Discussion:
The patients who responded to treatment with eculizumab were who have complement dysregulation either due to genetic causes or
and acquired causes (C3Nef/autoantibodies) with possible triggering factors including infections,
monoclonal immunoglobulin, and autoimmune diseases
level of evidence 1 (systematic review and meta-analysis study limitation:
1 no comparative studies, all were observational or case series.
2-No standard treatment for C3G to allow comparison of interventions.
3- no detailed data about those who didn’t receive treatment other than supportive
4- remissions or relapses have not been reported in the studies.
5-duration of follow-up and time elapsed till graft failure.
Excellent Radwa
This is how to summarise articles. Thank you for your structured writing
Excellent Radwa