Recurrence of immune complex and complement-mediated membranoproliferative glomerulonephritis in kidney transplantation

ABSTRACT

Introduction

Membranoproliferative glomerulonephritis (MPGN) represents a histologic pattern of glomerular injury that may be due to several aetiologies. Few studies have comprehensively analysed the recurrence of MPGN according to the current classification system.

Methods

We collected a multicentre, retrospective cohort of 220 kidney graft recipients with biopsy-proven native kidney disease due to MPGN between 1981 and 2021 in 11 hospitals. Demographic, clinical and histologic parameters of prognostic interest were collected. The main outcomes were time to kidney failure, time to recurrence of MPGN and disease remission after recurrence.

Results

The study group included 34 complement-mediated and 186 immune complex–mediated MPGN. A total of 81 patients (37%) reached kidney failure in a median follow-up of 79 months. The main predictors of this event were the development of rejection episodes and disease recurrence. In all, 54 patients (25%) had a disease recurrence in a median of 16 months after kidney transplantation. The incidence of recurrence was higher in patients with dysproteinaemia (67%) and complement-mediated MPGN (62%). In the multivariable model, complement-mediated MPGN emerged as a predictor of recurrence. A total of 33 patients reached kidney failure after recurrence. The main determinants of no remission were early time to recurrence (<15 months), estimated glomerular filtration rate <30 mL/min/1.73 m² and serum albumin <3.5 g/dL at the time of recurrence.

Conclusions

One-fourth of the patients with native kidney disease due to MPGN developed clinical recurrence in the allograft, especially in cases with complement-mediated disease or in those associated with dysproteinaemia. The kidney outcomes of disease recurrence with currently available therapies are heterogeneous and thus more effective and individualized therapies are needed.

Graphical Abstract

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INTRODUCTION

Membranoproliferative glomerulonephritis (MPGN) represents a histologic pattern of glomerular injury due to several causes [1]. This finding should prompt clinicians to search for a potential underlying aetiology [2, 3]. However, despite advances in the knowledge of the causative aetiologies and their pathogenesis, a number of MPGN cases—particularly those diagnosed a few decades ago—remain ‘idiopathic’ in clinical practice. This may pose a challenge for the clinician, especially when patients reach kidney failure and kidney transplantation is considered, as the risk of disease recurrence in the allograft remains a major concern.

Based on immunofluorescence staining of kidney biopsy specimens, MPGN is currently classified into immune complex/monoclonal immunoglobulin-mediated disease or complement-mediated MPGN [1, 4]. This latter group is further classified into C3/C4 glomerulopathy, which includes C3/C4 glomerulonephritis and C3/C4 dense deposit disease [3].

The overall reported recurrence rate of MPGN in the kidney allograft varies between 18 and 48% [5–10] and represents an important cause of allograft loss, particularly in younger recipients [11, 12]. However, there are great disparities in the recurrence rates according to the underlying aetiology of MPGN [12] and since most studies considered MPGN as a single disease, the actual recurrence rates may be underestimated according to the current classification. For instance, certain aetiologies, such as monoclonal gammopathies of renal significance—namely proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID)—or C3 glomerulopathy, are associated with a higher risk of recurrence, reaching up to 60–89% [12–20], although recurrent disease in subsequent allografts has scarcely been analysed.

Most of the studies that have previously addressed this topic were single centre with relatively small sizes, making the prognostic determinants and outcomes difficult to generalize. Additionally, given the rarity of these disorders, few studies have comprehensively analysed the recurrence of the different types of MPGN according to the current classification system.

Hence the aims of this study were to analyse the recurrence rates in the kidney allograft, predictors of recurrence, management and outcomes in a multicentre cohort of patients with biopsy-proven native kidney MPGN.

MATERIALS AND METHODS

Study patients

Kidney transplant patients (>16 years of age) with biopsy-proven native kidney disease due to MPGN between January 1981 and June 2021 in 11 kidney transplant units belonging to the Spanish Group for the Study of Glomerular Diseases (GLOSEN) and the Spanish Group of Kidney Transplant (SENTRA) were enrolled.

The histologic diagnosis of MPGN on the native kidneys was made in the pathology departments of the participating hospitals. Kidney biopsy specimens were evaluated with immunofluorescence staining for C3, C1q, immunoglobulin G (IgG), IgA, IgM, kappa and lambda (graded as 0–3+). When the immunofluorescence staining showed deposition of immunoglobulins and complement, the sample was classified as immune complex–mediated; when the immunofluorescence staining showed glomerular deposits of complement components in the absence of significant immunoglobulin deposition, the sample was classified as complement–mediated. The histologic evaluation of kidney samples was done according to current diagnostic standards, when available for re-evaluation.

Patients without immunofluorescence staining in the kidney biopsy, those with immediate graft loss and those with missing data were excluded.

Patients with immune complex–mediated MPGN were tested in their nephrology department for autoimmune diseases [systemic lupus erythematosus (SLE), Sjögren's syndrome], infections (hepatitis B and C) and monoclonal gammopathy to determine the underlying aetiological diagnosis. When the results were negative or unavailable (in those diagnosed before 1996), the MPGN was classified as idiopathic.

The study was approved by the Institutional Review Board of the Hospital Universitario 12 de Octubre (Madrid, Spain) and was conducted in accordance with the amended Declaration of Helsinki. Given the retrospective nature of the study, a waiver of informed consent from individual patients was granted.

Study design

We conducted a retrospective, multicentre observational cohort study to evaluate disease recurrence and prognostic determinants.

Clinical, laboratory and histopathologic data

Baseline and follow-up data were compiled from medical records of all participating centres, following a uniform protocol that included demographics, clinical presentation in native kidneys, time to kidney failure and time to kidney replacement therapy, type of donor, human leukocyte antigen (HLA) mismatch, best post-transplant estimated glomerular filtration (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [21], the development of rejection episodes and recurrences.

Kidney biopsy specimens of patients with recurrent MPGN were examined in the pathology departments of participating hospitals and the following histopathological features were recorded: mesangial proliferation, endocapillary proliferation, leukocyte infiltration, cellular/fibrocellular crescents, double contour lesions, interstitial inflammation, percentage of sclerosed glomeruli, degree of interstitial fibrosis/tubular atrophy and arteriosclerosis. All samples were further evaluated with immunofluorescence staining for C3, C1q, IgG, IgA, IgM, kappa and lambda (graded as 0–3+). Only a subset of patients had electron microscopy images.

All biochemical parameters were analysed using routine laboratory methods.

The information about the medication prescribed for each study patient was obtained from the medical records at baseline and throughout the follow-up period.

Molecular and genetic studies of the alternative complement pathway were performed only in a subset of patients with C3 glomerulopathy, as described elsewhere [22, 23].

Outcomes and definitions

The main outcomes were i) kidney graft failure, defined as an eGFR <15 mL/min/1.73 m² by the CKD-EPI [21] equation or the need for maintenance dialysis; death; and the composite outcome of kidney graft failure or death; ii) the development of biopsy-proven recurrence of MPGN; and iii) disease remission after recurrence of the MPGN.

Baseline was defined as the time at which the kidney transplantation was performed and the follow-up period as the interval of time elapsed between kidney transplantation and last outpatient visit, kidney failure or death.

Nephrotic syndrome was defined as proteinuria >3.5 g/day along with serum albumin <3 g/dL. Nephritic syndrome was defined as the combination of microscopic haematuria, non-nephrotic proteinuria, hypertension and kidney function impairment. Isolated non-nephrotic proteinuria was defined as urinary protein excretion <3.5 g/day. Isolated microscopic haematuria was defined as the presence of ≥5 erythrocytes/high-power field.

Complete remission was defined as the recovery of baseline eGFR and proteinuria <0.5 g/24 h. Partial remission was defined as a reduction of proteinuria >50% (and a proteinuria value <3.5 g/day in patients with nephrotic-range proteinuria at baseline) plus stabilization (±25%) or improvement in kidney function.

Statistical analysis

Descriptive statistics are presented as mean and standard deviation (SD) or median and interquartile range (IQR) for continuous variables and frequencies or percentages for categorical variables.

Comparisons of continuous variables between two groups were assessed by using the unpaired t-test or the Mann–Whitney U test, where appropriate. The chi-squared test or Fisher's exact test was used for categorical variables.

Cox proportional hazards regression models were used to analyse the main determinants of kidney failure, using a backward progressive conditional elimination process. The proportional hazards assumption was checked graphically (log-log survival curves) for all covariates and with the scaled Schoenfeld residuals.

Distributions of time to kidney failure were depicted by survival curves using the Kaplan–Meier method.

A P-value <.05 was considered to be significant. All P-values are reported two-sided. Analyses were performed using SPSS Statistics 24.0 (IBM, Armonk, NY, USA).

RESULTS

Cohort description and outcomes

During the study period, data from 246 patients were retrieved, 23 of whom were excluded due to incorrect diagnosis of MPGN or insufficient clinical information and 3 patients due to immediate graft loss (Figure 1). Thus the final study group consisted of 220 patients, 34 complement-mediated (16%) and 186 immune complex–mediated (84%) MPGN. The underlying aetiology of this latter group included 5 cases of hepatitis B (2%), 40 hepatitis C (18%), 3 autoimmune diseases (2 SLE, 1 Sjögren's syndrome; 1%), 6 patients with dysproteinaemia (3%) and 132 (60%) classified as idiopathic. All cases with complement-mediated disease corresponded to C3 glomerulopathy.

A total of 23 patients (10%) were originally diagnosed at <18 years of age and the underlying aetiologies included 13 (57%) idiopathic MPGN, 7 hepatitis C (30%), 1 SLE (4%) and 2 C3 glomerulopathy (9%).

Baseline clinical characteristics of patients according to immunofluorescence-based classification are shown in Table 1. The majority of patients had undergone deceased-donor transplantation. No significant differences were observed in age at transplantation, type of donor, cold ischaemia time or rate of immediate graft function. Conversely, significant differences were observed in the maintenance immunosuppressive regimen, with the prescription of a combination of corticosteroids, tacrolimus and mycophenolate mofetil being significantly more common in the subgroup of patients with complement-mediated MPGN than in the rest of the patients.

During a median follow-up of 79 months (IQR 30–143), 81 patients (37%) reached kidney failure. Supplementary data, Table S1 show uni- and multivariable Cox regression analyses for the main determinants of this outcome: the development of rejection episodes during the course of follow-up {hazard ratio [HR] 2.24 [95% confidence interval (CI) 1.32–3.71]; P = .004} and recurrence of MPGN [HR 3.19 (95% CI 2.07–5.22); P < .001] emerged as the main predictors. In all, 38 patients (17%) died at the end of follow-up.

Figure 2A shows death-censored kidney graft survival curves according to recurrence of the disease. Figure 2B shows the survival curves for the composite outcome (kidney failure or death) according to recurrence of the disease.

Recurrence of the disease

A total of 54 patients (25%) had a recurrence of the disease after a median time of 16 months (IQR 6–74) from kidney transplantation (3/100 patient-years follow-up).

At the time of diagnosis of recurrence, patients had a significant kidney function impairment [median eGFR 30 mL/min/1.73 m² (IQR 16–41)] and proteinuria [median 3.2 g/day (IQR 2–6.6)].

The recurrence rate was significantly higher among patients with complement-mediated MPGN compared with immune complex–mediated MPGN (62% versus 18%, respectively, P < .001; 10 versus 2/100 patient-years, respectively). In addition, there was a non-significant trend toward an earlier time of recurrence in the former group. However, no significant differences were observed in the type of clinical presentation or proteinuria between these groups (Table 1). As expected, patients with recurrent complement-mediated MPGN had significantly lower serum C3 levels. Regarding kidney biopsy findings, no significant differences were observed between groups, although there was a non-significant tendency toward a greater percentage of glomerulosclerosis and interstitial fibrosis/tubular atrophy in the group of patients with immune complex–mediated MPGN. A total of 12 patients (57%) with recurrent complement-mediated disease showed only C3 staining (without immunoglobulin staining), versus 9 cases (43%) with C3-dominant staining. Supplementary data, Table S2 shows baseline clinical characteristics according to recurrence of the disease and Supplementary data, Table S3 shows the characteristics according to time to recurrence.

Table 2 shows the clinical characteristics, management and outcomes of patients according to the aetiology of MPGN.

The incidence of recurrence was higher in patients with dysproteinaemia [4/6 patients (67%)] and complement-mediated MPGN (62%) and tended to recur earlier than the rest of the aetiologies (median of 14 and 7 months, respectively).

The lowest recurrence rate was found among the group of patients with idiopathic MPGN (15%). On the other hand, none of the patients with MPGN due to autoimmune disorders had a recurrence after kidney transplantation.

A total of 40 patients (18%) had MPGN due to hepatitis C and the rate of recurrence in this group was lower than the previous aetiologies [7 patients (18%)]. These patients with recurrent MPGN had been transplanted before 2009, three of whom had received interferon-based therapy without response. Conversely, 7 patients (18%) of the 40 with hepatitis C had received antiviral therapy before kidney transplantation (3 with direct-acting antivirals and 4 with interferon-based therapy), none of which recurred after transplantation.

In all, 2/5 patients (40%) with MPGN due to hepatitis B recurred and were characterized by a late recurrent disease. Patients without recurrence were under treatment with mammalian target of rapamycin (mTOR) inhibitors and/or entecavir.

Regarding the six patients with MPGN due to dysproteinaemia, three (50%) had a kidney biopsy compatible with PGNMID, one (16.7%) with type I cryoglobulinaemia, and one (16.7%) with C3 glomerulopathy in the setting of an IgG kappa monoclonal gammopathy, whereas in one patient (16.7%) with an IgM lambda monoclonal gammopathy diagnosed in 2001, we could not retrieve the complete kidney biopsy report to classify the type of kidney lesion. These patients with MPGN due to dysproteinaemia were significantly older than the rest of the aetiologies and two patients had received clone-targeted therapy before kidney transplantation. In all, two of the patients with PGNMID (67%), the one with C3 glomerulopathy in the setting of monoclonal gammopathy (100%) and the one with cryoglobulinemia (100%), recurred in the kidney allograft.

A total of 19/34 (56%) patients with complement-mediated MPGN had genetic studies of the alternative complement pathway (Supplementary data, Table S4): 10 variants were considered as pathogenic (29% of the patients with complement-mediated MPGN) and 1 as a variant of unknown significance (3%), whereas in 8 patients no genetic abnormalities were found (24%). On the other hand, four patients had a C3 nephritic factor (12%). In all, 26 patients (76%) fulfilled the criteria for C3 glomerulonephritis, of which 14 (42%) had a recurrence. Conversely, three patients (9%) were classified as dense deposit disease, all of which had a recurrent disease. In five cases (15%), no electron microscopy was available to classify histologic subtypes.

Supplementary data, Figure S1 displays the changes in the incidence of recurrence of MPGN over 4 decades according to underlying aetiology. A non-significant trend toward a decrease in the incidence of recurrence was observed in patients with idiopathic MPGN and those due to hepatitis B and C in the last decade.

Table 3 displays the uni- and multivariable Cox regression analyses for the main determinants of recurrence of the different types of MPGN. In the multivariable model, only the type of MPGN emerged as a predictor of recurrence, with complement-mediated MPGN being associated with higher risk [HR 5.32 (95% CI 2.88–9.43); P < .001]. Figure 3A shows Kaplan–Meier curves for recurrence-free survival according to the immunofluorescence-based classification of MPGN. Figure 3B shows the kidney survival curves according to the type of MPGN, with a non-significant trend toward worse survival in patients with complement-mediated MPGN.

Kidney outcomes after recurrence and therapeutic strategies

A total of 33/54 patients with recurrence (61%) reached kidney failure after the recurrence of the disease. Conversely, 13 patients (24%) achieved remission: 4 cases complete (7%) and 9 partial remission (17%). Supplementary data, Table S5 displays the characteristics of patients with recurrent MPGN according to kidney outcome.

Dysproteinaemia and complement-mediated MPGN were the aetiologies most frequently associated with kidney failure after recurrent disease. The therapeutic strategies used for recurrence differed according to the underlying aetiology and were prescribed at the discretion of the treating physician (Table 2).

Regarding the group of patients with recurrent disease due to idiopathic MPGN, one patient (5%) treated with corticosteroids achieved complete remission, whereas four patients (20%) achieved only partial remission after being treated with corticosteroids plus rituximab or increased doses of mycophenolate mofetil. A total of 13/20 patients reached kidney failure at the last follow-up (65%).

Only one patient with recurrent MPGN due to hepatitis C (14%) achieved partial remission after being treated with corticosteroids and interferon-based therapy. Likewise, only one patient with recurrent MPGN due to hepatitis B (50%) achieved partial remission after being treated with corticosteroids.

Patients with dysproteinaemia were treated with corticosteroids alone (25%), corticosteroids plus mycophenolate mofetil dose increase (25%), plasma exchange (25%) and rituximab (25%). This aetiology was associated with worse outcomes, as three of the four patients with recurrent diseases (75%) reached kidney failure. The only patient treated with rituximab (patient with type I cryoglobulinemia) achieved remission (Supplementary data, Table S6).

Patients with complement-mediated MPGN were treated with corticosteroids (48%), alone or in combination with rituximab (19%), eculizumab (43%), mycophenolate mofetil dose increase (19%), plasma exchange (14%) or, less frequently, with aliskiren (10%). In all, 12/21 patients with recurrent disease (57%) reached kidney failure. No significant differences in histopathological parameters were observed between patients who did or did not reach kidney failure (Supplementary data, Table S7). A total of three patients achieved partial remission (14%), after being treated with corticosteroids alone (one case) or corticosteroids plus mycophenolate mofetil and eculizumab (two cases). Two patients achieved complete remission (10%) after being treated with eculizumab (one case) or plasma exchange plus rituximab plus mycophenolate mofetil dose increase (one case).

Table 4 displays the uni- and multivariable Cox regression analyses for the main determinants of no remission after recurrence of MPGN. In the multivariable model, a time to recurrence ≤15 months [HR 4.23 (95% CI 2.09–9.41); P < .001], an eGFR at recurrence <30 mL/min/1.73 m² [HR 2.11 (95% CI 1.12–4.15); P = .02] and a serum albumin at recurrence <3.5 g/dL [HR 2.56 (95% CI 1.34–4.91); P = .005] emerged as the main predictors of no remission. Figure 4A shows the kidney survival curves according to early (≤15 months) and late (>15 months) recurrence of the disease. Patients with early recurrence showed significantly worse kidney survival. Figure 4B displays the kidney survival curves of patients with recurrent disease according to the achievement of remission (partial or complete) or not. Patients who achieved remission (partial or complete) after recurrence had significantly better kidney survival.

Disease recurrence in subsequent allografts

A total of 36 patients (16%) underwent a second kidney transplantation, 14 (39%) of whom had lost the previous allograft due to recurrence of the disease. The underlying aetiology of MPGN in this latter group included idiopathic disease [seven patients (50%)], C3 glomerulopathy [six patients (43%)], hepatitis C [one patient (7%)].

In a median follow-up of 16 months (IQR 7–48), seven patients (50%) had a subsequent recurrence of the disease in the second kidney allograft (three cases of C3 glomerulopathy and four with idiopathic disease). Of those, three patients (43%) eventually reached kidney failure (one case of C3 glomerulopathy and two cases with idiopathic MPGN) despite treatment with corticosteroids and the addition of cyclophosphamide in one case. Conversely, four patients (57%) achieved a partial or complete remission at the end of follow-up. These patients were treated with corticosteroids and an increased mycophenolate mofetil maintenance dose.

The patient with C3 glomerulopathy (carrying a pathogenic variant in the CFHR1 gene) underwent a third kidney transplantation with a new recurrence of the disease and subsequent kidney failure and has now received a fourth kidney transplant with an early recurrence of the disease on protocol biopsy.

DISCUSSION

Herein we report the outcomes and recurrence rates of an observational cohort of patients with biopsy-proven native kidney MPGN. There are several major findings in this study. First, our results confirm that the clinical recurrence rate of MPGN is 25% of patients and is significantly associated with worse kidney outcomes. Second, the recurrence rate was significantly higher among patients with complement-mediated MPGN and tended to recur earlier compared with immune complex–mediated MPGN. Third, dysproteinaemia and C3 glomerulopathy represent rare causes of kidney disease associated with a high risk of recurrence in the transplanted kidney. Moreover, this latter aetiology can recur in subsequent kidney allografts, particularly in those with known pathogenic variants in complement genes. Fourth, a small number of patients (24%) may achieve remission after recurrent disease and the main determinants of no remission were time to recurrence <15 months, eGFR <30 mL/min/1.73 m² and serum albumin <3.5 g/dL at the time of recurrence.

To the best of our knowledge, this is the largest case series that has analysed the recurrence of MPGN according to the current classification system. This allowed us to compare the recurrence rates of the different types of MPGN as well as the different outcomes. Moreover, this is the largest case series that has analysed recurrent disease among patients with C3 glomerulopathy, of which ˃50% had genetic studies of the alternative complement pathway.

The overall incidence of recurrence found in our cohort was similar to that reported in other cohorts [5–10]. Additionally, we found a non-significant trend toward a decrease in the incidence of hepatitis B and C–associated MPGN and recurrence over time, consistent with the therapeutic advances made in these diseases in recent years.

Several factors have previously been associated with an increased risk of MPGN recurrence in the kidney allograft. Older studies found a higher risk of disease recurrence among recipients of living related-donor kidneys and those with the HLA-B8DR3 haplotype [5, 6]. More recently, the HLA loci DQA1*05:01, DQB1*02:01 and DRB1*03:01 have been associated with MPGN [24]. Type I and II MPGN have classically been associated with a higher rate of recurrence and consequent worse kidney survival [16, 17, 25]. However, one study suggested that the severity of the glomerular injury on the initial biopsy—and particularly the degree of mesangial proliferation and the presence of cellular crescents—rather than the type of MPGN per se determined the overall kidney survival and the risk of recurrence [26, 27]. In addition, younger age at diagnosis of MPGN [7], low serum C3 levels [6, 7] and higher proteinuria [17] have previously been implicated in the risk of recurrence.

Contrary to the aforementioned studies, we found that the most important factor associated with disease recurrence was the underlying pathogenic mechanism involved, with complement-mediated forms being associated with higher risk. Few studies have analysed the outcomes of C3 glomerulopathy after kidney transplantation, showing an overall poor prognosis after disease recurrence, with almost 50% reaching kidney failure [16–19]. We found disease recurrence in 21/34 patients with C3 glomerulopathy (62%). Of those, 12 cases (57%) eventually reached kidney failure after recurrence. Regarding the management of disease recurrence in this subset of patients, only a few showed a therapeutic response after being treated with a combination of agents (corticosteroids, increased doses of mycophenolate mofetil, eculizumab, or plasma exchange). However, given the small number of patients, it is difficult to draw firm conclusions, and the optimal approach should be defined in prospective studies.

There is a scarcity of data about treatment strategies in C3 glomerulopathy among kidney transplant recipients. Previous case series have reported the experience with rituximab or eculizumab with similar results [18, 19]. A systematic review of the literature showed that eculizumab was associated with lower rates of graft loss, particularly in cases with C3 glomerulonephritis compared with dense deposit disease [28]. Interestingly, although several case series have described a potential benefit of corticosteroids plus mycophenolate mofetil in native kidney C3 glomerulopathy [22, 29], this therapeutic strategy has not been shown to be effective among kidney transplant recipients, as most of these patients receive this type of maintenance immunosuppression. One might speculate that C3 glomerulopathy patients with recurrent disease in the kidney allograft could represent a subset with a more aggressive phenotype associated with greater resistance to treatments. In fact, in our study we found a case of persistent recurrence in subsequent kidney allografts in a patient with a well-characterized pathogenic variant. Thus our data highlight the need for newer more effective therapies in C3 glomerulopathy in kidney transplant recipients with disease recurrence.

Another important group of patients was that of MPGN in the setting of dysproteinaemia. The majority corresponded to PGNMID and were associated with a high recurrence rate, although the number of patients was small. In addition, the only patient with C3 glomerulopathy had a disease recurrence. It is likely that the older age of patients with MPGN due to dysproteinaemia could also influence the overall outcomes. These results are in line with those reported in larger series, which have shown the importance of achieving haematologic response to reduce recurrence risk and graft loss [13, 15, 30].

The main predictors of no remission after recurrence were an earlier time to recurrence, together with the presence of hypoalbuminaemia and decreased eGFR, pointing towards a more aggressive clinical presentation.

Several limitations should be acknowledged. First, due to the observational and retrospective nature of the study, no causal relationships can be established. Second, in a significant number of MPGN cases, an underlying aetiology could not be found and thus patients were classified as idiopathic. Thus, given the potential heterogeneity of this idiopathic MPGN group, the results for this group can only be descriptive. Third, only a small number of patients had protocol biopsies, which may have underdiagnosed some cases of recurrent disease with atypical presentations. Fourth, since C3 glomerulopathy can present with patterns of glomerular lesions other than MPGN, several cases of recurrent C3 glomerulopathy may have been overlooked. Last, the clinical management of recurrent disease was done at the discretion of the treating physician, which could explain, at least partially, the heterogeneity in the outcomes of some cases. In addition, therapeutic strategies were used according to the availability of agents or the state of knowledge of the diseases at the time of recurrence. Despite these limitations, this study collected data on one of the largest case series for these rare diseases and further contributes to the understanding of their natural history in the kidney transplant recipient.

In conclusion, the results of this study show that one-fourth of patients with native kidney disease due to MPGN had a recurrence in the allograft, especially in cases with complement-mediated disease and those associated with dysproteinaemia. The kidney outcomes of disease recurrence with currently available therapies are heterogeneous and thus more effective and individualized therapies are needed. Prospective studies are warranted to better elucidate the best therapeutic strategies.

AUTHORS’ CONTRIBUTIONS

F.C.-F., N.P., M.J.P-S. and M.P. were responsible for the research idea and study design. F.C.-F., N.P., B.V., A.B., A.C., A.A., R.M.-G., C.G., R.V., N.R., N.A., L.C.-V., M.J.P.-S., A.S., E.G., A.H., E.R., M.F.-R., J.M.A., M.A.P.V., A.A. and M.P. were responsible for data acquisition. F.C.-F., A.A. and M.P. were responsible for statistical analysis and supervision or mentoring. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual's own contributions and questions pertaining to the accuracy or integrity of any portion of the work.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no relevant financial interests.

FUNDING

Work in this study was supported by the Instituto de Salud Carlos III/Fondo Europeo de Desarrollo Regional (ISCIII/FEDER) grant PI16/01 685 and PI19/1624 and Red de Investigación Renal (RedInRen) (RD12/0021/0029) (to M.P.), PI16/00 617, PI19/0037 and RD16/0009/0013 (to J.P.), the Autonomous Region of Madrid (S2017/BMD-3673) (to M.P.). None of the funders had any role in the study design, data collection, analysis, reporting or the decision to submit for publication.

APPENDIX

The authors acknowledge the valuable contribution of all collaborators of the MPGN recurrence study group from GLOSEN and SENTRA: Marina Alonso, Oscar Toldos-González (Hospital Universitario 12 de Octubre, Madrid); Rocío Cabrera-Pérez (Hospital Universitario Virgen del Rocío, Sevilla); Javier Gimeno (Hospital del Mar, Barcelona); Luisa Pérez-Ebri (Hospital Universitario Doctor Peset, Valencia); José María Gómez Ortega, José Javier Gómez Román (Hospital UniversitarioMarqués de Valdecilla); Ana Saiz (Hospital Universitario Ramón y Cajal, Madrid); Alejandra Gabaldón Domínguez, Marta Garrido, Alexandra Navarro (Hospital Universitario Vall d'Hebron, Barcelona); Carles Saus (Hospital Universitario Son Espases, Palma de Mallorca); María Cabezas Macian (Hospital General Universitario de Elche, Elche).

REFERENCES