Recurrence of Primary Glomerular Diseases After Kidney Transplantation: Incidence, Predictors, Characteristics and Treatment

Abstract

Recurrent primary glomerulonephritis is a frequent and severe disease that represents the second or third leading cause of graft loss. The purpose of this study is to address the rates of recurrence for all types of glomerulonephritis, detailing their characteristics and the treatments adopted. The authors collected the main studies and meta-analyses published on PubMed. In addition, the main clinical trials ongoing on the topic were collected. The results highlighted the different frequency of recurrence in relation to the glomerulone-phritis considered, assessing the different characteristics and the different treatments adopted. In conclusion, this review confirms the severity of this disease. The treatment possibilities differ among glomerulonephritis variants. Frequently, a pre-transplant period should be distinguished from a peri-transplant period and a post-transplant period. Fi-nally, new drugs are being discovered to treat recurrent glomerulonephritis and several ongoing trials are also discussed. Some of them have shown important results already.

1. Introduction and Background

Recurrent glomerular diseases are increasingly recognized as major causes of renal allograft loss, especially in the long term. In general, there are several reports of recurrence based on single-center and pool data.

El-Zoghby et al. [1] identified the specific causes of kidney allograft loss and reported that transplant glomerulopathy accounts for 41% of glomerular diseases, whereas recurrent GN accounts for 41% and de novo GN accounts for 17.9%. Sellares et al. [2] reported that recurrent glomerular disease increases over time; at 10 years, it is the second leading histopathological diagnosis after lesions that can be ascribed to antibody-mediated rejection.

The risk of primary glomerulonephritis (GN) recurrence in the kidney allograft is based on the type of GN and is the second or third most common cause of death-censored graft loss [3,4], as shown in Figure 1. Recognizing and managing this risk before and after kidney transplantation is critical to long-term outcomes. All forms of primary GN may recur, but the risk of recurrence differs by subtype of GN.

In old research as in recent studies, the risk for post-transplant recurrence is extremely variable for any nephropathy considered. This high variability can be attributed to different factors, such as the different populations studied, selection bias, different clinical approaches to transplant patients, and the frequency of kidney biopsy. In a recent retrospective study conducted at two kidney transplant centers between 2005 and 2020 [5], recurrent GN was diagnosed in 17%, 20%, 25% and 13% of recipients with IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and membranoproliferative glomerulonephritis (MPGN), respectively. The mean time to recurrence was shorter in FSGS patients (0.6 years) and longer in MN patients (6.3 years). The time to graft loss was shorter in MPGN patients (0.3 years) and longer in IgAN patients (2.9 years).

In two large series, GN recurrence was the third most frequent cause of late graft failure after chronic allograft nephropathy and death, accounting for 8–12% of graft losses at 10 years after transplantation [6,7]. As mentioned above, all GN subtypes may recur after kidney transplantation, with the prevalence of GN recurrence ranging between 3% and 15% [8,9,10,11,12]. For particular types of primary GN, the recurrence incidence may be as high as 100%, such as for dense deposit disease and some types of atypical uremic syndrome (aHUS).

The aim of this review is to clarify the recurrence rate of glomerulonephritis after kidney transplantation and its impact on long-term kidney allograft outcomes. Additionally, we review the characteristics of these issues and the current protocols for the prevention and management of recurrent glomerular disease post-transplant.

In particular, specific recurrent primitive glomerular diseases and their risk factors, outcomes, ancillary testing, and treatment are discussed in depth: IgA nephropathy, focal segmental glomerular sclerosis (FSGS), membranous nephropathy (MN), and membranoproliferative glomerulonephritis (MPGN, C3G, PGNMID).

2. Prevalence, Predictors and Risk Factors

The prevalence of recurrence of primary GN varies by subtypes and divergence recurrent rates are reported in the literature.

Table 1. Prevalence of GN recurrence.

Recurrence Prevalence	Overall	IgAN	FSGS	MN	MPGN
ANZDATA (1985–2014)	10.3%	10% at 10 years	9% at 10 years	16% at 10 years	16% at 10 years
Mayo/Toronto	39.5% at 5 years	42% at 3 years	31% at 3 years	45% at 3 years	41% at 3 years
British Columbia (1990–2005)	13% at 10 years	15.4%	9.7%	10%	4.8%
Korea (1995–2010)	17.8%	14.8%	6.3%	0%	12.5%
France	NR	36% at 10 years	NR	NR	NR

shows this variability for various registries and regions, such as ANZDATA [13], Mayo/Toronto [14], British Columbia [15], Korea [16], and France [17].

The reported data exhibits large differences, which may be due to the subtypes of GN, attitudes toward performing renal biopsies, and the effects of new immunosuppressive therapies.

Similar discordant data on both the risk of recurrence risk and the risk of graft loss due to recurrence were reported in a study by Choy et al. [18].

Table 2. Risk of recurrence and graft loss for different types of primary GN [18].

	Recurrent Risk	Risk of Graft Loss Due to Recurrence
IgAN	13–46%	2–16%
FSGS	20–50%	13–20%
MPGN
Type 1	20–25%	15%
Type 2	80–100%	15–30%
MN	10–30%	10–15%

shows these data.

Similarly, a study by Sprangers et al. [19] also reported variability based on whether recurrence is evaluated only via pathological findings evaluation or via clinical–pathologic findings. Specifically, the recurrence percentage is greater for diagnosis based only on pathological findings, as shown in

Table 3. Recurrence rate of primitive GN.

Disease	Recurrence Rate
	Pathological	Clinical–pathological
Membranous nephropathy	7–44%	10%
FSGS	30–50%	30%
IgA nephritis	9–61%	5%
MPGN	27–65%	Depending on type (40%)

.

Moreover, Cosio et al. [7] analyzed the recurrence of primary GN, diagnosed by protocol or clinical biopsy, to evaluate actual graft survival at the end of the study. They compared transplant recipients without GN with patients treated via FSGS, MN, MPGN, and IgAN. Actual graft survival rates were highest for patients without GN, followed by patients with IgAN recurrence. The graft survival rate was lowest for patients with MPGN, at 53.8%, and this difference was significant (p < 0.0001). Notably, the relatively low number of patients in each group did not allow the accurate determination of the incidence of recurrence beyond 5 years’ post-transplantation. In addition, the log rank test was used to compare death-censoring graft survival in recipients diagnosed with GN and those with pre-transplantation diagnoses other than GN. Finally, patients with IgAN had a significantly longer follow-up time (p = 0.028), likely because of longer survival.

Additionally, the study revealed that patients with primary MN who were negative for anti-PLA2R antibodies had a 30% recurrence rate post-transplantation, whereas patients who were positive for anti-PLA2R antibodies had a 70% recurrence risk post-transplantation.

Several factors are predictors of the recurrence of primary GN. A study by Chukwu [5] revealed several of these factors in relation to the different types of nephropathy. In the case of IgA nephropathy, the predictors of recurrence are ethnicity (HR 1.48, p 0.09), the use of cyclosporine (HR 2.82, p 0.035), acute rejection (HR 2.33, p 0.02), and glomerular deposits of IgG (HR 2.75, p 0.01). The significance ethnicity is borderline, but in one study performed in New Mexico, the frequency of IgAN in transplanted kidneys in Native American patients was 2.7 times higher than in Caucasian graft recipients. In the case of FSGS, the predictors of recurrence are the urine protein/creatinine ratio at first diagnosis (HR 1.15, p 0.002), induction with alemtuzumab (HR 3.38, p 0.035), biopsy-proven acute rejection (BPAR) (HR 3.17, p 0.039), mesangial proliferation in native biopsy (HR 5.38, p 0.043), IgG deposits in native kidney (HR 20.49, p 0.033), and IgA deposits in native biopsy (HR 12.11, p 0.003). In the same study, no significant predictors of MN recurrence were identified.

The predictors of MPGN recurrence are a lower body mass index (BMI) at transplantation (HR 0.21, p 0.01), the presence of crescents in the original biopsy (HR 34.5, p 0.003), and the proportion of glomeruli with crescents in the native biopsy (HR 28.8, p 0.03). As observed for FSGS, alemtuzumab induction may also favor recurrence in MPGN patients (HR 1.5, p 0.05).

Lim et al. also broadly studied these predictors [20]. Specifically, they collected the observations of different authors, published in the literature, related to the prognostic and predictive biomarkers of glomerulonephritis and the recurrence of disease after kidney transplantation. The results of the study and related references are reported in

Table 4. Prognostic and predictive biomarkers of glomerulonephritis and recurrence of disease after kidney transplantation.

Potential Predictive Biomarkers in GN Subtypes	Clinical Utility	Predict Post-Transplant Recurrence
IgA nephropathy
Serum IgA level [21]	↑ Post-transplant predict recurrence	Yes
Serum galactose deficient IgA1 [22]	↑ Pre-transplant predicts post-transplant recurrence	Yes
Serum IgA-IgG complexes [22]	↑ Pre-transplant predicts post-transplant recurrence	Yes
Serum IgA-sCD89 complexes [22]	↓ Pre-transplant predicts post-transplant recurrence	Yes
Normalized Gd-IgA1 specific autoantibody [23]	↑ Pre-transplant predicts post-transplant recurrence	Yes
Serum APRIL [24]	↑ Post-transplant predicts recurrence	Yes
Urine proteomics (SERPINA 1, Transferrin, APOA4 and RBP4) [25]	↑ Post-transplant predicts recurrence	Yes
FSGS
Serum suPAR [26]	↑ Pre-transplant predicts post-transplant recurrence	Yes
Urine suPAR [27]	↑ Post-transplant predicts recurrence	Yes
Anti CD40 autoAb [28]	↑ Pre-transplant predicts post-transplant recurrence	Yes
Urine apolipoprotein A-1b [29,30]	↑ In relapses	No data
A1AT [31]	Differentiate from other causes	No data
CLC-1 [32]	↑ Recurrent disease	No data
Anti AT1R Ab	↑ Pre-transplant predicts post-transplant recurrence	Yes
Membranous GN
PLA2R antibody [33]	↑ Pre-transplant predicts post-transplant recurrence	Yes
THSD7A autoantibody [34,35]	↑ Primary membranous GN	No data
Autoantigens of AR, SOD2, αENO [36]	↑ Primary membranous GN	No data
MPGN
Complement and C3NF [37,38,39]	Possible association with disease recurrence	Uncertain

GN, glomerulonephritis; FSGS, focal segmental glomerulosclerosis; MPGN, membranoproliferative glomerulonephritis; CLC-1, Cardiotrophin-like cytokine 1; THSD7A, Thrombospondin type 1 domain-containing 7A; AR, aldose reductase; AT1R Ab, angiotensin receptor II type 1 antibodies; PLA2R, phospholipase A2 receptor; C3NF, C3 nephritic factor; Gd, galactose deficient; APRIL, a proliferation-inducing ligand; suPAR, soluble urokinase receptor; Ig, immunoglobulin.

.

3. Main Characteristics

3.1. IgA Nephropathy

IgA nephropathy is the most common primary glomerulonephritis worldwide.

The incidence of recurrent IgA nephropathy after transplantation increases with the time elapsing after transplantation [40]. Clinical recurrence typically occurs beyond 5 years, and the rate of silent histological recurrence is much greater than that of clinical recurrence (51% at years). A study by Moroni et al. [41] reported that recurrence rates depend on the frequency of renal biopsies. Indeed, the incidence of recurrence varies from 10% to 30% in studies with for cause biopsy to 25–53% in studies with protocol biopsies. A small proportion of patients experience early aggressive recurrence (typically those with crescentic IgAN pre-transplant). In addition, IgAN recurrence has a low effect on short-term graft survival. The graft outcome is poorer in patients who experience recurrence long after transplantation than in those who do not. As mentioned above, the recurrence rate is extremely variable. Wyld et al. [42] reported the results of several studies; the histological recurrence rate was lowest in a study by Sato et al. [43], at 15%, and highest in a study by Wang et al. [44], at 78%. The clinical predictors of GN recurrence are a younger age, a more aggressive pre-transplant course, steroid-free treatment, early steroid withdrawal, and an absence of induction therapy [20]. The reduction in or withdrawal of steroids, as well as the absence of thymoglobulin, favor an increase in dangerous immune complexes [45]. Interestingly, a recent study by Uffing et al. [46] revealed the existence of a relationship between the presence of donor-specific antibodies (DSAs) and the recurrence rate of IgA nephropathy. Indeed, the presence of DSAs before transplantation is associated with an HR of 2.74 for recurrence after transplantation. The presence of post-transplantation DSA is associated with an HR of 6.65 for recurrence.

In addition, IgA nephropathy has genetic implications. Indeed, IgA nephropathy is a genetically heterogeneous entity that does not have classic Mendelian inheritance attributable to a single gene locus. Instead, is a complex polygenic disease involving both MHC (HLA) and non-MHC susceptibility alleles. In addition, the multi-hit hypothesis emphasizes both the role of genetic susceptibility and environmental exposure in pathogenesis.

3.2. FSGS

Disease recurrence after transplantation is present in 1 of 3 patients with primary FSGS with a high risk of allograft failure (5 times greater than that of patients without recurrence) [1,5]. The risk of recurrence is relatively high, but the data are uncertain because of the frequent difficulty in distinguishing primary from secondary forms. Indeed, familial FSGS, which includes mutations in podocin or structural podocyte proteins, has a low risk of disease recurrence or none, suggesting the importance of performing genetic testing in patients affected by FSGS [47,48,49,50,51,52,53,54]. The pathogenesis of disease recurrence for primary FSGS is still unknown. The role of the circulating permeability factor is discussed, but the circulating serum soluble urokinase receptor (suPAR) is very likely to play a role. The serum suPAR level was elevated in two studies [55,56]. Other biomarkers with the potential to distinguish primary FSGS and predict disease recurrence risk are urine suPAR, anti-CD40 autoantibodies, and angiotensin receptor II type 1 antibodies. FSGS may be distinguished in several histologic variants such as collapsing, tip lesions and cellular, perihilar lesions, but none of them affect recurrence [57]. In a more recent study [58], the author performed multivariate Cox hazard analysis in patients without FSGS recurrence and compared them with patients with FSGS recurrence. This study included 11,742 kidney transplant recipients screened for FSGS; 176 had a diagnosis of idiopathic FSGS and were included in the study. The results are shown in

Table 5. Multivariate Cox hazard analysis in patients without FSGS recurrence compared with patients with FSGS.

Predictors	Multivariate Analysis (HR)	p Value
Brazil	0.45 (0.21–0.98)	0.05
Europe	0.39 (0.18–0.87)	0.02
Age at diagnosis	1.37 (1.12–1.68)	0.002
White race	2.39 (1.16–4.96)	0.02
BMI	0.89 (0.83–0.96)	0.002
Native kidney nephrectomy	2.89 (1.09–7.66)	0.03

HR, h ratio; BMI, body mass index.

and illustrate the risk factors.

In summary, the risk of recurrence in FSGS patients relies on the following clinical parameters:

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Presentation with nephrotic syndrome;

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Rapid progression of native disease (<3 years to ESRD);

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Whether the pathological type of FSGS has no predictive value;

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Whether diffuse foot process effacement has no predictive value;

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Whether the most reliable risk factor for recurrence is a prior history of recurrence in a kidney transplant, with an 80% chance of recurrence in a second transplant;

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Whether genetic forms of FSGS are associated with a low risk of recurrence [56].

Recently, a study by Watts et al. [59] revealed that autoantibodies targeting nephrin in minimal-change disease support a novel autoimmune etiology.

Two years later, a multi-institutional study revealed the possible role of anti-nephrin antibodies in post-transplant focal segmental glomerulosclerosis recurrence [60]. Hence, pre-transplant anti-nephrin antibodies are specific predictors of the recurrence of FSGS with diffuse podocytopathy in the kidney allograft [61].

As documented in a comprehensive study by El Ters et al. [62], genetics are only involved in a few cases of FSGS recurrence.

The correct classification of FSGS is key to the appropriate treatment of recurrence.

FSGS classification relies on the integration of findings from clinical history, laboratory testing, kidney biopsies, and, in a subset of patients, genetic testing.

Correct classification has implications for the appropriate counseling of the risk of recurrence post-transplant and the risk of allograft loss, appropriate preconditioning, and enrollment in clinical trials.

3.3. Membranous Nephropathy

Overall, approximately 50% of primary MN cases recur in the allograft [63,64,65]. However, the risk of recurrence depends on the pathogenic subtype of MN. The mean risk of recurrence is evaluated to be approximately 25%, and generally, the time of recurrence in MN patients is greater than that in other GN patents. Recurrent membranous nephropathy and de novo membranous nephropathy lead to the same injuries, which is related to the formation of subepithelial immune complexes. However, the composition and triggers of these immune complexes are different: they are principally associated with the action of IgG4 against PLA2R1 antigens, as well as other antigens, in MN recurrence [66]. The discovery that 70% of patients with primary MN have autoantibodies against the podocyte antigen phospholipase A2 receptor (PLA2R) [67] changed this view. Indeed, 70% of patients with primary MN have anti-PLA2R in the serum, and the risk of recurrence is approximately 70%. The presence of anti-phospholipase A2 receptor antibodies has positive predictive value for recurrence (83%), and patients with positive anti-PLA2R Ab SHOW an approximately 60–76% chance of recurrence, whereas this risk is 30% among patients who are negative for this Ab pre-transplant [68]. In addition, high pre-transplant PLA2R Ab levels are associated with earlier recurrence [69]. High antibody titers before and/or after transplantation are associated with a greater risk of progressive disease after recurrence. This picture of MN is expected to change in the near future, as several new antigens responsible for primary MN have been discovered [70] and the recurrence rate is continuously changing. Cyclosporine and mycophenolate mofetil, which are used to treat primary MN, do not prevent or change the course of recurrent disease [71].

3.4. Membranoproliferative Glomerulonephritis

The new classification of MPGN (complement-related vs. immunoglobulin-mediated) has improved our understanding of the recurrence rate. Given the highly variable behavior of MPGN subtypes, the post-transplant and pre-transplant classification of these diseases is crucial. Indeed, the risk of recurrence varies by type (complement vs. immunoglobulin mediated) and according to the presence of monoclonal vs. polyclonal Ig.

According to Figure 2, MPGN can be divided into several entities. First, it may be divided into immune-mediated MPGN and C3 glomerulopathies. The former may be further stratified into MPGN with polyclonal immunoglobulin and MPGN with monoclonal immunoglobulin. The latter is divided into C3-GN and dense deposit disease.

The recurrence rate and the time of recurrence differ according to the type of MPGN. According to Cosio [7], MPGN with polyclonal immunoglobulin has a 35% rate of recurrence post-transplantation and a 10% rate of graft failure. The MPGN with monoclonal immunoglobulin has a recurrence rate of 66% and a graft failure rate of 50%. Complement 3 MPGN has a recurrence risk of 70% and a graft failure rate of 50%, whereas dense deposit disease (DDD) has a recurrence rate of 80–90% and a graft failure rate of 25%. In the case of C3GN, clinical data from the Mayo Clinic yielded a median time to recurrence of 14–28 months and half of the patients with recurrent disease developed allograft failure at a median of 18 months after recurrence [72].

Due to the high risk of recurrence, several factors should be taken into consideration before transplantation.

First, the course of disease in the native kidney should not be considered predictive of the post-transplant course.

Figure 3 shows the acquired and genetic abnormalities associated with complement-mediated MPGN.

In the case of C3 glomerulopathy, a pre-transplant work-up should include the following:

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Comprehensive complement genetic panel;

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Complement functional testing;

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Monoclonal gammopathy screen;

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Factor H autoantibodies;

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C3 nephritic factor.

The avoidance of transplantation during the acute period of kidney loss and acute inflammation suggests that rapid progression to kidney failure in native kidneys is associated with the highest risk of recurrence. Monoclonal gammopathy, associated with C3G, also has a high risk of recurrence [73].

Zand et al. [72] reported that 66.7% of patients with C3 glomerulopathy developed C3GN recurrence in the allograft. The median time to disease recurrence was 28 months. Graft failure occurred in 50% of patients with recurrence, with a median time of 77 months to graft failure.

In this study, 21% of patients were positive for monoclonal gammopathy and had a faster rate of recurrence and graft loss. Monoclonal Ig is hypothesized to inhibit the function of complement-regulating proteins, probably by acting as an autoantibody (C3 Nef or Factor H autoantibody) [74].

A study by Regunathan-Scenk et al. [75] compared recurrent C3 GN with dense deposit disease (DDD) in French, Mayo Clinic, Columbia University, and Dutch research cohorts. The recurrence rate for C3GN was higher at Columbia University, and graft failure for C3GN was greater in the cohort from the Mayo Clinic. For DDD, the recurrence rate and rate of graft failure were greater in the Columbia cohort.

Said et al. [76] reviewed proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and reported a recurrence rate of 89% and a median time from transplant to diagnosis of 5.5 months.

4. Treatment for Primitive GN Recurrence

4.1. IgA Nephropathy

Studies from Japan reported favorable tonsillectomy outcomes in patients with recurrent IgA [77].

Small case series indicate the potential positive role of rituximab in improving proteinuria and delaying graft loss following recurrence [78].

Octreotide has been shown to be beneficial because it inhibits insulin-like growth factor 1 activation [79].

The APPLAUSE-IgAN trial has recently shown the benefit of using iptacopan to treat native IgA nephropathy. Studies on recurrence are awaited [80].

SGLT2 inhibitors (dapagliflozin) may be used as adjunct therapies.

4.2. Focal Segmental Glomerular Sclerosis

FSGS recurrence after transplantation requires both prevention and treatment.

The use of plasmapheresis to remove putative circulating factors and rituximab remain the mainstays of treatment or recurrent FSGS [81]. Rituximab is thought to target B cells and podocyte protein (SMPDL-3b) [5,73]. To date, the results have been inconsistent and unpredictable.

The PRIVENT-FSGS study is a multicenter randomized trial to assess the efficacy of RTX-plasmapheresis in the prevention of FSGS [82].

Obinuzumab, a fully humanized CD20 mAb, appears more effective than rituximab [83].

Alternative therapies are currently being developed:

The LIPOSORBER study is an ongoing trial of lipophoresis in recurrent FSGS patients who are resistant to the standard of care [84].

Bleselumab (a humanized CD40 antibody mAb) was studied in a phase 2a randomized open-label trial for the prevention of recurrent FSGS in 63 adult recipients [85]. In at-risk kidney transplant recipients, bleselumab numerically reduced proteinuria occurrence versus the standard of care, but no notable difference in occurrence of biopsy-proven rFSGS was observed.

The combination of daratumumab (a CD38 mAb) with rituximab has been studied in refractory cases with success [86].

In summary, the best treatment for FSGS can be divided into three stages:

During the pre-transplant period, a complete history of the patient, including the patient’s family history, should be collected. In addition, biopsy slides should be obtained, and genetic testing should be performed if necessary.

During the peri-transplant period, patients should be divided into three categories: low-risk FSGS, likely secondary; moderate-risk FSGS, probably primary; and high-risk FSGS (patients with prior recurrence and failure).

During the post-transplant period, patients with low-risk FSGS should be enrolled in the GN recurrence protocol, but no preconditioning therapy is indicated. Patients with moderate-risk FSGS should be considered for inclusion in clinical trials for prevention treatment. Patients at high risk for FSGS should receive pre-transplant rituximab or obinutuzumab plus plasmapheresis.

4.3. Membranous Nephropathy

Rituximab is currently the first-line therapy for recurrent membranous nephropathy, with a partial/complete response rate of 70% [69].

When rituximab is administered for prevention, a progressive decrease in anti-PLA2R Ab titers may be observed. Monitoring anti-PLA2R Ab titers can help in predicting the response to therapy.

Second-line therapy involves alkylating agents, such as cyclophosphamide or chlorambucil. This requires the discontinuation of mycophenolate mofetil.

Obinutuzumab has shown efficacy in resistant patients [87].

With respect to FSGS, the prevention and treatment of membranous nephropathy may also be divided into several stages.

During the pre-transplant period, biopsy slides should be obtained for review and staining for PLA2R and other markers.

Monoclonal screening should be performed.

In addition, cancer screening should be performed because cancer is often the cause of membranous nephropathy.

In the peri-transplant period, patients should be rescreened for PLA2R Ab, and rituximab induction is warranted in cases of high titers, especially pre-transplant prior recurrence/loss.

In the third phase, over the long term, patients should be enrolled in the GN recurrence protocol.

PLA2R should be monitored every 2–3 months.

In the case of recurrence, patients should be treated with rituximab and obinutuzumab should be considered for nonresponding patients.

4.4. Membranoproliferative Glomerulonephritis

C3 glomerulopathy (C3G) requires a pre-transplant work-up that consists of a comprehensive complement genetic panel (aHUS complement gene panel and internal testing, complement functional testing, a monoclonal gammopathy screen, the search for factor H autoantibody, and the search for C3 nephritic factor).

The treatment of C3G recurrence was widely studied by Regunathan-Schenk et al. [75]. They used rituximab in 3 patients post-transplantation. Not all patients had detectable autoantibodies directed at the alternative complement pathway (anti-factor H antibody or C3 nephritic factor). Rituximab did not appear to have any benefit, with all 3 patients progressing to graft failure.

Eculizumab was used in 7 patients with no response if it started > 6 months from recurrence.

Gonzalez-Suarez et al. [88] compared rituximab, plasmapheresis, and eculizumab. Patients treated with rituximab had a graft loss percent of 81%, and patients treated with plasmapheresis had a graft loss percent of 42%. The best results were obtained with eculizumab, with a graft loss percent of 33%.

Obata et al. [89] evaluated the different complement inhibitors used in C3G. These inhibitors included eculizumab, pegetacoplan, iptacopan, danicopan, avacopan, and narsoplimab.

Wong et al. [90] evaluated iptacopan in particular for the treatment of C3G in a multicenter, open-label, single-arm, nonrandomized study. The endpoints were the change in the urine protein–creatinine ratio (UPCR) in the native cohort and the C3 deposit score of kidney biopsy samples in the recurrent kidney transplant cohort.

The conclusion of the study was that iptacopan resulted in significant, clinically important reductions in UPCR and the normalization of C3 levels in the native cohort and reduced C3 deposit scores in the recurrent kidney transplant cohort, with favorable safety and tolerability.

In summary, there is no proven therapy for C3G recurrence, but eculizumab appears to have the best data to support its efficacy. Novel complement blockers upstream of C5 (C3 and Factor B) are being studied in clinical trials. Data are lacking on the predictive value of genetic/acquired factors for the risk of recurrence. Monoclonal gammopathy associated with C3GN has the worst outcomes and needs to be ruled out. Treatment involves eradicating the monoclonal protein pre-transplant.

Treatment of Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits (PGNMID).

Some patients exhibit a response to rituximab that limits progression but does not prevent recurrence. Daratumumab has shown promise in a trial of native PGNMID but has limited experience in pre-transplant conditioning. Due to the high risk of recurrence, pre-treating all patients with a diagnosis of PGNMID, either with B-cell or plasma cell depletion therapy is preferred. An updated review of outcomes since the implementation of pre-transplant therapy is underway [72,91].

Summary of MPGN Recurrence

Identifying the type of MPGN pre-transplant is key because the risk of recurrence and therapy varies. Native biopsies should be obtained if possible for confirmation and further testing.

Monoclonal screening and appropriate complement testing should be performed on the basis of clinical suspicion. The course of native disease does not predict the post-transplant course.

5. Conclusions

The recurrence of primary glomerulonephritis in the kidney is a common and severe condition. It represents one of the most important causes of graft loss, particularly over long periods of time. The rate of recurrence differs among the different diseases; it is lower in patients with IgA nephropathy and higher in patients with membranoproliferative glomerulonephritis. In addition, the graft loss differs among different types of glomerulonephritis. With respect to the risk of recurrence, each glomerulonephritis subtype has unique risks. Similarly, the different pre-transplant biomarkers among glomerulonephritis subtypes are associated with a risk of recurrence after re-transplantation.

The treatment options differ among glomerulonephritis patient subtypes. The pre-transplant period should often be distinguished from the peri-transplant period and the post-transplant phase. Finally, new drugs are being discovered to treat recurrent glomerulonephritis; several ongoing trials are being attempted, and some of them already have shown important results.