Version May 2024
INTRODUCTION — Membranous nephropathy (MN) may occur in the transplanted kidney, either as recurrent disease in patients who had MN as the cause of end-stage kidney disease (ESKD) in the native kidney or de novo in patients who had another cause of ESKD initially. This topic reviews both recurrent and de novo MN in the transplanted kidney.
The causes, diagnosis, and treatment of MN in the native kidney are discussed elsewhere:
●(See "Membranous nephropathy: Pathogenesis and etiology".)
●(See "Membranous nephropathy: Clinical manifestations and diagnosis".)
●(See "Membranous nephropathy: Treatment and prognosis".)
PRETRANSPLANT CONSIDERATIONS
Evaluation of PLA2R status — In patients with end-stage kidney disease (ESKD) due to MN who are being evaluated for kidney transplantation, every effort should be made to establish the type of MN that was present in the native kidney, if not already known. It is especially important to determine whether the patient's MN was related to autoantibodies to the phospholipase A2 receptor (PLA2R), which is the most important target antigen in patients with primary MN (see "Membranous nephropathy: Pathogenesis and etiology", section on 'Phospholipase A2 receptor'). This can be achieved by retrieving the patient's native kidney biopsy (when available) and immunostaining for the presence of PLA2R within immune deposits, or by determining if anti-PLA2R antibodies have ever been detected in the patient's serum. If the patient has never been tested for serum anti-PLA2R antibodies, testing should be performed. The detection of PLA2R antigen in the native kidney biopsy or presence of anti-PLA2R antibodies in the serum confirms a diagnosis of PLA2R-associated MN.
In patients known or found by these methods to have had PLA2R-associated MN in the native kidneys, testing for the presence of circulating anti-PLA2R antibodies should be performed as part of the initial pretransplant evaluation to assess the risk for recurrence. Further management is determined based upon the results of testing:
●If serum anti-PLA2R antibodies are undetectable, no further testing is required. Such patients are considered to be at low risk of recurrent MN. Some experts would repeat testing for anti-PLA2R antibodies at the time of transplantation as certain stimuli (such as vaccinations and infections) may be able to trigger re-emergence of anti-PLA2R antibodies. However, there are no data to support this approach. (See 'Pathogenesis and risk factors' below.)
●If serum anti-PLA2R antibodies are detected, monitoring of anti-PLA2R antibody levels should be performed at least annually up until the time of transplantation. Such patients are considered to be at higher risk of recurrent MN. (See 'Pathogenesis and risk factors' below.)
●In patients who have high anti-PLA2R titers (eg, >150 RU/mL by enzyme-linked immunosorbent assay [ELISA]), we and others feel that the risk of recurrence is high enough to justify consideration of preemptive treatment [1]. If the patient is undergoing a living-donor kidney transplant or is otherwise expected to receive a transplant in the near future (within four to six months), we make every effort to lower the anti-PLA2R antibody titers by at least 50 percent (and preferably to less than 150 RU/mL) before transplantation, although this threshold is arbitrary and there is no evidence to support our approach. Treatment may involve rituximab (1 g followed 14 days later by another 1 g dose) and possibly plasmapheresis (if transplant is imminent) prior to transplantation, with documentation of a decrease in anti-PLA2R antibody levels prior to proceeding with the surgery. However, the added risk of this additive immunosuppression (ie, B cell depletion) at the time of transplant must be weighed against the potential benefit of decreasing or eliminating anti-PLA2R antibodies to reduce the risk of recurrent disease. If rituximab is given, the patient should ideally be fully vaccinated and boosted against coronavirus disease 2019 (COVID-19) infection prior to receiving rituximab since rituximab may impair vaccine response. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals'.)
In patients who have non-PLA2R-associated MN, additional serologic testing for anti-PLA2R antibodies is not needed. However, if the patient is known to have primary MN associated with an antigen other than PLA2R (such as thrombospondin-1 domain-containing 7A [THSD7A]) and a clinical test is available, we would screen for relevant autoantibodies prior to transplantation.
For those patients who receive a kidney allograft in the presence of circulating anti-PLA2R antibodies, posttransplant surveillance of anti-PLA2R is recommended [2]. (See 'Posttransplant surveillance' below.)
Choice of donor type — For most kidney transplant candidates, including those with MN as the cause of ESKD in the native kidneys, living-donor kidney transplantation is preferred over deceased-donor transplantation given the higher long-term graft survival associated with living-donor kidneys (see "Kidney transplantation in adults: Risk factors for graft failure", section on 'Type of kidney donor'). Although some studies have suggested a higher risk of recurrent MN among recipients of a living, related kidney, we believe that a living-donor kidney, even if from a related donor, should be preferred over a deceased-donor kidney given the much-abbreviated wait time and the likely low absolute increased risk of developing recurrent MN. (See 'Pathogenesis and risk factors' below.)
RECURRENT MEMBRANOUS NEPHROPATHY
Epidemiology — The reported incidence of recurrent MN in kidney transplant recipients with a history of MN in the native kidneys ranges between 10 and 45 percent [3-13]. The reason for the wide variability is that the diagnosis is made only by biopsy, and the indications for biopsy vary between transplant centers [14]. Centers that perform protocol biopsies in the absence of symptoms generally report a higher incidence. As an example, in a study of 19 patients with MN who underwent surveillance biopsies after transplantation, recurrent MN was detected in eight (42 percent) [10].
Pathogenesis and risk factors — The pathogenesis of MN in the native kidneys is discussed elsewhere. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Pathogenesis'.)
●Anti-phospholipase A2 receptor (PLA2R) antibodies – The occasionally rapid recurrence of MN following transplantation has suggested the potential presence of a circulating factor at the time of transplantation [11]. This factor is likely a circulating autoantibody such as the autoantibody to the M-type PLA2R, which has been implicated in the pathogenesis of MN in the native kidneys [15]. Autoantibodies against PLA2R have been reported in patients with recurrent MN [16-18]. In one such patient, who developed recurrent disease 13 days after transplantation, PLA2R and monotypic immunoglobulin G3 (IgG3) were colocalized in glomerular deposits [19]. This patient was also shown to have circulating anti-PLA2R antibodies of the same IgG3 kappa subclass that was present in glomerular deposits of both the native kidney and the allograft, strongly suggesting that this antibody caused the glomerular disease [20].
Several studies have identified circulating anti-PLA2R antibodies at or after the time of kidney transplantation as a risk factor for the development of recurrent MN. A positive test and high titers of anti-PLA2R antibodies at the time of transplantation are associated with an increased risk of recurrent MN, with a positive predictive value greater than 80 percent [21-24]. The disappearance of anti-PLA2R antibodies with maintenance transplant immunosuppression or after specific treatment of recurrent MN results in clinical improvement with resolution of proteinuria [23,25]. The persistence or reappearance of anti-PLA2R after kidney transplantation predicts a worsening clinical course of recurrent MN with increasing proteinuria [23,25]. Thus, testing for anti-PLA2R antibodies at the time of kidney transplantation and serial monitoring of the antibody levels after transplantation might help the clinician to identify patients who need further intervention with either increasing maintenance immunosuppression or other drugs (eg, rituximab) [1,26]. (See 'Evaluation of PLA2R status' above and 'Posttransplant surveillance' below.)
●Other autoantibodies – Other autoantibodies implicated in primary MN have been identified in patients with recurrent MN [27,28]. In one case report, circulating antibodies to thrombospondin type-1 domain-containing 7A (THSD7A) were present pretransplant and associated with the development of recurrent MN in which THSD7A antigen could be detected within immune deposits in the kidney allograft [27]. In another case report, anti-semaphorin 3B antibodies, which had caused MN in an infant and led to end-stage kidney disease (ESKD) by age seven, were present at the time of transplantation and led to early recurrence of semaphorin 3B-associated MN in the allograft [28]. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Other antigens'.)
●Genetic factors – Genetic polymorphisms in both PLA2R1 (the gene for PLA2R) and within human leukocyte antigen (HLA) loci are associated with risk of recurrence. One study demonstrated a 2.5-fold increased risk for recurrence when the recipient carried the HLA-A3 antigen [29]. Another study reported the unexpected finding that polymorphisms in donor PLA2R1 and HLA-D were associated with increased risk of recurrent MN, leading the authors to speculate that modulation of antigen presentation by the allograft might play a role in disease recurrence [30].
●Living, related donor transplantation – Although initial reports suggested that the risk of recurrent MN was higher among recipients of living, related transplants than among recipients of deceased-donor grafts [4,31], this has not been confirmed by larger studies [10-12,32]. In one study of 35 patients with MN who received a kidney allograft between 1975 and 2008, 12 patients (34 percent) developed recurrent MN [12]. Although the rate of recurrence was modestly higher among patients who had a living, related transplant compared with those who received a deceased-donor allograft (4 of 8, or 50 percent, versus 8 of 27, or 30 percent, respectively), the difference was not statistically significant. Two other series that included a total of 53 patients were also unable to confirm a higher risk associated with living, related transplantation [10,11]. However, despite these observational findings, there is a theoretical increased genetic risk of recurrent MN due to shared inheritance of PLA2R1 and HLA-D alleles since these two loci are known to be associated with MN in the native kidney and may be associated with increased risk of recurrence when carried by the donor kidney [30].
Clinical presentation — Clinical manifestations of recurrent MN are typically observed 13 to 15 months after transplantation although they may be observed much earlier (within weeks to months) [10,11,14]. The most common clinical manifestation is proteinuria, the degree of which may vary on presentation. In one study of 15 patients with recurrent MN, 12 (80 percent) had protein excretion greater than 150 mg/24 hours (or a protein-to-creatinine ratio greater than 200 mg/g), with eight having nephrotic-range proteinuria (ie, greater than 3.5 g/day) [11].
Protein excretion may be lower among those with recurrent MN detected by protocol biopsy and without overt signs or symptoms of disease [10,11]. In one study of eight patients with recurrent MN diagnosed by surveillance biopsies, three had normal protein excretion, and five had protein excretion greater than 150 mg/day but less than 3 g/day at the time of biopsy [10].
Progression of proteinuria is common even among patients with mild or no proteinuria on presentation. As an example, in the study cited above, of seven patients who did not receive additional immunosuppression for recurrent MN, five had significant increases in protein excretion, and three developed nephrotic-range proteinuria [10]. In another study, among 29 patients, the median proteinuria increased from 331 mg/day at diagnosis to 1409 mg/day during a mean of 19 months of follow-up [33].
The glomerular filtration rate (GFR) is often normal or only mildly decreased on initial presentation. In the study cited above of 15 patients with recurrent MN, there was no significant difference in serum creatinine at the time of diagnosis compared with patients who did not have recurrent MN [11]. However, the GFR often falls with progression of disease. (See 'Prognosis' below.)
Surveillance and diagnosis
Posttransplant surveillance — Kidney transplant recipients with MN as the cause of ESKD in the native kidney should be monitored after transplantation for signs of recurrent disease:
●In all patients, we measure the serum creatinine level and a spot urine protein-to-creatinine ratio (UPCR) monthly for at least 6 to 12 months after transplantation and every three to six months thereafter.
●In patients with PLA2R-associated MN, we regularly measure serum anti-PLA2R antibody levels every one to three months for the first 6 to 12 months after transplantation depending upon the patient's pretransplant antibody status. More frequent measurements (ie, once per month) may be indicated in patients who had elevated anti-PLA2R antibody titers at the time of transplant (see 'Evaluation of PLA2R status' above). Persistently high or increasing titers of anti-PLA2R antibodies may anticipate the onset of disease recurrence and should prompt consideration of an allograft biopsy. (See 'Diagnostic evaluation' below.)
We do not routinely perform surveillance/protocol biopsies to monitor for recurrent MN.
Diagnostic evaluation — Recurrent MN should be suspected in any transplant patient with a history of MN in the native kidneys who develops new and progressive proteinuria with or without an elevated serum creatinine level. Among patients with a prior history of PLA2R-associated MN, persistently high or increasing titers of anti-PLA2R antibodies after transplant are also suggestive of disease recurrence. (See 'Posttransplant surveillance' above.)
The diagnosis of recurrent MN is established by kidney allograft biopsy. Indications for biopsy vary among transplant centers. We generally perform a biopsy in all transplant recipients with a history of MN who develop any persistent increase in protein excretion above baseline. The characteristic pathologic findings of MN on kidney biopsy are discussed separately. (See "Membranous nephropathy: Clinical manifestations and diagnosis", section on 'Pathology'.)
The association of the PLA2R antigen/autoantibody system in the majority of primary MN cases also holds true in recurrent MN. In one study, 50 percent (5 of 10) of recurrent MN cases were seropositive for anti-PLA2R, and all five stained positively for the PLA2R antigen within immune deposits on biopsy of the allograft [17]. In another study, PLA2R staining within deposits had a sensitivity of 83 percent and a specificity of 92 percent for recurrent MN [34]. Similar to findings in primary MN of the native kidney, immunoglobulin G4 (IgG4) is the dominant or codominant immunoglobulin G (IgG) subclass in recurrent MN [35,36]. These associations may be helpful in distinguishing recurrent MN from de novo MN. (See 'De novo membranous nephropathy' below.)
Treatment
Initial therapy — Initial treatment for recurrent MN includes nonimmunosuppressive and/or immunosuppressive therapies. Our approach varies based upon disease severity, as determined by the degree of proteinuria and/or kidney dysfunction.
Mild disease — Patients with recurrent MN who have mild disease (characterized by proteinuria <1 g/day, stable kidney function, and only histologic evidence of recurrent MN, as detected, for example, by protocol biopsy) typically do not require immunosuppressive therapy and can be initially managed with supportive measures alone. Such measures include renin-angiotensin system inhibition, rigorous blood pressure control, and treatment of hyperlipidemia [14]. We do not augment maintenance immunosuppressive therapy in patients with mild disease, given the excellent prognosis in those in whom disease manifestations do not progress. (See "Membranous nephropathy: Treatment and prognosis", section on 'General measures in all patients'.)
Since proteinuria may increase with duration of disease [37], patients with mild disease should be monitored periodically for disease progression that might warrant therapy. We typically monitor urine protein excretion (by spot UPCR) and serum creatinine every three months. In patients with known PLA2R-associated MN, we also measure serum anti-PLA2R antibody levels every three months.
No studies have conclusively demonstrated a benefit of angiotensin inhibition or good blood pressure control on the progression of recurrent MN in transplant recipients, and support for these interventions is primarily derived from studies of nontransplanted patients with primary MN. In one small observational study of seven patients with recurrent MN, tight blood pressure control (with target of <130/80 mmHg) and angiotensin inhibition did not prevent progression of proteinuria in six patients at 18 months, although GFR remained stable [33]. The optimal target blood pressure for patients who have had a kidney transplantation is discussed elsewhere. (See "Hypertension after kidney transplantation", section on 'Blood pressure goal'.)
Moderate to severe disease — For patients with moderate to severe disease (characterized by proteinuria >1 g/day), we suggest initial therapy with rituximab plus supportive measures, rather than supportive measures alone or combined with other immunosuppressive agents. Supportive measures are the same as those for patients with mild disease. (See 'Mild disease' above.)
●The optimal dose of rituximab is not known. Some experts give one to four doses of 375 mg/m2, with measurement of B-cell CD19 levels after each administration. If this regimen is used, further rituximab dosing is stopped as soon as lymphocytes are undetectable. Other experts give one dose of 200 mg of rituximab, based upon data that lower doses of rituximab can effectively deplete B cells among kidney transplant recipients [38-40]. Infusion reactions are common with rituximab and may be prevented with premedication with antihistamines and acetaminophen with or without a glucocorticoid. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Infusion reactions'.)
●All other immunosuppressive therapies that are used to prevent rejection are continued among patients who receive rituximab. We generally do not modify the doses of other immunosuppressive agents, since the risk of leukopenia is low with rituximab.
B cell depletion in response to rituximab generally occurs within a few weeks and can be best assessed by measuring the percentage of CD19+ B cells. Among patients who respond, the percentage of CD19+ B cells generally decreases to less than 1 percent [41,42]. In addition, we monitor urine protein excretion every two to three months. If the patient has PLA2R-associated MN, we also monitor anti-PLA2R antibody levels every two to three months until levels are undetectable (<2 RU/mL by enzyme-linked immunosorbent assay [ELISA]; some labs now report <4 RU/mL as undetectable). Any consistent decrease in protein excretion or anti-PLA2R antibody levels is regarded as a positive response.
Among patients who have a decline in the CD19+ B-cell count to less than 1 percent but do not have a decrease in protein excretion or anti-PLA2R antibody levels after four to six months, rituximab may be readministered, but we generally wait until the CD19+ B cell count increases to greater than 1 percent or proteinuria increases to >1 gram per day. If there is no consistent decline in protein excretion or anti-PLA2R antibody levels despite two courses of rituximab given four to six months apart, we consider the patient to have resistant disease. (See 'Resistant disease' below.)
The rationale for this approach is based upon clinical experience as there are no well-designed studies to guide the approach to the initiation of therapy for recurrent MN. The approach to immunosuppressive treatment of recurrent MN in the transplanted patient is different from that of nontransplanted patients who develop MN. As an example, nontransplanted patients who develop MN and who have only mild or moderate proteinuria are often not given immunosuppressive therapies, because the rate of spontaneous remission is high. However, patients with recurrent MN are more likely to have aggressive disease since they have a history of end-stage kidney disease due to MN and since MN recurs despite immunosuppressive therapy to prevent rejection. Thus, patients with recurrent MN are generally treated more aggressively than those who present with MN for the first time. (See "Membranous nephropathy: Treatment and prognosis", section on 'Initial therapy for primary MN'.)
Evidence supporting the use of rituximab in patients with recurrent MN is limited to case reports and series [11,16,33,43-45]. As examples:
●In one series, eight patients with recurrent MN and protein excretion of approximately 4.5 g/day were given rituximab (two doses of 1 gram each given two weeks apart) [33]. By 12 months, six of eight patients had either complete (protein excretion <250 mg/day or less) or partial (50 percent decrease in protein excretion) remission. By 24 months, six of seven patients had remissions, and one patient had relapsed. Posttreatment biopsies showed at least partial resolution of histologic changes with resorption of electron-dense immune deposits in six of seven patients and negative staining for C3 and IgG in four of seven and three of seven patients, respectively. Two patients were hospitalized with serious infections, including pneumonia and histoplasmosis.
●Rituximab stabilized or reduced proteinuria and stabilized GFR in four patients with recurrent MN [11]. Two patients received four weekly doses of 375 mg/m2, and two received two doses of 1 g with a two-week interval. Depletion of B cells was demonstrated in all patients.
●In one study of eight patients with recurrent MN and protein excretion >1 g/day, rituximab reduced protein excretion in all patients [37].
Other immunosuppressive agents have not been shown to be effective. The standard doses of cyclosporine, tacrolimus, and mycophenolate mofetil used for immunosuppression after transplantation do not seem to protect against or change the course of recurrent disease [3,9]. There are no rigorous studies that have examined the effect of cyclophosphamide or chlorambucil in recurrent MN [14], and case reports of patients treated with cyclophosphamide have reported contradictory results [7,11]. Small series and case reports that have studied the effect of glucocorticoids have also yielded conflicting results [4,46].
Resistant disease — For patients with recurrent MN who do not respond to initial therapy with rituximab, we suggest cyclophosphamide rather than other immunosuppressive agents. We generally administer oral cyclophosphamide 2 mg/kg per day for 8 to 12 weeks. Patients who are started on cyclophosphamide should discontinue any antimetabolites that they are on (such as mycophenolate or azathioprine) though other antirejection medications, including calcineurin inhibitors and glucocorticoids, may be continued. Patients should be followed closely since cyclophosphamide increases the risk of bone marrow suppression or malignancy in this high-risk population. (See "General principles of the use of cyclophosphamide in rheumatic diseases".)
There are no data evaluating the use of cyclophosphamide in patients with recurrent MN, and support for its use is based upon studies of nontransplanted patients with primary MN. (See "Membranous nephropathy: Treatment and prognosis", section on 'Cytotoxic therapy plus glucocorticoids'.)
Prognosis — Recurrent disease can lead to loss of the allograft [7,13,47]. Estimates of the incidence of graft loss due to recurrent MN are provided by the following studies:
●Among 81 kidney transplant recipients with MN on biopsy of their native kidney, the incidence of allograft loss at 10 years due to recurrent disease was 12.5 percent [47].
●Among 28 kidney transplant patients, recurrent disease was associated with a 10 percent risk of death-censored graft loss over 50 months of follow-up [48].
●Among 49 kidney transplant recipients with recurrent MN (representing 13.7 percent of the total cohort of patients transplanted after reaching end-stage kidney disease due to MN in their native kidneys), five-year graft survival was only 59 percent. Greater than 60 percent of this graft loss was attributed solely to the recurrent MN [13].
DE NOVO MEMBRANOUS NEPHROPATHY
Epidemiology — The reported incidence of de novo MN is approximately 1.5 to 2 percent [46,49,50]. However, the incidence increases with time after transplantation and was 5.3 percent at eight years in one report [51].
De novo MN may be even more prevalent in children with kidney transplants. In one report, de novo MN was present in 48 of 530 allograft biopsies in children (9 percent) [52].
Pathogenesis — De novo MN appears to be associated with chronic and/or antibody-mediated rejection. Support for this association is provided by the kidney biopsy, which often shows signs of both rejection and the classic findings of MN, and by the presence of donor-specific antibodies (DSAs), which are characteristic of antibody-mediated rejection, in patients with de novo MN [29,51,53,54]. In one study of five patients with de novo MN following transplantation, all five who were tested had DSAs at the time of biopsy [53]. In contrast, DSAs were not detected in any patients without MN in this study. Capillaritis and C4d deposition in the peritubular capillaries were common in the de novo MN group, even in those cases with undetectable DSAs [53]. In another report, the titer of DSAs decreased in response to immunosuppressive therapy in one patient with de novo MN [54].
The mechanisms underlying the association between de novo MN and rejection are unknown although several theories have been proposed, all of which focus on the excessive formation of antigen-antibody complexes at the glomerular basement membrane. As examples [46,53]:
●Rejection leads to exposure of previously undetected glomerular antigens, leading to a humoral response.
●Circulating antibodies directed against human leukocyte antigens (HLAs) or other minor histocompatibility antigens expressed in the allograft predispose the recipient to both antibody-mediated rejection and de novo MN.
●Infections that occur in the setting of increased immunosuppression lead to the deposition of antigens in the glomerular basement membrane, with subsequent antibody deposition.
●Rejection-mediated glomerular injury alters the glomerular basement membrane, which facilitates the formation of subepithelial immune deposits.
Host factors may also be important in the susceptibility of the individual to de novo MN. One small study reported a high incidence of recurrent MN (four out of seven) in patients who had a second transplant and a history of de novo MN in the first allograft [52]. In comparison, de novo MN was rare when the second transplant was performed in patients who did not have de novo MN in the first graft, in this study.
Exogenous agents such as medications and supplements, which may lead to MN in the native kidney, may also cause de novo MN in the allograft in individuals not previously known to have had MN. As an example, the use of alpha lipoic acid and dimercaptopropane sulfonate in a 56-year-old male kidney transplant recipient also suffering from amyotrophic lateral sclerosis seems to have been the trigger for the development of de novo MN associated with antibodies to neural epidermal growth factor-like 1 (NELL1) [55]. An association with the use of alpha lipoic acid and NELL1-associated MN has also been demonstrated in individuals who have developed this form of MN in their native kidney [56].
Histologic changes of early de novo MN, including granular staining for phospholipase A2 receptor (PLA2R), have also been reported in a kidney transplant recipient following receipt of the BNT162b2 mRNA COVID-19 vaccine [57].
Clinical manifestations — Proteinuria due to de novo MN typically occurs many years after transplantation, which is a much later onset than that which characterizes recurrent MN [3,4,9]. As examples, in two of the largest retrospective studies, the mean times from transplantation until biopsy diagnosis of de novo MN were 63 and 102 months [51,53] compared with 13 to 15 months noted among patients with recurrent MN. In another study, the median time from transplantation to biopsy diagnosis was over 71 months for de novo MN and less than 6 months for recurrent MN, despite equivalent degrees of proteinuria at the time of biopsy [29]. (See 'Clinical presentation' above.)
Many patients are asymptomatic, and protein excretion remains in the subnephrotic range in approximately one-third or more of cases [51,53].
Diagnosis — The diagnosis of MN is made by classic findings of the disorder on kidney allograft biopsy. Determining whether MN in the allograft is recurrent or de novo requires an accurate diagnosis of the original cause of kidney disease, which may require reassessment of the native kidney biopsy, when available. Since there are many cases in which the exact cause of end-stage kidney disease (ESKD) in the native kidneys was never established, evaluating for PLA2R-associated MN in the allograft with immunostaining and serologic testing of anti-PLA2R antibodies is reasonable.
De novo MN is not typically associated with either circulating autoantibodies to the PLA2R or with positive tissue staining for the PLA2R antigen within immune deposits. In one study, none of the nine subjects with de novo MN had circulating anti-PLA2R or biopsy staining for PLA2R [17]. In another study, only 1 of 11 cases of de novo MN exhibited positive PLA2R staining of the allograft biopsy [34]. In contrast to recurrent MN, in which IgG4 is the dominant or codominant IgG subtype within immune deposits, immunoglobulin G1 (IgG1) tends to predominate in de novo MN [34,35]. Confirming these findings, another study showed that only 1 of 18 (6 percent) de novo MN cases was suggestive of primary MN due to the presence of PLA2R or predominance of IgG4 in the deposits whereas 20 of 33 (61 percent) cases of recurrent MN exhibited these features of primary disease [29].
The kidney biopsy in de novo MN often shows findings of both MN and rejection, as well as the presence of DSAs, which are characteristic of antibody-mediated rejection [29,51,53,54]. DSAs are found in 29 to 67 percent of cases of de novo MN [17,53]. Evidence of transplant glomerulopathy, such as C4d staining in peritubular capillaries or duplication of glomerular basement membrane, may indicate the additional presence of chronic antibody-mediated rejection. The exact proportion of cases of de novo MN that have such additional features is not known.
Treatment — The natural history of de novo MN is unclear. Although some small studies have reported a very poor outcome (50 percent graft loss), it is not known whether the loss was due to de novo MN and other concurrent factors, particularly active and/or chronic antibody-mediated rejection [46]. Another study reported graft failure occurring at event rates of 11.7 versus 3.7 per 100 person-years of follow-up for de novo MN versus recurrent MN, respectively, but acknowledged that the increased presence of antibody-mediated rejection in the de novo MN group could partially explain the poorer outcome [29]. As result, the optimal treatment of de novo MN in the transplanted patient is not known. In particular, it is not clear whether patients with de novo MN should be treated with additional immunosuppressive therapy such as rituximab or cytotoxic agents, since no data have conclusively shown that de novo MN causes graft loss in the absence of other factors such as rejection.
Our approach, which is based upon clinical experience, is determined by the degree of proteinuria that is present and on the stability of kidney function:
●Due to the strong association of de novo MN and antibody-mediated rejection, when de novo MN is identified in this context, the treatment of the rejection is paramount. (See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection".)
●We generally treat all patients with de novo MN with general supportive measures as described above. (See 'Mild disease' above.)
●We treat patients with protein excretion <4 g/day and stable kidney function with an increase in the maintenance dose of one or more components of the immunosuppressive regimen though there are no good data that support this approach.
●We treat patients with protein excretion that is ≥4 g/day or deteriorating kidney function with rituximab as described above. (See 'Moderate to severe disease' above.)
The standard use of calcineurin inhibitors for immunosuppression posttransplantation has not changed the incidence of de novo MN, and pulse therapy with methylprednisolone does not appear to lower protein excretion [51].
Among patients who do not respond to rituximab, we treat with cyclophosphamide (2 mg/kg per day) or high-dose, alternate-day glucocorticoids for 8 to 12 weeks. Patients who are started on cyclophosphamide should discontinue any antimetabolites that they are on (such as mycophenolate or azathioprine) though other antirejection medications, including calcineurin inhibitors and glucocorticoids, may be continued. (See "Membranous nephropathy: Treatment and prognosis", section on 'Initial therapy for primary MN'.)
Plasmapheresis may be considered among patients who have features of chronic rejection in addition to de novo MN.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)
SUMMARY AND RECOMMENDATIONS
●General principles – Membranous nephropathy (MN) may occur in the transplanted kidney, either as recurrent disease in patients who had MN as the initial cause of end-stage kidney disease (ESKD) in the native kidney or de novo in patients who originally had another cause of ESKD. (See 'Introduction' above.)
●Pretransplant considerations – In patients with ESKD due to MN who are being evaluated for kidney transplantation, every effort should be made to establish the type of MN that was present in the native kidney, if not already known. It is especially important to determine whether the patient's MN was related to autoantibodies to the phospholipase A2 receptor (PLA2R). In patients known to have had PLA2R-associated MN in the native kidneys, testing for the presence of circulating anti-PLA2R antibodies should be performed as part of the pretransplant evaluation to assess the risk for recurrence. Circulating anti-PLA2R antibodies at or after the time of kidney transplantation are a risk factor for the development of recurrent MN (See 'Evaluation of PLA2R status' above and 'Pathogenesis and risk factors' above.)
●Recurrent MN
•Clinical presentation – Recurrent MN typically presents 13 to 15 months after transplantation. Patients present with variable amounts of proteinuria that increase over time. Glomerular filtration rate (GFR) is often normal or only mildly decreased on initial presentation but frequently falls with progression of disease. (See 'Clinical presentation' above.)
•Posttransplant surveillance – Transplant recipients with MN as the cause of ESKD in the native kidney should be monitored posttransplant for recurrent MN. In all patients, we measure the serum creatinine and a spot urine protein-to-creatinine ratio (UPCR) monthly for at least 6 to 12 months after transplant and every three to six months thereafter. In those with PLA2R-associated MN, we also measure serum anti-PLA2R antibody levels every one to three months for the first 6 to 12 months after transplant. (See 'Posttransplant surveillance' above.)
•Diagnosis – Recurrent MN should be suspected in any transplant patient with a history of MN in the native kidneys who develops new and progressive proteinuria with or without an elevated serum creatinine level. Among patients with a prior history of PLA2R-associated MN, persistently high or increasing titers of anti-PLA2R antibodies after transplant are also suggestive of disease recurrence. The diagnosis of recurrent MN is established by kidney allograft biopsy. (See 'Diagnostic evaluation' above.)
•Treatment – Our approach to the treatment of recurrent MN varies based upon disease severity:
-Patients with mild disease (characterized by proteinuria <1 g/day, stable kidney function, and only histologic evidence of recurrent MN, as detected, for example, by protocol biopsy) typically do not require immunosuppressive therapy and can be initially managed with supportive measures alone. Such measures include renin-angiotensin inhibition, blood pressure control, and treatment of hyperlipidemia. Since proteinuria may increase with duration of disease, patients with mild disease should be monitored periodically for disease progression that might warrant therapy. (See 'Mild disease' above.)
-For patients with moderate to severe disease (characterized by proteinuria >1 g/day), we suggest initial therapy with rituximab plus supportive measures, rather than supportive measures alone or combined with other immunosuppressive agents (Grade 2C). Supportive measures are the same as those for patients with mild disease. (See 'Moderate to severe disease' above.)
-For patients with recurrent MN who do not respond to initial therapy with rituximab, we suggest cyclophosphamide rather than other immunosuppressive agents (Grade 2C). (See 'Resistant disease' above.)
●De novo MN – De novo MN appears to be associated with chronic and/or antibody-mediated rejection. (See 'Pathogenesis' above.)
•Clinical manifestations – Proteinuria due to de novo MN typically occurs many years after transplantation, which is a much later onset than that of recurrent MN. Many patients are asymptomatic, and protein excretion remains in the subnephrotic range in approximately one-third or more of cases. (See 'Clinical manifestations' above.)
•Diagnosis – The diagnosis of MN is made by classic findings of the disorder on kidney allograft biopsy. Determining whether MN in the allograft is recurrent or de novo requires an accurate diagnosis of the original cause of kidney disease, which may require reassessment of the native kidney biopsy, when available. (See 'Diagnosis' above.)
•Treatment – Our treatment approach, which is based upon clinical experience, is determined by disease severity (see 'Treatment' above):
-All patients should receive general supportive measures as described for patients with recurrent MN. (See 'Mild disease' above.)
-For patients with de novo MN who have proteinuria <4 g/day and stable kidney function, we suggest augmenting the maintenance immunosuppressive regimen rather than rituximab therapy (Grade 2C).
-For patients with de novo MN who have proteinuria ≥4 g/day or deteriorating kidney function, we suggest rituximab rather than other immunosuppressive therapies (Grade 2C). For patients who do not to respond to rituximab, we suggest cyclophosphamide or high-dose glucocorticoids (Grade 2C).
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