Membranous nephropathy (MN) is estimated to cause end-stage renal disease in 5% of patients, in whom renal transplantation is the therapy of choice. Among patients receiving a transplant for MN, the disease will recur in the graft in 30–50%; among these, graft loss will occur in 50% within 10 years. Several studies have suggested that phospholipase A2 receptor autoantibody (aPLA2R) levels before transplantation might be useful in predicting recurrence, and their titration after transplantation is clinically relevant to assess the risk of recurrence and progression, to guide treatment indications and to monitor treatment response. In this review we describe the evolving role of aPLA2R as a biomarker in primary MN and its current usefulness in predicting recurrence of this autoimmune podocytopathy after renal transplantation. Key words: kidney transplantation, phospholipase A2 receptor autoantibody, primary membranous nephropathy, recurrence Introduction reported in one-third of patients. A similar number of patients Membranous nephropathy (MN) is a podocytopathy caused by will develop end-stage renal disease (ESRD), for whom kidney subepithelial immune deposits that produce glomerular base- transplantation is the treatment of choice. Like other autoim- mune diseases, MN can also recur and cause graft loss. ment membrane thickening and podocyte foot process efface- ment. It is the most common cause of adult-onset nephrotic Knowledge of the pathophysiology of MN and identification of syndrome and can be secondary to various autoimmune factors associated with its recurrence are crucial for its preven- diseases, infections, drugs or cancer; however, in most cases tion. In this review we describe the evolving role of phospholi- ( 80%) it is a primary autoimmune disease limited to the kid- pase A2 receptor antibodies (aPLA2R) as a biomarker in pMN ney, also known as primary membranous nephropathy (pMN). and their current usefulness in predicting recurrence of this The clinical course is variable, with spontaneous remission autoimmune podocytopathy after renal transplantation. Received: June 29, 2017. Editorial decision: September 28, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact email@example.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/422/4653511 by Ed 'DeepDyve' Gillespie user on 20 June 2018 aPLA2R after kidney transplantation | 423 secondary process is a challenge. In addition to anamnesis and pMN: an overview of the autoimmune physical examination, some histological data may help to deter- podocytopathy mine whether the pMN is of secondary origin, such as deposi- In 1959, an experimental model by Heymann et al. reproduced tion in the mesangium and intramembranous C1q deposition clinical and morphological features of MN in rats similar to those and positivity for an immunoglobulin G (IgG) subclass other of human MN by intravenous injection of anti-rat kidney serum than IgG4 . This differentiation is highly important to pre- obtained from rabbits. In the late 1970s, other observational stud- scribe a more specific treatment. ies in animal models demonstrated that rat MN was caused Subsequently, another minor target protein was described: when circulating autoantibodies bind to an intrinsic antigen in thrombospondin type 1 domain-containing 7A (THSD7A). Anti- the glomerular podocyte and form in situ immune deposits. THSD7A antibodies can be detected in a small proportion (<5%) Subsequently, that antigen was identified as megalin . Those of patients with pMN without aPLA2R . A higher incidence of models consistently supported the autoimmune nature of MN in neoplasias in these patients has been reported, but the precise rats, but the initial excitement faded quickly as subsequent stud- role of this antigen in this clinical context is currently a matter ies failed to identify megalin in human podocytes . Many of investigation . aspects of the pathogenesis of pMN remained elusive until 2009, No autoantibodies have yet been identified in the remaining when Beck et al.  reported the identification of the M-type phos- pMN patients (15–20%). pholipase A2 receptor (PLA2R) as a major target antigen in human In terms of therapy, circulating aPLA2R levels have been pMN by using a Western blotting approach associated with mass repeatedly shown to correlate with treatment response, disease spectrometry. Nowadays, it is known that 70% of patients with activity and outcome and have become a helpful tool for decid- active pMN have circulating aPLA2R. ing the timing of treatment. Since this finding in 2009, many The presence of PLA2R has been known for many years. In groups have studied the correlation of these antibodies and the fact, Lambeau et al.  determined its nucleotide sequence in clinical activity of MN and have found a strong association rabbits in 1994, after the identification of phospholipase A2 between the evolution of antibody levels and the immunologi- (PLA2), a membrane lytic enzyme, in the organs of different cal activity of the disease in native kidneys [14–17]. Moreover, a mammals and their circulation . Although PLA2R is now high level of circulating aPLA2R at disease onset indicates a known to reside in the plasma membrane of podocytes, the lower likelihood of spontaneous remission and might therefore physiologic function of the PLA2/PLA2R system in the kidney be used as a rationale for early therapy in patients with less and elsewhere remains unknown. severe disease. Conversely, in patients with low levels of In the last few years we have learned many aspects of the nat- aPLA2R at diagnosis, a delay in treatment initiation might be ural history of the MN. The use of enzyme-linked immunosorb- appropriate because these findings may herald a subsequent ent assay (ELISA) kits has allowed detailed knowledge of the role partial or complete spontaneous remission. Furthermore, of aPLA2R in the pathogenesis of this autoimmune podocytop- patients who are PLA2R antigen positive in glomeruli and athy. aPLA2R bind to the protein antigens and form in situ aPLA2R negative in serum but have persistent proteinuria may immune complexes responsible for glomerular damage. Thus, have immunologically inactive disease and chronic glomerular knowledge of the role of these antibodies in MN has allowed new damage. For these reasons, serial aPLA2R measurement during diagnostic techniques. However, aPLA2R are not only detected in and at the end of a scheduled treatment regimen should be rou- the circulation, but also on immunostaining for subepithelial tine as a biomarker of treatment response and in the near PLA2R deposits in kidney biopsy specimens . In fact, some future it may determine the duration of treatment in aPLA2R- patients show positive histological immunostaining but negative associated MN patients. circulating levels. This situation could correspond to a very early In addition to clinical practice optimization, the use of stage of the disease, where very low initial levels of antibodies aPLA2R has generated some fundamental questions on the deposit on the antigen, or could correspond to an immunologi- autoimmunity process associated with pMN. Genome-wide cally inactive aPLA2R MN. The detection of these antibodies has association studies of single-nucleotide polymorphisms have ushered in a new era in the care of patients with pMN. suggested that autoimmunity against PLA2R may be correlated Three techniques have been described to identify circulating with some specific alleles involving the HLA-DQA1 genes, and aPLA2R in serum samples. Indirect immunofluorescence is the several studies from Asia and Europe have linked antibody lev- more sensitive technique but, despite its good performance, it is els and disease severity with certain HLA Class II antigens, limited by its semi-quantitative method and by being observer including DQA1 and DQB1. The role of these antigen associa- dependent. ELISA is currently the diagnostic test of choice in tions has yet to be determined [18, 19]. the clinical setting because it is uncomplicated and allows Two studies have recently shown that the critical epitope in quantification of antibody levels over time with a sensitivity PLA2R is composed of a 31-residue stretch within the folded and specificity of 0.68 and 0.97 , respectively. Other tests, cysteine-rich domain (CysR) at the outmost portion of the such as the original Western blotting, are costly and highly PLA2R molecule. Other epitopes have been also related, such as laborious. CTLD1 [20, 21]. A study by Seitz-Polski et al.  has also investi- As previously stated, the specificity for pMN for the presence gated this, and in addition to identifying CTDL7 as another epit- of aPLA2R is 97%. Thus the presence of these antibodies in the ope, they have linked the identified epitopes and disease context of MN is almost always indicative of primary disease. activity: aPLA2R against CysR was associated with favourable However, some studies have found positivity for aPLA2R in a outcome while reactivity against CTLD1 and CTLD7 was associ- few patients with MN and concurrent disease, such as lupus, ated with active disease and poor renal prognosis. Furthermore, hepatitis B, sarcoidosis, graft-versus-host disease in the setting in that study they suggest that epitope profiles could change of allogeneic bone marrow transplantation or cancer [9, 10]. during follow-up. This finding has opened the door to personal- Some of these cases may represent pMN superimposed on a ized medicine in pMN, with a potential molecular inhibitor of concurrent disease, but determining whether the MN is a this identified epitope. Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/422/4653511 by Ed 'DeepDyve' Gillespie user on 20 June 2018 424 | M. Xipell et al. Taken together, the results in pMN-affected native kidneys variability of presentation over time, it was of vital importance suggest that aPLA2R concentration is an important predictor of to find non-invasive tools to identify the first signs of the long-term renal outcomes. disease. In this regard, a finding of great interest was that recurrence was more likely in patients showing the presence of aPLA2R aPLA2R may also predict pMN recurrence after renal than in those with non-aPLA2R related-MN. For example, transplantation Kattah et al.  evaluated 26 patients with MN and compared a Overall, this glomerular disease is estimated to be the cause of group with recurrent MN and another without recurrence. They ESRD in 5% of the patients. In fact, one-third of patients with established that having aPLA2R before transplantation had a MN will have ESRD; in these patients, renal transplantation is positive predictive value of 83% of recurrent MN, compared with the replacement therapy of choice. MN will recur in the graft in patients with negative aPLA2R prior transplantation, who 30–50% of transplant recipients , with graft loss occurring in relapse in 58% of cases. 50% of patients by 10 years. These figures reflect differences However, recurrence risk has not only been associated with the between centres performing protocol biopsies and those that presence of aPLA2R before transplantation but also with their lev- only perform biopsies for clinical indication [24, 25]. The time of els, and several studies have suggested cut-off values to identify presentation of the MN recurrence varies widely, the main at-risk patients. In 21 Spanish patients, aPLA2R concentrations period being the first post-transplant year (sometimes mani- were evaluated, measured with ELISA, to determine if they could fested only as histological findings in protocol biopsies per- predict pMN recurrence. The results showed that there was a sig- formed in the initial period after transplantation). Relapse has nificant correlation between pMN recurrence and a high level of even been described in the very first week after transplantation aPLA2R before transplantation (P ¼ 0.03) and also with the exis- . A second group of patients are at increased risk of relapse tence of a positive ELISA assay at graft biopsy (P ¼ 0.017) independ- at 5 years, and a third group develops the disease after this ent of titres. They established a cut-off level of 45 U/mL during the period. Some groups have suggested that biopsies performed by pre-transplant period as a strong predictor of recurrence, with a protocol, instead of performing them when there is a clinical sensitivity of 85.3% and a specificity of 85.1%. An association was indication, detected earlier and in a mild stage of the disease also found between HLA-DQA1*05:01 and HLA-DQB1*02:01 in the recurrence in the allograft . Nevertheless, due to this almost all the patients with recurrence in that study (six of seven), Table 1. Main studies evaluating recurrent MN in transplanted patients, relevant highlights Kattah et al.  In all, 26 patients with pMN with kidney transplantation: 18 with recurrent MN, 8 without recurrence. Protocol Bx. PPV of positive pre-Tx aPLA2R for recurrence: 83%. NPV of 42%. Median time for recurrence: 4.1 months (2.6–38 months), median proteinuria at time of recurrence: 0.5 g/day (253–1679 g/day), median creati- nine at time of recurrence 1.8 mg/dL (61.05). Four patients with aPLA2R pre-Tx became seronegative without additional immunosuppression. Four patients were seronegative at time of recurrence and had positive tissue staining for aPLA2R. Quintana et al.  A total of 21 patients with pMN biopsied for clinical indications: proved recurrence in 7 patients (median at 22 months, 0.23–73 months). rMN was correlated with existence of positive ELISA at graft biopsy (P¼ 0.017) or with high aPLA2R activity before transplantation (P¼ 0.03). A cut-off level of 45 U/mL during pre-transplantation period predicted rMN with a sensitivity of 85%, speciﬁcity of 85% and NPV of 92%. An association was also found between HLA-DQA1*05:01 and HLA-DQB1*02:01 in almost all the patients with recurrence in that study (6/7), and this association of DQ alleles was linked with the highest aPLA2R levels before transplantation. Gupta et al.  In all, 16 patients with history of pMN for pre-transplant aPLA2R. A total of six of them had proven biopsy of recurrence, of which ﬁve had positivity aPLA2R in serum pre-Tx (median 82 RU/mL, range 31–1500). The rest (10 patients) had no recurrence in biopsy, and none of them had previous aPLA2R in serum PreTx. Combining these data with those of Quintana et al.,Pre-Tx aPLA2R >29 RU/mL predicted rMN with a sensitivity of 85% and a speciﬁcity of 92%. Debiec et al.  In all, 19 patients: 10 with rMN and 9 with de novo MN. aPLA2R was involved in ﬁve and zero patients of each group, respectively. Association of aPLA2R with rMN is not as marked as in the other cases, but it should be noted that they used a qualitative method of detection and some patients had incomplete sampling before and after Tx. Median time for recurrence: 15 months (8 days–49 months). Median time for the novo MN 54.4 months (19–99 months). Seitz-Polski et al.  A total of 15 transplanted patients with MN. In all, 10 patients had aPLA2R positive at the time of Tx, of which only 4 patients had proven rMN. Five patients had negative aPLA2R, and only one presented rMN. Presence of IgG4 aPLA2R at the time of kidney transplantation does not imply MN recurrence (P¼ 0.6). However, positive IgG4 aPLA2R activity during follow-up (>6 months) was a signiﬁcant risk factor for rMN (P¼ 0.004, 10 patients). It should be noted that four patients of this cohort never had a kidney graft biopsy for rule out the presence of rMN, because they did not present with a urinary protein:creatinine ratio >0.5 g/g. Bx, Biopsy; pMN, primary membranous nephropathy; PPV, positive predictive value; Tx, treatment; NPV, negative predictive value; MN, membranous nephropathy; rMN, recurrent membranous nephropathy. Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/422/4653511 by Ed 'DeepDyve' Gillespie user on 20 June 2018 aPLA2R after kidney transplantation | 425 and this association of DQ alleles was linked with the highest There is very little information on the clinical course of aPLA2R levels before transplantation . After combining these aPLA2R in the post-transplant period, and more data including data from the Spanish cohort with data from an American cohort protocol biopsy findings are needed to determine the role of these of 16 patients, Gupta et al.  found a cut-off level of antibodies antibodies in the follow-up of recurrence of pMN in the allograft. pre-transplantation >29 RU/mL (sensitivity 85%, specificity 92). A Given that an association has been established between limitation of these data was that they came from retrospective aPLA2R titres and the development of active disease, probably studies performed in stored samples. Prospective studies are because of an inherent pathogenicity of these antibodies to the needed to set a reliable titre for monitoring these antibodies. glomeruli, a sensible approach might be to prevent pMN or its Although several case series have reported that high aPLA2R recurrence before transplantation on detection of a certain level titres at the time of transplantation strongly predicted subsequent of antibodies. Moreover, due to the high risk of recurrence of MN recurrence, others such as Debiec et al. orSeitz-Polski et al.  in the allograft despite established anti-rejection immunosup- found only a low positive predictive value (50% and 40%, respec- pression, and the potentially severe recurrent disease form that tively) (more data about these studies evaluating recurrence in MN previously led to renal failure, it seems reasonable to have a more is available in Table 1). The more feasible explanations for this active attitude than in the case of disease over native kidney. inconsistency could be related to the role of anti-rejection therapy Currently there are no established guidelines for the treat- to induce immunologic remission and the not infrequent possibil- ment of these transplant recipients to prevent or treat recur- ity of a subclinical recurrence with low-grade proteinuria that rence. Many drugs are effective for pMN ; anti-rejection could be masked by treatment with renin–angiotensin system therapy itself in kidney transplantation, including calcineurin blockers associated with calcineurin inhibitors. inhibitors, has a beneficial effect in decreasing the production Follow-up studies after transplantation have also suggested of these antibodies and sometimes the induction therapy for that serial titration of aPLA2R is clinically relevant to assess the transplantation might be sufficient to achieve a negative PLA2R risk of recurrence. Kattah et al.  found that persistence or antibody titre. However, the long-term nephrotoxic effect of reappearance of antibodies after transplantation were associ- calcineurin inhibitors is concerning. Levels may also decrease ated with increasing proteinuria and resistant disease in many because of binding to the free phospholipase receptors of the patients. This would be consistent with the hypothesis that the graft early in the post-transplant period, causing harm instead amount of antibody titre after transplantation is a strong risk of the expected benefit of a negative serum level. Other alterna- factor for recurrence. tives, including alkylating agents such as cyclophosphamide, Fig. 1. Treatment algorithm in MN after kidney transplantation. IS, immunosuppression. Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/422/4653511 by Ed 'DeepDyve' Gillespie user on 20 June 2018 426 | M. Xipell et al. are available, but the adverse effects, such as leucopoenia, asso- specificity of 83% and 90%, respectively, in recurrent MN if these ciated with this therapy in the transplantation setting makes antibodies were present . the use of other alternatives advisable. Histologic features may also help in this differential diagno- Rituximab, an anti-CD20 antibody, is increasingly being used in sis. Mild or moderate mesangial proliferation might be more fre- the treatment of post-transplant MN recurrence, based on favour- quent in de novo MN , or at different stages of the disease in the image of the electron microscopy. Other characteristics of able data from rituximab treatment in patients with MN in native kidney , but currently there are no randomized controlled trials immunostaining, such as localization of antibody deposition, with focal segmental distribution of subepithelial deposits on the topic and rituximab use is based on observational data, both for prevention (if elevated antibody titres are present before instead of diffuse distribution, can also aid diagnosis . The appearance of MN in the graft in patients with well- transplantation) and for treatment, in case of early recurrence [36, documented primary renal disease different from MN, associ- 37]. El-Zoghby et al.  evaluated eight patients with recurrent MN ated with clear signs of humoral rejection and the presence of who received rituximab. At 12 and 24 months, 75% and almost 90% donor-specific anti-HLA antibodies (DSA), raises the possibility of patients, respectively, had partial or complete remission. that de novo MN may also appear in the transplanted kidney as Furthermore, post-treatment biopsies showed resorption of elec- an allogenic manifestation of antibody-mediated rejection tron dense immune deposits in six patients. Similar favourable results were found in four patients treated with rituximab in a (AMR) . In fact, Honda et al. identified one patient with de novo MN who presented donor-derived HLA in the subepithelial study of Sprangers et al. , where it was an effective treatment in deposits on the capillary walls combined with IgG. Moreover, El all patients in stabilizing or reducing proteinuria and stabilizing Kossi et al.  reported a case of MN in a kidney graft in which renal function. A possible advantage of this therapy, beside the levels of proteinuria where clearly associated with DSA levels. large number of patients with complete or partial remission, is In these cases, concomitant histologic findings are those of that it is not necessary to modify anti-rejection therapy. Moreover, allograft rejection, such as peritubular capillaritis or transplant rituximab rapidly decreases aPLA2R, and the B-cell depletion glomerulopathy. In addition, other tests, such as determination appears to last longer in transplanted patients, as observed in the El-Zoghby et al. study , likely the result of the additional immu- nosupressants, but it is usually necessary to wait >1year to achieve proteinuria remission . Prospective trials using rituxi- Summary mab in recurrent MN are needed to confirm these data. In this sense, our proposal (Figure 1) to prevent recurrence in • M-type PLA2R is the major target antigen in human pMN transplantation would be to measure aPLA2R levels before ( 70% of patients). The remaining patients have anti- transplantation and individualize the immunosuppression bodies against THSD7A (5%) or no currently identiﬁed depending on the titre. Patients with documented aPLA2R-asso- antibodies. ciated MN with low or negative levels before transplantation ELISA is currently the diagnostic test of choice because could receive a standard immunosuppression scheme, but if its use is straightforward and allows quantiﬁcation of during the follow-up aPLA2R or proteinuria levels rise, a renal antibody levels over time with a sensitivity and specif- biopsy should be performed and the immunosuppressive treat- icity of 0.68 and 0.97, respectively. ment should be intensified in case of recurrence, including con- Typically aPLA2R in pMN is only deposited in subepi- thelial space of podocytes. Deposition elsewhere, such sidering the use of rituximab. In patients with high aPLA2R levels before transplantation, we strongly recommend a rituxi- as the mesangium or within membranes, might suggest mab-based immunosuppresion scheme. a secondary cause. aPLA2R is usually in IgG4 subclass 4 The usual dose of rituximab consists of 375 mg/m once in pMN, and there is no C1q deposition in kidney biopsy. weekly for 4 weeks or the alternative protocol of 1 g rituximab on days 1 and 15, with the regimen repeated at 6 months if B cells MN is the cause of ESRD in 5% of patients. From 30 to are >15/lL or elevated aPLA2R levels persist. Proteinuria may per- 50% of patients transplanted for MN transplanted will recur in the graft, leading to graft loss in 50% of them sist after the administration of rituximab, but this persistence within 10 years. over months should provoke a new course of treatment. Levels of aPLA2R correlate well with treatment response, disease activity and outcomes in native kid- Recurrent versus de novo MN neys. In transplant recipients, aPLA2R levels before In patients with ESRD due to MN who have received a kidney transplantation might be useful in predicting recur- transplant, the appearance of MN in the graft requires a differen- rence and their titration after transplantation predicts tial diagnosis between primary disease recurrence and MN sec- the risk of recurrence and progression and are a good ondary to another underlying process, representing de novo MN. indication for treatment initiation and for monitoring In such cases, this distinction is a diagnostic challenge. treatment response. These patients should be evaluated for hepatitis B and C virus MN may appear in the transplanted kidney as an allo- infection and other causes of secondary MN such as cancer (espe- genic manifestation of AMR. In these situations, cially in patients with late presentation years after transplanta- aPLA2R may help to distinguish recurrent from de novo tion). aPLA2R levels are also useful in this regard. Negative MN. circulating aPLA2R or on biopsy staining is more common in de Treatment with rituximab may be considered in novo disease [30, 39]. However, when present, identification of the patients with high aPLA2R levels pre-transplantation, subclass mayserve as aguide.IgG subclass 4ishighlypredictive or when serial aPLA2R levels increase during the ﬁrst of recurrent disease, whereas IgG subclass 1 predominates in de year after transplantation, especially when proteinuria novo MN . However, it is worth mentioning that positivity for increases. Other therapeutic alternatives may be inten- aPLA2R in de novo MN is rare and it is more common in recurrent siﬁcation of maintenance immunosuppression. disease. Larsen and Walker  reported a sensitivity and Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/422/4653511 by Ed 'DeepDyve' Gillespie user on 20 June 2018 aPLA2R after kidney transplantation | 427 of DSA or immunostaining of C4d in histologic samples, are 7. Francis JM, Beck LH, Salant DJ. Membranous nephropathy: helpful for diagnosis. Treatment in these cases should be man- a journey from bench to bedside. Am J Kidney Dis 2016; 68: aged according to the standard treatment for rejection . 138–147 Nevertheless, the aetiology of de novo MN after kidney trans- 8. Dai H, Zhang H, He Y. Diagnostic accuracy of PLA2R autoan- plantation is still uncertain. DSA and AMR might play a role in tibodies and glomerular staining for the differentiation of the pathogenesis in some patients. However, signs of rejection idiopathic and secondary membranous nephropathy: an were absent in a number of cases, and in some instances the updated meta-analysis. Sci Rep 2015; 5: 8803 disease developed in recipients of ‘full house’ HLA-matched kid- 9. Dauvergne M, Mokteﬁ A, Rabant M et al. Membranous nephr- neys. 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Clinical Kidney Journal – Oxford University Press
Published: Nov 22, 2017
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