Antiphospholipase 2 receptor antibody levels to predict complete spontaneous remission in primary membranous nephropathy

Antiphospholipase 2 receptor antibody levels to predict complete spontaneous remission in primary... Background: M-type phospholipase A2 receptor (APLA2R) is considered the major antigen involved in the pathogenesis of adult primary membranous nephropathy (MN), which is the leading cause of non-diabetic nephrotic syndrome. Antibodies to this antigen have been proved to be an excellent biomarker of disease activity in primary MN. In fact, preliminary data suggest that the higher the antibody level the more proteinuria, and that a decrease in antibody level precedes the remission of proteinuria, but more solid evidence is needed. Methods: The present work aims to characterize the predictive value of the level of antibodies against PLA2R as a biomarker of disease course and treatment response in a well-defined cohort of 62 patients from University Hospitals Clinic of Barcelona and Josep Trueta in Girona. The primary outcome was the appearance of a spontaneous complete remission (CR), defined as induction of a CR without the use of immunosuppressive agents. Results: In common with other reports, this work confirms that spontaneous CR is more frequent in patients with low titre of APLA2R at diagnosis, but strikingly, in this cohort we found that spontaneous CR was achieved in patients with APLA2R levels<40 UI/mL. Furthermore, spontaneous CR were less frequently observed in patients with proteinuria>8 g/day. Conclusions: In conclusion, these findings point out the important role of APLA2R as a tool to predict the disease course and establish personalized therapeutic options at the moment of diagnosis of primary MN. Specifically, patients with low titre of APLA2R (<40 UI/mL) and proteinuria<4/day could obtain benefit of a longer period of follow-up with conservative treatment after diagnosis. Key words: antibody, biomarkers, membranous nephropathy, phospholipase A2 receptor, spontaneus remission Received: 31.1.2017. Editorial decision: 27.12.2017 V C The Author(s) 2018. 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 journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy005/4925498 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| L. M. Rodas et al. The present work aims to characterize the predictive value Introduction of APLA2R levels as a biomarker of disease course and treat- Membranous nephropathy (MN) remains the leading cause of ment response in a well-defined cohort of pMN patients from nephrotic syndrome in non-diabetic adults, accounting for up University Hospitals Clinic of Barcelona and Josep Trueta in to one-third of biopsy diagnoses in many regions [1, 2]. It is a Girona, Cataluna, Spain. major cause of end-stage renal disease (ESRD) in patients with primary glomerulonephritis, and 40% of untreated patients Materials and methods require renal replacement therapy. MN recurs in 30–50% of recipients of renal transplantation, with graft loss occurring in Study design and patient cohort 50% of patients by 10 years [1–3]. The clinical course of this disease is quite variable; approxi- The initial population of this observational study consisted of 111 adults >18 years old with biopsy-proven PLA2R antibody mately one-third of patients have a complete and spontaneous pMN from a cohort of patients from Hospital Clinic of Barcelona remission of their proteinuria; one-third experience a partial and Hospital Josep Trueta in Girona, Spain, for whom serum remission (PR) persisting with subnephrotic range proteinuria; samples were available. and the remaining third stay nephrotic and progress to ESRD The inclusion criteria were pMN diagnosis established by even with immunosuppressive agents [1–4]. renal biopsy with the presence of a compatible morphologic The pathogenesis of MN involves in situ formation of pattern, PLA2R detection in immune complexes at renal tissue immune deposits on the outer aspect of the glomerular base- by immunohistochemistry and no evidence of secondary aetiol- ment membrane (GBM) resulting in complement activation, cell ogy. Secondary MN cases were excluded after performing a injury and urinary protein loss [4–6]. These immune deposits complete physical examination, serologic studies, autoimmun- are formed by circulating Immunoglobulin (Ig)G antibodies spe- ity, viral serology and thoracoabdominal computed tomography cific to endogenous antigens expressed on the podocyte foot scan, which confirmed the absence of anti-nuclear antibodies, processes, or with specificity against circulating cationic or low hepatitis B or C serologies, or neoplasia. molecular weight antigens coming from the other side of the Baseline characteristics that were obtained from all patients GBM [1, 5–8]. included APLA2R status, proteinuria, serum creatinine and esti- In terms of aetiology, MN is most often primary (pMN 80%)— mated glomerular filtration rate (GFR) at the time of renal formerly named idiopathic MN—but may be secondary to a vari- biopsy. Medical records were retrospectively reviewed for ety of conditions, including systemic lupus erythematosus, hep- outcome. atitis B antigenaemia, malignancy and the use of certain drugs The study was approved, according to the guidelines of the or toxins [1, 5]. It was not until 2009, when antibodies against M- Helsinki Declaration, by the local ethics committee of the Clinic type phospholipase A2 receptor (APLA2R) were discovered, that Hospital in Barcelona. All patients gave written informed con- an underlying cause could be identified to explain the pMN in a sent for their participation. great proportion of cases [2–4, 6, 9]. APLA2R is a protein expressed in glomerular podocytes that is considered the major antigen involved in the pathogenesis of Renal outcomes adult idiopathic MN (70%) [2, 10–12]. About 30% of patients The primary outcome was the appearance of a spontaneous with MN have no circulating antibodies against PLA2R complete remission (CR), defined as induction of a CR without (APLA2R), and in those with no evidence of aetiology, it is the use of immunosuppressive agents. Secondary outcomes believed that other endogenous glomerular antigens may be were (i) induced remission, defined as induction of a CR with involved in the pathogenesis [2, 3, 5, 10–14]. In recent years, the use of immunosuppressive agents; (ii) relapse of proteinu- another podocyte autoantigen was found to be involved in adult ria, defined as recurrent proteinuria within the nephrotic range; pMN, the thrombospondin type-1 domain-containing 7 A and (iii) ESRD, defined as the need of renal replacement therapy (THSD7A), which is considered the minor antigen, accounting or GFR <15 mL/min. CR was defined by proteinuria of <0.3 g/ for up to 5% of cases of pMN, although a recent report points out day. PR was defined by proteinuria of <2.0 g/day but 0.3 g/day. that this kind of antibody is more frequent in patients with MN Quantification of circulating APLA2 was tested for anti- and neoplasia [5, 6]. PLA2R IgG antibodies with an ELISA test (EUROIMMUN, Lubeck, These major scientific breakthroughs have been rapidly Germany), and also, with an indirect immunofluorescence test translated to clinical practice, specifically with the design of an (IFI) in the initial sample. Positivity for the test was considered enzyme-linked immunosorbent assay (ELISA) to detect and with absolute values of 14 RU/mL (14 to<20 RU/mL ¼ low quantify antibodies against PLA2R, in order to have reliable bio- positive,>20R U/mL¼ positive), according to the manufacturer’s markers to evaluate disease activity and treatment response [7, recommendations. 12, 15]. Thus, these antibodies have been studied since they were discovered, proving to have high specificity (100%), sensi- Evaluation of clinical parameters tivity (70–80%) and good predictive value [1, 3, 15]. Furthermore, an association between proteinuria and antibody At the moment of the sampling for the ELISA, an analytical pro- concentration has been established. The higher the antibody file was performed with measurements of serum total choles- level the more proteinuria, and a decrease in antibody level pre- terol, albumin levels, renal function features such as creatinine, cedes the remission of proteinuria [1–5, 7–9, 15–19]. Moreover, 24-h proteinuria and GFR estimated by the MDRD-4 formula. PLA2R detection in immune complexes at renal tissue is useful Nephrotic syndrome was considered when the combination for the retrospective diagnosis of pMN, in addition to which the of proteinuria >3.5 g/day, hypoalbuminaemia <3.5 g/dL and titre of pre-transplant APLA2R could help in the prediction of hyperlipidaemia were confirmed. MN recurrence in kidney transplant recipients or in Other relevant features, such as hypertension, diabetes, the prediction of the response to immunosuppressive therapy ischaemic cardiopathy or previous diuretic, blood pressure (BP) [1–5, 7–12]. medications [angiotensin-converting enzyme inhibitor (ACE Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy005/4925498 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Antiphospholipase 2 receptor levels and CSR | 3 Table 1. Basal characteristics of the clinical cohort inhibitor)/angiotensin receptor blockers (ARBs)] or immunosup- pressive treatment were also recorded. n¼ 62 Mean r ¼ SD Data were prospectively collected at three intervals and compiled on standardized forms that included baseline assess- Age, years 55 5.12063 ments of the patient’s laboratory parameters. Evolution (months) since diagnosis 54.60 2.063 Albumin, g/L 3.307 0.1173 Cholesterol, mg/dL 274.25 14.162 Histopathology Creatinine, mg/dL 1.1918 0.09693 A minimum of 10 glomeruli was considered adequate for a GFR, mL/min 89.36 5.577 biopsy to be included. Standard processing of renal biopsies Proteinuria, g/24 h 5.96087 0.685940 included light microscopy and IFI. All specimens were stained APLA2R levels, IU/mL 117.4277 33.96458 with haematoxylin and eosin, periodic acid–Schiff, Masson’s tri- chrome and Jones methenamine silver. For IFI, 3 lm cryostat sections were stained with polyclonal fluorescein isothiocya- treatment following the Toronto score and workflow [7, 8]. nate-conjugated antibodies to IgG, IgM, IgA, C3, C1q, kappa, Outcome data were available for 56% of patients (n¼ 62) after a lambda, fibrinogen, albumin and C4d, as per routine clinical median follow-up of 99 months. During follow-up, four patients testing. Paraffin-embedded kidney biopsies were analysed by (6.45%) did not receive RAS blockage or immunosuppressive immunohistochemistry using rabbit affinity-purified specific drugs, whereas 58 (93%) patients had received BP medication polyclonal anti-PLA2R antibodies (Atlas Antibodies, Cambridge, including ACE inhibitors or ARB. Twenty-six out of 58 (44.8%) UK). patients received exclusively conservative therapy, and 55.17% (n¼ 32) of the patients had received immunosuppressive Statistics therapy. Among this last group of patients who received immuno- Descriptive data are presented as the median or mean [stand- suppressive therapy 6 patients (19%) received only PDN, ard deviation (SD)] for continuous variables and as frequency 5 patients (16%) received tacrolimus (FK), 2 patients (<1%) (%) for categorical data. The Mann–Whitney, Kruskal–Wallis received mycophenolate mofetil (MMF) and the 19 remaining and t-test were used for comparisons between groups. patients were given a combination of immunosuppressive Correlation was assessed with Spearman coefficient and out- agents, including cyclophosphamide (CFM)þPrednisone (19%), come data, including the associated risk of recurrence of FKþ PDN (10.5%), CFMþ FK (<1%) and other combinations APLA2R titres, were analysed with Cox regression analysis. such as FKþ CFMþ rituximab, FKþ MMFþ PDN or Coefficients are expressed as hazard ratios (HRs) with 95% con- MMFþ FK, which account for the remaining 34%. Table 2 pro- fidence interval (CI). All P-values were two-tailed and were vides differential baseline characteristics among patients considered significant at <0.05. The software used for the stat- treated with conservative therapy versus immunosuppressive istical analyses was SPSS 22 version for Windows (SPSS, Inc., therapy. Chicago, IL, USA). Remission of proteinuria Results Thirty-three (53%) out of 62 patients showed a remission of pro- Patient characteristics and treatment teinuria during follow-up; 20 of these had a PR and 13 a CR. Cumulative remission rates were 5, 40 and 55% at 1, 3 and Sixty-two patients with pMN with an average of 99 months of 5 years of follow-up, respectively. Six (18%) remitting patients follow-up met the inclusion criteria including the PLA2R detec- achieved a CR during conservative therapy only, whereas seven tion in immune complexes at renal tissue by immunohisto- patients (21%) were treated with immunosuppression and chemistry, and had serum samples collected in the three achieved a CR after this treatment. intervals, so they were included in the analysis. The majority of Proteinuria was lower in patients with negative APLA2R the cohort was male (66.1%) and the average age of onset for the ELISA (5.08 6 0.85) than in those with ELISA positive (8.37 6 1.4) entire cohort was 556 15 years; 30 out of the 62 patients (48%) during the follow-up (P< 0.05) (Figure 1). However, it is worth had complete nephrotic syndrome and 33% patients presented highlighting that CR was more related to basal APLA2R level with nephrotic-range proteinuria and preserved kidney func- tion. The mean proteinuria and GFR were 5.96 g/24 h and than with just the presence of a positive ELISA test. In fact, the appearance of CR during the follow-up was more frequent in 87.5 mL/min, respectively. At time of diagnosis, mean serum creatinine was 1.19 mg/dL, mean serum albumin was 3.307 g/L patients with APLA2R titre <40 IU/mL (log rank 5.64, P¼ 0.018) (Figure 2), during the first 5 years. Spontaneous CRs were more and mean cholesterol was 274.25 mg/dL (Table 1). frequent in patients with APLA2R levels >40 IU/mL (P< 0.001) Regarding other clinical features, 24.2% suffered from high BP, 4.8% were diabetic and 4.8% had been diagnosed with and occurred after a median follow-up of 3.1 (95% CI 0.8–5.0) years. Moreover, spontaneous CR rates were higher among both ischaemic cardiomyopathy. Anti-PLA2R antibodies in serum were considered positive in patients with mild and moderate proteinuria as compared with patients with proteinuria >8 g/day. 24 of the 62 patients (39%), with a mean value of 108.516 247.23 RU/mL. The test showed a good correlation with the IFI method, The basal proteinuria and APLA2R levels were lower in which was positive in 24 of 57 patients (42.11%), with a concord- patients that afterwards developed a spontaneous CR during ance of 100% in the negatives and 91% in the positives. In the the follow-up, comparing with patients that achieved induced renal biopsy, 100% of the patients had positive detection of CR (P¼ 0.00 and P¼ 0.03, respectively) (Table 3). PLA2R in the immune complexes. Ten out 32 patients who received IS therapy developed PR. All the patients had clinical follow-up after the diagnosis of Mean age, albumin, clearance, proteinuria and APLA2R levels at least 6 months, before prescription of immunosuppressive (baseline) were 45.3 years, 3.1 g/L, 89 mL/min, 6.1 g/day and Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy005/4925498 by Ed 'DeepDyve' Gillespie user on 12 July 2018 4| L. M. Rodas et al. Table 2. Differential baseline characteristics among patients treated with conservative therapy versus immunosuppressive therapy Conservative therapy (n¼ 26, M 15, W 11) Immunosuppressive therapy (n¼ 32, M 24, W 8) Mean r ¼ SD Mean r ¼ SD P-value Albumin, g/L 3.661 0.1476 2.954 0.158 0.02 Cholesterol, mg/dL 252.61 15.923 295.14 22.82 0.13 Creatinine, mg/dL 1.08 0.0978 1.2997 0.165 0.26 Clearance, mL/min 93.21 8.182 85.04 7.551 0.4 Proteinuria, g/24 h 4.85125 0.835 7.25542 1.082 0.08 Ab levels, UI/mL 73.8643 33.068 159.489 58.21 0.2 M, men; W, women; Ab, antibody. survival was statistically significantly better in patients with negative APLA2R during the follow-up (Breslow 5.29, P¼ 0.02) (Figure 3). Discussion APLA2R is considered the major antigen involved in the patho- genesis of adult idiopathic MN. This major advance in molecular FIGURE 1: Basal proteinuria and APLA2R. Proteinuria was lower in patients medicine not only contributes to understanding the pathophy- with negative APLA2R ELISA (5.08 6 0.85) than in those with ELISA positive siological basis of MN, but also allows the use of precision medi- (8.37 6 1.4) during the follow-up (P < 0.05). cine for the diagnosis and monitoring of patients with pMN. In the present study, we found that spontaneous CR rates were higher in patients with PLA2R-related MN with APLA2R levels <40 UI/mL as compared with those patients with higher antibody levels. Worthy of attention is the fact that spontaneous CR were not present in patients with APLA2R>40 IU/mL and was less fre- quently observed in patients with proteinuria >8 g/day. Furthermore, patients with high antibody levels had higher risk of developing ESRD, and the necessity of renal replacement therapy was lower in patients with negative APLA2R during the follow-up. Therefore, these findings point out the important role of APLA2R in the clinical prediction of disease course at the moment of diagnosis and suggest that patients with low titre of APLA2R (<40 UI/mL) and proteinuria <4 g/day could benefit from a longer period of follow-up with conservative treatment, and conversely, immunosuppressive treatment has no role in this clinical setting. Previously, several observational studies related APLA2R lev- els to the amount of proteinuria and clinical activity [3, 10, 11, 14, 15]. In common with these reports, this work confirms FIGURE 2: Renal survival. CR was related to the antibody level. Cutoff threshold that spontaneous remission is more frequent in patients with level ¼ 40 UI/mL. low titre of APLA2R, as was reported by other authors [3, 15], but strikingly in this cohort, spontaneous CR almost always was 87 IU/mL, respectively, in this group of patients. There were no achieved with levels of APLA2R<40 IU/mL. Another relevant significant baseline differences between patients with induced finding of this study is the confirmation of prior reports [13, 15, complete or partial remission, but there were significant differ- 17] that evaluated the disease course in patients with PLA2R- ences in baseline proteinuria and APLA2R levels among patients related MN who were treated with immunosuppression and with spontaneous CR and patients with induced PR (Table 3). observed that the decrease of APLA2R preceded the decrease in The clinical significance of both APLA2R status and rate of the amount of proteinuria, suggesting that APLA2R is a good proteinuria was analysed by a multivariate Cox regression. marker of disease activity [18]. In this study, 100% of the patients had positive detection of Interestingly, an antibody level <40 IU/mL at baseline was the PLA2R in the immune complexes at renal tissue but only 40% most pronounced independent predictor of a spontaneous CR: had APLA2R positive in serum, and there were no patients on HR was 2.7 (95% CI 1.2–6.0, P¼ 0.01). immunosuppressive therapy at the time of entry on the study. It should be highlighted that cases with negative serum APLA2R ESRD but positive PLA2R staining on renal biopsy could be related to During follow-up, five patients required renal replacement ther- an important proportion of patients with early stage of disease apy after a mean follow-up period of 8.36 1.7 (95% CI 3.9–38.6) or to an immunologically inactive disease, but these hypotheses years. Renal survival was 98.95% after 1.5 years. Of note, renal have to be tested in future prospective studies. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy005/4925498 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Antiphospholipase 2 receptor levels and CSR | 5 Table 3. Differences in basal proteinuria and APLA2R levels among patients who developed a CR: spontaneous versus induced Spontaneous remission Induced remission PSR (n¼ 10, M 6, W 4 CSR (n¼ 6, M 3, W 3) CIR (n¼ 7, M 4, W 3) PIR (n¼ 10, M 7, W3) Mean (SD) P-value Mean (SD) Age, years 46 (4.4) 53 (7) 0.692 56 (2.5) 4.3 (5) Albumin, g/L 3.2 (0.3) 3.3 (0.38) 0.671 3.4 (0.12) 3.1 (0.4) Ab levels, UI/mL 72 (14) 29 (0.49) 0.003 143 (44) 87 (24) Proteinuria, g/24h 3 (0.8) 1.4 (0.12) 0.001 4.3 (0.6) 6.1 (0.7) GFR, mL/min 87 (7) 98 (16) 0.49 84 (7) 89 (6) Patients with partial induced and spontaneous remission are included as a reference. PSR, partial spontaneous remission; CSR, complete spontaneous remission; CIR, complete induced remission; PIR, partial induced remission; Ab, antibody;M,men;W,women. *P-value expresses differences among patients with CR (induced versus spontaneous). of remission three times higher in patients from the lowest titre of antibody [20]. Conversely, patients with nephrotic-range proteinuria and high levels of APLA2R (not estimated by this observational study) at the moment of diagnosis should benefit from early treatment in the next 3 months, in order to decrease the antibody titre as soon as possible and then induce remission of proteinuria. This study is limited by its retrospective design, despite pro- spective serum collection from two centres. The findings described in the present work need to be validated in a prospec- tive and variable multi-centric cohort of patients. Very little is known about the earliest stages of human MN because biopsies are typically taken once the disease is more established. Despite the major and rapid progress made in eluci- dating the mechanisms of pMN, much work remains to be done before we can set up completely the kinetics of APLA2R during the course of pMN. Many unanswered questions remain, and in the FIGURE 3: Renal survival among different APLA2R statuses. next few years, randomized controlled trials should clarify if serum APLA2R antibody profiles reliably predict response to ther- apy, specifically if patients with higher antibody levels should be treated earlier and independently of renal function, than those Because more than half of the patients of this cohort were with lower titres. In accordance with the results of this work, De treated with immunosuppressive agents without taking into Vriese et al. have proposed recently that low baseline and decreas- account the APLA2R level (samples were collected prospectively ing anti-PLA2R antibody levels strongly predict spontaneous but analysed retrospectively), these data do not allow concluding remission, thus favouring conservative therapy. They also sug- that antibody levels can help to identify patients who will gested that an individualized serology-based approach could opti- develop spontaneous remission in this specific group of patients. mize efficacy and safety of treatment, and that levels at Since the clinical course of pMN is very variable and many completion of therapy may forecast long-term outcome [21]. This patients with mild disease undergo spontaneous remission and novel proposal has been also adopted in more recent review by immunosuppressive drugs have important toxicity, currently Couser that strongly recommended an antibody-guided diagnosis the decision to treat is based upon the probability that the and treatment algorithm for pMN [22]. patient will have progressive disease, defined in the Toronto In conclusion, APLA2R levels at the time of diagnosis are of Glomerulonephritis Registry study as persistent severe protei- predictive value in patients with PLA2R-related MN. Levels of nuria for at least 3 months, a reduced creatinine clearance at <40 IU/mL are associated with spontaneous CR in this cohort of presentation and a decline in creatinine clearance over the patients and represent another step towards a more personal- assessed proteinuria period [7, 8]. ized care in this organ-specific, antibody-mediated, autoim- The present work supports the utility of APLA2R as an mune glomerular disease. important tool that optimizes the prediction power of the Toronto algorithm at the moment of diagnosis, decreasing the Conflict of interest statement uncertainty about the clinical course. This is due to the fact that patients with proteinuria <4 g/day and APLA2R level <40 IU/mL None declared. The results presented in this paper have not are more prone to develop a spontaneous CR and should benefit been published previously in whole or part, except in abstract from nephroprotection, and be periodically monitored every 6 format. months to assess for disease progression. In accordance with the findings of this study, Jullien et al. References recently confirmed in a retrospective French cohort, the role of APLA2R titres as a promising tool for the early identification of 1. Francis JM, Beck LH Jr, Salant DJ. Membranous nephropathy: a patients likely to achieve spontaneous remission, with a chance journey from bench to bedside. Am J Kidney Dis 2016; 68: 138–147 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy005/4925498 by Ed 'DeepDyve' Gillespie user on 12 July 2018 6| L. M. Rodas et al. 12. Beck LH, Bonegio RGB, Lambeau G et al. M-type phospholi- 2. Quintana LF, Blasco M, Seras M et al. 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Hofstra JM, Beck LH Jr, Beck DM et al. Anti-phospholipase A2 neousremission of idiopathic membranous nephropathy. receptor antibodies correlate with clinical status in idio- Clin Kidney J 2017; 10: 209–214 pathic membranous nephropathy. Clin J Am Soc Nephrol 2011; 21. De Vriese AS, Glassock RJ, Nath KA et al. A proposal for a 6: 1286–1291 serology-based approach to membranous nephropathy. 11. Qin W, Beck LH, Zeng C et al. Anti-phospholipase A2 receptor J Am Soc Nephrol 2017; 28: 421–430 antibody in membranous nephropathy. J Am Soc Nephrol 22. Couser WG. Primary membranous nephropathy. Clin J Am 2011; 22: 1137–1143 Soc Nephrol 2017; 12: 983–997 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy005/4925498 by Ed 'DeepDyve' Gillespie user on 12 July 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Antiphospholipase 2 receptor antibody levels to predict complete spontaneous remission in primary membranous nephropathy

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Abstract

Background: M-type phospholipase A2 receptor (APLA2R) is considered the major antigen involved in the pathogenesis of adult primary membranous nephropathy (MN), which is the leading cause of non-diabetic nephrotic syndrome. Antibodies to this antigen have been proved to be an excellent biomarker of disease activity in primary MN. In fact, preliminary data suggest that the higher the antibody level the more proteinuria, and that a decrease in antibody level precedes the remission of proteinuria, but more solid evidence is needed. Methods: The present work aims to characterize the predictive value of the level of antibodies against PLA2R as a biomarker of disease course and treatment response in a well-defined cohort of 62 patients from University Hospitals Clinic of Barcelona and Josep Trueta in Girona. The primary outcome was the appearance of a spontaneous complete remission (CR), defined as induction of a CR without the use of immunosuppressive agents. Results: In common with other reports, this work confirms that spontaneous CR is more frequent in patients with low titre of APLA2R at diagnosis, but strikingly, in this cohort we found that spontaneous CR was achieved in patients with APLA2R levels<40 UI/mL. Furthermore, spontaneous CR were less frequently observed in patients with proteinuria>8 g/day. Conclusions: In conclusion, these findings point out the important role of APLA2R as a tool to predict the disease course and establish personalized therapeutic options at the moment of diagnosis of primary MN. Specifically, patients with low titre of APLA2R (<40 UI/mL) and proteinuria<4/day could obtain benefit of a longer period of follow-up with conservative treatment after diagnosis. Key words: antibody, biomarkers, membranous nephropathy, phospholipase A2 receptor, spontaneus remission Received: 31.1.2017. Editorial decision: 27.12.2017 V C The Author(s) 2018. 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 journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy005/4925498 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| L. M. Rodas et al. The present work aims to characterize the predictive value Introduction of APLA2R levels as a biomarker of disease course and treat- Membranous nephropathy (MN) remains the leading cause of ment response in a well-defined cohort of pMN patients from nephrotic syndrome in non-diabetic adults, accounting for up University Hospitals Clinic of Barcelona and Josep Trueta in to one-third of biopsy diagnoses in many regions [1, 2]. It is a Girona, Cataluna, Spain. major cause of end-stage renal disease (ESRD) in patients with primary glomerulonephritis, and 40% of untreated patients Materials and methods require renal replacement therapy. MN recurs in 30–50% of recipients of renal transplantation, with graft loss occurring in Study design and patient cohort 50% of patients by 10 years [1–3]. The clinical course of this disease is quite variable; approxi- The initial population of this observational study consisted of 111 adults >18 years old with biopsy-proven PLA2R antibody mately one-third of patients have a complete and spontaneous pMN from a cohort of patients from Hospital Clinic of Barcelona remission of their proteinuria; one-third experience a partial and Hospital Josep Trueta in Girona, Spain, for whom serum remission (PR) persisting with subnephrotic range proteinuria; samples were available. and the remaining third stay nephrotic and progress to ESRD The inclusion criteria were pMN diagnosis established by even with immunosuppressive agents [1–4]. renal biopsy with the presence of a compatible morphologic The pathogenesis of MN involves in situ formation of pattern, PLA2R detection in immune complexes at renal tissue immune deposits on the outer aspect of the glomerular base- by immunohistochemistry and no evidence of secondary aetiol- ment membrane (GBM) resulting in complement activation, cell ogy. Secondary MN cases were excluded after performing a injury and urinary protein loss [4–6]. These immune deposits complete physical examination, serologic studies, autoimmun- are formed by circulating Immunoglobulin (Ig)G antibodies spe- ity, viral serology and thoracoabdominal computed tomography cific to endogenous antigens expressed on the podocyte foot scan, which confirmed the absence of anti-nuclear antibodies, processes, or with specificity against circulating cationic or low hepatitis B or C serologies, or neoplasia. molecular weight antigens coming from the other side of the Baseline characteristics that were obtained from all patients GBM [1, 5–8]. included APLA2R status, proteinuria, serum creatinine and esti- In terms of aetiology, MN is most often primary (pMN 80%)— mated glomerular filtration rate (GFR) at the time of renal formerly named idiopathic MN—but may be secondary to a vari- biopsy. Medical records were retrospectively reviewed for ety of conditions, including systemic lupus erythematosus, hep- outcome. atitis B antigenaemia, malignancy and the use of certain drugs The study was approved, according to the guidelines of the or toxins [1, 5]. It was not until 2009, when antibodies against M- Helsinki Declaration, by the local ethics committee of the Clinic type phospholipase A2 receptor (APLA2R) were discovered, that Hospital in Barcelona. All patients gave written informed con- an underlying cause could be identified to explain the pMN in a sent for their participation. great proportion of cases [2–4, 6, 9]. APLA2R is a protein expressed in glomerular podocytes that is considered the major antigen involved in the pathogenesis of Renal outcomes adult idiopathic MN (70%) [2, 10–12]. About 30% of patients The primary outcome was the appearance of a spontaneous with MN have no circulating antibodies against PLA2R complete remission (CR), defined as induction of a CR without (APLA2R), and in those with no evidence of aetiology, it is the use of immunosuppressive agents. Secondary outcomes believed that other endogenous glomerular antigens may be were (i) induced remission, defined as induction of a CR with involved in the pathogenesis [2, 3, 5, 10–14]. In recent years, the use of immunosuppressive agents; (ii) relapse of proteinu- another podocyte autoantigen was found to be involved in adult ria, defined as recurrent proteinuria within the nephrotic range; pMN, the thrombospondin type-1 domain-containing 7 A and (iii) ESRD, defined as the need of renal replacement therapy (THSD7A), which is considered the minor antigen, accounting or GFR <15 mL/min. CR was defined by proteinuria of <0.3 g/ for up to 5% of cases of pMN, although a recent report points out day. PR was defined by proteinuria of <2.0 g/day but 0.3 g/day. that this kind of antibody is more frequent in patients with MN Quantification of circulating APLA2 was tested for anti- and neoplasia [5, 6]. PLA2R IgG antibodies with an ELISA test (EUROIMMUN, Lubeck, These major scientific breakthroughs have been rapidly Germany), and also, with an indirect immunofluorescence test translated to clinical practice, specifically with the design of an (IFI) in the initial sample. Positivity for the test was considered enzyme-linked immunosorbent assay (ELISA) to detect and with absolute values of 14 RU/mL (14 to<20 RU/mL ¼ low quantify antibodies against PLA2R, in order to have reliable bio- positive,>20R U/mL¼ positive), according to the manufacturer’s markers to evaluate disease activity and treatment response [7, recommendations. 12, 15]. Thus, these antibodies have been studied since they were discovered, proving to have high specificity (100%), sensi- Evaluation of clinical parameters tivity (70–80%) and good predictive value [1, 3, 15]. Furthermore, an association between proteinuria and antibody At the moment of the sampling for the ELISA, an analytical pro- concentration has been established. The higher the antibody file was performed with measurements of serum total choles- level the more proteinuria, and a decrease in antibody level pre- terol, albumin levels, renal function features such as creatinine, cedes the remission of proteinuria [1–5, 7–9, 15–19]. Moreover, 24-h proteinuria and GFR estimated by the MDRD-4 formula. PLA2R detection in immune complexes at renal tissue is useful Nephrotic syndrome was considered when the combination for the retrospective diagnosis of pMN, in addition to which the of proteinuria >3.5 g/day, hypoalbuminaemia <3.5 g/dL and titre of pre-transplant APLA2R could help in the prediction of hyperlipidaemia were confirmed. MN recurrence in kidney transplant recipients or in Other relevant features, such as hypertension, diabetes, the prediction of the response to immunosuppressive therapy ischaemic cardiopathy or previous diuretic, blood pressure (BP) [1–5, 7–12]. medications [angiotensin-converting enzyme inhibitor (ACE Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy005/4925498 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Antiphospholipase 2 receptor levels and CSR | 3 Table 1. Basal characteristics of the clinical cohort inhibitor)/angiotensin receptor blockers (ARBs)] or immunosup- pressive treatment were also recorded. n¼ 62 Mean r ¼ SD Data were prospectively collected at three intervals and compiled on standardized forms that included baseline assess- Age, years 55 5.12063 ments of the patient’s laboratory parameters. Evolution (months) since diagnosis 54.60 2.063 Albumin, g/L 3.307 0.1173 Cholesterol, mg/dL 274.25 14.162 Histopathology Creatinine, mg/dL 1.1918 0.09693 A minimum of 10 glomeruli was considered adequate for a GFR, mL/min 89.36 5.577 biopsy to be included. Standard processing of renal biopsies Proteinuria, g/24 h 5.96087 0.685940 included light microscopy and IFI. All specimens were stained APLA2R levels, IU/mL 117.4277 33.96458 with haematoxylin and eosin, periodic acid–Schiff, Masson’s tri- chrome and Jones methenamine silver. For IFI, 3 lm cryostat sections were stained with polyclonal fluorescein isothiocya- treatment following the Toronto score and workflow [7, 8]. nate-conjugated antibodies to IgG, IgM, IgA, C3, C1q, kappa, Outcome data were available for 56% of patients (n¼ 62) after a lambda, fibrinogen, albumin and C4d, as per routine clinical median follow-up of 99 months. During follow-up, four patients testing. Paraffin-embedded kidney biopsies were analysed by (6.45%) did not receive RAS blockage or immunosuppressive immunohistochemistry using rabbit affinity-purified specific drugs, whereas 58 (93%) patients had received BP medication polyclonal anti-PLA2R antibodies (Atlas Antibodies, Cambridge, including ACE inhibitors or ARB. Twenty-six out of 58 (44.8%) UK). patients received exclusively conservative therapy, and 55.17% (n¼ 32) of the patients had received immunosuppressive Statistics therapy. Among this last group of patients who received immuno- Descriptive data are presented as the median or mean [stand- suppressive therapy 6 patients (19%) received only PDN, ard deviation (SD)] for continuous variables and as frequency 5 patients (16%) received tacrolimus (FK), 2 patients (<1%) (%) for categorical data. The Mann–Whitney, Kruskal–Wallis received mycophenolate mofetil (MMF) and the 19 remaining and t-test were used for comparisons between groups. patients were given a combination of immunosuppressive Correlation was assessed with Spearman coefficient and out- agents, including cyclophosphamide (CFM)þPrednisone (19%), come data, including the associated risk of recurrence of FKþ PDN (10.5%), CFMþ FK (<1%) and other combinations APLA2R titres, were analysed with Cox regression analysis. such as FKþ CFMþ rituximab, FKþ MMFþ PDN or Coefficients are expressed as hazard ratios (HRs) with 95% con- MMFþ FK, which account for the remaining 34%. Table 2 pro- fidence interval (CI). All P-values were two-tailed and were vides differential baseline characteristics among patients considered significant at <0.05. The software used for the stat- treated with conservative therapy versus immunosuppressive istical analyses was SPSS 22 version for Windows (SPSS, Inc., therapy. Chicago, IL, USA). Remission of proteinuria Results Thirty-three (53%) out of 62 patients showed a remission of pro- Patient characteristics and treatment teinuria during follow-up; 20 of these had a PR and 13 a CR. Cumulative remission rates were 5, 40 and 55% at 1, 3 and Sixty-two patients with pMN with an average of 99 months of 5 years of follow-up, respectively. Six (18%) remitting patients follow-up met the inclusion criteria including the PLA2R detec- achieved a CR during conservative therapy only, whereas seven tion in immune complexes at renal tissue by immunohisto- patients (21%) were treated with immunosuppression and chemistry, and had serum samples collected in the three achieved a CR after this treatment. intervals, so they were included in the analysis. The majority of Proteinuria was lower in patients with negative APLA2R the cohort was male (66.1%) and the average age of onset for the ELISA (5.08 6 0.85) than in those with ELISA positive (8.37 6 1.4) entire cohort was 556 15 years; 30 out of the 62 patients (48%) during the follow-up (P< 0.05) (Figure 1). However, it is worth had complete nephrotic syndrome and 33% patients presented highlighting that CR was more related to basal APLA2R level with nephrotic-range proteinuria and preserved kidney func- tion. The mean proteinuria and GFR were 5.96 g/24 h and than with just the presence of a positive ELISA test. In fact, the appearance of CR during the follow-up was more frequent in 87.5 mL/min, respectively. At time of diagnosis, mean serum creatinine was 1.19 mg/dL, mean serum albumin was 3.307 g/L patients with APLA2R titre <40 IU/mL (log rank 5.64, P¼ 0.018) (Figure 2), during the first 5 years. Spontaneous CRs were more and mean cholesterol was 274.25 mg/dL (Table 1). frequent in patients with APLA2R levels >40 IU/mL (P< 0.001) Regarding other clinical features, 24.2% suffered from high BP, 4.8% were diabetic and 4.8% had been diagnosed with and occurred after a median follow-up of 3.1 (95% CI 0.8–5.0) years. Moreover, spontaneous CR rates were higher among both ischaemic cardiomyopathy. Anti-PLA2R antibodies in serum were considered positive in patients with mild and moderate proteinuria as compared with patients with proteinuria >8 g/day. 24 of the 62 patients (39%), with a mean value of 108.516 247.23 RU/mL. The test showed a good correlation with the IFI method, The basal proteinuria and APLA2R levels were lower in which was positive in 24 of 57 patients (42.11%), with a concord- patients that afterwards developed a spontaneous CR during ance of 100% in the negatives and 91% in the positives. In the the follow-up, comparing with patients that achieved induced renal biopsy, 100% of the patients had positive detection of CR (P¼ 0.00 and P¼ 0.03, respectively) (Table 3). PLA2R in the immune complexes. Ten out 32 patients who received IS therapy developed PR. All the patients had clinical follow-up after the diagnosis of Mean age, albumin, clearance, proteinuria and APLA2R levels at least 6 months, before prescription of immunosuppressive (baseline) were 45.3 years, 3.1 g/L, 89 mL/min, 6.1 g/day and Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy005/4925498 by Ed 'DeepDyve' Gillespie user on 12 July 2018 4| L. M. Rodas et al. Table 2. Differential baseline characteristics among patients treated with conservative therapy versus immunosuppressive therapy Conservative therapy (n¼ 26, M 15, W 11) Immunosuppressive therapy (n¼ 32, M 24, W 8) Mean r ¼ SD Mean r ¼ SD P-value Albumin, g/L 3.661 0.1476 2.954 0.158 0.02 Cholesterol, mg/dL 252.61 15.923 295.14 22.82 0.13 Creatinine, mg/dL 1.08 0.0978 1.2997 0.165 0.26 Clearance, mL/min 93.21 8.182 85.04 7.551 0.4 Proteinuria, g/24 h 4.85125 0.835 7.25542 1.082 0.08 Ab levels, UI/mL 73.8643 33.068 159.489 58.21 0.2 M, men; W, women; Ab, antibody. survival was statistically significantly better in patients with negative APLA2R during the follow-up (Breslow 5.29, P¼ 0.02) (Figure 3). Discussion APLA2R is considered the major antigen involved in the patho- genesis of adult idiopathic MN. This major advance in molecular FIGURE 1: Basal proteinuria and APLA2R. Proteinuria was lower in patients medicine not only contributes to understanding the pathophy- with negative APLA2R ELISA (5.08 6 0.85) than in those with ELISA positive siological basis of MN, but also allows the use of precision medi- (8.37 6 1.4) during the follow-up (P < 0.05). cine for the diagnosis and monitoring of patients with pMN. In the present study, we found that spontaneous CR rates were higher in patients with PLA2R-related MN with APLA2R levels <40 UI/mL as compared with those patients with higher antibody levels. Worthy of attention is the fact that spontaneous CR were not present in patients with APLA2R>40 IU/mL and was less fre- quently observed in patients with proteinuria >8 g/day. Furthermore, patients with high antibody levels had higher risk of developing ESRD, and the necessity of renal replacement therapy was lower in patients with negative APLA2R during the follow-up. Therefore, these findings point out the important role of APLA2R in the clinical prediction of disease course at the moment of diagnosis and suggest that patients with low titre of APLA2R (<40 UI/mL) and proteinuria <4 g/day could benefit from a longer period of follow-up with conservative treatment, and conversely, immunosuppressive treatment has no role in this clinical setting. Previously, several observational studies related APLA2R lev- els to the amount of proteinuria and clinical activity [3, 10, 11, 14, 15]. In common with these reports, this work confirms FIGURE 2: Renal survival. CR was related to the antibody level. Cutoff threshold that spontaneous remission is more frequent in patients with level ¼ 40 UI/mL. low titre of APLA2R, as was reported by other authors [3, 15], but strikingly in this cohort, spontaneous CR almost always was 87 IU/mL, respectively, in this group of patients. There were no achieved with levels of APLA2R<40 IU/mL. Another relevant significant baseline differences between patients with induced finding of this study is the confirmation of prior reports [13, 15, complete or partial remission, but there were significant differ- 17] that evaluated the disease course in patients with PLA2R- ences in baseline proteinuria and APLA2R levels among patients related MN who were treated with immunosuppression and with spontaneous CR and patients with induced PR (Table 3). observed that the decrease of APLA2R preceded the decrease in The clinical significance of both APLA2R status and rate of the amount of proteinuria, suggesting that APLA2R is a good proteinuria was analysed by a multivariate Cox regression. marker of disease activity [18]. In this study, 100% of the patients had positive detection of Interestingly, an antibody level <40 IU/mL at baseline was the PLA2R in the immune complexes at renal tissue but only 40% most pronounced independent predictor of a spontaneous CR: had APLA2R positive in serum, and there were no patients on HR was 2.7 (95% CI 1.2–6.0, P¼ 0.01). immunosuppressive therapy at the time of entry on the study. It should be highlighted that cases with negative serum APLA2R ESRD but positive PLA2R staining on renal biopsy could be related to During follow-up, five patients required renal replacement ther- an important proportion of patients with early stage of disease apy after a mean follow-up period of 8.36 1.7 (95% CI 3.9–38.6) or to an immunologically inactive disease, but these hypotheses years. Renal survival was 98.95% after 1.5 years. Of note, renal have to be tested in future prospective studies. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy005/4925498 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Antiphospholipase 2 receptor levels and CSR | 5 Table 3. Differences in basal proteinuria and APLA2R levels among patients who developed a CR: spontaneous versus induced Spontaneous remission Induced remission PSR (n¼ 10, M 6, W 4 CSR (n¼ 6, M 3, W 3) CIR (n¼ 7, M 4, W 3) PIR (n¼ 10, M 7, W3) Mean (SD) P-value Mean (SD) Age, years 46 (4.4) 53 (7) 0.692 56 (2.5) 4.3 (5) Albumin, g/L 3.2 (0.3) 3.3 (0.38) 0.671 3.4 (0.12) 3.1 (0.4) Ab levels, UI/mL 72 (14) 29 (0.49) 0.003 143 (44) 87 (24) Proteinuria, g/24h 3 (0.8) 1.4 (0.12) 0.001 4.3 (0.6) 6.1 (0.7) GFR, mL/min 87 (7) 98 (16) 0.49 84 (7) 89 (6) Patients with partial induced and spontaneous remission are included as a reference. PSR, partial spontaneous remission; CSR, complete spontaneous remission; CIR, complete induced remission; PIR, partial induced remission; Ab, antibody;M,men;W,women. *P-value expresses differences among patients with CR (induced versus spontaneous). of remission three times higher in patients from the lowest titre of antibody [20]. Conversely, patients with nephrotic-range proteinuria and high levels of APLA2R (not estimated by this observational study) at the moment of diagnosis should benefit from early treatment in the next 3 months, in order to decrease the antibody titre as soon as possible and then induce remission of proteinuria. This study is limited by its retrospective design, despite pro- spective serum collection from two centres. The findings described in the present work need to be validated in a prospec- tive and variable multi-centric cohort of patients. Very little is known about the earliest stages of human MN because biopsies are typically taken once the disease is more established. Despite the major and rapid progress made in eluci- dating the mechanisms of pMN, much work remains to be done before we can set up completely the kinetics of APLA2R during the course of pMN. Many unanswered questions remain, and in the FIGURE 3: Renal survival among different APLA2R statuses. next few years, randomized controlled trials should clarify if serum APLA2R antibody profiles reliably predict response to ther- apy, specifically if patients with higher antibody levels should be treated earlier and independently of renal function, than those Because more than half of the patients of this cohort were with lower titres. In accordance with the results of this work, De treated with immunosuppressive agents without taking into Vriese et al. have proposed recently that low baseline and decreas- account the APLA2R level (samples were collected prospectively ing anti-PLA2R antibody levels strongly predict spontaneous but analysed retrospectively), these data do not allow concluding remission, thus favouring conservative therapy. They also sug- that antibody levels can help to identify patients who will gested that an individualized serology-based approach could opti- develop spontaneous remission in this specific group of patients. mize efficacy and safety of treatment, and that levels at Since the clinical course of pMN is very variable and many completion of therapy may forecast long-term outcome [21]. This patients with mild disease undergo spontaneous remission and novel proposal has been also adopted in more recent review by immunosuppressive drugs have important toxicity, currently Couser that strongly recommended an antibody-guided diagnosis the decision to treat is based upon the probability that the and treatment algorithm for pMN [22]. patient will have progressive disease, defined in the Toronto In conclusion, APLA2R levels at the time of diagnosis are of Glomerulonephritis Registry study as persistent severe protei- predictive value in patients with PLA2R-related MN. Levels of nuria for at least 3 months, a reduced creatinine clearance at <40 IU/mL are associated with spontaneous CR in this cohort of presentation and a decline in creatinine clearance over the patients and represent another step towards a more personal- assessed proteinuria period [7, 8]. ized care in this organ-specific, antibody-mediated, autoim- The present work supports the utility of APLA2R as an mune glomerular disease. important tool that optimizes the prediction power of the Toronto algorithm at the moment of diagnosis, decreasing the Conflict of interest statement uncertainty about the clinical course. This is due to the fact that patients with proteinuria <4 g/day and APLA2R level <40 IU/mL None declared. The results presented in this paper have not are more prone to develop a spontaneous CR and should benefit been published previously in whole or part, except in abstract from nephroprotection, and be periodically monitored every 6 format. months to assess for disease progression. In accordance with the findings of this study, Jullien et al. References recently confirmed in a retrospective French cohort, the role of APLA2R titres as a promising tool for the early identification of 1. Francis JM, Beck LH Jr, Salant DJ. Membranous nephropathy: a patients likely to achieve spontaneous remission, with a chance journey from bench to bedside. Am J Kidney Dis 2016; 68: 138–147 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy005/4925498 by Ed 'DeepDyve' Gillespie user on 12 July 2018 6| L. M. Rodas et al. 12. Beck LH, Bonegio RGB, Lambeau G et al. M-type phospholi- 2. Quintana LF, Blasco M, Seras M et al. 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Hofstra JM, Beck LH Jr, Beck DM et al. Anti-phospholipase A2 neousremission of idiopathic membranous nephropathy. receptor antibodies correlate with clinical status in idio- Clin Kidney J 2017; 10: 209–214 pathic membranous nephropathy. Clin J Am Soc Nephrol 2011; 21. De Vriese AS, Glassock RJ, Nath KA et al. A proposal for a 6: 1286–1291 serology-based approach to membranous nephropathy. 11. Qin W, Beck LH, Zeng C et al. Anti-phospholipase A2 receptor J Am Soc Nephrol 2017; 28: 421–430 antibody in membranous nephropathy. J Am Soc Nephrol 22. Couser WG. Primary membranous nephropathy. Clin J Am 2011; 22: 1137–1143 Soc Nephrol 2017; 12: 983–997 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy005/4925498 by Ed 'DeepDyve' Gillespie user on 12 July 2018

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Clinical Kidney JournalOxford University Press

Published: Mar 9, 2018

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