Abstract
Background
The aim of this study was to define the clinicopathologic features of phospholipase A2 receptor (PLA2R) and/or thrombospondin type-1 domain-containing 7A (THSD7A) associated membranous nephropathy(MN) focusing on their impact to disease relapse and response to treatment.
Methods
A total of 201 patients were enrolled for baseline clinical and histopathological features and 102 patients with a clinical follow-up for more than 1 year were evaluated for outcomes. Immunohistochemical staining was performed with PLA2R and THSD7A antibodies on kidney biopsies and glomerular staining was evaluated.
Results
PLA2R expression was observed in 75% of the patients’ biopsies; however, THSD7A expression was present only in 7 patients’ biopsies (3.5%). No significant difference was found between histopathological and clinical features of PLA2R positive and negative patients, collectively. Glomerular PLA2R expression was significantly associated with complete and complete/partial remission with first-line treatment; however, overall complete, and complete/partial remission rates did not differ from PLA2R negative patients (p = 0.2 and p = 0.8). Male gender, the presence of IgG4 staining and a necessity of immunosuppressive treatment were significantly associated with glomerular PLA2R expression. One patient, who developed end-stage renal disease, had glomerular expression for both PLA2R and THSD7A. Three patients with THSD7A-positive MN achieved complete remission.
Conclusions
The probability of achieving complete remission is high in patients with PLA2R-positive MN for whom the relapse rate was also higher. The overall renal outcome did not differ from PLA2R negative cases. Low incidence of THSD7A-positive MN reduces the possibility of future randomized controlled trials.
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References
Cattran DC, Brenchley PE. Membranous nephropathy: integrating basic science into improved clinical management. Kidney Int. 2017;91(3):566–74.
Safar-Boueri L, Piya A, Beck LH, Ayalon R. Membranous nephropathy: diagnosis, treatment, and monitoring in the post-PLA2R era. Pediatr Nephrol. 2019;36:1–12.
Couser WG. Primary membranous nephropathy. Clin J Am Soc Nephrol. 2017;12(6):983–97.
Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361(1):11–21.
Hofstra JM, Beck LH, Beck DM, Wetzels JF, Salant DJ. Anti-phospholipase A2 receptor antibodies correlate with clinical status in idiopathic membranous nephropathy. Clin J Am Soc Nephrol. 2011;6(6):1286–91.
van de Logt A-E, Hofstra JM, Wetzels JF. Serum anti-PLA2R antibodies can be initially absent in idiopathic membranous nephropathy: seroconversion after prolonged follow-up. Kidney Int. 2015;87(6):1263–4.
Tomas NM, Beck LH Jr, Meyer-Schwesinger C, Seitz-Polski B, Ma H, Zahner G, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med. 2014;371(24):2277–87.
Sharma SG, Larsen CP. Tissue staining for THSD7A in glomeruli correlates with serum antibodies in primary membranous nephropathy: a clinicopathological study. Mod Pathol. 2018;31(4):616.
Xian L, Dong D, Luo J, Zhuo L, Li K, Zhang P, et al. Expression of THSD7A in neoplasm tissues and its relationship with proteinuria. BMC Nephrol. 2019;20(1):332.
Ren S, Wu C, Zhang Y, Wang AY, Li G, Wang L, et al. An update on clinical significance of use of THSD7A in diagnosing idiopathic membranous nephropathy: a systematic review and meta-analysis of THSD7A in IMN. Ren Fail. 2018;40(1):306–13.
Hoxha E, Beck LH, Wiech T, Tomas NM, Probst C, Mindorf S, et al. An indirect immunofluorescence method facilitates detection of thrombospondin type 1 domain–containing 7A–specific antibodies in membranous nephropathy. J Am Soc Nephrol. 2017;28(2):520–31.
Radhakrishnan J, Cattran DC. The KDIGO practice guideline on glomerulonephritis: reading between the (guide) lines—application to the individual patient. Kidney Int. 2012;82(8):840–56.
Liu W, Gao C, Dai H, Zheng Y, Dong Z, Gao Y, et al. Immunological pathogenesis of membranous nephropathy: focus on PLA2R1 and its role. Front Immunol. 2019;10:1809.
Liu L, Chang B, Wu X, Guo Y, Pan Y, Yang L. Expression of phospholipase A2 receptor and IgG4 in patients with membranous nephropathy. Vasc Health Risk Manag. 2018;14:103.
Larsen CP, Messias NC, Silva FG, Messias E, Walker PD. Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor staining in renal biopsies. Mod Pathol. 2013;26(5):709–15.
Zhang D, Zou J, Zhang C, Zhang W, Lin F, Jiang G. Clinical and histological features of phospholipase A2 receptor-associated and Thrombospondin type-I domain-containing 7A-associated idiopathic membranous nephropathy: a single center retrospective study from China. Med Sci Monit. 2018;24:5076.
Xu N-X, Xie Q-H, Sun Z-X, Wang J, Li Y, Wang L, et al. Renal phospholipase A2 receptor and the clinical features of idiopathic membranous nephropathy. Chin Med J. 2017;130(8):892.
Dong D, Fan T-T, Wang Y-Y, Zhang L, Song L, Zhang L. Relationship between renal tissues phospholipase A2 receptor and its serum antibody and clinical condition and prognosis of idiopathic membranous nephropathy: a meta-analysis. BMC Nephrol. 2019;20(1):444.
Liu H, Luo W, Gong S, Ding X. Detection and clinical significance of glomerular M-type phospholipase A2 receptor in patients with idiopathic membranous nephropathy. Intern Med J. 2016;46(11):1318–22.
Wang J, Xie Q, Sun Z, Xu N, Li Y, Wang L, et al. Response to immunosuppressive therapy in PLA 2 R-associated and non-PLA 2 R-associated idiopathic membranous nephropathy: a retrospective, multicenter cohort study. BMC Nephrol. 2017;18(1):227.
Yu X, Ruan L, Qu Z, Cui Z, Zhang Y, Wang X, et al. Low-dose cyclosporine in treatment of membranous nephropathy with nephrotic syndrome: effectiveness and renal safety. Ren Fail. 2017;39(1):688–97.
Alexopoulos E, Papagianni A, Tsamelashvili M, Leontsini M, Memmos D. Induction and long-term treatment with cyclosporine in membranous nephropathy with the nephrotic syndrome. Nephrol Dial Transpl. 2006;21(11):3127–32.
Fervenza FC, Appel GB, Barbour SJ, Rovin BH, Lafayette RA, Aslam N, et al. Rituximab or cyclosporine in the treatment of membranous nephropathy. N Engl J Med. 2019;381(1):36–46.
Cattran DC, Kim ED, Reich H, Hladunewich M, Kim SJ. Membranous nephropathy: quantifying remission duration on outcome. J Am Soc Nephrol. 2017;28(3):995–1003.
Alfaadhel T, Cattran D. Management of membranous nephropathy in western countries. Kidney Dis. 2015;1(2):126–37.
Herwig J, Skuza S, Sachs W, Sachs M, Failla AV, Rune G, et al. Thrombospondin type 1 domain–containing 7A localizes to the slit diaphragm and stabilizes membrane dynamics of fully differentiated podocytes. J Am Soc Nephrol. 2019;30(5):824–39.
Hara S, Tsuji T, Fukasawa Y, Hisano S, Morito S, Hyodo T, et al. Clinicopathological characteristics of thrombospondin type 1 domain-containing 7A-associated membranous nephropathy. Virchows Arch. 2019;474(6):735–43.
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Gazi University Internal Medicine Postgraduate Education Association and Hypertension Dialysis Transplantation Association
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The design and procedures of the study were approved by the Ethics Committee of Gazi University (Protocol ID: 37 Date: 14/01/2019) in agreement with the principles of the Declaration of Helsinki and ethical standards for human experimentation.
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Yeter, H.H., Isik Gonul, I., Eraslan, E. et al. Effects of phospholipase A2 receptor and thrombospondin type-1 domain-containing 7A expression in glomerular basement membranes on treatment response and renal outcome in membranous nephropathy. Clin Exp Nephrol 25, 488–500 (2021). https://doi.org/10.1007/s10157-020-02011-6
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DOI: https://doi.org/10.1007/s10157-020-02011-6