PMID- 38151224 OWN - NLM STAT- MEDLINE DCOM- 20240423 LR - 20240423 IS - 1523-6838 (Electronic) IS - 0272-6386 (Linking) VI - 83 IP - 5 DP - 2024 May TI - Anti-Phospholipase A2 Receptor 1 and Anti-Cysteine Rich Antibodies, Domain Recognition and Rituximab Efficacy in Membranous Nephropathy: A Prospective Cohort Study. PG - 588-600.e1 LID - S0272-6386(23)00993-9 [pii] LID - 10.1053/j.ajkd.2023.10.013 [doi] AB - RATIONALE & OBJECTIVE: Proteinuria and anti-phospholipase A(2) receptor 1 (anti-PLA(2)R1) antibody titers are associated with primary membranous nephropathy (MN) outcomes. We evaluated the association of antibodies against the cysteine-rich (CysR) and C-type lectin 1, 7, and 8 (CTLD1, CTLD7, and CTLD8) domains of PLA(2)R1 with MN outcomes. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: One-hundred-thirteen consecutive, consenting patients referred to the Nephology Unit of the Azienda-Socio-Sanitaria-Territoriale (ASST) Papa Giovanni XXIII (Bergamo, Italy) with PLA(2)R1-related, biopsy-proven MN whose persistent nephrotic syndrome (NS) was managed conservatively for>6 months and were monitored with serial evaluations of proteinuria, autoantibodies (by enzyme-linked immunosorbent assay), and clinical outcomes. EXPOSURE: Rituximab. OUTCOME: Complete (proteinuria<0.3g/24h) or partial (proteinuria>/=0.3g/24h and<3.0g/24h with>50% reduction vs basal) NS remission. ANALYTICAL APPROACH: Univariable and multivariable Cox regression analyses. RESULTS: All patients had anti-CysR antibodies; 62 (54.9%) were multidomain recognizers. Anti-PLA(2)R1 and anti-CysR antibody titers were strongly correlated at baseline (P<0.001, r=0.934), 6 months (P<0.001, r=0.964), and 12 months (P<0.001, r=0.944). During a median follow-up of 37.1 (IQR, 20.3-56.9) months, 71 patients (62.8%) achieved either complete or partial remission of their NS. Lower baseline anti-PLA(2)R1 (HR, 0.997 [95% CI, 0.996-0.999], P=0.002) and anti-CysR [HR, 0.996 [95% CI, 0.993-0.998], P=0.001) titers were associated with a higher probability of remission, along with female sex, lower proteinuria, and lower serum creatinine levels (P<0.05 for all comparisons). Anti-CTLD antibodies were not associated with outcomes. At 6 and 12 months, compared to baseline, anti-PLA(2)R1 and anti-CysR antibody titers decreased more in patients progressing to partial or complete remission than in those without remission (P<0.05 for all comparisons). LIMITATIONS: Observational design. CONCLUSIONS: In PLA(2)R1-related MN, anti-PLA(2)R1 and anti-CysR antibodies similarly predict rituximab efficacy independent of PLA(2)R1 domain recognition. The choice between these tests should be dictated by feasibility and costs. Evaluating anti-CTLD antibodies appears unnecessary. PLAIN-LANGUAGE SUMMARY: Primary membranous nephropathy (MN), a leading cause of nephrotic syndrome (NS) in adults, is an autoimmune disease caused by autoantibodies binding to the podocyte antigen phospholipase A2 receptor 1 (PLA(2)R1). We assessed whether the effects of anti-CD20 cytolytic therapy with the monoclonal antibody rituximab are associated with detection rates and levels of anti-PLA(2)R1 antibodies and antibodies against PLA(2)R1 domains such as cysteine-rich (CysR), and C-type lectin 1, 7, and 8 (CTLD1, 7, and 8), in patients with PLA(2)R1-related MN and persistent NS. The probability of rituximab-induced complete or partial NS remission was associated with baseline anti-PLA(2)R1 and anti-CysR antibody titers, but not with anti-CTLD1, 7 and 8 antibodies or multidomain recognition. Integrated evaluation of anti-PLA(2)R1 or anti-CysR antibodies with proteinuria and kidney function may play a role in monitoring the effects of rituximab in patients with PLA(2)R1-related NS and MN. CI - Copyright (c) 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. FAU - Ruggenenti, Piero AU - Ruggenenti P AD - Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy. FAU - Reinhard, Linda AU - Reinhard L AD - 3III, Department of Internal Medicine, University Medical Center Hamburg, Eppendorf, Hamburg, Germany. FAU - Ruggiero, Barbara AU - Ruggiero B AD - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy. FAU - Perna, Annalisa AU - Perna A AD - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy. FAU - Perico, Luca AU - Perico L AD - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy. FAU - Peracchi, Tobia AU - Peracchi T AD - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy. FAU - Fidone, Diego AU - Fidone D AD - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy. FAU - Gennarini, Alessia AU - Gennarini A AD - Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy. FAU - Benigni, Ariela AU - Benigni A AD - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy. FAU - Cortinovis, Monica AU - Cortinovis M AD - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy. FAU - Hoxha, Elion AU - Hoxha E AD - 3III, Department of Internal Medicine, University Medical Center Hamburg, Eppendorf, Hamburg, Germany. Electronic address: e.hoxha@uke.de. FAU - Remuzzi, Giuseppe AU - Remuzzi G AD - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy. Electronic address: giuseppe.remuzzi@marionegri.it. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20231225 PL - United States TA - Am J Kidney Dis JT - American journal of kidney diseases : the official journal of the National Kidney Foundation JID - 8110075 RN - 0 (Receptors, Phospholipase A2) RN - 4F4X42SYQ6 (Rituximab) RN - 0 (Autoantibodies) RN - 0 (PLA2R1 protein, human) RN - 0 (Immunologic Factors) RN - K848JZ4886 (Cysteine) SB - IM MH - Humans MH - *Glomerulonephritis, Membranous/drug therapy/immunology MH - *Receptors, Phospholipase A2/immunology MH - Female MH - Male MH - *Rituximab/therapeutic use MH - Prospective Studies MH - Middle Aged MH - *Autoantibodies/blood/immunology MH - Cohort Studies MH - Immunologic Factors/therapeutic use MH - Adult MH - Treatment Outcome MH - Proteinuria/drug therapy MH - Aged MH - Cysteine OTO - NOTNLM OT - CysR OT - PLA(2)R1 OT - domain recognition OT - membranous nephropathy OT - nephrotic syndrome OT - rituximab OT - sex EDAT- 2023/12/28 00:42 MHDA- 2024/04/23 15:49 CRDT- 2023/12/27 19:21 PHST- 2023/03/28 00:00 [received] PHST- 2023/09/08 00:00 [revised] PHST- 2023/10/15 00:00 [accepted] PHST- 2024/04/23 15:49 [medline] PHST- 2023/12/28 00:42 [pubmed] PHST- 2023/12/27 19:21 [entrez] AID - S0272-6386(23)00993-9 [pii] AID - 10.1053/j.ajkd.2023.10.013 [doi] PST - ppublish SO - Am J Kidney Dis. 2024 May;83(5):588-600.e1. doi: 10.1053/j.ajkd.2023.10.013. Epub 2023 Dec 25.