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. 2023 Oct 1;18(10):1283-1293.
doi: 10.2215/CJN.0000000000000237. Epub 2023 Jul 20.

Anti-PLA2R Antibody Levels and Clinical Risk Factors for Treatment Nonresponse in Membranous Nephropathy

Sean J Barbour  1   2 , Fernando C Fervenza  3 , Dilshani Induruwage  2 , Paul E Brenchley  4 , Brad Rovin  5 , Michelle A Hladunewich  6 , Heather N Reich  7 , Richard Lafayette  8 , Nabeel Aslam  9 , Gerald B Appel  10 , Ladan Zand  3 , Krzysztof Kiryluk  10 , Lili Liu  10 , Daniel C Cattran  7 ; MENTOR Trial Investigators
Collaborators, Affiliations

Anti-PLA2R Antibody Levels and Clinical Risk Factors for Treatment Nonresponse in Membranous Nephropathy

Sean J Barbour et al. Clin J Am Soc Nephrol. .

Abstract

Background: The 2021 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend following anti-phospholipase A2 receptor (PLA2R) antibody levels as a marker of treatment response in membranous nephropathy; however, the optimal timing to evaluate antibody levels and how to combine them with other clinical variables are currently unknown.

Methods: We used a cohort of 85 patients from the Membranous Nephropathy Trial Of Rituximab (MENTOR) with anti-PLA2R antibodies ≥14 RU/ml to identify risk factors for not experiencing proteinuria remission after 12 months of treatment with cyclosporine or rituximab. Three landmark times were considered: at baseline and after 3 and 6 months of treatment. Logistic regression model performance was evaluated using C-statistics and model fit (Akaike information criterion [AIC], R 2 ).

Results: The model at baseline that best predicted no remission included anti-PLA2R antibodies >323 RU/ml and creatinine clearance; the best model after 3 months included the change from baseline in both antibody and albumin levels; and the best model after 6 months included antibody levels >14 RU/ml, creatinine clearance, and the change from baseline in albumin. Compared with the model at baseline, the model at 3 months had better model fit (AIC 70.9 versus 96.4, R 2 51.8% versus 30.1%) and higher C-statistic (0.93 versus 0.83, P = 0.008). The model at 6 months had no difference in performance compared with the model at 3 months (AIC 68.6, R 2 53.0%, C-statistic 0.94, P = 0.67).

Conclusions: In patients with membranous nephropathy treated with cyclosporine or rituximab in the MENTOR trial, we found that the optimal method to evaluate risk factors for the probability of treatment response was to use anti-PLA2R antibody levels combined with albumin levels after 3 months of treatment, which was significantly better than using antibody levels alone or risk factor evaluation at baseline, with no added benefit of waiting until 6 months of treatment.

Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_10_09_CJN0000000000000237.mp3.

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Conflict of interest statement

G.B. Appel reports consultancy for Achillion, Alexion, Apellis, Arrowhead, Aurinia, Bristol Myers Squibb, Chemocentryx, Chinook, EMD Serono, Genentech, Genzyme-Sanofi, GlaxoSmithKline, E. Lilly, Mallinkrodt, Merck, Novartis, Omeros, Pfizer, Reata, Travere Therapeutics, and Vertex Therapeutics; research funding from Achillion-Alexion, Apellis, Calliditas, Chemocentryx, Equillium, Genentech-Roche, Goldfinch, Mallinkrodt, Novartis, Reata, Sanofi-Genzyme, and Vertex—all through Columbia University; honoraria from Aurinia, Calliditas, and GlaxoSmithKline; royalties from UpToDate; advisory or leadership roles for UpToDate Editorial Board and Med Advisory board for Alexion, Alexion-Achillion, Apellis, Arrowhead, Aurinia, BM Squib, Chinook, Genentech, GlaxoSmithKline, Lilly, Reata, Roche, and Sanofi—no role as officer or board member of any pharmaceutical or other; and speakers bureau for Aurinia lectures on lupus nephritis, for GSK for lectures on lupus nephritis, and Calliditas for lecture on the gut and IgAN. N. Aslam reports ownership interest in Doximity; research funding from AstraZeneca, Baxter, Idorsia, Novartis, and Otsuka; and advisory or leadership roles for Chinook Advisory Board, Florida Society of Nephrology Board of Directors, and Travere Therapeutics Advisory Board. S.J. Barbour reports consultancy for Achillion, Alexion, Eledon, HIBio, Inception Sciences, Novartis, Pfizer, Vera, and Visterra; research funding from Alexion, Novartis, and Roche; and honoraria from Alexion and Roche. D.C. Cattran reports consultancy for Alexi, Alnylam, Aurinia, Calliditis, Chemocentrx, Chinook Therapeutics, Forsee, Horizon, Reistone, Vera Therapeutics, and Zyversa Therapeutics; research funding from Alnylam; honoraria from Alexion, Calliditis, and Kyowa Hakko Kirin Co; advisory or leadership roles for Alnylam, Calliditis, NephCure, SONG-GD, UpToDate, and Vera; and other interests or relationships with Aurinea, Dimerix, Novartis, and Vera Therapeutics. F.C. Fervenza reports employment with Mayo Clinic; consultancy for Alexion Pharmaceuticals, ByoCrystal, Galapagos, GSK, Novartis, Otsuka, and Takeda; research funding from Chemocentryx, Genentech, Hoffman La Roche, Janssen Pharmaceutical, Morphosys, and Retrophin; honoraria from UpToDate; and advisory or leadership roles for JASN, Kidney International, Nephrology, Nephrology Dialysis and Transplantation, and UpToDate. M.A. Hladunewich reports research funding from Calliditas Therapeutics, Chemocentryx, Chinook, Ionis, Pfizer, and Roche; honoraria from UpToDate; and other interests or relationships as medical lead for the Glomerular Disease Ontario Renal Network. D. Induruwage reports employment with the BC Provincial Renal Agency. K. Kiryluk reports consultancy for Calvariate and HiBio and research funding from Aevi Genomics, AstraZeneca, Bioporto, Vanda, and Visterra. R. Lafayette reports consultancy for Alexion, Inc., Aurinia, Calliditas, Inc., Chinook, Inc., Novartis, Omeros, Inc., Otsuka, Inc., Travere, Inc., Vera, Inc., and Visterra, Inc. and research funding from Apellis, Calliditas, Chemocentryx, Chinook, NIH, Omeros, Otsuka, Pfizer, Roche, Travere, and Vera. H.N. Reich reports consultancy for Calliditas, Chinook, Novartis, Omeros, Pfizer, and Retrophin (Travere); research funding from clinical trial recruitment: Alnylam, Calliditas, Chemocentryx, Omeros, and Pfizer and national coordinating investigator: Calliditas and Chinook; advisory or leadership roles for Academic advisory—Omeros, Academic leadership committee—Calliditas, Calliditas, Chinook, and Kidney International Editorial Board, and Steering Committee—Eledon; peer-reviewed funding from the Kidney Foundation of Canada; other interests or relationships with Canadian Institutes for Health Research and Pearson Foundation; fellowship support from the Fast Foundation; and consultation for the Canadian Agency for Drugs and Technologies in Health. B. Rovin reports consultancy for Alexion, AstraZeneca, Aurinia, Biocryst, Biogen, BMS, Calliditas, Chemocentryx, Corrona, EMD-Serono/Merck, Exagen, Galapagos, Genentech, Horizon, Human Genome Sciences (GSK), Idorsia, Janssen, Morphosys, MedImmune, Novartis, Omeros, Otsuka, Resonance, Retrophin, RILITE Foundation, Roche, and Vistera; research funding from Biogen; honoraria from Alexion, AstraZeneca, Aurinia, Biocryst, Biogen, BMS, Calliditas, Chemocentryx, Corrona, EMD-Serono/Merck, Exagen, Galapagos, Genentech, Horizon, Human Genome Sciences (GSK), Idorsia, Janssen, MedImmune, Morphosys, Novartis, Omeros, Otsuka, Resonance, Retrophin, RILITE Foundation, Roche, and Vistera; advisory or leadership roles for ASN Kidney Week, CureGN, KDIGO, Kidney International, Kidney International Reports, Lupus Foundation of America, Nephrology Dialysis and Transplantation, and UpToDate; a lot of work with the ASN, mostly educational courses; work with the NKF and the ISN; and work with the LFA. L. Zand reports employment with Mayo Clinic, Rochester, MN, and research funding from Genentech, Janssen Pharmaceuticals, and Mallinckrodt. All remaining authors have nothing to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Anti-PLA2R antibody and albumin levels over time based on remission status at 12 months. Data in the figure are presented as median and interquartile range. (A) Anti-PLA2R antibody levels over time. (B) Albumin levels over time.
Figure 2
Figure 2
Receiver-operating curves comparing models that include only anti-PLA2R antibody levels to multivariable models that also include clinical variables at each landmark time. The univariable, bivariable, and multivariable models are those from Table 3 and Supplemental Tables 3 and 4. This figure allows comparison, at each landmark time, of the receiver-operating curves for models with anti-PLA2R antibody levels alone with models that include antibody levels and clinical variables. The significant clinical predictor variables (P < 0.05) in the multivariable model at baseline include creatinine clearance, in the multivariable model at 3 months include albumin, and in the multivariable model at 6 months include creatinine clearance and albumin. The C-statistic values for each model are provided in the figure legends. Ab, antibodies; CI, confidence interval; PLA2R, phospholipase A2 receptor; Ref, reference model. Figure 2 can be viewed in color online at www.cjasn.org.
Figure 3
Figure 3
Receiver-operating curves comparing multivariable models at each landmark time that include clinical variables and anti-PLA2R antibody levels. The multivariable models are those from Table 3 and Supplemental Tables 3 and 4. This figure allows comparison of the receiver-operating curves for models with anti-PLA2R antibody levels and clinical variables across different landmark times. The significant clinical predictor variables (P < 0.05) in the multivariable model at baseline include creatinine clearance, in the multivariable model at 3 months include albumin, and in the multivariable model at 6 months include creatinine clearance and albumin. The C-statistic values for each model are provided in the figure legend. Figure 3 can be viewed in color online at www.cjasn.org.
Figure 4
Figure 4
The relative risk of not being in remission at 12 months associated with anti-PLA2R antibody levels at baseline and changes in anti-PLA2R antibody and albumin levels over 3 months. The y-axis is the odds ratio for the risk not being in remission at 12 months on the basis of the multivariable model in Table 3 at the 3-month landmark time. The shaded region is the 95% confidence interval.
See this image and copyright information in PMC

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