Delayed but Durable Remission to Rituximab in PLA2R-Associated Membranous Nephropathy Despite B-Cell Reconstitution: A Case Report

Delayed but Durable Remission to Rituximab in PLA2R-Associated Membranous Nephropathy Despite B-Cell Reconstitution: A Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Delayed but Durable Remission to Rituximab in PLA2R-Associated Membranous Nephropathy Despite B-Cell Reconstitution: A Case Report rushuang Yang, Ziyan Luo, Tingting He, Mei Jiang, Hongjie Zhu, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8533075/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Apr, 2026 Read the published version in BMC Nephrology → Version 1 posted 11 You are reading this latest preprint version Abstract Rituximab (RTX) is widely used as first-line therapy for PLA2R-associated membranous nephropathy (MN), but the optimal timing for assessing response and guiding retreatment remains uncertain, particularly in patients with slow clinical improvement. We report a 46-year-old man with PLA 2 R-associated MN who showed poor response to high-dose glucocorticoids and was subsequently treated with a low-dose, fractionated RTX regimen (total 3.6 g over 14 months).Notably, a significant reduction in proteinuria was not observed until 19 months after treatment initiation, when partial remission (proteinuria < 3.5 g/day) was first achieved. During 44 months of follow-up, proteinuria continued to decline and remission was maintained, while anti-PLA 2 R antibodies remained negative despite gradual reconstitution of circulating CD19⁺ B cells, and no further immunosuppressive therapy was administered.This case demonstrates a markedly delayed but durable clinical response to rituximab and illustrates that B-cell repopulation does not necessarily indicate disease relapse when anti-PLA 2 R antibodies remain suppressed, supporting the value of antibody-guided rather than B-cell-guided monitoring in slow responders. case report Rituximab membranous nephropathy PLA2R Delayed remission B-Cell Reconstitution Figures Figure 1 Figure 2 1 Introduction MN is one of the most common pathological causes of nephrotic syndrome in adults [ 1 ] . In primary MN, M-type phospholipase A 2 receptor (PLA 2 R) are considered the main pathogenic factor, and their serum levels are closely associated with disease activity and treatment response [ 2 , 3 ] . RTX, a monoclonal antibody targeting CD20-positive B cells, has been widely used in the treatment of PLA 2 R-associated MN [ 4 ] . By depleting B cells and suppressing autoantibody production, RTX typically induces immunological remission first, whereas improvement in proteinuria often occurs with a relative delay [ 5 , 6 ] . In clinical practice, the efficacy of RTX is usually evaluated 6–12 months after treatment using both proteinuria and immunological parameters [ 7 , 8 ] , and the need for retreatment is commonly determined based on proteinuria control and B-cell reconstitution [ 9 , 10 ] . However, substantial inter-individual variability exists in the temporal relationship between immunological response and clinical remission. Against this background, we report a patient with PLA 2 R-associated MN who showed a markedly delayed clinical response after low-dose, fractionated RTX therapy, but maintained stable proteinuric remission during a 44-month follow-up, despite gradual recovery of peripheral CD19⁺ B cells and persistently negative anti-PLA 2 R antibodies. This case provides a representative long-term observation of the dynamic relationship between immunological markers and clinical outcomes after RTX therapy. 2 Case report During physical and laboratory examination on January 13, 2022, a 46-year-old man presented with bilateral lower-limb edema and proteinuria of 2+. The 24-hour urinary protein excretion was 10.92 g, 12.65 g, and 13.58 g in three consecutive measurements, and the serum albumin level was 25.5 g/L. Immunological tests showed antinuclear antibodies at a titer of 1:100, with positive anti-SSA, anti-SSB, and anti-Ro52 antibodies. Serum anti-PLA 2 R antibody was positive. 2.1 Kidney biopsy results The results of immunofluorescence were as follows: IgG, +++; IgA, −; IgM, −; C3, +; C1q, −; Fib, −; ALB, −; kappa, +; lambda, +; AA, −; C4c, −; IgG1, +++; IgG2, +; IgG3, +; and IgG4, +++. IgG showed fine granular and diffuse deposition along the glomerular capillary loops, and ALB reabsorption droplets were observed in tubular epithelial cells.Light microscopy showed 39 glomeruli, including one globally sclerotic glomerulus and one with segmental sclerosis. The remaining glomeruli showed mild mesangial cell and matrix proliferation, with patent capillary loops and a rigid appearance. The basement membrane was thickened with spike formation, and subepithelial eosinophilic deposits were observed. No fibrinoid necrosis, wire-loop lesions, or crescent formation was found. Focal periglomerular fibrosis was noted. Tubular epithelial cells showed vacuolar and granular degeneration, with partial tubular dilatation, loss of brush border, and focal tubular atrophy. The interstitium showed mild edema with focal inflammatory cell infiltration, without obvious fibrosis. Small arteries showed mild wall thickening.Congo red and oxidized Congo red staining were negative.Immunofluorescence of PLA2R was positive, while immunohistochemistry of THSD7A was negative.Electron microscopic examination showed the following results. The glomerular basement membrane was irregularly thickened, with a maximum thickness of approximately 1200 nm, and podocyte foot processes were diffusely fused. Numerous electron-dense deposits were observed in the subepithelial and intramembranous regions, accompanied by basement membrane reaction. Some deposits were partially embedded within the basement membrane with evidence of absorption.Pathological diagnosis was membranous nephropathy, stage II, with acute tubulointerstitial injury. (Fig. 1 ). Chest computed tomography (CT) was performed, and tumor markers, hepatitis B virus, hepatitis C virus, and human immunodeficiency virus were screened. The results of all of these tests were negative. There was no history of nonsteroidal anti-inflammatory drug use. 3 Discussion This case reports a patient with PLA 2 R-associated MN who, after receiving low-dose, fractionated RTX therapy, exhibited a pronounced delayed yet sustained clinical remission. Notably, during follow-up, peripheral B-cell counts gradually recovered, while proteinuria and anti-PLA 2 R antibody levels remained stably controlled.This clinical course provides real-world evidence that deviates from the traditional “B-cell–driven retreatment” paradigm, suggesting that relying solely on B-cell reconstitution as an indicator for retreatment may not be appropriate in certain patients. The 2021 KDIGO guidelines recommend RTX as a first-line therapy for patients with moderate-to-high risk PLA 2 R-associated MN, aiming primarily to eliminate pathogenic anti-PLA 2 R antibodies and induce immunological remission. Multiple randomized controlled trials, including MENTOR, GEMRITUX, and STARMEN, have consistently shown that the decline in antibody levels typically precedes proteinuria remission, with a considerable proportion of patients achieving clinical improvement only beyond 12 months post-treatment [ 8 , 11 , 12 ] . This immunologic–clinical lag is thought to reflect the slow clearance of immune complexes from the glomerular basement membrane and the gradual restoration of podocyte architecture [ 13 , 14 ] . In the present case, the patient achieved early anti-PLA 2 R antibody negativity after RTX treatment; however, proteinuria did not reach partial remission until approximately 19 months post-initiation of therapy, closely aligning with the classical trajectory of “immunological remission preceding clinical remission.” Consequently, if RTX efficacy were assessed solely based on proteinuria changes at 6–12 months, this patient could have been misclassified as a “treatment failure,” potentially prompting unnecessary additional immunosuppressive therapy. Clinically more significant is that during later follow-up, despite gradual recovery of CD19⁺ B cells, anti-PLA 2 R antibodies remained negative and proteinuria continued to be stably controlled without further immunosuppressive intervention. This observation indicates that, in PLA 2 R-associated MN, peripheral B-cell counts do not necessarily equate to the reemergence of pathogenic immune activity; rather, anti-PLA 2 R antibody levels appear to be the key biomarker reflecting the immunologic state of the disease [ 15 ] . From a pathophysiological perspective, PLA 2 R-associated MN is driven by autoantibodies targeting podocyte surface antigens, forming subepithelial immune complexes along the glomerular basement membrane, activating complement, and inducing podocyte injury and proteinuria [ 16 ] . RTX exerts its therapeutic effect by depleting CD20⁺ B cells, thereby suppressing autoantibody production and inducing immunological remission [ 17 ] . Once pathogenic B-cell clones are adequately eradicated and immunological remission is established, newly generated B cells may not possess the same autoreactive potential; thus, B-cell reconstitution does not necessarily imply disease relapse. This notion is supported by clinical cohort studies, which have demonstrated that patients with persistently negative PLA 2 R antibodies have a significantly lower risk of relapse compared to those with antibody reappearance [ 18 , 19 ] . Therefore, using CD19 or CD20 cell counts alone to guide repeat RTX administration may fail to distinguish true immunologic relapse from benign B-cell recovery, potentially resulting in overtreatment. Accordingly, this case supports an antibody-centered management strategy, integrating anti-PLA 2 R antibody monitoring with dynamic proteinuria assessment. In the setting of sustained antibody negativity, careful observation rather than immediate retreatment can be pursued, thereby maintaining disease control while minimizing risks associated with additional immunosuppression. The main limitation of this report is that it represents a single-patient observation and cannot define universally applicable retreatment thresholds. Nevertheless, its value lies in the 44-month longitudinal follow-up, directly illustrating that delayed remission and B-cell recovery without disease relapse can coexist in the same patient, providing important clinical evidence for an antibody-guided rather than cell count–guided long-term management approach in PLA 2 R-associated MN. Abbreviations PLA 2 R Phospholipase A2 receptor MN Membranous nephropathy RTX Rituximab. Declarations Ethics approval and consent to participate This case report was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from the patient. Consent for publication Written informed consent was obtained from the patient for the publication of this case report and any potentially identifiable images or data included in this article. Competing interests The authors declare that they have no competing interests. Funding No funding was received for this study. Author Contribution RSY drafted and revised the manuscript. ZYL and HJZ contributed to the methodology and manuscript revision. MJ and TTH contributed to data collection and manuscript revision. TW supervised and revised the manuscript. All authors read and approved the final manuscript. Acknowledgements Not applicable. Data Availability The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. References Cai Q, Hendricks AR. Membranous nephropathy: A ten-year journey of discoveries[J/OL]. Semin Diagn Pathol. 2020;37(3):116–20. Barbour SJ, Fervenza FC, Induruwage D, et al. Anti-PLA2R Antibody Levels and Clinical Risk Factors for Treatment Nonresponse in Membranous Nephropathy[J/OL]. Clin J Am Soc Nephrol. 2023;18(10):1283–93. Li X, Wei D, Zhou Z, et al. Anti-PLA2R Antibodies in Chinese Patients with Membranous Nephropathy[J/OL]. Med Sci Monit. 2016;22:1630–6. Gao S, Cui Z, Wang X, et al. Rituximab Therapy for Primary Membranous Nephropathy in a Chinese Cohort[J/OL]. Front Med. 2021;8:663680. Zhang L, Chen M, Le W, et al. Efficacy of Long-Term Repeated Rituximab Treatment in Refractory Phospholipase A2 Receptor-Antibody-Related Membranous Nephropathy[J/OL]. Immunotherapy. 2022;14(15):1237–44. Ruggenenti P, Debiec H, Ruggiero B, et al. Anti-Phospholipase A2 Receptor Antibody Titer Predicts Post-Rituximab Outcome of Membranous Nephropathy[J/OL]. J Am Soc Nephrol. 2015;26(10):2545–58. Rovin BH, Adler SG, Barratt J, et al. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases[J/OL]. Kidney Int. 2021;100(4):S1–276. Fervenza FC, Appel GB, Barbour SJ, et al. Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy[J/OL]. N Engl J Med. 2019;381(1):36–46. Marinaki S, Skalioti C, Boletis JN. B Cell Depletion: Rituximab in Glomerular Disease and Transplantation[J/OL]. Nephron Extra. 2013;3(1):125–30. Del Vecchio L, Allinovi M, Rocco P, et al. Rituximab Therapy for Adults with Nephrotic Syndromes: Standard Schedules or B Cell-Targeted Therapy?[J/OL]. J Clin Med. 2021;10(24):5847. Barbour SJ, Ronco P, Praga M, et al. Predicting Remission in Antiphospholipase A2 Receptor Antibody-Associated Membranous Nephropathy: A Secondary Analysis of the GEMRITUX, MENTOR, and STARMEN Trials[J/OL]. Clin J Am Soc Nephrol. 2025;20(6):854–65. Dahan K, Debiec H, Plaisier E, et al. Rituximab for Severe Membranous Nephropathy: A 6-Month Trial with Extended Follow-Up[J/OL]. J Am Soc Nephrol. 2017;28(1):348–58. Beck LH, Fervenza FC, Beck DM, et al. Rituximab-Induced Depletion of Anti-PLA2R Autoantibodies Predicts Response in Membranous Nephropathy[J/OL]. J Am Soc Nephrol. 2011;22(8):1543–50. Huang L, Dong QR, Zhao YJ, et al. Rituximab for the management of idiopathic membranous nephropathy: a meta-analysis[J/OL]. Int Urol Nephrol. 2021;53(1):111–9. Tesar V, Hruskova Z. Autoantibodies in the Diagnosis, Monitoring, and Treatment of Membranous Nephropathy[J/OL]. Front Immunol. 2021;12:593288. Sinico RA, Mezzina N, Trezzi B, et al. Immunology of membranous nephropathy: from animal models to humans[J/OL]. Clin Exp Immunol. 2016;183(2):157–65. Ruggenenti P, Cravedi P, Remuzzi G. Rituximab for membranous nephropathy and immune disease: less might be enough[J/OL]. Nat Clin Pract Nephrol. 2009;5(2):76–7. Stefan G, Stancu S, Zugravu A, et al. Negative anti-phospholipase A2 receptor antibody status at three months predicts remission in primary membranous nephropathy[J/OL]. Ren Fail. 2022;44(1):258–68. Jatem-Escalante E, Martín-Conde ML, Gràcia-Lavedan E, et al. Monitoring anti-PLA2R antibody titres to predict the likelihood of spontaneous remission of membranous nephropathy[J/OL]. Clin Kidney J. 2021;14(12):2556–62. Additional Declarations No competing interests reported. Supplementary Files CAREchecklist.docx rawdata.xlsx Cite Share Download PDF Status: Published Journal Publication published 13 Apr, 2026 Read the published version in BMC Nephrology → Version 1 posted Editorial decision: Revision requested 29 Jan, 2026 Reviews received at journal 27 Jan, 2026 Reviews received at journal 18 Jan, 2026 Reviewers agreed at journal 18 Jan, 2026 Reviewers agreed at journal 17 Jan, 2026 Reviewers agreed at journal 15 Jan, 2026 Reviewers invited by journal 14 Jan, 2026 Editor assigned by journal 14 Jan, 2026 Editor invited by journal 14 Jan, 2026 Submission checks completed at journal 12 Jan, 2026 First submitted to journal 12 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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14:46:07","extension":"html","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":54747,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8533075/v1/199ff66ce83f7ca913e8ad82.html"},{"id":100600222,"identity":"bdce408f-8fcc-447f-8a99-81513a71ae7d","added_by":"auto","created_at":"2026-01-19 14:46:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2499983,"visible":true,"origin":"","legend":"\u003cp\u003eBiopsy findings. (A) Periodic acid–silver methenamine (PASM) staining (×400); (B) Immunofluorescence staining for IgG (×400); (C) \u0026nbsp;Immunofluorescence staining for PLA2R (×400); (D, E) Electron microscopy (×5,000 and ×10,000, respectively); (F) Masson trichrome staining (×400).\u003c/p\u003e","description":"","filename":"figure18.png","url":"https://assets-eu.researchsquare.com/files/rs-8533075/v1/3d9648e3c768a0a7d90f834c.png"},{"id":100600125,"identity":"5c2adead-b175-43f9-8002-f1504935848a","added_by":"auto","created_at":"2026-01-19 14:46:26","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":222102,"visible":true,"origin":"","legend":"\u003cp\u003eOver view of the treatment course.\u003c/p\u003e\n\u003cp\u003eRituximab(RTX).\u003c/p\u003e\n\u003cp\u003eThe figure shows longitudinal changes in urinary protein (UP), serum albumin (Alb), serum creatinine (Scr), CD19+ B-cell counts, anti-PLA2R antibody titers, and albumin-to-creatinine ratio (ACR) in relation to rituximab administration and concomitant therapies.For anti-PLA2R antibody values, “5” and “1” indicate measurements below the lower limits of detection (\u0026lt;5 RU/mL and \u0026lt;1 RU/mL, respectively), and were displayed as 5 and 1 for graphical visualization.\u003c/p\u003e","description":"","filename":"figure27.png","url":"https://assets-eu.researchsquare.com/files/rs-8533075/v1/7893671c7e2fe10eee26f7e1.png"},{"id":107351015,"identity":"e589898a-4bfc-493f-8270-bc33f4bbc8f8","added_by":"auto","created_at":"2026-04-20 16:07:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3388215,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8533075/v1/bb5533d5-1819-4d89-a145-f6637796fa4b.pdf"},{"id":100600402,"identity":"0accb3b9-c469-4ccf-a996-e3101121dea7","added_by":"auto","created_at":"2026-01-19 14:47:54","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":35744,"visible":true,"origin":"","legend":"","description":"","filename":"CAREchecklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-8533075/v1/ae08a1957130b5c420c0259b.docx"},{"id":100600144,"identity":"f82b2155-bcec-42ba-a229-2cb5ecf47ad7","added_by":"auto","created_at":"2026-01-19 14:46:38","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":68924,"visible":true,"origin":"","legend":"","description":"","filename":"rawdata.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8533075/v1/7447e4201b8aa378ee663efc.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Delayed but Durable Remission to Rituximab in PLA2R-Associated Membranous Nephropathy Despite B-Cell Reconstitution: A Case Report","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eMN is one of the most common pathological causes of nephrotic syndrome in adults\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. In primary MN, M-type phospholipase A\u003csub\u003e2\u003c/sub\u003e receptor (PLA\u003csub\u003e2\u003c/sub\u003eR) are considered the main pathogenic factor, and their serum levels are closely associated with disease activity and treatment response\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. RTX, a monoclonal antibody targeting CD20-positive B cells, has been widely used in the treatment of PLA\u003csub\u003e2\u003c/sub\u003eR-associated MN\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. By depleting B cells and suppressing autoantibody production, RTX typically induces immunological remission first, whereas improvement in proteinuria often occurs with a relative delay\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn clinical practice, the efficacy of RTX is usually evaluated 6\u0026ndash;12 months after treatment using both proteinuria and immunological parameters\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e, and the need for retreatment is commonly determined based on proteinuria control and B-cell reconstitution \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. However, substantial inter-individual variability exists in the temporal relationship between immunological response and clinical remission.\u003c/p\u003e \u003cp\u003eAgainst this background, we report a patient with PLA\u003csub\u003e2\u003c/sub\u003eR-associated MN who showed a markedly delayed clinical response after low-dose, fractionated RTX therapy, but maintained stable proteinuric remission during a 44-month follow-up, despite gradual recovery of peripheral CD19⁺ B cells and persistently negative anti-PLA\u003csub\u003e2\u003c/sub\u003eR antibodies. This case provides a representative long-term observation of the dynamic relationship between immunological markers and clinical outcomes after RTX therapy.\u003c/p\u003e"},{"header":"2 Case report","content":"\u003cp\u003eDuring physical and laboratory examination on January 13, 2022, a 46-year-old man presented with bilateral lower-limb edema and proteinuria of 2+. The 24-hour urinary protein excretion was 10.92 g, 12.65 g, and 13.58 g in three consecutive measurements, and the serum albumin level was 25.5 g/L. Immunological tests showed antinuclear antibodies at a titer of 1:100, with positive anti-SSA, anti-SSB, and anti-Ro52 antibodies. Serum anti-PLA\u003csub\u003e2\u003c/sub\u003eR antibody was positive.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Kidney biopsy results\u003c/h2\u003e \u003cp\u003eThe results of immunofluorescence were as follows: IgG, +++; IgA, \u0026minus;; IgM, \u0026minus;; C3, +; C1q, \u0026minus;; Fib, \u0026minus;; ALB, \u0026minus;; kappa, +; lambda, +; AA, \u0026minus;; C4c, \u0026minus;; IgG1, +++; IgG2, +; IgG3, +; and IgG4, +++. IgG showed fine granular and diffuse deposition along the glomerular capillary loops, and ALB reabsorption droplets were observed in tubular epithelial cells.Light microscopy showed 39 glomeruli, including one globally sclerotic glomerulus and one with segmental sclerosis. The remaining glomeruli showed mild mesangial cell and matrix proliferation, with patent capillary loops and a rigid appearance. The basement membrane was thickened with spike formation, and subepithelial eosinophilic deposits were observed. No fibrinoid necrosis, wire-loop lesions, or crescent formation was found. Focal periglomerular fibrosis was noted. Tubular epithelial cells showed vacuolar and granular degeneration, with partial tubular dilatation, loss of brush border, and focal tubular atrophy. The interstitium showed mild edema with focal inflammatory cell infiltration, without obvious fibrosis. Small arteries showed mild wall thickening.Congo red and oxidized Congo red staining were negative.Immunofluorescence of PLA2R was positive, while immunohistochemistry of THSD7A was negative.Electron microscopic examination showed the following results. The glomerular basement membrane was irregularly thickened, with a maximum thickness of approximately 1200 nm, and podocyte foot processes were diffusely fused. Numerous electron-dense deposits were observed in the subepithelial and intramembranous regions, accompanied by basement membrane reaction. Some deposits were partially embedded within the basement membrane with evidence of absorption.Pathological diagnosis was membranous nephropathy, stage II, with acute tubulointerstitial injury. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Chest computed tomography (CT) was performed, and tumor markers, hepatitis B virus, hepatitis C virus, and human immunodeficiency virus were screened. The results of all of these tests were negative. There was no history of nonsteroidal anti-inflammatory drug use.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Discussion","content":"\u003cp\u003eThis case reports a patient with PLA\u003csub\u003e2\u003c/sub\u003eR-associated MN who, after receiving low-dose, fractionated RTX therapy, exhibited a pronounced delayed yet sustained clinical remission. Notably, during follow-up, peripheral B-cell counts gradually recovered, while proteinuria and anti-PLA\u003csub\u003e2\u003c/sub\u003eR antibody levels remained stably controlled.This clinical course provides real-world evidence that deviates from the traditional \u0026ldquo;B-cell\u0026ndash;driven retreatment\u0026rdquo; paradigm, suggesting that relying solely on B-cell reconstitution as an indicator for retreatment may not be appropriate in certain patients.\u003c/p\u003e \u003cp\u003eThe 2021 KDIGO guidelines recommend RTX as a first-line therapy for patients with moderate-to-high risk PLA\u003csub\u003e2\u003c/sub\u003eR-associated MN, aiming primarily to eliminate pathogenic anti-PLA\u003csub\u003e2\u003c/sub\u003eR antibodies and induce immunological remission. Multiple randomized controlled trials, including MENTOR, GEMRITUX, and STARMEN, have consistently shown that the decline in antibody levels typically precedes proteinuria remission, with a considerable proportion of patients achieving clinical improvement only beyond 12 months post-treatment \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. This immunologic\u0026ndash;clinical lag is thought to reflect the slow clearance of immune complexes from the glomerular basement membrane and the gradual restoration of podocyte architecture \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn the present case, the patient achieved early anti-PLA\u003csub\u003e2\u003c/sub\u003eR antibody negativity after RTX treatment; however, proteinuria did not reach partial remission until approximately 19 months post-initiation of therapy, closely aligning with the classical trajectory of \u0026ldquo;immunological remission preceding clinical remission.\u0026rdquo; Consequently, if RTX efficacy were assessed solely based on proteinuria changes at 6\u0026ndash;12 months, this patient could have been misclassified as a \u0026ldquo;treatment failure,\u0026rdquo; potentially prompting unnecessary additional immunosuppressive therapy.\u003c/p\u003e \u003cp\u003eClinically more significant is that during later follow-up, despite gradual recovery of CD19⁺ B cells, anti-PLA\u003csub\u003e2\u003c/sub\u003eR antibodies remained negative and proteinuria continued to be stably controlled without further immunosuppressive intervention. This observation indicates that, in PLA\u003csub\u003e2\u003c/sub\u003eR-associated MN, peripheral B-cell counts do not necessarily equate to the reemergence of pathogenic immune activity; rather, anti-PLA\u003csub\u003e2\u003c/sub\u003eR antibody levels appear to be the key biomarker reflecting the immunologic state of the disease \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFrom a pathophysiological perspective, PLA\u003csub\u003e2\u003c/sub\u003eR-associated MN is driven by autoantibodies targeting podocyte surface antigens, forming subepithelial immune complexes along the glomerular basement membrane, activating complement, and inducing podocyte injury and proteinuria \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. RTX exerts its therapeutic effect by depleting CD20⁺ B cells, thereby suppressing autoantibody production and inducing immunological remission \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Once pathogenic B-cell clones are adequately eradicated and immunological remission is established, newly generated B cells may not possess the same autoreactive potential; thus, B-cell reconstitution does not necessarily imply disease relapse.\u003c/p\u003e \u003cp\u003eThis notion is supported by clinical cohort studies, which have demonstrated that patients with persistently negative PLA\u003csub\u003e2\u003c/sub\u003eR antibodies have a significantly lower risk of relapse compared to those with antibody reappearance\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Therefore, using CD19 or CD20 cell counts alone to guide repeat RTX administration may fail to distinguish true immunologic relapse from benign B-cell recovery, potentially resulting in overtreatment.\u003c/p\u003e \u003cp\u003eAccordingly, this case supports an antibody-centered management strategy, integrating anti-PLA\u003csub\u003e2\u003c/sub\u003eR antibody monitoring with dynamic proteinuria assessment. In the setting of sustained antibody negativity, careful observation rather than immediate retreatment can be pursued, thereby maintaining disease control while minimizing risks associated with additional immunosuppression.\u003c/p\u003e \u003cp\u003eThe main limitation of this report is that it represents a single-patient observation and cannot define universally applicable retreatment thresholds. Nevertheless, its value lies in the 44-month longitudinal follow-up, directly illustrating that delayed remission and B-cell recovery without disease relapse can coexist in the same patient, providing important clinical evidence for an antibody-guided rather than cell count\u0026ndash;guided long-term management approach in PLA\u003csub\u003e2\u003c/sub\u003eR-associated MN.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePLA\u003csub\u003e2\u003c/sub\u003eR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePhospholipase A2 receptor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMembranous nephropathy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRTX\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRituximab.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":" \u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e \u003cp\u003eThis case report was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from the patient.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eWritten informed consent was obtained from the patient for the publication of this case report and any potentially identifiable images or data included in this article.\u003c/p\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNo funding was received for this study.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eRSY drafted and revised the manuscript. ZYL and HJZ contributed to the methodology and manuscript revision. MJ and TTH contributed to data collection and manuscript revision. TW supervised and revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCai Q, Hendricks AR. Membranous nephropathy: A ten-year journey of discoveries[J/OL]. Semin Diagn Pathol. 2020;37(3):116\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarbour SJ, Fervenza FC, Induruwage D, et al. Anti-PLA2R Antibody Levels and Clinical Risk Factors for Treatment Nonresponse in Membranous Nephropathy[J/OL]. Clin J Am Soc Nephrol. 2023;18(10):1283\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi X, Wei D, Zhou Z, et al. Anti-PLA2R Antibodies in Chinese Patients with Membranous Nephropathy[J/OL]. Med Sci Monit. 2016;22:1630\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGao S, Cui Z, Wang X, et al. Rituximab Therapy for Primary Membranous Nephropathy in a Chinese Cohort[J/OL]. Front Med. 2021;8:663680.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang L, Chen M, Le W, et al. Efficacy of Long-Term Repeated Rituximab Treatment in Refractory Phospholipase A2 Receptor-Antibody-Related Membranous Nephropathy[J/OL]. Immunotherapy. 2022;14(15):1237\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRuggenenti P, Debiec H, Ruggiero B, et al. Anti-Phospholipase A2 Receptor Antibody Titer Predicts Post-Rituximab Outcome of Membranous Nephropathy[J/OL]. J Am Soc Nephrol. 2015;26(10):2545\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRovin BH, Adler SG, Barratt J, et al. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases[J/OL]. Kidney Int. 2021;100(4):S1\u0026ndash;276.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFervenza FC, Appel GB, Barbour SJ, et al. Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy[J/OL]. N Engl J Med. 2019;381(1):36\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarinaki S, Skalioti C, Boletis JN. B Cell Depletion: Rituximab in Glomerular Disease and Transplantation[J/OL]. Nephron Extra. 2013;3(1):125\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDel Vecchio L, Allinovi M, Rocco P, et al. Rituximab Therapy for Adults with Nephrotic Syndromes: Standard Schedules or B Cell-Targeted Therapy?[J/OL]. J Clin Med. 2021;10(24):5847.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarbour SJ, Ronco P, Praga M, et al. Predicting Remission in Antiphospholipase A2 Receptor Antibody-Associated Membranous Nephropathy: A Secondary Analysis of the GEMRITUX, MENTOR, and STARMEN Trials[J/OL]. Clin J Am Soc Nephrol. 2025;20(6):854\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDahan K, Debiec H, Plaisier E, et al. Rituximab for Severe Membranous Nephropathy: A 6-Month Trial with Extended Follow-Up[J/OL]. J Am Soc Nephrol. 2017;28(1):348\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeck LH, Fervenza FC, Beck DM, et al. Rituximab-Induced Depletion of Anti-PLA2R Autoantibodies Predicts Response in Membranous Nephropathy[J/OL]. J Am Soc Nephrol. 2011;22(8):1543\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang L, Dong QR, Zhao YJ, et al. Rituximab for the management of idiopathic membranous nephropathy: a meta-analysis[J/OL]. Int Urol Nephrol. 2021;53(1):111\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTesar V, Hruskova Z. Autoantibodies in the Diagnosis, Monitoring, and Treatment of Membranous Nephropathy[J/OL]. Front Immunol. 2021;12:593288.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSinico RA, Mezzina N, Trezzi B, et al. Immunology of membranous nephropathy: from animal models to humans[J/OL]. Clin Exp Immunol. 2016;183(2):157\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRuggenenti P, Cravedi P, Remuzzi G. Rituximab for membranous nephropathy and immune disease: less might be enough[J/OL]. Nat Clin Pract Nephrol. 2009;5(2):76\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStefan G, Stancu S, Zugravu A, et al. Negative anti-phospholipase A2 receptor antibody status at three months predicts remission in primary membranous nephropathy[J/OL]. Ren Fail. 2022;44(1):258\u0026ndash;68.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJatem-Escalante E, Mart\u0026iacute;n-Conde ML, Gr\u0026agrave;cia-Lavedan E, et al. Monitoring anti-PLA2R antibody titres to predict the likelihood of spontaneous remission of membranous nephropathy[J/OL]. Clin Kidney J. 2021;14(12):2556\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"case report, Rituximab, membranous nephropathy, PLA2R, Delayed remission, B-Cell Reconstitution","lastPublishedDoi":"10.21203/rs.3.rs-8533075/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8533075/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eRituximab (RTX) is widely used as first-line therapy for PLA2R-associated membranous nephropathy (MN), but the optimal timing for assessing response and guiding retreatment remains uncertain, particularly in patients with slow clinical improvement. We report a 46-year-old man with PLA\u003csub\u003e2\u003c/sub\u003eR-associated MN who showed poor response to high-dose glucocorticoids and was subsequently treated with a low-dose, fractionated RTX regimen (total 3.6 g over 14 months).Notably, a significant reduction in proteinuria was not observed until 19 months after treatment initiation, when partial remission (proteinuria\u0026thinsp;\u0026lt;\u0026thinsp;3.5 g/day) was first achieved. During 44 months of follow-up, proteinuria continued to decline and remission was maintained, while anti-PLA\u003csub\u003e2\u003c/sub\u003eR antibodies remained negative despite gradual reconstitution of circulating CD19⁺ B cells, and no further immunosuppressive therapy was administered.This case demonstrates a markedly delayed but durable clinical response to rituximab and illustrates that B-cell repopulation does not necessarily indicate disease relapse when anti-PLA\u003csub\u003e2\u003c/sub\u003eR antibodies remain suppressed, supporting the value of antibody-guided rather than B-cell-guided monitoring in slow responders.\u003c/p\u003e","manuscriptTitle":"Delayed but Durable Remission to Rituximab in PLA2R-Associated Membranous Nephropathy Despite B-Cell Reconstitution: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-19 13:42:50","doi":"10.21203/rs.3.rs-8533075/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-29T07:02:35+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-28T03:19:46+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-19T03:08:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"134175900042536215646177052148902907089","date":"2026-01-18T23:39:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"211473410089244490703099944440249530317","date":"2026-01-17T16:39:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"197234278656573594859123920506603035091","date":"2026-01-15T13:57:37+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-15T04:14:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-14T12:40:22+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-14T08:19:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-12T17:08:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2026-01-12T17:03:39+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fcaafab0-06c4-4542-a26d-4f91daf58ba2","owner":[],"postedDate":"January 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-20T16:05:21+00:00","versionOfRecord":{"articleIdentity":"rs-8533075","link":"https://doi.org/10.1186/s12882-026-04830-3","journal":{"identity":"bmc-nephrology","isVorOnly":false,"title":"BMC Nephrology"},"publishedOn":"2026-04-13 15:56:51","publishedOnDateReadable":"April 13th, 2026"},"versionCreatedAt":"2026-01-19 13:42:50","video":"","vorDoi":"10.1186/s12882-026-04830-3","vorDoiUrl":"https://doi.org/10.1186/s12882-026-04830-3","workflowStages":[]},"version":"v1","identity":"rs-8533075","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8533075","identity":"rs-8533075","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}