Low-Dose Daratumumab for the Treatment of Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits (PGNMID): A Case Report

Low-Dose Daratumumab for the Treatment of Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits (PGNMID): 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 Low-Dose Daratumumab for the Treatment of Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits (PGNMID): A Case Report Jiaomei Zhu, Limin Zhang, Huibo Zhao, Li Tian, Huaying Pei, Shaomei Li, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8549293/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Proliferative glomerulonephritis with monoclonal immunoglobu- lin deposits (PGNMID) is an exceptionally rare glomerular disease, accounting for only 0.17–0.21% of all renal biopsies, with no consensus–based treatment algo- rithm established. Although daratumumab, a humanized anti–CD38 monoclonal antibody, has shown promising efficacy in PGNMID, the existing evidence base is confined to small case series employing standard–dose regimens (16 mg/kg). Crit- ically, data regarding reduced–dose daratumumab strategies for elderly patients with bortezomib–refractory disease and multiple comorbidities remain markedly limited. This case report documents a successful dose–reduction approach in a high–risk elderly patient, addressing a pivotal knowledge gap in the management of refractory PGNMID. Case presentation: A 73–year–old Chinese male with biopsy–proven PGNMID (IgG3– κ subtype) and chronic kidney disease stage 3b (baseline serum creatinine 1.5 mg/dL, proteinuria 5.61 g/24 h) with multiple comorbidities (hypertension, coronary artery disease, prior cerebral infarction) demonstrated treatment failure after four cycles of first–line CyBorD therapy (cyclophosphamide, bortezomib, dexamethasone). Post–treatment, he experienced progressive renal deterioration (serum creatinine elevation to 2.7 mg/dL), severe nephrotic–range proteinuria (10.61 g/24 h), hypoalbuminemia (22.8 g/L), and decompensated heart failure. Considering his advanced age and elevated infection susceptibility, a risk–adapted regimen comprising reduced–dose daratumumab (400 mg, 6 mg/kg; 37.5% of standard 16 mg/kg dosing) combined with bortezomib 2.2 mg was adminis- tered monthly over nine cycles. Following this nine–month treatment course, the patient attained partial renal remission, evidenced by substantial proteinuria reduction (to 1.12 g/24 h), serum albumin normalization (to 38.1 g/L), serum creatinine stabilization (at 1.6 mg/dL), negative immunofixation electrophore- sis conversion, and complete resolution of heart failure. Notably, no infectious complications were documented throughout the treatment period. Conclusions: This case provides proof–of–concept evidence that low–dose dara- tumumab combined with bortezomib constitutes a viable and well–tolerated salvage therapeutic option for elderly patients with bortezomib–refractory PGNMID and substantial comorbidity burden. The favorable clinical outcome achieved despite marked dose reduction (to 37.5% of standard dosing) suggests that adaptive dose–de–escalation strategies may preserve therapeutic efficacy while mitigating toxicity in high–risk patient populations. This report enriches the limited global evidence base for daratumumab application in PGNMID and underscores the imperative for investigation of personalized, risk–stratified dosing paradigms in managing this rare and therapeutically challenging glomerulopathy among vulnerable individuals. proliferative glomerulonephritis with monoclonal immunoglobulin deposits daratumumab dose de–escalation bortezomib–refractory disease monoclonal gammopathy of renal significance elderly patients Figures Figure 1 Figure 2 Figure 3 1 Introduction Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits (PGN- MID), formally defined in 2004, is recognized as a distinct subtype of Monoclonal Gammopathy of Renal Significance (MGRS) and has long posed a formidable chal- lenge in clinical nephrology [ 1 , 2 ]. The central pathological feature is the selective deposition of monoclonal immunoglobulins in the glomeruli, without systemic multi- organ involvement. Clinically rare, it accounts for merely 0.17% to 0.21% of all renal biopsy cases, predominantly affecting middle–aged and elderly populations. The com- bined effects of low incidence and nonspecific clinical manifestations mean that most patients present with impaired renal function at diagnosis—approximately 60% of patients are in the advanced stages of chronic kidney disease (CKD) at initial presen- tation, and nearly half of patients exhibit nephrotic syndrome. This often shrinks the window for clinical intervention [ 3 , 4 ]. The mechanisms underlying PGNMID remain poorly understood. Current research suggests that it may involve abnormal immune response regulation—triggered by infections, solid tumors, or other environmental factors—against a background of underlying hematologic malignancies. This dysregulation leads to the abnormal secre- tion of monoclonal immunoglobulins by clonal B cells or plasma cells [ 5 – 8 ]. These pathogenic immunoglobulins drive excessive complement activation, precipitating glomerular inflammation and proliferative lesions that typically manifest as membra- noproliferative glomerulonephritis (MPGN), mesangial proliferative glomerulonephri- tis (MsPGN), or occasionally membranous nephropathy (MN) on histopathology [ 1 , 4 ]. Immunofluorescence studies characteristically reveal deposits of a single immunoglob- ulin subclass (predominantly IgG3, accounting for 60%–87% of cases) and a single light chain, while electron microscopy identifies granular electron–dense deposits in the mesangial and subendothelial regions without specific ultrastructural features [ 1 , 9 ]. Clonally directed therapy stands as the cornerstone of PGNMID management. For plasma cell clones, bortezomib–based regimens are the recommended first–line approach, while rituximab–based protocols target B–cell clones [ 10 , 11 ]. Nevertheless, treatment resistance remains a significant challenge, especially among elderly patients with comorbidities who face elevated risks of adverse events and disease progression. Therapeutic options for such refractory cases remain limited, highlighting an urgent unmet clinical need for alternative treatment agents. Daratumumab, a humanized IgG1 κ monoclonal antibody targeting CD38, has emerged as a transformative therapy in multiple myeloma (MM) and systemic light chain amyloidosis [ 12 , 13 ]. Beyond direct cytolytic effects, recent evidence suggests daratumumab modulates the renal immune microenvironment by eliminating immuno- suppressive cells, creating a favorable milieu for renal repair [ 12 ]. Preliminary data from small–sample studies and case reports have demonstrated promising efficacy in PGNMID [ 14 , 15 ]. However, the utility of low–dose daratumumab in elderly, high–risk patients with bortezomib–refractory disease remains underexplored, as does its tolerability profile in this vulnerable population. We present a case of a 73–year–old male with PGNMID (IgG3– κ subtype) and CKD Stage 3b who failed to respond to the CyBorD regimen (bortezomib + cyclophos- phamide + dexamethasone) and developed progressive renal dysfunction, severe edema, and heart failure. The patient was subsequently treated with low–dose daratu- mumab combined with bortezomib, resulting in significant reductions in proteinuria, stabilization of renal function, and resolution of heart failure. This case not only adds to the limited body of evidence supporting daratumumab’s efficacy in refractory PGNMID but also highlights the potential feasibility of dose de–escalation for elderly patients with multiple comorbidities. By documenting this successful therapeutic out- come, we aim to inform clinical decision–making for refractory PGNMID and advocate for further investigation into personalized dosing strategies for high–risk populations. 2 Case Presentation 2.1 Baseline Information and Laboratory Tests A 73–year–old Chinese male presented to the Second Hospital of Hebei Medical Uni- versity with facial and lower limb edema persisting for two years. The patient weighed 69 kg and measured 160 cm in height. Laboratory tests revealed: hematuria 2+, proteinuria 4+, serum albumin 36.6 g/L, serum creatinine 1.5 mg/dL, and hemoglobin 97 g/L. Twenty–four–hour urine protein quantification was 5.61 g/24 h. Serum free light chain analysis showed: κ 42.10 mg/L (reference range: 6.7–22.4 mg/L), λ 46.80 mg/L (reference range: 8.3–27.0 mg/L), with a κ / λ ratio of 0.90 (reference range: 0.31–1.56). Blood and urine immunofixation electrophoresis demonstrated IgG κ –positive monoclonal protein. The patient’s medical history included hypertension, coronary artery disease, and prior cerebral infarction. Physical examination revealed symmetrical mild pitting edema in both lower extremities. Bone marrow evaluation demonstrated: bone marrow smear with 1% mature plasma cells, flow cytometry with no abnormalities, and bone marrow biopsy revealing active proliferation of hematopoietic tissue with granulocyte–erythroid lineage pro- portions within normal limits. Granulocyte lineage consisted primarily of mid–to–late myeloid precursors, while erythroid lineage cells were present at all developmental stages. 2.2 Renal Biopsy Renal biopsy obtained two small pieces of cortical tissue. Frozen section immunoflu- orescence staining indicated: IgG (-), IgA (-), IgM (+) mesangial (MS) + glomeru- lar capillary wall (GCW) segmental, C1q (++) MS + GCW segmental, C3 (+) MS + GCW segmental, fibrin–related antigen (FRA) (-), κ (+), λ (-). Paraffin–embedded immunofluorescence demonstrated: IgG1 (-), IgG2 (-), IgG3 (+ to ++), IgG4 (-), IgA (-), IgM (-), C1q (-), C3 (-), FRA (-), κ (+), λ (-). The entire specimen contained 17 glomeruli, one of which exhibited global glomeru- losclerosis. Light microscopy revealed severe diffuse proliferation of mesangial cells and matrix, presenting a nodular pattern. Substantial hemosiderin deposition was visible in the subendothelial space, with minimal hemosiderin deposition in the mesangial area. Approximately 25% of tubules demonstrated atrophy with corresponding renal interstitial fibrosis and lymphomononuclear cell infiltration. Three interlobular arter- ies were visible; no arcuate arteries were observed. Minimal haptoglobin deposition was noted subendothelially in the afferent arterioles. No crystal deposits were detected in frozen renal tissue sections under polarized light microscopy. Congo red staining and polarized light examination were both negative. Electron microscopy revealed electron–dense deposits in the subendothelial and mesangial regions without specific ultrastructural features. Colloidal gold immuno- electron microscopy demonstrated κ (+) and λ (-) reactivity. These findings were consistent with proliferative glomerulonephritis with mon- oclonal immunoglobulin deposits (PGNMID IgG3– κ ). The final diagnoses were: PGNMID IgG3– κ , Stage 3b chronic kidney disease (CKD), Grade 3 hypertension (very high risk), coronary artery disease, and prior cerebral infarction (Figure 1 ). 2.3 Treatment and Follow–up According to the 2012 International Kidney Disease and Monoclonal Immunoglobulin Research Group (IKMG) treatment recommendations, chemotherapy is indicated for patients presenting with serum creatinine 1.5 mg/dL, proteinuria 5.61 g/24 h (classi- fied as CKD Stage 3b), and age > 65 years. Based on the patient’s weight (69 kg) and renal function (CKD Stage 3b), we administered four cycles of the CyBorD regimen: bortezomib 2.2 mg intravenously on days 1, 8, 15, and 22; cyclophosphamide 0.4 g intravenously weekly; and dexamethasone 15 mg orally on alternate days. Concurrent antiviral prophylaxis with valacyclovir 500 mg daily was administered to prevent her- pes zoster reactivation, given the patient’s immunosuppressed state. The patient had a 10–year history of hypertension and had been receiving long–term valsartan therapy, which was continued following the diagnosis of PGNMID. Despite this treatment, the patient’s condition deteriorated. Serum creatinine lev- els ranged from 245 to 230 µ mol/L (2.8–2.6 mg/dL), 24–hour urine protein ranged from 10.61 to 5.56 g, and serum albumin levels declined to 24.4–22.8 g/L. Addition- ally, the patient developed severe generalized edema and decompensated heart failure (Figure 2). The standard recommended dose of daratumumab is 16 mg/kg. Considering the patient’s advanced age and elevated infection risk attributable to polypharmacy and immunosuppression, a risk–adapted regimen was implemented: daratumumab 400 mg (∼6 mg/kg, vs. standard 16 mg/kg) combined with bortezomib 2.2 mg, administered intravenously monthly for nine cycles. Prior to each daratumumab infusion, pre- medication consisted of intravenous methylprednisolone sodium succinate 20 mg and calcium gluconate 1 g, along with intramuscular promethazine hydrochloride 25 mg. No infectious complications or other significant adverse events occurred throughout the treatment period. Following nine months of treatment, substantial clinical improvement was observed: 24–hour urine protein decreased to 1.12 g/24 h, serum albumin normalized to 38.1 g/L, and serum creatinine stabilized at 1.6 mg/dL. The patient achieved partial renal remission with negative conversion of immunofixation electrophoresis. Complete resolution of heart failure was also documented (Figure 3). 3 Discussion and Conclusions Proliferative glomerulonephritis with monoclonal immunoglobulin deposition (PGN- MID) was first formally defined by Nasr’s team in 2004 and is now clearly classified as an independent subtype of Monoclonal Gammopathy with Renal Involvement (MGRS)[1, 2]. From a clinical perspective, this disease primarily affects middle–aged and elderly individuals, with a nearly equal incidence rate between men and women. The pathological changes are confined to the kidneys—meaning they are localized to this organ without involvement of other systems[3]. Its clinical symptoms lack speci- ficity. According to previous studies, approximately half of patients exhibit nephrotic syndrome manifestations, around 80% of patients present with hematuria, and 60% already have renal insufficiency at diagnosis. In terms of incidence, PGNMID accounts for approximately 0.17% to 0.21% of all renal biopsy cases, making it a clinically rare kidney disease[1, 4]. The pathogenesis of this disease remains uncertain, charac- terized by the deposition of monoclonal immunoglobulins within the glomeruli. This Fig. 3 Clinical response to low–dose daratumumab therapy. Trends in urine protein, serum creatinine, and serum albumin demonstrating substantial clinical improvement with achievement of partial renal remission and complete resolution of heart failure. leads to excessive activation of the complement system, triggering inflammatory and proliferative changes in the glomeruli[4]. Li et al[5] proposed the following hypotheses regarding the pathogenesis of PGNMID: (1) Presence of hematologic malignancies, where malignant B cells or plasma cells in bone marrow or serum secrete large amounts of abnormal Ig; (2) Absence of primary hematologic disease, where normal B cells or plasma cells, influenced by multiple factors, secrete abnormal Ig. Additionally, factors such as infections and solid tumors may also trigger PGNMID[6–8]. The evaluation of renal biopsy pathology is crucial for diagnosing PGNMID. Light microscopy reveals typical proliferative changes in the glomeruli, including membra- noproliferative glomerulonephritis (MPGN) changes, mesangial proliferative glomeru- lonephritis (MsPGN) changes, and a few cases showing membranous nephropathy (MN) changes, with MPGN being the most common presentation[1, 4]. Immunofluo- rescence reveals deposits of a single immunoglobulin subtype and a single light chain, with the IgG3 subtype being the predominant form (60–87%). Electron microscopy reveals granular electron–dense deposits in the mesangial region and subendothe- lial areas, without any specific identifiable structures[1, 9]. Theoretically, PGNMID should exhibit a single light chain deposition. However, in actual immunofluorescence detection, factors such as reagents and antigen retrieval may mask some monoclonal immunoglobulin deposits in the glomeruli, to the extent that they cannot be detected in frozen sections. These deposits only become visible after enzyme digestion of paraf- fin–embedded tissue[16–18]. In this case, the patient’s frozen tissue showed negative IgG staining with polyclonal anti–IgG antibodies, while IgG subclass staining on paraffin–embedded tissue revealed monoclonal IgG3 deposition. This suggests that the patient’s IgG may have been masked and thus undetected. Further paraffin tis- sue examination revealed light chain κ deposition, with IgG3 κ slightly predominant. Light microscopy demonstrated membranoproliferative glomerulonephritis. Electron microscopy excluded identifiable structures such as fibers, microtubules, or crys- tals. No electron–dense deposits were observed in the tubular basement membranes. Consequently, diagnoses such as monoclonal protein deposition disease, fibrin–like glomerulonephritis, immunotactoid glomerulonephritis, or type I cryoglobulinemic glomerulonephritis were excluded. The final diagnosis was PGNMID. When clin- ical suspicion of PGNMID arises but fluorescence IgG subclass and light chain deposition tests are negative, paraffin–embedded fluorescence staining must be per- formed. Diagnosis should also incorporate findings from light microscopy and electron microscopy. In 2012, the International Kidney and Monoclonal Gammopathy Study Group (IKMG) established tiered treatment recommendations for PGNMID, the core approach of which revolves around the patient’s renal function status and disease pro- gression risk: For patients with chronic kidney disease (CKD) stages 1–2, 24–hour urine protein < 1 g, and no clear risk of progression, clinical management may involve symptomatic supportive care alone, with close monitoring of disease changes through regular follow–up of renal function and quantitative urine protein levels. If CKD stages 1–2 patients also exhibit > 1 g/day urinary protein or high–risk factors for dis- ease progression, or have advanced to CKD stages 3–4, chemotherapy intervention should be initiated. Among these, patients < 65 years old may undergo further eval- uation for autologous stem cell transplantation feasibility. For patients with CKD stage 5 who meet criteria for kidney transplantation, high–dose melphalan combined with autologous hematopoietic stem cell transplantation is recommended prior to transplantation to reduce the risk of disease recurrence postoperatively[10]. Currently, the internationally recognized treatment regimen for PGNMID is clonally directed therapy. For plasma cell clones, a bortezomib–based regimen is recommended, while for B–cell clones, a rituximab–based regimen is recommended[11]. This patient was diagnosed with plasma cell–clonally–directed PGNMID (IgG3– κ ), and was therefore treated with the CyBorD regimen. However, after four cycles of treatment, there was no improvement in the condition. The urine protein level increased to 10.61 g/24 h, serum albumin decreased to 22.8 g/L, creatinine rose to 2.7 mg/dL, and severe edema and heart failure were observed. Daratumumab, as a humanized IgG1 κ monoclonal antibody targeting CD38, exerts its core mechanism of action not only by inducing abnormal plasma cell apoptosis through antibody–dependent cellular cytotoxicity (ADCC), antibody–dependent cel- lular phagocytosis (ADCP), and complement–dependent cytotoxicity (CDC), but also by modulating the local renal immune microenvironment and eliminating immunosup- pressive cells, thereby creating favorable conditions for renal repair[12]. Daratumumab is also recommended for the treatment of systemic light chain amyloidosis[13]. Therefore, it holds promise as a potential treatment option for patients with PGNMID. This drug is currently approved for the treatment of relapsed/refractory multiple myeloma, and its efficacy in the PGNMID setting is supported by clinical research. A Phase 2 clinical trial conducted by Mayo Clinic enrolled 10 patients with PGNMID. All subjects received at least one dose of daratumumab (standard dose 16 mg/kg), including 7 treatment–naive patients, 2 patients who had failed prior rituximab ther- apy, and one who had failed to respond to mycophenolate mofetil plus prednisone. Follow–up results at 6 months (Day 161) showed two patients achieved complete remis- sion (CR), six achieved partial remission (PR), yielding an overall response rate of 80%, with two patients initially showing no response (NR). However, extended fol- low–up to 12 months (day 365) revealed that the 2 initially non–responders converted to PR, and the 2 original PR patients further progressed to CR, ultimately achieving a 100% overall response rate. Consistent with the Phase 2 trial by Zand et al[14], our patient also showed a delayed therapeutic response to daratumumab: after 4 cycles of treatment, immunofixation electrophoresis turned negative, and renal function gradu- ally stabilized, which further supports that long–term administration of daratumumab may be necessary for refractory PGNMID. Notably, our patient received a low dose (400 mg/month, equivalent to ∼6 mg/kg) compared to the standard 16 mg/kg, but still achieved partial remission, suggesting that dose adjustment based on patient tolerance may be feasible for elderly high–risk populations. The Almaani team conducted a small–sample study on PGNMID patients who failed bortezomib therapy, enrolling five female patients. The median age of this cohort was 25.8 years (significantly younger than the typical middle–aged and elderly onset group for PGNMID), and all patients exhibited nephrotic–range proteinuria prior to treatment, with a median urine protein quantification of 9.3 g/day. Following treat- ment with daratumumab and a median follow–up of 11.2 months, four of the five patients demonstrated disease improvement, with three achieving renal response cri- teria. Notably, one patient with detectable plasma cell clonality achieved not only complete urinary protein remission but also hematologic remission, suggesting that detectable plasma cell clonality may serve as a potential predictor of daratumumab efficacy. Only one patient progressed to end–stage renal disease (ESRD) due to sep- sis–associated acute kidney injury, indicating that concurrent infection may represent a significant prognostic risk factor for PGNMID patients[15]. The standard regimen for daratumumab in multiple myeloma is 16 mg/kg intra- venously once weekly for 8 weeks, followed by once every 2 weeks for 16 weeks. However, due to the patient’s advanced age, concomitant heart failure, and ele- vated creatinine levels, daratumumab was reduced to 400 mg subcutaneous injection combined with 2.2 mg bortezomib monthly to mitigate infection risk. After four daratumumab treatments, follow–up blood immunofixation electrophoresis showed negative results, urinary protein decreased significantly, serum albumin levels markedly increased, serum creatinine returned to baseline, and both edema and heart failure resolved. Studies indicate that PGNMID has an overall relapse rate of 37.5% with a median relapse time of 15 months[11]. For PGNMID patients who relapse after initial therapy, treatment with daratumumab involves administering a maintenance dose of 16 mg/kg every 2 months once renal remission is achieved[14]. However, long–term follow–up data for bortezomib–refractory patients treated with daratumumab remain limited[15]. The patient currently continues to receive daratumumab at 400 mg every two months to maintain remission and prevent relapse. The patient’s kidneys are in partial remission, with persistent negative results on immunofixation electrophoresis and resolution of hematuria. Edema and heart failure symptoms have been completely resolved. In summary, this case demonstrates that low–dose daratumumab combined with bortezomib holds promise as a viable treatment option for patients with refractory pro- liferative glomerulonephritis with monoclonal immunoglobulin deposition (PGNMID). Given the limited number of reported cases both domestically and internationally, large–scale, multicenter clinical trials are still needed to optimize the application of daratumumab in the treatment of PGNMID. Abbreviations ADCC: Antibody–Dependent Cellular Cytotoxicity; ADCP: Antibody–Dependent Cellular Phagocytosis; CARE: CAse REport; CDC: Complement–Dependent Cytotox- icity; CKD: Chronic Kidney Disease; CR: Complete Remission; CyBorD: Cyclophos- phamide, Bortezomib, and Dexamethasone; ESRD: End–Stage Renal Disease; FRA: Fibrin–Related Antigen; GCW: Glomerular Capillary Wall; IgA: Immunoglobulin A; IgG: Immunoglobulin G; IgG1: Immunoglobulin G1; IgG2: Immunoglobulin G2; IgG3: Immunoglobulin G3; IgG4: Immunoglobulin G4; IgM: Immunoglobulin M; IKMG: International Kidney and Monoclonal Gammopathy Research Group; MGRS: Mono- clonal Gammopathy of Renal Significance; MM: Multiple Myeloma; MN: Membranous Nephropathy; MPGN: Membranoproliferative Glomerulonephritis; MS: Mesangial; MsPGN: Mesangial Proliferative Glomerulonephritis; NR: No Response; PGNMID: Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits; PR: Partial Remission; κ : Kappa light chain; λ : Lambda light chain Declarations Ethics approval and consent to participate Ethical approval was waived by the Ethics Committee of The Second Hospital of Hebei Medical University as this is a retrospective single case report based on routine clinical care and does not involve any experimental intervention. Consent for publication Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor–in–Chief of this journal. Availability of data and materials All data generated or analysed during this study are included in this published article. Competing interests The authors declare that they have no competing interests. Funding This study was supported by the Medical Science Research Project of Hebei (20250443). Authors’ contributions – All authors contributed equally to the conceptualization, data collection, clinical management, pathological analysis, manuscript drafting, and critical revision of this case report. All authors read and approved the final manuscript. Acknowledgements – The authors thank the nephrologists, hematologists, pathologists, and clinical researchers whose pioneering work on proliferative glomerulonephritis with mono- clonal immunoglobulin deposits (PGNMID) and monoclonal gammopathy of renal significance (MGRS) has advanced our understanding and treatment of these rare kidney diseases. We also thank the patient for his cooperation and consent to share this case for the benefit of the medical community. We thank the Depart- ment of Nephrology, Peking University First Hospital, for providing the paraffin immunofluorescence images, and the Electron Microscopy Unit for providing the electron microscopy images. References Nasr, S.H., Markowitz, G.S., Stokes, M.B., Seshan, S.V., Valderrama, E., Appel, G.B., Aucouturier, P., D’Agati, V.D.: Proliferative glomerulonephritis with monoclonal igg deposits: a distinct entity mimicking immune-complex glomerulonephritis. 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Zhang","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Limin","middleName":"","lastName":"Zhang","suffix":""},{"id":577707828,"identity":"041e2b1f-86b3-4d36-9f86-acde00d45bca","order_by":2,"name":"Huibo Zhao","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Huibo","middleName":"","lastName":"Zhao","suffix":""},{"id":577707829,"identity":"8176f609-db9a-441b-b9a7-f927865fb172","order_by":3,"name":"Li Tian","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Tian","suffix":""},{"id":577707830,"identity":"a4130659-731d-4191-acc6-f4f8ca63d4a4","order_by":4,"name":"Huaying Pei","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Huaying","middleName":"","lastName":"Pei","suffix":""},{"id":577707831,"identity":"afc5bcf6-9577-40c9-8dfe-5341c064e9b1","order_by":5,"name":"Shaomei 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1","display":"","copyAsset":false,"role":"figure","size":110041,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRenal biopsy findings of PGNMID with IgG3–\u003c/strong\u003e\u003cem\u003eκ \u003c/em\u003e\u003cstrong\u003edeposits. \u003c/strong\u003e(A–H) Images from the renal biopsy. (A) Light microscopy reveals severe diffuse proliferation of mesangial cells and matrix, presenting a nodular pattern; substantial hemosiderin deposition is visible in the subendothelial space; minimal hemosiderin deposition is observed in the mesangial area, consistent with a membranoprolif- erative glomerulonephritis (MPGN) pattern of injury (periodic acid–silver methenamine + Masson’s Trichrome stain, 400×); (B) Paraffin immunofluorescence \u003cem\u003eκ \u003c/em\u003e(+); (C) Paraffin immunofluorescence \u003cem\u003eλ \u003c/em\u003e(-\u003c/p\u003e\n\u003cp\u003e); (D) Paraffin immunofluorescence IgG3 (+ to ++); (E, F) Subendothelial electron–dense deposits;\u003c/p\u003e\n\u003cp\u003e(G) Colloidal gold immunoelectron microscopy \u003cem\u003eλ \u003c/em\u003e(-); (H) Colloidal gold immunoelectron microscopy\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eκ \u003c/em\u003e(+).\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8549293/v1/02a1049aa210bd2a1a8fbab5.jpeg"},{"id":100855485,"identity":"99154e0c-56e4-47d7-a2e7-71ce4df34b5c","added_by":"auto","created_at":"2026-01-22 06:56:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":14683,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eClinical course during first–line CyBorD therapy. \u003c/strong\u003eTrends in urine protein, serum creatinine, and serum albumin demonstrating treatment failure with progressive renal deterioration and development of heart failure.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8549293/v1/a9866d8dd56001a24ad17767.png"},{"id":100855443,"identity":"f3ed1050-00fb-4318-9449-461d15c40646","added_by":"auto","created_at":"2026-01-22 06:56:13","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":14801,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eClinical response to low–dose daratumumab therapy. \u003c/strong\u003eTrends in urine protein, serum creatinine, and serum albumin demonstrating substantial clinical improvement with achievement of partial renal remission and complete resolution of heart failure.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8549293/v1/6ef65074d83eaca9d41a6363.png"},{"id":102290923,"identity":"0d218635-65aa-4141-aa0d-dd49460d8604","added_by":"auto","created_at":"2026-02-10 09:12:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":739352,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8549293/v1/1254dffc-5670-4a78-a09e-8a42692cc5be.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Low-Dose Daratumumab for the Treatment of Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits (PGNMID): A Case Report","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eProliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits (PGN- MID), formally defined in 2004, is recognized as a distinct subtype of Monoclonal Gammopathy of Renal Significance (MGRS) and has long posed a formidable chal- lenge in clinical nephrology [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The central pathological feature is the selective deposition of monoclonal immunoglobulins in the glomeruli, without systemic multi- organ involvement. Clinically rare, it accounts for merely 0.17% to 0.21% of all renal biopsy cases, predominantly affecting middle\u0026ndash;aged and elderly populations. The com- bined effects of low incidence and nonspecific clinical manifestations mean that most patients present with impaired renal function at diagnosis\u0026mdash;approximately 60% of patients are in the advanced stages of chronic kidney disease (CKD) at initial presen- tation, and nearly half of patients exhibit nephrotic syndrome. This often shrinks the window for clinical intervention [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe mechanisms underlying PGNMID remain poorly understood. Current research suggests that it may involve abnormal immune response regulation\u0026mdash;triggered by infections, solid tumors, or other environmental factors\u0026mdash;against a background of underlying hematologic malignancies. This dysregulation leads to the abnormal secre- tion of monoclonal immunoglobulins by clonal B cells or plasma cells [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. These pathogenic immunoglobulins drive excessive complement activation, precipitating\u003c/p\u003e \u003cp\u003eglomerular inflammation and proliferative lesions that typically manifest as membra- noproliferative glomerulonephritis (MPGN), mesangial proliferative glomerulonephri- tis (MsPGN), or occasionally membranous nephropathy (MN) on histopathology [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Immunofluorescence studies characteristically reveal deposits of a single immunoglob- ulin subclass (predominantly IgG3, accounting for 60%\u0026ndash;87% of cases) and a single light chain, while electron microscopy identifies granular electron\u0026ndash;dense deposits in the mesangial and subendothelial regions without specific ultrastructural features [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClonally directed therapy stands as the cornerstone of PGNMID management. For plasma cell clones, bortezomib\u0026ndash;based regimens are the recommended first\u0026ndash;line approach, while rituximab\u0026ndash;based protocols target B\u0026ndash;cell clones [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Nevertheless, treatment resistance remains a significant challenge, especially among elderly patients with comorbidities who face elevated risks of adverse events and disease progression. Therapeutic options for such refractory cases remain limited, highlighting an urgent unmet clinical need for alternative treatment agents.\u003c/p\u003e \u003cp\u003eDaratumumab, a humanized IgG1\u003cem\u003eκ\u003c/em\u003e monoclonal antibody targeting CD38, has emerged as a transformative therapy in multiple myeloma (MM) and systemic light chain amyloidosis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Beyond direct cytolytic effects, recent evidence suggests daratumumab modulates the renal immune microenvironment by eliminating immuno- suppressive cells, creating a favorable milieu for renal repair [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Preliminary data from small\u0026ndash;sample studies and case reports have demonstrated promising efficacy in PGNMID [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, the utility of low\u0026ndash;dose daratumumab in elderly, high\u0026ndash;risk patients with bortezomib\u0026ndash;refractory disease remains underexplored, as does its tolerability profile in this vulnerable population.\u003c/p\u003e \u003cp\u003eWe present a case of a 73\u0026ndash;year\u0026ndash;old male with PGNMID (IgG3\u0026ndash;\u003cem\u003eκ\u003c/em\u003e subtype) and CKD Stage 3b who failed to respond to the CyBorD regimen (bortezomib\u0026thinsp;+\u0026thinsp;cyclophos- phamide\u0026thinsp;+\u0026thinsp;dexamethasone) and developed progressive renal dysfunction, severe edema, and heart failure. The patient was subsequently treated with low\u0026ndash;dose daratu- mumab combined with bortezomib, resulting in significant reductions in proteinuria, stabilization of renal function, and resolution of heart failure. This case not only adds to the limited body of evidence supporting daratumumab\u0026rsquo;s efficacy in refractory PGNMID but also highlights the potential feasibility of dose de\u0026ndash;escalation for elderly patients with multiple comorbidities. By documenting this successful therapeutic out- come, we aim to inform clinical decision\u0026ndash;making for refractory PGNMID and advocate for further investigation into personalized dosing strategies for high\u0026ndash;risk populations.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"2 Case Presentation","content":"\u003ch2\u003e2.1 Baseline Information and Laboratory Tests\u003c/h2\u003e\n\u003cp\u003eA 73\u0026ndash;year\u0026ndash;old Chinese male presented to the Second Hospital of Hebei Medical Uni- versity with facial and lower limb edema persisting for two years. The patient weighed 69 kg and measured 160 cm in height.\u003c/p\u003e\n\u003cp\u003eLaboratory tests revealed: hematuria 2+, proteinuria 4+, serum albumin 36.6 g/L, serum creatinine 1.5 mg/dL, and hemoglobin 97 g/L. Twenty\u0026ndash;four\u0026ndash;hour urine protein quantification was 5.61 g/24 h. Serum free light chain analysis showed: \u003cem\u003e\u0026kappa;\u0026nbsp;\u003c/em\u003e42.10 mg/L (reference range: 6.7\u0026ndash;22.4 mg/L), \u003cem\u003e\u0026lambda;\u0026nbsp;\u003c/em\u003e46.80 mg/L (reference range: 8.3\u0026ndash;27.0 mg/L),\u003c/p\u003e\n\u003cp\u003ewith a \u003cem\u003e\u0026kappa;\u003c/em\u003e/\u003cem\u003e\u0026lambda;\u0026nbsp;\u003c/em\u003eratio of 0.90 (reference range: 0.31\u0026ndash;1.56). Blood and urine immunofixation electrophoresis demonstrated IgG \u003cem\u003e\u0026kappa;\u003c/em\u003e\u0026ndash;positive monoclonal protein.\u003c/p\u003e\n\u003cp\u003eThe patient\u0026rsquo;s medical history included hypertension, coronary artery disease, and prior cerebral infarction. Physical examination revealed symmetrical mild pitting edema in both lower extremities.\u003c/p\u003e\n\u003cp\u003eBone marrow evaluation demonstrated: bone marrow smear with 1% mature plasma\u0026nbsp;cells,\u0026nbsp;flow\u0026nbsp;cytometry\u0026nbsp;with\u0026nbsp;no\u0026nbsp;abnormalities,\u0026nbsp;and\u0026nbsp;bone\u0026nbsp;marrow\u0026nbsp;biopsy\u0026nbsp;revealing active proliferation of hematopoietic tissue with granulocyte\u0026ndash;erythroid lineage pro- portions within normal limits. Granulocyte lineage consisted primarily of mid\u0026ndash;to\u0026ndash;late myeloid precursors, while erythroid lineage cells were present at all developmental stages.\u003c/p\u003e\n\u003ch2\u003e2.2 Renal Biopsy\u003c/h2\u003e\n\u003cp\u003eRenal biopsy obtained two small pieces of cortical tissue. Frozen section immunoflu- orescence staining indicated: IgG (-), IgA (-), IgM (+) mesangial (MS) + glomeru- lar capillary wall (GCW) segmental, C1q (++) MS + GCW segmental, C3 (+) MS + GCW segmental, fibrin\u0026ndash;related antigen (FRA) (-), \u003cem\u003e\u0026kappa;\u0026nbsp;\u003c/em\u003e(+), \u003cem\u003e\u0026lambda;\u0026nbsp;\u003c/em\u003e(-).\u003c/p\u003e\n\u003cp\u003eParaffin\u0026ndash;embedded immunofluorescence demonstrated: IgG1 (-), IgG2 (-), IgG3 (+ to ++), IgG4 (-), IgA (-), IgM (-), C1q (-), C3 (-), FRA (-), \u003cem\u003e\u0026kappa;\u0026nbsp;\u003c/em\u003e(+), \u003cem\u003e\u0026lambda;\u0026nbsp;\u003c/em\u003e(-).\u003c/p\u003e\n\u003cp\u003eThe\u0026nbsp;entire\u0026nbsp;specimen\u0026nbsp;contained\u0026nbsp;17\u0026nbsp;glomeruli,\u0026nbsp;one\u0026nbsp;of\u0026nbsp;which\u0026nbsp;exhibited\u0026nbsp;global\u0026nbsp;glomeru- losclerosis.\u0026nbsp;Light\u0026nbsp;microscopy\u0026nbsp;revealed\u0026nbsp;severe\u0026nbsp;diffuse\u0026nbsp;proliferation\u0026nbsp;of\u0026nbsp;mesangial\u0026nbsp;cells\u0026nbsp;and matrix, presenting a nodular pattern. Substantial hemosiderin deposition was visible\u0026nbsp;in the subendothelial space, with minimal hemosiderin deposition in the mesangial area. Approximately 25% of tubules demonstrated atrophy with corresponding renal interstitial fibrosis and lymphomononuclear cell infiltration. Three interlobular arter- ies were visible; no arcuate arteries were observed. Minimal haptoglobin deposition was\u0026nbsp;noted\u0026nbsp;subendothelially\u0026nbsp;in\u0026nbsp;the\u0026nbsp;afferent\u0026nbsp;arterioles.\u0026nbsp;No\u0026nbsp;crystal\u0026nbsp;deposits\u0026nbsp;were\u0026nbsp;detected in frozen renal tissue sections under polarized light microscopy. Congo red staining\u0026nbsp;and polarized light examination were both negative.\u003c/p\u003e\n\u003cp\u003eElectron microscopy revealed electron\u0026ndash;dense deposits in the subendothelial and mesangial regions without specific ultrastructural features. Colloidal gold immuno- electron microscopy demonstrated \u003cem\u003e\u0026kappa;\u0026nbsp;\u003c/em\u003e(+) and \u003cem\u003e\u0026lambda;\u0026nbsp;\u003c/em\u003e(-) reactivity.\u003c/p\u003e\n\u003cp\u003eThese findings were consistent with proliferative glomerulonephritis with mon- oclonal immunoglobulin deposits (PGNMID IgG3\u0026ndash;\u003cem\u003e\u0026kappa;\u003c/em\u003e). The final diagnoses were: PGNMID IgG3\u0026ndash;\u003cem\u003e\u0026kappa;\u003c/em\u003e, Stage 3b chronic kidney disease (CKD), Grade 3 hypertension (very high risk), coronary artery disease, and prior cerebral infarction (Figure \u003ca href=\"#_bookmark0\"\u003e1\u003c/a\u003e).\u003c/p\u003e\n\u003ch2\u003e2.3 Treatment and Follow\u0026ndash;up\u003c/h2\u003e\n\u003cp\u003eAccording to the 2012 International Kidney Disease and Monoclonal Immunoglobulin Research Group (IKMG) treatment recommendations, chemotherapy is indicated for patients presenting with serum creatinine 1.5 mg/dL, proteinuria 5.61 g/24 h (classi- fied as CKD Stage 3b), and age \u003cem\u003e\u0026gt;\u003c/em\u003e65 years. Based on the patient\u0026rsquo;s weight (69 kg) and renal function (CKD Stage 3b), we administered four cycles of the CyBorD regimen: bortezomib 2.2 mg intravenously on days 1, 8, 15, and 22; cyclophosphamide 0.4 g\u003c/p\u003e\n\u003cp\u003eintravenously weekly; and dexamethasone 15 mg orally on alternate days. Concurrent antiviral prophylaxis with valacyclovir 500 mg daily was administered to prevent her- pes zoster reactivation, given the patient\u0026rsquo;s immunosuppressed state. The patient had a 10\u0026ndash;year history of hypertension and had been receiving long\u0026ndash;term valsartan therapy, which was continued following the diagnosis of PGNMID.\u003c/p\u003e\n\u003cp\u003eDespite this treatment, the patient\u0026rsquo;s condition deteriorated. Serum creatinine lev- els ranged from 245 to 230 \u003cem\u003e\u0026micro;\u003c/em\u003emol/L (2.8\u0026ndash;2.6 mg/dL), 24\u0026ndash;hour urine protein ranged from 10.61 to 5.56 g, and serum albumin levels declined to 24.4\u0026ndash;22.8 g/L. Addition- ally, the patient developed severe generalized edema and decompensated heart failure (Figure 2).\u003c/p\u003e\n\u003cp\u003eThe standard recommended dose of daratumumab is 16 mg/kg. Considering the patient\u0026rsquo;s advanced age and elevated infection risk attributable to polypharmacy and immunosuppression, a risk\u0026ndash;adapted regimen was implemented: daratumumab 400 mg (\u0026sim;6 mg/kg, vs. standard 16 mg/kg) combined with bortezomib 2.2 mg, administered intravenously monthly for nine cycles. Prior to each daratumumab infusion, pre- medication consisted of intravenous methylprednisolone sodium succinate 20 mg and calcium gluconate 1 g, along with intramuscular promethazine hydrochloride 25 mg. No infectious complications or other significant adverse events occurred throughout the treatment period.\u003c/p\u003e\n\u003cp\u003eFollowing nine months of treatment, substantial clinical improvement was observed: 24\u0026ndash;hour urine protein decreased to 1.12 g/24 h, serum albumin normalized to 38.1 g/L, and serum creatinine stabilized at 1.6 mg/dL. The patient achieved partial renal remission with negative conversion of immunofixation electrophoresis. Complete resolution of heart failure was also documented (Figure 3).\u003c/p\u003e"},{"header":"3 Discussion and Conclusions","content":"\u003cp\u003eProliferative glomerulonephritis with monoclonal immunoglobulin deposition (PGN- MID) was first formally defined by Nasr\u0026rsquo;s team in 2004 and is now clearly classified as an independent subtype of Monoclonal Gammopathy with Renal Involvement (MGRS)[1, 2]. From a clinical perspective, this disease primarily affects middle\u0026ndash;aged and elderly individuals, with a nearly equal incidence rate between men and women. The pathological changes are confined to the kidneys\u0026mdash;meaning they are localized to this organ without involvement of other systems[3]. Its clinical symptoms lack speci- ficity. According to previous studies, approximately half of patients exhibit nephrotic syndrome manifestations, around 80% of patients present with hematuria, and 60% already have renal insufficiency at diagnosis. In terms of incidence, PGNMID accounts for approximately 0.17% to 0.21% of all renal biopsy cases, making it a clinically rare kidney disease[1, 4]. The pathogenesis of this disease remains uncertain, charac- terized by the deposition of monoclonal immunoglobulins within the glomeruli. This\u003c/p\u003e\n\n\n\u003cp\u003e\u003cstrong\u003eFig. 3 Clinical response to low\u0026ndash;dose daratumumab therapy. \u003c/strong\u003eTrends in urine protein, serum creatinine, and serum albumin demonstrating substantial clinical improvement with achievement of partial renal remission and complete resolution of heart failure.\u003c/p\u003e\n\n\u003cp\u003eleads to excessive activation of the complement system, triggering inflammatory and proliferative changes in the glomeruli[4]. Li et al[5] proposed the following hypotheses regarding the pathogenesis of PGNMID: (1) Presence of hematologic malignancies, where malignant B cells or plasma cells in bone marrow or serum secrete large amounts of abnormal Ig; (2) Absence of primary hematologic disease, where normal B cells or plasma cells, influenced by multiple factors, secrete abnormal Ig. Additionally, factors such as infections and solid tumors may also trigger PGNMID[6\u0026ndash;8].\u003c/p\u003e\n\u003cp\u003eThe evaluation of renal biopsy pathology is crucial for diagnosing PGNMID. Light microscopy reveals typical proliferative changes in the glomeruli, including membra- noproliferative glomerulonephritis (MPGN) changes, mesangial proliferative glomeru- lonephritis (MsPGN) changes, and a few cases showing membranous nephropathy (MN) changes, with MPGN being the most common presentation[1, 4]. Immunofluo- rescence reveals deposits of a single immunoglobulin subtype and a single light chain, with the IgG3 subtype being the predominant form (60\u0026ndash;87%). Electron microscopy reveals granular electron\u0026ndash;dense deposits in the mesangial region and subendothe- lial areas, without any specific identifiable structures[1, 9]. Theoretically, PGNMID should exhibit a single light chain deposition. However, in actual immunofluorescence detection, factors such as reagents and antigen retrieval may mask some monoclonal immunoglobulin deposits in the glomeruli, to the extent that they cannot be detected in frozen sections. These deposits only become visible after enzyme digestion of paraf- fin\u0026ndash;embedded tissue[16\u0026ndash;18]. In this case, the patient\u0026rsquo;s frozen tissue showed negative IgG staining with polyclonal anti\u0026ndash;IgG antibodies, while IgG subclass staining on paraffin\u0026ndash;embedded tissue revealed monoclonal IgG3 deposition. This suggests that the patient\u0026rsquo;s IgG may have been masked and thus undetected. Further paraffin tis- sue examination revealed light chain \u003cem\u003e\u0026kappa; \u003c/em\u003edeposition, with IgG3\u003cem\u003e\u0026kappa; \u003c/em\u003eslightly predominant. Light microscopy demonstrated membranoproliferative glomerulonephritis. Electron microscopy excluded identifiable structures such as fibers, microtubules, or crys- tals. No electron\u0026ndash;dense deposits were observed in the tubular basement membranes. Consequently, diagnoses such as monoclonal protein deposition disease, fibrin\u0026ndash;like\u003c/p\u003e\n\u003cp\u003eglomerulonephritis, immunotactoid glomerulonephritis, or type I cryoglobulinemic glomerulonephritis were excluded. The final diagnosis was PGNMID. When clin- ical suspicion of PGNMID arises but fluorescence IgG subclass and light chain deposition tests are negative, paraffin\u0026ndash;embedded fluorescence staining must be per- formed. Diagnosis should also incorporate findings from light microscopy and electron microscopy.\u003c/p\u003e\n\u003cp\u003eIn 2012, the International Kidney and Monoclonal Gammopathy Study Group (IKMG) established tiered treatment recommendations for PGNMID, the core approach of which revolves around the patient\u0026rsquo;s renal function status and disease pro- gression risk: For patients with chronic kidney disease (CKD) stages 1\u0026ndash;2, 24\u0026ndash;hour urine protein \u003cem\u003e\u0026lt;\u003c/em\u003e1 g, and no clear risk of progression, clinical management may involve symptomatic supportive care alone, with close monitoring of disease changes through regular follow\u0026ndash;up of renal function and quantitative urine protein levels. If CKD stages 1\u0026ndash;2 patients also exhibit \u003cem\u003e\u0026gt;\u003c/em\u003e1 g/day urinary protein or high\u0026ndash;risk factors for dis- ease progression, or have advanced to CKD stages 3\u0026ndash;4, chemotherapy intervention should be initiated. Among these, patients \u003cem\u003e\u0026lt;\u003c/em\u003e65 years old may undergo further eval- uation for autologous stem cell transplantation feasibility. For patients with CKD stage 5 who meet criteria for kidney transplantation, high\u0026ndash;dose melphalan combined with autologous hematopoietic stem cell transplantation is recommended prior to transplantation to reduce the risk of disease recurrence postoperatively[10]. Currently, the internationally recognized treatment regimen for PGNMID is clonally directed therapy. For plasma cell clones, a bortezomib\u0026ndash;based regimen is recommended, while for B\u0026ndash;cell clones, a rituximab\u0026ndash;based regimen is recommended[11]. This patient was diagnosed with plasma cell\u0026ndash;clonally\u0026ndash;directed PGNMID (IgG3\u0026ndash;\u003cem\u003e\u0026kappa;\u003c/em\u003e), and was therefore treated with the CyBorD regimen. However, after four cycles of treatment, there was no improvement in the condition. The urine protein level increased to 10.61 g/24 h, serum albumin decreased to 22.8 g/L, creatinine rose to 2.7 mg/dL, and severe edema and heart failure were observed.\u003c/p\u003e\n\u003cp\u003eDaratumumab, as a humanized IgG1\u003cem\u003e\u0026kappa; \u003c/em\u003emonoclonal antibody targeting CD38, exerts its core mechanism of action not only by inducing abnormal plasma cell apoptosis through antibody\u0026ndash;dependent cellular cytotoxicity (ADCC), antibody\u0026ndash;dependent cel- lular phagocytosis (ADCP), and complement\u0026ndash;dependent cytotoxicity (CDC), but also by modulating the local renal immune microenvironment and eliminating immunosup- pressive cells, thereby creating favorable conditions for renal repair[12]. Daratumumab is also recommended for the treatment of systemic light chain amyloidosis[13]. Therefore, it holds promise as a potential treatment option for patients with PGNMID. This drug is currently approved for the treatment of relapsed/refractory multiple myeloma, and its efficacy in the PGNMID setting is supported by clinical research. A Phase 2 clinical trial conducted by Mayo Clinic enrolled 10 patients with PGNMID. All subjects received at least one dose of daratumumab (standard dose 16 mg/kg), including 7 treatment\u0026ndash;naive patients, 2 patients who had failed prior rituximab ther- apy, and one who had failed to respond to mycophenolate mofetil plus prednisone. Follow\u0026ndash;up results at 6 months (Day 161) showed two patients achieved complete remis- sion (CR), six achieved partial remission (PR), yielding an overall response rate of\u003c/p\u003e\n\u003cp\u003e80%, with two patients initially showing no response (NR). However, extended fol- low\u0026ndash;up to 12 months (day 365) revealed that the 2 initially non\u0026ndash;responders converted to PR, and the 2 original PR patients further progressed to CR, ultimately achieving a 100% overall response rate. Consistent with the Phase 2 trial by Zand et al[14], our patient also showed a delayed therapeutic response to daratumumab: after 4 cycles of treatment, immunofixation electrophoresis turned negative, and renal function gradu- ally stabilized, which further supports that long\u0026ndash;term administration of daratumumab may be necessary for refractory PGNMID. Notably, our patient received a low dose (400 mg/month, equivalent to \u0026sim;6 mg/kg) compared to the standard 16 mg/kg, but\u003c/p\u003e\n\u003cp\u003estill achieved partial remission, suggesting that dose adjustment based on patient\u003c/p\u003e\n\u003cp\u003etolerance may be feasible for elderly high\u0026ndash;risk populations.\u003c/p\u003e\n\u003cp\u003eThe Almaani team conducted a small\u0026ndash;sample study on PGNMID patients who failed bortezomib therapy, enrolling five female patients. The median age of this cohort was 25.8 years (significantly younger than the typical middle\u0026ndash;aged and elderly onset group for PGNMID), and all patients exhibited nephrotic\u0026ndash;range proteinuria prior to treatment, with a median urine protein quantification of 9.3 g/day. Following treat- ment with daratumumab and a median follow\u0026ndash;up of 11.2 months, four of the five patients demonstrated disease improvement, with three achieving renal response cri- teria. Notably, one patient with detectable plasma cell clonality achieved not only complete urinary protein remission but also hematologic remission, suggesting that detectable plasma cell clonality may serve as a potential predictor of daratumumab efficacy. Only one patient progressed to end\u0026ndash;stage renal disease (ESRD) due to sep- sis\u0026ndash;associated acute kidney injury, indicating that concurrent infection may represent a significant prognostic risk factor for PGNMID patients[15].\u003c/p\u003e\n\u003cp\u003eThe standard regimen for daratumumab in multiple myeloma is 16 mg/kg intra- venously once weekly for 8 weeks, followed by once every 2 weeks for 16 weeks. However, due to the patient\u0026rsquo;s advanced age, concomitant heart failure, and ele- vated creatinine levels, daratumumab was reduced to 400 mg subcutaneous injection combined with 2.2 mg bortezomib monthly to mitigate infection risk. After four daratumumab treatments, follow\u0026ndash;up blood immunofixation electrophoresis showed negative results, urinary protein decreased significantly, serum albumin levels markedly increased, serum creatinine returned to baseline, and both edema and heart failure resolved. Studies indicate that PGNMID has an overall relapse rate of 37.5% with a median relapse time of 15 months[11]. For PGNMID patients who relapse after initial therapy, treatment with daratumumab involves administering a maintenance dose of 16 mg/kg every 2 months once renal remission is achieved[14]. However, long\u0026ndash;term follow\u0026ndash;up data for bortezomib\u0026ndash;refractory patients treated with daratumumab remain limited[15]. The patient currently continues to receive daratumumab at 400 mg every two months to maintain remission and prevent relapse. The patient\u0026rsquo;s kidneys are in partial remission, with persistent negative results on immunofixation electrophoresis and resolution of hematuria. Edema and heart failure symptoms have been completely resolved.\u003c/p\u003e\n\u003cp\u003eIn summary, this case demonstrates that low\u0026ndash;dose daratumumab combined with bortezomib holds promise as a viable treatment option for patients with refractory pro- liferative glomerulonephritis with monoclonal immunoglobulin deposition (PGNMID).\u003c/p\u003e\n\u003cp\u003eGiven the limited number of reported cases both domestically and internationally, large\u0026ndash;scale, multicenter clinical trials are still needed to optimize the application of daratumumab in the treatment of PGNMID.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eADCC: Antibody\u0026ndash;Dependent Cellular Cytotoxicity; ADCP: Antibody\u0026ndash;Dependent Cellular Phagocytosis; CARE: CAse REport; CDC: Complement\u0026ndash;Dependent Cytotox- icity; CKD: Chronic Kidney Disease; CR: Complete Remission; CyBorD: Cyclophos- phamide, Bortezomib, and Dexamethasone; ESRD: End\u0026ndash;Stage Renal Disease; FRA: Fibrin\u0026ndash;Related Antigen; GCW: Glomerular Capillary Wall; IgA: Immunoglobulin A; IgG: Immunoglobulin G; IgG1: Immunoglobulin G1; IgG2: Immunoglobulin G2; IgG3: Immunoglobulin G3; IgG4: Immunoglobulin G4; IgM: Immunoglobulin M; IKMG: International Kidney and Monoclonal Gammopathy Research Group; MGRS: Mono- clonal Gammopathy of Renal Significance; MM: Multiple Myeloma; MN: Membranous Nephropathy; MPGN: Membranoproliferative Glomerulonephritis; MS: Mesangial; MsPGN: Mesangial Proliferative Glomerulonephritis; NR: No Response; PGNMID: Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits; PR: Partial Remission; \u003cem\u003e\u0026kappa;\u003c/em\u003e: Kappa light chain;\u0026nbsp;\u003cem\u003e\u0026lambda;\u003c/em\u003e: Lambda light chain\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cul\u003e\n \u003cli\u003e\n \u003ch3\u003eEthics\u0026nbsp;approval\u0026nbsp;and\u0026nbsp;consent\u0026nbsp;to\u0026nbsp;participate\u003c/h3\u003e\n \u003cul\u003e\n \u003cli\u003eEthical\u0026nbsp;approval\u0026nbsp;was\u0026nbsp;waived\u0026nbsp;by\u0026nbsp;the\u0026nbsp;Ethics\u0026nbsp;Committee\u0026nbsp;of\u0026nbsp;The\u0026nbsp;Second\u0026nbsp;Hospital of Hebei Medical University as this is a retrospective single case report based on routine clinical care and does not involve any experimental intervention.\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003ch3\u003eConsent\u0026nbsp;for\u0026nbsp;publication\u003c/h3\u003e\n \u003cul\u003e\n \u003cli\u003eWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor\u0026ndash;in\u0026ndash;Chief of this journal.\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003ch3\u003eAvailability\u0026nbsp;of\u0026nbsp;data\u0026nbsp;and\u0026nbsp;materials\u003c/h3\u003e\n \u003cul\u003e\n \u003cli\u003eAll data generated or analysed during this study are included in this published article.\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003ch3\u003eCompeting\u0026nbsp;interests\u003c/h3\u003e\n \u003cul\u003e\n \u003cli\u003eThe\u0026nbsp;authors\u0026nbsp;declare\u0026nbsp;that\u0026nbsp;they\u0026nbsp;have\u0026nbsp;no\u0026nbsp;competing\u0026nbsp;interests.\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003ch3\u003eFunding\u003c/h3\u003e\n \u003cul\u003e\n \u003cli\u003eThis study was supported by the Medical Science Research Project of Hebei (20250443).\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003ch3\u003eAuthors\u0026rsquo;\u0026nbsp;contributions\u003cstrong\u003e\u003cbr\u003e\u003c/strong\u003e\u003c/h3\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026ndash;\u0026nbsp;All authors contributed equally to the conceptualization, data collection, clinical management, pathological analysis, manuscript drafting, and critical revision of this case report. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003ch3\u003eAcknowledgements\u003c/h3\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026ndash; The authors thank the nephrologists, hematologists, pathologists, and clinical researchers whose pioneering work on proliferative glomerulonephritis with mono- clonal immunoglobulin deposits (PGNMID) and monoclonal gammopathy of renal significance (MGRS) has advanced our understanding and treatment of these rare kidney diseases. We also thank the patient for his cooperation and consent to share this case for the benefit of the medical community. We thank the Depart- ment of Nephrology, Peking University First Hospital, for providing the paraffin immunofluorescence images, and the Electron Microscopy Unit for providing the electron microscopy images.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eNasr, S.H., Markowitz, G.S., Stokes, M.B., Seshan, S.V., Valderrama, E., Appel, G.B., Aucouturier, P., D\u0026rsquo;Agati, V.D.: Proliferative glomerulonephritis with monoclonal igg deposits: a distinct entity mimicking immune-complex glomerulonephritis. 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Kidney International \u003cstrong\u003e94\u003c/strong\u003e(1), 199\u0026ndash;205 (2018)\u003c/li\u003e\n \u003cli\u003eKrejcik, J., Casneuf, T., Nijhof, I.S., Verbist, B., Bald, J., Plesner, T., Syed, K., Liu, K., Donk, N.W., Weiss, B.M., \u003cem\u003eet al.\u003c/em\u003e: Daratumumab depletes cd38+ immune regulatory cells, promotes t-cell expansion, and skews t-cell repertoire in multiple myeloma. Blood, The Journal of the American Society of Hematology \u003cstrong\u003e128\u003c/strong\u003e(3), 384\u0026ndash;394 (2016)\u003c/li\u003e\n \u003cli\u003eSanchorawala, V.: Systemic light chain amyloidosis. New England Journal of Medicine \u003cstrong\u003e390\u003c/strong\u003e(24), 2295\u0026ndash;2307 (2024)\u003c/li\u003e\n \u003cli\u003eZand, L., Rajkumar, S.V., Leung, N., Sethi, S., El Ters, M., Fervenza, F.C.: Safety and\u0026nbsp;efficacy\u0026nbsp;of\u0026nbsp;daratumumab\u0026nbsp;in\u0026nbsp;patients\u0026nbsp;with\u0026nbsp;proliferative\u0026nbsp;gn\u0026nbsp;with\u0026nbsp;monoclonal immunoglobulin\u0026nbsp;deposits.\u0026nbsp;Journal\u0026nbsp;of\u0026nbsp;the\u0026nbsp;American\u0026nbsp;Society\u0026nbsp;of\u0026nbsp;Nephrology\u0026nbsp;\u003cstrong\u003e32\u003c/strong\u003e(5), 1163\u0026ndash;1173 (2021)\u003c/li\u003e\n \u003cli\u003eAlmaani, S., Parikh, S.V., Satoskar, A.A., Bumma, N., Rovin, B.H., Sharma, N., Efebera, Y., Ayoub, I.: Daratumumab in patients with bortezomib-refractory pro- liferative glomerulonephritis with monoclonal immunoglobulin deposits. Kidney International Reports \u003cstrong\u003e6\u003c/strong\u003e(8), 2203\u0026ndash;2206 (2021)\u003c/li\u003e\n \u003cli\u003eHowlader, A., Thajudeen, B., Sussman, A.N., Bracamonte, E., Krahl, L., Nasr, S.H.: Proliferative glomerulonephritis with masked monoclonal deposits responsive to myeloma therapy. Kidney International Reports \u003cstrong\u003e2\u003c/strong\u003e(6), 1233\u0026ndash;1237 (2017)\u003c/li\u003e\n \u003cli\u003eLarsen, C.P., Ambuzs, J.M., Bonsib, S.M., Boils, C.L., Cossey, L.N., Messias, N.C., Silva, F.G., Wang, Y.H., Gokden, N., Walker, P.D.: Membranous-like glomerulopathy with masked igg kappa deposits. Kidney international \u003cstrong\u003e86\u003c/strong\u003e(1), 154\u0026ndash;161 (2014)\u003c/li\u003e\n \u003cli\u003eLarsen, C., Boils, C., Cossey, L., Sharma, S., Walker, P.: Clinicopathologic fea- tures of membranous-like glomerulopathy with masked igg kappa deposits. Kidney international reports \u003cstrong\u003e1\u003c/strong\u003e(4), 299\u0026ndash;305 (2016)\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"proliferative glomerulonephritis with monoclonal immunoglobulin deposits, daratumumab, dose de–escalation, bortezomib–refractory disease, monoclonal gammopathy of renal significance, elderly patients","lastPublishedDoi":"10.21203/rs.3.rs-8549293/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8549293/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eProliferative glomerulonephritis with monoclonal immunoglobu- lin deposits (PGNMID) is an exceptionally rare glomerular disease, accounting for only 0.17–0.21% of all renal biopsies, with no consensus–based treatment algo- rithm established. Although daratumumab, a humanized anti–CD38 monoclonal antibody, has shown promising efficacy in PGNMID, the existing evidence base is confined to small case series employing standard–dose regimens (16 mg/kg). Crit- ically, data regarding reduced–dose daratumumab strategies for elderly patients with bortezomib–refractory disease and multiple comorbidities remain markedly limited. This case report documents a successful dose–reduction approach in a high–risk elderly patient, addressing a pivotal knowledge gap in the management of refractory PGNMID.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation: \u003c/strong\u003eA 73–year–old Chinese male with biopsy–proven PGNMID (IgG3–\u003cem\u003e\u003cstrong\u003eκ \u003c/strong\u003e\u003c/em\u003esubtype) and chronic kidney disease stage 3b (baseline serum creatinine 1.5 mg/dL, proteinuria 5.61 g/24 h) with multiple comorbidities (hypertension, coronary artery disease, prior cerebral infarction) demonstrated treatment failure after four cycles of first–line CyBorD therapy (cyclophosphamide, bortezomib, dexamethasone). Post–treatment, he experienced progressive renal deterioration (serum creatinine elevation to 2.7 mg/dL), severe nephrotic–range proteinuria (10.61 g/24 h), hypoalbuminemia (22.8 g/L), and decompensated heart failure. Considering his advanced age and elevated infection susceptibility, a risk–adapted regimen comprising reduced–dose daratumumab (400 mg, 6 mg/kg; 37.5% of\u003c/p\u003e\n\u003cp\u003estandard 16 mg/kg dosing) combined with bortezomib 2.2 mg was adminis- tered monthly over nine cycles. Following this nine–month treatment course, the patient attained partial renal remission, evidenced by substantial proteinuria reduction (to 1.12 g/24 h), serum albumin normalization (to 38.1 g/L), serum creatinine stabilization (at 1.6 mg/dL), negative immunofixation electrophore- sis conversion, and complete resolution of heart failure. Notably, no infectious complications were documented throughout the treatment period.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eThis case provides proof–of–concept evidence that low–dose dara- tumumab combined with bortezomib constitutes a viable and well–tolerated salvage therapeutic option for elderly patients with bortezomib–refractory PGNMID and substantial comorbidity burden. The favorable clinical outcome achieved despite marked dose reduction (to 37.5% of standard dosing) suggests that adaptive dose–de–escalation strategies may preserve therapeutic efficacy while mitigating toxicity in high–risk patient populations. This report enriches the limited global evidence base for daratumumab application in PGNMID and underscores the imperative for investigation of personalized, risk–stratified dosing paradigms in managing this rare and therapeutically challenging glomerulopathy among vulnerable individuals.\u003c/p\u003e","manuscriptTitle":"Low-Dose Daratumumab for the Treatment of Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits (PGNMID): A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-22 06:53:56","doi":"10.21203/rs.3.rs-8549293/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0cce61a0-1d3b-4c48-8570-b390f9863284","owner":[],"postedDate":"January 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-10T09:11:01+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-22 06:53:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8549293","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8549293","identity":"rs-8549293","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}