A single-center experience of Obinutuzumab in children with refractory kidney disease

A single-center experience of Obinutuzumab in children with refractory kidney disease | 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 Research Article A single-center experience of Obinutuzumab in children with refractory kidney disease Shefali Vyas, Ursula Nath, Isabel Roberti This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8338986/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 12 You are reading this latest preprint version Abstract Background This is a retrospective review of children with refractory kidney disease treated with Obinutuzumab. Sparse published data exist in children with nephrotic syndrome and refractory membranous nephropathy treated with Obinutuzumab. Methods The study included all children who received Obinutuzumab and one Ofatumumab. Demographic data, etiology, biopsy results, therapies, eGFR (ml/min/1.73), first AM urine protein/creatinine, follow-up time, and side effects were noted. Clinical response was defined as AM Urine protein/creatinine 30% improvement in eGFR. Results 46 infusions were given in 29 patients. Etiology: 22 primary nephrotic syndrome (76%), (SDNS 59% and SRNS 41%, 2 were post kidney txp), 5 (17%) chronic GN (C3GN, Lupus nephritis, IgAN, C1QN), and 2 (7%) AIN/AKI. Biopsy diagnosis was obtained in 25 (86%). Failed therapies : all with steroids, Rituximab = 20 (69%), CNI = 19 (66%), MMF = 17(59%), Cytoxan = 7(30%). Twenty-three (82%) had complete remission of the primary nephropathy, and 73% were off all medications. eGFR improved from 49 to 64. Adverse events : 1 had a severe reaction and was unable to get the infusion, 3 patients had infections needing hospitalization (varicella, PCP pneumonia, and septic shock). Follow-up time : 3 to 44 months. Post infusion, all patients were off steroids, except 2 txp patients. Time to relapse was significantly longer with obinutuzumab vs rituximab (19 mos vs 10 mos). Conclusions Obinutuzumab was well tolerated and associated with a high and sustained remission rate in children with various resistant nephropathies. Significant reductions in proteinuria and improvement in eGFR were observed. Nephrotic syndrome B cell depleting therapies chronic glomerulonephritis refractory nephrotic syndrome Figures Figure 1 Figure 2 Figure 3 Background Nephrotic syndrome (NS) in children, though common, can be challenging if it becomes steroid-dependent or steroid-resistant ( 1 ). Children with steroid dependence and frequent relapses are exposed to multiple courses of steroids and other immunosuppressive steroid-sparing therapies aimed at avoiding steroid toxicity. Rituximab, a monoclonal anti-CD20 has been used at various centers (as in ours) for patients who had failed second-line steroid-sparing agents like mycophenolate mofetil (MMF), calcineurin inhibitors (CNI) (cyclosporine or tacrolimus), and in some cases, cyclophosphamide ( 2 ). However, we noted after multiple doses of rituximab some patients had short remission periods, severe reactions, or failed to achieve complete remission (CR), possibly related to the formation of antibodies, which has been reported in one third of the patients ( 3 ). Obinutuzumab is a glycoengineered type II anti-CD20 monoclonal antibody initially developed to overcome rituximab resistance in B-cell malignancies. It was noted to be superior to rituximab for hematologic malignancies, such as B-cell lymphoma. Obinutuzumab induces prolonged B-cell depletion. A recent study in children with SDNS and frequently relapsing NS noted that low-dose Obinutuzumab was an option, including for those with rituximab resistance ( 4 ). Obinutuzumab was recently shown to be effective for the treatment of membranous nephropathy ( 5 , 6 ) and lupus nephritis in adults ( 7 ). To date, the data in pediatrics remains scarce with no randomized control trials and few anecdotal reports ( 4 , 8 , 9 , 10 ). The aim of the study was to review the clinical data of children with refractory kidney disease treated with Obinutuzumab at our center. Methods Study Design: A retrospective chart review was done on children followed at our children’s kidney center who received obinutuzumab/ofatumumab between January 2020 and May 2024. Included in this group were children with refractory NS and resistant to multiple treatments chronic glomerulonephritis, such as IgAN, lupus nephritis, C3GN, C1QN, and acute interstitial nephritis (AIN). All children received obinutuzumab 1000 mg/1.73 m 2 /dose, and one patient received ofatumumab (300 mg/1.73 m 2 /dose). Children with NS received only 1 dose while those with glomerulonephritis received 2 doses, 15 days apart. If a patient with NS had persistent proteinuria, then a second dose was given. All patients were given pre-medication with oral acetaminophen (15 mg/kg/dose, max 650 mg), IV methylprednisolone (2mg/kg/dose, max 60 mg)/ hydrocortisone (2mg/kg/dose, max 100 mg) and IV or oral diphenhydramine (0.5 mg/kg/dose, max 25 mg) 30 minutes before the infusion and then as needed. Indications for obinutuzumab were adverse reaction to rituximab, no response or relapse within 6 months of Rituximab treatment in children with NS, and for refractory nephropathies to standard therapy (persistent abnormal eGFR and/or severe proteinuria, urine pr/cr > 2.5). The primary end points were remission of nephrotic syndrome and/or improvement in renal function. We also compared the NS relapse-free rate between rituximab and obinutuzumab at 24 months after therapy. undefined Demographic data as age of presentation, sex, and race were collected. Etiology of the NS, kidney biopsy results, treatments given, and renal function (serum creatinine- SCr, cystatin C, and eGFR) were reviewed. Degree of proteinuria : all measurements were done in first AM urines (UP/C); Proteinuria was defined as mild (0.3–2.4 g/g Cr) or as nephrotic range (> 2.5g/g Cr). The degree of proteinuria at diagnosis and after treatment was compared. Medications used before obinutuzumab, such as tacrolimus, MMF, prednisone, rituximab, angiotensin converting enzyme inhibitors (ACEi), and angiotensin receptor blockers (ARBs) were noted. Age at which obinutuzumab was given and the number of infusions were reviewed. The outcome measures included : improvement in renal function, as per eGFR (ml/min/1.73m2), degree of proteinuria, and discontinuation of steroids or other immunosuppressants. The time to first relapse after obinutuzumab and rituximab administration was and compared. All side effects were noted. Statistical Analysis: A two-tailed Fisher's Exact Test was performed with GraphPad Prism (Version 10.6.1 (799) for Mac, GraphPad Software, Boston, Massachusetts, USA) to compare changes in proteinuria, eGFR pre and post infusion in all treated children. A significance level of P < 0.05 was considered statistically significant. The Kaplan-Meier analysis was calculated with significant events being patient relapse. Relapse free time was analyzed using the Kaplan-Meier method for rituximab and obinutuzumab. Statistical analysis was performed using Microsoft Excel (Version 16.102.2) with the Data Analysis ToolPak add-in, and calculations were cross-checked against written calculations. Results We had a total of 29 patients who received 46 infusions (17 patients had a single infusion, 6 patients had 2 infusions, and 6 had more than 2 infusions). We noted a slight male predominance of 52%, and the median age of presentation of the nephropathy was 5 years. There was a predominance of Hispanics, at 52%, followed by AA, 27%, Caucasians, 7%, and other races, 14%. The main etiology in our cohort was primary nephrotic syndrome in 22 (76%), of which 1 patient did not complete the infusion, so was excluded; in the final analysis and a total of 21 patients with NS were included. Of the 21, 12 (57%) were steroid-responsive and 9 (23%) were steroid-resistant. We had 2 children with post-transplant NS (1 FSGS recurrence; 1 de novo MCNS). The other etiologies were chronic nephropathies (N = 7): 2 patients with C3GN, 1 SLE, 1 Ig AN, 1 C1QN; 2 AIN with AKI. A total of 25 children (86%) had kidney biopsies. Initially, all patients received steroids; subsequent therapies included rituximab in 20 (69%), CIN in 19 (66%), MMF in 17 (59%), and cyclophosphamide in 7 (30%). The median age at the time of obinutuzumab was 13 years, and the median time to response was 25 days. Time between obinutuzumab administration and initial diagnosis varied from 2 months to 14 years (median = 4 years). A total of 12 children received 2 or more doses of obinutuzumab. Follow-up time was 3 to 44 months (median = 10 months). At presentation, AKI/ CKD was noted in 6 (20%) of the children. The amount of proteinuria was compared between the time of first obinutuzumab infusion and after therapy (34 infusions in 29 patients); 1 patient was excluded as infusion was not completed due to a severe allergic reaction. Data was analyzed at the time of first infusion and last follow-up. Pre-treatment (34 infusions): no proteinuria in 1, mild proteinuria in 6, and nephrotic range proteinuria in 27. Post-treatment 6 had mild proteinuria and one had nephrotic range proteinuria (p-value 0.001), when compared to pre-treatment. Proteinuria details shown in Fig. 1 . Box-Plot showing UP/C measured before Obinutuzumab infusion, 4 weeks after the infusion, and at the latest follow-up, in a total of 36 infusions. ACEi/ARBs were given in 14/29 (48%) patients; Seven (24%) had associated hypertension. Adverse events : We had 1 patient with a severe reaction and was not able to complete the infusion. On follow-up, 3 patients had infections needing hospitalization (varicella, PCP pneumonia, and septic shock). The child with septic shock presented 6 months after the infusion and, unfortunately, expired. This patient has severe steroid-resistant nephrotic syndrome and did not respond to any therapies. He was dependent on home infusions of IV 25% albumin daily and furosemide. He was admitted in septic shock with acute respiratory distress and unfortunately deteriorated rapidly with multiorgan failure. All patients with nephrotic syndrome were off steroids at the last follow-up (except the 2 kidney txp); 1 patient remained on tacrolimus post-infusion for 6 months. 3 patients were lost to follow-up. Only 1 patient at presentation had Acute Kidney Injury and the renal function and eGFR became normal post-treatment. CKD was noted in 5 patients at presentation, and all had improvement in eGFR with an average increase of 30% (49 to 64 ml/min/1.73 m 2 ); 1 expired as above mentioned; eGFR details shown in Fig. 2 . Patients with primary NS achieved complete remission in 90.4%. Children with chronic resistant GNs had AKI/CKD in 57% cases and remained on immunosuppressive meds after obinutuzumab infusions in 71% cases. Overall, 17 of the 22 (77%) children were able to come off all immunosuppression as of last visit. A total of 20 patients had rituximab before IV obinutuzumab; 1 patient had pre-txp rituximab for steroid-resistant NS and did not tolerate it. Post txp, he had de novo MCNS and was given obinutuzumab. The number of rituximab infusions given were 1 to 7 doses/ patient (mean 3.3 doses/ patient). Post-rituximab relapses median relapse-free time was 8 months (mean = 10.2). Post-obinutuzumab relapses median relapse-free time was 16 months (mean = 19) – data shown in Fig. 3 . Obinutuzumab- treated patients had a significant longer remission period when compared to rituximab-treated patients (p = 0.02) One patient had a severe reaction with rituximab; he received Obinutuzumab and tolerated it well and is in remission; another patient moved, so there is no data for them beyond 24 months. Discussion Our study is a single-center retrospective study in children who received obinutuzumab for refractory nephropathies. Initially, rituximab was used in our patients with frequently relapsing NS syndrome, but we noted short times to relapses and significant adverse effects. That led us to the use of obinutuzumab in patients with multiple relapses or a lack of response after rituximab and also patients with previous severe reaction to rituximab. Dossier et al. , reported a retrospective, single-center cohort study in 41 children with frequently relapsing or steroid dependent nephrotic syndrome who were treated with single dose of obinutuzumab infusion (300 mg/1.73m 2 /dose) ( 4 ). They were able to discontinue all other immunosuppressive therapy after 2 months. The indication was rituximab resistance in 20%, short duration of B-cell depletion in 15%, or relapse after rituximab in 66%. All children achieved B-cell depletion post-obinutuzumab (including five cases with anti-rituximab antibodies) for a median 8-month duration. Sustained remission was present in 92% of children by 1 year and 68% by 2 years post-obinutuzumab. In our study, a total of 12 patients with SDNS and 9 with SRNS received obinutuzumab. Similarly, to Dossier et al ( 4 ), we noted a very good response with 90.5% in complete remission and 5% with partial remission. One patient failed to respond to all therapies. In our study 17/22 (71%) were off all medications as of the last follow-up. We used a single dose of 1000 mg/m 2 /dose in patients with NS and 2 doses, 2 weeks apart, in patients with other glomerulonephritis, such as Lupus nephritis and IgAN. The reasoning was to avoid excessive immunosuppression and hypogammaglobulinemia. Based on its half-life (28.4 days), obinutuzumab is expected to be nearly eliminated (97% cleared) in approximately 142 days, or roughly 4.7 months, after the last dose. Dossier et al ( 4 ) reported observed adverse events comparable with rituximab; 12% experienced infusion reactions and 21% neutropenia (all resolved after stopping trimethoprim-sulfamethoxazole prophylaxis). Our rate of severe reactions was rare and even a child who didn’t tolerate rituximab pre-transplant, had no reaction to obinutuzumab. Our goal with the use of obinutuzumab was to allow patients to be free of immunosuppressive medications (particularly steroids). This was achieved, as at last follow-up, among children with primary NS, only 1 remained on tacrolimus long-term post-infusion and now has been off tacrolimus. All patients were weaned off the steroids, except the 2 post-transplant patients who continued with their baseline low-dose steroids and maintenance doses of MMF and tacrolimus. Our study also compared the remission-free period after the infusions with rituximab and Obinutuzumab and observed a definite advantage in patients who received obinutuzumab, as the relapse-free time was significantly longer. Xiaole et ( 6 ) used obinutuzumab in 59 adult patients with membranous nephropathy ( 7 ). Twenty patients received obinutuzumab as initial therapy, and 39 patients had previously received other therapies. They noted 84.7% had complete or partial remission with a median follow-up of 9.4 months. Our study had a longer median follow-up time compared to previous published studies. Recently, a randomized controlled trial in 271 adult patients with lupus was published ( 7 ); 135 were assigned to the obinutuzumab group (combined dose schedules) and 136 to the placebo group. A complete renal response at week 76 (the primary end point) was observed in 46.4% of the patients in the obinutuzumab group and 33.1% of those in the placebo group. Serious adverse events occurred in 44 of 136 patients (32.4%) in the obinutuzumab group and 24 of 132 patients (18.2%) in the placebo group. The most frequent serious adverse events observed among the obinutuzumab-treated patients were infections, including coronavirus disease 2019. A significant reduction in proteinuria, a surrogate for enhanced long-term kidney survival, was observed at week 76 after IV Obinutuzumab. The authors concluded that B cell depletion therapy with the addition of obinutuzumab to standard therapy led to a significantly greater percentage of patients with a complete renal response. We gave Obinutuzumab in seven (24%) children with various refractory immune-mediated and complement-mediated glomerulonephritis and found statistically significant improvement in eGFR (by 30%) and the degree of proteinuria. There are no published studies or reports of the use of Obinutuzumab in IgAN. Our single patient had an improved response with improvement in her proteinuria from UP/Cr of 5.2 to 2.1 and improvement in her renal function (serum creatinine and cystatin C). The two patients with C3GN had a transient response by way of reduction in proteinuria, but it wasn’t sustained. Patient #1 with C3GN UP/Cr improved from 8.0 to 1.5, but subsequently, due to a relapsing course, was started on eculizumab. Patient #2 with C3GN had no significant response. Both patients remain with normal eGFR. Two patients with AKI and AIN were treated with obinutuzumab and both had significant improvement in renal function that persisted at last follow-up (> 2yrs). Hypogammaglobulinemia was noted in only one of our patients, and he received IVIG. Dossier et al ( 10 ) in their retrospective study used sequentially combined Obinutuzumab, a second-generation anti-CD20 monoclonal antibody targeting naïve and memory B cells, and daratumumab, an anti-CD38 monoclonal antibody targeting plasma cells. They noted transient hypogammaglobulinemia in all their patients, with 3 requiring monthly and 9 intermittently IVIG infusions. This could have been related to 2 agents – obinutuzumab and daratumumab, leading to significant B cell depletion. The shortcoming of our study was its retrospective nature with the absence of a control arm. However, we were able to compare remission periods post-infusions between those who had received rituximab previously with the use of obinutuzumab. We did not do anti-rituximab antibodies or have complete data on B cell depletion. Also further studies are needed with larger sample size. Our study does highlight the use of one dose of obinutuzumab in relapsing treatment-responsive NS with a longer duration of remission and successful therapy option for children with resistant forms of chronic GNs. Conclusions Overall, obinutuzumab was well tolerated in children, allowing for prompt withdrawal of all other immunosuppressive therapy in children with NS. It was effective in inducing remission in children with steroid-sensitive and steroid-resistant NS who were having short remission times after rituximab or were intolerant to it. obinutuzumab should be considered as a therapeutic option in children with frequently relapsing NS, including as an initial therapy, to minimize steroid toxicity and avoid maintenance medications in such patients. obinutuzumab should be included as a treatment option for those children with resistant forms of GNs. Abbreviations Estimated glomerular filtration rate (eGFR), Ig A nephropathy (IgAN), months (mos), transplant (txp), Urine protein/ creatinine (UP/C), Angiotensin receptor inhibitors (ACEi), Angiotensin receptor blocker (ARB), Acute Kidney injury (AKI), Acute Interstitial nephritis (AIN), chronic kidney disease (CKD), Mycophenolate Mofetil (MMF), Calcineurin inhibitors (CIN) Declarations IRB approval obtained from Cooperman Barnabas Medical Center IRB. IRB ID number: 24-08 The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate: This study was approved by the Ethics Committee of Cooperman Barnabas Medical Center (IRB approval No24-08), with the requirement for informed consent waived in accordance with the retrospective observational study design. Ethics approval was applied in accordance with the Declaration of Helsinki. Consent for publication: Not applicable as no patient identifiers were included in the study Data Availability: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing Interests: We declare that the authors have no competing interests as defined by BMC, or other interests that might be perceived to influence the results and/or discussion reported in this paper. Funding : No research funding was available Author’s Contribution: SV conceptualized the study, collected the data and formatted the data for analysis and did the writing of the paper UN helped with the graphs, statistical analysis and edited the paper IR helped with writing of the paper, reviewed all the data analysis helped with editing the paper. All authors were involved editing the paper and reviewed the manuscript. Acknowledgements: None References Webb NJA, Woolley RL, Lambe T, Frew E, Brettell EA, Barsoum EN et al. 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04:29:49","extension":"xml","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":50976,"visible":true,"origin":"","legend":"","description":"","filename":"e635ec7f406a4c29b7c9faf8ae04e9701structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8338986/v1/2bf0b9f50f05b218c4221d4c.xml"},{"id":98845847,"identity":"9e99765b-e580-4fdb-b2e0-f05ae0944518","added_by":"auto","created_at":"2025-12-23 04:29:50","extension":"html","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":58791,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8338986/v1/a6ac851306626793b14edd2e.html"},{"id":99308507,"identity":"42eba718-b10f-4afd-9888-cf4c83662e41","added_by":"auto","created_at":"2025-12-31 16:08:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":82240,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in patients’ UP/C values over time before and after Obinutuzumab treatment.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8338986/v1/ee22661dfd00470730e6629b.png"},{"id":98845838,"identity":"2b70f2b8-2286-4f26-b389-ec49d6a4399a","added_by":"auto","created_at":"2025-12-23 04:29:49","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":265978,"visible":true,"origin":"","legend":"\u003cp\u003eEstimated glomerular filtration rate (eGFR, mL/min/1.73m²) from baseline (pre-infusion) to follow-up (post-infusion) in those with decrease eGFR at presentation.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8338986/v1/c39df586e5b51d2204253d50.jpeg"},{"id":98845842,"identity":"4e513a00-f858-418b-8ca9-e8b053118102","added_by":"auto","created_at":"2025-12-23 04:29:49","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":335595,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan Meier graph showing comparison between rituximab and obinutuzumab relapse-free time post-infusions\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8338986/v1/80af283da63c4d6635cf1c2b.jpeg"},{"id":99322545,"identity":"0e08dd9c-c337-4e57-a57f-d41ba886b607","added_by":"auto","created_at":"2025-12-31 16:43:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1125225,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8338986/v1/3566a0d4-6890-46c0-bcac-43d32708a9d1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A single-center experience of Obinutuzumab in children with refractory kidney disease","fulltext":[{"header":"Background","content":"\u003cp\u003eNephrotic syndrome (NS) in children, though common, can be challenging if it becomes steroid-dependent or steroid-resistant (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Children with steroid dependence and frequent relapses are exposed to multiple courses of steroids and other immunosuppressive steroid-sparing therapies aimed at avoiding steroid toxicity. Rituximab, a monoclonal anti-CD20 has been used at various centers (as in ours) for patients who had failed second-line steroid-sparing agents like mycophenolate mofetil (MMF), calcineurin inhibitors (CNI) (cyclosporine or tacrolimus), and in some cases, cyclophosphamide (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). However, we noted after multiple doses of rituximab some patients had short remission periods, severe reactions, or failed to achieve complete remission (CR), possibly related to the formation of antibodies, which has been reported in one third of the patients (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eObinutuzumab is a glycoengineered type II anti-CD20 monoclonal antibody initially developed to overcome rituximab resistance in B-cell malignancies. It was noted to be superior to rituximab for hematologic malignancies, such as B-cell lymphoma. Obinutuzumab induces prolonged B-cell depletion. A recent study in children with SDNS and frequently relapsing NS noted that low-dose Obinutuzumab was an option, including for those with rituximab resistance (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eObinutuzumab was recently shown to be effective for the treatment of membranous nephropathy (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) and lupus nephritis in adults (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). To date, the data in pediatrics remains scarce with no randomized control trials and few anecdotal reports (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e The aim of the study was to review the clinical data of children with refractory kidney disease treated with Obinutuzumab at our center.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design:\u003c/h2\u003e \u003cp\u003e A retrospective chart review was done on children followed at our children\u0026rsquo;s kidney center who received obinutuzumab/ofatumumab between January 2020 and May 2024.\u003c/p\u003e \u003cp\u003eIncluded in this group were children with refractory NS and resistant to multiple treatments chronic glomerulonephritis, such as IgAN, lupus nephritis, C3GN, C1QN, and acute interstitial nephritis (AIN).\u003c/p\u003e \u003cp\u003eAll children received obinutuzumab 1000 mg/1.73 m\u003csup\u003e2\u003c/sup\u003e/dose, and one patient received ofatumumab (300 mg/1.73 m\u003csup\u003e2\u003c/sup\u003e/dose). Children with NS received only 1 dose while those with glomerulonephritis received 2 doses, 15 days apart. If a patient with NS had persistent proteinuria, then a second dose was given. All patients were given pre-medication with oral acetaminophen (15 mg/kg/dose, max 650 mg), IV methylprednisolone (2mg/kg/dose, max 60 mg)/ hydrocortisone (2mg/kg/dose, max 100 mg) and IV or oral diphenhydramine (0.5 mg/kg/dose, max 25 mg) 30 minutes before the infusion and then as needed.\u003c/p\u003e \u003cp\u003eIndications for obinutuzumab were adverse reaction to rituximab, no response or relapse within 6 months of Rituximab treatment in children with NS, and for refractory nephropathies to standard therapy (persistent abnormal eGFR and/or severe proteinuria, urine pr/cr\u0026thinsp;\u0026gt;\u0026thinsp;2.5).\u003c/p\u003e \u003cp\u003eThe primary end points were remission of nephrotic syndrome and/or improvement in renal function. We also compared the NS relapse-free rate between rituximab and obinutuzumab at 24 months after therapy.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eundefined\u003c/h3\u003e\n\u003cp\u003eDemographic data as age of presentation, sex, and race were collected. Etiology of the NS, kidney biopsy results, treatments given, and renal function (serum creatinine- SCr, cystatin C, and eGFR) were reviewed.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eDegree of proteinuria\u003c/span\u003e: all measurements were done in first AM urines (UP/C); Proteinuria was defined as mild (0.3\u0026ndash;2.4 g/g Cr) or as nephrotic range (\u0026gt;\u0026thinsp;2.5g/g Cr).\u003c/p\u003e \u003cp\u003eThe degree of proteinuria at diagnosis and after treatment was compared.\u003c/p\u003e \u003cp\u003eMedications used before obinutuzumab, such as tacrolimus, MMF, prednisone, rituximab, angiotensin converting enzyme inhibitors (ACEi), and angiotensin receptor blockers (ARBs) were noted.\u003c/p\u003e \u003cp\u003eAge at which obinutuzumab was given and the number of infusions were reviewed.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eThe outcome measures included\u003c/span\u003e: improvement in renal function, as per eGFR (ml/min/1.73m2), degree of proteinuria, and discontinuation of steroids or other immunosuppressants.\u003c/p\u003e \u003cp\u003eThe time to first relapse after obinutuzumab and rituximab administration was and compared. All side effects were noted.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis:\u003c/h2\u003e \u003cp\u003eA two-tailed Fisher's Exact Test was performed with GraphPad Prism (Version 10.6.1 (799) for Mac, GraphPad Software, Boston, Massachusetts, USA) to compare changes in proteinuria, eGFR pre and post infusion in all treated children. A significance level of P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003cp\u003eThe Kaplan-Meier analysis was calculated with significant events being patient relapse.\u003c/p\u003e \u003cp\u003eRelapse free time was analyzed using the Kaplan-Meier method for rituximab and obinutuzumab.\u003c/p\u003e \u003cp\u003eStatistical analysis was performed using Microsoft Excel (Version 16.102.2) with the Data Analysis ToolPak add-in, and calculations were cross-checked against written calculations.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eWe had a total of 29 patients who received 46 infusions (17 patients had a single infusion, 6 patients had 2 infusions, and 6 had more than 2 infusions). We noted a slight male predominance of 52%, and the median age of presentation of the nephropathy was 5 years. There was a predominance of Hispanics, at 52%, followed by AA, 27%, Caucasians, 7%, and other races, 14%.\u003c/p\u003e \u003cp\u003eThe main etiology in our cohort was primary nephrotic syndrome in 22 (76%), of which 1 patient did not complete the infusion, so was excluded; in the final analysis and a total of 21 patients with NS were included. Of the 21, 12 (57%) were steroid-responsive and 9 (23%) were steroid-resistant. We had 2 children with post-transplant NS (1 FSGS recurrence; 1 de novo MCNS). The other etiologies were chronic nephropathies (N\u0026thinsp;=\u0026thinsp;7): 2 patients with C3GN, 1 SLE, 1 Ig AN, 1 C1QN; 2 AIN with AKI.\u003c/p\u003e \u003cp\u003eA total of 25 children (86%) had kidney biopsies.\u003c/p\u003e \u003cp\u003eInitially, all patients received steroids; subsequent therapies included rituximab in 20 (69%), CIN in 19 (66%), MMF in 17 (59%), and cyclophosphamide in 7 (30%).\u003c/p\u003e \u003cp\u003eThe median age at the time of obinutuzumab was 13 years, and the median time to response was 25 days.\u003c/p\u003e \u003cp\u003eTime between obinutuzumab administration and initial diagnosis varied from 2 months to 14 years (median\u0026thinsp;=\u0026thinsp;4 years).\u003c/p\u003e \u003cp\u003eA total of 12 children received 2 or more doses of obinutuzumab.\u003c/p\u003e \u003cp\u003eFollow-up time was 3 to 44 months (median\u0026thinsp;=\u0026thinsp;10 months).\u003c/p\u003e \u003cp\u003eAt presentation, AKI/ CKD was noted in 6 (20%) of the children.\u003c/p\u003e \u003cp\u003eThe amount of proteinuria was compared between the time of first obinutuzumab infusion and after therapy (34 infusions in 29 patients); 1 patient was excluded as infusion was not completed due to a severe allergic reaction.\u003c/p\u003e \u003cp\u003eData was analyzed at the time of first infusion and last follow-up.\u003c/p\u003e \u003cp\u003e \u003cb\u003ePre-treatment\u003c/b\u003e (34 infusions): no proteinuria in 1, mild proteinuria in 6, and nephrotic range proteinuria in 27.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003ePost-treatment\u003c/strong\u003e \u003cp\u003e6 had mild proteinuria and one had nephrotic range proteinuria (p-value 0.001), when compared to pre-treatment. Proteinuria details shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eBox-Plot showing UP/C measured before Obinutuzumab infusion, 4 weeks after the infusion, and at the latest follow-up, in a total of 36 infusions.\u003c/p\u003e \u003cp\u003eACEi/ARBs were given in 14/29 (48%) patients; Seven (24%) had associated hypertension.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eAdverse events\u003c/span\u003e: We had 1 patient with a severe reaction and was not able to complete the infusion. On follow-up, 3 patients had infections needing hospitalization (varicella, PCP pneumonia, and septic shock). The child with septic shock presented 6 months after the infusion and, unfortunately, expired. This patient has severe steroid-resistant nephrotic syndrome and did not respond to any therapies. He was dependent on home infusions of IV 25% albumin daily and furosemide. He was admitted in septic shock with acute respiratory distress and unfortunately deteriorated rapidly with multiorgan failure.\u003c/p\u003e \u003cp\u003eAll patients with nephrotic syndrome were off steroids at the last follow-up (except the 2 kidney txp); 1 patient remained on tacrolimus post-infusion for 6 months. 3 patients were lost to follow-up.\u003c/p\u003e \u003cp\u003eOnly 1 patient at presentation had Acute Kidney Injury and the renal function and eGFR became normal post-treatment. CKD was noted in 5 patients at presentation, and all had improvement in eGFR with an average increase of 30% (49 to 64 ml/min/1.73 m\u003csup\u003e2\u003c/sup\u003e); 1 expired as above mentioned; eGFR details shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePatients with primary NS achieved complete remission in 90.4%. Children with chronic resistant GNs had AKI/CKD in 57% cases and remained on immunosuppressive meds after obinutuzumab infusions in 71% cases. Overall, 17 of the 22 (77%) children were able to come off all immunosuppression as of last visit.\u003c/p\u003e \u003cp\u003eA total of 20 patients had rituximab before IV obinutuzumab; 1 patient had pre-txp rituximab for steroid-resistant NS and did not tolerate it. Post txp, he had de novo MCNS and was given obinutuzumab. The number of rituximab infusions given were 1 to 7 doses/ patient (mean 3.3 doses/ patient).\u003c/p\u003e \u003cp\u003e \u003cstrong\u003ePost-rituximab relapses\u003c/strong\u003e \u003cp\u003emedian relapse-free time was 8 months (mean\u0026thinsp;=\u0026thinsp;10.2).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003ePost-obinutuzumab relapses\u003c/strong\u003e \u003cp\u003emedian relapse-free time was 16 months (mean\u0026thinsp;=\u0026thinsp;19) \u0026ndash; data shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Obinutuzumab- treated patients had a significant longer remission period when compared to rituximab-treated patients (p\u0026thinsp;=\u0026thinsp;0.02)\u003c/p\u003e\u003cp\u003eOne patient had a severe reaction with rituximab; he received Obinutuzumab and tolerated it well and is in remission; another patient moved, so there is no data for them beyond 24 months.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study is a single-center retrospective study in children who received obinutuzumab for refractory nephropathies. Initially, rituximab was used in our patients with frequently relapsing NS syndrome, but we noted short times to relapses and significant adverse effects. That led us to the use of obinutuzumab in patients with multiple relapses or a lack of response after rituximab and also patients with previous severe reaction to rituximab.\u003c/p\u003e\n\u003cp\u003eDossier \u003cem\u003eet al.\u003c/em\u003e, reported a retrospective, single-center cohort study in 41 children with frequently relapsing or steroid dependent nephrotic syndrome who were treated with single dose of obinutuzumab infusion (300 mg/1.73m\u003csup\u003e2\u003c/sup\u003e/dose) (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e). They were able to discontinue all other immunosuppressive therapy after 2 months. The indication was rituximab resistance in 20%, short duration of B-cell depletion in 15%, or relapse after rituximab in 66%. All children achieved B-cell depletion post-obinutuzumab (including five cases with anti-rituximab antibodies) for a median 8-month duration. Sustained remission was present in 92% of children by 1 year and 68% by 2 years post-obinutuzumab.\u003c/p\u003e\n\u003cp\u003eIn our study, a total of 12 patients with SDNS and 9 with SRNS received obinutuzumab. Similarly, to Dossier et al (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e), we noted a very good response with 90.5% in complete remission and 5% with partial remission. One patient failed to respond to all therapies.\u003c/p\u003e\n\u003cp\u003eIn our study 17/22 (71%) were off all medications as of the last follow-up.\u003c/p\u003e\n\u003cp\u003eWe used a single dose of 1000 mg/m\u003csup\u003e2\u003c/sup\u003e/dose in patients with NS and 2 doses, 2 weeks apart, in patients with other glomerulonephritis, such as Lupus nephritis and IgAN. The reasoning was to avoid excessive immunosuppression and hypogammaglobulinemia.\u003c/p\u003e\n\u003cp\u003eBased on its half-life (28.4 days), obinutuzumab is expected to be nearly eliminated (97% cleared) in approximately 142 days, or roughly 4.7 months, after the last dose.\u003c/p\u003e\n\u003cp\u003eDossier et al (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e) reported observed adverse events comparable with rituximab; 12% experienced infusion reactions and 21% neutropenia (all resolved after stopping trimethoprim-sulfamethoxazole prophylaxis). Our rate of severe reactions was rare and even a child who didn\u0026rsquo;t tolerate rituximab pre-transplant, had no reaction to obinutuzumab.\u003c/p\u003e\n\u003cp\u003eOur goal with the use of obinutuzumab was to allow patients to be free of immunosuppressive medications (particularly steroids). This was achieved, as at last follow-up, among children with primary NS, only 1 remained on tacrolimus long-term post-infusion and now has been off tacrolimus. All patients were weaned off the steroids, except the 2 post-transplant patients who continued with their baseline low-dose steroids and maintenance doses of MMF and tacrolimus.\u003c/p\u003e\n\u003cp\u003eOur study also compared the remission-free period after the infusions with rituximab and Obinutuzumab and observed a definite advantage in patients who received obinutuzumab, as the relapse-free time was significantly longer.\u003c/p\u003e\n\u003cp\u003eXiaole et (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e) used obinutuzumab in 59 adult patients with membranous nephropathy (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e). Twenty patients received obinutuzumab as initial therapy, and 39 patients had previously received other therapies. They noted 84.7% had complete or partial remission with a median follow-up of 9.4 months.\u003c/p\u003e\n\u003cp\u003eOur study had a longer median follow-up time compared to previous published studies.\u003c/p\u003e\n\u003cp\u003eRecently, a randomized controlled trial in 271 adult patients with lupus was published (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e); 135 were assigned to the obinutuzumab group (combined dose schedules) and 136 to the placebo group. A complete renal response at week 76 (the primary end point) was observed in 46.4% of the patients in the obinutuzumab group and 33.1% of those in the placebo group. Serious adverse events occurred in 44 of 136 patients (32.4%) in the obinutuzumab group and 24 of 132 patients (18.2%) in the placebo group. The most frequent serious adverse events observed among the obinutuzumab-treated patients were infections, including coronavirus disease 2019. A significant reduction in proteinuria, a surrogate for enhanced long-term kidney survival, was observed at week 76 after IV Obinutuzumab. The authors concluded that B cell depletion therapy with the addition of obinutuzumab to standard therapy led to a significantly greater percentage of patients with a complete renal response.\u003c/p\u003e\n\u003cp\u003eWe gave Obinutuzumab in seven (24%) children with various refractory immune-mediated and complement-mediated glomerulonephritis and found statistically significant improvement in eGFR (by 30%) and the degree of proteinuria.\u003c/p\u003e\n\u003cp\u003eThere are no published studies or reports of the use of Obinutuzumab in IgAN. Our single patient had an improved response with improvement in her proteinuria from UP/Cr of 5.2 to 2.1 and improvement in her renal function (serum creatinine and cystatin C). The two patients with C3GN had a transient response by way of reduction in proteinuria, but it wasn\u0026rsquo;t sustained. Patient #1 with C3GN UP/Cr improved from 8.0 to 1.5, but subsequently, due to a relapsing course, was started on eculizumab. Patient #2 with C3GN had no significant response. Both patients remain with normal eGFR.\u003c/p\u003e\n\u003cp\u003eTwo patients with AKI and AIN were treated with obinutuzumab and both had significant improvement in renal function that persisted at last follow-up (\u0026gt;\u0026thinsp;2yrs).\u003c/p\u003e\n\u003cp\u003eHypogammaglobulinemia was noted in only one of our patients, and he received IVIG. Dossier et al (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e) in their retrospective study used sequentially combined Obinutuzumab, a second-generation anti-CD20 monoclonal antibody targeting na\u0026iuml;ve and memory B cells, and daratumumab, an anti-CD38 monoclonal antibody targeting plasma cells. They noted transient hypogammaglobulinemia in all their patients, with 3 requiring monthly and 9 intermittently IVIG infusions. This could have been related to 2 agents \u0026ndash; obinutuzumab and daratumumab, leading to significant B cell depletion.\u003c/p\u003e\n\u003cp\u003eThe shortcoming of our study was its retrospective nature with the absence of a control arm. However, we were able to compare remission periods post-infusions between those who had received rituximab previously with the use of obinutuzumab. We did not do anti-rituximab antibodies or have complete data on B cell depletion. Also further studies are needed with larger sample size.\u003c/p\u003e\n\u003cp\u003eOur study does highlight the use of one dose of obinutuzumab in relapsing treatment-responsive NS with a longer duration of remission and successful therapy option for children with resistant forms of chronic GNs.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOverall, obinutuzumab was well tolerated in children, allowing for prompt withdrawal of all other immunosuppressive therapy in children with NS.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eIt was effective in inducing remission in children with steroid-sensitive and steroid-resistant NS who were having short remission times after rituximab or were intolerant to it. obinutuzumab should be considered as a therapeutic option in children with frequently relapsing NS, including as an initial therapy, to minimize steroid toxicity and avoid maintenance medications in such patients. obinutuzumab should be included as a treatment option for those children with resistant forms of GNs.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eEstimated glomerular filtration rate (eGFR), Ig A nephropathy (IgAN), months (mos), transplant (txp), Urine protein/ creatinine (UP/C), Angiotensin receptor inhibitors (ACEi), Angiotensin receptor blocker (ARB), Acute Kidney injury (AKI), Acute Interstitial nephritis (AIN), chronic kidney disease (CKD), Mycophenolate Mofetil (MMF), Calcineurin inhibitors (CIN)\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eIRB approval obtained from Cooperman Barnabas Medical Center IRB.\u003c/p\u003e\n\u003cp\u003eIRB ID number: 24-08\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Cooperman Barnabas Medical Center (IRB approval No24-08), with the requirement for informed consent waived in accordance with the retrospective observational study design. Ethics approval was applied in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot applicable as no patient identifiers were included in the study\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;We declare that the authors have no competing interests as defined by BMC, or other interests that might be perceived to influence the results and/or discussion reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo research funding was available\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s Contribution:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSV conceptualized the study, collected the data and formatted the data for analysis and did the writing of the paper\u003c/p\u003e\n\u003cp\u003eUN helped with the graphs, statistical analysis and edited the paper\u003c/p\u003e\n\u003cp\u003eIR helped with writing of the paper, reviewed all the data analysis helped with editing the paper.\u003c/p\u003e\n\u003cp\u003eAll authors were involved editing the paper and reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements: \u003c/strong\u003eNone\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWebb NJA, Woolley RL, Lambe T, Frew E, Brettell EA, Barsoum EN et al. Long-term tapering versus standard prednisolone treatment for first episode of childhood nephrotic syndrome. Phase III randomized controlled trial and economic evaluation BMJ. 2019; 365: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1136/bmj.l1800\u003c/span\u003e\u003cspan address=\"10.1136/bmj.l1800\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKazumoto Iijima M, Sako K, Nozu R, Mori N, Tuchida K, Kamei K, Miura K, Aya K, Nakanishi Y, Ohtomo S, Takahashi R, Tanaka H, Kaito. Hidefumi Nakamura, Kenji Ishikura, Shuichi Ito, Yasuo Ohashi. Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicenter, double-blind, randomized, placebo-controlled trial. 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Obinutuzumab in frequently relapsing and steroid-dependent nephrotic syndrome in children. Clin J Am Soc Nephrol. 2023;18:1555\u0026ndash;62. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2215/cjn.0000000000000288\u003c/span\u003e\u003cspan address=\"10.2215/cjn.0000000000000288\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSethi S, Kumar S, Lim K, Jordan SC. Obinutuzumab is Effective for the Treatment of Refractory Membranous Nephropathy. Kidney Int Rep. 2020;5:1515\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ekir.2020.06.030\u003c/span\u003e\u003cspan address=\"10.1016/j.ekir.2020.06.030\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSu X, Wu B, Tie X, Guo X, Feng R, Qiao X. Wang Obinutuzumab as initial or second-lime therapy in patients with primary membranous nephropathy. Kidney Intern Rep. 2024;9:2386\u0026ndash;98. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ekir.2024.05.004\u003c/span\u003e\u003cspan address=\"10.1016/j.ekir.2024.05.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFurie RF, Rovin BH, Garg JP, Santiago MB, Aroca-Mart\u0026iacute;nez G, Santill\u0026aacute;n AEZ, Alvarez D. Efficacy and Safety of Obinutuzumab in Active Lupus Nephritis. 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Obinutuzumab as a viable therapeutic strategy in rituximab-refractory childhood frequently relapsing, steroid-dependent nephrotic syndrome that relapsed during B-cell depletion. Pediatr Nephrol. 2025;40:771\u0026ndash;714. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00467-024-06570-8\u003c/span\u003e\u003cspan address=\"10.1007/s00467-024-06570-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDossier C, Prim B, Moreau C, Kwon T, Maisin A, Nathanson S, De Gennes C, Barsotti K, Bourrassi A, Hogan J, et al. anti-Bal anti-B cell strategy combining Obinutuzumab and daratumumab in severe pediatric nephrotic syndrome. Pediatr Nephrol. 2021;36:1175\u0026ndash;82. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00467-020-04811-0\u003c/span\u003e\u003cspan address=\"10.1007/s00467-020-04811-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChan EY, Ma AL, Tullus K. Hypogammaglobulinaemia following rituximab therapy in childhood nephrotic syndrome. Pediatr Nephrol. 2002;37:927\u0026ndash;31. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00467-021-05345-9\u003c/span\u003e\u003cspan address=\"10.1007/s00467-021-05345-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\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":false,"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":"Nephrotic syndrome, B cell depleting therapies, chronic glomerulonephritis, refractory nephrotic syndrome","lastPublishedDoi":"10.21203/rs.3.rs-8338986/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8338986/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThis is a retrospective review of children with refractory kidney disease treated with Obinutuzumab. Sparse published data exist in children with nephrotic syndrome and refractory membranous nephropathy treated with Obinutuzumab.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe study included all children who received Obinutuzumab and one Ofatumumab. Demographic data, etiology, biopsy results, therapies, eGFR (ml/min/1.73), first AM urine protein/creatinine, follow-up time, and side effects were noted. Clinical response was defined as AM Urine protein/creatinine\u0026thinsp;\u0026lt;\u0026thinsp;0.3 and/or \u0026gt;\u0026thinsp;30% improvement in eGFR.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e46 infusions were given in 29 patients. Etiology: 22 primary nephrotic syndrome (76%), (SDNS 59% and SRNS 41%, 2 were post kidney txp), 5 (17%) chronic GN (C3GN, Lupus nephritis, IgAN, C1QN), and 2 (7%) AIN/AKI. Biopsy diagnosis was obtained in 25 (86%). \u003cb\u003eFailed therapies\u003c/b\u003e: all with steroids, Rituximab\u0026thinsp;=\u0026thinsp;20 (69%), CNI\u0026thinsp;=\u0026thinsp;19 (66%), MMF\u0026thinsp;=\u0026thinsp;17(59%), Cytoxan\u0026thinsp;=\u0026thinsp;7(30%). Twenty-three (82%) had complete remission of the primary nephropathy, and 73% were off all medications. eGFR improved from 49 to 64. \u003cb\u003eAdverse events\u003c/b\u003e: 1 had a severe reaction and was unable to get the infusion, 3 patients had infections needing hospitalization (varicella, PCP pneumonia, and septic shock). \u003cb\u003eFollow-up time\u003c/b\u003e: 3 to 44 months. Post infusion, all patients were off steroids, except 2 txp patients. \u003cb\u003eTime to relapse\u003c/b\u003e was significantly longer with obinutuzumab vs rituximab (19 mos vs 10 mos).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eObinutuzumab was well tolerated and associated with a high and sustained remission rate in children with various resistant nephropathies. Significant reductions in proteinuria and improvement in eGFR were observed.\u003c/p\u003e","manuscriptTitle":"A single-center experience of Obinutuzumab in children with refractory kidney disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-23 04:29:45","doi":"10.21203/rs.3.rs-8338986/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-10T18:30:55+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-17T21:32:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"7718470245434720158695761995191317195","date":"2026-01-16T09:30:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-09T17:40:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"238031163557185887785286860728521556633","date":"2025-12-24T15:46:26+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-19T09:44:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"54162431260246661989729953226141294972","date":"2025-12-19T09:13:58+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-19T07:32:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-19T07:21:05+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-19T04:07:37+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-18T19:53:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2025-12-18T19:47:37+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":"7ee22616-f790-40c0-bc6c-952121522834","owner":[],"postedDate":"December 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-02-10T18:39:21+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-23 04:29:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8338986","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8338986","identity":"rs-8338986","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}