Rituximab as Initial Therapy in Adult Patients With Minimal Change Disease

Minimal change disease (MCD) accounts for 10% to 15% of primary nephrotic syndrome in adults.1Vivarelli M. Massella L. Ruggiero B. Emma F. Minimal change disease.Clin J Am Soc Nephrol CJASN. 2017; 12: 332-345https://doi.org/10.2215/cjn.05000516Crossref PubMed Scopus (0) Google Scholar Although spontaneous remission can occur in MCD, untreated nephrotic syndrome leads to increased morbidity, including acute kidney injury, thromboembolic events, and infections.2Waldman M. Crew R.J. Valeri A. et al.Adult minimal-change disease: clinical characteristics, treatment, and outcomes.Clin J Am Soc Nephrol. 2007; 2: 445-453https://doi.org/10.2215/cjn.03531006Crossref PubMed Scopus (0) Google Scholar Therefore, the goal of treatment is to achieve and sustain remission. Glucocorticoids are currently the firstline therapy of MCD. However, drug related adverse effects remain a big concern for many patients.3Jefferson J.A. Complications of immunosuppression in glomerular disease.Clin J Am Soc Nephrol. 2018; 13: 1264-1275https://doi.org/10.2215/cjn.01920218Crossref PubMed Scopus (0) Google Scholar Recently, several studies showed that tacrolimus monotherapy is noninferior to glucocorticoids for inducing remission in new-onset MCD in adults, which provides alternative regimen for patients concerned about the side effects of glucocorticoids. However, relapse after complete remission and the timings of relapses were similar between the 2 treatments.4Medjeral-Thomas N.R. Lawrence C. Condon M. et al.Randomized, controlled trial of tacrolimus and prednisolone monotherapy for adults with de novo minimal change disease: a multicenter, randomized, controlled trial.Clin J Am Soc Nephrol. 2020; 15: 209-218https://doi.org/10.2215/cjn.06180519Crossref PubMed Scopus (0) Google Scholar,5Li X. Liu Z. Wang L. et al.Tacrolimus monotherapy after intravenous methylprednisolone in adults with minimal change nephrotic syndrome.J Am Soc Nephrol. 2017; 28: 1286-1295https://doi.org/10.1681/asn.2016030342Crossref PubMed Scopus (0) Google Scholar,S1 Therefore, new therapeutic approaches with a good efficacy and safety profile are still yet to be explored. Rituximab is a monoclonal antibody that specifically binds to and depletes B lymphocytes.6Madanchi N. Bitzan M. Takano T. Rituximab in minimal change disease: mechanisms of action and hypotheses for future studies.Can J Kidney Health Dis. 2017; 42054358117698667https://doi.org/10.1177/2054358117698667Crossref PubMed Scopus (9) Google Scholar Recently, rituximab has been approved in some immune-mediated renal diseases such as membranous nephropathy.7Ruggenenti P. Debiec H. Ruggiero B. et al.Anti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy.J Am Soc Nephrol. 2015; 26: 2545-2558https://doi.org/10.1681/asn.2014070640Crossref PubMed Scopus (0) Google Scholar In frequently relapsing or glucocorticoids-dependent MCD, emerging data have shown rituximab can reduce relapses and facilitate glucocorticoids withdrawal.8Munyentwali H. Bouachi K. Audard V. et al.Rituximab is an efficient and safe treatment in adults with steroid-dependent minimal change disease.Kidney Int. 2013; 83: 511-516https://doi.org/10.1038/ki.2012.444Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar,9Heybeli C. Erickson S.B. Fervenza F.C. Hogan M.C. Zand L. Leung N. Comparison of treatment options in adults with frequently relapsing or steroid-dependent minimal change disease.Nephrol Dial Transplant. 2021; 36: 1821-1827https://doi.org/10.1093/ndt/gfaa133Crossref PubMed Scopus (2) Google Scholar,S2 However, whether rituximab alone could be used as initial therapy of new-onset MCD remains uncertain. In this study, we describe our experience in treating patients with new-onset MCD using rituximab monotherapy. Nine patients with new-onset MCD were included in this study (Table 1). Mean age of the patients was 47.56 years (20–73 years) and 8 were males. Patient #2 and patient #4 had the comorbidity of hypertension, and patient #5 and patient #6 had diabetes mellitus. All patients presented with nephrotic syndrome with a median urine protein quantification of 5.77 g/24h (3.49–8.88 g/24h) and a median serum albumin level of 20 g/l (14–29 g/l). Their renal function was normal when MCD was diagnosed. They were prescribed with rituximab rather than glucocorticoids because they were concerned about weight gain, cosmetic changes, or metabolic side effects related to glucocorticoids or had the comorbidities such as severe diabetes mellitus, osteoporosis, or gastric ulcer hemorrhage. The median follow-up duration from the first dose of rituximab to the last visit was 374 days (159–884 days).Table 1Baseline characteristics of patientsPatient No.GenderAge (yrs)Proteinuria (g/d)Scr (μmol/l)Salb (g/l)ComorbidityIndication for RTX1Male573.8110725noneOsteoporosis2Male663.497123HTNGastric ulcer hemorrhage3Male226.325818noneRefusal of GCsaConcerns about weight gain or cosmetic changes related to glucocorticoids.4Male738.887526HTNRefusal of GCsbConcerns about metabolic change related to glucocorticoids; note: patient #4 had an impaired glucose tolerance.5Male588.59514DMDM6Male674.657929DMDM7Male208.026115noneRefusal of GCsaConcerns about weight gain or cosmetic changes related to glucocorticoids.8Male265.226920noneRefusal of GCsaConcerns about weight gain or cosmetic changes related to glucocorticoids.9Female398.657215noneRefusal of GCsaConcerns about weight gain or cosmetic changes related to glucocorticoids.DM, diabetes mellitus; HTN, hypertension; Scr, serum creatinine; Salb, serum albumin; RTX, rituximab; GCs, glucocorticoids; yrs, years.a Concerns about weight gain or cosmetic changes related to glucocorticoids.b Concerns about metabolic change related to glucocorticoids; note: patient #4 had an impaired glucose tolerance. Open table in a new tab DM, diabetes mellitus; HTN, hypertension; Scr, serum creatinine; Salb, serum albumin; RTX, rituximab; GCs, glucocorticoids; yrs, years. The treatment regimen and clinical outcomes of these 9 patients are listed in Table 2. All patients received rituximab as initial therapy. They did not receive glucocorticoids or any other immunosuppressive therapy previously. Patient #1 to #5 received a single dose of rituximab (375 mg/m2) and they achieved complete remission after a median time of 24 days (12–48 days). No relapse was observed during a follow-up period of 303 to 884 days. Patient #6 had been diagnosed with diabetes for 11 years. He also received a single dose of rituximab (375 mg/m2), and achieved partial remission with a decreased protein-to-creatinine ratio from 7008.2 to 3249.4 mg/g 3 months later. Then a second dose of rituximab (375 mg/m2) further lowered protein-to-creatinine ratio to 698.8 mg/g. Serum albumin significantly increased in 6 patients. Patient #7 achieved partial remission after 1 dose of rituximab (375 mg/m2) and his proteinuria decreased from 8.0 g/24h to 2.5 g/24h 2 weeks later. However, he relapsed 4 weeks later and the proteinuria increased to 13.2 g/24h. He then received glucocorticoids and achieved complete remission 2 weeks later. He experienced another relapse 2 months after discontinuation of glucocorticoids (tapered with a duration of 6-month) and obtained complete remission following the second course of glucocorticoids. Patient #8 did not respond to 1 dose of rituximab (375 mg/m2) and his serum creatinine increased from 69 μmol/l to 123 μmol/l 3 weeks after the treatment. Then he was rescued with glucocorticoids and obtained complete remission 2 weeks later. Patient #9 received rituximab 1 g twice at a 3-week interval and did not respond during a 3-month follow-up. She then received glucocorticoids and obtained complete remission 2 weeks later. The renal function remained stable in all patients except for patient #8. Peripheral CD19+ cells were measured in 8 of the 9 patients. Among them, CD19+ cells were undetectable after the first dose of rituximab. Although patient #5 did not have his peripheral CD19+ cells detected, he achieved complete remission 24 days after the treatment. Of note, peripheral CD19+ cells remained depleted in patient #7, #8, and #9 while their proteinuria reoccurred or persisted. There were no serious treatment-related adverse events by the end of follow-up.Table 2Clinical outcomesPatient No.RTX regimenResponseTime to remission (d)Follow-up duration (d)Relapse1375 mg/m2 onceCR48339No2375 mg/m2 onceCR15303No3375 mg/m2 onceCR12884No4375 mg/m2 onceCR41407No5375 mg/m2 onceCR24657No6375 mg/m2 twicePR93789No7375 mg/m2 oncePR16374yes8375 mg/m2 onceNR/159/91 g twiceNR/351/CR, complete remission; NR, no remission; PR, partial remission; RTX, rituximab. Open table in a new tab CR, complete remission; NR, no remission; PR, partial remission; RTX, rituximab. The present study evaluated the effect of rituximab in 9 adult patients with new-onset MCD and 6 patients achieved sustained remission, suggesting rituximab may be a potential alternative induction regimen for MCD patients, especially for those relatively contraindicated to glucocorticoids. This is supported by a recent case series in which a regimen of 4 weekly doses of rituximab successfully induced complete remission in all 6 new-onset MCD patients without relapses during a follow-up period up to 36 months.S3 In our study, 1 patient achieved partial remission after a single infusion of rituximab but relapsed shortly. Two patients were resistant to the treatment of rituximab. These 3 patients responded well to glucocorticoids subsequently, indicating that rituximab as initial induction may not be as effective as glucocorticoids. This may be potentially explained by a significantly lower dosage of rituximab used in our patients. Compared to the 6 responders, the remaining 3 presented with a heavier proteinuria when rituximab was infused. It has been observed that rituximab was detected in the urine of nephrotic patients and its level was positively associated with the amount of urine IgG.S4 The nephrotic status might shorten the half-life of rituximab and result in a relative insufficiency. Therefore, whether a higher dosage of rituximab may increase response rate for patients with severe nephrotic syndrome needs further studies. Although MCD has long been recognized as a T-cell mediated disease, this notion has been challenged by therapeutic efficacy of rituximab. However, how rituximab unfolds its effect in MCD remains a mystery. In the previous studies about rituximab in MCD patients, the relapses usually developed simultaneously with the recovery of the B-cell count,8Munyentwali H. Bouachi K. Audard V. et al.Rituximab is an efficient and safe treatment in adults with steroid-dependent minimal change disease.Kidney Int. 2013; 83: 511-516https://doi.org/10.1038/ki.2012.444Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar S5–S7 indicating a direct causal link between B cells and disease activity. However, the 3 patients in our study failed to respond to rituximab despite the complete elimination of peripheral B cells. This phenomenon was mirrored in a case report in which the patient relapsed 1 year after the treatment with rituximab while CD19+ B cells were still undetectable. However, he achieved complete remission again after another course of rituximab. Further study revealed that rituximab targeted and eliminated CD19−CD20+ T cells to a great extent as well.S8 In contrast, some patients remained relapse-free despite repletion of B cells,8Munyentwali H. Bouachi K. Audard V. et al.Rituximab is an efficient and safe treatment in adults with steroid-dependent minimal change disease.Kidney Int. 2013; 83: 511-516https://doi.org/10.1038/ki.2012.444Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar,S9,S10 These findings suggest that rituximab may interfere with both autoreactive T cells and B cells to induce remission in MCD. Taken these observations together, we doubt the predictive value of B-cell count in monitoring disease and guiding clinical decisions. There are several limitations of this study. First, this is a retrospective single arm study, and whether rituximab monotherapy is noninferior to glucocorticoids in inducing remission for new-onset MCD remains unknown. Second, most of our patients received a single dose of rituximab (375 mg/m2) and whether a larger dose can increase response rate is unknown. Third, the follow-up duration is short, whether a single dose of rituximab could maintain long-term remission of MCD is unclear. Despite these limitations, our study offers significant implications for large, prospective trials with adequate follow-up to assess the long-term outcomes and safety of rituximab in new-onset MCD. In summary, rituximab may be used as an alternative therapy for adult new-onset MCD. This option is of particular value for patients relatively contraindicated to glucocorticoids. Peripheral B-cell count is not an appropriate marker for assessing the treatment effects. Whether rituximab is as effective as glucocorticoids and whether a larger dosage should be individualized for patients presenting with severe nephrotic syndrome need further studies. The authors have no conflicting interest to disclose. This work was supported by Natural Science Foundation of China grants NSFC: 82170735 (Q. X.), 82000679 (R. C) and 81930120 (C. M. H.). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. QX conceived the idea and designed the study. NG, MZ, RC and MZ collected the data. NG and QX analyzed the data and were the main contributors in writing the manuscript. QX and CH critically reviewed and revised the manuscript. All authors were involved in the design, interpretation of data, and final approval of the manuscript. All authors had access to the data and played a role in writing this article. Download .pdf (.16 MB) Help with pdf files Supplementary File (PDF) Supplementary Methods. Supplementary References.