Background: Persistent signiﬁcant proteinuria has been associated with increased risk of progression to end-stage kidney disease in patients with idiopathic membranous nephropathy (IMN). Rituximab (RTX) therapy has given encouraging results in IMN, but most of the studies have used a higher dose, which is limited by the high cost as well as a potential increased risk of infections. Our study aimed to assess the efﬁcacy and safety of low-dose RTX in patients with immunosuppression-resistant IMN. Methods: A total of 21 patients with treatment-resistant IMN treated with RTX from 2015 to 2016 at our center were included in the study. They received two doses of RTX (500 mg each) infusion 7 days apart. CD19 count was performed after 4 weeks. A single dose of RTX was repeated after 4–6 weeks if CD19 count was not depleted. Results: The mean standard deviation age of patients was 33.36 12.3 years and 33.3% were females. Mean proteinuria before RTX therapy was 6.26 2.2 g/day, serum creatinine was 0.96 0.3 mg/dL and estimated glomerular ﬁltration rate (eGFR) was 95.86 26.9 mL/min/1.73 m . All the patients were non-responders to prior immunosuppressive treatment. Twenty (95.2%) patients achieved targeted CD19 depletion with two doses of RTX. One patient required one additional RTX dose due to inadequate B-cell suppression. A total of 13 (61.9%) patients achieved remission with RTX therapy: 4 (19.0%) complete and 9 (42.9%) partial remission. Patients who did not respond to RTX had a signiﬁcantly lower baseline eGFR compared with those who achieved remission (P¼ 0.022). One patient developed respiratory tract infection following RTX during the follow-up, which responded to a course of oral antibiotics. During median follow-up of 13.1 (10–23.9) months, four (19%) patients had deterioration in renal function and one patient relapsed after achieving partial remission. Renal survival was signiﬁcantly better in patients who responded to RTX therapy as compared with those who did not achieve remission (P¼ 0.0037). Conclusion: Low-dose RTX therapy is effective and safe in immunosuppression-resistant IMN. Key words: immunosuppression, membranous nephropathy, outcome, proteinuria, rituximab Received: May 24, 2017. Editorial decision: August 15, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact firstname.lastname@example.org Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/337/4430994 by Ed 'DeepDyve' Gillespie user on 20 June 2018 338 | S. Bagchi et al. secondary causes of MN including hepatitis B and C, malig- Introduction nancy and systemic lupus erythematosus. Serum anti-PLA2R Idiopathic membranous nephropathy (IMN) is a common cause antibody was assessed by ELISA before giving RTX to patients of proteinuria and nephrotic syndrome (NS) in adults . In a when possible. large multicentric retrospective study, 32% of patients with All patients were screened for infections with complete IMN were found to achieve spontaneous remission 14 months blood count, chest, X-ray and urinalysis before giving RTX. after diagnosis . Persistent proteinuria due to IMN is associ- Therapy comprised of two doses (500 mg each) given as intrave- ated with progression to end-stage kidney disease in 10 years nous infusion 7–10 days apart. All patients were given premedi- with increased risk of mortality . Therefore, in patients with cation with hydrocortisone and paracetamol. CD19 count was significant proteinuria, who do not achieve spontaneous remis- done 4 weeks after the second dose of RTX. B-cell depletion was sion with conservative management, the Kidney Disease: defined as CD19 count<1%. Complete blood counts, serum crea- Improving Global Outcomes (KDIGO) guidelines (2012) recom- tinine, 24-h urinary protein and creatinine and serum albumin mended the modified Ponticelli regimen (MPR) comprising were assessed at the time of initiation of treatment and alternating courses of corticosteroids and cyclophosphamide as repeated every 4 weeks. Estimated glomerular filtration rate the first-line therapy . Calcineurin inhibitors (CNIs), that is, (eGFR) was calculated using the four-variable Modification of tacrolimus or cyclosporine, were suggested as alternative Diet in Renal Disease (MDRD) formula. therapy in patients resistant/intolerant to the MPR. However, Additional doses of RTX (one to two) were planned after 4– MPR [5, 6] and CNIs [7, 8] achieve remission in 60–70% patients. 6 weeks if CD19 count did not show adequate depletion. Co-tri- MPR is limited by the high incidence of adverse effects moxazole prophylaxis was given to all patients for at least requiring withdrawal or hospitalization , while the use of CNI 6 months after RTX therapy. is associated with high-relapse rates and decline in renal Complete remission was defined as 24-h urinary protein function [7–9]. <500 mg/day and partial remission as 24-h urinary protein Rituximab (RTX) is a monoclonal antibody against CD20 between 500 mg and 3.5 g/day with at least 50% reduction in expressed on B cells, which was initially used for the treatment proteinuria from the time of initiation of therapy with eGFR of lymphoma. With the identification of auto-antibodies to maintained within 25% of the baseline. Non-responders were podocyte antigens, phospholipase A2 receptor (PLA2R)  and defined by <50% decrease in proteinuria with or without sus- now thrombospondin type-1 domain containing 7 A (THSD7A) tained decline in eGFR. Renal deterioration was defined as sus-  in IMN, the use of RTX has emerged as an important thera- tained decline in eGFR50% from baseline documented at least peutic option in these patients . twice. There are multiple studies using RTX as first-line therapy as The study was approved by the Institute Ethics Committee well as in patients resistant to other immunosuppressive regi- of our hospital. mens in Western populations since 2002 . However, there is a paucity of data from Asia . Also, though the available data about RTX in IMN is encouraging, there is no consensus about Statistical methods the optimum dose. Most centers [15–19] have used 375 mg/m Statistical analysis was carried out using STATA 12.0 (College weekly 4 doses or 1 g on Days 1 and 15, sometimes repeated Station, TX, USA). Data were summarized as frequency (%) or after 6 months . This dosing regimen is limited by the high mean6 standard deviation (SD)/median (range) as appropriate. cost. There is also a potential risk of infections with use of bio- The baseline categorical and continuous variables were com- logic agents like RTX , especially in patients who have been pared between those who achieved remission and were non- previously treated with other immunosuppressive drugs. responders using the chi-square test/Fisher’s exact test and Higher doses of RTX will increase the cumulative immunosup- independent t-test/Wilcoxon rank sum test, respectively. The pression exposure in such patients, which is especially signifi- impact of remission on renal survival was assessed using the cant in low- and middle-income countries like India where the Kaplan–Meier method and log-rank test for comparisons. A P- infectious disease burden in the community is very high. value of<0.05 was considered statistically significant. Studies [21–23] using lower doses of RTX have reported con- flicting outcomes. Our study aimed to assess the efficacy and safety of low-dose RTX in patients with immunosuppression- resistant IMN. Results A total of 23 patients with biopsy-proven resistant IMN received low-dose RTX therapy during the study period. Two patients Materials and methods were lost to follow-up within 3 months and thus 21 were In this retrospective study, we included patients who had resist- included in the final analysis. Their characteristics are shown in ant IMN and were treated with low-dose RTX during 2015–16 in Table 1. The mean age of patients was 33.36 12.3 years and our nephrology department. Resistant IMN was defined as per- 33.3% were females. Two patients had associated diabetes and sistent NS or persistent edema with significant proteinuria six had hypertension. Mean proteinuria before RTX therapy was despite completion of MPR (6 months) with an additional fol- 6.26 2.2 g/day. As shown in Table 2, two patients had less than low-up of 6 months and/or tacrolimus therapy for at least nephrotic range proteinuria (3.4 g/day) but were symptomatic 6 months with tacrolimus trough level of 5–10 ng/mL. NS was with edema and responded to treatment subsequently. Mean defined as 24-h urine protein3.5 g/day with serum albumin serum creatinine level was 0.96 0.3 mg/dL and mean eGFR was <3 g/dL and edema. Patients with 24-h urinary protein>1.5 g/ 95.86 26.9 mL/min/1.73 m . Two patients had eGFR <60 mL/ day with significant edema were also considered to have min/1.73 m . significant proteinuria and treated with immunosuppression as Immunosuppression received before RTX by these patients is the practice in our center. Low-dose RTX was defined as two were (Table 2): six MPR, two tacrolimus, eight MPR and doses of 500 mg of RTX. All these patients had been screened for tacrolimus, two tacrolimus and mycophenolate mofetil (MMF), Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/337/4430994 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Rituximab in membranous nephropathy | 339 Table 1. Characteristics of patients with and without response to RTX therapy Total (n ¼ 21) Remission (n ¼ 13) No remission (n ¼ 8) P Age (years), mean 6 SD, median (range) 33.3 6 12.3, 32 (15–62) 32.6 6 14.1, 32 (15–62) 34.5 6 9.5, 35.5 (22–46) 0.446 Gender (females) [n (%)] 7 (33.3) 6 (85.7) 1 (14.3) 0.133 Baseline serum creatinine (mg/dL), mean 6 SD 0.9 6 0.3 0.8 6 0.3 1.1 6 0.2 0.033 Baseline eGFR (mL/min/1.73m ), mean 6 SD 95.8 6 26.9 104.6 6 28.8 81.5 6 16.4 0.022 Baseline urinary protein (g/day), mean 6 SD 6.2 6 2.2 5.9 6 2.6 6.7 6 1.6 0.157 Baseline serum albumin (g/dL), mean6SD 2.5 6 0.5 2.5 6 0.6 2.4 6 0.5 0.423 ACEi/ARB [n (%)] 19 (90.5) 11 (84.6) 8 (100) 0.371 Worsening renal function [n (%)] 4 (19.0) 0 4 (50%) 0.012 Table 2. Treatment details of individual patients Urinary Prior IS Serum anti-PLA2R Follow-up after Urinary Age SCr 1 SAlb 1 protein 1 before antibody before RTX therapy SCr 2 SAlb 2 protein 2 Status at last No. (years) Gender (mg/dL) (g/dL) (g/day) RTX RTX therapy (months) (mg/dL) (g/dL) (g/day) follow-up 1 19 M 0.8 1.8 12.2 MPR ND 20.5 0.6 4.3 0.2 CR 2 32 M 0.8 3.1 8.8 MPR POS 12.8 0.8 5 0.3 CR 3 43 F 0.6 2.8 7.1 MPR/TAC POS 11.1 0.5 4.7 0.4 CR 4 18 M 0.8 1.6 6 TAC NEG 11.2 0.7 3.8 0.2 CR 5 20 M 1.5 2.5 6.5 MPR/TAC POS 22 1.4 5 2.2 PR 6 32 M 0.7 2.4 6 MPR ND 23.9 0.8 4.8 0.8 PR 7 15 F 0.6 2.1 3.6 MPR NEG 18.6 0.6 3.8 1.8 PR–relapsed during follow-up, responded to TAC 8 21 F 0.7 2.6 3.7 MPR/MMF/TAC POS 18 0.6 3.6 1.2 PR 9 51 M 0.8 3.1 3.4 MPR/TAC/MMF ND 16.5 0.8 4.7 1.3 PR 10 62 F 0.5 2.6 6.2 MPR NEG 13.1 0.5 4.2 1.8 PR 11 37 F 0.8 3 3.4 TAC/MMF ND 17.4 0.7 4.5 1.2 PR 12 34 M 0.8 2.4 6.2 MPR/TAC POS 12.6 0.8 4.2 1.0 PR 13 40 F 1.5 3.1 3.6 MPR/TAC POS 10 1.5 4.1 1.5 PR 14 40 M 0.9 1.6 4.7 TAC ND 10.8 3.4 3.8 4.5 NR 15 46 M 1 2.8 7 MPR/TAC POS 18.8 3.3 2.9 10.0 NR 16 33 M 1.3 2.4 5 MPR/TAC NEG 14.3 2 3.6 11.0 NR 17 46 M 1.1 2.9 9.6 MPR/TAC POS 12.2 1.2 1.7 15.4 NR 18 22 F 0.7 2.6 6.3 MPR/TAC/MMF POS 13.8 0.5 2.2 6.0 NR 19 27 M 1 1.8 8 MPR ND 12.4 5 2 6.3 NR 20 24 M 1 2.5 7.1 MPR/TAC NEG 11.7 1.2 3.9 7.7 NR 21 38 M 1.4 2.9 6.4 TAC/MMF POS 10.3 2.9 2.9 7.3 NR M, male; F, female. SCr 1, SAlb 1, urinary protein 1—before giving RTX, TAC; SCr 2, SAlb 2, urinary protein 2—at last follow-up; CR, complete remission; PR, partial remission; NR, no response; ND, not done; POS, positive; NEG, negative; TAC, tacrolimus; IS, immunosuppressive therapy; SCr, serum creatinine; SAlb, serum albumin. and three MPR, tacrolimus and MMF. All the patients had not subsequently developed partial remission. Median time to responded to the prior immunosuppressive treatment. remission after last dose of RTX was 2.7 months (1.2–7 months). Pre-treatment serum anti-PLA2R antibody levels were avail- One patient developed respiratory tract infection following RTX able in 15 patients, of which 10 were positive. Five patients who during the follow-up, which responded to a course of oral anti- were PLA2R-negative did not have any evidence of secondary biotics. No other adverse effect was reported in any other cause and were therefore considered as IMN. Nineteen (90.5%) patient. patients were on angiotensin-converting enzyme inhibitors During a median follow-up of 13.1 (10–23.9) months, four (ACEi)/angiotensin receptor blockers (ARBs). Patients who did (19%) patients had deterioration in renal function. Renal sur- not respond to RTX had a significantly lower baseline eGFR vival was significantly better in patients who responded to RTX compared with those who achieved remission (P¼ 0.022). All therapy as compared with those who did not achieve remission other baseline characteristics were similar in the two groups. (Figure 1,P¼ 0.0037). Of eight patients who did not respond to A total of 13 (61.9%) patients achieved remission with RTX, six received additional doses (one or two) of RTX and two RTX therapy: 4 (19.0%) complete and 9 (42.9%) partial remission. patients received subcutaneous adrenocortical hormone ther- Twenty (95.2%) patients achieved targeted CD19 depletion apy but with no response. Four patients who had not responded with two doses of RTX. One patient required one additional RTX to RTX therapy underwent repeat kidney biopsy, of which three dose due to inadequate B-cell suppression after two doses and showed increase in interstitial fibrosis and tubular atrophy. One Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/337/4430994 by Ed 'DeepDyve' Gillespie user on 20 June 2018 340 | S. Bagchi et al. There are conflicting data about the efficacy of low-dose RTX Kaplan-Meier survival estimates in IMN. Cravedi et al.  found low-dose RTX therapy titrated based on B-cell depletion to be equally effective as standard protocol of four weekly doses of 375 mg/m , with a remission rate of >60%. In a cohort of 100 patients, Ruggenenti et al. reported remission in 65% following RTX therapy . The patients in this study had received four doses of RTX (375 mg/ m ) until 2005 and subsequently lower doses were given using a Log rank=0.0037 B-cell-driven protocol. The GEMRITUX trial , which random- ized patients with IMN and NS to two doses of RTX (375 m/m ) versus no immunosuppressive therapy after an adequate period of conservative management, did not show any significant dif- ference between the two groups at 6 months, but with extended 0 5 10 15 20 25 Time in months follow-up the remission rate was significantly higher in the RTX group (64.9% versus 34.2%, P< 0.01) with no significant adverse No response Remission (Complete/Partial) effects compared with the untreated patients. However, the study by Moroni et al.  concluded that low-dose RTX was less Fig. 1. Renal survival in patients with and without remission following RTX efficacious in IMN. In this study, RTX was given to 34 patients therapy. with IMN (19 as first-line therapy, 15 had previously received immunosuppressive therapy with resistant or relapsing dis- ease). At 6 and 12 months, 44.1% patients had achieved remis- patient who had achieved initial remission relapsed during the sion, which was lower than other studies though all their study period. patients had achieved adequate B-cell depletion. Though this was a prospective study, 18 patients had received a single dose and 16 had received two doses of RTX. The authors have not Discussion mentioned the criteria based on which the dose was decided for each patient. In their cohort, 41% patients had eGFR <60 mL/ There has been a paradigm shift in the management of IMN min/1.73 m , suggesting higher chronicity. We had only 14.3% of with the discovery of the pathogenic role of PLA2R antibodies patients with eGFR <60 mL/min/1.73 m in our study. We also and the use of RTX therapy. MPR and CNIs have conventionally observed that our patients who did not respond to RTX therapy been used for treating persistent NS due to IMN. These drugs, had a significantly lower baseline eGFR compared with those though effective, have been associated with significant adverse who achieved remission. Some of these patients had features of effects [7–9] and high-relapse rates. In this context, RTX is an chronicity on repeat biopsy, which may explain the lack of attractive treatment option, considering its ease of administra- response to immunosuppression [10, 24]. There were no signifi- tion and minimal risk of noncompliance. Initial experience with cant adverse effects observed in our study barring an episode of RTX in IMN has been positive with multiple studies using it as lower respiratory tract infection in one patient. The absence of first as well as second-line immunosuppressive therapy in cardiovascular events, as observed in other studies [18, 22, 23], these patients [15–19, 21]. However, ambiguity about the opti- following RTX infusion may be attributed to the younger age of mum dose of RTX continues. Initial studies [15–19] have used our patients. the conventional higher doses of RTX. This is limited by the Our study, being retrospective, has some limitations. We high cost and the potential risk of infections, which are espe- did not have serum anti-PLA2R levels for all the patients. cially relevant in low- and middle-income countries. The follow-up period of 13 months was short and the response Subsequently, lower doses of RTX have been used using CD19 rate may improve with longer follow-up. Since the use of low- counts to decide the dose and monitor response. dose RTX in Caucasian populations has shown variable results, We analyzed our experience with low-dose RTX in 21 patients further studies are needed to determine whether the Indian with resistant IMN. All these patients had initially received MPR patients per se require lower doses of RTX for B-cell depletion. and/or tacrolimus, which are currently considered to be the To conclude, low-dose RTX is safe and efficacious for the standard immunosuppressive therapy offered to patients of IMN treatment of resistant IMN. Further studies with longer follow- with persistent NS. Two doses of RTX achieved B-cell depletion in up and more frequent anti-PLA2R antibody and CD19 count all except one patient, who required one additional dose. Other monitoring are needed to determine the lowest possible effec- studies have also reported adequate B-cell depletion with two tive dose of this antibody. doses of RTX [21–23]. In a study evaluating the efficacy of B-cell- driven therapy, even a single dose of RTX (375 mg/m ) was suffi- cient to achieve full CD19 depletion . In our study, 61.9% patients achieved remission during a Conflict of interest statement median follow-up of 13 months. All our patients had received prior immunosuppressive therapy with no response, thus they None declared. had difficult-to-treat disease. Despite this, our response rate was similar to other studies, which have shown remission in References 60–70% of patients [15–19, 21, 23]. The time to remission after last dose of RTX was 2.7 months (1.2–7 months) in our study. 1. Hofstra JM, Fervenza FC, Wetzels JF. Treatment of idiopathic This response time is shorter than that reported from other membranous nephropathy. Nat Rev Nephrol 2013; 9: 443–458 studies, where patients have responded even after 12 months 2. Polanco N, Gutie ´ rrez E, Covarsı´A et al.; Grupo de Estudio de [18, 19, 23]. Whether more patients will ultimately achieve las Enfermedades Glomerulares de la Sociedad Espanola de remission with longer follow-up in our cohort needs to be seen. Nefrologı ´a. 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Beck LH Jr, Fervenza FC, Beck DM et al. Rituximab induced 24. Ruggenenti P, Chiurchiu C, Abbate M et al. Rituximab for idio- depletion of anti-PLA2R autoantibodies predicts response in pathic membranous nephropathy: who can beneﬁt? Clin J membranous nephropathy. J Am Soc Nephrol 2011; 22: Am Soc Nephrol 2006; 1: 738–748 1543–1550 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/337/4430994 by Ed 'DeepDyve' Gillespie user on 20 June 2018
Clinical Kidney Journal – Oxford University Press
Published: Oct 11, 2017
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