Part 1: The starmen Trial Indicates That Alternating Treatment With Corticosteroids And Cyclophosphamide Is Superior To Sequential Treatment With Tacrolimus And Rituximab in Primary Membranous Nephropathy
Mar 11, 2022
Part 1: The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy
Contact: joanna.jia@wecistanche.com / WhatsApp: 008618081934791
Gema Ferna´ndez-Jua´rez, and ect.
A cyclical corticosteroid-cyclophosphamide regimen is recommended for patients with primary membranous nephropathy at high risk of progression. We hypothesized that sequential therapy with tacrolimus and rituximab is superior to cyclical alternating treatment with corticosteroids and cyclophosphamide in inducing persistent remission in these patients. This was tested in a randomized, open-label controlled trial of 86 patients with primary membranous nephropathy and persistent nephrotic syndrome after six-month observation and assigned 43 each to receive six-month cyclical treatment with corticosteroid and cyclophosphamide or sequential treatment with tacrolimus (full dose for six months and tapering for another three months) and rituximab (one gram at month six). The primary outcome was complete or partial remission of nephrotic syndrome at 24 months. This composite outcome occurred in 36 patients (83.7%) in the corticosteroid-cyclophosphamide group and 25 patients (58.1%) in the tacrolimus-rituximab group (relative risk 1.44; 95% confidence interval 1.08 to 1.92). Complete remission at 24 months occurred in 26 patients (60%) in the corticosteroid-cyclophosphamide group and 11 patients (26%) in the tacrolimus-rituximab group (2.36; 1.34 to 4.16). Anti-PLA2R titers showed a significant decrease in both groups but the proportion of anti-PLA2R-positive patients who achieved immunological response (depletion of anti-PLA2R antibodies) was significantly higher at three and six months in the corticosteroid-cyclophosphamide group (77% and 92%, respectively), as compared to the tacrolimus-rituximab group (45% and 70%, respectively). Relapses occurred in one patient in the corticosteroid-cyclophosphamide group, and three patients in the tacrolimus-rituximab group. Serious adverse events were similar in both groups. Thus, treatment with corticosteroid- cyclophosphamide-induced remission in a significantly greater number of patients with primary membranous nephropathy than tacrolimus-rituximab.
Kidney International (2021) 99, 986–998;
j.kint.2020.10.014
cistanche can treat kidney disease improve renal function
KEYWORDS: renal function, kidney disease, end-stage kidney disease, acute kidney injury, chronic kidney disease, primary membranous nephropathy, rituximab, corticosteroids, cyclophosphamide
Copyright ª 2020, International Society of Nephrology. Published by Elsevier Inc. This is an open-access article under the CC BY-NC-ND license
Primary membranous nephropathy (PMN) is one of the most common causes of nephrotic syndrome in adults. 1 In 70%–80% of cases, the disease is mediated by autoantibodies targeting the phospholipase A2 receptor (PLA2R) expressed in podocytes and 3%–5% by autoantibodies to thrombospondin type 1 domain-containing 7A (THSD7A). 2–4 Spontaneous remission occurs in one-third of patients, 5 and therefore an observational period of at least 6 months is recommended. 6–8 Conversely, about 50% of cases with persistent nephrotic syndrome eventually progress to end-stage kidney disease, and immunosuppressive therapy is recommended for these patients.
Controversy persists about the most effective type of immunosuppressive regimen. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for glomerulonephritis recommended a 6-month cyclic regimen of alternating alkylating agents (usual cyclophosphamide) plus corticosteroids for patients at high risk of progression since it was the only regimen that was shown to be effective in preventing end-stage kidney disease. 8–12 However, given the important number of serious adverse events associated with cumulative doses of alkylating agents, treatment alternatives were introduced. Calcineurin inhibitors (both cyclosporine and tacrolimus) have shown efficacy in inducing remission of nephrotic syndrome in about 70% of patients. 13,14 However, the main limitation of these drugs is the high rate of relapse after discontinuation. An observational study found a reduction in relapse rates when rituximab was administered at the time of tapering off cyclosporine or tacrolimus, 15 and a pilot study reported encouraging results of combined therapy with cyclosporine plus rituximab in high-risk PMN patients. 16
Immunosuppressive therapy is recommended for end-stage kidney disease and primary membranous nephropathy.
More recently, the efficacy of rituximab monotherapy has received great attention.17 A single dose of rituximab was suggested to be effective for induction of remission in an observational cohort,18 although, in recent clinical trials, higher doses were needed for optimal efficacy.19–21 Indeed, the superior efficacy of rituximab versus cyclosporine in the recent MENTOR (Membranous Nephropathy Trial of Rituximab) study was achieved using a total dose of 4 g rituximab.20
The need for head-to-head trials comparing the 6-month cyclic alternating treatment with corticosteroids and cyclophosphamide with the newer therapeutic alternatives (calcineurin inhibitors, rituximab) was stressed in a recent KDIGO conference.22 We designed the STARMEN (Sequential Treatment with Tacrolimus and Rituximab Versus Alternating Corticosteroids and Cyclophosphamide in PMN) study to compare the cyclic alternating treatment of corticosteroids and cyclophosphamide with a sequential treatment of tacrolimus and rituximab in the induction and maintenance of nephrotic syndrome remission for up 24 months. In addition, we studied the occurrence of relapses after remission and the role of anti-PLA2R autoantibodies for the treatment.
RESULTS
Patients
From June 2014 through June 2017, 130 patients were assessed for eligibility, of whom 44 (33%) were excluded from the study. The main reasons for screening failure were not meeting the eligibility criteria (21 patients), unwillingness to participate in the study (14 patients), and diagnosis of a secondary cause of membranous nephropathy (9 patients). The remaining 86 patients who met the eligibility criteria were randomly assigned to the corticosteroid-cyclophosphamide group (43 patients) or the tacrolimus-rituximab group (43 patients) (Figure 1). As presented in Table 1, no significant differences between groups were observed at baseline. Baseline stored serum samples were available in 69 patients, and anti-PLA2R was positive in 53 (77%). Sensitivity analyses showed no differences at baseline between anti-PLA2R–positive and anti-PLA2R–negative patients nor between patients with or without anti-PLA2R determinations at baseline (Supplementary Tables S1 and S2). One patient was anti-THSD7A positive. Kidney biopsies were performed 8 (range, 6–18) months before randomization. Seventy-three patients (85%) had de novo PMN and 13 (15%) relapsing PMN (Table 1).
All patients received at least 1 month of the assigned therapeutic intervention. Two patients in the corticosteroid-cyclophosphamide group (4.6%) and 6 (13.9%) in the tacrolimus-rituximab group discontinued the intervention (Figure 1). The remaining 41 in the corticosteroid-cyclophosphamide group and 37 in the tacrolimus-rituximab group) received the complete intervention. Patients assigned to the corticosteroid-cyclophosphamide group received a median dose of oral methylprednisolone of 0.49 ± 0.05 mg/kg/ day in months 1, 3, and 5, with a total cumulative dose of 3.4 ± 0.9 g. The total cumulative dose of intravenous methylprednisolone was 8.2 ± 1.4 g. The total cumulative dose of cyclophosphamide was 10 ± 3.5 g. Doses and blood levels of tacrolimus in the tacrolimus-rituximab group are presented in Supplementary Table S3. Three patients in this group received a second dose of rituximab (0.5 g in 2 patients, 1 g in 1 patient) at months 12, 12, and 18, respectively, and 2 others received additional doses of tacrolimus beyond month 9.
During the follow-up period after the end of the assigned intervention, 5 patients in each group were switched to a nonstudy intervention owing to a lack of efficacy of the assigned treatment. In the corticosteroid-cyclophosphamide group, 2 patients were treated with rituximab at month 14, 2 patients received tacrolimus from month 18, and 1 patient cyclosporine from month 16. In the tacrolimus-rituximab group, the 5 patients received a 6-month cyclic treatment with corticosteroid and cyclophosphamide at month 12 (2 patients), month 14 (2 patients), or month 21 (1 patient). All the patients who were switched to a nonstudy intervention were considered to be non-responders (Figure 1). Follow-up was complete in all of the 86 enrolled patients.
Primary outcome Thirty-six patients (83.7%) in the corticosteroid-cyclophosphamide group and 25 patients (58.1%) in the tacrolimus-rituximab group had a primary outcome of complete/partial remission at 24 months (relative risk [RR] 1.44, 95% confidence interval [CI] 1.08 to 1.92) (Table 2; Figure 2a). The per-protocol analysis confirmed significant differences in the primary outcome between groups: 35 of 41 (85%) in the corticosteroid-cyclophosphamide group and 22 of 37 (59%) in the tacrolimus-rituximab group (RR 1.44, 95% CI 1.07 to 1.93) (Table 2). The difference in the number of patients with complete or partial remission in both groups was already significant at month 3 and was maintained throughout the study (Table 2; Figure 2a).
As shown in Table 3 and Figure 2b, 26 patients (60%) in the corticosteroid-cyclophosphamide group achieved a complete remission at 24 months. In the tacrolimus-rituximab group, 11 patients (26%) achieved a complete remission at 24 months (RR 2.36, 95% CI 1.34 to 4.16).
A tendency for greater efficacy of the corticosteroid-cyclophosphamide treatment was found across different non-prespecified subgroups defined by baseline values of proteinuria, serum albumin, serum creatinine, anti-PLA2R levels. and age, although no differences were found in female patients (Supplementary Figure S1). When baseline characteristics of patients were compared between those who achieved complete/partial remission and those with no response, a significantly higher proportion of men (80% vs. 57%) and significantly higher proteinuria was observed among nonresponders (Supplementary Table S4).
Secondary outcomes
Proteinuria decreased from a median of 7.4 g/24 h (interquartile range 4.8–11.3) at baseline to 0.35 g/24 h (0.2–9) at 24 months in the corticosteroid-cyclophosphamide group and from 7.4 g/24 h (6.7–11.6) at baseline to 1 g/24 h (0.3–3.3) at 24 months in the tacrolimus-rituximab group (between-group difference P ¼ 0.005) (Figure 3a; Supplementary Table S5). Serum albumin increased from a mean 2.6 ± 0.1 g/dl at baseline to 4 ± 0.1 g/dl at 24 months in the corticosteroid-cyclophosphamide group and from 2.6 ± 0.1 g/dl at baseline to 3.9 ± 0.1 g/dl at 24 months in the tacrolimus-rituximab group (between-group difference P ¼ 0.2) (Figure 3b; Supplementary Table S5). There was a nonsignificant trend for higher values of estimated glomerular filtration rate (eGFR) in the corticosteroid cyclophosphamide group than in the tacrolimus-rituximab group throughout the follow-up (Figure 3c; Supplementary Table S6). At 24 months, the numbers of patients with a ≥50% increase of baseline serum creatinine were 1 (2%) in the corticosteroid-cyclophosphamide group and 5 (12%) in the tacrolimus-rituximab group (P ¼ 0.2). The numbers of patients with preserved renal function (eGFR ≥45 ml/min per 1.73 m2 ) at 24 months were 40 (93%) in the corticosteroid-cyclophosphamide group and 37 (86%) in the tacrolimus-rituximab group (P ¼ 0.48). The only patient who developed end-stage kidney disease was a 73-year-old man who had been assigned to the corticosteroid-cyclophosphamide group. Three months after treatment completion he was excluded from the study because of persistent massive proteinuria and declining renal function and switched to rituximab (2 doses of 1 g, 15 days apart). No response was observed, and chronic dialysis was initiated 16 months after randomization.
Anti-PLA2R levels showed a significant decrease in both groups (Table 4; Figure 3a). The proportions of anti-PLA2R– positive patients who achieved immunologic response at 3 and 6 months were significantly higher in the corticosteroid cyclophosphamide group (77% and 92%, respectively) than in the tacrolimus-rituximab group (45% and 70%, respectively) (Table 4). Most patients (80%) who achieved immunologic response during the study presented remission of nephrotic syndrome at 24 months. Immunologic response at 3 months (P ¼ 0.036) and 6 months (P ¼ 0.005) was associated with remission at 24 months. Nonresponding patients showed a slower decline in anti-PLA2R levels and a significantly lower proportion of immunologic responses, compared with patients who achieved complete or partial remission of nephrotic syndrome (Supplementary Table S7).
One out of the 36 patients (2.7%) in the corticosteroid cyclophosphamide group, and 3 out of the 25 patients (12%) in the tacrolimus-rituximab group who had achieved partial remission presented a relapse (Supplementary Table S8). The 3 relapses in the tacrolimus-rituximab group occurred at month 12, 3 months after tacrolimus discontinuation. Two of them occurred in anti-PLA2R–positive patients who had reached an immunologic response at month 6 and were not accompanied by a reappearance of anti-PLA2R antibodies. The remaining relapse occurred in a patient in whom anti-PLA2R antibodies had not been measured at baseline. Tacrolimus was restarted in 2 patients and the other one was treated with rituximab. The relapse in the corticosteroid-cyclophosphamide group occurred at month 9 in an anti-PLA2R–a positive patient who had reached immunologic response at month 3. In this case, the relapse was accompanied by a reappearance of anti-PLA2R antibodies, and the patient was treated with tacrolimus.
Adverse events All patients except 6 (1 from the corticosteroid-cyclophosphamide group and 5 from the tacrolimus-rituximab group) had at least 1 adverse event (Table 5). Most adverse events were of low (345, 84%) or medium (56, 13%) severity, but 17 (4%) were serious. There were more adverse events and more adverse events per patient in the corticosteroid-cyclophosphamide group than in the tacrolimus-rituximab group (P ¼ 0.04). More patients in the corticosteroid cyclophosphamide group had leukopenia and Cushing syndrome, while acute kidney injury, hyperkalemia, diarrhea, and distal tremor were more common in the tacrolimus-rituximab group. There was a statistically significant association between the presence of leukopenia and the development of infections, both in the total trial cohort and in each treatment group (P < 0.0001 for the total group and the cyclophosphamide group, P ¼ 0.041 for the tacrolimus/rituximab group). Most adverse events occurred within the first 9 months of the trial (304 of 409, 74%), but only 5 of the 17 serious adverse events occurred within this period.
There were no statistically significant differences in the frequency of serious adverse events between groups. The only case of serious acute kidney injury occurred in the tacrolimus-rituximab group, while 4 of the 5 serious infections occurred in the corticosteroid-cyclophosphamide group. Three cases of cancer were reported, although none of them was deemed to be related to the treatment received. Two cancers occurred in the corticosteroid cyclophosphamide group (gastric adenocarcinoma and breast carcinoma, detected at 12 and 11 months, respectively) and 1 in the tacrolimus-rituximab group (rectal carcinoma, detected at 1 month). Anti-PLA2R was positive at baseline in the 3 patients with cancer. At the time of tumor detection, the 2 patients in the corticosteroid-cyclophosphamide group were in clinical remission.
Cistanche can benefit primary membranous nephropathy.
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