Alternating treatment with corticosteroids and cyclophosphamide appears superior to sequential treatment with tacrolimus and rituximab in patients with primary membranous nephropathy (MN), according to study findings published in Kidney International.

In the STARMEN trial, investigators randomly assigned 86 patients with biopsy-proven primary MN and persistent nephrotic syndrome to receive either 6-month cyclical treatment with methylprednisolone and cyclophosphamide, an alkylating agent, or sequential treatment with tacrolimus, a calcineurin inhibitor (full-dose for 6 months, following by tapering for 3 months), and rituximab (1 g at month 6). At baseline, patients had an estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m2 or higher, nephrotic range proteinuria, and hypoalbuminemia. All patients received standard of care angiotensin converting enzyme inhibitors or angiotensin II receptor blockers.

At 24 months, 36 patients (83.7%) in the corticosteroid-cyclophosphamide group and 25 patients (58.1%) in the tacrolimus-rituximab group experienced the primary endpoint of complete or partial remission of nephrotic syndrome. The corticosteroid-cyclophosphamide group had a significant 44% greater likelihood of achieving this endpoint, Manuel Praga, MD, PhD, of the Research Institute University Hospital in Madrid, Spain, and colleagues reported. A secondary endpoint of complete remission occurred in 26 patients (60%) vs 11 patients (26%), respectively. The corticosteroid-cyclophosphamide group had a significant 2.4-fold greater likelihood of complete remission compared with the tacrolimus-rituximab group, according to Dr Praga’s team.

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Approximately three-quarters of patients in each group had autoantibodies targeting the phospholipase A2 receptor (Anti-PLA2R) in podocytes. Anti-PLA2R significantly decreased with both treatment regimens, but a significantly higher proportion of anti-PLA2R-positive patients achieved immunologic response at 3 and 6 months in the corticosteroid-cyclophosphamide group (77% and 92%, respectively) compared with the tacrolimus-rituximab group (45% and 70%, respectively).

Proteinuria decreased significantly more in the corticosteroid-cyclophosphamide group from baseline to 24 months (from 7.4 to 0.35 g/24h), compared with the tacrolimus-rituximab group (from 7.4 to 1 g/24h). Serum albumin increased from 2.6 g/dL at baseline to 4.0 and 3.9 g/dL, respectively.

“Early immunological response was followed by clinical remission in the vast majority of patients, which confirms the usefulness of anti-PLA2R monitoring for a personalized treatment of the disease,” according to Dr Praga and colleagues.

Relapses of nephrotic syndrome occurred in 1 patient (2.7%) in the corticosteroid-cyclophosphamide group and 3 patients (12%) in the tacrolimus-rituximab group.

More adverse events (AEs) occurred among patients receiving corticosteroid-cyclophosphamide, but serious AEs occurred in similar proportions of both groups. Notably, the cumulative dose of cyclophosphamide was lower (1.0–2.0 mg/kg/d, adjusted for age and renal function) than in some previous studies.

Dr Praga and colleagues concluded that “treatment with corticosteroid-cyclophosphamide induced remission (mostly complete) of nephrotic syndrome in a significantly greater number of patients than treatment with tacrolimus-rituximab, although side effects were more frequent in the former group.”

The investigators encouraged future trials of cyclophosphamide “pulses” along with lower doses of corticosteroids to see which, if any, regimens reduce AEs. They also requested trials of tacrolimus treatment beyond 6 months, or higher and earlier doses of rituximab.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Fernández-Juárez G, Rojas-Rivera J, van de Logt A-E, et al; for the STARMEN investigators. The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy. Published online November 6, 2020. Kidney Int. doi:10.1016/j.kint.2020.10.014