Long-Term Follow-Up of Cyclical Cyclophosphamide and Steroids Versus Tacrolimus and Steroids in Primary Membranous Nephropathy

Abstract

Introduction Kidney Disease: Improving Global Outcomes (KDIGO) 2012 recommends cyclical cyclophosphamide plus glucocorticoids (GC) (modified Ponticelli regimen) or calcineurin inhibitors (CNIs) such as tacrolimus (TAC) or cyclosporine as the first-line agents for the management of primary membranous nephropathy (PMN) that is resistant to antiproteinuric therapy with renin-angiotensin system blockers. However, the long-term outcome of patients treated with CNIs is not known. Methods We report the outcomes of 70 patients randomized 1:1 to receive modified Ponticelli regimen or TAC/GC for renin-angiotensin system–resistant PMN who were prospectively followed for 6 years. Patients were followed monthly for 12 months, then quarterly for 12 months, and then every 6 months through the end of 6 years. Results At the end of 6 years, 21 (61.76%) and 9 (28.12%) patients maintained relapse-free remission in modified Ponticelli regimen and TAC/GC groups, respectively (relative risk [RR]: 2.19, 95% confidence interval [CI]: 1.23 to 4.15), and 30 (88.23%) and 17 (53.12%) patients were in remission (including relapses) in modified Ponticelli regimen and TAC/GC groups (RR: 1.66; 95% CI: 1.21 to 2.45), respectively. There was no significant difference in the proportion of patients who had a 40% decline in the estimated glomerular filtration rate (eGFR), death, or end-stage kidney disease between the groups. None of the patients treated with modified Ponticelli regimen reported a solid organ or hematological malignancy. Conclusions To conclude, in the long-term, modified Ponticelli regimen is superior to TAC/GC as first-line therapy for the management of antiproteinuric-resistant PMN.

Advances in the Management of Primary Membranous Nephropathy and Rituximab-Refractory Membranous Nephropathy

“…At the end-point of six years after the beginning of treatment, 62% of participants in the cyclophosphamide/glucocorticoid group and 28% in the tacrolimus group maintained remission without relapse, and 88% of patients in the cyclophosphamide/glucocorticoid group vs 53% of patients in the tacrolimus group were in remission. This study confirmed the long-term superiority of six months of cyclophosphamide/glucocorticoid therapy vs one year of tacrolimus ( 62 ).…”

B Cells in Primary Membranous Nephropathy: Escape from Immune Tolerance and Implications for Patient Management

“…However, neither cyclosporin A nor tacrolimus affects B cell differentiation [136,137]. Importantly, in studies of MN patients, both cyclophosphamide-and calcineurin inhibitor-based treatment regimens are clinically useful in MN, and can effectively reduce anti-PLA 2 R antibody titres in PLA 2 Rassociated MN, although greater, earlier and more sustained decreases were typically seen with cyclophosphamide-based regimens [138]. Patients on calcineurin inhibitors do not tend to go into durable remissions and have a high rate of immunological and clinical relapse after cessation of treatment.…”

An Updated Review of Membranous Nephropathy

“…The efficacy of CNIs was also inferior in sustaining the remission in the long-term compared to the cyclic regimen with cyclophosphamide and steroids at 6 years post-treatment, 62% versus 28%, respectively. 85 Effective CNI regimens can include both tacrolimus 0.05–1 mg/kg/d aiming of 3–8 ng/mL, or cyclosporin 3.5 mg/kg/d with a goal of 125–225 ng/mL for 12 months. It is often used with low-dose prednisone (i.e., 10 mg/day).…”