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Ragy O. , Hamilton P. , Pathi A. , Mohamed Ahmed A. A. , Mitra S. , Kanigicherla D. AK. : Long-Term Safety, Clinical and Immunological Outcomes in Primary Membranous Nephropathy with Severe Renal Impairment Treated with Cyclophosphamide and Steroid-Based Regimen. Glomerular Diseases DOI  10.1159/000529605

The treatment of membranous nephropathy (MN; PLA2R associated) has improved greatly in recent years, but uncertainties still exist concerning the treatment of such patients who have already advanced to stage 4 chronic kidney disease (CKD) or beyond. Whether therapy with oral (or IV) cyclophosphamide (CYC), rituximab (RTX), or mycophenolate mofetil (MMF) can achieve a reasonable level of remission in patients with MN and advanced CKD is still not well understood. Calcineurin inhibitors are generally contraindicated in such patients because of the fear of nephrotoxicity.

In a small (n = 18) prospective, uncontrolled, open-label study with moderately long-term follow-up (67 months) in patients with MN (67% PLA2R associated) and advanced CKD (eGFR <30 mL/min/1.73 m2), Ragy and colleagues assessed the benefits (complete or partial remission) of a 6-month course of IV CYC (10 mg/kg, monthly X6 for age <70 years and 7.5 mg/kg monthly X6 for age >70 years) plus tapering doses of oral steroids.

At baseline (prior to starting CYC), the mean eGFR was 23ml/min/1.73m2 (IQR = 18–27); serum albumin level was 2.2 g/dL (IQR = 1.8–2.7); UPCR was ≥ 8.4 (IQR = 6.9–16.7); and the median level of anti-PLA2R antibody was 301.5 RU/mL (IQR = 196–2,651). By any criteria, these were all very high-risk patients.

At the end of follow-up, there were 7 complete remissions, 9 partial remissions, and 2 patients failed to develop a remission and progressed to ESKD. The tine to remission did not vary by anti-PLA2R antibody levels. Five patients developed infection, 2 requiring hospitalization. Four cancers were noted (bladder, mesothelioma, colon, and skin). Four patients died (cancer, CVA, and ischemic heart disease). The eGFR increased in those with remission, but not to over 60 mL/min/1.73 m2. Serum albumin levels improved in most patients.

The lack of parallel groups treated with oral CYC, RTX, or MMF precludes any statements regarding superiority of IV CYC over other regimens. Nevertheless, these preliminary results strongly indicate that advanced CKD (stage 4 CKD) is not a reason to declare futility, at least if anti-PLA2R antibody levels remain greatly elevated. The regimen used can be associated with side effects, some serious.

Quoted Karger Article

Long-Term Safety, Clinical and Immunological Outcomes in Primary Membranous Nephropathy with Severe Renal Impairment Treated with Cyclophosphamide and Steroid-Based Regimen

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