Cyclical cyclophosphamide and steroids is effective in resistant or relapsing nephrotic syndrome due to M-type phospholipase A2 receptor–related membranous nephropathy after tacrolimus therapy
Authors: Raja Ramachandran, Vinod Kumar, Vivekanand Jha
Journal: Kidney International (2016)

The 2011 Kidney Disease: Improving Global Outcomes (KDIGO) Guidelines recommend the use of cyclical alkylating agent and steroids or calcineurin inhibitors as first-line agents in the management of persistent nephrotic syndrome due to primary membranous nephropathy.1Kidney Disease Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis.Kidney Int Suppl. 2012; 2: 139-274Abstract Full Text Full Text PDF Scopus (789) Google Scholar In patients who are refractory to or relapse after treatment with one of these regimes, use of the alternate protocol is recommended. However, there are few data on the efficacy of either approach. Earlier, we have reported clinical and serologic remission rates of 30% and 17%, respectively, with the use of calcineurin inhibitor–based therapy in patients refractory to the modified Ponticelli regimen (cyclophosphamide and prednisolone). Two-thirds of the cases relapsed on stopping tacrolimus.2Ramachandran R. Sharma V. Nada R. et al.Role of tacrolimus only therapy in modified Ponticelli regimen resistant idiopathic membranous glomerulonephritis.Nephrology (Carlton). 2015; 20: 44-46Crossref PubMed Scopus (5) Google Scholar We report our experience of treating with the modified Ponticelli regimen 10 patients with m-type phospholipase A2 receptor (PLA2R)–related membranous nephropathy who were resistant (n = 6), dependent (n = 3), or relapsed (n = 1) on treatment with a combination of tacrolimus and glucocorticoids.3Ramachandran R. Hn H.K. Kumar V. et al.Tacrolimus combined with corticosteroids versus modified Ponticelli regimen in treatment of idiopathic membranous nephropathy: randomized control trial.Nephrology (Carlton). 2016; 21: 139-146Crossref PubMed Scopus (65) Google Scholar All cases had enhanced PLA2R staining in glomeruli. Seven (70%) patients were positive for antibodies to PLA2R at baseline and 3 (30%) turned positive during the course of the disease. The clinical course of all patients before starting tacrolimus and glucocorticoids, before starting the modified Ponticelli regimen, and during therapy is shown in Table 1. A total of 8 and 6 cases achieved clinical and serologic remission, respectively. Proteinuria remission was associated with reduction in antibody titer. Two patients developed respiratory tract infection during the course of therapy. To conclude, cyclical alkylating agent and steroids are effective in inducing remission in PLA2R-related primary membranous nephropathy refractory to tacrolimus and glucocorticoids.Table 1Proteinuria, serum albumin, and aPLA2R titer at end of therapyPrior to TAC/GCPrior to cCTX/GC2 months4 months6 monthsaPLA2R (RU/ml)Proteinuria (g/d)Serum albumin (g/dl)Proteinuria (g/d)Serum albumin (g/dl)Proteinuria (g/d)Serum albumin (g/dl)Proteinuria (g/d)Serum albumin (g/dl)Proteinuria (g/d)Serum albumin (g/dl)12324/MResistant2.301.624.702.902.502.321.203.590.64.320.45aCases with baseline aPLA2R negative, but serial aPLA2R positive (enhanced staining for PLA2R in glomeruli positive).27.270.1045/MResistant10.301.423.002.162.401.802.702.073.002.19938.21201.95182.3926/MResistant6.601.807.502.471.303.050.764.100.713.68217.09186.6752.2341/FDependent5.002.204.202.913.762.640.863.650.884.01203.46364.230.8118/FResistant5.701.503.902.594.501.101.502.162.502.481468.54440.92359.3022/MRelapse7.381.9011.502.622.403.211.403.570.804.10118.80235.180.3755/MResistant6.234.4014.703.193.203.702.013.800.283.960.45aCases with baseline aPLA2R negative, but serial aPLA2R positive (enhanced staining for PLA2R in glomeruli positive).156.510.2945/FDependent7.402.405.002.831.003.420.154.500.204.1321.4132.520.3116/FResistant4.601.904.502.742.702.721.202.601.403.531.73aCases with baseline aPLA2R negative, but serial aPLA2R positive (enhanced staining for PLA2R in glomeruli positive).1285.96154.4848/MDependent6.001.854.002.771.502.201.003.900.963.9050.55135.900.59aPLA2R, antibodies to m-type phospholipase A2 receptor; cCTX/GC, cyclical cyclophosphamide and glucocorticoids; F, female; M, male; PLA2R, phospholipase A2 receptor; RU, reference unit; TAC/GC, tacrolimus and glucocorticoids; 1, before starting tacrolimus; 2, before starting cCTX/GC; 3, at completion of 6 months of cCTX/GC.a Cases with baseline aPLA2R negative, but serial aPLA2R positive (enhanced staining for PLA2R in glomeruli positive). Open table in a new tab aPLA2R, antibodies to m-type phospholipase A2 receptor; cCTX/GC, cyclical cyclophosphamide and glucocorticoids; F, female; M, male; PLA2R, phospholipase A2 receptor; RU, reference unit; TAC/GC, tacrolimus and glucocorticoids; 1, before starting tacrolimus; 2, before starting cCTX/GC; 3, at completion of 6 months of cCTX/GC.