Sequential therapy with cyclophosphamide and mycophenolic acid in patients with progressive immunoglobulin A nephropathy: a long-term follow-up

Abstract

SummaryIn progressive immunoglobulin (Ig)A nephropathy (IgAN), cyclophosphamide pulse therapy (CyP), high-dose intravenous immunoglobulins (IVIg) and mycophenolic acid (MPA) have been used to stop progressive loss of renal function, but disease progression may occur after the end of the initial treatment. Here, we report the long-term follow-up of patients with progressive IgAN with MPA as maintenance therapy after CyP (CyP-MPA). In a median observation time of 6Á2 years, we analysed the slopes of the loss of renal function of 47 patients with biopsy-proven IgAN and treated with CyP. Thirtyone patients with further progression were treated with MPA maintenance for a median time of 5Á2 years. Follow-up was compared with symptomatic therapy and IVIg as historically matched control groups. Median loss of renal function was reduced significantly from 20Á9 ml/min to 20Á1 ml/min per month with CyP (P < 0Á05), and with MPA in patients with a relapse from 20Á4 ml/min to 20Á1 ml/min per month (P < 0Á05) until the end of the study. Proteinuria decreased significantly from 1Á6 g/l to 1Á0 g/l after CyP, and during MPA treatment to 0Á6 g/l (P 5 0Á001 Friedman test). Median renal survival time was in patients with CyP 10Á5 years (range 5 3Á2-17Á8), with CyP-MPA 10Á7 years (range 5 8Á3-13Á1), with IVIg 4Á7 years (range 5 2Á6-6Á6), and in untreated patients 1Á2 years (range 5 0Á8-1Á6; log-rank test P < 0Á01). In patients with progressive IgAN, our long-term follow-up observation indicates that sequential CyP-MPA therapy maintains renal survival significantly.

Why, when and how should immunosuppressive therapy considered in patients with immunoglobulin A nephropathy?

“…In our study, sequential MPA maintenance therapy was effective in patients with progressive IgAN in reducing further loss of renal function (ΔGFR) from −0·4 to −0·1 ml/min/month with a trend in reduction of the proteinuria from 1·0 to 0·6 g/l . The full effect of MPA on renal function was observed after an average time lag of 6 months and in reduction of proteinuria after 5 months.…”

“…In order of the deficiencies, also confirmed by the authors themselves [51], we do not recommend the Oxford Classification. Clearly, no histological grading correlated with clinical outcomes after therapy in most studies [4,[60][61][62][63][64][65][66][67][68][69][70]. However, therapeutic interventions should be based not only or decided upon isolated histological findings [71].…”

“…It has been suggested that untreated patients with a serum creatinine exceeding 2Á5-2Á7 mg/dl ('the point of no return') will develop end-stage renal disease within a period of approximately 1 year [92,93], but this judgement should be revised with immunosuppressive therapy [4,[61][62][63][64]77,94,95].…”

“…Therefore, IVIg is an option as induction therapy for 6 months. However, 3 years after IVIg, further loss of renal function was observed [4,60,63], and further maintenance therapy will be needed with prednisolone and/or mycophenolate mofetil (MMF)/MPA plus prednisolone [60][61][62][63]77].…”

“…1). Corticosteroids will be a necessary standard in addition to mycophenolate [60][61][62][63], even in other autoimmune diseases [121]. These effects may be responsible for a reduction of the proliferative lesions, glomerular sclerosis and tubular fibrosis in IgAN with a superior renal survival compared with patients receiving only ARB/ACEI [35,36,67,122].…”