Complete and Partial Remission as Surrogate End Points in Membranous Nephropathy

Abstract

Absent a remission of proteinuria, primary membranous nephropathy (MN) can lead to ESRD over many years. Therefore, use of an earlier end point could facilitate the conduct of clinical trials. This manuscript evaluates complete remission (CR) and partial remission (PR) of proteinuria as surrogate end points for a treatment effect on ESRD in patients with primary MN with heavy proteinuria. CR is associated with a low relapse rate and excellent long-term renal survival, and it plausibly reflects remission of the disease process that leads to ESRD. Patients who achieve PR have better renal outcomes than those who do not but may have elevated relapse rates. How long PR must be maintained to yield a benefit on renal outcomes is also unknown. Hence, available data suggest that CR could be used as a surrogate end point in primary MN, whereas PR seems reasonably likely to predict clinical benefit. In the United States, surrogate end points that are reasonably likely to predict clinical benefit can be used as a basis for accelerated approval; treatments approved under this program must verify the clinical benefit in postmarketing trials. Additional analyses of the relationship between treatment effects on CR and PR and subsequent renal outcomes would inform the design of future clinical trials in primary MN.

Keywords: glomerular disease; membranous nephropathy; nephrotic syndrome; outcomes; surrogate outcomes.

Figure 1.

Relation between time-average proteinuria and the rate of renal function decline in MN, FSGS, and IgA nephropathy. Declines in renal function are associated with higher levels of sustained proteinuria in patients with MN (where a decline is observed at levels of sustained proteinuria >5 g/d) than in patients with FSGS (where a decline in renal function is observed with sustained proteinuria around 2–3 g/d) or patients with IgA nephropathy (where a decline in renal function is observed with sustained proteinuria >1 g/d). Thus, the severity of proteinuria alone does not fully explain the rate of loss of renal function, and other disease–specific factors likely play a role. Black circles, men; white circles, women. Reprinted from ref. , with permission.