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. J Am Soc Nephrol 26: 2930-2937, 2015. doi: 10.1681 Primary membranous nephropathy (MN) is an important cause of nephrotic syndrome in adults, and it is associated with significant morbidity, including the progressive loss of renal function, leading to ESRD.Primary MN affects patients of all ages and races, but it affects men more commonly than women and adults more commonly than children, with a peak incidence occurring during the fourth and fifth decades of life; 70%-80% of patients with MN present with nephrotic syndrome (proteinuria $3.5 g/24 h per 1.73 m 2 , hypoalbuminemia, hyperlipidemia, and edema). 1,2 The remaining 20%-30% of patients present with subnephrotic levels of proteinuria (,3.5 g/24 h) and are usually asymptomatic. 3,4 Primary MN has a variable course ranging from spontaneous remission to progressive loss of GFR over several years. Studies of the natural course (without immunotherapy) of idiopathic MN reveal that spontaneous remissions occur in approximately one third of patients, most commonly within the first 2 years of diagnosis. [5][6][7][8][9] Although patients who attain a spontaneous remission typically have a good long-term prognosis, patients with heavy and persistent proteinuria are at high risk of progressive loss of renal function, leading to ESRD. In the absence of remission of proteinuria to at least subnephrotic levels, ESRD occurs in about 25% of patients by 8 years and 50% of patients by 10-15 years. 9 Given the extended time frame for progression to ESRD, there has been great interest in identifying an earlier end point that could be used in clinical trials to establish the efficacy of therapies for patients with primary MN who are at high risk of developing ESRD. In April...

Clinical Predictors of Response to Prednisone Plus Cyclophosphamide in Patients with Idiopathic Membranous Nephropathy

“…Although patients with iMN experience varying history, remission of proteinuria, (including both of CR and PR), whether spontaneous or induced by immunosuppressive treatment, is associated with favorable outcomes for these patients [1,5,7,10,20] . In iMN patients with remission, the slope of decline in creatinine clearance for those who experienced a CR was better than for those who attained a PR [20] .…”

“…The result was similar to those of previous studies, where the relapse rates ranged from 8.8 to 28% [22,[24][25][26] . However, few studies have focused on the factors associated with relapses in CP treatment [10] . In this study, a PR versus CR increased the probability of relapses by 21.521 folds (p < 0.001).…”

“…Recently, an article from the US Food and Drug Administration discusses an establishment of proteinuria reduction as surrogate end points for a treatment effect on ESRD prevention in patients with primary MN at high risk of progression [10] . Long-term renal outcomes are favorable in patients who have achieved remission after treatment of immunosuppressive therapy [11][12][13] .…”

Drug discovery in focal and segmental glomerulosclerosis

“…Secondly, dialysis and transplantation remain a lucrative therapeutic alternative to preventive or curative strategies in kidney diseases, thus decreasing the attractiveness of drug development. Finally, the lack of alternative, regulatory acceptable outcome measures 4–6 as well as methods for better stratifying patients on their risk profile has discouraged industry to invest in drug development and requires further studies. Alternative biomarkers are being explored, for instance the measurement of podocyturia and urinary podocyte mRNA, which maybe especially relevant in FSGS where damage to the podocyte appears to be a key determinant in the disease pathogenesis.…”

Glomerular Diseases: Registries and Clinical Trials

“…Histopathology alone does not adequately predict the heterogeneous natural history or response to therapy for individuals within a given glomerular disease category. There are difficulties in identifying appropriate druggable targets and clinically useful biomarkers that could serve as indicators of disease activity or surrogate end points in primary glomerular disease (7)(8)(9). One promising target for the treatment of membranous nephropathy (MN) is the phospholipase A2 receptor, and circulating levels may also be a marker of disease activity (10).…”