Proteinuria Reduction as a Surrogate Endpoint in IgA Nephropathy Studies

A study sought to discern surrogate endpoints that could serve as robust predictors of treatment efficacy on long-term kidney outcomes in IgA nephropathy (IgAN). The results were published in the Clinical Journal of the American Society of Nephrology.

“Patients with decreased GFR at diagnosis of IgAN (e.g., eGFR<60 ml/min per 1.73 m²) are at higher risk of progression to ESKD. Although patients with severe kidney dysfunction (e.g., eGFR<30 ml/min per 1.73 m²) are at greatest risk of reaching ESKD, these patients have usually been excluded from clinical trials because of concern that the disease is too advanced to respond to immune-modulating therapy or that the risks of therapy may outweigh the potential benefits. In general, when selecting criteria for enrollment, it is important to consider patients for whom a drug may provide benefit based on its mechanism of action and targeted effect,” the researchers wrote.

In March 2016, the Kidney Health Initiative started a project to identify endpoints that could be used as a basis for IgAN therapy approval. To date, as the researchers noted, the most widely recognized and well-studied risk factor for progression to ESKD in patients with IgAN is proteinuria. Thus, a workgroup focused on whether there were sufficient data to support the use of proteinuria reduction as a surrogate endpoint for a treatment efficacy in end-stage kidney disease (ESKD) patients with IgAN.

At project initiation, the workgroup considered several candidate surrogate endpoints for clinical trials in IgAN. These endpoints included proteinuria, biopsy findings, and other urine and serum biomarkers that are under active investigation in IgAN. While small studies of repeat kidney biopsy specimens suggest that “active” lesions in IgAN may change with therapy, the correlation between short-term pathologic changes and long-term kidney survival is not well established, the researchers noted. Therefore, the workgroup sought to go beyond the available evidence to support the use of changes in histopathologic findings from repeat kidney biopsy specimens as a surrogate end point in registration trials in IgAN.

Several novel urine and serum biomarkers have been suggested to reflect progression of kidney disease in IgAN, including urinary chemokine CXCL1, monocyte chemoattractant protein-1 and EGF, serum galactose-deficient IgA, TNF receptors 1 and 2, and complement factor C3. However, current evidence is lacking with respect to changes in these biomarkers to track clinical measures of disease activity and/or response to therapy.

Analysis of data from 13 randomized, controlled trials showed an association between treatment effects on proteinuria and treatment effects on a composite of the time to the first occurrence of a doubling of serum creatinine level, ESKD, or death. The researchers wrote that these data “support the use of proteinuria reduction as a reasonably likely surrogate end point for a treatment’s effect on the loss of kidney function and progression to ESKD in future trials enrolling a similar population.”