Association Between Surrogate Endpoints and Clinical Outcomes in Immunoglobulin A Nephropathy: A Systematic Literature Review

Introduction

At least 50% of patients with immunoglobulin A nephropathy (IgAN) reach kidney failure within 12 years of diagnosis. Delayed progression to kidney failure remains the gold standard treatment endpoint in IgAN, but the prolonged time course limits feasibility as a primary endpoint in clinical trials. Earlier measurable endpoints may serve as surrogate endpoints for clinically important long-term kidney outcomes. Regulatory bodies recognize surrogate endpoints like proteinuria reduction. However, other stakeholders, like payers, health technology assessment agencies, and policymakers, may require additional evidence. This literature review assessed data on associations between surrogate endpoints, including proteinuria and estimated glomerular filtration rate (eGFR), and long-term kidney outcomes in IgAN.

Methods

A systematic search of IgAN studies conducted in any country was performed in MEDLINE, Embase, and CENTRAL via Ovid (January 1, 2006–September 1, 2023), supplemented by conference abstracts (2019–2023) and relevant literature reviews and meta-analyses. Eligible studies evaluated the association of surrogate endpoints of kidney disease progression with long-term outcomes in IgAN.

Results

Among 1833 unique citations screened, 23 publications met inclusion criteria. Proteinuria was associated with progression to kidney failure (p < 0.001–0.021; n = 5 studies), reaching a composite kidney event (p < 0.001–0.02; n = 6), doubling of serum creatinine (p = 0.009; n = 1), and long-term eGFR decline (p < 0.001–0.910; n = 5); absolute eGFR at months 3 and 6 was associated with composite kidney events (p ≤ 0.001–0.03; n = 2); and eGFR slope was associated with kidney failure (p < 0.001; n = 1) and doubling of serum creatinine (p < 0.001–0.007; n = 1).

Conclusion

The literature supports associations of proteinuria and eGFR with long-term clinical outcomes in IgAN across multiple studies and geographic regions. Despite regional variability in standard of care, which introduces heterogeneity in the strength of associations, the consistency of findings across regions supports the utility of proteinuria and eGFR as surrogate endpoints for clinically important long-term kidney outcomes.