MO256THE TREATMENT EFFECT OF RAS BLOCKADE ON PROTEINURIA IN IGA NEPHROPATHY PATIENTS AS A SURROGATE FOR RENAL EVENTS AND DECLINE IN EGFR: AN ANALYSIS OF RANDOMIZED CONTROLLED TRIALS
Authors: Mercer Alex , Carroll Kevin , Conley Leah , Barratt Jonathan 
Published: May 2021

Abstract

Background and Aims
Renin-Angiotensin System Blockade (RASB) is the cornerstone of standard-of-care in IgA nephropathy. Randomized controlled trials (RCTs) have shown the treatment benefit of RASB therapy on proteinuria and risk of renal failure. The objective of this study was to describe the relationships between the treatment effect of RASB on proteinuria and (i) risk of renal events, and (ii) decline in eGFR, as an endpoint proximal to renal failure. To this aim, trial level (TL) and simple weighted linear regression (SWR) analyses were conducted on RCTs identified through a systematic literature review, with RASB as the active intervention.

Methods
A systematic literature review of available peer-reviewed literature from 1990 to 2020 was performed applying the following inclusion criteria: RCT in patients with biopsy-proven IgAN, investigating the effects of RASB as an intervention, sample size &gt;25, measurement of proteinuria at baseline and at &gt;3 months. At least 1 renal event (defined as ≥50% decline in eGFR, CKD Stage 5, dialysis or transplantation) was required for the renal event analysis and similarly, at least 12 months follow-up was required for the decline in eGFR analysis. For the relationship between proteinuria and risk of renal events, 4 studies including 5 comparisons were identified, while 9 studies including 10 comparisons were identified for the analysis of proteinuria vs eGFR decline. Proteinuria change from baseline was calculated from the value closest to 6 months. If annualized change in eGFR was reported, these data were used, otherwise annualized change in eGFR was calculated per year of follow-up. Methods as described by Burzykoski & Buyse (2006) and Joffe & Greene (2008) were used for TL meta-regression analyses; the resulting meta-regression line was displayed with an 80% credible interval band (CB). Given the assumptions made in this analysis, a SWR analysis was also performed; to compensate for potential underestimation of error associated with the regression line, a 99.9% CB was applied in the SWR analysis.

Results
For RASB treatment effects on renal events, a statistical association was found with treatment effects on proteinuria with a TL slope estimate = 15.30 95% CI (0.57, 38.79), R2 = 0.88 95% CI (0.22, 1.00); using the lower CI of 0.75 for the estimated slope, a 30% treatment effect on proteinuria would be expected to result in at least a 25% reduction in the risk of renal events. As individual subject level data were not available, the correlation between errors on treatment effects for proteinuria and treatment effects for renal events were unknown, resulting in a wide CB on the meta-regression line and a wide CI for the slope estimate. The SWR approach is not hampered by lack of subject level data and gave a slope estimate of 3.5 95% CI (2.1, 5.0) with R2 = 0.97, such that a 30% treatment effect on proteinuria would be expected to result in at least a 64% reduction in the risk of renal events. For treatment effects on annualized eGFR versus effects on proteinuria, the TL slope estimate was -5.1 95% CI (-30.2, 35.0), R2 = 0.89 95% CI (0.15, 1.00); the corresponding SWR slope estimate was -7.6, 95% CI (-12.3, -2.8) with R2 = 0.71. A 30% treatment effect on proteinuria would be expected to result in a 2.6 mL/min (TL analysis) to 3.9 mL/min slower decline (SWR analysis) in annualized eGFR.

Conclusion
In patients with IgAN, associations were seen between treatment effects of RASB on proteinuria and on the clinically relevant endpoints of renal events and annualized change in eGFR. Consistent with TL analyses of RCTs across a variety of mechanisms of actions, these data, specific to RASB, contribute to the growing evidence base supporting the use of proteinuria as a valid surrogate endpoint in IgAN.