Is Chronic Dialysis the Right Hard Renal End Point To Evaluate Renoprotective Drug Effects?

Abstract

Background and objectives: RRT and doubling of serum creatinine are considered the objective hard end points in nephrology intervention trials. Because both are assumed to reflect changes in the filtration capacity of the kidney, drug effects, if present, are attributed to kidney protection. However, decisions to start RRT are not only on the basis of filtration capacity of the kidney, but also on other factors. We therefore compared the time to RRT with the time to a fixed eGFR threshold and assessed the effect of the renoprotective drug irbesartan on both components.

Design, setting, participants, & measurements: Post hoc analysis of two clinical trials, the Irbesartan Diabetic Nephropathy Trial (IDNT) and Reduction of End points in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan Trial, in patients with type 2 diabetes and nephropathy. The time to a predefined eGFR level of 11 ml/min per 1.73 m² (eGFR₁₁), calculated by within-patient linear regression, was compared with the time to RRT or sustained serum creatinine ≥6 mg/dl.

Results: A large difference was observed in the median time to RRT (779 days) compared with eGFR₁₁ (678 days; P=0.01). We also observed a large variation in the difference between the time to RRT and eGFR₁₁. In IDNT, the hazard ratio for the effect of irbesartan on the serum creatinine ≥6.0 mg/dl end point was 0.60 (95% confidence interval, 0.39 to 0.91; P=0.02), whereas it was smaller for the RRT end point (hazard ratio, 0.78; 95% confidence interval, 0.58 to 1.07; P=0.12).

Conclusions: This study shows a difference in the time to RRT and a fixed eGFR threshold, and shows that the effect of an angiotensin receptor blocker on a filtration-based end point versus RRT varies. This implies that evaluating renoprotective effects of drugs with a combined RRT and doubling of serum creatinine end point may result in evaluating other effects beyond renoprotection alone. Future trials should consider registering all parameters that lead to RRT decisions.

Keywords: Angiotensin II; Biphenyl Compounds; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Linear Models; Losartan; Renal Replacement Therapy; Tetrazoles; creatinine; glomerular filtration rate; irbesartan; kidney; nephrology; renal dialysis.

Graphical abstract

Figure 1.

Examples of two patients who initiated RRT approximately 1 year before reaching eGFR₁₁ (A) or initiated RRT 1 year after reaching eGFR₁₁ (B). The purple dotted line indicates the initiation of dialysis, the vertical dotted blue line indicates the time point when eGFR₁₁ was reached, and the vertical straight red line indicates the censor date of the individual. eGFR₁₁, time to a predefined eGFR level of 11 ml/min per 1.73 m².

Figure 2.

Large variability between the time to reach RRT and eGFR₁₁. The solid vertical line at 0 represents the time to RRT (779 days). The white bars show patients who reached eGFR₁₁ before RRT and gray bars show patients who reached eGFR₁₁ after RRT. (A) Time to eGFR₁₁ calculated on the basis of the individual eGFR slope. (B) Time to eGFR₁₁ on the basis of the time to first confirmed eGFR measurement of 11 ml/min per 1.73 m². During patient follow-up, 228 patients reached eGFR₁₁ but not RRT. A total of 18 patients had an estimated time to eGFR₁₁ beyond the range of the histogram. The time interval extended to 1 year beyond the histogram for eight patients, 1 and 2 years for three patients, 2 and 4 years for two patients, and beyond 4 years for five patients. eGFR₁₁, time to a predefined eGFR level of 11 ml/min per 1.73 m².