Urinary Biomarkers and Kidney Injury in VA NEPHRON-D: Phenotyping Acute Kidney Injury in Clinical Trials

Abstract

Rationale & objective: Urinary biomarkers of injury, inflammation, and repair may help phenotype acute kidney injury (AKI) observed in clinical trials. We evaluated the differences in biomarkers between participants randomized to monotherapy or to combination renin-angiotensin-aldosterone system (RAAS) blockade in VA NEPHRON-D, where an increased proportion of observed AKI was acknowledged in the combination arm.

Study design: Longitudinal analysis.

Setting & participants: A substudy of the VA NEPHRON-D trial.

Predictor: Primary exposure was the treatment arm (combination [RAAS inhibitor] vs monotherapy). AKI is used as a stratifying variable.

Outcome: Urinary biomarkers, including albumin, EGF (epidermal growth factor), MCP-1 (monocyte chemoattractant protein-1), YKL-40 (chitinase 3-like protein 1), and KIM-1 (kidney injury molecule-1).

Analytical approach: Biomarkers measured at baseline and at 12 months in trial participants were compared between treatment groups and by AKI. AKI events occurring during hospitalization were predefined safety end points in the original trial. The results were included in a meta-analysis with other large chronic kidney disease trials to assess global trends in biomarker changes.

Results: In 707 participants followed for a median of 2.2 years, AKI incidence was higher in the combination (20.7%) versus the monotherapy group (12.7%; relative risk [RR], 1.64 [95% CI, 1.16-2.30]). Compared with the monotherapy arm, in the combination arm the urine biomarkers at 12 months were either unchanged (MCP-1: RR, -3% [95% CI, -13% to 9%], P_adj=0.8; KIM-1: RR, -10% [95% CI, -20% to 1%], P_adj=0.2; EGF, RR-7% [95% CI, -12% to-1%], P_adj=0.08) or lower (albuminuria: RR, -24% [95% CI, -37% to-8%], P_adj=0.02; YKL: RR, -40% to-44% [95% CI, -58% to-25%], P_adj<0.001). Pooled meta-analysis demonstrated reduced albuminuria in the intervention arm across 3 trials and similar trajectories in other biomarkers.

Limitations: Biomarker measurement was limited to 2 time points independent of AKI events.

Conclusions: Despite the increased risk of serum creatinine-defined AKI, combination RAAS inhibitor therapy was associated with unchanged or decreased urinary biomarkers at 12 months. This suggests a possible role for kidney biomarkers to further characterize kidney injury in clinical trials.

Plain-language summary: The VA NEPHRON-D trial investigated inhibition of the renin-angiotensin-aldosterone system (RAAS) hormonal axis on kidney outcomes in a large population of diabetic chronic kidney disease patients. The trial was stopped early due to increased events of serum creatinine-defined acute kidney injury in the combination therapy arm. Urine biomarkers can serve as an adjunct to serum creatinine in identifying kidney injury. We found that urinary biomarkers in the combination therapy group were not associated with a pattern of harm and damage to the kidney, despite the increased number of kidney injury events in that group. This suggests that serum creatinine alone may be insufficient for defining kidney injury and supports further exploration of how other biomarkers might improve identification of kidney injury in clinical trials.

Keywords: AKI; RAAS-I; albuminuria; biomarkers; creatinine.

Figure 1.

Comparison of 12-Months Biomarkers Between ACE-i/ARB Combination Therapy and Mono Therapy, Urine Creatinine Indexed Biomarker distributions are represented with boxplots with the inter-quartile range (IQR) plotted as a rectangle with median as the middle line, 25^th percentile as the lower horizontal line and 75^th percentile as the upper horizontal line. Whiskers extend to the farthest value within (25^th percentile −1.5*IQR) and (75^th percentile+1.5*IQR) with points outside the range plotted individually. Values for medians and 25^th and 75^th percentiles can be found in Supplemental Table 2. Urinary biomarkers are indexed to urine creatinine.

Figure 2.

Effect of Trial Therapies on Kidney Function and Urinary Biomarkers in Large Clinical Trials *Urinary biomarkers from NEPHRON-D at 12-months. ACCORD trial participants with urinary biomarkers at 24-months. SPRINT trial participants with urinary biomarkers at 12-months. The Ratio presented is the transformed least-square means (95% CI) from linear mixed models. Negative ratios indicate levels in the intervention arm were lower than the standard of care arm. The squares represent the mean value and error bars represent the 95% confidence interval. The error bars not crossing zero demonstrates statistical significance. Pooled estimates and heterogeneity estimates are shown.