The SPRINT trial suggests that markers of tubule cell function in the urine associate with risk of subsequent acute kidney injury while injury markers elevate after the injury

Abstract

Urine markers can quantify tubular function including reabsorption (α-1 microglobulin [α1m]) and β-2-microglobulin [β2m]) and protein synthesis (uromodulin). Individuals with tubular dysfunction may be less able to compensate to insults than those without, despite similar estimated glomerular filtration rate (eGFR) and albuminuria. Among Systolic Blood Pressure Intervention Trial (SPRINT) participants with an eGFR under 60 ml/min/1.73m², we measured urine markers of tubular function and injury (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule-1 [KIM-1], interleukin-18 [IL-18], monocyte chemoattractant protein-1, and chitinase-3-like protein [YKL-40]) at baseline. Cox models evaluated associations with subsequent acute kidney injury (AKI) risk, adjusting for clinical risk factors, baseline eGFR and albuminuria, and the tubular function and injury markers. In a random subset, we remeasured biomarkers after four years, and compared changes in biomarkers in those with and without intervening AKI. Among 2351 participants, 184 experienced AKI during 3.8 years mean follow-up. Lower uromodulin (hazard ratio per two-fold higher (0.68, 95% confidence interval [0.56, 0.83]) and higher α1m (1.20; [1.01, 1.44]) were associated with subsequent AKI, independent of eGFR and albuminuria. None of the five injury markers were associated with eventual AKI. In the random subset of 947 patients with repeated measurements, the 59 patients with intervening AKI versus without had longitudinal increases in urine NGAL, IL-19, and YKL-40 and only 1 marker of tubule function (α1m). Thus, joint evaluation of tubule function and injury provided novel insights to factors predisposing to AKI, and responses to kidney injury.

Keywords: acute kidney injury; alpha-1 microglobulin; beta-2 microglobulin; chitinase-3-like protein; interleukin-18; kidney injury molecule-1; monocyte chemoattractant protein-1; neutrophil gelatinase-associated lipocalin; uromodulin.

FIGURE 1. Baseline levels urine biomarkers of kidney tubular function, injury, inflammation and repair and relative hazard of AKI among SPRINT participants with baseline CKD (n=2531).

Squares denote the adjusted hazard ratio of AKI per doubling or per quartile higher of baseline urine biomarker concentration while the brackets denote the 95% confidence intervals. Model adjusted for age, gender, race, randomization arm, urine creatinine, baseline eGFR and urine albumin, baseline systolic and diastolic blood pressures, prevalent cardiovascular disease, and baseline use of ACE-inhibitors, angiotensin receptor blockers or diuretics. (“Model 2”) Abbreviations: Q1, quartile 1; Q2, quartile 2; Q3, quartile 3; Q4, quartile 4; α1m, alpha-1-microglobulin; β2m, beta-2-microglobulin; UMOD, uromodulin; KIM-1, kidney injury molecule-1; NGAL, neutrophil gelatinase-associated lipocalin; IL-18, interleukin-18; MCP-1, monocyte chemoattractant protein-1; YKL-40, chitinase-3-like protein

FIGURE 2a

Change in tubule function markers from baseline to year four among a random sample of 947 individuals with CKD, stratified by those with intervening AKI (N=59) vs. all others (N=888)

FIGURE 2b

Change in tubule injury markers from baseline to year four among a random sample of 947 individuals with CKD, stratified by those with intervening AKI (N=59) vs. all others (N=888)