Association of Urine Biomarkers of Kidney Tubular Injury and Dysfunction With Frailty Index and Cognitive Function in Persons with CKD in SPRINT.

RATIONALE AND OBJECTIVE: The associations of glomerular markers of kidney disease (eGFR and albuminuria) with frailty and cognition are well established. However, the relationship of kidney tubular injury and dysfunction with frailty and cognition are unknown.

STUDY DESIGN: Observational cross-sectional study; SETTING: & Participants: 2,253 participants with eGFR < 60 ml/min/1.73m2 in the Systolic Blood Pressure Intervention Trial EXPOSURES: Eight urine biomarkers: Interleukin-18 [IL-18, pg/mL], kidney injury molecule-1 [KIM-1, pg/mL], neutrophil gelatinase-associated lipocalin [NGAL, ng/mL], chitinase-3-like protein-1 [YKL-40, pg/mL], monocyte chemoattractant protein-1 [MCP-1, pg/mL], α-1 microglobulin [α1M mg/g], beta-2 microglobulin [β2M ng/mL], and uromodulin [Umod ng/mL].

OUTCOMES: Frailty was measured using a previously validated frailty index (FI), categorized as fit (FI < 0.10), less fit (0.10 < FI < 0.21) and frail (FI > 0.21). Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA).

ANALYTICAL APPROACH: Associations between kidney tubule biomarkers with categorical FI were evaluated using multinomial logistic regression with the fit group as the reference. Cognitive function was evaluated using linear regression. Models were adjusted for demographic, behavioral and clinical variables including eGFR and urine albumin.

RESULTS: Three of the 8 urine biomarkers of tubule injury and dysfunction were independently associated with FI. Each two-fold higher level of urine KIM-1, a marker of tubule injury, was associated with a 1.22 [95% CI: 1.01, 1.49) fold greater odds of being in frail group. MCP-1, a marker of tubulo-interstitial fibrosis, was associated with a 1.30 [95% CI 1.04, 1.64] greater odds of being in frail group, and α1M, a marker of tubule re-absorptive capacity, was associated with a 1.48 [95% CI 1.11, 1.96] greater odds. These associations were independent of confounders including eGFR and urine albumin, and were stronger than those of urine albumin with frailty index (1.15 [95% CI 0.99, 1.34]). Higher urine β2M, another marker of tubule reabsorptive capacity, was associated with worse cognitive scores at baseline (β: -0.09; 95% CI -0.17, -0.01). Urine albumin was not associated with cognitive function.

LIMITATIONS: Cross-sectional design, FI may not be generalizable in other populations.

CONCLUSIONS: Urine biomarkers of tubule injury, fibrosis and proximal tubule reabsorptive capacity are variably associated with FI and worse cognition, independent of glomerular markers of kidney health. Future studies are needed to validate these results among other patient populations.