Associations of urinary levels of kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) with kidney function decline in the Multi-Ethnic Study of Atherosclerosis (MESA)

Abstract

Background: Whether elevations in levels of urinary biomarkers of tubular injury (urine neutrophil gelatinase-associated lipocalin [NGAL] and kidney injury molecule 1 [KIM-1]) are associated with future risk of kidney disease has not been investigated.

Study design: 1:1 nested case-control study.

Setting & participants: 686 participants in the Multi-Ethnic Study of Atherosclerosis (MESA).

Predictor: NGAL and KIM-1 were measured at baseline, expressed as log-transformed continuous variables, and categorized into deciles.

Outcomes: Kidney function was estimated by cystatin C level using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. Incident CKD stage 3 was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) and an eGFR decrease >1 mL/min/1.73 m(2) per year, and rapid kidney function decrease was defined as decrease ≥3 mL/min/1.73 m(2) per year.

Measurements: Cases were defined as persons with eGFR >60 mL/min/1.73 m(2) who subsequently developed incident CKD stage 3 and/or had rapid kidney function decrease by the MESA year-5 visit. Controls were matched for age, sex, race, diabetes, and baseline eGFR. We adjusted for age, hypertension, and presence of albuminuria (albumin-creatinine ratio ≥30 mg/g).

Results: Of 343 cases, 145 had incident CKD stage 3, 141 had rapid kidney function decrease, and 57 had both. Mean eGFR for controls was 81 ± 10 mL/min/1.73 m(2) at baseline and 80 ± 10 mL/min/1.73 m(2) at follow-up compared with 82 ± 13 and 58 ± 10 mL/min/1.73 m(2) for cases. Each doubling of KIM-1 level (in picograms per milliliter) was associated with an OR of 1.15 (95% CI, 1.02-1.29) for incident CKD stage 3 and/or rapid kidney function decrease. Compared with the lowest 90%, the highest decile of KIM-1 level was associated with an OR of 2.02 (95% CI, 1.15-3.56) for the outcome; these associations were independent of albuminuria. NGAL levels (in nanograms per milliliter) were not associated with incident CKD stage 3 and/or rapid kidney function decrease (OR, 1.04; 95% CI, 0.99-1.10). Results were similar when KIM-1 and NGAL levels were standardized for urine creatinine.

Limitations: The case-control design limits the ability to account for persons who died or were not available for follow-up.

Conclusions: Urinary KIM-1 level is associated with future risk of kidney disease independent of albuminuria. Urinary biomarkers of tubular injury are a promising tool for identifying persons at risk of CKD.

Figure 1

Proportion of Persons with Incident CKD Stage 3 and/or Rapid Kidney Function Decline by Decile of KIM-1 or NGAL. Proportion of cases in each decile category is represented. By design, the total proportion of cases was 50% in this nested case-control study. Upper panel, KIM-1: *p=0.04 for 8^th decile and p=0.004 for 10^th decile when compared to the 1^st decile. Lower panel, NGAL: *p <0.05 when compared to the 1^st decile

Figure 1

Proportion of Persons with Incident CKD Stage 3 and/or Rapid Kidney Function Decline by Decile of KIM-1 or NGAL. Proportion of cases in each decile category is represented. By design, the total proportion of cases was 50% in this nested case-control study. Upper panel, KIM-1: *p=0.04 for 8^th decile and p=0.004 for 10^th decile when compared to the 1^st decile. Lower panel, NGAL: *p <0.05 when compared to the 1^st decile