Relationship of proximal tubular injury to chronic kidney disease as assessed by urinary kidney injury molecule-1 in five cohort studies

Abstract

Background: The primary biomarkers used to define CKD are serum creatinine and albuminuria. These biomarkers have directed focus on the filtration and barrier functions of the kidney glomerulus even though albuminuria results from tubule dysfunction as well. Given that proximal tubules make up ∼90% of kidney cortical mass, we evaluated whether a sensitive and specific marker of proximal tubule injury, urinary kidney injury molecule-1 (KIM-1), is elevated in individuals with CKD or with risk factors for CKD.

Methods: We measured urinary KIM-1 in participants of five cohort studies from the USA and Sweden. Participants had a wide range of kidney function and were racially and ethnically diverse. Multivariable linear regression models were used to test the association of urinary KIM-1 with demographic, clinical and laboratory values.

Results: In pooled, multivariable-adjusted analyses, log-transformed, creatinine-normalized urinary KIM-1 levels were higher in those with lower eGFR {β = -0.03 per 10 mL/min/1.73 m(2) [95% confidence interval (CI) -0.05 to -0.02]} and greater albuminuria [β = 0.16 per unit of log albumin:creatinine ratio (95% CI 0.15-0.17)]. Urinary KIM-1 levels were higher in current smokers, lower in blacks than nonblacks and lower in users versus nonusers of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

Conclusion: Proximal tubule injury appears to be an integral and measurable element of multiple stages of CKD.

Keywords: KIM-1; albuminuria; chronic kidney disease.

FIGURE 1:

Median (10th–90th percentiles) levels of urinary KIM-1 in the five cohorts according to albuminuria [albumin:creatinine ratio (ACR)] and estimated glomerular filtration rate (eGFR). Urinary KIM-1 is reported as pg/mg, albuminuria as mg/gm and eGFR as mL/min/1.73 m². Individual cells are shaded green to red based on median urinary KIM-1 levels to facilitate qualitative comparisons.

FIGURE 2:

(A) Scatterplot of urinary ACR and KIM-1/creatinine in the Chronic Renal Insufficiency Cohort (CRIC) study. The lowest value reported for ACR was 0.05 mg/g. (B) Scatterplot of urinary ACR and KIM-1/creatinine in four cohort studies. The lowest ACR value reported in the ULSAM cohort was 1.77 mg/g. ° Atherosclerosis Risk in Communities (ARIC); * Pima Indian cohort (PIMA); Δ Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS); • Uppsala Longitudinal Study of Adult Men (ULSAM). ACR, albumin/creatinine ratio; cr, creatinine; KIM-1, kidney injury molecule-1.

FIGURE 3:

(A) Scatterplot of urinary eGFR and KIM-1/creatinine in the Chronic Renal Insufficiency Cohort (CRIC) study. (B) Scatterplot of urinary ACR and KIM-1/creatinine in four cohort studies. ° Atherosclerosis Risk in Communities (ARIC); * Pima Indian cohort (PIMA); Δ Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS); • Uppsala Longitudinal Study of Adult Men (ULSAM). cr, creatinine; eGFR, estimated glomerular filatration rate; KIM-1, kidney injury molecule-1.