Association of urinary KIM-1, L-FABP, NAG and NGAL with incident end-stage renal disease and mortality in American Indians with type 2 diabetes mellitus

Abstract

Aims/hypothesis Kidney injury molecule 1 (KIM-1), liver fatty acid-binding protein (L-FABP), N-acetyl-β-D-glucosaminidase (NAG) and neutrophil gelatinase-associated lipocalin (NGAL) are urinary biomarkers of renal tubular injury. We examined their association with incident end-stage renal disease (ESRD) and all-cause mortality in American Indians with type 2 diabetes. Methods Biomarker concentrations were measured in baseline urine samples in 260 Pima Indians who were followed for a median of 14 years. HRs were reported per SD of creatinine (Cr)-normalised log-transformed KIM-1, NAG and NGAL, and for three categories of L-FABP. Results During follow-up, 74 participants developed ESRD and 101 died. Median concentrations of KIM-1/Cr, NAG/Cr and NGAL/Cr and the proportion of detectable L-FABP were highest in those with macroalbuminuria (p < 0.001 for KIM-1/Cr, NAG/Cr and L-FABP; p = 0.006 for NGAL/Cr). After multivariable adjustment, NGAL/Cr was positively associated with ESRD (HR 1.59, 95% CI 1.20, 2.11) and mortality (HR 1.39, 95% CI 1.06, 1.82); L-FABP/Cr was inversely associated with ESRD (HR [for highest vs lowest tertile] 0.40, 95% CI 0.19, 0.83). Addition of NGAL/Cr to models that included albuminuria and glomerular filtration rate increased the c-statistic for predicting ESRD from 0.828 to 0.833 (p = 0.001) and for death from 0.710 to 0.722 (p = 0.018). Addition of L-FABP/Cr increased the c-statistic for ESRD from 0.828 to 0.832 (p = 0.042). Conclusions/interpretation In Pima Indians with type 2 diabetes, urinary concentrations of NGAL and L-FABP are associated with important health outcomes, but they are unlikely to add to risk prediction with standard markers in a clinically meaningful way given the small increase in the c-statistic.

Urinary Biomarkers and Risk of ESRD in the Atherosclerosis Risk in Communities Study

“…For example, earlier work in the ARIC Study showed that urinary NGAL but not KIM-1 was associated with higher risk of stage 3 CKD (6), whereas in the Multi-Ethnic Study of Atherosclerosis, higher urinary KIM-1 but not NGAL was associated with increased incident stage 3 CKD and rapid eGFR decline (5). Similar to the prior study in the ARIC Study, in Pima Indians with type 2 diabetes, NGAL/Cr but not KIM-1/Cr was associated with increased ESRD risk over 13.5 years median follow-up (15). In the Chronic Renal Insufficiency Cohort (CRIC), higher absolute NGAL levels were associated with a higher risk of progressive CKD, defined as incident ESRD or halving of eGFR; L-FABP, NAG, and KIM-1 were not measured in that report (8).…”

“…Urinary biomarkers were indexed to urinary creatinine in our primary analyses for consistency with other analyses of urinary biomarkers in the CKD Biomarkers Consortium (15). KIM-1 indexed to creatinine (KIM-1/Cr), NAG/Cr, and NGAL/Cr were evaluated categorically as quartiles and continuously with a log 10 transformation to account for their skewed distributions.…”

Urinary biomarkers are associated with incident cardiovascular disease, all-cause mortality and deterioration of kidney function in type 2 diabetic patients with microalbuminuria

“…In a cross-sectional study, we previously found urinary adiponectin excretion to be positively related to albuminuria in type 1 diabetes [9]. Moreover, prospective studies have shown that high urinary adiponectin is associated with the development of end-stage renal disease [10,11]. The association between these urinary markers, incident CVD and all-cause mortality, when adjusted for levels of Nterminal pro-brain natriuretic peptide (NT-proBNP) and the coronary artery calcium (CAC) score is, however, unknown.…”

“…1. Based on their graphical distribution and a significant result in the ShapiroWilk test (p ≤ 0.001; indicating non-normal distribution), both biomarkers were log-transformed using log 10 .…”

Novel Biomarkers for Early Diagnosis and Progression of Diabetic Nephropathy

“…All the data mentioned above indicated that tubular damage is common at the early stage of type 2 diabetic patients and urinary NGAL, KIM-1 and NAG could be early promising biomarkers for renal impairment in DN patients. A recent study showed that urinary KIM-1, NAG and NGAL were not only urinary biomarkers of renal tubular injury, but also showed that median concentrations of KIM-1/Cr, NAG/Cr and NGAL/Cr were highest in diabetic patients with macroalbuminuria and NGAL/Cr was positively associated with ESRD and mortality (Fufaa et al 2014). …”