Blood Kidney Injury Molecule-1 Is a Biomarker of Acute and Chronic Kidney Injury and Predicts Progression to ESRD in Type I Diabetes

Abstract

Currently, no blood biomarker that specifically indicates injury to the proximal tubule of the kidney has been identified. Kidney injury molecule-1 (KIM-1) is highly upregulated in proximal tubular cells following kidney injury. The ectodomain of KIM-1 is shed into the lumen, and serves as a urinary biomarker of kidney injury. We report that shed KIM-1 also serves as a blood biomarker of kidney injury. Sensitive assays to measure plasma and serum KIM-1 in mice, rats, and humans were developed and validated in the current study. Plasma KIM-1 levels increased with increasing periods of ischemia (10, 20, or 30 minutes) in mice, as early as 3 hours after reperfusion; after unilateral ureteral obstruction (day 7) in mice; and after gentamicin treatment (50 or 200 mg/kg for 10 days) in rats. In humans, plasma KIM-1 levels were higher in patients with AKI than in healthy controls or post-cardiac surgery patients without AKI (area under the curve, 0.96). In patients undergoing cardiopulmonary bypass, plasma KIM-1 levels increased within 2 days after surgery only in patients who developed AKI (P,0.01). Blood KIM-1 levels were also elevated in patients with CKD of varous etiologies. In a cohort of patients with type 1 diabetes and proteinuria, serum KIM-1 level at baseline strongly predicted rate of eGFR loss and risk of ESRD during 5-15 years of follow-up, after adjustment for baseline urinary albuminto-creatinine ratio, eGFR, and Hb1Ac. These results identify KIM-1 as a blood biomarker that specifically reflects acute and chronic kidney injury.

ABT‐719 for the Prevention of Acute Kidney Injury in Patients Undergoing High‐Risk Cardiac Surgery: A Randomized Phase 2b Clinical Trial

“…Biomarkers of AKI, such as NGAL, KIM‐1, and IL‐18, may be potentially beneficial for early detection, diagnosis, and prognosis of AKI after cardiac surgery 35, 36. However, in our study and others, these markers are commonly elevated at baseline, and thus a relatively large change from baseline (doubling or tripling) would be needed to detect AKI in this setting 37, 38, 39. In our study, the results in functional and novel injury markers were concordant in demonstrating no benefit of ABT‐719 treatment.…”

Serum levels of 12 renal function and injury markers in patients with glomerulonephritis

“…The mean levels of KIM-1 (65.9 pg/ml) and β 2 M (1.124 µg/ml) in our study were comparable to those described for healthy people in other studies, and were much lower than those in patients with kidney diseases. [11][12][13][14][15] As for osteopontin, its mean level in our study was 614.2 ng/ml, while in the literature, its levels in patients with chronic kidney disease were reported to be, depending on the study, in the range between 1.71 and 53 ng/ml. [16][17][18][19][20] Of note, cystatin C concentrations were in the range between 0.4 and 2.7 mg/l in our study, which is consistent with existing literature data.…”

Progression after AKI

“…For example, KIM-1 has been shown to be a predictor of both AKI and progression of CKD in patients with type 1 diabetes. 49 Increases in serum levels of FGF23 and parathyroid hormone 50 or decreased levels of Klotho 51 occur in response to increased severity of CKD. Biomarkers, such as urinary albumin, neutrophil gelatinaseassociated lipocalin, KIM-1, IL-18, L-FABP MCP-1, nephrin, podocalyxin, and podocin, are markers of tubular or glomerular damage.…”

“…Newer biomarkers combined with functional markers hold promise to identify the phase, nature, and severity of injury. 7 Although currently, there are only a few studies that have assessed the prognostic value of novel biomarkers, except for perhaps, recently, blood KIM-1 levels in patients with type 1 diabetes, 49 the sequential assessment of new markers and functional parameters could characterize the progression or resolution of injury more precisely than is possible at present. Specific biomarkers for fibrosis are also under development, and these coupled with novel imaging techniques will likely enhance capabilities for targeted interventions.…”