Urinary Netrin-1 Research Articles

Netrin-1: A Novel Universal Biomarker of Human Kidney Injury

Currently available diagnostic markers representing kidney injury or function such as serum creatinine and blood urea nitrogen are insensitive and often increased late in the disease process. Netrin-1 protein, a laminin-related secreted molecule, is minimally or not expressed in tubular epithelial cells of normal kidneys. However, it is highly expressed in injured kidneys. Netrin-1 protein has been shown to be detected in urine from mice with acute kidney injury. The current study was carried out to evaluate whether netrin-1 is also induced in human acute kidney injury (AKI) and can serve as a urinary biomarker of the condition. We analyzed netrin-1 levels by sandwich enzyme-linked immunosorbent assay in urine samples from 10 healthy controls, 22 recipients of a renal allograft, 11 patients with ischemic AKI, 13 with AKI associated with sepsis, 9 with radiocontrast-induced AKI, and 8 with drug-induced AKI. Urinary netrin-1 levels normalized for urinary creatinine were significantly higher in all subject groups. The highest values were observed in patients with sepsis and in transplant patients immediately postoperatively. The level of NGAL was similarly increased in transplant patients. In conclusion, urinary netrin-1 levels are increased in patients with various forms of AKI/ATN and may serve as a universal biomarker for AKI.

Urinary Netrin-1 Is an Early Predictive Biomarker of Acute Kidney Injury after Cardiac Surgery

Netrin-1, a laminin-related axon guidance molecule, is highly induced and excreted in the urine after acute kidney injury (AKI) in animals. Here, we determined the utility of urinary netrin-1 levels to predict AKI in humans undergoing cardiopulmonary bypass (CPB). Serial urine samples were analyzed by enzyme-linked immunosorbent assay for netrin-1 in 26 patients who developed AKI (defined as a 50% or greater increase in serum creatinine after CPB) and 34 controls (patients who did not develop AKI after CPB). Using serum creatinine, AKI was detected on average only 48 hours after CPB. In contrast, urine netrin-1 increased at 2 hours after CPB, peaked at 6 hours (2462 +/- 370 pg/mg creatinine), and remained elevated up to 48 hours after CPB. The predictive power of netrin-1 as demonstrated by area under the receiver-operating characteristics curve for diagnosis of AKI at 2, 6, and 12 hours after CPB was 0.74, 0.86, and 0.89, respectively. The 6-hour urine netrin-1 measurement strongly correlated with duration and severity of AKI, as well as length of hospital stay (all P < 0.05). Adjusting for CPB time, the 6-hour netrin-1 remained a powerful independent predictor of AKI, with an odds ratio of 1.20 (95% confidence interval: 1.08 to 1.41; P = 0.006). Our results suggest that netrin-1 is an early, predictive biomarker of AKI after CPB and may allow for the reliable early diagnosis and prognosis of AKI after CPB, before the rise in serum creatinine.

Netrin-1: a potential universal biomarker for acute kidney injury

acute kidney injury (AKI) is commonly associated with high mortality and morbidity rates, which strongly depend on the time of the diagnosis to allow therapeutic interventions. Recent studies clearly indicate that routine assessments of kidney function based on serum creatinine and blood urea

Netrin-1 and kidney injury. II. Netrin-1 is an early biomarker of acute kidney injury

Acute kidney injury is an important complication in hospitalized patients often diagnosed late and associated with high mortality and morbidity. Although biomarkers for nephrotoxicity are available, they often lack sensitivity and specificity for detecting tubular injury. Netrin-1 is a laminin-like molecule highly expressed in many organs including kidney. To determine the value of netrin-1 as a biomarker of renal injury, we analyzed its urinary excretion following ischemia-reperfusion-, cisplatin-, folic acid-, and endotoxin-induced renal injury in mice. Urinary netrin-1 levels increased markedly within 3 h of ischemia-reperfusion (40 +/- 14-fold, P < 0.01 vs. baseline), reached a peak level at 6 h, and decreased thereafter, returning to near baseline by 72 h. Serum creatinine significantly increased only after 24 h of reperfusion. Similarly, in cisplatin-, folic acid-, and lipopolysaccharide-treated mice, urine netrin-1 excretion increased as early as 1 h and reached a peak level at 6 h after injection. However, serum creatinine was raised significantly after 6, 24, and 72 h after folic acid, lipopolysaccharide, and cisplatin administration, respectively. NGAL excretion in folic acid- and lipopolysaccharide-treated mice urine samples could only be detected by 24 h after drug administration. Furthermore, urinary netrin-1 excretion increased dramatically in 13 acute renal failure patients, whereas none was detected in 6 healthy volunteer urine samples. Immunohistochemical localization showed that netrin-1 is highly expressed in tubular epithelial cells in transplanted human kidney. We conclude that urinary netrin-1 is a promising early biomarker of renal injury.