MO275: A Biomarker of Acute Kidney Injury from Proven Renal Origin

Abstract

Abstract BACKGROUND AND AIMS Acute kidney injury (AKI) is a threatening, multi-aetiological syndrome encompassing a variety of forms and damage patterns. AKI lacks sufficiently specific diagnostic tools to evaluate the distinct combination of pathophysiological events underlying each case, which limits personalized and optimized handling. Therefore, a pathophysiological diagnosis based on new urinary biomarkers is sought for practical (readiness and non-invasiveness) and conceptual reasons, as the urine is a direct product of the kidneys. However, biomarkers found in the urine may also have extra-renal origin, thus conveying pathophysiological information from other organs or tissues. In fact, very few biomarkers of AKI have been proven to have a renal origin. Urinary plasminogen activator inhibitor 1 (PAI-1) has been associated to AKI in experimental models, although its origin and traffic to the urine are not known. The aim of this study was to investigate whether the urinary PAI-1 found in the urine following AKI is shed directly by renal structures or has a blood-borne origin. A further objective was to study whether urinary PAI-1 also associates to human AKI. METHOD AKI was induced in male Wistar rats by a single dose of cisplatin or by ischemia-reperfusion to study the blood or renal origin of urinary PAI-1. Blood and urine samples were collected on day 0 (basal) and on the day of maximal damage. The kidneys were collected at sacrifice (i.e. the day of maximal damage). The origin of urinary PAI-1 was studied with the in situ renal perfusion method. At maximal damage time, the right kidney was ligated, and the left kidney was perfused with Krebs-dextran solution. Urine was collected during perfusion. If PAI-1 was secreted by tubule cells directly to the urine, it should be detected in the urine during perfusion. If PAI-1 had a blood borne origin, PAI-1 should disappear from the urine during perfusion. The level of PAI-1 was also analyzed in the urine of AKI patients. RESULTS Our results show that urinary PAI-1 levels increase after AKI and correlate with an increased expression in kidney tissue. During in situ renal perfusion with Krebs–dextran solution, PAI-1 remained in the urine of AKI rats, suggesting that renal cells shed this protein directly to the urine. PAI-1 is also significantly increased in the urine of AKI patients. Its low correlation with other urinary markers such as neutrophil gelatinase-associated lipocalin or NAG suggests that PAI-1 provides complementary and distinct pathophysiological information. CONCLUSION Urinary PAI-1 is produced by the kidneys after AKI and secreted directly to the urine providing specific pathological information, which needs to be explored further. Urinary PAI-1 is one of the few biomarkers of AKI with proven renal origin and therefore a potentially valuable tool for a prospective pathophysiological diagnostic panel.