No abstract

Acute kidney injury (AKI) is a frequent complication of cardiopulmonary bypass (CPB). The lack of early biomarkers for AKI has impaired our ability to intervene in a timely manner. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is recently demonstrated as an early biomarker of AKI after CPB, increasing 25-fold within 2 h and declining 6 h after surgery. In the present study, we tested whether interleukin-18 (IL-18) is a predictive biomarker for AKI in the same group of patients following CPB. Exclusion criteria included pre-existing renal insufficiency and nephrotoxin use. Serial urine samples were analyzed by enzyme-linked immunosorbent assay for IL-18 in 20 patients who developed AKI (defined as a 50% or greater increase in serum creatinine after CPB) and 35 controls (age, race, and gender-matched patients who did not develop AKI after CPB). Using serum creatinine, AKI was detected only 48-72 h after CPB. In contrast, urine IL-18 increased at 4-6 h after CPB, peaked at over 25-fold at 12 h, and remained markedly elevated up to 48 h after CPB. The performance of IL-18 as demonstrated by area under the receiver operating characteristics curve for diagnosis of AKI at 4, 12, and 24 h after CPB was 61, 75, and 73% respectively. Also, on multivariate analysis, both IL-18 and NGAL were independently associated with number of days in AKI among cases. Our results indicate that IL-18 is an early, predictive biomarker of AKI after CPB, and that NGAL and IL-18 are increased in tandem after CPB. The combination of these two biomarkers may allow for the reliable early diagnosis and prognosis of AKI at all times after CPB, much before the rise in serum creatinine.

Abstract. Acute renal failure secondary to ischemic injury remains a common problem, with limited and unsatisfactory therapeutic options. Neutrophil gelatinase-associated lipocalin (NGAL) was recently shown to be one of the maximally induced genes early in the postischemic kidney. In this study, the role of NGAL in ischemic renal injury was explored. Intravenous administration of purified recombinant NGAL in mice resulted in a rapid uptake of the protein predominantly by proximal tubule cells. In an established murine model of renal ischemia-reperfusion injury, intravenous NGAL administered before, during, or after ischemia resulted in marked amelioration of the morphologic and functional consequences, as evidenced by a significant decrease in the histopathologic damage to tubules and in serum creatinine measurements. NGALtreated animals also displayed a reduction in the number of apoptotic tubule cells and an increase in proliferating proximal tubule cells after ischemic injury. The results indicate that NGAL may represent a novel therapeutic intervention in ischemic acute renal failure, based at least in part on its ability to tilt the balance of tubule cell fate toward survival.Acute renal failure (ARF) secondary to ischemic injury remains a common and potentially devastating problem in clinical nephrology, with a persistently high rate of mortality despite significant advances in supportive care (1-4). Pioneering studies over several decades have illuminated the roles of persistent vasoconstriction, tubular obstruction, cellular structural and metabolic alterations, and the inflammatory response in the pathogenesis of ARF (4 -7). Although these studies have paved the way for successful therapeutic approaches in animal models, translational research efforts in humans have yielded disappointing results (2-4). The reasons for this may include the multifaceted response of the kidney to ischemia and a lack of early markers for ARF (4 -8). Recent advances in cellular and molecular biology of ischemic renal injury have revealed that proximal tubule cells undergo a complex temporal sequence of events. These include loss of cell polarity, cell death as a result of apoptosis and necrosis, dedifferentiation and proliferation of viable cells, and reestablishment of the epithelial phenotype (6,7). An improved understanding of the early cell injury and repair mechanisms is critical for innovative and effective therapy. Identification of interventions that may oppose tubule cell death and/or enhance the recovery phase therefore is of considerable interest.Attempts to unravel the molecular basis of the myriad early renal responses have been facilitated by recent advances in functional genomics that have yielded new tools for genomewide analysis of complex biologic processes such as ischemic ARF (8 -11). Using cDNA microarray techniques, we recently identified neutrophil gelatinase-associated lipocalin (NGAL) as one of the most dramatically induced transcripts in the kidney early after ischemic injury (11,12). Although previ...