Keratinocyte-derived chemokine is an early biomarker of ischemic acute kidney injury

Abstract

. Keratinocyte-derived chemokine is an early biomarker of ischemic acute kidney injury. Am J Physiol Renal Physiol 290: F1187-F1193, 2006. First published December 20, 2005 doi:10.1152/ajprenal.00342.2005.-Renal ischemia-reperfusion injury (IRI) is the leading cause of acute kidney injury [AKI; acute renal failure (ARF)] in native kidneys and delayed graft function in deceased donor kidney transplants. Serum creatinine rises late after renal IRI, which results in delayed diagnosis. There is an important need to identify novel biomarkers for early diagnosis and prognosis in renal IRI. Given the inflammatory pathophysiology of renal IRI, we used a protein array to measure 18 cytokines and chemokines in a mouse model of renal IRI at 3, 24, and 72 h postischemia. A rise in renal keratinocyte-derived chemokine (KC) was the earliest and most consistent compared with other molecules, with 3-h postischemia values being 9-and 13-fold greater than sham and normal animals, respectively. Histological changes were evident within 1 h of IRI but serum creatinine only increased 24 h after IRI. With the use of an ELISA, KC levels in serum and urine were highest 3 h postischemia, well before a significant rise in serum creatinine. The human analog of KC, Gro-␣, was markedly elevated in urine from humans who received deceased donor kidney transplants that required dialysis, compared with deceased donor kidney recipients with good graft function and live donor recipients with minimal ischemia. Measurement of KC and its human analog, Gro-␣, could serve as a useful new biomarker for ischemic ARF.growth-related oncogene-␣; transplantation; acute renal failure; allograft ACUTE RENAL FAILURE (ARF), also recently known as acute kidney injury (AKI), is a syndrome with high mortality and morbidity, for which there is no specific therapy except supportive care (5, 17). There is an urgent need to develop effective therapeutics for ARF. Histologically, ischemic ARF is characterized by acute tubular necrosis; however, a major limitation in approaching the disease is the lack of clinically feasible diagnostics for early detection of ischemic ARF, such as the use of serum troponin and creatine phosphokinase (CPK) for myocardial ischemia-reperfusion injury (IRI) (4). Recent studies have identified proteins including KIM-1, lipocalin, IL-18, NHE3, actin, and retinol binding protein among others as potential biomarker candidates in ischemic ARF (13). However, none of them has been fully validated or is in routine clinical use, and there remains a strong need for discovery and validation of additional candidate markers (1).There are significant data that early inflammatory changes underlie the pathogenesis of renal IRI (3,8,11,15,21). We therefore used a mouse model of renal IRI to examine kidney, blood, and urine for evidence of changes in cytokine and chemokine expression using a protein array adapted to small volume samples. The earliest and most striking change was an increase in keratinocyte-derived chemokine (KC), a CXC chemokine that is stru...

C3a Is Required for the Production of CXC Chemokines by Tubular Epithelial Cells after Renal Ishemia/Reperfusion

“…In human renal allografts, the level of urinary IL-8 correlated with sustained ARF which was presumably due to ischemic injury at the time of transplantation (50). In another report, urinary levels of GRO-␣, the human analog of KC, were higher in transplant recipients with delayed graft function than in those with prompt graft function (16). The authors also reported that these patients had evidence ATN on renal biopsy.…”

“…Cells of the cognate immune system have also been implicated in ischemic acute renal failure (ARF), including T cells (8 -10), and possibly B cells (11,12). Human acute tubular necrosis is characterized by engagement of many of the same inflammatory factors seen in animal models (13)(14)(15)(16). Inflammatory cytokines and chemokines are generated in the ischemic kidney (7,17) and likely orchestrate this broad inflammatory response.…”

TLR2 Is Constitutively Expressed within the Kidney and Participates in Ischemic Renal Injury through Both MyD88-Dependent and -Independent Pathways

“…To investigate proinflammatory cytokines and chemokines known to participate in the inflammatory response to kidney IR injury (28,36), we compared and contrasted cytokine and chemokine secretion in serum and tissue homogenates 24 h after IR injury in WT, Trif-deficient, (MyD88 ϫ Trif)-deficient, MyD88-deficient, and TLR2-deficient mice (Fig. 5).…”

Role of Protein C in Renal Dysfunction after Polymicrobial Sepsis

“…Wu et al (13) suggested that GRO chemokines are expressed coordinately by mesangial cells and inflamed glomeruli and are key mediators that amplify acute kidney injury (AKI). Moreover, CXCL1 seems to be a useful biomarker for renal injury in both rodent models and humans (14). In both humans and model systems, the accumulation of leukocytes has been well demonstrated during ARF (15,16), and activated leukocytes can initiate an inflammatory cascade that leads to endothelial cell injury and disruption of the endothelial permeability barrier, thereby contributing to renal injury (17).…”