Urine interleukin-6 is an early biomarker of acute kidney injury in children undergoing cardiac surgery

Abstract

IntroductionInterleukin-6 (IL-6) is a proinflammatory cytokine that increases early in the serum of patients with acute kidney injury (AKI). The aim of this study was to determine whether urine IL-6 is an early biomarker of AKI and determine the source of urine IL-6. Numerous proteins, including cytokines, are filtered by the glomerulus and then endocytosed and metabolized by the proximal tubule. Since proximal tubule injury is a hallmark of AKI, we hypothesized that urine IL-6 would increase in AKI due to impaired proximal tubule metabolism of filtered IL-6.MethodsUrine was collected in 25 consecutive pediatric patients undergoing cardiac bypass surgery (CPB). AKI was defined as a 50% increase in serum creatinine at 24 hours (RIFLE (Risk, Injury, Failure, Loss, End stage), R). Mouse models of AKI and freshly isolated proximal tubules were also studied.ResultsUrine IL-6 increased at six hours in patients with AKI versus no AKI (X2 = 8.1750; P < 0.0042). Urine IL-6 > 75 pg/mg identified AKI with a sensitivity of 88%. To assess whether increased urine IL-6 occurs in functional versus structural renal failure, mouse models of pre-renal azotemia after furosemide injection (no tubular injury), ischemic AKI (tubular injury) and cisplatin AKI (tubular injury) were studied. Urine IL-6 did not significantly increase in pre-renal azotemia but did increase in ischemic and cisplatin AKI. To determine if circulating IL-6 appears in the urine in AKI, recombinant human (h)IL-6 was injected intravenously and urine collected for one hour; urine hIL-6 increased in ischemic AKI, but not pre-renal azotemia. To determine the effect of AKI on circulating IL-6, serum hIL-6 was determined one hour post-intravenous injection and was increased in ischemic AKI, but not pre-renal azotemia. To directly examine IL-6 metabolism, hIL-6 was added to the media of normal and hypoxic isolated proximal tubules; hIL-6 was reduced in the media of normal versus injured hypoxic proximal tubules.ConclusionsUrine IL-6 increases early in patients with AKI. Animal studies demonstrate that failure of proximal tubule metabolism of IL-6 results in increased serum and urine IL-6. Impaired IL-6 metabolism leading to increased serum IL-6 may contribute to the deleterious systemic effects and increased mortality associated with AKI.

Genetic deficiency of Smad3 protects against murine ischemic acute kidney injury

“…For example, the administration of a neutralizing IL-6 antibody leads to greater preservation of renal function and less histological injury following acute renal ischemic injury (22,38); IL-6 Ϫ/Ϫ mice evince less renal dysfunction and histological injury in response to an acute ischemic insult (22,38); HO-1 Ϫ/Ϫ mice, compared with HO-1 ϩ/ϩ mice, exhibit an exaggerated induction of IL-6, increased renal dysfunction, and increased mortality following renal ischemia (47), while the administration of a neutralizing IL-6 antibody attenuates such renal dysfunction and mortality observed in HO-1 Ϫ/Ϫ mice following ischemia (47). Clinical observations support the pathogenetic significance of increased IL-6 production as increased urinary excretion of IL-6 is a predictor for human acute kidney injury (9,25). Our finding that IL-6 mRNA was markedly induced in the ischemic kidney, and that such expression of IL-6 was drastically reduced in the ischemic kidney in Smad3 Ϫ/Ϫ mice, raises the possibility that the protection conferred by Smad3 deficiency may reflect reduced production of IL-6.…”

Mechanisms and mediators of lung injury after acute kidney injury

“…In this scenario there is no kidney injury and no kidneys to account for the increase in serum IL-6, suggesting that increased extrarenal production and/or impaired renal clearance contributes to increased serum IL-6 levels after AKI; indeed, data suggest that both conditions are present ( Figure 3). 114,133,137 Specifically, mRNA levels of Il-6 increase in the spleen and liver after bilateral nephrectomy. Macrophage depletion reduces serum IL-6 in mice with bilateral nephrectomy, indicating that macrophages are a key source of cytokine production in AKI.…”

“…133 Data suggest that IL-6 is normally filtered, and then resorbed and metabolized in the proximal tubule. 137 Interestingly, mice with pre-renal azotaemia and uninjured proximal tubules are able to effectively clear intravenous IL-6, unlike mice with ischaemic AKI and injured proximal tubules. 137 IL-8 in AKI-mediated lung injury IL-8 is a cytokine and neutrophil chemokine that is well studied in human and animal models of ALI, AKI, and AKI-mediated lung injury.…”

“…137 Interestingly, mice with pre-renal azotaemia and uninjured proximal tubules are able to effectively clear intravenous IL-6, unlike mice with ischaemic AKI and injured proximal tubules. 137 IL-8 in AKI-mediated lung injury IL-8 is a cytokine and neutrophil chemokine that is well studied in human and animal models of ALI, AKI, and AKI-mediated lung injury. IL-8 is increased in the serum and BAL fluid of patients with ALI, and is a predictor of increased mortality.…”

Early Predictors of Acute Kidney Injury: A Narrative Review

“…It was significantly increased in animal models of ischemic and toxic AKI. In the study of AKI following cardiac surgery, IL-6 was increased in AKI group within 6 h postoperatively, with the sensitivity in diagnosing AKI reaching 88% [95]. For kidney allograft, compared to clinical acute inflammation, subclinical acute kidney inflammation has lower extend of transcriptional profile of immune injury and inflammatory mediator such as cytokine receptors (CCRL2, CCR1, CXCR5, IL1RAPL2), proinflammatory cytokines (LTA, IL12A), complement protein C3 and inflammatory mediator (PTAFR) [96].…”