The online version of this article (doi:10.1186/cc9289) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
PD designed the study and prepared the manuscript. CA, CK, AAH and NA carried out biomarker measurements. JK designed the study and collected human samples. MC designed the study. AK performed statistical analyses. CLE assisted with drafting of the manuscript. SF performed animal surgeries, prepared and performed the proximal tubule experiments, developed the pre-renal azotemia model, conceived of the study, and drafted the manuscript. All authors read and approved the final manuscript.
Interleukin-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.
Urine 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.
Urine 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.
Urine 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.
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Yende S, D'Angelo G, Kellum JA, Weissfeld L, Fine J, Welch RD, Kong L, Carter M, Angus DC, GenIMS Investigators: Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis. Am J Respir Crit Care Med. 2008, 177: 1242-1247. 10.1164/rccm.200712-1777OC. PubMedCentralCrossRefPubMed
Simmons EM, Himmelfarb J, Sezer MT, Chertow GM, Mehta RL, Paganini EP, Soroko S, Freedman S, Becker K, Spratt D, Shyr Y, Ikizler TA, PICARD Study Group: Plasma cytokine levels predict mortality in patients with acute renal failure. Kidney Int. 2004, 65: 1357-1365. 10.1111/j.1523-1755.2004.00512.x. CrossRefPubMed
Meduri GU, Headley S, Kohler G, Stentz F, Tolley E, Umberger R, Leeper K: Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time. Chest. 1995, 107: 1062-1073. 10.1378/chest.107.4.1062. CrossRefPubMed
Oberholzer A, Souza SM, Tschoeke SK, Oberholzer C, Abouhamze A, Pribble JP, Moldawer LL: Plasma cytokine measurements augment prognostic scores as indicators of outcome in patients with severe sepsis. Shock. 2005, 23: 488-493. PubMed
Parsons PE, Eisner MD, Thompson BT, Matthay MA, Ancukiewicz M, Bernard GR, Wheeler AP; NHLBI Acute Respiratory Distress Syndrome Clinical Trials Network: Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury. Crit Care Med. 2005, 33: 1-6. 10.1097/01.CCM.0000149854.61192.DC. discussion 230-232 CrossRefPubMed
Geppert A, Dorninger A, Delle-Karth G, Zorn G, Heinz G, Huber K: Plasma concentrations of interleukin-6, organ failure, vasopressor support, and successful coronary revascularization in predicting 30-day mortality of patients with cardiogenic shock complicating acute myocardial infarction. Crit Care Med. 2006, 34: 2035-2042. 10.1097/01.CCM.0000228919.33620.D9. CrossRefPubMed
Liu KD, Altmann C, Smits G, Krawczeski CD, Edelstein CL, Devarajan P, Faubel S: Serum Interleukin-6 and interleukin-8 are early biomarkers of acute kidney injury and predict prolonged mechanical ventilation in children undergoing cardiac surgery: a case-control study. Crit Care. 2009, 13: R104-10.1186/cc7940. PubMedCentralCrossRefPubMed
Rachmawati H, Beljaars L, Reker-Smit C, Van Loenen-Weemaes AM, Hagens WI, Meijer DK, Poelstra K: Pharmacokinetic and biodistribution profile of recombinant human interleukin-10 following intravenous administration in rats with extensive liver fibrosis. Pharm Res. 2004, 21: 2072-2078. 10.1023/B:PHAM.0000048199.94510.b0. CrossRefPubMed
Tanaka H, Tokiwa T: Influence of renal and hepatic failure on the pharmacokinetics of recombinant human granulocyte colony-stimulating factor (KRN8601) in the rat. Cancer Res. 1990, 50: 6615-6619. PubMed
Hepburn TW, Hart TK, Horton VL, Sellers TS, Tobia LP, Urbanski JJ, Shi W, Davis CB: Pharmacokinetics and tissue distribution of SB-251353, a novel human CXC chemokine, after intravenous administration to mice. J Pharmacol Exp Ther. 2001, 298: 886-893. PubMed
Faubel S, Lewis EC, Reznikov L, Ljubanovic D, Hoke TS, Somerset H, Oh DJ, Lu L, Klein CL, Dinarello CA, Edelstein CL: Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil infiltration in the kidney. J Pharmacol Exp Ther. 2007, 322: 8-15. 10.1124/jpet.107.119792. CrossRefPubMed
American Society of Nephrology: American Society of Nephrology Renal Research Report. J Am Soc Nephrol. 2005, 16: 1886-1903. 10.1681/ASN.2005030285. CrossRef
Endre ZH, Walker RJ, Pickering JW, Shaw GM, Frampton CM, Henderson SJ, Hutchison R, Mehrtens JE, Robinson JM, Schollum JB, Westhuyzen J, Celi LA, McGinley RJ, Campbell IJ, George PM: Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial). Kidney Int. 2010, 77: 1020-1030. 10.1038/ki.2010.25. CrossRefPubMed
- Urine interleukin-6 is an early biomarker of acute kidney injury in children undergoing cardiac surgery
Christina L Klein
Nilesh H Ahuja
Charles L Edelstein
Melissa A Cadnapaphornchai
- BioMed Central
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