Kidney Injury Molecule-1 Outperforms Traditional Biomarkers of Kidney Injury in Preclinical Biomarker Qualification Studies

Overview

Journal Nat Biotechnol

Specialty Biotechnology

Date 2010 May 12

PMID 20458318

Citations 244

Authors

Vishal S Vaidya

Josef S Ozer

Frank Dieterle

Fitz B Collings

Victoria Ramirez

Sean Troth

Nagaraja Muniappa

Douglas Thudium

David Gerhold

Daniel J Holder

Norma A Bobadilla

Estelle Marrer

Elias Perentes

Andre Cordier

Jacky Vonderscher

Gerard Maurer

Peter L Goering

Frank D Sistare

Joseph V Bonventre

Affiliations

Soon will be listed here.

Abstract

Kidney toxicity accounts both for the failure of many drug candidates as well as considerable patient morbidity. Whereas histopathology remains the gold standard for nephrotoxicity in animal systems, serum creatinine (SCr) and blood urea nitrogen (BUN) are the primary options for monitoring kidney dysfunction in humans. The transmembrane tubular protein kidney injury molecule-1 (Kim-1) was previously reported to be markedly induced in response to renal injury. Owing to the poor sensitivity and specificity of SCr and BUN, we used rat toxicology studies to compare the diagnostic performance of urinary Kim-1 to BUN, SCr and urinary N-acetyl-beta-D-glucosaminidase (NAG) as predictors of kidney tubular damage scored by histopathology. Kim-1 outperforms SCr, BUN and urinary NAG in multiple rat models of kidney injury. Urinary Kim-1 measurements may facilitate sensitive, specific and accurate prediction of human nephrotoxicity in preclinical drug screens. This should enable early identification and elimination of compounds that are potentially nephrotoxic.

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References

Vaidya V, Ford G, Waikar S, Wang Y, Clement M, Ramirez V . A rapid urine test for early detection of kidney injury. Kidney Int. 2009; 76(1):108-14. PMC: 2737345. DOI: 10.1038/ki.2009.96. View

Vaidya V, Ramirez V, Ichimura T, Bobadilla N, Bonventre J . Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury. Am J Physiol Renal Physiol. 2005; 290(2):F517-29. DOI: 10.1152/ajprenal.00291.2005. View

Pencina M, DAgostino Sr R, DAgostino Jr R, Vasan R . Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med. 2007; 27(2):157-72. DOI: 10.1002/sim.2929. View

Amin R, Vickers A, Sistare F, Thompson K, Roman R, Lawton M . Identification of putative gene based markers of renal toxicity. Environ Health Perspect. 2004; 112(4):465-79. PMC: 1241901. DOI: 10.1289/ehp.6683. View

van Timmeren M, Vaidya V, van Ree R, Oterdoom L, de Vries A, Gans R . High urinary excretion of kidney injury molecule-1 is an independent predictor of graft loss in renal transplant recipients. Transplantation. 2008; 84(12):1625-30. PMC: 2745062. DOI: 10.1097/01.tp.0000295982.78039.ef. View

Sing T, Sander O, Beerenwinkel N, Lengauer T . ROCR: visualizing classifier performance in R. Bioinformatics. 2005; 21(20):3940-1. DOI: 10.1093/bioinformatics/bti623. View

Zhou Y, Vaidya V, Brown R, Zhang J, Rosenzweig B, Thompson K . Comparison of kidney injury molecule-1 and other nephrotoxicity biomarkers in urine and kidney following acute exposure to gentamicin, mercury, and chromium. Toxicol Sci. 2007; 101(1):159-70. PMC: 2744478. DOI: 10.1093/toxsci/kfm260. View

Perez-Rojas J, Blanco J, Cruz C, Trujillo J, Vaidya V, Uribe N . Mineralocorticoid receptor blockade confers renoprotection in preexisting chronic cyclosporine nephrotoxicity. Am J Physiol Renal Physiol. 2006; 292(1):F131-9. DOI: 10.1152/ajprenal.00147.2006. View

Bonventre J, Vaidya V, Schmouder R, Feig P, Dieterle F . Next-generation biomarkers for detecting kidney toxicity. Nat Biotechnol. 2010; 28(5):436-40. PMC: 3033582. DOI: 10.1038/nbt0510-436. View

10.

Vaidya V, Waikar S, Ferguson M, Collings F, Sunderland K, Gioules C . Urinary biomarkers for sensitive and specific detection of acute kidney injury in humans. Clin Transl Sci. 2009; 1(3):200-8. PMC: 2638059. DOI: 10.1111/j.1752-8062.2008.00053.x. View

11.

Liangos O, Perianayagam M, Vaidya V, Han W, Wald R, Tighiouart H . Urinary N-acetyl-beta-(D)-glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure. J Am Soc Nephrol. 2007; 18(3):904-12. DOI: 10.1681/ASN.2006030221. View

12.

Hanley J, McNeil B . A method of comparing the areas under receiver operating characteristic curves derived from the same cases. Radiology. 1983; 148(3):839-43. DOI: 10.1148/radiology.148.3.6878708. View

13.

Ichimura T, Hung C, Yang S, Stevens J, Bonventre J . Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury. Am J Physiol Renal Physiol. 2003; 286(3):F552-63. DOI: 10.1152/ajprenal.00285.2002. View

14.

Prozialeck W, Vaidya V, Liu J, Waalkes M, Edwards J, Lamar P . Kidney injury molecule-1 is an early biomarker of cadmium nephrotoxicity. Kidney Int. 2007; 72(8):985-93. PMC: 2747605. DOI: 10.1038/sj.ki.5002467. View

15.

Zhang P, Rothblum L, Han W, Blasick T, Potdar S, Bonventre J . Kidney injury molecule-1 expression in transplant biopsies is a sensitive measure of cell injury. Kidney Int. 2007; 73(5):608-14. PMC: 2915578. DOI: 10.1038/sj.ki.5002697. View

16.

Chertow G, Burdick E, Honour M, Bonventre J, Bates D . Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. 2005; 16(11):3365-70. DOI: 10.1681/ASN.2004090740. View

17.

Ichimura T, Bonventre J, Bailly V, Wei H, Hession C, Cate R . Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem. 1998; 273(7):4135-42. DOI: 10.1074/jbc.273.7.4135. View

18.

Bailly V, Zhang Z, Meier W, Cate R, Sanicola M, Bonventre J . Shedding of kidney injury molecule-1, a putative adhesion protein involved in renal regeneration. J Biol Chem. 2002; 277(42):39739-48. DOI: 10.1074/jbc.M200562200. View

19.

Han W, Bailly V, Abichandani R, Thadhani R, Bonventre J . Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int. 2002; 62(1):237-44. DOI: 10.1046/j.1523-1755.2002.00433.x. View

20.

Choudhury D, Ahmed Z . Drug-associated renal dysfunction and injury. Nat Clin Pract Nephrol. 2006; 2(2):80-91. DOI: 10.1038/ncpneph0076. View