Urinary Markers of Kidney Injury and Kidney Function Decline in HIV-Infected Women

Objective:HIV-infected persons have substantially higher risk of kidney failure than persons without HIV, but serum creatinine levels are insensitive for detecting declining kidney function. We hypothesized that urine markers of kidney injury would be associated with declining kidney function among HIV-infected women. Methods:In the Women's Interagency HIV Study, we measured concentrations of albumin-to-creatinine ratio, interleukin-18 (IL-18), kidney injury marker-1 (KIM-1), and neutrophil gelatinase-associated lipocalin from stored urine among 908 HIV-infected and 289 HIV-uninfected participants. Primary analyses used cystatin C-based estimated glomerular filtration rate (CKD-EPI eGFRcys) as the outcome, measured at baseline and 2 follow-up visits over 8 years; secondary analyses used creatinine (CKD-EPI eGFRcr). Each urine biomarker was categorized into tertiles, and kidney decline was modeled with both continuous and dichotomized outcomes. Results:Compared with the lowest tertiles, the highest tertiles of albumin-to-creatinine ratio (−0.15 mL/min per 1.73 m2, P < 0.0001), IL-18 (−0.09 mL/min per 1.73 m2, P < 0.0001) and KIM-1 (−0.06 mL/min per 1.73 m2, P < 0.001) were independently associated with faster eGFRcys decline after multivariate adjustment including all 3 biomarkers among HIV-infected women. Among these biomarkers, only IL-18 was associated with each dichotomized eGFRcys outcome: ≥3% (relative risk = 1.40; 95% confidence interval: 1.04 to 1.89); ≥5% (1.88; 1.30 to 2.71); and ≥10% (2.16; 1.20 to 3.88) for the highest versus lowest tertile. In alternative models using eGFRcr, the high tertile of KIM-1 had independent associations with 5% (1.71; 1.25 to 2.33) and 10% (1.78; 1.07 to 2.96) decline, and the high IL-18 tertile with 10% decline (1.97; 1.00 to 3.87). Conclusions:Among HIV-infected women in the Women's Interagency HIV Study cohort, novel urine markers of kidney injury detect risk for subsequent declines in kidney function.

[1]  D. Siscovick,et al.  Associations of urinary levels of kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) with kidney function decline in the Multi-Ethnic Study of Atherosclerosis (MESA). , 2012, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[2]  A. Köttgen,et al.  Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) as predictors of incident CKD stage 3: the Atherosclerosis Risk in Communities (ARIC) Study. , 2012, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[3]  M. Shlipak,et al.  Association of tenofovir exposure with kidney disease risk in HIV infection , 2012, AIDS.

[4]  Josef Coresh,et al.  Expressing the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) cystatin C equations for estimating GFR with standardized serum cystatin C values. , 2011, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[5]  H. Feldman,et al.  Measured GFR does not outperform estimated GFR in predicting CKD-related complications. , 2011, Journal of the American Society of Nephrology : JASN.

[6]  K. Tsuchiya,et al.  Kidney tubular damage in the absence of glomerular defects in HIV-infected patients on highly active antiretroviral therapy. , 2011, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[7]  C. Edelstein,et al.  Clinical applications of biomarkers for acute kidney injury. , 2011, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[8]  L. Szczech,et al.  Cystatin C, albuminuria, and 5-year all-cause mortality in HIV-infected persons. , 2010, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[9]  Shi-Xian Deng,et al.  The Ngal Reporter Mouse Detects the Response of the Kidney to Injury in Real Time , 2010, Nature Medicine.

[10]  Mardge H. Cohen,et al.  Microalbuminuria Is Associated With All-Cause and AIDS Mortality in Women With HIV Infection , 2010, Journal of acquired immune deficiency syndromes.

[11]  C. Parikh,et al.  Tubular proteinuria in acute kidney injury: a critical evaluation of current status and future promise , 2010, Annals of clinical biochemistry.

[12]  P. Volberding,et al.  Association Between Kidney Function and Albuminuria With Cardiovascular Events in HIV-Infected Persons , 2010, Circulation.

[13]  Richard D Moore,et al.  Kidney function and the risk of cardiovascular events in HIV-1-infected patients , 2010, AIDS.

[14]  B. Kestenbaum,et al.  Rapid decline of kidney function increases cardiovascular risk in the elderly. , 2009, Journal of the American Society of Nephrology : JASN.

[15]  B. Astor,et al.  Change in estimated GFR associates with coronary heart disease and mortality. , 2009, Journal of the American Society of Nephrology : JASN.

[16]  J. Bonventre Kidney injury molecule-1 (KIM-1): a urinary biomarker and much more. , 2009, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[17]  C. Lewis,et al.  HIV viremia and changes in kidney function , 2009, AIDS.

[18]  V. D’Agati,et al.  The spectrum of kidney disease in patients with AIDS in the era of antiretroviral therapy. , 2009, Kidney international.

[19]  S. Chaturvedi,et al.  Assay Validation for KIM-1: human urinary renal dysfunction biomarker , 2009, International journal of biological sciences.

[20]  D. Siscovick,et al.  Rapid kidney function decline and mortality risk in older adults. , 2008, Archives of internal medicine.

[21]  C. Parikh,et al.  Screening for kidney diseases: older measures versus novel biomarkers. , 2008, Clinical journal of the American Society of Nephrology : CJASN.

[22]  Richard D Moore,et al.  Chronic kidney disease incidence, and progression to end-stage renal disease, in HIV-infected individuals: a tale of two races. , 2008, The Journal of infectious diseases.

[23]  F. Grenier,et al.  Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a prospective study. , 2008, Clinical journal of the American Society of Nephrology : CJASN.

[24]  C. Schmid,et al.  Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD. , 2008, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[25]  Richard D Moore,et al.  End-stage renal disease and chronic kidney disease in a cohort of African-American HIV-infected and at-risk HIV-seronegative participants followed between 1988 and 2004 , 2007, AIDS.

[26]  S. Sidney,et al.  Cystatin C level as a marker of kidney function in human immunodeficiency virus infection: the FRAM study. , 2007, Archives of internal medicine.

[27]  D. Bolignano,et al.  Neutrophil Gelatinase-Associated Lipocalin in Patients with Autosomal-Dominant Polycystic Kidney Disease , 2007, American Journal of Nephrology.

[28]  S. Sidney,et al.  Microalbuminuria in HIV infection , 2007, AIDS.

[29]  Tom Greene,et al.  Assessing kidney function--measured and estimated glomerular filtration rate. , 2006, The New England journal of medicine.

[30]  R. Vasan,et al.  Biomarkers of Cardiovascular Disease: Molecular Basis and Practical Considerations , 2006, Circulation.

[31]  M. Young,et al.  The Women's Interagency HIV Study: an Observational Cohort Brings Clinical Sciences to the Bench , 2005, Clinical Diagnostic Laboratory Immunology.

[32]  Mardge H. Cohen,et al.  Association between renal disease and outcomes among HIV-infected women receiving or not receiving antiretroviral therapy. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[33]  P. Klotman,et al.  Recent progress in HIV-associated nephropathy. , 2002, Journal of the American Society of Nephrology : JASN.

[34]  C. Edelstein,et al.  Neutrophil-independent mechanisms of caspase-1- and IL-18-mediated ischemic acute tubular necrosis in mice. , 2002, The Journal of clinical investigation.

[35]  V. D’Agati,et al.  Nephropathy and establishment of a renal reservoir of HIV type 1 during primary infection. , 2001, The New England journal of medicine.

[36]  M. Lucia,et al.  Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. , 2001, The Journal of clinical investigation.

[37]  V. D’Agati,et al.  J Am Soc Nephrol 11: 2079–2087, 2000 Renal Epithelium Is a Previously Unrecognized Site of HIV-1 Infection , 2022 .

[38]  J. Robins,et al.  Correcting for Noncompliance and Dependent Censoring in an AIDS Clinical Trial with Inverse Probability of Censoring Weighted (IPCW) Log‐Rank Tests , 2000, Biometrics.

[39]  Joseph Feldman,et al.  The Women's Interagency HIV Study , 1998 .

[40]  Sylvia Richardson,et al.  Markov Chain Monte Carlo in Practice , 1997 .

[41]  Michael G. Kenward,et al.  A Method for Comparing Profiles of Repeated Measurements , 1987 .

[42]  A. Garg,et al.  Postoperative biomarkers predict acute kidney injury and poor outcomes after adult cardiac surgery. , 2011, Journal of the American Society of Nephrology : JASN.

[43]  Peter Green,et al.  Markov chain Monte Carlo in Practice , 1996 .