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1.  Host APOL1 genotype is independently associated with proteinuria in HIV infection 
Kidney international  2013;84(4):834-840.
Proteinuria is associated with adverse clinical outcomes in HIV infection. Here we evaluated whether APOL1 risk alleles, previously associated with advanced kidney disease, is independently associated with proteinuria in HIV infection in a cross-sectional study of HIV-infected women in the Women’s Interagency HIV Study. We estimated the percent difference in urine protein excretion and odds of proteinuria (200 mg/g and higher) associated with two versus one or no APOL1 risk allele using linear and logistic regression, respectively. Of 1285 women successfully genotyped, 379 carried one and 80 carried two risk alleles. Proteinuria was present in 124 women; 78 of whom had proteinuria confirmed on a second sample. In women without prior AIDS, two risk alleles were independently associated with a 69% higher urine protein excretion (95% CI: 36%, 108%) and 5-fold higher odds of proteinuria (95% CI: 2.45, 10.37) versus one or no risk allele. No association was found in women with prior AIDS. Analyses in which women with impaired kidney function were excluded and proteinuria was confirmed by a second urine sample yielded similar estimates. Thus, APOL1 risk alleles are associated with significant proteinuria in HIV-infected persons without prior clinical AIDS, independent of clinical factors traditionally associated with proteinuria. Trials are needed to determine whether APOL1 genotyping identifies individuals who could benefit from earlier intervention to prevent overt renal disease.
doi:10.1038/ki.2013.203
PMCID: PMC3788838  PMID: 23715117
2.  Does HIV infection promote early kidney injury in women? 
Antiviral therapy  2013;19(1):79-87.
Background
In HIV-infected women, urine concentrations of novel tubulointerstitial injury markers, interleukin-18 (IL-18) and kidney injury marker-1 (KIM-1) are associated with kidney function decline and all-cause mortality. We hypothesized that HIV-infected individuals with preserved kidney filtration function would have more extensive kidney injury, as determined by urine injury markers, compared to the uninfected controls, and that risk factors for tubulointerstitial injury would differ from risk factors for albuminuria.
Methods
In this cross-sectional study, we compared urine concentrations of IL-18, KIM-1, and ACR in 908 HIV-infected and 289 HIV-uninfected women enrolled in the Women’s Interagency HIV Study, utilizing stored urine specimens from visits between 1999 and 2000.
Results
After multivariate-adjusted linear regression analysis, mean urine concentrations were higher in HIV-infected individuals by 38% for IL-18 (p<0.0001), 12% for KIM-1 (p=0.081), and 47% for ACR (p<0.0001). Higher HIV RNA level (15% per 10-fold increase, p<0.0001), lower CD4 count (8% per doubling, p=0.0025), HCV infection (30%, p=0.00018), and lower HDL (5% per 10 mg/dL, p=0.0024) were each associated with higher IL-18 concentrations. In contrast, hypertension (81%, p<0.0001) and diabetes (47%, p=0.018) were among the strongest predictors of higher ACR, though HIV RNA level (15% per 10-fold increase, p=0.0004) was also associated with higher ACR.
Conclusions
HIV-infected women had more extensive tubulointerstitial and glomerular injury than uninfected women, but the associated factors differed among the urine biomarkers. Combinations of urinary biomarkers should be investigated to further characterize early kidney injury in HIV-infected women.
doi:10.3851/IMP2677
PMCID: PMC3933452  PMID: 23970313
3.  Decreased limb muscle and increased central adiposity are associated with 5-year all-cause mortality in HIV infection 
AIDS (London, England)  2011;25(11):1405-1414.
Background
Unintentional loss of weight and muscle due to aging and disease has been associated with increased mortality. Wasting and weight loss occur in HIV infection even in the modern era of effective antiretroviral therapy.
Methods
We determined the association of MRI-measured regional and total skeletal muscle and adipose tissue with 5-year, all-cause mortality in 922 HIV-infected persons in the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM).
Results
After 5 years of follow-up, HIV-infected participants with arm skeletal muscle in the lowest tertile had a mortality rate of 23%, compared with 11 and 8% for those in the middle and highest tertiles. After multivariable adjustment for demographics, cardiovascular risk factors, HIV-related factors, inflammatory markers, and renal disease, we found that lower arm skeletal muscle, lower leg skeletal muscle and higher visceral adipose tissue (VAT) were each independently associated with increased mortality. Those in the lowest tertile of arm or leg skeletal muscle had higher odds of death [arm: odds ratio (OR)=2.0, 95% confidence interval (CI) 0.96–4.0; leg: OR=2.4, 95% CI 1.2–4.8] compared with the highest respective tertiles. Those in the highest tertile of VAT had 2.1-fold higher odds of death (95% CI 1.1–4.0) compared with the lowest VAT tertile.
Conclusion
Lower muscle mass and central adiposity appear to be important risk factors for mortality in HIV-infected individuals. A substantial proportion of this risk may be unrecognized because of the current reliance on body mass index in clinical practice.
doi:10.1097/QAD.0b013e32834884e6
PMCID: PMC3933309  PMID: 21572308
body composition; cachexia; fat redistribution; HIV infection; lipoatrophy; lipodystrophy; mortality; sarcopenia
4.  Long-term clinical consequences of acute kidney injury in the HIV-infected 
Kidney international  2010;78(5):478-485.
To evaluate the long-term consequences of acute kidney injury (AKI) in human immunodeficiency virus (HIV)-infected persons, we studied 17,325 patients in a national HIV registry during their first hospitalization. We determined the association of AKI with risk for heart failure, cardiovascular events, end-stage renal disease (ESRD), and mortality beginning 90 days after discharge. Based on AKI Network criteria, 2453 had stage 1; 273 had stage 2 or 3; and 334 had dialysis-requiring AKI. Over a mean follow-up period of 5.7 years, 333 had heart failure, 673 had cardiovascular diseases (CVDs), 348 developed ESRD, and 8405 deaths occurred. In multivariable-adjusted analyses, AKI stage 1 was associated with death and ESRD, but not heart failure or other CVD. Dialysis-requiring AKI had much stronger and significant associations with increased risk for long-term ESRD, and death in addition to heart failure and cardiovascular events. When AKI was reclassified to account for recovery, stage 1 with recovery was still associated with death, but not ESRD. Thus, in this national sample of HIV-infected persons, we found the clinical repercussions of AKI appear to extend beyond the hospital setting contributing to excess cardiovascular risks, ESRD, and mortality. Additionally, AKI affected almost one of six patients with HIV who survived at least 90 days following discharge.
doi:10.1038/ki.2010.171
PMCID: PMC3913062  PMID: 20520594
acute kidney injury; cardiovascular disease; end-stage renal disease; HIV; mortality
5.  Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons 
AIDS (London, England)  2011;25(10):1289-1298.
Objective
Abacavir use has been associated with cardiovascular risk, but it is unknown whether this association may be partly explained by patients with kidney disease being preferentially treated with abacavir to avoid tenofovir. Our objective was to compare associations of abacavir and tenofovir with cardiovascular risks in HIV-infected veterans.
Design
Cohort study of 10 931 HIV-infected patients initiating antiretroviral therapy in the Veterans Health Administration from 1997 to 2007, using proportional hazards survival regression.
Methods
Primary predictors were exposure to abacavir or tenofovir within the past 6 months, compared with no exposure to these drugs, respectively. Outcomes were time to first atherosclerotic cardiovascular event, defined as coronary, cerebrovascular, or peripheral arterial disease; and time to incident heart failure.
Results
Over 60 588 person-years of observation, there were 501 cardiovascular and 194 heart failure events. Age-standardized event rates among abacavir and tenofovir users were 12.5 versus 8.2 per 1000 person-years for cardiovascular disease, and 3.9 and 3.7 per 1000 person-years for heart failure, respectively. In multivariate-adjusted models, including time-updated measurements of kidney function, recent abacavir use was significantly associated with incident cardiovascular disease [hazard ratio 1.48, 95% confidence interval (CI) 1.08–2.04]; the association was similar but nonsignificant for heart failure (1.45, 0.85–2.47). In contrast, recent tenofovir use was significantly associated with heart failure (1.82, 1.02–3.24), but not with cardiovascular events (0.78, 0.52–1.16).
Conclusion
Recent abacavir exposure was independently associated with increased risk for cardiovascular events. We also observed an association between recent tenofovir exposure and heart failure, which needs to be confirmed in future studies.
doi:10.1097/QAD.0b013e328347fa16
PMCID: PMC3910369  PMID: 21516027
antiretroviral therapy; cardiovascular disease; heart failure; HIV
6.  Kidney Function and Mortality in Octogenarians: Cardiovascular Health Study All Stars 
OBJECTIVES:
To examine the association between kidney function and all-cause mortality in octogenarians.
DESIGN:
Retrospective analysis of prospectively collected data.
SETTING:
Community.
PARTICIPANTS:
Serum creatinine and cystatin C were measured in 1,053 Cardiovascular Health Study (CHS) All Stars participants.
MEASUREMENTS:
Estimated glomerular filtration rate (eGFR) was determined using the Chronic Kidney Disease Epidemiology Collaboration creatinine (eGFRCR) and cystatin C one-variable (eGFRCYS) equations. The association between quintiles of kidney function and all-cause mortality was analyzed using unadjusted and adjusted Cox proportional hazards models.
RESULTS:
Mean age of the participants was 85, 64% were female, 66% had hypertension, 14% had diabetes mellitus, and 39% had prevalent cardiovascular disease. There were 154 deaths over a median follow-up of 2.6 years. The association between eGFRCR and all-cause mortality was U-shaped. In comparison with the reference quintile (64–75 mL/min per 1.73 m2), the highest (≥75 mL/min per 1.73 m2) and lowest (≤43 mL/min per 1.73 m2) quintiles of eGFRCR were independently associated with mortality (hazard ratio (HR) = 2.49, 95% confidence interval (CI) = 1.36–4.55; HR = 2.28, 95% CI = 1.26–4.10, respectively). The association between eGFRCYS and all-cause mortality was linear in those with eGFRCYS of less than 60 mL/min per 1.73 m2, and in the multivariate analyses, the lowest quintile of eGFRCYS (<52 mL/min per 1.73 m2) was significantly associated with mortality (HR = 2.04, 95% CI = 1.12–3.71) compared with the highest quintile (>0.88 mL/min per 1.73 m2).
CONCLUSION:
Moderate reduction in kidney function is a risk factor for all-cause mortality in octogenarians. The association between eGFRCR and all-cause mortality differed from that observed with eGFRCYS; the relationship was U-shaped for eGFRCR, whereas the risk was primarily present in the lowest quintile for eGFRCYS. J Am Geriatr Soc 2012.
doi:10.1111/j.1532-5415.2012.04046.x
PMCID: PMC3902776  PMID: 22724391
octogenarians; kidney function; mortality
7.  Association of Tenofovir Exposure with Kidney Disease Risk in HIV Infection 
AIDS (London, England)  2012;26(7):867-875.
Objective
Despite widespread highly active antiretroviral therapy use, HIV disease remains associated with increased risk of kidney disease. Whether tenofovir use is associated with higher risk of kidney disease is controversial.
Design
We evaluated the association of cumulative and ever exposure to tenofovir on kidney outcomes in 10,841 HIV-infected patients from the Veterans Health Administration who initiated antiretroviral therapy from 1997-2007.
Methods
Cox proportional hazards and marginal structural models evaluated associations between tenofovir and time to first occurrence of 1) proteinuria (two consecutive urine dipstick measurements ≥30mg/dL), 2) rapid decline in kidney function (≥3ml/min/1.73m2 annual decline), and 3) CKD (estimated glomerular filtration rate <60ml/min/1.73m2).
Results
Median follow-up ranged from 3.9 years (proteinuria) to 5.5 years (CKD), during which 3400 proteinuria, 3078 rapid decline, and 533 CKD events occurred. After multivariable adjustment, each year of exposure to tenofovir was associated with 34% increased risk of proteinuria (95%CI 25-45%, p<0.0001), 11% increased risk of rapid decline (3-18%, p=0.0033), and 33% increased risk of CKD (18-51%; p<0.0001). Pre-existing renal risk factors did not appear to worsen the effects of tenofovir. Other ARVs showed weaker or inconsistent associations with kidney disease events. Among those who discontinued tenofovir use, risk of kidney disease events did not appear to decrease during follow-up.
Conclusions
Tenofovir exposure was independently associated with increased risk for three types of kidney disease events, and did not appear to be reversible. Because subtle kidney function decline affects long-term morbidity and mortality, the balance between efficacy and probable adverse effects requires further study.
doi:10.1097/QAD.0b013e328351f68f
PMCID: PMC3736566  PMID: 22313955
HIV; antiretroviral therapy; kidney disease; tenofovir
8.  Apolipoprotein E and kidney function in older adults 
Clinical nephrology  2012;78(3):174-180.
Background
Previous studies suggest that the ε4 and ε2 alleles of apolipoprotein E (APOE) may be associated with decreased and increased risks of CKD, respectively, but there are limited data in older adults. We evaluated the associations of apolipoprotein E alleles with kidney function among older adults in the cardiovascular health study (CHS).
Methods
Caucasian participants had APOE allelic analysis and serum creatinine and cystatin C measured at baseline (n = 3,844 for cross sectional analysis) and in follow up (n = 3,226 for longitudinal analysis). APOE variation was evaluated as an additive model with number of ε2, ε3 and ε4 alleles. GFR was estimated using the CKD epidemiology equation (eGFRcreat) and the cystatin C demographic equation (eGFRcys). The primary outcome was CKD defined by eGFR < 60 ml/min/1.73 m2. The secondary outcome was rapid progression defined by annual loss of eGFR > 3 ml/min/1.73 m2.
Results
Mean eGFRcreat was 72 ml/min/1.73 m2 (25% CKD). Compared with the ε3 allele, the APOE ε4 allele was associated with reduced risk of CKD by eGFRcreat: unadjusted odds ratio (OR) and 95% confidence interval (CI) 0.79 (0.67 – 0.93) per allele, fully adjusted OR (95% CI) 0.80 (0.68 – 0.96) per allele. Results were consistent using eGFRcys. There was no association of the ε2 allele with CKD or between the apolipoprotein E gene with rapid progression.
Conclusions
The apolipoprotein ε4 allele was associated with lower odds of CKD in elderly Caucasian individuals. Future research should confirm these findings in other races and explore mechanisms to explain these results.
PMCID: PMC3874583  PMID: 22874105
apolipoprotein E; chronic kidney disease; kidney function; elderly
9.  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 (WIHS), we measured concentrations of albumin-to-creatinine ratio (ACR), interleukin-18 (IL-18), kidney injury marker-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) from stored urine among 908 HIV-infected and 289 uninfected participants. Primary analyses used cystatin C based estimated glomerular filtration rate (CKD-EPI eGFRcys) as the outcome, measured at baseline and two follow-up visits over eight 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 ACR (−0.15ml/min/1.73m2, p<0.0001), IL-18 (−0.09ml/min/1.73m2, p<0.0001) and KIM-1 (−0.06ml/min/1.73m2, p<0.001) were independently associated with faster eGFRcys decline after multivariate adjustment including all three biomarkers among HIV-infected women. Among these biomarkers, only IL-18 was associated with each dichotomized eGFRcys outcome: ≥3% (Relative Risk 1.40; 95%CI 1.04-1.89); ≥5% (1.88; 1.30-2.71); and ≥10% (2.16; 1.20-3.88) for the highest versus lowest tertile. In alternative models using eGFRcr, the high tertile of KIM-1 had independent associations with 5% (1.71; 1.25-2.33) and 10% (1.78; 1.07-2.96) decline, and the high IL-18 tertile with 10% decline (1.97; 1.00-3.87).
Conclusions
Among HIV-infected women in the WIHS cohort, novel urine markers of kidney injury detect risk for subsequent declines in kidney function.
doi:10.1097/QAI.0b013e3182737706
PMCID: PMC3509242  PMID: 23023103
HIV; KIM-1; NGAL; IL-18; albumin-to-creatinine ratio; cystatin C; kidney injury
10.  Urine Calcium Excretion, Cardiovascular Events and Mortality in Outpatients with Stable Coronary Artery Disease (From the Heart and Soul Study) 
The American journal of cardiology  2012;110(12):1729-1734.
We sought to evaluate the association of urine calcium excretion (UCaE), which reflects systemic calcium absorption, with CV events and mortality in outpatients with prevalent coronary heart disease (CHD). Calcium supplementation is associated with vascular calcification and adverse cardiovascular (CV) outcomes in patients with end-stage renal disease. Recent studies have raised concern that this phenomenon may also extend to the general population. However, prior studies assessed oral calcium intake, which correlates poorly with systemic calcium absorption. We measured UCaE from 24 hour urine collections provided by 903 outpatients who were recruited from 2000 to 2002. We used Cox proportional hazard models to evaluate the association of baseline UCaE with a primary endpoint of any CV event (myocardial infarction, heart failure, stroke, or CV mortality). During a mean follow-up of 6±3 years, 287 subjects (32%) had a CV event. Following multivariate adjustment for demographics, traditional CV risk factors, and kidney function, there was no association between UCaE and the primary endpoint of any CV event (per 10 mg/day greater UCaE: HR 1.00 95% CI 0.98–1.02). Evaluation of individual CV outcomes revealed a lower rate of MI with higher UCaE (HR 0.97, 95% CI 0.94–1.00). Greater UCaE is not associated with higher overall CV event rates or mortality in outpatients with stable CHD. In contrast, greater UCaE is associated with a modestly lower rate of MI. These findings suggest that greater systemic calcium absorption does not confer CV harm in outpatients with prevalent CHD.
doi:10.1016/j.amjcard.2012.08.007
PMCID: PMC3511634  PMID: 22975467
Calcium; Calcium Supplements; Cardiovascular Events; Coronary Artery Disease; Urine Calcium Excretion; Vascular Calcification
11.  Chronic kidney disease and cardiac remodelling in patients with mild heart failure: results from the REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction (REVERSE) study 
European Journal of Heart Failure  2012;14(12):1420-1428.
Aims
Chronic kidney disease (CKD) is a risk factor for left ventricular hypertrophy (LVH) and heart failure. We evaluated the effect of CKD on left ventricular (LV) remodelling among patients with mild heart failure.
Methods and results
REVERSE was a randomized, controlled trial evaluating cardiac resynchronization therapy (CRT) in patients with New York Heart Association (NYHA) class I/II heart failure. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. We compared changes in LV function and size over the course of 12 months by CKD status using linear mixed models adjusted for demographics, co-morbidities, medications, cardiomyopathy aetiology, and CRT status. Finally, we evaluated the effect of CKD on cardiac remodelling among patients randomized to CRT on or off. CKD was associated with worsening LV function and dilation compared with the non-CKD group {adjusted, 12-month β coefficients for the CKD group compared with the non-CKD referent group: LV ejection fraction (%) [–1.80, 95% confidence interval (CI) –3.36 to –0.24], LV end-systolic volume (mL) (14.16, 95% CI 3.96–24.36), LV end-diastolic volume (mL) (14.88, 95% CI 2.88–26.76), LV end-systolic diameter (cm) (0.36, 95% CI 0.12–0.48), LV end-diastolic diameter (cm) (0.24, 95% CI 0.012–0.36), mitral regurgitation (%) (3.12, 95% CI 0.48–5.76), and LV shape (0.036, 95% CI 0.012–0.060)}. In participants assigned to CRT, those without CKD had significantly greater improvements in LV structural parameters compared with the CKD group.
Conclusions
In comparison with participants with normal kidney function, CKD is an independent risk factor for ventricular dysfunction and dilation. CRT improves LV function and structure to a lesser extent in patients with CKD than in those with normal kidney function.
doi:10.1093/eurjhf/hfs135
PMCID: PMC3506959  PMID: 22956574
Chronic kidney disease; Heart failure; Cardiac resynchronization therapy
12.  Serum Cystatin C– Versus Creatinine-Based Definitions of Acute Kidney Injury Following Cardiac Surgery: A Prospective Cohort Study 
Background
The primary aim of this study was to compare the sensitivity and rapidity of AKI detection by cystatin C relative to creatinine following cardiac surgery.
Study Design
Prospective cohort study
Settings and Participants
1,150 high-risk, adult cardiac surgery patients in the TRIBE-AKI (Translational Research Investigating Biomarker Endpoints for Acute Kidney Injury) Consortium.
Predictor
Changes in serum creatinine and cystatin C
Outcome
Post-surgical incidence of AKI
Measurements
Serum creatinine and cystatin C were measured at the preoperative visit and daily on postoperative days 1–5. To allow comparisons between changes in creatinine and cystatin C, AKI endpoints were defined by the relative increases in each marker from baseline (25, 50 and 100%) and the incidence of AKI was compared based upon each marker. Secondary aims were to compare clinical outcomes among patients defined as having AKI by cystatin C and/or creatinine.
Results
Overall, serum creatinine detected more cases of AKI than cystatin C: 35% developed a ≥25% increase in serum creatinine, whereas only 23% had ≥25% increase in cystatin C (p < 0.001). Creatinine also had higher proportions meeting the 50% (14% and 8%, p<0.001) and 100% (4% and 2%, p=0.005) thresholds for AKI diagnosis. Clinical outcomes were generally not statistically different for AKI cases detected by creatinine or cystatin C. However, for each AKI threshold, patients with AKI confirmed by both markers had significantly higher risk of the combined mortality/dialysis outcome compared with patients with AKI detected by creatinine alone (p=0.002).
Limitations
There were few adverse clinical outcomes, limiting our ability to detect differences in outcomes between subgroups of patients based upon their definitions of AKI.
Conclusion
In this large multicenter study, we found that cystatin C was less sensitive for AKI detection compared with creatinine. However, confirmation by cystatin C appeared to identify a subset of AKI patients with substantially higher risk of adverse outcomes.
doi:10.1053/j.ajkd.2012.06.002
PMCID: PMC3496012  PMID: 22809763
13.  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) 
Background
Whether elevations of urinary biomarkers of tubular injury (urine neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1)) are associated with future risk of kidney disease has not been investigated.
Study Design
1:1 nested case-control study
Setting & Participants
686 participants in the Multi-Ethnic Study of Atherosclerosis (MESA).
Predictor
NGAL and KIM-1 were measured at baseline and expressed as log-transformed continuous variables and categorized into deciles.
Outcomes
Kidney function was estimated by cystatin C using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. Incident CKD Stage 3 was defined as eGFR <60 ml/min/1.73m2 and a eGFR decline >1 ml/min/1.73m2 per year, and rapid kidney function decline (RKFD) was defined as decline of ≥3 ml/min/1.73m2 per year.
Measurements
Cases were defined as persons with eGFR >60 ml/min/1.73m2 who subsequently developed incident CKD Stage 3 and/or had RKFD by MESA year 5 visit. Controls were matched for age, gender, race, diabetes, and baseline eGFR. We adjusted for age, hypertension and presence of albuminuria (ACR ≥30 mg/g).
Results
Of the 343 cases, 145 had incident CKD Stage 3, 141 had RKFD and 57 had both. Mean eGFR for controls was 81 (±10) ml/min/1.73m2 at baseline and 80 (±10) at follow-up, compared with 82 (±13) and 58 (±10) for cases. Each doubling of KIM-1 (pg/ml) was associated with an OR of 1.15 (95% CI, 1.02-1.29) for incident CKD Stage 3 and/or RKFD. Compared to the lowest 90%, the highest decile of KIM-1 was associated with an OR of 2.02 (95% CI, 1.15-3.56) for the outcome; these associations were independent of albuminuria. NGAL levels (ng/ml) were not associated with incident CKD Stage 3 and/or RKFD (OR, 1.04; 95% CI, 0.99-1.10). Results were similar when KIM-1 and NGAL were standardized for urine creatinine.
Limitations
The case-control design limits ability to account for persons who died or were not available for follow-up.
Conclusions
Urinary KIM-1 is associated with future risk of kidney disease independent of albuminuria. Urinary biomarkers of tubular injury are a promising tool for identifying persons at risk for CKD.
doi:10.1053/j.ajkd.2012.05.014
PMCID: PMC3690926  PMID: 22749388
KIM-1; NGAL; kidney function decline
14.  The Electrocardiographic PR Interval and Adverse Outcomes in Older Adults: the Health, Aging and Body Composition Study 
Background
The electrocardiographic PR interval increases with aging, differs by race, and is associated with atrial fibrillation (AF), pacemaker implantation and all-cause mortality. We sought to determine the associations between PR interval and heart failure, AF, and mortality in a biracial cohort of older adults.
Methods and results
The Health, Aging, and Body Composition (Health ABC) Study is a prospective, biracial cohort. We employed multivariable Cox proportional hazards models to examine PR interval (hazard ratios expressed per standard deviation (SD) increase) and 10-year risks of heart failure, AF, and all-cause mortality. Multivariable models included demographic, anthropometric, and clinical variables in addition to established cardiovascular risk factors. We examined 2722 Health ABC participants (age 74±3 years, 51.9% women, and 41% black). We did not identify significant effect modification by race for the outcomes studied. Following multivariable adjustment, every SD increase (29 ms) in PR interval was associated with a 13% greater 10-year risk of heart failure (95% confidence interval [CI], 1.02 to 1.25) and a 13% increased risk of incident AF (95% CI, 1.04 to 1.23). PR interval >200 ms was associated with a 46% increased risk of incident heart failure (95% CI, 1.11 to 1.93). PR interval was not associated with increased all-cause mortality.
Conclusions
We identified significant relations of PR interval to heart failure and AF in older adults. Our findings extend prior investigations by examining PR interval and associations with adverse outcomes in a biracial cohort of older men and women.
doi:10.1161/CIRCEP.112.975342
PMCID: PMC3613778  PMID: 23243193
PR interval; epidemiology; heart failure; atrial fibrillation; mortality; aging
15.  Inflammation and Coagulation Markers and Kidney Function Decline: The Multi-Ethnic Study of Atherosclerosis 
Background
The strength and direction of the associations between inflammation and coagulation biomarkers with kidney disease onset and progression remains unclear, especially in a population-based setting.
Study Design
Prospective observational study.
Setting & Participants
4,966 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with a cystatin C-based estimate of glomerular filtration rate (eGFRcys) > 60 ml/min/1.73m2 and least one follow-up measure of kidney function. All participants were free of cardiovascular disease (CVD) at entry.
Predictor
We evaluated the associations of C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen, factor VIII, and D-dimer with kidney function decline.
Outcomes and Measurements
Kidney function decline was assessed primarily by repeated measures of eGFRcys over 5 years. Rapid decline of kidney function was defined as an eGFR decrease of more than 3 ml/min/1.73m2 per year. Incident low eGFR was defined as the onset of eGFRcys<60 ml/min/1.73m2 at any follow up exam and eGFRcys decline ≥1 ml/min/1.73m2 per year.
Results
Mean age was 60 years, 39% were white, 52% were women, and 11% had diabetes. Mean eGFRcys was 96 mL/min/1.73 m2 and 7% had albuminuria. Median follow up time was 4.77 years. Higher Factor VIII levels (per 1-standard deviation [SD] of biomarker) had the strongest association with kidney function decline (β= −0.25; 95% CI, −0.38 to −0.12; p<0.001), followed by IL-6 (β= −0.16; 95% CI, −0.29 to −0.03; p=0.01), CRP (β= −0.09; 95% CI, −0.22 to 0.03; p=0.1), and fibrinogen (β= −0.09; 95% CI, −0.22 to 0.04; p=0.2). Each 1-SD higher concentration of IL-6 (OR, 1.15; 95% CI, 1.07–1.23), Factor VIII (OR, 1.11; 95% CI, 1.03–1.18), and CRP (OR, 1.09; 95% CI, 1.02–1.16) at baseline was significantly associated with rapid kidney function decline. Only IL-6 was significantly associated with incident low eGFR (OR, 1.09; 95% CI, 1.00–1.19).
Limitations
Observational study design and absence of measured GFR.
Conclusions
Inflammation and coagulation biomarkers are associated with declining kidney function in ambulatory adults without established CVD or CKD.
doi:10.1053/j.ajkd.2012.02.335
PMCID: PMC3745301  PMID: 22560844
16.  Occult chronic kidney disease among persons with hypertension in the United States: data from the national health and nutrition surveys 1988–1994 and 1999–2002 
Journal of hypertension  2013;31(6):1196-1202.
Objectives
Hypertension guidelines recommend screening for chronic kidney disease (CKD) using serum creatinine and urine dipstick; this strategy may lead to misclassification. Persons with occult CKD [i.e. missed by creatinine but detected by cystatin C or albumin-to-creatinine ratio (ACR)] have higher risks for death, cardiovascular events, and end-stage renal disease.
Methods
We studied occult CKD prevalence among nondiabetic, hypertensive adults in National Health and Nutrition Examination Survey 1988–1994 (N = 2088) and 1999–2002 (N = 737). We defined occult CKD as estimated glomerular filtration rate by cystatin C (eGFRcys) less than 60 ml/min per 1.73m2 and/or ACR at least 30 mg/g among persons with eGFRcreat more than 60 ml/min per 1.73m2. We studied occult CKD prevalence by either marker, stratified by age, race/ethnicity, and assessed clinical predictors associated with occult CKD presence.
Results
In 1988–1994, occult CKD was prevalent among 25% of nondiabetic hypertensive persons, and it was 22% in 1999–2002. Each marker’s ability to detect occult CKD varied by age and race. Cystatin C detected occult CKD among 8.9% of persons more than 65 years, and among 3.8% of whites. ACR detected occult CKD among 9.3% of persons less than 45 years, 16.6% of Blacks, and 20.6% of Mexican–Americans. In multivariate models, each decade of advancing age was associated with a higher occult CKD prevalence by cystatin C (OR 3.1, 95% CI 2.5–3.8) in 1988–1994 and 1999–2002 (OR 2.9, 1.8–4.6).
Conclusion
Current hypertension guidelines may fail to detect a large proportion of high-risk individuals with CKD who can be identified by cystatin C or ACR. Future studies are needed to evaluate targeted use of multimarker renal panels among hypertensives.
doi:10.1097/HJH.0b013e328360ae2d
PMCID: PMC3733337  PMID: 23640605
albumin-to-creatinine ratio; chronic kidney disease; cystatin C; National Health and Nutrition Examination Survey
17.  Intermuscular Adipose Tissue and Metabolic Associations in HIV Infection 
Obesity (Silver Spring, Md.)  2010;19(2):283-291.
Intermuscular adipose tissue (IMAT) is associated with metabolic abnormalities similar to those associated with visceral adipose tissue (VAT). Increased IMAT has been found in obese human immunodeficiency virus (HIV)-infected women. We hypothesized that IMAT, like VAT, would be similar or increased in HIV-infected persons compared with healthy controls, despite decreases in subcutaneous adipose tissue (SAT) found in HIV infection. In the second FRAM (Study of Fat Redistribution and Metabolic Change in HIV infection) exam, we studied 425 HIV-infected subjects and 211 controls (from the Coronary Artery Risk Development in Young Adults study) who had regional AT and skeletal muscle (SM) measured by magnetic resonance imaging (MRI). Multivariable linear regression identified factors associated with IMAT and its association with metabolites. Total IMAT was 51% lower in HIV-infected participants compared with controls (P = 0.003). The HIV effect was attenuated after multivariable adjustment (to −28%, P < 0.0001 in men and −3.6%, P = 0.70 in women). Higher quantities of leg SAT, upper-trunk SAT, and VAT were associated with higher IMAT in HIV-infected participants, with weaker associations in controls. Stavudine use was associated with lower IMAT and SAT, but showed little relationship with VAT. In multivariable analyses, regional IMAT was associated with insulin resistance and triglycerides (TGs). Contrary to expectation, IMAT is not increased in HIV infection; after controlling for demographics, lifestyle, VAT, SAT, and SM, HIV+ men have lower IMAT compared with controls, whereas values for women are similar. Stavudine exposure is associated with both decreased IMAT and SAT, suggesting that IMAT shares cellular origins with SAT.
doi:10.1038/oby.2010.115
PMCID: PMC3731045  PMID: 20539305
18.  HIV viremia and changes in kidney function 
AIDS (London, England)  2009;23(9):1089-1096.
Objective
To evaluate the effect of HIV infection on longitudinal changes in kidney function and to identify independent predictors of kidney function changes in HIV-infected individuals.
Design
A prospective cohort.
Methods
Cystatin C was measured at baseline and at the 5-year follow-up visit of the Study of Fat Redistribution and Metabolic Change in HIV infection in 554 HIV-infected participants and 230 controls. Control participants were obtained from the Coronary Artery Risk Development in Young Adults study. Glomerular filtration rate (eGFRcys) was estimated using the formula 76.7 × cysC−1.19.
Results
Compared with controls, HIV-infected participants had a greater proportion of clinical decliners (annual decrease in eGFRcys > 3 ml/min per 1.73 m2; 18 versus 13%, P=0.002) and clinical improvers (annual increase in eGFRcys > 3 ml/min per 1.73 m2; 26 versus 6%, P< 0.0001). After multivariable adjustment, HIV infection was associated with higher odds of both clinical decline (odds ratio 2.2; 95% confidence interval 1.3, 3.9, P = 0.004) and clinical improvement (odds ratio 7.3; 95% confidence interval 3.9, 13.6, P ≤ 0.0001). Among HIV-infected participants, a decrease in HIV viral load during follow-up was independently associated with clinical improvement; conversely, higher baseline and an increase in viral load during follow-up were associated with clinical decline. No individual antiretroviral drug or drug class appeared to be substantially associated with clinical decline or improvement.
Conclusion
Compared with controls, HIV-infected persons were more likely both to have clinical decline and clinical improvement in kidney function during 5 years of follow-up. The extent of viremic control had a strong association with longitudinal changes in kidney function.
doi:10.1097/QAD.0b013e32832a3f24
PMCID: PMC3725756  PMID: 19352136
cystatin C; glomerular filtration rate; HIV; kidney; viral load
19.  Risk Factors for Peripheral Arterial Disease among Patients with Chronic Kidney Disease 
The American journal of cardiology  2012;110(1):136-141.
Patients with chronic kidney disease (CKD) have an increased risk of developing peripheral arterial disease (PAD). We examined the cross-sectional association between novel risk factors and prevalent PAD among patients with CKD. A total of 3,758 patients with an estimated glomerular filtration rate (eGFR) of 20-70 mL/min/1.73 m2 who participated in the chronic renal insufficiency cohort (CRIC) study were included in the current analysis. PAD was defined as an ankle-brachial index <0.9 or a history of arm or leg revascularization. After adjustment for age, sex, race, cigarette smoking, physical activity, history of hypertension and diabetes, pulse pressure, high-density lipoprotein cholesterol, eGFR, and CRIC clinical sites, several novel risk factors were significantly associated with PAD. For example, odds ratios (95% confidence intervals) for a one standard deviation higher level of risk factors were 1.18 (1.08–1.29) for log-transformed high sensitivity-C reactive protein, 1.18 (1.08–1.29) for white blood cell count, 1.15 (1.05–1.25) for fibrinogen, 1.13 (1.03–1.24) for uric acid, 1.14 (1.02–1.26) for hemoglobin A1c, 1.11 (1.00–1.23) for log-transformed homeostasis model assessment-insulin resistance, and 1.35 (1.18–1.55) for cystatin C. In conclusion, these data indicate that inflammation, prothrombotic state, oxidative stress, insulin resistance, and cystatin C were associated with an increased prevalence of PAD in patients with CKD. Further studies are warranted to examine the causal effect of these risk factors on PAD in CKD patients.
doi:10.1016/j.amjcard.2012.02.061
PMCID: PMC3586781  PMID: 22465315
peripheral arterial disease; novel risk factors; chronic kidney disease
20.  Detection of Chronic Kidney Disease With Creatinine, Cystatin C, and Urine Albumin-to-Creatinine Ratio and Association With Progression to End-Stage Renal Disease and Mortality 
Context
A triple-marker approach for chronic kidney disease (CKD) evaluation has not been well studied.
Objective
To evaluate whether combining creatinine, cystatin C, and urine albumin-to-creatinine ratio (ACR) would improve identification of risks associated with CKD compared with creatinine alone.
Design, Setting, and Participants
Prospective cohort study involving 26 643 US adults enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study from January 2003 to June 2010. Participants were categorized into 8 groups defined by estimated glomerular filtration rate (GFR) determined by creatinine and by cystatin C of either <60 or ≥60 mL/min/1.73 m2 and ACR of either <30 or ≥30 mg/g.
Main Outcome Measures
All-cause mortality and incident end-stage renal disease with median follow-up of 4.6 years.
Results
Participants had a mean age of 65 years, 40% were black, and 54% were women. Of 26 643 participants, 1940 died and 177 developed end-stage renal disease. Among participants without CKD defined by creatinine, 24% did not have CKD by either ACR or cystatin C. Compared with those with CKD defined by creatinine alone, the hazard ratio for death in multivariable-adjusted models was 3.3 (95% confidence interval [CI], 2.0–5.6) for participants with CKD defined by creatinine and ACR; 3.2 (95% CI, 2.2–4.7) for those with CKD defined by creatinine and cystatin C, and 5.6 (95% CI, 3.9–8.2) for those with CKD defined by all biomarkers. Among participants without CKD defined by creatinine, 3863 (16%) had CKD detected by ACR or cystatin C. Compared with participants who did not have CKD by any measure, the HRs for mortality were 1.7 (95% CI, 1.4–1.9) for participants with CKD defined by ACR alone, 2.2 (95% CI, 1.9–2.7) for participants with CKD defined by cystatin C alone, and 3.0 (95% CI, 2.4–3.7) for participants with CKD defined by both measures. Risk of incident end-stage renal disease was higher among those with CKD defined by all markers (34.1 per 1000 person-years; 95% CI, 28.7–40.5 vs 0.33 per 1000 person-years; 95% CI, 0.05–2.3) for those with CKD defined by creatinine alone. The second highest end-stage renal disease rate was among persons missed by the creatinine measure but detected by both ACR and cystatin C (rate per 1000 person-years, 6.4; 95% CI, 3.6–11.3). Net reclassification improvement for death was 13.3% (P<.001) and for end-stage renal disease was 6.4% (P<.001) after adding estimated GFR cystatin C in fully adjusted models with estimated GFR creatinine and ACR.
Conclusion
Adding cystatin C to the combination of creatinine and ACR measures improved the predictive accuracy for all-cause mortality and end-stage renal disease.
doi:10.1001/jama.2011.468
PMCID: PMC3697771  PMID: 21482744
21.  Risk Factors for ESRD in HIV-Infected Individuals: Traditional and HIV-Related Factors 
Background
Despite improvements in survival with HIV infection, kidney disease remains an important complication. Few studies have evaluated risk factors associated with development of end-stage renal disease (ESRD) in HIV-infected individuals. We sought to identify traditional and HIV-related risk factors for ESRD in HIV-infected individuals, and to compare ESRD risk by eGFR and proteinuria levels.
Study design
Retrospective cohort study.
Setting and Participants
22,156 HIV-infected veterans without preexisting ESRD receiving healthcare in the Veterans’ Affairs medical system between 1996 and 2004.
Predictors
Hypertension, diabetes, cardiovascular disease, hypoalbuminemia (serum albumin<3.5mg/dL), CD4 lymphocyte count, HIV viral load, hepatitis C virus coinfection, proteinuria, and estimated glomerular filtration rate (eGFR) were identified using the Veterans’ Affairs electronic record system.
Outcomes
ESRD was ascertained by the United States Renal Data System.
Results
366 cases of ESRD occurred, corresponding to 3 cases per 1,000 person-years. Hypertension (HR, 1.9; 95% CI, 1.5–2.4), diabetes (HR, 1.7; 95% CI, 1.3–2.2), and cardiovascular disease (HR, 2.2; 95% CI, 1.7–2.7) were independently associated with ESRD risk in multivariate-adjusted models, as were CD4 lymphocyte count <200 cells/mm3 (HR, 1.5; 95% CI, 1.2–2.0), HIV viral load ≥30,000 copies/mL (HR, 2.0; 95% CI, 1.5–2.8), hepatitis C virus coinfection (HR, 1.9; 95% CI, 1.5–2.4), and hypoalbuminemia (HR, 2.1; 95% CI, 1.8–2.5). Compared to persons without chronic kidney disease (CKD), defined as eGFR>60mg/min/1.73m2 and no proteinuria, lower eGFR and higher proteinuria categories were jointly associated with exponentially higher ESRD rates, ranging from 6.6 per 1000 person-years for persons with proteinuria 30–100 mg/dL and eGFR>60ml/min/1.73m2, to 193 per 1000 person-years for persons with proteinuria ≥300mg/dL and eGFR<30ml/min/1.73m2.
Limitations
Results may not be generalizable to female and nonveteran populations.
Conclusions
In HIV-infected persons, ESRD risk appears attributable to a combination of traditional and HIV-related risk factors for kidney disease. Combining eGFR and proteinuria for CKD staging is most effective for stratifying risk for ESRD.
doi:10.1053/j.ajkd.2011.10.050
PMCID: PMC3324595  PMID: 22206742
End-stage renal disease; HIV; chronic kidney disease; risk factors
22.  Incidence and Risk Factors for Acute Kidney Injury in HIV Infection 
American Journal of Nephrology  2012;35(4):327-334.
Background/Aims
Although HIV-infected persons are at higher risk for acute kidney injury (AKI) during hospitalization compared with their uninfected counterparts, risk factors for AKI are not well-defined. We aimed to describe the evolving incidence of AKI among HIV-infected individuals and to identify important AKI risk factors.
Methods
We conducted a prospective cohort study of 56,823 HIV-infected persons in the Department of Veterans Affairs Clinical Case Registry. Outcomes were: AKI (acute in-hospital serum creatinine increase of ≥0.3 mg/dl, or a relative increase by 50% or greater), and dialysis-requiring AKI. We used proportional hazards regressions to identify risk factors.
Results
From its peak in 1995 at 62 per 1,000 person-years, the incidence of AKI declined after the introduction of highly active antiretroviral therapy (HAART) in 1996 to a low point of 25 per 1,000 person-years in 2006. Incidence of dialysis-requiring AKI declined in the early 1990s, but doubled between 2000 and 2006. Using multivariate proportional hazard regression, we identified the following strong risk factors for AKI: chronic kidney disease (eGFR <60 ml/min/1.73 m2) (5.38, 95% CI: 5.11–5.67), proteinuria (1.78, 1.70–1.87), low serum albumin (<3.7 mg/dl) (5.24, 4.82–5.71), low body mass index (<18.5 kg/m2) (1.69, 1.54–1.86), cardiovascular disease (1.77, 1.66–1.89), low CD4 count (<200 cells/mm3) (2.54, 2.33–2.77), and high viral load (≥100,000 copies/ml) (2.51, 2.28–2.75). In addition, there was substantial heterogeneity in the strengths of risk factors for dialysis-requiring AKI before and after the introduction of HAART.
Conclusions
Although AKI incidence has decreased during the HAART era, it remains common in HIV-infected persons and appears attributable to both kidney- and HIV-related factors.
doi:10.1159/000337151
PMCID: PMC3362304  PMID: 22456100
Acute kidney injury; HIV; Chronic kidney disease; Proteinuria; Hypoalbuminemia
23.  Pre-Operative Serum Brain Natriuretic Peptide and Risk of Acute Kidney Injury after Cardiac Surgery 
Circulation  2012;125(11):1347-1355.
Background
Acute kidney injury (AKI) following cardiac surgery is associated with poor outcomes and is difficult to predict. We conducted a prospective study to evaluate whether pre-operative brain natriuretic peptide (BNP) levels predict postoperative AKI among patients undergoing cardiac surgery.
Methods and Results
The TRIBE-AKI Consortium enrolled 1,139 adults undergoing cardiac surgery at six hospitals from 2007–2009, who were selected for high AKI risk. Pre-operative BNP was categorized into quintiles. AKI was common using Acute Kidney Injury Network definitions; at least mild AKI was a ≥0.3mg/dL or 50% rise in creatinine, n=407 (36%), and severe AKI was either a doubling of creatinine or the requirement of acute renal replacement therapy, n=58 (5.1%). In analyses adjusted for pre-operative characteristics, pre-operative BNP was a strong and independent predictor of mild and severe AKI. Compared with the lowest BNP quintile the highest quintile had significantly higher risk of at least mild AKI (risk ratio [RR] 1.87; 1.40–2.49) and severe AKI (RR 3.17; 1.06–9.48). After adjustment for clinical predictors, addition of BNP improved the area under the curve to predict at least mild AKI (0.67 to 0.69, p=0.02) and severe AKI (0.73 to 0.75, p=0.11). Compared with clinical parameters alone, BNP modestly improved risk prediction of AKI cases into lower and higher risk (continuous net reclassification index at least mild AKI 0.183; 0.061, 0.314; severe AKI 0.231; 0.067, 0.506).
Conclusions
Pre-operative BNP level is associated with post-operative AKI in high-risk patients undergoing cardiac surgery. If confirmed in other types of patients and surgeries, pre-operative BNP may be a valuable component of future efforts to improve pre-operative risk stratification and discrimination among surgical candidates.
doi:10.1161/CIRCULATIONAHA.111.029686
PMCID: PMC3312808  PMID: 22322531
brain natriuretic peptide; cardiac surgery; acute renal failure; creatinine
24.  Urine Biomarkers Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Injury Molecule-1 (KIM-1) Have Different Patterns in Heart Failure Exacerbation 
Biomarker Insights  2013;8:15-18.
Individuals with acute heart failure exacerbation often experience a deterioration in renal function. We sought to determine whether this deterioration is ischemic in nature and detectable by sensitive urine biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). We measured serial biomarker levels and evaluated the associations of these biomarkers with renal recovery in a cohort of hospitalized patients with acute heart failure exacerbation.
doi:10.4137/BMI.S11479
PMCID: PMC3603387  PMID: 23531625
acute kidney injury; urine biomarkers; heart failure
25.  The Risk of Infection-Related Hospitalization With Decreased Kidney Function 
Background
Moderate kidney disease may predispose to infection. We sought to determine whether decreased kidney function, as estimated by serum cystatin C, was associated with the risk of infection-related hospitalization in older individuals.
Study Design
Cohort Study.
Setting & Participants
5,142 Cardiovascular Health Study participants with measured serum creatinine and cystatin C and without eGFR <15 ml/min/1.73 m2 at enrollment.
Predictor
The primary exposure of interest was estimated glomerular filtration rate using serum cystatin C (eGFRSCysC).
Outcome
Infection-related hospitalizations during a median follow-up of 11.5 years.
Results
In adjusted analyses, eGFRSCysC categories of 60–89, 45–59, and 15–44 ml/min/1.73 m2 were associated with 16%, 37%, and 64% greater risk of all-cause infection-related hospitalization, respectively, compared with an eGFRSCysC ≥90 ml/min/1.73 m2. When cause specific infection was examined, an eGFRSCysC of 15–44 ml/min/1.73 m2 was associated with an 80% greater risk of pulmonary and 160% greater risk of genitourinary infection compared with an eGFRSCysC ≥90 ml/min/1.73 m2.
Limitations
No measures of urinary protein, study limited to principal discharge diagnosis.
Conclusions
Lower kidney function, estimated using cystatin C, was associated with a linear and graded risk of infection-related hospitalization. These findings highlight that even moderate degrees of reduced kidney function are associated with clinically significant higher risks of serious infection in older individuals.
doi:10.1053/j.ajkd.2011.07.012
PMCID: PMC3288732  PMID: 21906862
renal disease; chronic kidney disease; infection; clinical epidemiology

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