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1.  Common Clinical Conditions – Age, Low BMI, Ritonavir Use, Mild Renal Impairment - Affect Tenofovir Pharmacokinetics in a Large Cohort of HIV-Infected Women 
AIDS (London, England)  2014;28(1):59-66.
Objective
Tenofovir is used commonly in HIV treatment and prevention settings, but factors that correlate with tenofovir exposure in real-world setting are unknown.
Design
Intensive pharmacokinetic (PK) studies of tenofovir in a large, diverse cohort of HIV-infected women over 24-hours at steady-state were performed and factors that influenced exposure (assessed by areas-under-the-time-concentration curves, AUCs) identified
Methods
HIV-infected women (n=101) on tenofovir-based therapy underwent intensive 24-hour PK sampling. Data on race/ethnicity, age, exogenous steroid use, menstrual cycle phase, concomitant medications, recreational drugs and/or tobacco, hepatic and renal function, weight and body mass index (BMI) were collected. Multivariable models using forward stepwise selection identified factors associated with effects on AUC. Glomerular filtration rates (GFR) prior to starting tenofovir were estimated by the CKD-EPI equation using both creatinine and cystatin-C measures
Results
The median (range) of tenofovir AUCs was 3350 (1031–13,911) ng x h/mL. Higher AUCs were associated with concomitant ritonavir use (1.33-fold increase, p 0.002), increasing age (1.21-fold increase per decade, p=0.0007) and decreasing BMI (1.04-fold increase per 10% decrease in BMI). When GFR was calculated using cystatin-C measures, mild renal insufficiency prior to tenofovir initiation was associated with higher subsequent exposure (1.35-fold increase when pre-tenofovir GFR <70mL/min, p=0.0075).
Conclusions
Concomitant ritonavir use, increasing age, decreasing BMI and lower GFR prior to tenofovir initiation as estimated by cystatin C were all associated with elevated tenofovir exposure in a diverse cohort of HIV-infected women. Clinicians treating HIV-infected women should be aware of common clinical conditions that affect tenofovir exposure when prescribing this medication.
doi:10.1097/QAD.0000000000000033
PMCID: PMC3956315  PMID: 24275255
Tenofovir; pharmacokinetics; HIV-infected women; diverse populations; GFR; cystatin C
2.  Association of a Cystatin C Gene Variant With Cystatin C Levels, CKD, and Risk of Incident Cardiovascular Disease and Mortality 
Background
Carriers of the T allele of the single-nucleotide polymorphism rs13038305 tend to have lower cystatin C levels and higher cystatin C-based estimated glomerular filtration rate (eGFRcys). Adjusting for this genetic effect on cystatin C concentrations may improve GFR estimation, reclassify cases of CKD, and strengthen risk estimates for cardiovascular disease (CVD) and mortality.
Study Design
Observational.
Setting & Population
Four population-based cohorts: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health (CHS), Framingham Heart (FHS), and Health, Aging, and Body Compostion (Health ABC) studies.
Predictors
We estimated the association of rs13038305 with eGFRcys and eGFRcr, and performed longitudinal analyses of the associations of eGFRcys with mortality and cardiovascular events following adjustment for rs13038305.
Outcomes
We assessed reclassification by genotype-adjusted eGFRcys across CKD categories: <45, 45–59, 60–89, and ≥90 mL/min/1.73 m2. We compared mortality and CVD outcomes in those reclassified to a worse eGFRcys category with those unaffected. Results were combined using fixed-effect inverse-variance meta-analysis.
Results
In 14,645 participants, each copy of the T allele of rs13038305 (frequency, 21%), was associated with 6.4% lower cystatin C concentration, 5.5 mL/min/1.73 m2 higher eGFRcys, and 36% [95% CI, 29%–41%] lower odds of CKD. Associations with CVD (HR, 1.17; 95% CI, 1.14–1.20) and mortality (HR, 1.22; 95% CI, 1.19–1.24) per 10- ml/min/1.73 m2 lower eGFRcys were similar with or without rs13038305 adjustment. In total, 1134 participants (7.7%) were reclassified to a worse CKD category following rs13038305 adjustment, and rates of CVD and mortality were higher in individuals who were reclassified. However, the overall net reclassification index was not significant for either outcome, at 0.009 (95% CI, −0.003 to 0.022) for mortality and 0.014 (95% CI, 0.0 to 0.028) for CVD.
Limitations
rs13038305 only explains a small proportion of cystatin C variation.
Conclusions
Statistical adjustment can correct a genetic bias in GFR estimates based on cystatin C in carriers of the T allele of rs13038305 and result in changes in disease classification. However, on a population level, the effects on overall reclassification of CKD status are modest.
doi:10.1053/j.ajkd.2013.06.015
PMCID: PMC3872167  PMID: 23932088
Cystatin C; chronic kidney disease; genetics; single nucleotide polymorphism; net reclassification improvement
3.  HIV/HCV coinfection ameliorates the atherogenic lipoprotein abnormalities of HIV infection 
AIDS (London, England)  2014;28(1):49-58.
Background
Higher levels of small low-density lipoprotein (LDL) and lower levels of high-density lipoprotein (HDL) subclasses have been associated with increased risk of cardiovascular disease. The extent to which HIV infection and HIV/HCV coinfection are associated with abnormalities of lipoprotein subclasses is unknown.
Methods
Lipoprotein subclasses were measured by nuclear magnetic resonance (NMR) spectroscopy in plasma samples from 569 HIV-infected and 5948 control participants in the FRAM, CARDIA and MESA studies. Multivariable regression was used to estimate the association of HIV and HIV/HCV coinfection with lipoprotein measures with adjustment for demographics, lifestyle factors, and waist-to-hip ratio.
Results
Relative to controls, small LDL levels were higher in HIV-monoinfected persons (+381 nmol/L, p<.0001), with no increase seen in HIV/HCV coinfection (−16.6 nmol/L). Levels of large LDL levels were lower (−196 nmol/L, p<.0001) and small HDL were higher (+8.2 μmol/L, p<.0001) in HIV-monoinfection with intermediate values seen in HIV/HCV-coinfection. Large HDL levels were higher in HIV/HCV-coinfected persons relative to controls (+1.70 μmol/L, p<.0001), whereas little difference was seen in HIV-monoinfected persons (+0.33, p=0.075). Within HIV-infected participants, HCV was associated independently with lower levels of small LDL (−329 nmol/L, p<.0001) and small HDL (−4.6 μmol/L, p<.0001), even after adjusting for demographic and traditional cardiovascular risk factors.
Conclusion
HIV-monoinfected participants had worse levels of atherogenic LDL lipoprotein subclasses compared with controls. HIV/HCV coinfection attenuates these changes, perhaps by altering hepatic factors affecting lipoprotein production and/or metabolism. The effect of HIV/HCV coinfection on atherosclerosis and the clinical consequences of low small subclasses remain to be determined.
doi:10.1097/QAD.0000000000000026
PMCID: PMC4267724  PMID: 24136113
HIV infection; HCV infection; lipoproteins; cardiovascular disease
4.  Fibroblast Growth Factor 23, Left Ventricular Mass, and Left Ventricular Hypertrophy in Community-Dwelling Older Adults 
Atherosclerosis  2013;231(1):10.1016/j.atherosclerosis.2013.09.002.
Objectives
In chronic kidney disease (CKD), high FGF23 concentrations are associated with left ventricular hypertrophy (LVH), cardiovascular events, and death. The associations of FGF23 with left ventricular mass (LVM) and LVH in the general population and the influence of CKD remains uncertain.
Methods
C-terminal plasma FGF23 concentrations were measured, and LVM and LVH evaluated by echocardiogram among 2255 individuals ≥65 years in the Cardiovascular Health Study. Linear regression analysis adjusting for demographics, cardiovascular, and kidney related risk factors examined the associations of FGF23 concentrations with LVM. Analyses were stratified by CKD status and adjusted linear and logistic regression analysis explored the associations of FGF23 with LVM and LVH.
Results
Among the entire cohort, higher FGF23 concentrations were associated with greater LVM in adjusted analyses (β=6.71 [95% CI 4.35–9.01] g per doubling of FGF23). 32% (n=624) had CKD (eGFR <60 mL/min/1.73m2 and/or urine albumin-to-creatinine ratio >30 mg/g). Associations were stronger among participants with CKD (p interaction = 0.006): LVM β=9.71 [95% CI 5.86–13.56] g per doubling of FGF23 compared to those without CKD (β=3.44 [95% CI 0.77, 6.11] g per doubling of FGF23). While there was no significant interaction between FGF23 and CKD for LVH (p interaction = 0.25), the OR (1.46 95% CI [1.20–1.77]) in the CKD group was statistically significant and of larger magnitude than the OR for in the no CKD group (1.12 [95% CI 0.97–1.48]).
Conclusion
In a large cohort of older community-dwelling adults, higher FGF23 concentrations were associated with greater LVM and LVH with stronger relationships in participants with CKD.
doi:10.1016/j.atherosclerosis.2013.09.002
PMCID: PMC3840534  PMID: 24125420
Left ventricular mass; left ventricular hypertrophy; chronic kidney disease; fibroblast growth factor 23; older adults; cardiovascular disease
5.  A chronic kidney disease risk score to determine tenofovir safety in a prospective cohort of HIV-positive male veterans 
AIDS (London, England)  2014;28(9):1289-1295.
Objective
Tenofovir disoproxil fumarate is a widely used antiretroviral for HIV infection that has been associated with an increased risk of chronic kidney disease (CKD). Our objective was to derive a scoring system to predict 5-year risk of developing CKD in HIV-infected individuals and to estimate difference in risk associated with tenofovir use.
Design
We evaluated time to first occurrence of CKD (estimated glomerular filtration rate <60 ml/min per 1.73 m2) in 21 590 HIV-infected men from the Veterans Health Administration initiating antiretroviral therapy from 1997 to 2010.
Methods
We developed a point-based score using multivariable Cox regression models. Median follow-up was 6.3 years, during which 2059 CKD events occurred.
Results
Dominant contributors to the CKD risk score were traditional kidney risk factors (age, glucose, SBP, hypertension, triglycerides, proteinuria); CD4+ cell count was also a component, but not HIV RNA. The overall 5-year event rate was 7.7% in tenofovir users and 3.8% in nonusers [overall adjusted hazard ratio 2.0, 95% confidence interval (CI) 1.8–2.2]. There was a progressive increase in 5-year CKD risk, ranging from less than 1% (zero points) to 16% (≥9 points) in nonusers of tenofovir, and from 1.4 to 21.4% among tenofovir users. The estimated number-needed-to-harm (NNH) for tenofovir use ranged from 108 for those with zero points to 20 for persons with at least nine points. Among tenofovir users with at least 1 year exposure, NNH ranged from 68 (zero points) to five (≥9 points).
Conclusion
The CKD risk score can be used to predict an HIV-infected individual’s absolute risk of developing CKD over 5 years and may facilitate clinical decision-making around tenofovir use.
doi:10.1097/QAD.0000000000000258
PMCID: PMC4188545  PMID: 24922479
chronic kidney disease; HIV; risk score; tenofovir
6.  Influence of Urine Creatinine Concentrations on the Relation of Albumin-Creatinine Ratio With Cardiovascular Disease Events: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Higher urine albumin-creatinine ratio (ACR) is associated with cardiovascular disease (CVD) events, an association that is stronger than that between spot urine albumin on its own and CVD. Urine creatinine is correlated with muscle mass, and low muscle mass is also associated with CVD. Whether low urine creatinine in the denominator of the ACR contributes to the association of ACR with CVD is uncertain.
Study Design
Prospective cohort study.
Setting & Participants
6,770 community-living individuals without CVD.
Predictors
Spot urine albumin, the reciprocal of the urine creatinine concentration (1/UCr), and ACR.
Outcome
Incident CVD events.
Results
During a mean of 7.1 years’ follow-up, 281 CVD events occurred. Geometric means for spot urine creatinine, urine albumin and ACR were 95 ± 2 (SD) mg/dl, 0.7 ± 3.7 mg/dl and 7.0 ± 3.1 mg/g. Adjusted HRs per 2-fold higher increment in each urinary measures with CVD events were similar (1/UCr: 1.07 [95% CI, 0.94-1.22]; urine albumin: 1.08 [95% CI, 1.01-1.14]; and ACR: 1.11 [95% CI, 1.04-1.18]). Urine creatinine was lower in older, female, and low weight individuals. ACR ≥10 mg/g was more strongly associated with CVD events in individuals with low weight (HR for lowest vs. highest tertile: 4.34 vs. 1.97; p for interaction=0.006). Low weight also modified the association of urine albumin with CVD (p for interaction=0.06), but 1/urine creatinine did not (p for interaction=0.9).
Limitations
We lacked 24-hour urine data.
Conclusions
While ACR is more strongly associated with CVD events among persons with low body weight, this association is not driven by differences in spot urine creatinine. Overall, the associations of ACR with CVD events appear to be driven primarily by urine albumin and less by urine creatinine.
doi:10.1053/j.ajkd.2013.05.010
PMCID: PMC3783582  PMID: 23830183
7.  Association of Obesity and Kidney Function Decline among Non-Diabetic Adults with eGFR > 60 ml/min/1.73m2: Results from the Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Obesity is associated with higher end-stage renal disease incidence, but associations with earlier forms of kidney disease remain incompletely characterized.
Methods
We studied the association of body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) with rapid kidney function decline and incident chronic kidney disease in 4573 non-diabetic adults with eGFR ≥ 60 ml/min/1.73m2 at baseline from longitudinal Multi-Ethnic Study of Atherosclerosis cohort. Kidney function was estimated by creatinine and cystatin C. Multivariate analysis was adjusted for age, race, baseline eGFR, and hypertension.
Results
Mean age was 60 years old, BMI 28 kg/m2, baseline eGFRCr 82 and eGFRCys 95 ml/min/1.73m2. Over 5 years of follow up, 25% experienced rapid decline in renal function by eGFRCr and 22% by eGFRCys. Incident chronic kidney disease (CKD) developed in 3.3% by eGFRCys, 11% by eGFRCr, and 2.4% by both makers. Compared to persons with BMI < 25, overweight (BMI 25 – 30) persons had the lowest risk of rapid decline by eGFRCr (0.84, 0.71 – 0.99). In contrast, higher BMI categories were associated with stepwise higher odds of rapid decline by eGFRCys, but remained significant only when BMI ≥ 35 kg/m2 (1.87, 1.41 – 2.48). Associations of BMI with incident CKD were insignificant after adjustment. Large WC and WHR were associated with increased risk of rapid decline only by eGFRCys, and of incident CKD only when defined by both filtration markers.
Conclusions
Obesity may be a risk factor for kidney function decline, but associations vary by filtration marker used.
PMCID: PMC4157691  PMID: 25210651
Kidney Function Decline; MESA; Obesity; Waist Circumference; Waist-to-Hip Ratio
8.  Cystatin C versus Creatinine in Determining Risk Based on Kidney Function 
The New England journal of medicine  2013;369(10):932-943.
BACKGROUND
Adding the measurement of cystatin C to that of serum creatinine to determine the estimated glomerular filtration rate (eGFR) improves accuracy, but the effect on detection, staging, and risk classification of chronic kidney disease across diverse populations has not been determined.
METHODS
We performed a meta-analysis of 11 general-population studies (with 90,750 participants) and 5 studies of cohorts with chronic kidney disease (2960 participants) for whom standardized measurements of serum creatinine and cystatin C were available. We compared the association of the eGFR, as calculated by the measurement of creatinine or cystatin C alone or in combination with creatinine, with the rates of death (13,202 deaths in 15 cohorts), death from cardiovascular causes (3471 in 12 cohorts), and end-stage renal disease (1654 cases in 7 cohorts) and assessed improvement in reclassification with the use of cystatin C.
RESULTS
In the general-population cohorts, the prevalence of an eGFR of less than 60 ml per minute per 1.73 m2 of body-surface area was higher with the cystatin C–based eGFR than with the creatinine-based eGFR (13.7% vs. 9.7%). Across all eGFR categories, the reclassification of the eGFR to a higher value with the measurement of cystatin C, as compared with creatinine, was associated with a reduced risk of all three study outcomes, and reclassification to a lower eGFR was associated with an increased risk. The net reclassification improvement with the measurement of cystatin C, as compared with creatinine, was 0.23 (95% confidence interval [CI], 0.18 to 0.28) for death and 0.10 (95% CI, 0.00 to 0.21) for end-stage renal disease. Results were generally similar for the five cohorts with chronic kidney disease and when both creatinine and cystatin C were used to calculate the eGFR.
CONCLUSIONS
The use of cystatin C alone or in combination with creatinine strengthens the association between the eGFR and the risks of death and end-stage renal disease across diverse populations. (Funded by the National Kidney Foundation and others.)
doi:10.1056/NEJMoa1214234
PMCID: PMC3993094  PMID: 24004120
9.  Update on Cystatin C: Incorporation Into Clinical Practice 
Kidney function monitoring using creatinine-based GFR estimation is a routine part of clinical practice. Emerging evidence has shown that cystatin C may improve classification of GFR for defining chronic kidney disease (CKD) in certain clinical populations, and assist in understanding the complications of CKD. In this review and update, we summarize the overall literature on cystatin C, critically evaluate recent high-impact studies, highlight the role of cystatin C in recent kidney disease guidelines, and suggest a practical approach for clinicians to incorporate cystatin C into practice. We conclude by addressing frequently asked questions related to implementing cystatin C use in a clinical setting.
doi:10.1053/j.ajkd.2013.03.027
PMCID: PMC3755100  PMID: 23701892
cystatin C; GFR estimation; chronic kidney disease
10.  Trajectories of Kidney Function Decline in Young Black and White Adults With Preserved GFR: Results From the Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Background
Strong racial discrepancies in end-stage renal disease exist. Whether there are race differences in kidney function loss in younger, healthy persons is not well established.
Study Design
Longitudinal.
Setting & Participants
3348 Black and White adults with at least two measures of cystatin C-based estimated glomerular filtration rate (eGFRcys) at scheduled Coronary Artery Risk Development in Young Adults (CARDIA) examinations (Years 10, 15, 20).
Predictor
Race.
Outcomes & Measurements
We used linear mixed models (LMM) to examine race differences in annualized rates of eGFRcys decline, adjusting for age, sex, lifetime exposure to systolic blood pressure above 120mmHg, diabetes, and albumin-creatinine ratio. We used Poisson regression to compare racial differences in rapid decline (eGFRcys decline >3% per year) by study period (10–15 years after baseline exam defining period 1 and >15–20 years after baseline exam defining period 2).
Results
Mean age was 35 ± 3.6 (SD) years, mean eGFRcys was 110 ± 20 ml/min/1.73m2 for Blacks and 104 ± 17 ml/min/1.73m2 for Whites at baseline. For both Blacks and Whites, eGFRcys decline was minimal at younger ages (<35 years) and eGFRcys loss accelerated at older ages. However, acceleration of eGFRcys decline occurred at earlier ages for Blacks than Whites. Blacks had somewhat faster annualized rates of decline compared with whites, but differences were attenuated after adjustment in period 1 (0.13 ml/min/1.73m2 per year faster; p=0.2). In contrast, during period 2, Blacks had significantly faster annualized rates of decline, even after adjustment (0.32 ml/min/1.73m2 per year faster; p=0.003). Prevalence of rapid decline was significantly higher among Blacks vs. Whites with prevalence rate ratios of 1.31 (95% CI, 1.04–1.63) for period 1 and 1.24 (95% CI, 1.09–1.41) for period 2. Differences were attenuated after full adjustment: adjusted prevalence rate ratios were 1.20 (95% CI, 0.95–1.49) for period 1 and 1.10 (95% CI, 0.96–1.26) for period 2.
Limitations
No measured GFR.
Conclusions
eGFRcys decline differs by race at early ages, with faster annualized rates of decline among blacks. Future studies are required to explain observed differences.
doi:10.1053/j.ajkd.2013.01.012
PMCID: PMC3714331  PMID: 23473985
11.  Blood Pressure Components and Decline in Kidney Function in Community-Living Older Adults: The Cardiovascular Health Study 
American Journal of Hypertension  2013;26(8):1037-1044.
BACKGROUND
Although hypertension contributes to kidney dysfunction in the general population, the contributions of elevated systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) to kidney function decline in community-dwelling older adults are unknown.
METHODS
We used linear and logistic regression to examine the separate and combined associations of SBP, DBP, and PP at baseline with kidney function decline among 4,365 older adults in the Cardiovascular Health Study. We used cystatin C to estimate glomerular filtration rate on 3 occasions over 7 years of follow-up. We defined rapid decline ≥ 3ml/min/year.
RESULTS
Average age was 72.2 and mean (standard deviation) SBP, DBP, and PP were 135 (21), 71 (11), and 65 (18) mm Hg, respectively. SBP and PP, rather than DBP, were most significantly associated with kidney function decline. In adjusted linear models, each 10-mm Hg increment in SBP and PP was associated with 0.13ml/min/year (–0.19, –0.08, P < 0.001) and 0.15-ml/min/year faster decline (–0.21, –0.09, P < 0.001), respectively. Each 10-mm Hg increment in DBP was associated with a nonsignificant 0.10-ml/min/year faster decline (95% confidence interval, –0.20, 0.01). In adjusted logistic models, SBP had the strongest associations with rapid decline, with 14% increased hazard of rapid decline (95% confidence interval, 10% to 17%, P < 0.01) per 10mm Hg. In models combining BP components, only SBP consistently had independent associations with rapid decline.
CONCLUSIONS
Our findings suggest that elevated BP, particularly SBP, contributes to declining kidney function in older adults.
doi:10.1093/ajh/hpt067
PMCID: PMC3816322  PMID: 23709568
blood pressure; cystatin C; diastolic blood pressure; elderly; hypertension; kidney function; systolic blood pressure.
12.  Estimated Kidney Function Based on Serum Cystatin C and Risk of Subsequent Coronary Artery Calcium in Young and Middle-aged Adults With Preserved Kidney Function: Results From the CARDIA Study 
American Journal of Epidemiology  2013;178(3):410-417.
Whether kidney dysfunction is associated with coronary artery calcium (CAC) in young and middle-aged adults who have a cystatin C–derived estimated glomerular filtration rate (eGFRcys) greater than 60 mL/min/1.73 m2 is unknown. In the Coronary Artery Risk Development in Young Adults (CARDIA) cohort (recruited in 1985 and 1986 in Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California), we examined 1) the association of eGFRcys at years 10 and 15 and detectable CAC over the subsequent 5 years and 2) the association of change in eGFRcys and subsequent CAC, comparing those with stable eGFRcys to those whose eGFRcys increased (>3% annually over 5 years), declined moderately (3%–5%), or declined rapidly (>5%). Generalized estimating equation Poisson models were used, with adjustment for age, sex, race, educational level, income, family history of coronary artery disease, diabetes, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and tobacco use. Among 3,070 participants (mean age 35.6 (standard deviation, 4.1) years and mean eGFRcys 106.7 (standard deviation, 18.5) mL/min/1.73 m2), 529 had detectable CAC. Baseline eGFRcys was not associated with CAC. Moderate eGFRcys decline was associated with a 33% greater relative risk of subsequent CAC (95% confidence interval: 5, 68; P = 0.02), whereas rapid decline was associated with a 51% higher relative risk (95% confidence interval: 10, 208; P = 0.01) in adjusted models. In conclusion, among young and middle-aged adults with eGFRcys greater than 60 mL/min/1.73 m2, annual decline in eGFRcys is an independent risk factor for subsequent CAC.
doi:10.1093/aje/kws581
PMCID: PMC3816347  PMID: 23813702
calcification; cardiovascular diseases; chronic kidney insufficiency; coronary arteries; coronary disease; cystatin C; glomerular filtration rate; kidney
13.  Risk Factors for ESRD in Individuals With Preserved Estimated GFR With and Without Albuminuria: Results From the Kidney Early Evaluation Program (KEEP) 
Background
Given the increasing costs and poor outcomes of end-stage renal disease (ESRD), we sought to identify risk factors for ESRD in people with preserved estimated glomerular filtration rate (eGFR), with or without albuminuria, who were at high risk of ESRD.
Methods
This cohort study included participants in the National Kidney Foundation’s Kidney Early Evaluation Program (KEEP) with eGFR ≥60 mL/min/1.73 m2 at baseline stratified by the presence or absence of albuminuria. The Chronic Kidney Disease Epidemiology Collaboration equation was used to calculate eGFR. Urine was tested for albuminuria by semiquantitative dipstick. The outcome was the development of treated chronic kidney failure, defined as initiation of maintenance dialysis therapy or kidney transplantation, determined by linkage to the US Renal Data System. We used a Cox model with the Fine-Gray method to assess risk factors for treated chronic kidney failure while accounting for the competing risk of death.
Results
During a median follow-up of 4.8 years, 126 of 13,923 participants with albuminuria (16/10,000 patient-years) and 56 of 109,135 participants without albuminuria (1.1/10,000 patient-years) developed treated chronic kidney failure. Diabetes was a strong risk factor for developing treated chronic kidney failure in participants with and without albuminuria (adjusted HRs of 9.3 [95% CI, 5.7–15.3] and 7.8 [95% CI, 4.1–14.8], respectively). Black race, lower eGFR, and higher systolic blood pressure also were associated with higher adjusted risks of developing treated chronic kidney failure.
Conclusions
In a diverse high-risk cohort of KEEP participants with preserved eGFR, we showed that diabetes, higher systolic blood pressure, lower eGFR, and black race were risk factors for developing treated chronic kidney failure irrespective of albuminuria status, although the absolute risk of kidney failure in participants without albuminuria was very low. Our findings support testing for kidney disease in high-risk populations, which often have otherwise unrecognized kidney disease.
doi:10.1053/j.ajkd.2012.12.016
PMCID: PMC4117734  PMID: 23507268
Albuminuria; blood pressure; chronic kidney disease; diabetes; dialysis risk factors; end-stage renal disease; public health
14.  Role of Soluble Endothelial Cell–Selective Adhesion Molecule Biomarker in Albuminuria and Kidney Function Changes in Patients With Coronary Artery Disease 
Objective
Endothelial dysfunction is a possible mechanism to explain the association between atherosclerosis and kidney disease. This study evaluated circulating soluble endothelial cell–selective adhesion molecule (sESAM), a marker of endothelial dysfunction, as a risk factor for kidney function decline and albuminuria.
Approach and Results
In the Heart and Soul Study, we measured sESAM from baseline serum samples and defined elevated levels of sESAM by the highest quartile (quartile 4 [Q4]: >65.4 ng/mL). We evaluated the associations of high sESAM with baseline estimated glomerular filtration rate (eGFR) and ratio of urine albumin to creatinine (ACR), and with longitudinal changes in eGFR and ACR. Among 990 participants with sESAM measurements, median sESAM was 54.5 ng/mL (interquartile range, 45.3–65.8). After multivariable adjustment, elevated levels of sESAM were strongly and independently associated with baseline reduced eGFR <60 mL/min per 1.73 m2 (odds ratio [OR], 11.44; P<0.0001) and ACR ≥30 mg/g (OR, 5.23; P<0.0001). Associations of sESAM (Q4 versus quartile 1 [Q1]) with change in ACR (β=54.47; P<0.0001) were also significant after full adjustment. The association with change in eGFR (1.56%; P=0.0049) was not statistically significant after application of the Bonferroni correction for multiple markers. In unadjusted models, sESAM was associated with rapid kidney function loss, defined as 3% annual eGFR decline (OR, 2.28; P=0.0003), although this was attenuated by adjustment (OR, 2.11; P=0.0095).
Conclusions
sESAM is associated with albuminuria and reduced kidney function in both cross-sectional and longitudinal analyses. These findings implicate endothelial dysfunction as a potential contributor to the elevated kidney disease risk in persons with cardiovascular disease.
doi:10.1161/ATVBAHA.113.301806
PMCID: PMC4059045  PMID: 24177327
albuminuria; atherosclerosis; kidney diseases
15.  Serum albumin and short-term risk for mortality and cardiovascular disease among HIV-infected veterans 
AIDS (London, England)  2013;27(8):1339-1343.
Objective
We examined the short-term and long-term associations of serum albumin with mortality and cardiovascular disease among HIV-infected veterans.
Design
Retrospective cohort analysis using a national database of US veterans with HIV infection.
Methods
This analysis evaluated all HIV-infected veterans in the Department of Veterans Affairs HIV Clinical Case Registry (CCR), a national database consisting of demographic, clinical, laboratory, pharmaceutical, and viral status data. There were 25 522 patients enrolled between 1986 and 2007. We evaluated the associations of baseline and time-updated serum albumin levels with all-cause mortality, atherosclerotic cardiovascular disease, and heart failure by multivariate proportional hazards models.
Results
Over 21 years, there were 10 869 deaths; the cumulative mortality was 73.2 per 1000 person-years. After multivariate adjustment for covariates measured at baseline, the lowest category of serum albumin (<2.5 g/dl) was associated with a higher mortality risk compared with the highest category (>4 g/dl; hazard ratio 3.00; 2.67–3.37). When analyzed as a time-dependent model, the association strengthened substantially (15.1; 14.0–16.4). Findings were similar for atherosclerotic cardiovascular disease and heart failure. We stratified the baseline mortality model by year of follow-up and found that albumin was more strongly associated with deaths that occurred within 1 year of baseline (9.29; 7.85–11.0) than in the second (1.66; 1.18–2.33) or third (1.22; 0.77–1.96) year after measurement.
Conclusion
Among ambulatory HIV-infected patients, lower serum albumin levels are strongly predictive of mortality risk, particularly within 1 year.
doi:10.1097/QAD.0b013e32835f1dd6
PMCID: PMC4026018  PMID: 23343914
albumin; cardiovascular disease; end-stage renal disease; glomerular filtration rate; kidney
16.  Urinary Cystatin C and Acute Kidney Injury After Cardiac Surgery 
Background
Acute Kidney Injury (AKI) is common following cardiac surgery and is associated with adverse patient outcomes. Urinary cystatin C (CysC) is a biomarker of proximal tubule function and may rise earlier in AKI than serum creatinine.
Study Design
Prospective cohort study
Settings & Participants
The TRIBE AKI (Translational Research Investigating Biomarker Endpoints in AKI) Consortium prospectively enrolled 1,203 adults and 299 children at 8 institutions from 2007–2009.
Index Test
Urinary CysC (mg/L) within the first 12 hours after surgery
Outcome
Serum Creatinine based AKI was defined as AKI Network stage 1 (Mild AKI) as well as a doubling of serum creatinine from the pre-operative value or the need for dialysis during hospitalization (Severe AKI).
Other Measurements
Analyses were adjusted for characteristics used clinically for AKI risk stratification including age, sex, race, eGFR, diabetes, hypertension, heart failure, non-elective surgery, cardiac catheterization within 72 hours, type of surgery, myocardial infarction, and cardiopulmonary bypass time greater than 120 minutes.
Results
Urinary CysC measured in the early post-operative period (0–6 and 6–12 hours postoperatively) correlated with both mild and severe AKI in adults and children. However after analyses were adjusted for other factors the effect was attenuated for both forms of AKI in both cohorts.
Limitations
Limited numbers of patients with severe AKI and short-term dialysis
Conclusions
Urinary CysC values are not significantly associated with the development of AKI following cardiac surgery in adults and children.
doi:10.1053/j.ajkd.2012.12.006
PMCID: PMC3627833  PMID: 23332602
Acute kidney injury Biomarkers; Cystatin C; Dialysis; Peri-operative
17.  Association of Cardiac Troponin T With Left Ventricular Structure and Function in CKD 
Background
Serum cardiac troponin T (cTnT) is associated with increased risk of heart failure and cardiovascular death in several population settings. We evaluated associations of cTnT with cardiac structural and functional abnormalities in a cohort of chronic kidney disease (CKD) patients without heart failure.
Study Design
Cross-sectional.
Setting & Participants
Chronic Renal Insufficiency Cohort (CRIC; N= 3,243)
Predictor
The primary predictor was cTnT. Secondary predictors included demographic and clinical characteristics, hemoglobin level, high-sensitivity C-reactive protein, and estimated glomerular filtration rate using cystatin C.
Outcomes
Echocardiography was used to determine left ventricular (LV) mass and LV systolic and diastolic function.
Measurements
Circulating cTnT was measured in stored sera using the highly sensitive assay. Logistic and linear regression models were used to examine associations of cTnT with each echocardiographic outcome.
Results
cTnT was detectable in 2,735 (84%) persons; the median was 13.3 (IQR, 7.7–23.8) pg/mL. Compared with undetectable cTnT (<3.0 pg/mL), the highest quartile (23.9 – 738.7 pg/mL) was associated with approximately two times as likely to experience LV hypertrophy (OR, 2.43; 95% CI, 1.44–4.09) in the fully adjusted model. cTnT had a more modest association with LV systolic dysfunction; as a log-linear variable, a significant association was present in the fully adjusted model (OR of 1.4 [95% CI, 1.1–1.7] per 1-log unit; p<0.01). There was no significant independent association between cTnT and LV diastolic dysfunction. When evaluated as a screening test, cTnT functioned only modestly for LV hypertrophy and concentric hypertrophy detection (area under the curve, 0.64 for both) with weaker areas under the curve for the other outcomes.
Limitations
The presence of coronary artery disease was not formally assessed using either noninvasive or angiographic techniques in this study.
Conclusions
In this large CKD cohort without heart failure, detectable cTnT had a strong association with LV hypertrophy, a more modest association with LV systolic dysfunction, and no association with diastolic dysfunction. These findings indicate that circulating cTnT levels in CKD are predominantly an indicator of pathological LV hypertrophy.
doi:10.1053/j.ajkd.2012.11.034
PMCID: PMC3627820  PMID: 23291148
Troponin T; left ventricular structure; chronic kidney disease
18.  Fetuin-A, Type 2 Diabetes, and Risk of Cardiovascular Disease in Older Adults 
Diabetes Care  2013;36(5):1222-1228.
OBJECTIVE
Fetuin-A, a hepatic secretory protein that simultaneously inhibits arterial calcification and insulin action, is associated with type 2 diabetes, but its association with cardiovascular disease (CVD) is uncertain. Preliminary studies suggest that the association of fetuin-A with CVD might differ among individuals with or without type 2 diabetes.
RESEARCH DESIGN AND METHODS
This was a prospective study of 3,810 community-living individuals older than 65 years (511 with type 2 diabetes) and free of CVD in 1992 when fetuin-A levels were measured. Participants were followed-up for incident CVD through June 2008.
RESULTS
Mean age was 75 years, and 61% were women; 1,456 participants had an incident CVD event (248 among individuals with type 2 diabetes). The association of fetuin-A with CVD was modified by type 2 diabetes (P interaction = 0.02). Higher fetuin-A was associated with lower CVD risk among persons without type 2 diabetes [hazard ratio per SD 0.1 g/L higher fetuin-A, 0.93 (95% CI, 0.88–0.99)], whereas a trend in the opposite direction was observed among individuals with type 2 diabetes, although it was not statistically significant [1.07 (0.93–1.22)]. Among individuals without type 2 diabetes, similar effect modification was observed by obesity and insulin resistance. Consistently, higher fetuin-A was associated with lower CVD risk only in the subgroups without obesity or with HOMA-IR below the median [0.91 (0.85–0.97) and 0.87 (0.79–0.95), respectively].
CONCLUSIONS
The association of fetuin-A with risk of CVD differs among elderly individuals with and without insulin resistance or type 2 diabetes.
doi:10.2337/dc12-1591
PMCID: PMC3631840  PMID: 23250801
19.  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
20.  Early Trends in Cystatin C and Outcomes in Patients with Cirrhosis and Acute Kidney Injury 
Background. Acute kidney injury (AKI) is a common and severe complication in patients with cirrhosis. Progression of AKI to a higher stage associates with increased mortality. Intervening early in AKI when renal dysfunction is worsening may improve outcomes. However, serum creatinine correlates poorly with glomerular filtration in patients with cirrhosis and fluctuations may mask progression early in the course of AKI. Cystatin C, a low-molecular-weight cysteine proteinase inhibitor, is a potentially more accurate marker of glomerular filtration. Methods. We conducted a prospective multicenter study in patients with cirrhosis comparing changes in cystatin and creatinine immediately following onset of AKI as predictors of a composite endpoint of dialysis or mortality. Results. Of 106 patients, 37 (35%) met the endpoint. Cystatin demonstrated less variability between samples than creatinine. Patients were stratified into four groups reflecting changes in creatinine and cystatin: both unchanged or decreased 38 (36%) (Scr−/CysC−); only cystatin increased 25 (24%) (Scr−/CysC+); only creatinine increased 15 (14%) (Scr+/CysC−); and both increased 28 (26%) (Scr+/CysC+). With Scr−/CysC− as the reference, in both instances where cystatin rose, Scr−/CysC+ and Scr+/CysC+, the primary outcome was significantly more frequent in multivariate analysis, P = 0.02 and 0.03, respectively. However, when only creatinine rose, outcomes were similar to the reference group. Conclusions. Changes in cystatin levels early in AKI are more closely associated with eventual dialysis or mortality than creatinine and may allow more rapid identification of patients at risk for adverse outcomes.
doi:10.1155/2014/708585
PMCID: PMC3976933  PMID: 24757564
21.  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
22.  Hypertension and Low HDL-Cholesterol were Associated with Reduced Kidney Function Across the Age Spectrum: A Collaborative Study 
Annals of epidemiology  2013;23(3):106-111.
Purpose
To determine if the associations among established risk factors and reduced kidney function vary by age.
Methods
We pooled cross-sectional data from 14,788 non-diabetics aged 40–100 years in 4 studies: Cardiovascular Health Study, Health, Aging, and Body Composition Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-Stage Disease cohort.
Results
Hypertension and low HDL-cholesterol were associated with reduced cystatin C-based estimated glomerular filtration rate (eGFR) across the age spectrum. In adjusted analyses, hypertension was associated with a 2.3 (95% CI 0.1, 4.4), 5.1 (4.1, 6.1), and 6.9 (3.0, 10.4) mL/min/1.73 m2 lower eGFR in participants 40–59, 60–79, and 80+ years, respectively (p-value for interaction <0.001). The association of low HDL-cholesterol with reduced kidney function was also greater in the older age groups: 4.9 (3.5, 6.3), 7.1 (CI 6.0, 8.3), 8.9 (CI 5.4, 11.9) mL/min/1.73 m2 (p-value for interaction <0.001). Smoking and obesity were associated with reduced kidney function in participants under 80 years. All estimates of the potential population impact of the risk factors were modest.
Conclusions
Hypertension, obesity, smoking, and low HDL-cholesterol are modestly associated with reduced kidney function in non-diabetics. The associations of hypertension and HDL-cholesterol with reduced kidney function appear stronger in older adults.
doi:10.1016/j.annepidem.2012.12.004
PMCID: PMC3570601  PMID: 23313266
Chronic kidney insufficiency; aged; hypertension; cholesterol; obesity; smoking
23.  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
24.  Comparisons of creatinine and cystatin C for detection of kidney disease and prediction of all-cause mortality in HIV-infected women 
AIDS (London, England)  2013;27(14):2291-2299.
Background
Cystatin C could improve chronic kidney disease (CKD) classification in HIV-infected women relative to serum creatinine.
Design
Retrospective cohort analysis.
Methods
Cystatin C and creatinine were measured from specimens taken and stored during the 1999–2000 exam among 908 HIV-infected participants in the Women’s Interagency HIV study (WIHS). Mean follow-up was 10.2 years. The associations of baseline categories (<60, 60–90, and >90 mL/min/1.73m2) of creatinine eGFR (eGFRcr), cystatin C eGFR (eGFRcys), and combined creatinine-cystatin C eGFR (eGFRcr-cys) with all-cause mortality were evaluated using multivariable Cox regression. The net reclassification index (NRI) was calculated to evaluate the effect of cystatin C on reclassification of CKD staging.
Results
The prevalence of CKD (eGFR<60) at baseline was higher with eGFRcys (10.1%) compared to eGFRcr (6.7%, p=0.0006) and eGFRcr-cys (7.5%, p=0.011). Relative to eGFR >90, the eGFR <60 category by eGFRcys (Adjusted HR: 2.56; 95% CI: 1.63, 4.02), eGFRcr-cys (3.11; 1.94–5.00), and eGFRcr (2.34; 1.44–3.79) was associated with increased mortality risk. However, the eGFR 60–90 category was associated with increased mortality risk for eGFRcys (1.80; 1.28–2.53) and eGFRcr-cys (1.91; 1.38–2.66) but not eGFRcr (1.20; 0.85–1.67). The overall NRI for mortality was 26% when reclassifying from eGFRcr to eGFRcys (p<0.001) and was 20% when reclassifying from eGFRcr to eGFRcr-cys (p<0.001).
Conclusion
Cystatin C detected a higher prevalence of CKD relative to creatinine and improves CKD staging relative to creatinine by reclassifying individuals at the highest mortality risk to lower eGFR categories.
doi:10.1097/QAD.0b013e328362e874
PMCID: PMC3919542  PMID: 23669156
Creatinine; Cystatin C; Glomerular Filtration Rate; HIV; Mortality; Kidney; Women
25.  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

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