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1.  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
2.  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
3.  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
4.  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
5.  Ethnic Differences in the Development of Albuminuria: The DISTANCE Study 
Objectives
To determine whether ethnic differences in the incidence of albuminuria are present in patients with diabetes, and to identify social, behavioral, and provider factors that explain ethnic differences.
Study Design
Survey follow-up design with a race-stratified baseline survey (2005–2006) in diabetic patients from a nonprofit, fully integrated healthcare system in Northern California. We followed the 10,596 respondents (30% whites, 20% blacks, 23% Hispanics, 14% Asians, and 13% Filipinos) without evidence of prevalent albuminuria at baseline.
Methods
Incident albuminuria was defined by positive dipstick urinalysis (≥1) or urine albumin to creatinine level (≥30 mg/g), and confirmed with repeat testing at least 3 months later.
Results
The 27,292 person-years of observation yielded 981 incident albuminuria events. Age-standardized rates of albuminuria (per 1000 person-years) ranged from 13.6 (95% confidence interval [CI] 10.5–17.0) in whites to 27.8 (CI 18.2–38.3) in blacks. In fully adjusted Cox models, the hazard ratio for blacks (1.22, 95% CI 1.09–1.38), Asians (1.35, 95% CI 1.13–1.61), and Filipinos (1.93, 95% CI 1.61–2.32), but not Hispanics, was significantly greater than it was for whites. In some cases, point estimates changed markedly from the base model when fully adjusted for potential confounders. Moreover, adjustment for an array of potentially mediating factors explained only a small proportion of the observed ethnic disparities.
Conclusions
Despite uniform medical care coverage, Filipinos, blacks, and Asians with diabetes developed albuminuria at higher rates than white and Hispanic adults.
PMCID: PMC3557941  PMID: 22084893
6.  Association of Educational Attainment With Chronic Disease and Mortality: The Kidney Early Evaluation Program (KEEP) 
Background
Recent reports have suggested a close relationship between education and health, including mortality, in the United States.
Study Design
Observational cohort
Setting and Participants
We studied 61,457 participants enrolled in a national health screening initiative, the National Kidney Foundation’s Kidney Early Evaluation Program (KEEP).
Predictor
Self-reported educational attainment
Outcomes
Chronic diseases (hypertension, diabetes, cardiovascular disease, reduced kidney function, and albuminuria) and mortality
Measurements
We evaluated the cross-sectional associations between self-reported educational attainment with the chronic diseases listed above using logistic regression models adjusted for demographics, access to care, behaviors, and co-morbidities. The association of educational attainment with survival was determined by multivariable Cox proportional hazards regression.
Results
Higher educational attainment was associated with lower prevalence of each of the chronic conditions listed above. In multivariable models, compared with persons not completing high school, college graduates had a lower risk of each chronic condition, ranging from 11% lower odds of reduced kidney function to 37% lower odds of cardiovascular disease. Over a mean follow-up time of 3.9 years (median, 3.7 years), 2,384 (4%) deaths occurred. In the fully adjusted Cox model, those who had completed college had a 24% lower mortality, compared to participants who had completed at least some high school.
Limitations
A lack of income data does not allow us to disentangle the independent effects of education from income.
Conclusions
In this diverse, contemporary cohort, higher educational attainment was independently associated with lower prevalence of chronic diseases and short-term mortality among all age and race/ethnicity groups.
doi:10.1053/j.ajkd.2011.02.388
PMCID: PMC3144262  PMID: 21601328
education; mortality; chronic kidney disease
7.  Reduced Kidney Function and Preclinical Atherosclerosis in HIV-Infected Individuals: The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) 
American Journal of Nephrology  2011;33(5):453-460.
Background/Aims
Reduced kidney function and albuminuria are associated with higher risk for cardiovascular disease (CVD) and mortality in HIV-infected individuals. We investigated whether reduced estimated glomerular filtration rate (eGFR) and albuminuria are associated with subclinical vascular disease, as assessed by carotid intima-medial thickness (cIMT).
Methods
Cross-sectional analysis of 476 HIV-infected individuals without clinical evidence of CVD enrolled in the Fat Redistribution and Metabolic Change in HIV infection (FRAM) study, using multivariable linear regression. eGFRCys and eGFRCr were calculated from cystatin C and creatinine levels. Albuminuria was defined as a positive urine dipstick (≥1+) or urine albumin-to-creatinine ratio ≥30 mg/g. Common and internal cIMT were measured by high-resolution B-mode ultrasound.
Results
In unadjusted analyses, eGFRCys and eGFRCr were strongly associated with common and internal cIMT. Each 10 ml/min/1.73 m2 decrease in eGFRCys and eGFRCr was associated with a 0.008 mm higher common cIMT (p = 0.003, p = 0.01) and a 0.024 and 0.029 mm higher internal cIMT (p = 0.003), respectively. These associations were eliminated after adjustment for age, gender, and race. Albuminuria showed little association with common or internal cIMT in all models.
Conclusions
In HIV-infected individuals without prior CVD, reduced kidney function and albuminuria were not independently associated with subclinical vascular disease, as assessed by cIMT. These results suggest that research should focus on searching for novel mechanisms by which kidney disease confers cardiovascular risk in HIV-infected individuals.
doi:10.1159/000327606
PMCID: PMC3100378  PMID: 21508633
Cystatin C; Intima-medial thickness; HIV; Atherosclerosis; Cardiovascular disease; Kidney
8.  Association of Vitamin D Insufficiency with Carotid Intima-Media Thickness in HIV-Infected Persons 
We observed an independent association between vitamin D insufficiency and higher carotid intima-media thickness in a cross-sectional analysis of 139 HIV-infected persons. If confirmed, these findings support a clinical trial of vitamin D supplementation to reduce cardiovascular events in HIV-infected persons.
doi:10.1093/cid/ciq239
PMCID: PMC3106229  PMID: 21273298
9.  Inflammation and Mortality in HIV-infected Adults: Analysis of the FRAM Study Cohort 
Objective
To determine the association of inflammatory markers, fibrinogen and C-reactive protein (CRP), with 5-year mortality risk.
Methods
Vital status was ascertained in 922 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV infection. Multivariable logistic regression estimated odds ratios (OR) after adjustment for demographic, cardiovascular and HIV-related factors.
Results
Over a 5-year period, HIV-infected participants with fibrinogen levels in the highest tertile(>406mg/dL) had 2.6-fold higher adjusted odds of death than those with fibrinogen in the lowest tertile(<319mg/dL). Those with high CRP(>3mg/L) had 2.7-fold higher adjusted odds of death than those with CRP<1mg/L. When stratified by CD4 count category, fibrinogen (as a linear variable) remained independently associated [OR(95% confidence intervals) per 100mg/dL increase in fibrinogen: 1.93(1.57,2.37);1.43(1.14,1.79);1.43(1.14,1.81);and 1.30(1.04,1.63) for CD4 <200,200–350,>350–500, and >500cells/μL, respectively. Higher CRP also remained associated with higher odds of death overall and within each CD4 subgroup.
Conclusion
Fibrinogen and CRP are strong and independent predictors of mortality in HIV-infected adults. Our findings suggest that even in those with relatively preserved CD4 counts >500cells/μL, inflammation remains an important risk factor for mortality. Further investigation should determine whether interventions to reduce inflammation might decrease mortality risk in HIV-infected individuals.
doi:10.1097/QAI.0b013e3181e66216
PMCID: PMC2955817  PMID: 20581689
HIV; inflammation; C-reactive protein; fibrinogen; mortality
10.  Cystatin C, Albuminuria, and 5-Year All-Cause Mortality in HIV-Infected Persons 
Background
Compared with controls, HIV-infected persons have a greater prevalence of kidney disease as assessed by high levels of cystatin C and albuminuria, but not as assessed by creatinine level. However, the clinical importance of elevated cystatin C and albuminuria in the HIV-infected population has not been studied.
Study Design
We conducted an observational cohort study to determine the association of kidney disease (measured by albuminuria, cystatin C, and serum creatinine) with mortality.
Setting & Participants
922 HIV-infected persons enrolled in the FRAM (Fat Redistribution and Metabolic Change in HIV infection) study.
Predictor
Serum cystatin C and serum creatinine were used to estimate glomerular filtration rate (eGFR). Albuminuria was defined as a positive urine dipstick (≥1+) or a urine albumin-creatinine ratio > 30 mg/g.
Outcome
5-year mortality
Results
At baseline, reduced kidney function (eGFRSCysC <60 mL/min/1.73m2) or albuminuria was present in 28% of participants. After five years of follow-up, mortality was 48% among those with both eGFRSCysC <60 mL/min/1.73m2 and albuminuria, 23% in those with eGFRSCysC <60 mL/min/1.73m2 alone, 20% in those with albuminuria alone, and 9% in those with neither condition. After multivariable adjustment for demographics, cardiovascular risk factors, HIV-related factors, and inflammatory markers, eGFRSCysC <60 mL/min/1.73m2 and albuminuria were associated with nearly a twofold increase in mortality, whereas eGFRSCr <60 mL/min/1.73m2 did not appear to have any substantial association with mortality. Together, eGFRSCysC <60 mL/min/1.73m2 and albuminuria accounted for 17% of the population-level attributable risk for mortality.
Limitations
Vital status was unknown in 261 participants from the original cohort.
Conclusions
Kidney disease marked by albuminuria or increased cystatin C levels appears to be an important risk factor for mortality in HIV-infected individuals. A substantial proportion of this risk may be unrecognized because of the current reliance on serum creatinine to estimate kidney function in clinical practice.
doi:10.1053/j.ajkd.2010.05.019
PMCID: PMC3164880  PMID: 20709438
kidney disease; mortality; HIV infection
11.  The Association Between Kidney Function and Albuminuria with Cardiovascular Events in HIV-Infected Persons 
Circulation  2010;121(5):651-658.
Background
Cardiovascular disease (CVD) is now a leading cause of death in HIV-infected persons; however, risk markers for CVD are ill-defined in this population. We examined the association between longitudinal measures of kidney function and albuminuria with risk of atherosclerotic CVD and heart failure in a contemporary cohort of HIV-infected individuals.
Methods and Results
We followed a national sample of 17,264 HIV-infected persons receiving care in the Veterans Health Administration for: (1) incident CVD, defined as coronary, cerebrovascular, or peripheral arterial disease; and (2) incident heart failure. Rates of CVD and heart failure were at least 6-fold greater in the highest risk patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 and albuminuria ≥300 mg/dL versus those with no evidence of kidney disease (eGFR ≥60 mL/min/1.73m2 and no albuminuria). After multivariable adjustment, eGFR levels 45–59, 30–44, and <30 mL/min/1.73m2 were associated with hazard ratios (HR) for incident CVD of 1.46 (95% confidence interval 1.15–1.86), 2.03 (1.47–2.82), and 1.99 (1.46–2.70), compared with eGFR ≥60 mL/min/1.73m2. Similarly, albuminuria levels 30, 100, and ≥300 mg/dL had HR’s for CVD of 1.28 (1.09–1.51), 1.48 (1.15–1.90), and 1.71 (1.30–2.27), compared with absent albuminuria. The associations between eGFR and albuminuria with heart failure were larger in magnitude and followed the same trends.
Conclusion
In this national sample of HIV-infected persons, eGFR and albuminuria levels were strongly associated with risk of CVD and heart failure. Kidney function and albuminuria provide complementary prognostic information which may aid CVD risk stratification in HIV-infected persons.
doi:10.1161/CIRCULATIONAHA.109.898585
PMCID: PMC2829672  PMID: 20100969
HIV; albuminuria; glomerular filtration rate; heart failure; cardiovascular disease
12.  White/Black Racial Differences in Risk of End-Stage Renal Disease and Death 
The American journal of medicine  2009;122(7):672-678.
Background
End-stage renal disease disproportionately affects black persons, but it is unknown when in the course of chronic kidney disease racial differences arise. Understanding the natural history of racial differences in kidney disease may help guide efforts to reduce disparities.
Methods
We compared white/black differences in the risk of end-stage renal disease and death by level of estimated glomerular filtration rate (eGFR) at baseline in a national sample of 2,015,891 veterans between 2001 to 2005.
Results
Rates of end-stage renal disease among black patients exceeded those among white patients at all levels of baseline eGFR. The adjusted hazard ratios (HR) for end-stage renal disease associated with black versus white race for patients with an eGFR ≥90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73m2, respectively were 2.14 (95% confidence interval [CI], 1.72-2.65), 2.30 (95% CI, 2.02-2.61), 3.08 (95% CI, 2.74-3.46), 2.47 (95% CI, 2.26-2.70), 1.86 (95% CI, 1.75-1.98), and 1.23 (95% CI, 1.12- 1.34). We observed a similar pattern for mortality, with equal or higher rates of death among black persons at all levels of eGFR. The highest risk of mortality associated with black race was also observed among those with an eGFR 45-59 mL/min/1.73m2 (HR 1.32, 95% CI, 1.27-1.36).
Conclusion
Racial differences in the risk of end-stage renal disease appear early in the course of kidney disease and are not explained by a survival advantage among blacks. Efforts to identify and slow progression of chronic kidney disease at earlier stages may be needed to reduce racial disparities.
doi:10.1016/j.amjmed.2008.11.021
PMCID: PMC2749005  PMID: 19559170
kidney disease; racial disparities; mortality
13.  HIV-infected persons continue to lose kidney function despite successful antiretroviral therapy 
AIDS (London, England)  2009;23(16):2143-2149.
Objective
To identify risk factors associated with kidney function decline in a contemporary cohort of treated and untreated HIV-infected patients.
Methods
We followed individuals enrolled in the Study of the Consequences Of the Protease inhibitor Era cohort for longitudinal changes in kidney function, defined as glomerular filtration rate estimated from serum creatinine (eGFR). eGFR slope was calculated using linear mixed effects models adjusted for age, sex, race, and time-updated CD4 cell count, viral load, antiretroviral therapy (ART), and comorbid conditions.
Results
We followed 615 patients for a mean of 3.4 (± 2.5) years. In multivariable adjusted analyses, predictors of eGFR decline included female sex, diabetes, and hyperlipidemia; CD4 cell count and viral load were not associated with eGFR loss. Among patients who initiated treatment, antiretroviral exposure was associated with a +2.8 (95% confidence interval 0.8–4.7) ml/min per 1.73 m2 per year effect on eGFR slope. Although these patients appeared to benefit from ART based on the slowing of their eGFR decline, they continued to lose kidney function at a rate of −1.9 (95% confidence interval −3.7 to −0.1) ml/min per 1.73 m2 per year. In the subgroup of individuals receiving suppressive ART with viral loads maintained below 500 copies/ml, intermittent viremic episodes (blips) were strongly associated with more rapid rates of eGFR loss [−6.7 (95% confidence interval −11.1 to −2.4) ml/min per 1.73 m2 per - year].
Conclusion
Although ART appears to help curb kidney function decline, patients who achieved durable viral suppression continue to manifest substantial loss of eGFR. Loss of kidney function may be attributable to treatment-related factors, intermittent viremia, and traditional risk factors for kidney disease.
doi:10.1097/QAD.0b013e3283313c91
PMCID: PMC2839451  PMID: 19684507
antiretroviral therapy; glomerular filtration rate; HIV; kidney diseases; viral load

Results 1-13 (13)