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.
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.
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.
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.
Vital status was unknown in 261 participants from the original cohort.
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.
kidney disease; mortality; HIV infection
Cystatin C could improve chronic kidney disease (CKD) classification in HIV-infected women relative to serum creatinine.
Retrospective cohort analysis.
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.
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).
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.
Creatinine; Cystatin C; Glomerular Filtration Rate; HIV; Mortality; Kidney; Women
Previous research has demonstrated an increase in carotid intima–media thickness (cIMT) in HIV-infected individuals compared to controls. However, the reason for this increased level of subclinical vascular disease is unknown.
To identify HIV-related risk factors for increased cIMT.
We evaluated the relationship between HIV-related characteristics (including markers of HIV disease severity and use of antiretroviral therapy) and cIMT measurements in the internal/bulb and common carotid regions among 538 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). We used Bayesian model averaging to estimate the posterior probability of candidate HIV and non-HIV-related risk factors being true predictors of increased cIMT. Variables with a posterior probability of more than 50% were used to develop a selected regression model for each of the anatomic regions.
For common cIMT, the Bayesian model selection process identified age, African-American race, and systolic and diastolic blood pressure with probability more than 95%, HDL cholesterol with probability 85% and Hispanic ethnicity with probability 51%. Among the HIV-related factors included in the analysis, only tenofovir use was selected (51% probability). In the selected model, duration of tenofovir use was associated with lower common cIMT (−0.0094 mm/year of use; 95% confidence interval: −0.0177 to −0.0010). For internal cIMT, no HIV-related risk factors were above the 50% posterior probability threshold.
We observed an inverse association between duration of tenofovir use and common carotid cIMT. Whether this association is causal or due to confounding by indication needs further investigation.
atherosclerosis; carotid intima–media thickness; HIV; tenofovir
Serum creatinine and cystatin C are used as markers of glomerular filtration rate (GFR). The performance of these GFR markers relative to exogenously measured GFR (mGFR) in HIV-positive individuals is not well established.
We assessed the performance of the chronic kidney disease epidemiology collaboration equations based on serum concentrations of creatinine (eGFRcr), cystatin C (eGFRcys) and both biomarkers combined (eGFRcr-cys) in 187 HIV-positive and 98 HIV-negative participants. Measured GFR was calculated by plasma iohexol clearance. Bias and accuracy were defined as the difference between eGFR and mGFR and the percentage of eGFR observations within 30% of mGFR, respectively. Activated CD4 and CD8 T-cells (CD38+ HLA-DR+) were measured by flow cytometry.
The median mGFR was >100 ml/min/1.73 m2 in both groups. All equations tended to be less accurate in HIV-positive than in HIV-negative subjects, with eGFRcr-cys being the most accurate overall. In the HIV-positive group, eGFRcys was significantly less accurate and more biased than eGFRcr and eGFRcr_cys. Additionally eGFRcys bias and accuracy were strongly associated with use of antiretroviral therapy, HIV RNA suppression, and percentages of activated CD4 or CD8 T-cells. Hepatitis C seropositivity was associated with larger eGFRcys bias in both HIV-positive and HIV-negative groups. In contrast, eGFRcr accuracy and bias were not associated with HIV-related factors, T-cell activation, or hepatitis C.
The performance of eGFRcys relative to mGFR was strongly correlated with HIV treatment factors and markers of T-cell activation, which may limit its usefulness as a GFR marker in this population.
Systematic differences between readers or equipment in imaging studies are not uncommon; failure to account for such differences when using Carotid Ultrasonography may introduce bias into associations between carotid intima media thickness (cIMT) and outcomes. We demonstrate the impact of this source of systematic measurement error (SME) using data on 5,521 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and 661 participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). Participants were between 37 and 78 years old. Two outcomes were considered: (1) the effect of HIV infection on cIMT (between study) and (2) the association of cIMT with cardiovascular events (within study). All estimates were adjusted for demographics (age, gender, and ethnicity) and for traditional cardiovascular disease risk factors (smoking, blood pressure, diabetes and cholesterol). When comparing the FRAM and MESA cohorts to estimate the association of HIV infection on common cIMT, accounting for machine and reader variability (between study variability) reduced the difference associated with HIV infection from +0.080 mm (95% Confidence Interval (CI):0.065–0.095) to +0.037 mm (95% CI:0.003 to 0.072) while internal cIMT declined from +0.254 mm (95% CI:0.205–0.303) to +0.192 mm (95% CI:0.076–0.308). Attenuation of the association between cIMT and cardiovascular endpoints occurred when within study reader variability was not accounted for. The effect of SME due to use of multiple readers or machines is most important when comparisons are made between two different study populations. Within-cohort measurement error dilutes the association with events.
Carotid intima media thickness; Measurement error; Bias; Carotid ultrasonography
Atrial fibrillation (AF) is common in end-stage renal disease (ESRD), but the relationship between more modest decrements in kidney function or albuminuria with AF is uncertain. Among 956 outpatients with coronary heart disease (CHD), we assessed kidney function by 3 methods (cystatin C-based [eGFRcys] and creatinine-based [eGFRCr] estimated glomerular filtration rate, and urinary albumin-to-creatinine ratio [ACR]) and prevalent AF by surface electrocardiogram. Multivariable logistic regression evaluated the associations of each measure of kidney function with AF. The mean eGFRcys was 71 ± 23 ml/min/1.73m2 and median ACR was 10 mg/g (interquartile range 6 – 19 mg/g). Forty subjects (4%) had prevalent AF. Compared to participants with eGFRcys in the highest tertile (eGFRcys > 79), those with eGFRcys in the lowest tertile (eGFRcys < 62) had more than 3-fold greater odds of AF (OR 3.43; 95% CI 1.18 – 9.97) after multivariate adjustment for traditional CVD risk factors. This association remained significant with further adjustment for ACR (OR 3.37; 95% 1.02 – 11.14). Results were similar for eGFRCr, but did not reach statistical significance (OR 1.59; 95% CI 0.57 – 4.40). Participants with ACR in the highest tertile (ACR > 15 mg/g) had more than 4-fold greater odds of AF compared to participants in the lowest ACR tertile (ACR < 7 mg/g); an association that remained significant after adjustment for eGFRcys (OR 4.36; 95% CI 1.45 – 13.05) or eGFRCr (OR 4.61; 95% CI 1.56 – 13.66). In conclusion, among outpatients with CHD, lower eGFRcys and higher ACR are each associated with prevalent AF, independent of one another.
Cardiovascular disease (CVD) is an increasing cause of morbidity and mortality in HIV-infected patients. However, it is controversial whether HIV infection contributes to accelerated atherosclerosis independent of traditional CVD risk factors.
Cross-sectional study of HIV-infected and control subjects without pre-existing CVD from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) and the Multi-Ethnic Study of Atherosclerosis (MESA). Pre-clinical atherosclerosis was assessed by carotid intima-medial thickness (IMT) measurements in the internal/bulb and common regions in HIV-infected and control subjects after adjusting for traditional CVD risk factors.
For internal carotid, mean IMT was 1.17±0.50mm for HIV-infected participants and 1.06±0.58mm for controls (p<0.0001). After multivariable adjustment for demographic characteristics, the mean difference of HIV-infected vs. controls was +0.188mm (95%CI 0.113-0.263, p<0.0001). Further adjustment for traditional CVD risk factors modestly attenuated the HIV association (+0.148mm, 95%CI 0.072-0.224, p=0.0001). For the common carotid, HIV infection was independently associated with greater IMT (+0.033mm, 95%CI 0.010, 0.056, p=0.005). The association of HIV infection with IMT was similar to that of smoking which was also associated with greater IMT (internal +0.173mm, common +0.020mm).
Even after adjustment for traditional CVD risk factors, HIV infection was accompanied by more extensive atherosclerosis measured by IMT. The stronger association of HIV infection with IMT in the internal/bulb region compared to the common carotid may explain previous discrepancies in the literature. The association of HIV infection with IMT was similar to that of traditional CVD risk factors, such as smoking.
HIV; carotid IMT; smoking; cholesterol; diabetes; atherosclerosis
Although studies have reported a high prevalence of end-stage renal disease in human immunodeficiency virus (HIV)-infected individuals, little is known about moderate impairments in kidney function. Cystatin C measurement may be more sensitive than creatinine for detecting impaired kidney function in persons with HIV.
We evaluated kidney function in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) cohort, a representative sample of 1008 HIV-infected persons and 290 controls from the Coronary Artery Risk Development in Young Adults (CARDIA) study in the United States.
Cystatin C level was elevated in HIV-infected individuals; the mean±SD cystatin C level was 0.92±0.22 mg/L in those infected with HIV and 0.76±0.15 mg/L in controls (P<.001). In contrast, both mean creatinine levels and estimated glomerular filtration rates appeared similar in HIV-infected individuals and controls (0.87±0.21 vs 0.85±0.19 mg/dL [to convert to micromoles per liter, multiply by 88.4] [P=.35] and 110±26 vs 106±23 mL/min/1.73 m2 [P=.06], respectively). Persons with HIV infection were more likely to have a cystatin C level greater than 1.0 mg/L (OR, 9.8; 95% confidence interval, 4.4-22.0 [P<.001]), a threshold demonstrated to be associated with increased risk for death and cardiovascular and kidney disease. Among participants with HIV, potentially modifiable risk factors for kidney disease, hypertension, and low high-density lipoprotein concentration were associated with a higher cystatin C level, as were lower CD4 lymphocyte count and coinfection with hepatitis C virus (all P<.001).
Individuals infected with HIV had substantially worse kidney function when measured by cystatin Clevel compared with HIV-negative controls, whereas mean creatinine levels and estimated glomerular filtration rates were similar. Cystatin C measurement could be a useful clinical tool to identify HIV-infected persons at increased risk for kidney and cardiovascular disease.
To examine the association between kidney function and all-cause mortality in octogenarians.
Retrospective analysis of prospectively collected data.
Serum creatinine and cystatin C were measured in 1,053 Cardiovascular Health Study (CHS) All Stars participants.
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.
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).
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.
octogenarians; kidney function; mortality
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.
A prospective cohort.
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.
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.
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.
cystatin C; glomerular filtration rate; HIV; kidney; viral load
Low birth weight has been shown to be associated with later renal function, but it is unclear to what extent this is explained by other established kidney disease risk factors. Here we investigate the roles of diabetes, hypertension, and obesity using data from the Medical Research Council National Survey of Health and Development, a socially stratified sample of 5362 children born in March 1946 in England, Scotland, and Wales, and followed since. The birth weight of 2192 study members with complete data was related to three markers of renal function at age 60–64 (estimated glomerular filtration rate (eGFR) calculated using cystatin C (eGFRcys), eGFR calculated using creatinine and cystatin C (eGFRcr-cys), and the urine albumin–creatinine ratio) using linear regression. Each 1 kg lower birth weight was associated with a 2.25 ml/min per 1.73 m2 (95% confidence interval 0.80–3.71) lower eGFRcys and a 2.13 ml/min per 1.73 m2 (0.69–3.58) lower eGFRcr-cys. There was no evidence of an association with urine albumin–creatinine ratio. These associations with eGFR were not confounded by socioeconomic position and were not explained by diabetes or hypertension, but there was some evidence that they were stronger in study members who were overweight in adulthood. Thus, our findings highlight the role of lower birth weight in renal disease and suggest that in those born with lower birth weight particular emphasis should be placed on avoiding becoming overweight.
birth weight; diabetes; estimated glomerular filtration rate; hypertension; kidney disease; obesity
Defined as estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, chronic kidney disease (CKD) is strongly and independently associated with cardiovascular and overall mortality. We hypothesized that reduced kidney function would be characterized by abnormalities of hemostasis.
We tested cross-sectional associations between (eGFR) and multiple hemostatic markers among 6751 participants representing a broad spectrum of kidney function in the Multi-Ethnic Study of Atherosclerosis (MESA). Kidney function was measured using cystatin C (eGFRcys) or creatinine, using CKD Epidemiology Collaboration (eGFRcr). Hemostatic markers included soluble thrombomodulin (sTM), soluble tissue factor (sTF), D-Dimer, von Willebrand factor (vWF), factor VIII, plasmin-antiplasmin complex (PAP), tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor-1 (PAI-1), and fibrinogen. Associations were tested using multivariable linear regression with adjustment for demographics and comorbidities.
In comparison to persons with eGFRcys >90 ml/min/1.73 m2, subjects with eGFRcys < 60 ml/min/1.73 m2 had adjusted levels of sTM, sTF, D-Dimer, PAP, Factor VIII, TFPI, vWF and fibrinogen that were respectively 86%, 68%, 44%, 22%, 17%, 15%, 12% and 6% higher. Subjects with eGFRcys 60-90 ml/min/1.73 m2 had adjusted levels that were respectively 16%, 14%, 12%, 6%, 6%, 6%, 11% and 4% higher (p < 0.05 for all). Percent differences were not significantly different when groups were categorized by eGFRcr.
Throughout a broad spectrum of kidney function, lower eGFR was associated with higher levels of hemostatic markers. Dysregulation of hemostasis may be a mechanism by which reduced kidney function promotes higher cardiovascular risk.
The role of host genetics in the development of subclinical atherosclerosis in the context of HIV infected persons who are being treated with highly active antiretroviral therapy (HAART) is not well understood.
The present genome-wide association study (GWAS) is based on 177 HIV-positive Caucasian males receiving HAART who participated in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) Study. Common and internal carotid intima-media thicknesses (cIMT) measured by B-mode ultrasound were used as a subclinical measure of atherosclerosis. Single nucleotide polymorphisms (SNPs) were assayed using the Illumina HumanCNV370-quad beadchip. Copy Number Variants (CNV) were inferred using a hidden Markov Model (PennCNV). Regression analyses were used to assess the association of common and internal cIMT with individual SNPs and CNVs, adjusting for age, duration of antiretroviral treatment, and principal components to account for potential population stratification.
Two SNPs in tight linkage disequilibrium, rs2229116 (a missense, nonsynonymous polymorphism (IIe to Val)) and rs7177922, located in the Ryanodine receptor (RYR3) gene on chromosome 15 were significantly associated with common cIMT (p-value<1.61×10−7). The RYR gene family has been known to play a role in the etiology of cardiovascular disease and has been shown to be regulated by HIV TAT protein.
These results suggest that in the context of HIV infection and HAART, a functional SNP in a biologically plausible candidate gene, RYR3, is associated with increased common carotid IMT, which is a surrogate for atherosclerosis.
HIV; HAART; atherosclerosis; GWAS; intima-media thickness
Serum cystatin C level has been shown to have a stronger association with clinical outcomes than serum creatinine level. However, little is known about the combined association of cystatin C–based estimated glomerular filtration rate (eGFRcys) and albuminuria with clinical outcomes, particularly at levels lower than current chronic kidney disease (CKD) cutoffs.
Setting & Participants
10,403 ARIC (Atherosclerosis Risk in Communities) Study participants followed up for a median of 10.2 years.
Mortality, coronary heart disease (CHD), and heart failure, as well as a composite of any of these separate outcomes.
Both decreased eGFRcys and albuminuria were associated independently with the composite outcome, as well as mortality, CHD, and heart failure. Although eGFRcys of 75-89 mL/min/1.73 m2 in the absence of albuminuria (albumin-creatinine ratio [ACR] <10 mg/g) or albuminuria with ACR of 10-29 mg/g with normal eGFRcys (90-104 mL/min/1.73 m2) was not associated significantly with any outcome compared with eGFRcys of 90-104 mL/min/1.73 m2 and ACR <10 mg/g, the risk of each outcome was significantly higher in those with both eGFRcys of 75-89 mL/min/1.73 m2 and ACR of 10-29 mg/g (for mortality, HR of 1.4 [95% CI, 1.1-2.0]; for CHD, HR of 1.9 [95% CI, 1.4-2.6]; for heart failure, HR of 1.8 [95% CI, 1.2-2.7]). Combining the 2 markers improved risk classification for all outcomes (P < 0.001), even in those without overt CKD.
Only one measurement of cystatin C.
Mildly decreased eGFRcys and mild albuminuria independently contributed to the risk of mortality, CHD, and heart failure. Even minimally decreased eGFRcys (75-89 mL/min/1.73 m2) is associated with increased risk in the presence of mild albuminuria. Combining the 2 markers is useful for improved risk stratification even in those without clinical CKD.
Epidemiology; kidney; outcomes
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.
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.
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).
Among HIV-infected women in the WIHS cohort, novel urine markers of kidney injury detect risk for subsequent declines in kidney function.
HIV; KIM-1; NGAL; IL-18; albumin-to-creatinine ratio; cystatin C; kidney injury
The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM), initiated in 2000, investigates the prevalence and correlates of changes in fat distribution, insulin resistance, and dyslipidemia among human immunodeficiency virus (HIV)-infected men and women compared with a population-based group of control men and women. Between June 2000 and September 2002, 1,480 participants (1,183 HIV-infected persons and 297 controls) were enrolled in FRAM. Measurements taken included whole-body magnetic resonance imaging for quantification of regional fat, anthropometric measurements, central laboratory analysis of metabolites, and assessment of symptoms, sociodemographic factors, and lifestyle. Similar measurements were repeated among FRAM participants 4 years later (FRAM 2) for investigation of the progression of fat distribution changes, insulin resistance, and hyperlipidemia. In FRAM 2, which is ongoing, investigators are also determining the associations of subclinical cardiovascular disease, as measured by carotid intimal-medial wall thickness, with HIV infection, fat distribution changes, insulin resistance, and other proatherogenic changes in serum lipid levels. The demographic characteristics of HIV-infected FRAM men and women were comparable to those reported from a national random sampling of HIV-infected men and women receiving medical care in the United States. The representativeness of the FRAM sample increases its value as a resource for studies on fat distribution, metabolic changes, and atherosclerosis in HIV infection.
body fat distribution; dyslipidemias; HIV infections; insulin resistance; lipodystrophy; metabolism
Upper body fat is associated with increased cardiometabolic risk. More recently, neck circumference (NC) and/or neck fat have been associated with hyperlipidemia, impaired glucose homeostasis, and hypertension. The objective of this study was to determine whether this relationship is evident in HIV-infected individuals, who often exhibit changes in relative fat distribution, and to determine whether NC is independently associated with carotid intima-media thickness (cIMT) in HIV and non–HIV-infected patients.
RESEARCH DESIGN AND METHODS
Body composition, including anthropometrics, visceral adipose tissue assessment by CT, and metabolic parameters, including lipids, cIMT, and oral glucose tolerance test, were measured in 174 men and women with HIV infection and 154 non–HIV-infected subjects. NC was measured in triplicate inferior to the laryngeal prominence.
In univariate analysis, NC was significantly and positively related to blood pressure, hemoglobin A1c, glucose, and insulin and significantly and negatively related to HDL cholesterol in HIV-infected individuals and HIV-negative control subjects. NC was significantly associated with cIMT in univariate regression analysis among HIV-infected (r = 0.21, P = 0.006) and non–HIV-infected (r = 0.31, P = 0.0001) patients. This relationship remained significant among non–HIV-infected patients (R2 = 0.45, P < 0.001) but not HIV-infected patients in multivariate modeling controlling for age, sex, race, smoking hypertension, glucose, and lipids.
Among both HIV and non–HIV-infected patients, increased NC is strongly associated with decreased HDL and impaired glucose homeostasis. Among non–HIV-infected subjects, NC also predicts increased cIMT when controlling for traditional risk factors.
Few studies have examined the impact of childhood obesity on later kidney disease, and consequently, our understanding is very limited.
Longitudinal population-based cohort.
Setting & Participants
The Medical Research Council National Survey of Health and Development, a socially stratified sample of 5,362 singletons born in 1 week in March 1946 in England, Scotland, and Wales, of which 4,340 were analyzed.
Early-life overweight latent classes (never, prepubertal only, pubertal onset, or always), derived from repeated measurements of body mass index between ages 2 and 20 years.
Outcomes & Measurements
The primary outcome was chronic kidney disease (CKD), defined as creatinine- or cystatin C–based estimated glomerular filtration rate (eGFRcr and eGFRcys, respectively) <60 mL/min/1.73 m2 or urine albumin-creatinine ratio (UACR) ≥3.5 mg/mmol measured at age 60-64 years. Associations were explored through regression analysis, with adjustment for socioeconomic position, smoking, physical activity level, diabetes, hypertension, and overweight at ages 36 and 53 years.
2.3% of study participants had eGFRcr <60 mL/min/1.73 m2, 1.7% had eGFRcys <60 mL/min/1.73 m2, and 2.9% had UACR ≥3.5 mg/mmol. Relative to being in the never-overweight latent class, being in the pubertal-onset– or always-overweight latent classes was associated with eGFRcys-defined CKD (OR, 2.04; 95% CI, 1.09-3.82). Associations with CKD defined by eGFRcr (OR, 1.27; 95% CI, 0.71-2.29) and UACR (OR, 1.33; 95% CI, 0.70-2.54) were less marked, but in the same direction. Adjustment for lifestyle and health factors had little impact on effect estimates.
A low prevalence of CKD resulted in low statistical power. No documentation of chronicity for outcomes. All-white study population restricts generalizability.
Being overweight in early life was found to be associated with eGFRcys-defined CKD in later life. The associations with CKD defined by eGFRcr and UACR were less marked, but in the same direction. Reducing or preventing overweight in the early years of life may significantly reduce the burden of CKD in the population.
Childhood obesity; chronic kidney disease; estimated glomerular filtration rate
Inflammation is a potential mechanism to explain the accelerated atherosclerosis observed in HIV- and hepatitis C virus (HCV)–infected persons. We evaluated C-reactive protein (CRP) in HIV-infected and HIV/HCV-coinfected individuals in the era of effective antiretroviral (ARV) therapy.
Cross-sectional study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) cohort and controls from the Coronary Artery Risk Development in Young Adults (CARDIA) study.
CRP levels were measured in 1135 HIV-infected participants from the FRAM cohort and 281 controls from the CARDIA study. The associations of HIV and HIV/HCV infection with CRP levels were estimated by multivariable linear regression.
Compared with controls, HIV monoinfection was associated with an 88% higher CRP level in men (P < 0.0001) but with no difference in women (5%; P = 0.80) in multivariate analysis. CRP levels were not associated with ARV therapy, HIV RNA level, or CD4 cell count. Compared with controls, HIV/HCV coinfection was associated with a 41% lower CRP level in women (P = 0.012) but with no difference in men (+4%; P = 0.90). Among HIV-infected participants, HCV coinfection was associated with 50% lower CRP levels after multivariable analysis (P < 0.0001) in men and women. Greater visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were strongly associated with CRP levels. Among HIV- infected participants, CRP levels were 17% (P < 0.001) and 21% (P = 0.002) higher per doubling of VAT and SAT; among controls, CRP levels were 34% (P < 0.001) and 61% (P = 0.009) higher, respectively.
In the absence of HCV coinfection, HIV infection is associated with higher CRP levels in men. HCV coinfection is associated with lower CRP levels in men and women.
cardiovascular disease; C-reactive protein; hepatitis C virus; HIV; inflammation
Both peripheral fat loss and central fat gain have been reported in women with HIV infection. We determined the fat changes that are specific to HIV infection in women.
HIV-infected and control women from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) were compared. Lipoatrophy or lipohypertrophy was defined as concordance between participant report of fat change and clinical examination. Whole-body magnetic resonance imaging measured regional adipose tissue volumes. The relationship among different adipose tissue depots was assessed. Factors associated with individual depots were analyzed using multivariate linear regression.
HIV-infected women reported more fat loss than controls in all peripheral and most central depots. Peripheral lipoatrophy was more frequent in HIV-infected women than controls (28% vs. 4%, P < 0.001), whereas central lipohypertrophy was similar (62% vs. 63%). Among HIV-infected women, those with central lipohypertrophy were less likely to have peripheral lipoatrophy (odds ratio, 0.39; 95% confidence interval, 0.20 to 0.75, P = 0.006) than those without central lipohypertrophy. On magnetic resonance imaging, HIV-infected women with clinical peripheral lipoatrophy had less subcutaneous adipose tissue (SAT) in peripheral and central sites and less visceral adipose tissue (VAT) than HIV-infected women without peripheral lipoatrophy. Compared with controls, HIV-infected women had less SAT in the legs, regardless of the presence or absence of lipoatrophy. However, those without lipoatrophy had more VAT and upper trunk SAT than controls. Use of the antiretroviral drug stavudine was associated with less leg SAT but was not associated with VAT. The use of highly active antiretroviral therapy, however, was associated with more VAT.
Peripheral lipoatrophy occurs commonly in HIV-infected women but is not associated with reciprocally increased VAT or trunk fat.
HIV; lipodystrophy; lipoatrophy; lipohypertrophy; visceral obesity; fat redistribution; body composition
Complaints of dry skin in HIV-infected individuals were reported after the advent of HAART. The objective of the study was to evaluate the prevalence of dry skin and associated factors in HIV-infected and control subjects.
A total of 1026 HIV-infected subjects and 274 controls [from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based study of cardiovascular risk assessment] in the Study of Fat Redistribution and Metabolic Change in HIV infection (FRAM) had skin assessed by self-report and examination. Multivariable logistic regression identified factors associated with dry skin.
Self-reported dry skin was more prevalent in HIV-infected subjects than controls. In multivariable analysis, HIV infection was associated with self-reported dry skin. In HIV-infected men, current indinavir use, CD4 cell count less than 200 cells/μl and recent opportunistic infections were associated with dry skin. Indinavir use had an elevated risk in men with CD4 cell counts of 200 cells/μl or greater but not with CD4 cell counts less than 200 cells/μl. In HIV-infected women, a CD4 cell count less than 200 cells/μl was associated with dry skin; indinavir use did not reach statistical significance but, as in men, indinavir use had an elevated risk in those with higher CD4 cell counts than in those with CD4 cell counts less than 200 cells/μl.
Dry skin is more common in HIV-infected individuals than controls. In HIV-infected individuals, low CD4 cell counts and indinavir use in those with higher CD4 cell counts are associated with dry skin.
complication; dermatology; opportunistic infection; protease inhibitors; retinoid
Chronic kidney disease risk factors may associate with the estimated glomerular filtration rate (eGFR) differently than with the measured GFR. To examine this, we evaluated 1150 patients (mean age 65) in two community cohorts for risk factors, measured GFR by iothalamate clearance, and eGFR based on creatinine (Cr), cystatin C (CysC), or both. The interaction between each risk factor and eGFR (relative to measured GFR) identified risk factor associations with eGFR along non-GFR pathways. In a subset of 40 patients with two visits, the mean coefficient of variation was 8.2% for measured GFR, 6.4% for eGFRCr, 8.2% for eGFRCr-CysC, and 10.7% for eGFRCysC. The measured GFR was better correlated with eGFRCr-CysC (r, 0.74) than eGFRCr (r, 0.70) or eGFRCysC (r, 0.68). Lower measured GFR associated with lower 24-hour urine creatinine, albuminuria, hypertension, diabetes, higher triglycerides, and higher uric acid. Lower eGFRCr had these same associations except for an association with higher 24-hour urine creatinine along a non-GFR pathway. Lower eGFRCysC and eGFRCr-CysC also had these same associations but also associated with obesity, albuminuria, hypertension, diabetes, higher triglycerides, higher C-reactive protein, and higher uric acid along non-GFR pathways. Thus, cystatin C improves estimation of GFR over creatinine alone; however, the association between most of the risk factors and GFR was more accurate by eGFR based on creatinine alone. This is explained by the association of these risk factors with the non-GFR determinants of cystatin C.
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.
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.
HIV; albuminuria; glomerular filtration rate; heart failure; cardiovascular disease
Visceral obesity is associated with insulin resistance, but the association of other regional adipose depots with insulin resistance is not understood. In HIV infection, buffalo hump (upper trunk fat) is associated, but the association of upper trunk fat with insulin resistance has not been examined in controls. To determine the independent association of adipose depots other than visceral with insulin resistance, we performed a cross-sectional analysis of controls and HIV-infected subjects in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study, who had measurements of glucose, insulin, and adipose tissue volumes by whole-body magnetic resonance imaging. We studied 926 HIV-positive persons from 16 academic medical center clinics and trials units with demographic characteristics representative of US patients with HIV infection and 258 FRAM controls from the population-based Coronary Artery Risk Development in Young Adults study. We measured visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volume in the legs, arms, lower trunk (back and abdomen), and upper trunk (back and chest) and assessed their association with the homeostasis model of assessment (HOMA) and HOMA >4 by stepwise multivariable analysis. The prevalence of HOMA >4 as a marker of insulin resistance was 28% among controls compared with 37% among HIV-infected subjects (P = 0.005). Among controls, those in the highest tertile of upper trunk SAT volume had an odds ratio (OR) of 9.0 (95% confidence interval [CI]: 2.4 to 34; P = 0.001) for having HOMA >4 compared with the lowest tertile, whereas in HIV-positive subjects, the OR was lower (OR = 2.09, 95% CI: 1.36 to 3.19; P = 0.001). Among controls, the highest tertile of VAT volume had an OR of 12.1 (95% CI: 3.2 to 46; P = 0.0002) of having HOMA >4 compared with the lowest tertile, whereas in HIV-positive subjects, the OR was 3.12 (95% CI: 2.0 to 4.8; P < 0.0001). After adjusting for VAT and upper trunk SAT, the association of other SAT depots with HOMA >4 did not reach statistical significance. Thus, VAT and upper trunk SAT are independently associated with insulin resistance in controls and in HIV-infected persons.
buffalo hump; fat distribution; insulin resistance; lipodystrophy; visceral obesity
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.
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.
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).
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.
albumin-to-creatinine ratio; chronic kidney disease; cystatin C; National Health and Nutrition Examination Survey