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1.  Is Renal Function associated with Early Age-Related Macular Degeneration? 
Age-related macular degeneration (AMD) and chronic kidney disease both involve immune dysregulation and may share underlying pathophysiologic changes to systemic homeostasis. Hence we aim to evaluate associations between impaired kidney function and early AMD, in a search for urinary biomarkers for AMD.
A population-based, cross-sectional analysis of persons aged 45-84 years was conducted with renal function measured using serum creatinine and cystatin C levels and the estimated glomerular filtration rate (eGFR) calculated. AMD status was ascertained from retinal photographs.
Of 5,874 participants, 221 had early AMD. High serum cystatin C and low eGFR (≤60ml/min/1.73m2) were not associated with early AMD in our multivariate analyses. Among normotensive persons, however, highest versus other deciles of cystatin C were associated with an increased prevalence of early AMD (odds ratio 1.80, 95% confidence interval 1.00-3.23).
Results could not confirm an association between kidney function and early AMD. The borderline association between cystatin C and early AMD in normotensives require further verification.
PMCID: PMC4111798  PMID: 24879085
age-related macular degeneration; kidney; renal function
2.  Association of kidney disease measures with ischemic versus hemorrhagic strokes: Pooled analyses of 4 prospective community-based cohorts 
Background and purpose
Although low glomerular filtration rate (GFR) and albuminuria are associated with increased risk of stroke, few studies compared their contribution to risk of ischemic versus hemorrhagic stroke separately. We contrasted the association of these kidney measures with ischemic versus hemorrhagic stroke.
We pooled individual participant data from four community-based cohorts: three from the United States and one from The Netherlands. GFR was estimated by using both creatinine and cystatin C, and albuminuria was quantified by urinary albumin-to-creatinine ratio (ACR). Associations of eGFR and ACR were compared for each stroke type (ischemic vs. intraparenchymal hemorrhagic) using study-stratified Cox-regression.
Amongst 29,595 participants (mean age 61 [SD 12.5] years, 46% males, 17% black), 1,261 developed stroke (12% hemorrhagic) during 280,549 person-years. Low eGFR was significantly associated with increased risk of ischemic, but not hemorrhagic, stroke risk, while high ACR was associated with both stroke types. Adjusted HRs for ischemic and hemorrhagic stroke at eGFR of 45 (vs. 95) ml/min/1.73m2 were 1.30 (95% CI, 1.01–1.68) and 0.92 (0.47–1.81), respectively. In contrast, the corresponding HR for ACR 300 (vs. 5) mg/g were 1.62 (1.27–2.07) for ischemic and 2.57 (1.37–4.83) for hemorrhagic stroke, with significantly stronger association with hemorrhagic stroke (P =0.04). For hemorrhagic stroke, the association of elevated ACR was of similar magnitude as that of elevated systolic blood pressure.
Whereas albuminuria showed significant association with both stroke types, the association of decreased eGFR was only significant for ischemic stroke. The strong association of albuminuria with both stroke types warrants clinical attention and further investigations.
PMCID: PMC4517673  PMID: 24876078
3.  Sex differences in the prevalence and clinical outcomes of subclinical peripheral artery disease in the Health, Aging, and Body Composition (Health ABC) study 
Vascular  2013;22(2):142-148.
The objective of the study was to determine if there are sex-based differences in the prevalence and clinical outcomes of subclinical peripheral artery disease (PAD). We evaluated the sex-specific associations of ankle–brachial index (ABI) with clinical cardiovascular disease outcomes in 2797 participants without prevalent clinical PAD and with a baseline ABI measurement in the Health, Aging, and Body Composition study. The mean age was 74 years, 40% were black, and 52% were women. Median follow-up was 9.37 years. Women had a similar prevalence of ABI < 0.9 (12% women versus 11% men; P=0.44), but a higher prevalence of ABI 0.9–1.0 (15% versus 10%, respectively; P < 0.001). In a fully adjusted model, ABI < 0,9 was significantly associated with higher coronary heart disease (CHD) mortality, incident clinical PAD and incident myocardial infarction in both women and men. ABI < 0.9 was significantly associated with incident stroke only in women. ABI 0.9–1.0 was significantly associated with CHD death in both women (hazard ratio 4.84, 1.53–15.31) and men (3.49, 1.39–8.721. However, ABI 0.9–1.0 was significantly associated with incident clinical PAD (3.33, 1.44–7.70) and incident stroke (2.45, 1.38–4.35) only in women. Subclinical PAD was strongly associated with adverse CV events in both women and men, but women had a higher prevalence of subclinical PAD.
PMCID: PMC4509626  PMID: 23512905
women; sex-specific; peripheral artery disease; epidemiology
4.  Kidney Function and Cognitive Health in Older Adults: The Cardiovascular Health Study 
American Journal of Epidemiology  2014;180(1):68-75.
Recent evidence has demonstrated the importance of kidney function in healthy aging. We examined the association between kidney function and change in cognitive function in 3,907 participants in the Cardiovascular Health Study who were recruited from 4 US communities and studied from 1992 to 1999. Kidney function was measured by cystatin C–based estimated glomerular filtration rate (eGFRcys). Cognitive function was assessed using the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test, which were administered up to 7 times during annual visits. There was an association between eGFRcys and change in cognitive function after adjustment for confounders; persons with an eGFRcys of less than 60 mL/minute/1.73 m2 had a 0.64 (95% confidence interval: 0.51, 0.77) points/year faster decline in Modified Mini-Mental State Examination score and a 0.42 (95% confidence interval: 0.28, 0.56) points/year faster decline in Digit Symbol Substitution Test score compared with persons with an eGFRcys of 90 or more mL/minute/1.73 m2. Additional adjustment for intermediate cardiovascular events modestly affected these associations. Participants with an eGFRcys of less than 60 mL/minute/1.73 m2 had fewer cognitive impairment–free life-years on average compared with those with eGFRcys of 90 or more mL/minute/1.73 m2, independent of confounders and mediating cardiovascular events (mean difference = −0.44, 95% confidence interval: −0.62, −0.26). Older adults with lower kidney function are at higher risk of worsening cognitive function.
PMCID: PMC4070934  PMID: 24844846
aging; chronic kidney disease; cognitive function; congestive heart failure; myocardial infarction; prospective study; stroke; successful aging
5.  Urinary Kidney Injury Molecule 1 (KIM-1) and Interleukin 18 (IL-18) as Risk Markers for Heart Failure in Older Adults: The Health, Aging, and Body Composition (Health ABC) Study 
Kidney damage and reduced kidney function are potent risk factors for heart failure (HF), but existing studies are limited to assessing albuminuria or estimated glomerular filtration rate (eGFR). We evaluated the associations of urinary biomarkers of kidney tubular injury (interleukin 18 [IL-18] and kidney injury molecule 1 [KIM-1]) with future risk of HF.
Study Design
Retrospective cohort study.
Setting & Participants
2921 participants without HF in the Health, Aging, and Body Composition (Health ABC) cohort.
Ratios of urine KIM-1, IL-18, and albumin to creatinine (KIM-1:Cr, IL-18:Cr, and ACR, respectively).
Incident HF over a median follow-up of 12 years.
Median values of each marker at baseline were 812 (IQR, 497–1235) pg/mg for KIM-1:Cr, 31 (IQR, 19–56) pg/mg for IL-18:Cr, and 8 (IQR, 5–19) mg/g for ACR. 596 persons developed HF during follow-up. The top quartile of KIM-1:Cr was associated with risk of incident HF after adjustment for baseline eGFR, HF risk factors, and ACR (HR, 1.32; 95% CI, 1.02–1.70) in adjusted multivariate proportional hazards models. The top quartile of IL-18:Cr was also associated with HF in a model adjusted for risk factors and eGFR (HR, 1.35; 95% CI, 1.05–1.73), but was attenuated by adjustment for ACR (HR, 1.15; 95% CI, 0.89–1.48). The top quartile of ACR had a stronger adjusted association with HF (HR, 1.96; 95% CI, 1.53–2.51).
Generalizability to other populations is uncertain.
Higher urine concentrations of KIM-1 were independently associated with incident HF risk, although the associations of higher ACR were of stronger magnitude.
PMCID: PMC4069223  PMID: 24656453
IL-18; KIM-1; cystatin C; heart failure; CKD; risk marker; cardiovascular disease (CVD); albuminuria; kidney tubular injury
6.  Dietary Protein Intake and Change in Estimated GFR in the Cardiovascular Health Study 
With aging, kidney function declines, as evidenced by reduced glomerular filtration rate. It is controversial whether or not high protein intake accelerates the kidney function decline.
Research Methods & Procedures
We examined whether dietary protein is associated with change in kidney function (mean follow-up 6.4 (SD=1.4, range = 2.5 to 7.9) years in the Cardiovascular Health Study (n =3,623). We estimated protein intake using a food frequency questionnaire (FFQ) and estimated glomerular filtration rate (eGFR) from cystatin C. Associations between protein intake and kidney function were determined by linear and logistic regression models.
Average protein intake was 19% of energy intake (SD=5%). Twenty-seven percent (n=963) of study participants had rapid decline in kidney function, as defined by (ΔeGFRcysC > 3 mL/min per 1.73 m2). Protein intake (characterized as g/day and % energy/day), was not associated with change in eGFR (P>0.05 for all comparisons). There were also no significant associations when protein intake was separated by source (animal and vegetable).
These data suggest that higher protein intake does not have a major impact on kidney function decline among elderly men and women.
PMCID: PMC4082792  PMID: 24984995
kidney; glomerular filtration rate; vegetable protein; animal protein; macronutrients
Hypertension  2014;64(1):103-110.
Prior studies have demonstrated that elevated aldosterone concentrations are an independent risk factor for death in patients with cardiovascular disease. Limited studies, however, have evaluated systematically the association between serum aldosterone and adverse events in the setting of chronic kidney disease (CKD). We investigated the association between serum aldosterone and death and end-stage renal disease (ESRD) in 3,866 participants from the Chronic Renal Insufficiency Cohort. We also evaluated the association between aldosterone and incident congestive heart failure (CHF) and atherosclerotic events in participants without baseline cardiovascular disease. Cox proportional hazards models were used to evaluate independent associations between elevated aldosterone concentrations and each outcome. Interactions were hypothesized and explored between aldosterone and sex, race, and the use of loop diuretics and RAAS inhibitors. Over a median follow-up period of 5.4 years, 587 participants died, 743 developed ESRD, 187 developed CHF, and 177 experienced an atherosclerotic event. Aldosterone concentrations (per standard deviation of the log transformed aldosterone) were not an independent risk factor for death (adjusted HR 1.00, 95% CI [0.93–1.12]), ESRD (adjusted HR 1.07, 95% CI [0.99–1.17]), or atherosclerotic events (adjusted HR 1.04, 95% CI [0.85–1.18]). Aldosterone was associated with CHF (adjusted HR 1.21, 95% CI [1.02–1.35]). Among participants with CKD, higher aldosterone concentrations were independently associated with the development of CHF, but not for death, ESRD, or atherosclerotic events. Further studies should evaluate whether mineralocorticoid receptor antagonists may reduce adverse events in individuals with CKD since elevated cortisol levels may activate the mineralocorticoid receptor.
PMCID: PMC4089190  PMID: 24752431
Aldosterone; Chronic kidney disease; Outcomes; Death; Congestive Heart Failure
8.  Association of Perioperative Plasma Neutrophil Gelatinase-Associated Lipocalin Levels with 3-Year Mortality after Cardiac Surgery: A Prospective Observational Cohort Study 
PLoS ONE  2015;10(6):e0129619.
Higher levels of plasma neutrophil gelatinase-associated lipocalin (pNGAL) are an early marker of acute kidney injury and are associated with increased risk of short-term adverse outcomes. The independent association between pNGAL and long-term mortality is unknown.
In this prospective observational cohort study, we studied 1191 adults who underwent cardiac surgery between 2007 and 2009 at 6 centers in the TRIBE-AKI cohort. We measured the pNGAL on the pre-operative and first 3 post-operative days and assessed the relationship of peri-operative pNGAL concentrations with all-cause mortality.
During a median follow-up of 3.0 years, 139 participants died (50/1000 person-years). Pre-operative levels of pNGAL were associated with 3-year mortality (unadjusted HR 1.96, 95% CI 1.34,2.85) and the association persisted after adjustment for pre-operative variables including estimated glomerular filtration rate (adjusted HR 1.48, 95% CI 1.04–2.12). After adjustment for pre- and intra-operative variables, including pre-operative NGAL levels, the highest tertiles of first post-operative and peak post-operative pNGAL were also independently associated with 3-year mortality risk (adjusted HR 1.31, 95% CI 1.0–1.7 and adjusted HR 1.78, 95% CI 1.2–2.7, respectively). However, after adjustment for peri-operative changes in serum creatinine, there was no longer an independent association between the first post-operative and peak post-operative pNGAL and long-term mortality (adjusted HR 0.98,95% CI 0.79–1.2 for first pNGAL and adjusted HR 1.19, 95% CI 0.87–1.61 for peak pNGAL).
Pre-operative pNGAL levels were independently associated with 3-year mortality after cardiac surgery. While post-operative pNGAL levels were also associated with 3-year mortality, this relationship was not independent of changes in serum creatinine. These findings suggest that while pre-operative pNGAL adds prognostic value for mortality beyond routinely available serum creatinine, post-operative pNGAL measurements may not be as useful for this purpose.
PMCID: PMC4460181  PMID: 26053382
9.  Association between preoperative statin use and acute kidney injury biomarkers in cardiac surgery 
The Annals of thoracic surgery  2014;97(6):2081-2087.
Acute kidney injury is a serious complication of cardiac surgery for which there remains no specific therapy. Animal data and several observational studies suggest that statins prevent acute kidney injury, but the results are not conclusive, and many studies are retrospective in nature.
We conducted a multi-center prospective cohort study of 625 adult patients undergoing elective cardiac surgery. All patients were on statins and were grouped on whether statins were continued or held in the 24 hours prior to surgery. The primary outcome was acute kidney injury defined by a doubling of serum creatinine or dialysis. The secondary outcome was the peak level of several kidney injury biomarkers. Results were adjusted for demographic and clinical factors.
Continuing (vs. holding) a statin prior to surgery was not associated with a lower risk of acute kidney injury defined by a doubling of serum creatinine or dialysis, [adjusted relative risk (RR) 1.09 (95% confidence interval (CI) 0.44, 2.70)]. However, continuing a statin was associated with a lower risk of elevation of the following AKI biomarkers: urine interleukin-18, urine neutrophil gelatinase-associated lipocalin, urine kidney injury molecule-1, and plasma neutrophil gelatinase-associated lipocalin [adjusted RR 0.34 (95% CI 0.18, 0.62), adjusted RR 0.41 (95% CI 0.22, 0.76), adjusted RR 0.37 (95% CI 0.20, 0.76), adjusted RR 0.62 (95% CI 0.39, 0.98), respectively].
Statins may prevent kidney injury after cardiac surgery as evidenced by lower levels of kidney injury biomarkers.
PMCID: PMC4068122  PMID: 24725831
CABG; kidney; renal failure
10.  Urinary Biomarkers of Kidney Injury Are Associated with All-Cause Mortality in the Women’s Interagency HIV Study (WIHS) 
HIV medicine  2013;15(5):291-300.
Chronic kidney disease (CKD) is common in HIV; CKD is associated with mortality. Urinary markers of tubular injury have been associated with future kidney disease risk, but associations with mortality are unknown.
We evaluated the association of urinary interleukin-18(IL-18), liver fatty acid binding protein(L-FABP), kidney injury molecule-1(KIM-1), neutrophil gelatinase-associated lipocalin(NGAL), albumin-to-creatinine ratio(ACR) with 10-year, all-cause death in 908 HIV-infected women. Kidney function was estimated using cystatin C (eGFRcys).
There were 201 deaths during 9,269 person-years of follow-up. After demographic adjustment, compared to the lowest tertile, highest tertiles of IL-18 (HR 2.54,95%CI 1.75–3.68), KIM-1 (2.04,1.44–2.89), NGAL(1.50,1.05–2.14), and ACR(1.63,1.13–2.36) were associated with higher mortality. After multivariable adjustment including eGFRcys, only the highest tertiles of IL-18, (1.88,1.29–2.74) and ACR (1.46,1.01–2.12) remained independently associated with mortality. Findings with KIM-1 were borderline (1.41, 0.99–2.02). We found a J-shaped association between L-FABP and mortality. Compared to persons in the lowest tertile, HR for middle tertile of L-FABP was 0.67 (0.46–0.98) after adjustment. Findings were stronger when IL-18, ACR and L-FABP were simultaneously included in models.
Among HIV-infected women, some urinary markers of tubular injury are associated with mortality risk, independently of eGFRcys and ACR. These markers represent potential tools to identify early kidney injury in persons with HIV.
PMCID: PMC3975680  PMID: 24313986
HIV; IL-18; KIM-1; L-FABP; NGAL; urinary biomarkers
11.  The association between body composition and cystatin C in South Asians: Results from the MASALA study 
While South Asians have high rates of obesity and kidney disease, little is known about the effect of regional body composition on kidney function. We investigated the association between body composition measures and cystatin C-based estimated glomerular filtration rate (eGFRcysC) in 150 immigrant South Asians. The inverse association between overall adiposity and eGFRcysC was attenuated by C-reactive protein (CRP), while the association of ectopic fat was completely attenuated by metabolic covariates and CRP. In immigrant South Asians, the associations between overall adiposity and ectopic fat with decreased kidney function are largely explained by metabolic alterations and inflammation.
PMCID: PMC4404210  PMID: 25465493
Body composition; Ectopic fat; Cystatin C; South Asian
12.  Body Mass Index and Early Kidney Function Decline in Young Adults: A Longitudinal Analysis of the CARDIA (Coronary Artery Risk Development in Young Adults) Study 
Identifying potentially modifiable risk factors is critically important for reducing the burden of chronic kidney disease. We sought to examine the association of body mass index (BMI) with kidney function decline in a cohort of young adults with preserved glomerular filtration at baseline.
Study Design
Longitudinal cohort.
Setting & Participants
2,891 black and white young adults with cystatin C-based estimated glomerular filtration rate (eGFRcys) >90 ml/min/1.73 m2 taking part in the year-10 examination (in 1995–1996) of the Coronary Artery Risk Development in Young Adults (CARDIA) Study.
BMI, categorized as 18.5–24.9 (reference), 25.0–29.9. 30.0–39.9, and ≥40.0 kg/m2.
Trajectory of kidney function decline, rapid decline (>3% per year), and incident eGFRcys <60 ml/min/1.73 m2 over 10 years of follow-up.
GFRcys estimated from the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation for calibrated cystatin C at CARDIA years 10, 15, and 20.
At year 10, participants had a mean age of 35.1 years, median eGFRcys of 114 ml/min/1.73 m2, and 24.5% had BMI ≥30.0 kg/m2. After age 30 years, average eGFRcys was progressively lower with each increment of BMI after adjustment for baseline age, race, sex, hyperlipidemia, smoking status, and physical activity. Higher BMI category was associated with successively higher odds of rapid decline (for 25.0–29.9, 30.0–39.9, and ≥40.0 kg/m2, the adjusted ORs were 1.50 [95% CI, 1.21–1.87], 2.01 [95% CI, 1.57–2.87], and 2.57 [95% CI, 1.67–3.94], respectively). Eighteen participants (0.6%) had incident eGFRcys <60 ml/min/1.73 m2. In unadjusted analysis, higher BMI category was associated with incident eGFRcys <60 ml/min/1.73 m2 (for 25.0–29.9, 30.0–39.9, and ≥40.0 kg/m2, the ORs were 5.17 [95% CI, 1.10–25.38], 7.44 [95% CI, 1.54–35.95], and 5.55 [95% CI, 0.50–61.81], respectively); adjusted associations were no longer significant.
Inability to describe kidney function before differences by BMI category were already evident. Absence of data on measured GFR or GFR estimated from serum creatinine.
Higher BMI categories are associated with greater declines in kidney function among a cohort of young adults with preserved GFR at baseline. Clinicians should vigilantly monitor overweight and obese patients for evidence of early kidney function decline.
PMCID: PMC3969447  PMID: 24295611
13.  Fibroblast Growth Factor 23, the Ankle-Brachial Index, and Incident Peripheral Artery Disease in the Cardiovascular Health Study 
Atherosclerosis  2014;233(1):91-96.
Fibroblast growth factor 23 (FGF23) has emerged as a novel risk factor for mortality and cardiovascular events. Its association with the ankle-brachial index (ABI) and clinical peripheral artery disease (PAD) is less known.
Using data (N=3,143) from the Cardiovascular Health Study (CHS), a cohort of community dwelling adults > 65 years of age, we analyzed the cross sectional association of FGF23 with ABI and its association with incident clinical PAD events during 9.8 years of follow up using multinomial logistic regression and Cox proportional hazards models respectively.
The prevalence of cardiovascular disease (CVD) and traditional risk factors like diabetes, coronary artery disease, and heart failure increased across higher quartiles of FGF23. Compared to those with ABI of 1.1–1.4, FGF23 at baseline was associated with prevalent PAD (ABI<0.9) although this association was attenuated after adjusting for CVD risk factors, and kidney function (OR 0.91, 95% CI 0.76–1.08). FGF23 was not associated with high ABI (>1.4) (OR 1.06, 95% CI 0.75–1.51). Higher FGF23 was associated with incidence of PAD events in unadjusted, demographic adjusted, and CVD risk factor adjusted models (HR 2.26, 95% CI 1.28–3.98; highest versus lowest quartile). The addition of estimated glomerular filtration and urine albumin to creatinine ratio to the model however, attenuated these findings (HR 1.46, 95% CI, 0.79–2.70).
In community dwelling older adults, FGF23 was not associated with baseline low or high ABI or incident PAD events after adjusting for confounding variables. These results suggest that FGF23 may primarily be associated with adverse cardiovascular outcomes through non atherosclerotic mechanisms.
PMCID: PMC3927151  PMID: 24529128
Fibroblast growth factor; peripheral artery disease; ankle-brachial index; chronic kidney disease; cardiovascular disease
14.  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.
Tenofovir is used commonly in HIV treatment and prevention settings, but factors that correlate with tenofovir exposure in real-world setting are unknown.
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
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
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).
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.
PMCID: PMC3956315  PMID: 24275255
Tenofovir; pharmacokinetics; HIV-infected women; diverse populations; GFR; cystatin C
15.  Association of a Cystatin C Gene Variant With Cystatin C Levels, CKD, and Risk of Incident Cardiovascular Disease and Mortality 
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
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.
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.
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.
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.
rs13038305 only explains a small proportion of cystatin C variation.
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.
PMCID: PMC3872167  PMID: 23932088
Cystatin C; chronic kidney disease; genetics; single nucleotide polymorphism; net reclassification improvement
16.  HIV/HCV coinfection ameliorates the atherogenic lipoprotein abnormalities of HIV infection 
AIDS (London, England)  2014;28(1):49-58.
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.
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.
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.
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.
PMCID: PMC4267724  PMID: 24136113
HIV infection; HCV infection; lipoproteins; cardiovascular disease
17.  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.
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.
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.
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]).
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.
PMCID: PMC3840534  PMID: 24125420
Left ventricular mass; left ventricular hypertrophy; chronic kidney disease; fibroblast growth factor 23; older adults; cardiovascular disease
18.  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.
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.
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.
We developed a point-based score using multivariable Cox regression models. Median follow-up was 6.3 years, during which 2059 CKD events occurred.
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).
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.
PMCID: PMC4188545  PMID: 24922479
chronic kidney disease; HIV; risk score; tenofovir
19.  Influence of Urine Creatinine Concentrations on the Relation of Albumin-Creatinine Ratio With Cardiovascular Disease Events: The Multi-Ethnic Study of Atherosclerosis (MESA) 
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.
Spot urine albumin, the reciprocal of the urine creatinine concentration (1/UCr), and ACR.
Incident CVD events.
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).
We lacked 24-hour urine data.
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.
PMCID: PMC3783582  PMID: 23830183
20.  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) 
Obesity is associated with higher end-stage renal disease incidence, but associations with earlier forms of kidney disease remain incompletely characterized.
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.
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.
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
21.  Cystatin C versus Creatinine in Determining Risk Based on Kidney Function 
The New England journal of medicine  2013;369(10):932-943.
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.
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.
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.
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.)
PMCID: PMC3993094  PMID: 24004120
22.  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.
PMCID: PMC3755100  PMID: 23701892
cystatin C; GFR estimation; chronic kidney disease
23.  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 
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
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).
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).
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.
No measured GFR.
eGFRcys decline differs by race at early ages, with faster annualized rates of decline among blacks. Future studies are required to explain observed differences.
PMCID: PMC3714331  PMID: 23473985
24.  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.
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.
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.
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.
Our findings suggest that elevated BP, particularly SBP, contributes to declining kidney function in older adults.
PMCID: PMC3816322  PMID: 23709568
blood pressure; cystatin C; diastolic blood pressure; elderly; hypertension; kidney function; systolic blood pressure.
25.  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.
PMCID: PMC3816347  PMID: 23813702
calcification; cardiovascular diseases; chronic kidney insufficiency; coronary arteries; coronary disease; cystatin C; glomerular filtration rate; kidney

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