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1.  Association of Serum Erythropoietin with Cardiovascular Events, Kidney Function Decline and Mortality: The Health ABC Study 
Circulation. Heart failure  2016;9(1):e002124.
Background
Studies suggest that in patients with heart failure (HF), high serum erythropoietin is associated with risk of recurrent HF and mortality. Trials of erythropoietin stimulating agents in persons with kidney disease have also suggested an increased incidence of adverse clinical events. No studies have evaluated the association of endogenous erythropoietin levels with clinical outcomes in the community living older adults.
Methods and Results
Erythropoietin concentration was measured in 2,488 participants aged 70–79 years in the Health, Aging and Body Composition Study. Associations of erythropoietin with incident HF, coronary heart disease (CHD), stroke, mortality, and ≥30% decline in estimated glomerular filtration rate (eGFR) were examined using Cox proportional hazards and logistic regression over 10.7 years of follow up. Mean (SD) age was 75 (3) years and median (quartile 1, quartile 3) erythropoietin was 12.3 (9.0, 17.2) mIU/mL. There were 503 incident HF events and each doubling of serum erythropoietin was associated with a 25% increased risk of incident HF 1.25 (95% CI 1.13, 1.48) after adjusting for demographics, prevalent cardiovascular disease (CVD), CVD risk factors, kidney function and serum hemoglobin. There was no interaction of serum erythropoietin with chronic kidney disease or anemia (p>0.50). There were 330 incident CHD events, 161 strokes, 1,112 deaths and 698 outcomes of ≥ 30% decline in eGFR. Serum erythropoietin was not significantly associated with these outcomes.
Conclusions
Higher levels of endogenous erythropoietin are associated with incident HF in older adults. Studies need to elucidate the mechanisms through which endogenous erythropoietin levels associate with specific outcomes.
doi:10.1161/CIRCHEARTFAILURE.115.002124
PMCID: PMC4698899  PMID: 26721912
erythropoietin; heart failure; chronic kidney disease; cardiovascular outcomes; death
2.  Potential Impact of Prescribing Metformin According to eGFR Rather Than Serum Creatinine 
Diabetes Care  2015;38(11):2059-2067.
OBJECTIVE
Many societies recommend using estimated glomerular filtration rate (eGFR) rather than serum creatinine (sCr) to determine metformin eligibility. We examined the potential impact of these recommendations on metformin eligibility among U.S. adults.
RESEARCH DESIGN AND METHODS
Metformin eligibility was assessed among 3,902 adults with diabetes who participated in the 1999–2010 National Health and Nutrition Examination Surveys and reported routine access to health care, using conventional sCr thresholds (eligible if <1.4 mg/dL for women and <1.5 mg/dL for men) and eGFR categories: likely safe, ≥45 mL/min/1.73 m2; contraindicated, <30 mL/min/1.73 m2; and indeterminate, 30–44 mL/min/1.73 m2). Different eGFR equations were used: four-variable MDRD, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine (CKD-EPIcr), and CKD-EPI cystatin C, as well as Cockcroft-Gault (CG) to estimate creatinine clearance (CrCl). Diabetes was defined by self-report or A1C ≥6.5% (48 mmol/mol). We used logistic regression to identify populations for whom metformin was likely safe adjusted for age, race/ethnicity, and sex. Results were weighted to the U.S. adult population.
RESULTS
Among adults with sCr above conventional cutoffs, MDRD eGFR ≥45 mL/min/1.73 m2 was most common among men (adjusted odds ratio [aOR] 33.3 [95% CI 7.4–151.5] vs. women) and non-Hispanic Blacks (aOR vs. whites 14.8 [4.27–51.7]). No individuals with sCr below conventional cutoffs had an MDRD eGFR <30 mL/min/1.73 m2. All estimating equations expanded the population of individuals for whom metformin is likely safe, ranging from 86,900 (CKD-EPIcr) to 834,800 (CG). All equations identified larger populations with eGFR 30–44 mL/min/1.73 m2, for whom metformin safety is indeterminate, ranging from 784,700 (CKD-EPIcr) to 1,636,000 (CG).
CONCLUSIONS
The use of eGFR or CrCl to determine metformin eligibility instead of sCr can expand the adult population with diabetes for whom metformin is likely safe, particularly among non-Hispanic blacks and men.
doi:10.2337/dc15-0542
PMCID: PMC4613912  PMID: 26307607
3.  Potential Impact of Prescribing Metformin According to eGFR Rather Than Serum Creatinine 
Diabetes care  2015;38(11):2059-2067.
OBJECTIVE
Many societies recommend using estimated glomerular filtration rate (eGFR) rather than serum creatinine (sCr) to determine metformin eligibility. We examined the potential impact of these recommendations on metformin eligibility among U.S. adults.
RESEARCH DESIGN AND METHODS
Metformin eligibility was assessed among 3,902 adults with diabetes who participated in the 1999–2010 National Health and Nutrition Examination Surveys and reported routine access to health care, using conventional sCr thresholds (eligible if <1.4 mg/dL for women and <1.5 mg/dL for men) and eGFR categories: likely safe, ≥45 mL/min/1.73 m2; contraindicated, <30 mL/min/1.73 m2; and indeterminate, 30–44 mL/min/1.73 m2). Different eGFR equations were used: four-variable MDRD, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine (CKD-EPIcr), and CKD-EPI cystatin C, as well as Cockcroft-Gault (CG) to estimate creatinine clearance (CrCl). Diabetes was defined by self-report or A1C ≥6.5% (48 mmol/mol). We used logistic regression to identify populations for whom metformin was likely safe adjusted for age, race/ethnicity, and sex. Results were weighted to the U.S. adult population.
RESULTS
Among adults with sCr above conventional cutoffs, MDRD eGFR ≥45 mL/min/1.73 m2 was most common among men (adjusted odds ratio [aOR] 33.3 [95%CI 7.4–151.5] vs. women) and non-Hispanic Blacks (aOR vs. whites 14.8 [4.27–51.7]). No individuals with sCr below conventional cutoffs had an MDRD eGFR <30 mL/min/1.73 m2. All estimating equations expanded the population of individuals for whom metformin is likely safe, ranging from 86,900 (CKD-EPIcr) to 834,800 (CG). All equations identified larger populations with eGFR 30–44mL/min/1.73 m2, for whom metformin safety is indeterminate, ranging from 784,700 (CKD-EPIcr) to 1,636,000 (CG).
CONCLUSIONS
The use of eGFR or CrCl to determine metformin eligibility instead of sCr can expand the adult population with diabetes for whom metformin is likely safe, particularly among non-Hispanic blacks and men.
doi:10.2337/dc15-0542
PMCID: PMC4613912  PMID: 26307607
4.  The Kansas City Cardiomyopathy Questionnaire Score Is Associated With Incident Heart Failure Hospitalization in Chronic Kidney Disease Patients Without Previously Diagnosed Heart Failure: The CRIC Study 
Circulation. Heart failure  2015;8(4):702-708.
Background
Chronic kidney disease (CKD) is a risk factor for heart failure (HF). Patients with CKD without diagnosed HF have an increased burden of symptoms characteristic of HF. It is not known whether these symptoms are associated with occurrence of new onset HF.
Methods and Results
We studied the association of a modified Kansas City Cardiomyopathy Questionnaire (KCCQ) with newly identified cases of hospitalized HF among 3,093 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study who did not report HF at baseline. The yearly-updated KCCQ score was categorized into quartiles (Q1–4) with the lower scores representing the worse symptoms. Multivariable-adjusted repeated measure logistic regression models were adjusted for demographic characteristics, clinical risk factors for HF, N-terminal pro-brain natriuretic peptide (NT-proBNP) level and left ventricular hypertrophy, left ventricular systolic and diastolic dysfunction. Over a mean (± standard deviation) follow up period of 4.3±1.6 years, there were 211 new cases of HF hospitalizations. The risk of HF hospitalization increased with increasing symptom quartiles; 2.62, 1.85, 1.14 and 0.74 events per 100 person-years, respectively. The median number of annual KCCQ assessments per participant was 5 (interquartile range 3 – 6). The annually updated KCCQ score was independently associated with higher risk of incident HF hospitalization in multivariable adjusted models (OR 3.30 (1.66 – 6.52); p=0.001 for Q1 compared with Q4).
Conclusions
Symptoms characteristic of HF are common in CKD patients and are associated with higher short-term risk for new hospitalization for HF, independent of level of kidney function and other known HF risk factors.
doi:10.1161/CIRCHEARTFAILURE.115.002097
PMCID: PMC4512877  PMID: 25985796
chronic kidney disease; heart failure; Kansas City Cardiomyopathy Questionnaire; hospitalization
5.  A Risk Score to Guide Cystatin C Testing to Detect Occult Reduced Estimated Glomerular Filtration Rate 
American journal of nephrology  2015;42(2):141-147.
Background/Aims
Persons with occult reduced eGFR (eGFR <60 ml/min/1.73m2 detected by serum cystatin C but missed by creatinine) have high risk for complications. Among persons with preserved kidney function by creatinine-based estimated glomerular filtration rate ((eGFRcreat) >60 ml/min/1.73m2), tools to guide cystatin C testing are needed.
Methods
We developed a risk score to estimate an individual's probability of reduced eGFR by cystatin C (eGFRcys<60 ml/min/1.73m2) in The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study and externally validated in the Third National Health and Nutrition Examination Survey (NHANES III). We used logistic regression with Bayesian model averaging and variables available in practice. We assessed performance characteristics using calibration and discrimination measures.
Results
Among 24,877 adults with preserved kidney function by creatinine, 13.5% had reduced eGFRcys. Older and Black participants, current smokers, and those with higher BMI, lower eGFRcreat, diabetes, hypertension, and history of cardiovascular disease were more likely to have occult reduced eGFR (p <0.001). The final risk function had a c-statistic of 0.87 in REGARDS, and 0.84 in NHANES. By risk score, 72% of occult reduced eGFR cases were detected by screening only 22% of participants.
Conclusions
A risk score using characteristics readily accessible in clinical practice can identify the majority of persons with reduced eGFRcys that is missed by creatinine.
doi:10.1159/000439231
PMCID: PMC4589276  PMID: 26381887
kidney disease; Serum Cystatin C; Creatinine; Creatinine-based estimated glomerular filtration rate (eGFRcreat); Cystatin C-based estimated glomerular filtration rate (eGFRcys)
6.  First Post-Operative Urinary Kidney Injury Biomarkers and Association with the Duration of AKI in the TRIBE-AKI Cohort 
PLoS ONE  2016;11(8):e0161098.
Background
We previously demonstrated that assessment of the duration of AKI, in addition to magnitude of rise in creatinine alone, adds prognostic information for long-term survival. We evaluated whether post-operative kidney injury biomarkers in urine collected immediately after cardiac surgery associate with duration of serum creatinine elevation.
Methods
We studied 1199 adults undergoing cardiac surgery in a prospective cohort study (TRIBE-AKI) and examined the association between the levels of five urinary biomarkers individually at 0–6 hours after surgery: interleukin-18 (IL-18), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver fatty acid binding protein (L-FABP) and albumin with duration of serum creatinine-based AKIN criteria for AKI (0 (no AKI), 1–2, 3–6, ≥7 days).
Results
Overall, 407 (34%) patients had at least stage 1 AKI, of whom 251 (61.7%) had duration of 1–2 days, 118 (28.9%) had duration 3–6 days, and 38 (9.3%) had duration of ≥7 days. Higher concentrations of all biomarkers (per log increase) were independently associated with a greater odds of a longer duration of AKI; odds ratios and 95% confidence intervals using ordinal logistic regression were the following: IL-18: 1.22, 1.13–1.32; KIM-1: 1.36, 1.21–1.52; albumin 1.20, 1.09–1.32; L-FABP 1.11, 1.04–1.19; NGAL 1.06, 1.00–1.14). AKI duration of 7 days or longer was associated with a 5-fold adjusted risk of mortality at 3 years.
Conclusions
There was an independent dose-response association between urinary levels of injury biomarkers immediately after cardiac surgery and longer duration of AKI. Duration of AKI was also associated with long term mortality. Future studies should explore the potential utility of these urinary kidney injury biomarkers to enrich enrollment of patients at risk for longer duration of AKI into trials of interventions to prevent or treat post-operative AKI.
doi:10.1371/journal.pone.0161098
PMCID: PMC4990204  PMID: 27537050
7.  Fibroblast Growth Factor 23 and Sudden Versus Nonsudden Cardiac Death: The Cardiovascular Health Study 
Background
Elevated fibroblast growth factor 23 (FGF-23) concentrations are associated with greater risk of cardiovascular events and mortality, especially among people with chronic kidney disease (CKD). Since individuals with CKD are at an increased risk of sudden cardiac death (SCD), we sought to understand whether FGF-23 is a stronger risk factor for SCD versus non-SCD.
Study Design
Cohort study.
Setting & Participants
3,244 participants in the community-based Cardiovascular Health Study, aged 65 years or older.
Predictor
Plasma FGF-23 concentrations.
Outcomes
We assessed SCD and non-SCD in these analyses. SCD was rigorously adjudicated and was defined as a sudden pulseless condition of cardiac origin in a previously stable person occurring out of hospital or in emergency department.
Measurements
We estimated associations of baseline FGF-23 concentrations with SCD and non-SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, comorbidities, and kidney function. We also tested whether associations differed by CKD status.
Results
During a median follow-up of 8.1 years, there were 118 adjudicated SCD and 570 non-SCD events. After multivariable adjustment for demographics, cardiovascular risk factors, comorbidities, and parameters of kidney function, higher FGF-23 concentrations were an independent risk factor for non-SCD (HR [per doubling], 1.17; 95% CI, 1.06-1.30). Elevated FGF-23 concentrations, however, were not independently associated with SCD (HR [per doubling], 1.07; 95% CI, 0.85-1.35). In stratified analysis by CKD status (36.5% of cohort), doubling of FGF-23 concentrations was independently associated with non-SCD (adjusted HR, 1.26; 95% CI, 1.10-1.45). A similar magnitude of association was observed between FGF-23 and SCD among the CKD subgroup; however, it was not significant (HR, 1.20; 95% CI, 0.89-1.62).
Limitations
Limited power to detect moderate-sized effects between FGF-23 and SCD in both the primary and stratified analyses.
Conclusions
In this population-based study, FGF-23 elevations were independently associated with non-SCD. Among individuals with CKD, the associations between FGF-23 and SCD and non-SCD were similar.
doi:10.1053/j.ajkd.2014.10.025
PMCID: PMC4485528  PMID: 25572028
fibroblast growth factor 23 (FGF-23); chronic kidney disease (CKD); sudden cardiac death (SCD); non-SCD; cardiovascular event; cardiovascular mortality; fatal arrhythmic event; renal function; Cardiovascular Health Study (CHS); cohort study
8.  APOL1 Genotype and Glomerular and Tubular Kidney Injury in Women With HIV 
Background
APOL1 genotype is associated with advanced kidney disease in African-Americans, but the pathogenic mechanisms are unclear. Here, associations of APOL1 genotype with urine biomarkers of glomerular and tubular injury, and with kidney function decline, were evaluated.
Study Design
Observational study.
Setting & Participants
431 HIV-infected African-American women enrolled in Women's Interagency HIV Study (WIHS).
Predictor
APOL1 genotype.
Outcomes
Albumin-creatinine ratio (ACR), four tubular injury biomarkers (interleukin 18 [IL-18], kidney injury molecule 1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL], and α1-microglobulin [α1m]), and kidney function estimated using the CKD-EPI cystatin C equation.
Measurements
Participants were genotyped for APOL1 single-nucleotide polymorphisms rs73885319 (G1 allele) and rs71785313 (G2 allele). Urine biomarker levels were measured using stored samples from 1999-2000. Cystatin C was measured using serum collected at baseline and 4- and 8-year follow-up.
Results
At baseline, ACR levels were higher among 47 women with 2 APOL1 risk alleles versus 384 women with 0/1 risk allele (median, 24 vs. 11 mg/g; p < 0.001). Compared to women with 0/1 risk allele, women with 2 risk alleles had 104% higher ACR (95% CI, 29-223 mg/g) and 2-fold greater risk of ACR > 30 mg/g (95% CI, 1.17-3.44) after multivariable adjustment. APOL1 genotype showed little association with urine IL-18:Cr, KIM-1:Cr, and NGAL:Cr (estimates of -5% [95% CI, -24% to 18%], -20% [95% CI, -36% to 1%], and 10% [95% CI, -26% to 64%], respectively), or detectable urine α1m (prevalence ratio, 1.13; 95% CI, 0.65-1.97) in adjusted analyses. Compared to women with 0/1 allele, women with 2 risk alleles had faster eGFR decline, by 1.2 (95% CI, -2.2 to -0.2) ml/min/1.73 m2 per year, and had 1.7- and 3.4-fold greater rates of incident chronic kidney disease (95% CI, 1.1-2.5) and 10% annual eGFR decline (95% CI, 1.7-6.7), respectively, with minimal attenuation after adjustment for glomerular and tubular injury biomarkers.
Limitations
Results may not be generalizable to men.
Conclusions
Among HIV-infected African-American women, APOL1-associated kidney injury appears to localize to the glomerulus, rather than the tubules.
doi:10.1053/j.ajkd.2015.02.329
PMCID: PMC4615696  PMID: 25921719
APOL1 genotype; risk variant; risk allele; G1 allele; G2 allele; single-nucleotide polymorphism (SNP); albumin-creatinine ratio (ACR); proteinuria; tubular injury biomarker; apolipoprotein L1; kidney disease; renal function; glomerular injury; African American; Women's Interagency HIV Study (WIHS)
9.  Urinary uromodulin, kidney function and cardiovascular disease in elderly adults 
Kidney international  2015;88(5):1126-1134.
Urinary uromodulin (uUMOD) is the most common secreted tubular protein in healthy adults. However, the relationship between uUMOD and clinical outcomes is still unclear. Here we measured uUMOD in 192 participants of the Cardiovascular Health Study with over a 30% decline in estimated glomerular filtration rate (eGFR) over 9 years, 54 with incident end stage renal disease (ESRD), and in a random sub-cohort of 958 participants. The association of uUMOD with eGFR decline was evaluated using logistic regression and with incident ESRD, cardiovascular disease, heart failure and mortality using Cox proportional regression. Mean age was 78 years and median uUMOD was 25.8 μg/mL. In a case-control study evaluating eGFR decline (192 cases and 231 controls), each standard deviation higher uUMOD was associated with a 23% lower odds of eGFR decline (odds ratio 0.77, (95% CI 0.62, 0.96)) and a 10% lower risk of mortality (hazard ratio 0.90, (95% CI 0.83, 0.98)) after adjusting for demographics, eGFR, albumin/creatinine ratio and other risk factors. There was no risk association of uUMOD with ESRD, cardiovascular disease or heart failure after multivariable adjustment. Thus, low uUMOD levels may identify persons at risk of progressive kidney disease and mortality above and beyond established markers of kidney disease, namely eGFR and the albumin/creatinine ratio. Future studies need to confirm these results and evaluate whether uUMOD is a marker of tubular health and/or whether it plays a causal role in preserving kidney function.
doi:10.1038/ki.2015.192
PMCID: PMC4653069  PMID: 26154925
uromodulin; tamm-horsfall protein; chronic kidney disease; cardiovascular disease; urinary biomarkers
10.  Association of fibroblast growth factor-23 with arterial stiffness in the Multi-Ethnic Study of Atherosclerosis 
Nephrology Dialysis Transplantation  2014;29(11):2099-2105.
Background
Serum fibroblast growth factor-23 (FGF-23) is associated with cardiovascular disease (CVD), yet the mechanisms remain uncertain. Our objective was to determine whether higher FGF-23 concentrations are associated with arterial stiffness.
Methods
In this cross-sectional study, serum FGF-23 concentrations were measured in 5977 participants without known CVD in the Multi-Ethnic Study of Atherosclerosis. The primary outcomes of interest were large (LAE) and small artery elasticity (SAE), pulse pressure and ankle-brachial index (ABI) > 1.30. LAE and SAE were measured by pulse contour analysis of the radial artery. Pulse pressure was measured with an automated sphygmomanometer using the average of two resting blood pressure measurements. ABI was calculated as the ratio of the ankle and brachial systolic blood pressures.
Results
Serum FGF-23 concentrations were not significantly associated with LAE [relative difference (RD) per doubling: 0%; 95% confidence interval (CI): −2–1%], SAE (RD per doubling: 0%; 95% CI: −3–2%), pulse pressure (β per doubling: 0.44; 95% CI: −0.31–1.19), or a high ABI (odds ratio per doubling: 1.14; 95% CI: 0.84–1.55). Findings were similar irrespective of chronic kidney disease status.
Conclusions
Higher serum FGF-23 concentrations are not associated with arterial stiffness, as measured by pulse pressure, LAE, SAE or high ABI, in a community-based population without CVD.
doi:10.1093/ndt/gfu101
PMCID: PMC4209876  PMID: 24782533
ABI; arterial elasticity; arterial stiffness; FGF-23; pulse pressure
11.  The associations of physical activity and television watching with change in kidney function in older adults 
BACKGROUND
Physical activity (PA) may play a role in preserving kidney health. The purpose of this study was to determine if PA and sedentary behavior are associated with incident chronic kidney disease (CKD) and change in kidney function in older adults.
METHODS
The Health, Aging and Body Composition study is a prospective cohort of 3,075 well-functioning older adults. PA and television watching was measured by self-report and serum cystatin C was used to estimate glomerular filtration rate (eGFR). CKD was defined as an eGFR <60 ml/min/1.73m2. Rapid kidney function decline was defined as an annual loss in eGFR of >3ml/min/1.73m2. Discrete survival analysis was used to determine if baseline PA and television watching were related to 10-year cumulative incidence of CKD and rapid decline in kidney function.
RESULTS
Individuals who reported watching television >3 hours/day had a higher risk of incident CKD (HR 1.34; 95% CI: 1.09, 1.65) and experiencing a rapid decline in kidney function (HR 1.26; 95% CI 1.05, 1.52) compared to individuals who watched television < 2 hours/day. PA was not related to either outcome.
CONCLUSIONS
High levels of television watching are associated with declining kidney function; the mechanisms that underlie this association need further study.
doi:10.1123/jpah.2013-0289
PMCID: PMC4816441  PMID: 24762526
sedentary lifestyle; chronic disease; aged; renal health
12.  Serum Albumin and Kidney Function Decline in HIV-Infected Women 
Background
Serum albumin concentrations are a strong predictor of mortality and cardiovascular disease in HIV-infected individuals. We studied the longitudinal associations between serum albumin levels and kidney function decline in a population of HIV-infected women.
Study Design
Retrospective cohort analysis.
Setting & Participants
The study participants were recruited from the Women’s Interagency HIV Study (WIHS), a large observational study designed to understand risk factors for the progression of HIV infection in women living in urban communities. 908 participants had baseline assessment of kidney function and two follow-up measures over an average of 8 years.
Predictor
The primary predictor was serum albumin concentration.
Outcomes
We examined annual change in kidney function. Secondary outcomes included rapid kidney function decline and incident reduced estimated glomerular filtration rate (eGFR).
Measurements
Kidney function decline was determined by cystatin C–based (eGFRcys) and creatinine-based eGFR (eGFRcr) at baseline and follow up. Each model was adjusted for kidney disease and HIV-related risk factors using linear and relative risk regression.
Results
After multivariate adjustment, each 0.5-g/dL decrement in baseline serum albumin concentration was associated with a 0.56-mL/min faster annual decline in eGFRcys (P<0.001), which was only slightly attenuated to 0.55-mL/min/1.73 m2 after adjustment for albuminuria. Results were similar whether using eGFRcys or eGFRcr. In adjusted analyses, each 0.5-g/dL lower baseline serum albumin was associated with a 1.71-fold greater risk of rapid kidney function decline (p<0.001) and a 1.72-fold greater risk of incident reduced eGFR (p<0.001).
Limitations
The cohort is composed of only female participants from urban communities within the United States.
Conclusions
Lower levels of serum albumin were strongly associated with kidney function decline and incident reduced eGFR in HIV-infected women, independent of HIV disease status, BMI and albuminuria.
doi:10.1053/j.ajkd.2014.05.015
PMCID: PMC4177337  PMID: 25059222
albumin; kidney function; HIV; incident reduced eGFR; albuminuria; disease trajectory; chronic kidney disease (CKD) progression
13.  The association of adiposity with kidney function decline among HIV-infected adults: Findings from the FRAM (Fat Redistribution and Metabolic Changes in HIV Infection) Study 
HIV medicine  2014;16(3):184-190.
Objectives
To study the association of adiposity with longitudinal kidney function change in 544 HIV-infected persons in Study of Fat Redistribution and Metabolic Change in HIV infection (FRAM) cohort over 5 years of follow-up.
Methods
Regional distribution of muscle and adipose tissue was quantified by whole-body MRI, and total adiponectin and leptin levels were measured in serum. Kidney function was assessed by estimated glomerular filtration rate from serum cystatin C (eGFRCys), obtained at baseline and follow-up. Rapid kidney function decline was defined as annual loss of eGFRCys ≥ 3 ml/min/1.73m2, and incident chronic kidney disease (CKD) was defined at eGFRCys < 60 ml/min/1.73m2. Multivariate regression analysis was adjusted for age, race, gender, glucose, antihypertensive use, serum albumin, baseline and change in HIV viral load.
Results
At baseline, mean age was 43 years, mean eGFRCys 86 ml/min/1.73m2, and 21% had albuminuria. Mean (standard deviation) eGFRCys decline was −0.11 ± 4.87 ml/min/1.73m2 per year; 23% of participants had rapid kidney function decline, and 10% developed incident CKD. Lowest tertile of visceral adipose tissue and highest tertile of adiponectin were both marginally associated with annual kidney function decline of −0.5 ml/min/1.73m2 each, but these associations were not statistically significant after adjustment. We found no statistically significant associations of MRI-measured regional adiposity or serum adipokines with rapid kidney function decline or incident CKD (all p-values > 0.1 in adjusted models).
Conclusions
Contrary to findings in the general population, adiposity did not have a substantial association with longitudinal change in kidney function among HIV-infected persons.
doi:10.1111/hiv.12196
PMCID: PMC4320665  PMID: 25251910
adiposity; FRAM; HIV; kidney decline
14.  Peri-operative heart-type fatty acid binding protein is associated with acute kidney injury after cardiac surgery 
Kidney international  2015;88(3):576-583.
Acute Kidney Injury (AKI) is a common complication after cardiac surgery and is associated with worse outcomes. Since heart fatty acid binding protein (H-FABP) is a myocardial protein that detects cardiac injury, we sought to determine if plasma H-FABP was associated with AKI in the TRIBE-AKI cohort; a multi-center cohort of 1219 patients at high risk for AKI who underwent cardiac surgery. The primary outcomes of interest were any AKI (Acute Kidney Injury Network (AKIN) stage 1 or higher) and severe AKI (AKIN stage 2 or higher). The secondary outcome was long-term mortality after discharge. Patients who developed AKI had higher levels of H-FABP pre- and post-operatively than patients who did not have AKI. In analyses adjusted for known AKI risk factors, first post-operative log(H-FABP) was associated with severe AKI (adjusted OR 5.39 [95% CI, 2.87-10.11] per unit increase), while pre-operative log(H-FABP) was associated with any AKI (2.07 [1.48-2.89]) and mortality (1.67 [1.17-2.37]). These relationships persisted after adjustment for change in serum creatinine (for first postoperative log(H-FABP)) and biomarkers of cardiac and kidney injury, including brain natriuretic peptide, cardiac troponin-I, interleukin-18, liver fatty acid binding protein, kidney injury molecule-1, and neutrophil gelatinase associated lipocalin. Thus, peri-operative plasma H-FABP levels may be used for risk-stratification of AKI and mortality following cardiac surgery.
doi:10.1038/ki.2015.104
PMCID: PMC4556547  PMID: 25830762
Heart-type fatty acid binding protein; Acute Kidney Injury; Mortality; Cardiac Surgery
15.  The Association Between APOL1 Risk Alleles and Longitudinal Kidney Function Differs by HIV Viral Suppression Status 
HIV-infected African Americans who carry the APOL1 high-risk genotype had faster kidney function decline than persons with the low-risk genotype; this was most pronounced among those without sustained HIV suppression. Associations were not observed among those with sustained viral suppression.
Background. Existing data suggest that human immunodeficiency virus (HIV)-infected African Americans carrying 2 copies of the APOL1 risk alleles have greater risk of kidney disease than noncarriers. We sought to determine whether HIV RNA suppression mitigates APOL1-related kidney function decline among African Americans enrolled in the Multicenter AIDS Cohort Study.
Methods. We genotyped HIV-infected men for the G1 and G2 risk alleles and ancestry informative markers. Mixed-effects models were used to estimate the annual rate of estimated glomerular filtration rate (eGFR) decline, comparing men carrying 2 (high-risk) vs 0–1 risk allele (low-risk). Effect modification by HIV suppression status (defined as HIV type 1 RNA level <400 copies/mL for >90% of follow-up time) was evaluated using interaction terms and stratified analyses.
Results. Of the 333 African American men included in this study, 54 (16%) carried the APOL1 high-risk genotype. Among HIV-infected men with unsuppressed viral loads, those with the high-risk genotype had a 2.42 mL/minute/1.73 m2 (95% confidence interval [CI], −3.52 to −1.32) faster annual eGFR decline than men with the low-risk genotype. This association was independent of age, comorbid conditions, baseline eGFR, ancestry, and HIV-related factors. In contrast, the rate of decline was similar by APOL1 genotype among men with sustained viral suppression (−0.16 mL/minute/1.73 m2/year; 95% CI, −.59 to .27; P for interaction <.001).
Conclusions. Unsuppressed HIV-infected African Americans with the APOL1 high-risk genotype experience an accelerated rate of kidney function decline; HIV suppression with antiretroviral therapy may reduce these deleterious renal effects.
doi:10.1093/cid/ciu765
PMCID: PMC4318914  PMID: 25281610
HIV; antiretroviral therapy; genetic; kidney disease
16.  Kidney Function and Mortality in Octogenarians: Cardiovascular Health Study All Stars 
OBJECTIVES:
To examine the association between kidney function and all-cause mortality in octogenarians.
DESIGN:
Retrospective analysis of prospectively collected data.
SETTING:
Community.
PARTICIPANTS:
Serum creatinine and cystatin C were measured in 1,053 Cardiovascular Health Study (CHS) All Stars participants.
MEASUREMENTS:
Estimated glomerular filtration rate (eGFR) was determined using the Chronic Kidney Disease Epidemiology Collaboration creatinine (eGFRCR) and cystatin C one-variable (eGFRCYS) equations. The association between quintiles of kidney function and all-cause mortality was analyzed using unadjusted and adjusted Cox proportional hazards models.
RESULTS:
Mean age of the participants was 85, 64% were female, 66% had hypertension, 14% had diabetes mellitus, and 39% had prevalent cardiovascular disease. There were 154 deaths over a median follow-up of 2.6 years. The association between eGFRCR and all-cause mortality was U-shaped. In comparison with the reference quintile (64–75 mL/min per 1.73 m2), the highest (≥75 mL/min per 1.73 m2) and lowest (≤43 mL/min per 1.73 m2) quintiles of eGFRCR were independently associated with mortality (hazard ratio (HR) = 2.49, 95% confidence interval (CI) = 1.36–4.55; HR = 2.28, 95% CI = 1.26–4.10, respectively). The association between eGFRCYS and all-cause mortality was linear in those with eGFRCYS of less than 60 mL/min per 1.73 m2, and in the multivariate analyses, the lowest quintile of eGFRCYS (<52 mL/min per 1.73 m2) was significantly associated with mortality (HR = 2.04, 95% CI = 1.12–3.71) compared with the highest quintile (>0.88 mL/min per 1.73 m2).
CONCLUSION:
Moderate reduction in kidney function is a risk factor for all-cause mortality in octogenarians. The association between eGFRCR and all-cause mortality differed from that observed with eGFRCYS; the relationship was U-shaped for eGFRCR, whereas the risk was primarily present in the lowest quintile for eGFRCYS. J Am Geriatr Soc 2012.
doi:10.1111/j.1532-5415.2012.04046.x
PMCID: PMC3902776  PMID: 22724391
octogenarians; kidney function; mortality
17.  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 
Background
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.
Predictors
Ratios of urine KIM-1, IL-18, and albumin to creatinine (KIM-1:Cr, IL-18:Cr, and ACR, respectively).
Outcomes
Incident HF over a median follow-up of 12 years.
Results
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).
Limitations
Generalizability to other populations is uncertain.
Conclusions
Higher urine concentrations of KIM-1 were independently associated with incident HF risk, although the associations of higher ACR were of stronger magnitude.
doi:10.1053/j.ajkd.2014.01.432
PMCID: PMC4069223  PMID: 24656453
IL-18; KIM-1; cystatin C; heart failure; CKD; risk marker; cardiovascular disease (CVD); albuminuria; kidney tubular injury
18.  Association of Albumin-Creatinine Ratio and Cystatin C With Change in Ankle-Brachial Index: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Low ankle-brachial index (ABI) is a reflection of atherosclerotic disease, and high ABI is an indicator of calcified vessels. The associations of albuminuria and cystatin C with incidence of either low or high ABI are unknown.
Study Design
Prospective longitudinal cohort study.
Setting & Participants
The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled community-dwelling adults (N=6,814) aged 45–84 years who were free of clinical cardiovascular disease (CVD) at baseline.
Predictors
Baseline albumin-creatinine ratio (ACR) and serum cystatin C levels.
Outcomes
Development of low (< 0.90), and high (> 1.40) ABI using multinomial regression among persons with ABI 0.90–1.40 at baseline.
Results
During 9.8 years of follow up, 221 and 89 participants progressed to low and high ABI, respectively. Baseline ACR and cystatin C were higher among progressors compared to non-progressors. In multivariable analyses, doubling of ACR was associated with increased risk of progression to low (OR, 1.08; 95% CI, 0.99–1.20) and high (OR, 1.16; 95% CI, 1.01–1.32) ABI. Compared to the lowest quintile, the highest quintile of ACR had a significantly increased risk of progression to low (OR, 1.79; 95% CI, 1.03–3.12) and high (OR, 2.76; 95% CI, 1.32–5.77) ABI. Higher cystatin C levels were associated with progression to low (OR per 1-SD greater, 1.12; 95% CI, 1.00–1.26) but not high (OR per 1-SD greater, 1.01; 95% CI, 0.81–1.25) ABI, but the highest quintile of cystatin C was not independently associated with either outcome.
Limitations
Single measure of albuminuria and low number of progressors to high ABI.
Conclusions
In adults free of clinical CVD, albuminuria was a strong, independent risk factor for the development of both high and low ABI, important and different measures of peripheral artery disease.
doi:10.1053/j.ajkd.2014.05.014
PMCID: PMC4272615  PMID: 24998036
Cystatin C; albuminuria; albumin-creatinine ratio (ACR); peripheral artery disease (PAD); ankle-brachial index (ABI); chronic kidney disease (CKD); cardiovascular disease (CVD); atherosclerotic disease
19.  Associations of kidney injury markers with subclinical cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis  
Clinical Nephrology  2015;84(6):358-364.
No abstract available.
doi:10.5414/CN108668
PMCID: PMC4776253  PMID: 26558369
kidney injury biomarkers; cardiovascular disease
20.  Associations of N-terminal pro–B-type natriuretic peptide with kidney function decline in persons without clinical heart failure in the Heart and Soul Study 
American heart journal  2014;168(6):931-939.e2.
Background
Subclinical volume overload in the absence of diagnosed heart failure (HF) may be an underrecognized contributor to kidney function decline in coronary artery disease (CAD) patients. We evaluated associations of circulating N-terminal pro–B-type natriuretic peptide (NT-proBNP), a marker of ventricular stretch, with change in estimated glomerular filtration rate (eGFR).
Methods
We evaluated 535 patients with stable CAD and no history of HF, who were enrolled in the Heart and Soul Study and followed up for 5 years. N-terminal pro–B-type natriuretic peptide was measured at baseline. We evaluated the associations of NT-proBNP with change in kidney function over 5 years: (a) annual percent change in eGFR, (b) rapid kidney function loss (>3% per year for 5 years), and (c) incident eGFR <60 mL/min per 1.73 m2. In multivariable models, we adjusted for demographics, comorbid conditions, echocardiographic parameters, medications, and baseline kidney function.
Results
Among 535 participants, median NT-proBNP was 130.6 (interquartile range 61.8-280.9) pg/mL, and median B-type natriuretic peptide (BNP) was 32.5 (14.4-75.9) pg/mL. Individuals with NT-proBNP levels in the highest quartile (>280.9 pg/mL) had a greater odds of rapid kidney function loss after full adjustment (odds ratio 2.95; 95% CI 1-8.65; P = .0492). Associations with incident eGFR <60 mL/min per 1.73 m2 were also significant (adjusted odds ratio 4.23; 95% CI 1.05-16.98; P = .0422). Results were similar when analyzed using BNP as the predictor.
Conclusions
N-terminal pro–B-type natriuretic peptide and BNP are strongly and independently associated with accelerated kidney function loss, even in the absence of clinical HF. These findings suggest that subclinical cardiovascular dysfunction may contribute to elevated kidney disease risk in persons with CAD.
doi:10.1016/j.ahj.2014.09.008
PMCID: PMC4254643  PMID: 25458658
21.  Clinical Practice Guideline for the Management of Chronic Kidney Disease in Patients Infected With HIV: 2014 Update by the HIV Medicine Association of the Infectious Diseases Society of America 
It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.
doi:10.1093/cid/ciu617
PMCID: PMC4271038  PMID: 25234519
HIV-1; chronic kidney disease; clinical practice guideline; HIV-associated nephropathy; kidney transplantation
22.  Risk Factors for Cardiovascular Disease across the Spectrum of Older Age: The Cardiovascular Health Study 
Atherosclerosis  2014;237(1):336-342.
Objective
The associations of some risk factors with cardiovascular disease (CVD) are attenuated in older age; whereas others appear robust. The present study aimed to compare CVD risk factors across older age.
Methods
Participants (n=4,883) in the Cardiovascular Health Study free of prevalent CVD, were stratified into three age groups: 65–74, 75–84, 85+ years. Traditional risk factors included systolic blood pressure (BP), LDL-cholesterol, HDL-cholesterol, obesity, and diabetes. Novel risk factors included kidney function, C-reactive protein (CRP), and N-terminal pro-B-type natriuretic peptide (NT pro-BNP).
Results
There were 1,498 composite CVD events (stroke, myocardial infarction, and cardiovascular death) over 5 years. The associations of high systolic BP and diabetes appeared strongest, though both were attenuated with age (p-values for interaction = 0.01 and 0.002, respectively). The demographic-adjusted hazard ratios (HR) for elevated systolic BP were 1.79 (95% confidence interval: 1.49, 2.15), 1.59 (1.37, 1.85) and 1.10 (0.86, 1.41) in participants aged 65–74, 75–84, 85+, and for diabetes, 2.36 (1.89, 2.95), 1.55 (1.27, 1.89), 1.51 (1.10, 2.09). The novel risk factors had consistent associations with the outcome across the age spectrum; low kidney function: 1.69 (1.31, 2.19), 1.61 (1.36, 1.90), and 1.57 (1.16, 2.14) for 65–74, 75–84, and 85+ years, respectively; elevated CRP: 1.54 (1.28, 1.87), 1.33 (1.13, 1.55), and 1.51 (1.15, 1.97); elevated NT pro-BNP: 2.67 (1.96, 3.64), 2.71 (2.25, 3.27), and 2.18 (1.43, 3.45).
Conclusions
The associations of most traditional risk factors with CVD were minimal in the oldest old, whereas diabetes, eGFR, CRP, and NT pro-BNP were associated with CVD across older age.
doi:10.1016/j.atherosclerosis.2014.09.012
PMCID: PMC4254262  PMID: 25303772
aging; epidemiology; risk factors
23.  Race and Other Risk Factors for Incident Proteinuria in a National Cohort of HIV-infected Veterans 
Background
Proteinuria in HIV-infected individuals has been associated with poorer outcomes. We examined risk factors associated with the development of proteinuria in a national registry of HIV-infected veterans.
Methods
21,129 HIV-infected veterans of black and white race without pre-existing kidney disease were receiving health care in the Veterans’ Health Administration (VHA) medical system between 1997 and 2011. Using the VHA electronic record system, we identified kidney-related risk factors (hypertension, diabetes, cardiovascular disease), and HIV-related risk factors (CD4 lymphocyte count, HIV RNA level, hepatitis C virus, and hepatitis B virus) for developing proteinuria. Proteinuria was defined by 2 consecutive dipstick measures of 1+ or higher. The Fine-Gray competing risk model was used to estimate association between clinical variables and incident proteinuria, while accounting for intervening mortality events.
Results
During follow-up (median=5.3 years), 7,031 patients developed proteinuria. Overall, black race compared with white race was associated with a higher risk of proteinuria (HR[95% CI]=1.51[1.43–1.59]), but the association was stronger at younger ages (p interaction<0.001). Age-stratified risk of proteinuria for blacks relative to whites was greatest amongst veterans<30 years (2.19[1.66–2.89]) and the risk diminished with increasing age (1.14[0.97–1.34] for >60 years). We found the race difference to be stronger for the outcome of 2+ or higher proteinuria (2.13[1.89–2.39]). Both HIV-related and traditional risk factors were also associated with incident proteinuria (p<0.05).
Conclusions
Compared with whites, risk of proteinuria was higher in black veterans with HIV-infection, particularly at younger ages. In both races, HIV and kidney-related risk factors were associated with higher proteinuria risk.
doi:10.1097/QAI.0000000000000285
PMCID: PMC4162813  PMID: 25072613
HIV; proteinuria; race
24.  Low Serum Bicarbonate and Kidney Function Decline: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Among populations with established chronic kidney disease (CKD), metabolic acidosis is associated with more rapid progression of kidney disease. The association of serum bicarbonate concentrations with early declines in kidney function is less clear.
Study Design
Retrospective cohort study.
Setting & Participants
6380 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with a baseline estimated glomerular filtration rate (eGFR) >60 mL/min/1.73m2 using the CKD-EPI (CKD Epidemiology Collaboration) creatinine–cystatin C equation.
Predictors
Serum bicarbonate concentrations.
Outcomes
Rapid kidney function decline (eGFR decline >5% per year) and incident reduced eGFR (eGFR<60 mL/min/1.73 m2 with minimum rate of eGFR loss of 1 mL/min/1.73 m2 per year).
Results
The average bicarbonate concentration was 23.2 ± 1.8 mEq/L. 1730 (33%) participants had rapid kidney function decline, and 487 had incident reduced eGFR during follow-up. Each 1-SD lower baseline bicarbonate concentration was associated with 12% higher adjusted odds of rapid kidney function decline (95% CI, 6%–20%) and higher risk of incident reduced eGFR (adjusted incidence rate ratio, 1.11; 95% CI, 1.03–1.20) in models adjusting for demographics, baseline eGFR, albuminuria, and CKD risk factors. The OR for the associations of bicarbonate <21mEq/L relative to 23–24 mEq/L was 1.35 (95% CI, 1.05–1.73) for rapid kidney function decline, and the incidence rate ratio was 1.16 (95% CI, 0.83–1.62) for incident reduced eGFR.
Limitations
Etiology of metabolic acidosis cannot be determined in this study.
Conclusions
Lower serum bicarbonate concentrations are independently associated with rapid kidney function decline independent of eGFR or albuminuria in community-living persons with a baseline eGFR >60 mL/min/1.73 m2. If confirmed, our findings suggest that metabolic acidosis may indicate either early kidney disease that is not captured by eGFR or albuminuria, or may have a causal role in the development of an eGFR <60 mL/min/1.73 m2.
doi:10.1053/j.ajkd.2014.05.008
PMCID: PMC4177290  PMID: 24953891
serum bicarbonate; metabolic acidosis; chronic kidney disease (CKD); kidney function; renal disease; disease progression; kidney disease trajectory
25.  Serum Bicarbonate Concentrations and Kidney Disease Progression in Community-Living Elders: The Health, Aging, and Body Composition (Health ABC) Study 
Background
In populations with prevalent chronic kidney disease (CKD), lower serum bicarbonate is associated with more rapid CKD progression, but whether lower bicarbonate is also associated with risk of incident estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 and progression among community-living persons with predominantly preserved kidney function is unknown.
Study Design
Longitudinal observational cohort study.
Setting & Participants
Well functioning community living elders aged 70–79 years at inception.
Predictor
Serum bicarbonate measured at the time of collection by arterialized venous blood sample using an arterial blood gas analyzer.
Outcomes
Change in eGFR, and new eGFR < 60 ml/min/1.73m2 and loss of ≥1 ml/min/1.73m2 per year at follow-up.
Measurements
Linear and logistic regressions were used to evaluate associations of baseline serum bicarbonate with change in eGFR and incident eGFR <60 mL/min/1.73m2.
Results
At baseline, mean eGFR was 84±16 (SD) mL/min/1.73m2, and serum bicarbonate was 25.2±1.9 mmol/L. Compared to participants with higher bicarbonate concentrations (23.0–28.0 mmol/L), those with bicarbonate concentrations < 23 mmol/L (n=85 [8%]) lost eGFR 0.55 (95%CI, 0.13–0.97) mL/min/1.73m2 per year faster in models adjusted for demographics, CKD risk factors, baseline eGFR, and urine albumin-creatinine ratio. Among the 989 (92%) participants with baseline eGFR>60 mL/min/1.73m2, 252 (25%) developed incident eGFR <60 mL/min/1.73m2 at follow-up. Adjusting for the same covariates, participants with bicarbonate concentrations < 23 mmol/L had nearly 2-fold greater odds of incident eGFR <60 mL/min/1.73m2 (OR, 1.72; 95% CI, 0.97–3.07) compared to those with higher bicarbonate concentrations.
Limitations
Only two measurements of kidney function separated by seven years and loss to follow up due to intervening mortality in this elderly population.
Conclusions
Lower serum bicarbonate concentrations are independently associated with decline in eGFR and incident eGFR <60 mL/min/1.73m2 in community-living older persons. If confirmed, serum bicarbonate levels may give insights into kidney tubule health among persons with preserved eGFR and suggest a possible new target for intervention to prevent CKD development.
doi:10.1053/j.ajkd.2014.05.009
PMCID: PMC4177317  PMID: 24953890
Acidosis; alkalosis; kidney disease; aging; risk factor; renal disease; disease progression; kidney disease trajectory

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