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1.  Physical Performance and Frailty in Chronic Kidney Disease 
American journal of nephrology  2013;38(4):307-315.
Poor physical performance and frailty are associated with elevated risks of death and disability. Chronic kidney disease (CKD) is also strongly associated with these outcomes. The risks of poor physical performance and frailty among CKD patients, however, are not well established.
We measured the Short Physical Performance Battery (SPPB, a summary test of gait speed, chair-raises and balance; range 0–12) and the five elements of frailty among 1111 Chronic Renal Insufficiency Cohort participants. Adjusting for demographics and multiple comorbidities, we fit a linear regression model for the outcome of SPPB score and an ordinal logistic regression model for frailty status.
Median (interquartile range [IQR]) age was 65 (57–71) years, median estimated glomerular filtration rate (eGFR) for non-dialysis patients was 49 (36–62) ml/min/1.73m2, and median SPPB score was 9 (7–10). Seven percent of participants were frail and 43% were pre-frail. Compared with the SPPB score for eGFR >60 ml/min/1.73m2, the SPPB was 0.51 points lower for eGFR 30 – 59; 0.61 points lower for eGFR 15 – 29; and 1.75 points lower for eGFR <15; (p<0.01 for all comparisons). eGFR 30 – 59 (OR 1.45; p=0.024), eGFR 15 – 29 (OR 2.02; p=0.002) and eGFR <15 (OR 4.83, p<0.001) were associated with worse frailty status compared with eGFR >60 ml/min/1.73m2.
CKD severity was associated with poor physical performance and frailty in a graded fashion. Future trials should determine if outcomes for CKD patients with frailty and poor physical performance are improved by targeted interventions.
PMCID: PMC4019506  PMID: 24107579
Physical performance; frailty; chronic kidney disease
2.  Candidate Gene Association Study of Coronary Artery Calcification in Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort Study 
To identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD).
CKD is associated with increased CAC and subsequent coronary heart disease (CHD) but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD.
We performed a candidate gene study (~2,100 genes; ~50,000 SNPs) of CAC within the Chronic Renal Insufficiency Cohort (CRIC) Study (n=1,509; 57% European, 43% African ancestry). SNPs with preliminary evidence of association with CAC in CRIC were examined for association with CAC in PennCAC (n=2,560) and Amish Family Calcification Study (AFCS; n=784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the Pakistan Risk of Myocardial Infarction study (PROMIS) (n=14,885).
Of 268 SNPs reaching P <5×10−4 for CAC in CRIC, 28 SNPs in 23 loci had nominal support (P <0.05 and in same direction) for CAC in PennCAC or AFCS. Besides chr9p21 and COL4A1, known loci for CHD, these included SNPs having reported GWAS association with hypertension (e.g., ATP2B1). In PROMIS, four of the 23 suggestive CAC loci (chr9p21, COL4A1, ATP2B1 and ABCA4) had significant associations with MI consistent with their direction of effect on CAC.
We identified several loci associated with CAC in CKD that also relate to MI in a general population sample. CKD imparts a high risk of CHD and may provide a useful setting for discovery of novel CHD genes and pathways.
PMCID: PMC3953823  PMID: 23727086
Coronary artery calcification (CAC); chronic kidney disease (CKD); Chronic Renal Insufficiency Cohort Study (CRIC); myocardial infarction (MI); risk factors; candidate genes; single nucleotide polymorphisms (SNPs)
3.  KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Management of Blood Pressure in CKD 
In response to the 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guideline for blood pressure management in patients with chronic kidney disease not on dialysis, the National Kidney Foundation organized a group of US experts in hypertension and transplant nephrology to review the recommendations and comment on their relevancy in the context of current US clinical practice and concerns. The overriding message was the dearth of clinical trial evidence to provide strong evidence-based recommendations. For patients with CKD with normal to mildly increased albuminuria, goal blood pressure has been relaxed to ≤140/90 mm Hg for both diabetic and nondiabetic patients. In contrast, KDIGO continues to recommend goal blood pressure ≤130/80 mm Hg for patients with chronic kidney disease with moderately or severely increased albuminuria and for all renal transplant recipients regardless of the presence of proteinuria, without supporting data. The expert panel thought the KDIGO recommendations were generally reasonable but lacking in sufficient evidence support and that additional studies are greatly needed.
PMCID: PMC3929429  PMID: 23684145
Kidney Disease: Improving Global Outcomes (KDIGO); guideline; blood pressure
4.  Changes in Biomarkers Associated With Living Kidney Donation 
American journal of nephrology  2013;38(3):10.1159/000354312.
Living donor kidneys have been associated with better graft and overall survival in kidney transplant recipients. Although living kidney donation is generally considered safe in carefully selected living donors, concerns of possible adverse effects related to kidney donation remain, especially in younger and high risk donors. In this study, we examined the changes in a panel of traditional and novel serum biomarkers linked with cardiovascular conditions in a cohort of 34 healthy living kidney donors with a mean age(SD) of 40±10 years and estimated pre-donation GFR of 86±10 ml/min/1.73m2. At 6 months post donation, there were no significant changes in the clinical parameters including body mass index (BMI) and blood pressure despite a significant decline in the mean estimated GFR to 60 ml/min/1.73m2. Among the panel of markers, the levels of symmetric dimethylarginine (SDMA) and fibroblast growth factor 23(FGF-23) increased significantly compared to baseline, suggesting that living kidney donation may result in changes in biomarkers that are associated with cardiovascular risk in other cohorts.
PMCID: PMC3838917  PMID: 23988698
biomarkers; cardiovascular; transplantation; risk factors
5.  Living Donor Kidney Donation: Another Form of White Coat Effect 
American Journal of Nephrology  2011;35(1):75-79.
Living donor nephrectomy can be associated with increases in blood pressure several years following the procedure, but the best method to assess blood pressure during the living donor evaluation process is unclear.
Living kidney donors underwent casual clinic and ambulatory blood pressure monitoring (ABPM) and measurement of central aortic pressures at baseline and 6 months following donor nephrectomy.
There was a significant decline in clinic systolic blood pressure (SBP; p = 0.001) and central aortic systolic pressure (p = 0.011) during the study period. However, average ABPM was unchanged and other measures of central arterial pressures and Augmentation Index were unchanged at 6 months compared to baseline.
The remarkable differences between clinic SBP and ambulatory SBP prior to donation, and the disappearance of these differences 6 months later, suggest a substantial white coat effect on SBP associated with living kidney donor evaluation. Also, ABPM represents a better way to assess blood pressure prior to kidney donation.
PMCID: PMC3254031  PMID: 22189100
Ambulatory blood pressure monitoring; Blood pressure; Living donors; Hemodynamics; Transplantation
6.  Arterial Wave Reflections and Incident Cardiovascular Events and Heart Failure: The Multiethnic Study of Atherosclerosis 
Experimental and physiologic data mechanistically implicate wave reflections in the pathogenesis of left ventricular failure and cardiovascular disease, but their association with these outcomes in the general population is unclear.
To assess the relationship between central pressure profiles and incident cardiovascular events.
Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveform recorded non-invasively from 5,960 participants in the Multiethnic Study of Atherosclerosis (MESA). The central pressure waveform was separated into forward and reflected waves using a physiologic flow waveform. Reflection magnitude (RM=[reflected/forward wave amplitude] ×100), augmentation index (AIx=[second/first systolic peak] ×100) and pulse pressure amplification (PPA=[radial/aortic pulse pressure] ×100) were assessed as predictors of cardiovascular events (CVE) and congestive heart failure (CHF) during median 7.61 years of follow-up.
After adjustment for established risk factors, aortic AIx independently predicted hard CVE (HR per 10%-increase=1.08; 95%CI=1.01-1.14; P=0.016), whereas PPA independently predicted all CVE (HR per 10%-increase=0.82; 95%CI=0.70-0.96; P=0.012). RM was independently predictive of all CVE (hazard ratio [HR] per 10%-increase=1.34; 95%CI=1.08-1.67; P=0.009), hard CVE (HR per 10%-increase=1.46; 95%CI=1.12-1.90; P=0.006) and strongly predictive of new-onset CHF (HR per 10%-increase=2.69; 95%CI=1.79-4.04; P<0.0001), comparing favorably to other risk factors for CHF as judged by various measures of model performance, reclassification and discrimination. In a fully-adjusted model, compared to non-hypertensive subjects with low RM, the HR for hypertensive subjects with low RM, non-hypertensive subjects with high RM and hypertensive subjects with high RM were 1.81 (95%CI=0.85-3.86), 2.16 (95%CI=1.07-5.01) and 3.98 (95%CI=1.96-8.05), respectively.
Arterial wave reflections represent a novel strong risk factor for CHF in the general population.
PMCID: PMC4065497  PMID: 23103044
wave reflections; cardiovascular risk; heart failure. arterial hemodynamics; left ventricular afterload
7.  Psychological reactivity to laboratory stress is associated with hormonal responses in postmenopausal women 
The present study examined associations between psychological reactivity and hormonal responses to a standardized laboratory stressor (the Trier Social Stress Test [TSST]) in postmenopausal women.
Forty postmenopausal women ages 50–74 completed anxiety and mood assessments prior to and following the TSST. Blood samples were drawn across multiple time points for assessment of cortisol, adrenocorticotropic hormone (ACTH), and DHEA.
As expected, significant increases in anxiety and negative affect and decreases in positive affect were observed from pre- to post-TSST; however, the magnitude of change in anxiety and mood varied considerably across individuals. Analyses indicated that greater increases in anxiety and negative affect from pre- to post-TSST were associated with higher levels of cortisol, ACTH, and DHEA, controlling for race, age, body mass index, and smoking status. Changes in positive affect were not associated with cortisol, ACTH, or DHEA.
These findings suggest that enhanced reactivity to stress is associated with higher hormone levels among postmenopausal women, which could have potential implications for health.
PMCID: PMC4046251  PMID: 24595153
Trier Social Stress Test; anxiety; negative affect; cortisol; DHEA; ACTH
8.  Metabolic Syndrome, Components, and Cardiovascular Disease Prevalence in Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study 
American Journal of Nephrology  2011;33(6):477-484.
Metabolic syndrome may increase the risk for incident cardiovascular disease (CVD) and all-cause mortality in the general population. It is unclear whether, and to what degree, metabolic syndrome is associated with CVD in chronic kidney disease (CKD). We determined metabolic syndrome prevalence among individuals with a broad spectrum of kidney dysfunction, examining the role of the individual elements of metabolic syndrome and their relationship to prevalent CVD.
We evaluated four models to compare metabolic syndrome or its components to predict prevalent CVD using prevalence ratios in the Chronic Renal Insufficiency Cohort (CRIC) Study.
Among 3,939 CKD participants, the prevalence of metabolic syndrome was 65% and there was a significant association with prevalent CVD. Metabolic syndrome was more common in diabetics (87.5%) compared with non-diabetics (44.3%). Hypertension was the most prevalent component, and increased triglycerides the least prevalent. Using the bayesian information criterion, we found that the factors defining metabolic syndrome, considered as a single interval-scaled variable, was the best of four models of metabolic syndrome, both for CKD participants overall and for diabetics and non-diabetics separately.
The predictive value of this model for future CVD outcomes will subsequently be validated in longitudinal analyses.
PMCID: PMC3095834  PMID: 21525746
Cardiovascular disease; Chronic kidney disease; Chronic Renal Insufficiency Cohort (CRIC) Study; Metabolic syndrome
9.  Screening for Severe Obstructive Sleep Apnea Syndrome in Hypertensive Outpatients 
We attempted to validate a two-stage strategy to screen for severe obstructive sleep apnea syndrome (s-OSAS) among hypertensive outpatients, with polysomnography (PSG) as the gold standard. Using a prospective design, we recruited outpatients with hypertension from medical outpatient clinics. Interventions included: 1) assessment of clinical data; 2) home sleep testing (HST); and 3) 12-channnel, in-laboratory PSG. We developed models using clinical or HST data alone (single-stage models) or clinical data in tandem with HST (two-stage models) to predict s-OSAS. For each model, we computed area-under-receiver-operating-characteristic curves (AUC), sensitivity, specificity, negative likelihood ratio, and negative post-test probability (NPTP). Models were then rank-ordered based upon AUC values and NPTP. HST used alone had limited accuracy (AUC=0.727, ,NPTP = 2.9%). However, models that used clinical data in tandem with HST were more accurate in identifying s-OSAS, with lower NPTP: 1) facial morphometrics (AUC=0.816, NPTP=0.6%); 2) neck circumference (AUC=0.803, NPTP=1.7%); and Multivariable Apnea Prediction Score (AUC = 0.799, NPTP =1.5%) where sensitivity, specificity and NPTP were evaluated at optimal thresholds. Therefore, HST combined with clinical data can be useful in identifying s-OSAS in hypertensive outpatients, without incurring greater cost and patient burden associated with in-laboratory PSG. These models were less useful in identifying OSAS of any severity.
PMCID: PMC3621016  PMID: 23551728
Obstructive Sleep Apnea Syndrome; Hypertension; Polysomnography; Home Sleep Testing
10.  Central Pulse Pressure in Chronic Kidney Disease: A CRIC Ancillary Study 
Hypertension  2010;56(3):518-524.
Central pulse pressure can be non-invasively derived using the radial artery tonometric methods. Knowledge of central pressure profiles has predicted cardiovascular morbidity and mortality in several populations of patients, particularly those with known coronary artery disease and those receiving dialysis. Few data exist characterizing central pressure profiles in patients with mild-moderate chronic kidney disease who are not on dialysis. We measured central pulse pressure cross-sectionally in 2531 participants in the Chronic Renal Insufficiency Cohort study to determine correlates of the magnitude of central pulse pressure in the setting of chronic kidney disease. Tertiles of central pulse pressure (CPP) were < 36 mmHg, 36–51 mmHg and > 51 mmHg with an overall mean (± S.D.) of 46 ± 19 mmHg. Multivariable regression identified the following independent correlates of central pulse pressure: age, gender, diabetes mellitus, heart rate (negatively correlated), glycosylated hemoglobin, hemoglobin, glucose and PTH concentrations. Additional adjustment for brachial mean arterial pressure and brachial pulse pressure showed associations for age, gender, diabetes, weight and heart rate. Discrete intervals of brachial pulse pressure stratification showed substantial overlap within the associated central pulse pressure values. The large size of this unique chronic kidney disease cohort provides an ideal situation to study the role of brachial and central pressure measurements in kidney disease progression and cardiovascular disease incidence.
PMCID: PMC2941985  PMID: 20660819
Elasticity; epidemiology; diabetic nephropathies; hemodynamics; gender
11.  Vascular Compliance during Insulin Infusion and Oral Glucose Challenge 
Artery research  2013;7(1):36-41.
PMCID: PMC3753035  PMID: 23997837
12.  Aortic PWV in Chronic Kidney Disease: A CRIC Ancillary Study 
American journal of hypertension  2009;23(3):282-289.
Aortic PWV is a measure of arterial stiffness and has proved useful in predicting cardiovascular morbidity and mortality in several populations of patients, including the healthy elderly, hypertensives and those with end stage renal disease receiving hemodialysis. Little data exist characterizing aortic stiffness in patients with chronic kidney disease who are not receiving dialysis, and in particular the effect of reduced kidney function on aortic PWV.
We performed measurements of aortic PWV in a cross-sectional cohort of participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study to determine factors which predict increased aortic PWV in chronic kidney disease.
PWV measurements were obtained in 2564 participants. The tertiles of aortic PWV (adjusted for waist circumference) were < 7.7 m/sec, 7.7–10.2 m/sec and > 10.2 m/sec with an overall mean (± S.D.) value of 9.48 ± 3.03 m/sec [95% CI = 9.35–9.61 m/sec]. Multivariable regression identified significant independent positive associations of age, blood glucose concentrations, race, waist circumference, mean arterial blood pressure, gender, and presence of diabetes with aortic PWV and a significant negative association with the level of kidney function.
The large size of this unique cohort, and the targeted enrollment of chronic kidney disease participants provides an ideal situation to study the role of reduced kidney function as a determinant of arterial stiffness. Arterial stiffness may be a significant component of the enhanced cardiovascular risk associated with kidney failure.
PMCID: PMC2822073  PMID: 20019670
13.  Diabetes, lower extremity amputation, loss of protective sensation, and NOS1AP in the CRIC study 
Lower extremity amputation (LEA) is a life-altering complication of diabetes. The goal of our study was to investigate the possibility that genetic variation in neuronal nitric oxide synthase associated protein (NOS1AP) is associated with LEA and diabetic peripheral neuropathy (DPN). Our work used data from the Chronic Renal Insufficiency Cohort (CRIC) study. CRIC is a multicenter investigation undertaken to pursue the relationship between chronic renal insufficiency and cardiovascular disease. We evaluated 3,040 CRIC study subjects, 1,490 individuals were African-Americans and 1,550 were whites. LEA occurred in 162 (5.3%) subjects, 93 (6.2%) of African-Americans and 69 (4.4%) of whites. In whites, NOS1AP SNP rs1963645 was most strongly associated with LEA (1.73 (1.23, 2.44)). In African-Americans three NOS1AP SNPs were associated with LEA: rs6659759 (1.65 (1.21, 2.24)); rs16849113 (1.58 (1.16, 2.14)); rs880296 (1.54 (1.14, 2.10)). We tested a subset of 100 CRIC participants for DPN using Simmes-Weinstein filaments. DPN in those with diabetes was associated with rs1963645 (16.97 (2.38, 120.97)) in whites and rs16849113 and rs6659759 (3.62 (1.11, 11.83) and 3.02 (0.82, 11.12) respectively) in African-Americans. In conclusion, this is one of the first studies to show that NOS1AP gene variants are associated with DPN and LEA.
PMCID: PMC3667959  PMID: 23228162
Hypertension  2012;60(5):1157-1168.
A previous genetic analysis comparing the Dahl salt-sensitive (S) rat to the spontaneously hypertensive rat (SHR) identified a major locus on chromosome 2 that influences proteinuria in the S rat. In the present study, blood pressure, proteinuria, and renal hemodynamics were evaluated in congenic strains with small segments of the protective SHR genome on the S background. Proteinuria and renal function were significantly improved in the congenic strains compared to the S. The causative locus interval was narrowed to <375 kb based on congenic strains, haplotype data, comparative mapping, and concordance with human genetic studies. Sequencing of the coding region of genes in this region identified 36 SNPs (13 nonsynonymous and 23 synonymous). Gene expression profiling indicated that only few genes exhibited differential expression. Arhgef11, Pear1, and Sh2d2 were identified as important candidate genes that may be linked to kidney injury in the S rat. In particular, Arhgef11 plays an important role in the activation of the Rho-ROCK signaling pathway. Inhibition of this pathway using fasudil resulted in a significant reduction of proteinuria in treated S rats (compared to untreated S). However, no difference was observed between treated or untreated SHR or congenic strains. The homologous region in humans was found to be associated with estimated glomerular filtration rate (eGFR) in the Candidate Gene Association Resource (CARe) population. In summary, these findings demonstrate that allelic variants in Arhgef11, acting through the Rho-ROCK pathway, could influence kidney injury in the S as well as provide insight into human kidney disease.
PMCID: PMC3505884  PMID: 22987919
renal hemodynamics; fibrosis; Dahl salt-sensitive rats; genetic association studies
15.  Carotid Plaque, Carotid Intima-Media Thickness, and Coronary Calcification Equally Discriminate Prevalent Cardiovascular Disease in Kidney Disease 
American journal of nephrology  2012;36(4):342-347.
Despite the significant morbidity and mortality attributable to cardiovascular disease (CVD), risk stratification remains an important challenge in the chronic kidney disease(CKD) population. We examined the discriminative ability of non-invasive measures of atherosclerosis, including carotid intima-media thickness(cIMT), carotid plaque, coronary artery calcification(CAC) and ascending and descending thoracic aorta calcification(TCAC), and Framingham Risk Score (FRS) to predict self-reported prevalent CVD.
Methods and Results
Participants were enrolled in the cIMT ancillary study of the Chronic Renal Insufficiency Cohort(CRIC) Study and also had all of the above measures within an 18 month period. CVD was present in 21% of study participants. C-statistics were used to ascertain the discriminatory power of each measure of atherosclerosis. The study population (n=220) was 64% male; 51% black and 45% white. The proportion of individuals with estimated glomerular filtration rate ≥60, 45–59, 30–44, and <30ml/min/1.73m2 was 21%, 41%, 28%, and 11%, respectively. In multivariable analyses adjusting for demographic factors, we failed to find a difference between CAC, carotid plaque, and cIMT as predictors of self-reported prevalent CVD (c-statistic 0.70, 95% confidence interval [CI]: 0.62–0.78; c-statistic 0.68, 95% CI: 0.60–0.75, and c-statistic 0.64, CI: 0.56–0.72, respectively). CAC was statistically better than FRS. FRS was the weakest discriminator of self-reported prevalent CVD (c-statistic 0.58).
There was a significant burden of atherosclerosis among individuals with CKD, ascertained by several different imaging modalities. We were unable to find a difference in the ability of CAC, carotid plaque, and cIMT to predict self-reported prevalent CVD.
PMCID: PMC3538165  PMID: 23107930
carotid intima media thickness; coronary artery calcification; kidney; plaque
16.  Estimating GFR Among Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study 
Glomerular filtration rate (GFR) is considered the best measure of kidney function, but repeated assessment is not feasible in most research studies.
Study Design
Cross-sectional study of 1,433 participants from the Chronic Renal Insufficiency Cohort (CRIC) Study (i.e., the GFR subcohort) to derive an internal GFR estimating equation using a split sample approach.
Setting & Participants
Adults from 7 US metropolitan areas with mild to moderate chronic kidney disease; 48% had diabetes and 37% were black.
Index Test
CRIC GFR estimating equation
Reference Test or Outcome
Urinary 125I-iothalamate clearance testing (measured GFR)
Other Measurements
Laboratory measures including serum creatinine and cystatin C, and anthropometrics
In the validation dataset, the model that included serum creatinine, serum cystatin C, age, gender, and race was the most parsimonious and similarly predictive of mGFR compared to a model additionally including bioelectrical impedance analysis phase angle, CRIC clinical center, and 24-hour urinary creatinine excretion. Specifically, the root mean square errors for the separate model were 0.207 vs. 0.202, respectively. The performance of the CRIC GFR estimating equation was most accurate among the subgroups of younger participants, men, non-blacks, non-Hispanics, those without diabetes, those with body mass index <30 kg/m2, those with higher 24-hour urine creatinine excretion, those with lower levels of high-sensitivity C-reactive protein, and those with higher mGFR.
Urinary clearance of 125I-iothalamate is an imperfect measure of true GFR; cystatin C is not standardized to certified reference material; lack of external validation; small sample sizes limit analyses of subgroup-specific predictors.
The CRIC GFR estimating equation predicts measured GFR accurately in the CRIC cohort using serum creatinine and cystatin C, age, gender, and race. Its performance was best among younger and healthier participants.
PMCID: PMC3565578  PMID: 22658574
glomerular filtration rate (GFR); kidney function; GFR estimation
17.  Plant Protein Intake Is Associated with Fibroblast Growth Factor 23 and Serum Bicarbonate in Patients with CKD: The Chronic Renal Insufficiency Cohort Study 
Journal of Renal Nutrition  2012;22(4):379-388.e1.
Protein from plant, as opposed to animal, sources may be preferred in chronic kidney disease (CKD), due to lower bioavailability of phosphate and lower nonvolatile acid load.
Study Design
Observational cross-sectional study.
Setting & Participants
2938 participants with chronic kidney disease and information on dietary intake at the baseline visit in the Chronic Renal Insufficiency Cohort Study.
Percentage of total protein from plant sources (% plant protein) was determined by scoring individual food items from the National Cancer Institute Diet History Questionnaire (DHQ).
Metabolic parameters, including serum phosphate, bicarbonate (HCO3), potassium, and albumin, plasma fibroblast growth factor 23 (FGF23), and parathyroid hormone (PTH), and hemoglobin.
We modeled the association between % plant protein and metabolic parameters using linear regression. Models were adjusted for age, sex, race, diabetes, body mass index, eGFR, income, smoking, total energy intake, total protein intake, 24 hour urinary sodium, use of angiotensin converting enzyme inhibitors/angiotensin receptor blockers and use of diuretics.
Higher % plant protein was associated with lower FGF23 (p=0.05) and higher HCO3 (p=0.01), but not with serum phosphate or PTH (p=0.9 and 0.5, respectively). Higher % plant protein was not associated with higher serum potassium (p=0.2), lower serum albumin (p=0.2) or lower hemoglobin (p=0.3). The associations of % plant protein with FGF23 and HCO3 did not differ by diabetes status, sex, race, CKD stage (2/3 vs. 4/5) or total protein intake (≤ 0.8 g/kg/d vs. >0.8 g/kg/d) (p-interaction > 0.10 for each).
Cross-sectional study; Determination of % plant protein using the DHQ has not been validated.
Consumption of a higher percentage of protein from plant sources may lower FGF23 and raise HCO3 in patients with CKD.
PMCID: PMC3383455  PMID: 22480598
chronic kidney disease; nutrition; mineral metabolism; acidosis
18.  Risk Factors for Peripheral Arterial Disease among Patients with Chronic Kidney Disease 
The American journal of cardiology  2012;110(1):136-141.
Patients with chronic kidney disease (CKD) have an increased risk of developing peripheral arterial disease (PAD). We examined the cross-sectional association between novel risk factors and prevalent PAD among patients with CKD. A total of 3,758 patients with an estimated glomerular filtration rate (eGFR) of 20-70 mL/min/1.73 m2 who participated in the chronic renal insufficiency cohort (CRIC) study were included in the current analysis. PAD was defined as an ankle-brachial index <0.9 or a history of arm or leg revascularization. After adjustment for age, sex, race, cigarette smoking, physical activity, history of hypertension and diabetes, pulse pressure, high-density lipoprotein cholesterol, eGFR, and CRIC clinical sites, several novel risk factors were significantly associated with PAD. For example, odds ratios (95% confidence intervals) for a one standard deviation higher level of risk factors were 1.18 (1.08–1.29) for log-transformed high sensitivity-C reactive protein, 1.18 (1.08–1.29) for white blood cell count, 1.15 (1.05–1.25) for fibrinogen, 1.13 (1.03–1.24) for uric acid, 1.14 (1.02–1.26) for hemoglobin A1c, 1.11 (1.00–1.23) for log-transformed homeostasis model assessment-insulin resistance, and 1.35 (1.18–1.55) for cystatin C. In conclusion, these data indicate that inflammation, prothrombotic state, oxidative stress, insulin resistance, and cystatin C were associated with an increased prevalence of PAD in patients with CKD. Further studies are warranted to examine the causal effect of these risk factors on PAD in CKD patients.
PMCID: PMC3586781  PMID: 22465315
peripheral arterial disease; novel risk factors; chronic kidney disease
19.  Is It Time for a Blood Pressure Measurement “Bundle”? 
PMCID: PMC3358387  PMID: 22328014
20.  Validation of the Kidney Disease Quality of Life Short Form 36 (KDQOL-36™) US Spanish and English Versions in a Cohort of Hispanics with Chronic Kidney Disease 
Ethnicity & disease  2013;23(2):202-209.
Evaluate the reliability and validity of the Kidney Disease Quality of Life Short Form 36 (KDQOL-36™) in Hispanics with mild-to-moderate chronic kidney disease (CKD).
Chronic Renal Insufficiency Cohort Study
420 Hispanic (150 English- and 270 Spanish-speakers), and 409 non-Hispanic White individuals, matched by age (mean 57 years), sex (60% male), kidney function (mean estimated glomerular filtration rate 36ml/min/1.73m2), and diabetes (70%).
To measure construct validity, we selected instruments, comorbidities, and laboratory tests related to at least one KDQOL-36™ subscale. Reliability was determined by calculating Cronbach’s alpha.
Reliability of each KDQOL-36™ subscale [SF-12 Physical Component Summary (PCS) and Mental Component Summary (MCS), Symptoms/Problems, Burden of Kidney Disease and Effects of Kidney Disease] was very good (Cronbach’s alpha >0.8). Construct validity was supported by expected negative correlation between MCS scores and the Beck Depression Inventory in all three subgroups (r= −0.56 to −0.61, P<.0001). There was inverse correlation between the Symptoms/Problems subscale and the Patient Symptom Form (r= −0.70 to −0.77, P<.0001). We also found significant, positive correlation between the PCS score and a physical activity survey (r= +0.29 to +0.38, P≤.003); and between the PCS and MCS scores and the Kansas City Questionnaire (r= +0.31 to +0.64, P<.0001). Reliability and validity were similar across all racial/ethnic groups analyzed separately.
Our findings support the use of the KDQOL-36™ as a measure of HRQOL in this cohort of US Hispanics with CKD.
PMCID: PMC3651651  PMID: 23530302
Validation; Quality of Life; Hispanics
21.  Earlier Onset and Greater Severity of Disordered Mineral Metabolism in Diabetic Patients With Chronic Kidney Disease 
Diabetes Care  2012;35(5):994-1001.
Disordered mineral metabolism is a common complication of chronic kidney disease (CKD) and a novel risk factor for CKD progression, cardiovascular disease, and mortality. Although diabetes is the leading cause of CKD and is associated with worse clinical outcomes than other etiologies, few studies have evaluated mineral metabolism in CKD according to diabetes status.
Using the Chronic Renal Insufficiency Cohort Study, we tested the hypothesis that diabetes is independently associated with lower serum calcium and higher serum phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23).
Compared with participants without diabetes (n = 1,936), those with diabetes (n = 1,820) were more likely to have lower estimated glomerular filtration rate (eGFR), lower serum albumin, and higher urinary protein excretion (all P < 0.001). Unadjusted serum phosphate, PTH, and FGF23 levels were higher and calcium was lower among those with compared with those without diabetes (all P < 0.001). After multivariate adjustment, diabetes remained a significant predictor of serum phosphate, PTH, and FGF23 but not calcium. The eGFR cut point at which 50% of participants met criteria for secondary hyperparathyroidism or elevated FGF23 was higher in participants with diabetes compared with those without (PTH: eGFR 30–39 vs. 20–29, P < 0.001; FGF23: eGFR 50–59 vs. 40–49, P < 0.001).
Disordered mineral metabolism begins earlier in the course of CKD and is more severe among CKD patients with compared with those without diabetes. Future studies should explore mechanisms for these differences and whether they contribute to excess risks of adverse clinical outcomes among diabetic patients with CKD.
PMCID: PMC3329844  PMID: 22446176
22.  Combined admixture mapping and association analysis identifies a novel blood pressure genetic locus on 5p13: contributions from the CARe consortium 
Human Molecular Genetics  2011;20(11):2285-2295.
Admixture mapping based on recently admixed populations is a powerful method to detect disease variants with substantial allele frequency differences in ancestral populations. We performed admixture mapping analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP), followed by trait-marker association analysis, in 6303 unrelated African-American participants of the Candidate Gene Association Resource (CARe) consortium. We identified five genomic regions (P< 0.001) harboring genetic variants contributing to inter-individual BP variation. In follow-up association analyses, correcting for all tests performed in this study, three loci were significantly associated with SBP and one significantly associated with DBP (P< 10−5). Further analyses suggested that six independent single-nucleotide polymorphisms (SNPs) contributed to the phenotypic variation observed in the admixture mapping analysis. These six SNPs were examined for replication in multiple, large, independent studies of African-Americans [Women's Health Initiative (WHI), Maywood, Genetic Epidemiology Network of Arteriopathy (GENOA) and Howard University Family Study (HUFS)] as well as one native African sample (Nigerian study), with a total replication sample size of 11 882. Meta-analysis of the replication set identified a novel variant (rs7726475) on chromosome 5 between the SUB1 and NPR3 genes, as being associated with SBP and DBP (P< 0.0015 for both); in meta-analyses combining the CARe samples with the replication data, we observed P-values of 4.45 × 10−7 for SBP and 7.52 × 10−7 for DBP for rs7726475 that were significant after accounting for all the tests performed. Our study highlights that admixture mapping analysis can help identify genetic variants missed by genome-wide association studies because of drastically reduced number of tests in the whole genome.
PMCID: PMC3090198  PMID: 21422096
23.  Diuretics, calciuria and secondary hyperparathyroidism in the Chronic Renal Insufficiency Cohort 
Nephrology Dialysis Transplantation  2011;26(4):1258-1265.
Background. Secondary hyperparathyroidism is a common complication of chronic kidney disease (CKD) that is associated with bone disease, cardiovascular disease and death. Pathophysiological factors that maintain secondary hyperparathyroidism in advanced CKD are well-known, but early mechanisms of the disease that can be targeted for its primary prevention are poorly understood. Diuretics are widely used to control volume status and blood pressure in CKD patients but are also known to have important effects on renal calcium handling, which we hypothesized could alter the risk of secondary hyperparathyroidism.
Methods. We examined the relationship of diuretic treatment with urinary calcium excretion, parathyroid hormone (PTH) levels and prevalence of secondary hyperparathyroidism (PTH ≥ 65 pg/mL) in a cross-sectional study of 3616 CKD patients in the Chronic Renal Insufficiency Cohort.
Results. Compared with no diuretics, treatment with loop diuretics was independently associated with higher adjusted urinary calcium (55.0 versus 39.6 mg/day; P < 0.001), higher adjusted PTH [67.9, 95% confidence interval (CI) 65.2–70.7 pg/mL, versus 52.8, 95% CI 51.1–54.6 pg/mL, P < 0.001] and greater odds of secondary hyperparathyroidism (odds ratio 2.1; 95% CI 1.7–2.6). Thiazide monotherapy was associated with lower calciuria (25.5 versus 39.6 mg/day; P < 0.001) but only modestly lower PTH levels (50.0, 95% CI 47.8–52.3, versus 520.8, 95% CI 51.1–54.6 pg/mL, P = 0.04) compared with no diuretics. However, coadministration of thiazide and loop diuretics was associated with blunted urinary calcium (30.3 versus 55.0 mg/day; P <0.001) and odds of hyperparathyroidism (odds ratio 1.3 versus 2.1; P for interaction = 0.05) compared with loop diuretics alone.
Conclusions. Loop diuretic use was associated with greater calciuria, PTH levels and odds of secondary hyperparathyroidism compared to no treatment. These associations were attenuated in patients who were coadministered thiazides. Diuretic choice is a potentially modifiable determinant of secondary hyperparathyroidism in CKD.
PMCID: PMC3108352  PMID: 21382989
calciuria; chronic kidney disease; diuretics; parathyroid hormone
24.  Renal impairment, hypertension and plasma urotensin II 
Background. Human urotensin II (UII) is a potent mammalian vasoconstrictor thought to be produced and cleared by the kidneys. Conflicting data exist regarding the relationship between UII concentrations, kidney function and blood pressure (BP). We measured the associations between kidney function [including end-stage renal disease (ESRD)] and levels of BP with plasma concentrations of UII.
Methods. Ninety-one subjects were enrolled. Thirty-one subjects had ESRD (undergoing haemodialysis), 30 subjects had chronic kidney disease (CKD) and 30 control subjects had no kidney disease. Plasma UII concentrations were measured by radioimmunoassay.
Results. Mean plasma UII concentrations were highest in controls, lower in subjects with ESRD and lowest in subjects with non-ESRD CKD (P < 0.0001). UII concentrations correlated negatively with serum creatinine (P = 0.0012) and CKD stage, and positively with creatinine clearance (P = 0.013). In ESRD subjects, plasma UII (P = 0.008) increased after dialysis, while SBP (P = 0.007), DBP (P = 0.009), serum creatinine (P < 0.0001) and serum urea nitrogen (P < 0.0001) decreased. UII concentrations were lower in patients with a history of hypertension (HTN) (P = 0.016). Age, race and gender did not appear to be associated with UII concentration. However, the distribution of African American race and male gender appear to be associated with increasing stages of chronic kidney disease.
Conclusions. These data suggest a potential vasodilatory role of UII in humans with kidney disease or hypertension. The reduction in UII levels in CKD also suggests either reduced production or greater clearance, or both, of UII.
PMCID: PMC3108358  PMID: 20621933
CKD; diabetes; dialysis; hypertension; urotensin II
25.  FGF23, PTH and Phosphorus Metabolism in the Chronic Renal Insufficiency Cohort 
Kidney international  2011;79(12):1370-1378.
Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. FGF23 has been proposed as an early biomarker of disordered phosphorus metabolism in earlier stages of chronic kidney disease (CKD), but data from large, well-characterized CKD cohorts are lacking. We measured FGF23 in baseline samples from 3,879 participants in the Chronic Renal Insufficiency Cohort study, a nationally representative, diverse CKD cohort with mean (± sd) estimated glomerular filtration rate (eGFR) of 42.8 ± 13.5 ml/min/1.73m2. Serum phosphate (3.7 ± 0.7 mg/dl) and parathyroid hormone (PTH; median 54, interquartile range [IQR] 35 – 89 pg/ml) levels were in the normal range, but FGF23 (median 145, IQR 96 – 239 RU/ml) was markedly greater than in healthy populations and increased significantly with decreasing eGFR. FGF23 excess, defined as ≥ 100 RU/ml, was more common than secondary hyperparathyroidism (≥ 65 pg/ml) and hyperphosphatemia (≥ 4.6 mg/dl) in all strata of eGFR, and the eGFR threshold at which the slope of FGF23 increased (57.8; 95%CI: 55.4 – 60.8 ml/min/1.73m2) was higher than the corresponding threshold for PTH (46.9; 95%CI: 45.5 – 51.4 ml/min/1.73m2). Thus, increased FGF23 is a common manifestation of CKD that develops earlier than increases in phosphate or PTH. These findings provide additional support for use of FGF23 as a sensitive early screening test to identify disordered phosphorus metabolism in CKD patients with normal serum phosphate levels.
PMCID: PMC3134393  PMID: 21389978

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