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1.  Vitamin D Level and Risk of Community-Acquired Pneumonia and Sepsis 
Nutrients  2014;6(6):2196-2205.
Previous research has reported reduced serum 25-hydroxyvitamin D (25(OH)D) levels is associated with acute infectious illness. The relationship between vitamin D status, measured prior to acute infectious illness, with risk of community-acquired pneumonia (CAP) and sepsis has not been examined. Community-living individuals hospitalized with CAP or sepsis were age-, sex-, race-, and season-matched with controls. ICD-9 codes identified CAP and sepsis; chest radiograph confirmed CAP. Serum 25(OH)D levels were measured up to 15 months prior to hospitalization. Regression models adjusted for diabetes, renal disease, and peripheral vascular disease evaluated the association of 25(OH)D levels with CAP or sepsis risk. A total of 132 CAP patients and controls were 60 ± 17 years, 71% female, and 86% Caucasian. The 25(OH)D levels <37 nmol/L (adjusted odds ratio (OR) 2.57, 95% CI 1.08–6.08) were strongly associated with increased odds of CAP hospitalization. A total of 422 sepsis patients and controls were 65 ± 14 years, 59% female, and 91% Caucasian. The 25(OH)D levels <37 nmol/L (adjusted OR 1.75, 95% CI 1.11–2.77) were associated with increased odds of sepsis hospitalization. Vitamin D status was inversely associated with risk of CAP and sepsis hospitalization in a community-living adult population. Further clinical trials are needed to evaluate whether vitamin D supplementation can reduce risk of infections, including CAP and sepsis.
PMCID: PMC4073143  PMID: 24918697
vitamin D deficiency; sepsis; community-acquired pneumonia; infection; epidemiology
2.  The effect of combined calcium and cholecalciferol supplementation on bone mineral density in elderly women with moderate chronic kidney disease 
Clinical nephrology  2012;77(5):358-365.
To examine the effect of combined calcium and vitamin D3 supplementation on bone mineral density (BMD) in patients with chronic kidney disease (CKD).
We performed a post-hoc analysis of the DECALYOS II, a 2-year randomized, double-blind, placebo-controlled study of 610 women randomized to: calcium-vitamin D3 fixed combination, calcium plus vitamin D3 separate combination, or placebo. Both active treatment groups received the same daily amount of calcium (1,200 mg) and vitamin D3 (800 IU). BMD of the distal radius was measured by single X-ray absorptiometry at baseline, 12 and 24 months.
At baseline 47.2%, 36.4% and 16.4% of the study population had an eGFR ≥ 60, 45 – 59, and < 45 ml/min/1.73 m2, respectively. Both active regimens vs. placebo markedly increased serum 25-hydroxyvitamin D levels from baseline in all eGFR groups (p < 0.0001). Analysis of variance demonstrated an overall treatment effect on distal radius BMD (p = 0.005), with the active treatment groups showing a lower rate of BMD loss when compared to the placebo group. The effects of the intervention on BMD did not differ significantly according to baseline eGFR (interaction p > 0.22 for all time points).
Combined calcium and vitamin D3 supplementation was effective in reducing rate of BMD loss in women with moderate CKD.
PMCID: PMC4030712  PMID: 22551881
cholecalciferol; vitamin D3; bone mineral density; chronic kidney disease
3.  Extra-skeletal effects of vitamin D deficiency in chronic kidney disease 
Annals of medicine  2011;43(4):273-282.
Cardiovascular diseases (CVD) and infectious diseases represent the two most important causes of death in patients with chronic kidney disease (CKD). The traditional risk factors of CVD do not appear to account sufficiently for the increased risk of CVD in patients with CKD, and vitamin D deficiency appears to be an important non-traditional, and potentially modifiable, CVD risk factor in this patient population. 25-Hydroxyvitamin D (25(OH)D) is converted to its biologically active form, 1,25-dihydroxyvitamin D (1,25(OH)2D), by the enzyme 1 α-hydroxylase in the kidneys. The recent discovery that many extrarenal tissues also possess both the 1 α-hydroxylase enzyme and the vitamin D receptors has provided new insights into the important physiologic autocrine and paracrine roles of vitamin D in various tissues and organs that are mainly dependent on the availability of 25(OH)D from the circulating plasma. Accordingly, the present review focuses on the rapidly expanding body of clinical and experimental evidence that supports a strong association between 25(OH)D deficiency/insufficiency and the risk of adverse CVD outcomes and infectious diseases as well as on the non-calcemic autocrine and paracrine actions of vitamin D both in the general population and in patients with CKD.
PMCID: PMC4030714  PMID: 21214426
Cardiovascular disease; chronic kidney disease; CKD; infectious diseases; vitamin D deficiency
4.  Association between Dietary Sodium and Potassium Intake with Chronic Kidney Disease in U.S. Adults: A Cross-Sectional Study 
American journal of nephrology  2013;37(6):526-533.
Clinical guidelines recommend a diet low in sodium and high in potassium to reduce blood pressure and cardiovascular events. Little is known about the relationship between dietary sodium and potassium intake and chronic kidney disease (CKD).
13,917 participants from the National Health and Nutrition Examination Survey (2001–2006) were examined. Sodium and potassium intake were calculated from 24-hour recall and evaluated in quartiles. CKD was defined as eGFR <60 mL/min, or eGFR ≥ 60mL/min with albuminuria (>30mg/g creatinine).
The mean (SE) age and eGFR of participants was 45.0 ± 0.4 years and 88.0 ± 0.60 ml/min/1.73m2, respectively. 2333 (14.2%) had CKD: 1146 (7.3%) had an eGFR < 60 ml/min/1.73m2 and 1514 (8.4%) had an eGFR ≥ 60 ml/min/1.73 m2 and albuminuria. After adjustment for age, sex, race, body mass index, diabetes, hypertension, cardiovascular disease and congestive heart failure subjects in the highest quartile of sodium intake had a lower odds of CKD compared to subjects in the lowest quartile (adjusted OR 0.79, 95% CI, 0.66 to 0.96; p<0.016). Compared to the highest quartile, participants in the lowest quartile of potassium intake had a 44% increased odds of CKD (adjusted OR 1.44, 95% CI 1.16–1.79, p=0.0011).
Higher intake of sodium and potassium is associated with lower odds of CKD among US adults. These results should be corroborated through longitudinal studies and clinical trials designed specifically to examine the effects of dietary sodium and potassium intake on kidney disease and its progression.
PMCID: PMC3919025  PMID: 23689685
Chronic Kidney Disease; Dietary sodium intake; Dietary potassium intake
5.  Phosphate and Cardiovascular Disease 
Hyperphosphatemia is a major risk factor for death, cardiovascular events and vascular calcification among patients with and without kidney disease. Even serum phosphate levels within the “normal laboratory range” associate with a greater risk of death and cardiovascular events. Potential mechanisms by which increased phosphate results in adverse outcomes are incompletely understood but current evidence suggests a direct effect of phosphate on vascular calcification and modulation of key hormones fibroblast growth factor-23 and calcitriol. Despite convincing epidemiologic connections between phosphate excess and cardiovascular disease, no clinical trials have been conducted to establish a causal relationship and large, randomized trials with hard endpoints are urgently needed to prove or disprove the benefits and risks of therapy.
PMCID: PMC4010180  PMID: 21406296
Experimental and observational studies suggest a role for uric acid in non-alcoholic fatty liver disease (NAFLD). We examined the association between serum uric acid levels and NAFLD in a large population-based study from the United States.
A cross-sectional analysis of 10,732 nondiabetic adults who participated in the National Health and Nutrition Examination Survey 1988–1994. Sex specific uric acid quartiles were defined: ≤5.2, 5.3–6.0, 6.1–6.9, and >6.9 mg/dL for men and ≤3.7, 3.8–4.5, 4.6–5.3, and >5.3 mg/dL for women. NAFLD presence and severity were defined by ultrasonographic detection of steatosis in the absence of other liver diseases. We modeled the probability that more severe NAFLD would be associated with the highest quartiles of uric acid.
Compared to the 1st quartile, the odds ratio for NAFLD was 1.79 (95% C.I. 1.49–2.15, p < 0.001) and 3.14 (95% C.I. 2.63–3.75, p < 0.001) for the 3rd and 4th quartiles, respectively. After adjusting for demographics, hypertension, waist circumference, triglycerides, high-density lipoprotein-cholesterol, homeostasis model assessment-estimated insulin resistance, estimated glomerular filtration rate, and aspartate aminotransferase, uric acid (4th quartile) was significantly associated with NAFLD (odds ratio 1.43; 95% C.I. 1.16–1.76, p < 0.001). Positive parameter estimates suggest increasing uric acid is associated with greater severity of NAFLD.
Elevated uric acid level is independently associated with ultrasound-diagnosed NAFLD in a nationally representative sample of United States nondiabetic adults. Increasing uric acid is associated with increasing severity of NAFLD on ultrasonography. These findings warrant further studies on the role of uric acid in NAFLD.
PMCID: PMC3565047  PMID: 23036645
hyperuricemia; NHANES; metabolic syndrome
7.  Low Body Mass Index and Dyslipidemia in Dialysis Patients linked to Elevated Plasma Fibroblast Growth Factor 23 
American journal of nephrology  2013;37(3):183-190.
Fibroblast growth factor 23 (FGF23) has been associated with death in dialysis patients. Since FGF23 shares structural features with FGF19-subfamily members that exert hormonal control of fat mass, we hypothesized that high circulating FGF23 concentrations would be associated with the development of a uremic lipid profile and lower body mass index.
This study was conducted among 654 patients receiving chronic hemodialysis. C-terminal FGF23 concentrations were measured in stored plasma samples. Linear regression was used to examine the cross-sectional associations of plasma FGF23 concentrations with body mass index (BMI), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG). Cox-proportional hazard models were used to examine the association between FGF23 concentrations and all-cause mortality.
Participants had a mean age of 60 ± 11 years and a median [IQR] FGF23 concentration of 4212 [1411-13816] RU/mL. An increase per SD in log10 FGF23 was associated with lower BMI (β= −1.11; p=0.008), TC (β= −6.46; p=0.02), LDL-C (β= −4.73; p=0.04) and HDL-C (β= −2.14; p=0.03); after adjusting for age, gender, race, cardiovascular risk factors, serum albumin, markers of mineral metabolism, and use of lipid lowering drugs. The association of FGF23 with death was attenuated after adjustment for HDL-C (HR of highest quartile 1.53, 95% CI 1.06-2.20 compared to lowest quartile).
These results indicate that higher plasma FGF23 levels are associated with lower BMI and dyslipidemia in dialysis patients. The association between FGF23 and death may be mediated through unexplored metabolic risk factors unrelated to mineral metabolism.
PMCID: PMC3717381  PMID: 23428834
Hemodialysis; fibroblast growth factor 23; dyslipidemia; body mass index
8.  Kidney Function and Mortality in Octogenarians: Cardiovascular Health Study All Stars 
To examine the association between kidney function and all-cause mortality in octogenarians.
Retrospective analysis of prospectively collected data.
Serum creatinine and cystatin C were measured in 1,053 Cardiovascular Health Study (CHS) All Stars participants.
Estimated glomerular filtration rate (eGFR) was determined using the Chronic Kidney Disease Epidemiology Collaboration creatinine (eGFRCR) and cystatin C one-variable (eGFRCYS) equations. The association between quintiles of kidney function and all-cause mortality was analyzed using unadjusted and adjusted Cox proportional hazards models.
Mean age of the participants was 85, 64% were female, 66% had hypertension, 14% had diabetes mellitus, and 39% had prevalent cardiovascular disease. There were 154 deaths over a median follow-up of 2.6 years. The association between eGFRCR and all-cause mortality was U-shaped. In comparison with the reference quintile (64–75 mL/min per 1.73 m2), the highest (≥75 mL/min per 1.73 m2) and lowest (≤43 mL/min per 1.73 m2) quintiles of eGFRCR were independently associated with mortality (hazard ratio (HR) = 2.49, 95% confidence interval (CI) = 1.36–4.55; HR = 2.28, 95% CI = 1.26–4.10, respectively). The association between eGFRCYS and all-cause mortality was linear in those with eGFRCYS of less than 60 mL/min per 1.73 m2, and in the multivariate analyses, the lowest quintile of eGFRCYS (<52 mL/min per 1.73 m2) was significantly associated with mortality (HR = 2.04, 95% CI = 1.12–3.71) compared with the highest quintile (>0.88 mL/min per 1.73 m2).
Moderate reduction in kidney function is a risk factor for all-cause mortality in octogenarians. The association between eGFRCR and all-cause mortality differed from that observed with eGFRCYS; the relationship was U-shaped for eGFRCR, whereas the risk was primarily present in the lowest quintile for eGFRCYS. J Am Geriatr Soc 2012.
PMCID: PMC3902776  PMID: 22724391
octogenarians; kidney function; mortality
9.  Dietary sodium restriction reverses vascular endothelial dysfunction in middle-aged/older adults with moderately elevated systolic blood pressure 
We determined the efficacy of dietary sodium restriction (DSR) for improving vascular endothelial dysfunction in middle-aged/older adults with moderately elevated systolic blood pressure (SBP; 130–159 mmHg) and the associated physiological mechanisms.
Vascular endothelial dysfunction develops with advancing age and elevated SBP, contributing to increased cardiovascular risk. DSR lowers BP, but its effect on vascular endothelial function and mechanisms involved are unknown.
Seventeen subjects (11M/6F; 62±7 yrs, mean±S.D.) completed a randomized, crossover study of 4 weeks of both low and normal sodium intake. Vascular endothelial function (endothelium-dependent dilation; EDD), nitric oxide (NO)/tetrahydrobiopterin (BH4) bioavailability and oxidative stress-associated mechanisms were assessed following each condition.
Urinary sodium excretion was reduced by ~50% (to 70±30 mmol/day), and conduit (brachial artery flow-mediated dilation [FMDBA]) and resistance (forearm blood flow responses to acetylcholine [FBFACh]) artery EDD were 68% and 42% (peak FBFACh) higher following the low sodium diet (p<0.005). Low sodium markedly enhanced NO- mediated EDD (greater ΔFBFACh with endothelial NO synthase [eNOS] inhibition) without changing eNOS expression/activation (Ser1177 phosphorylation), restored BH4 bioactivity (less ΔFMDBA with acute BH4), abolished tonic superoxide suppression of EDD (less ΔFMDBA and ΔFBFACh with ascorbic acid infusion), and increased circulating superoxide dismutase activity (p<0.05). These effects were independent of ΔSBP. Other subject characteristics/dietary factors and endothelium-independent dilation were unchanged.
DSR largely reverses both macro- and microvascular endothelial dysfunction by enhancing NO and BH4 bioavailability and reducing oxidative stress. Our findings support the emerging concept that DSR induces “vascular protection” beyond that attributable to its BP-lowering effects.
PMCID: PMC3549053  PMID: 23141486
aging; nitric oxide; hypertension; diet; oxidative stress
10.  Uric Acid as a Target of Therapy in CKD 
The prevalence of chronic kidney disease (CKD) has risen and will continue to rise in the United States and worldwide. This is alarming considering that CKD remains an irreversible condition and patients who progress to chronic kidney failure suffer reduced quality of life and high mortality rates. As such, it is imperative to identify modifiable risk factors to develop strategies to slow CKD progression. One such factor is hyperuricemia. Recent observational studies have associated hyperuricemia with kidney disease. In addition, hyperuricemia is largely prevalent in patients with CKD. Data from experimental studies have revealed several potential mechanisms by which hyperuricemia may contribute to the development and progression of CKD. In this manuscript we offer a critical review of the experimental evidence linking hyperuricemia to CKD, we highlight the gaps in our knowledge on the topic as it stands today, and we review the observational and interventional studies that have examined the potential nephro-protective effect of lowering uric acid in CKD patients . While uric acid may also be linked to cardiovascular disease and mortality in patients with CKD, this review will focus only on uric acid as a potential therapeutic target to prevent kidney disease onset and progression.
PMCID: PMC3525781  PMID: 23058478
kidney disease progression; uric acid
11.  25-hydroxyvitamin D Deficiency is Associated with an Increased Risk of Metabolic Syndrome in Patients with Non-Diabetic Chronic Kidney Disease 
Clinical nephrology  2012;78(6):432-441.
Patients with chronic kidney disease (CKD) not requiring dialysis have a high prevalence of 25(OH)D deficiency but the relationship between 25(OH)D levels and metabolic syndrome is unknown in this population.
This study analyzed stored plasma samples from 495 non-diabetic subjects with severe kidney disease, not yet on dialysis, who participated in the Homocysteine in Kidney and End Stage Renal Disease study. Metabolic syndrome was defined as the presence of all three of the following: (1) Serum triglycerides ≥150 mg/dL or drug treatment for hypertriglyceridemia; (2) serum high density lipoprotein-cholesterol (HDL-C) < 50 mg/dL for women or < 40 mg/dL for men or drug treatment for dyslipidemia; and (3) blood pressure ≥130/85 mmHg or drug treat ment for hypertension. Multivariate logistic regression models were used to evaluate the cross-sectional association between plasma 25(OH)D levels and metabolic syndrome.
The prevalence of metabolic syndrome increased as 25(OH)D levels declined, with the highest prevalence in participants with 25(OH)D levels < 20 ng/mL. Participants with 25(OH)D levels < 20 ng/mL had a significantly increased risk of metabolic syndrome compared to subjects with levels > 30 ng/mL after adjustment for multiple confounders (OR 2.25, 95% CI 1.25–4.07). Plasma 25(OH)D levels were inversely associated with diastolic blood pressure (R= −0.10, p=0.029) and serum triglyceride levels (R= −0.14, p=0.002).
25(OH)D deficiency is strongly associated with an increas ed risk of metabolic syndromein non-diabetic patients with severe CKD not yet on dialysis, independent of cardiometabolic risk factors and other important regulators of mineral metabolism.
PMCID: PMC3697908  PMID: 22784560
25-hydroxyvitamin D; Chronic kidney disease; Metabolic Syndrome
12.  Kidney Function and Progression of Coronary Artery Calcium in Community-Dwelling Older Adults (From the Rancho Bernardo Study) 
The American journal of cardiology  2012;110(10):1425-1433.
Longitudinal studies of the association of estimated glomerular filtration rate (eGFR) and albuminuria with coronary artery calcium, a measure of cardiovascular disease (CVD) burden, are few and contradictory. In this study, 421 community-dwelling men and women (mean age 67 years) without known heart disease had eGFR estimated by the Modification of Diet in Renal Disease equation and albuminuria assessed by urine albumin/creatinine ratio (ACR) between 1997–1999. Mean eGFR was 78 mL/min/1.73m2, median ACR was 10 mg/g. Coronary artery calcium (CAC) was measured by electron beam computed tomography between 2000–2001 when median total Agatston CAC score was 77; 4.5 years later 338 participants still without heart disease had a repeat scan (median CAC score 112); 46% of participants showed CAC progression, defined as an increase ≥2.5 mm3 in square-root transformed CAC volume score. Cross-sectional and longitudinal logistic regression analyses showed no separate or joint association between eGFR or ACR with CAC severity or progression. In conclusion, this study does not support the use of eGFR or ACR to identify asymptomatic older adults who should be screened for subclinical CVD with initial or sequential scanning for CAC. In the elderly, kidney function and CAC may not progress together.
PMCID: PMC3483450  PMID: 22883164
albuminuria; chronic kidney disease; coronary artery calcium; coronary heart disease; elderly; glomerular filtration rate
13.  Relationships Between Serum and Urine Phosphorus with All-Cause and Cardiovascular Mortality: the Osteoporotic Fractures in Men (MrOS) Study 
Serum phosphorus is associated with cardiovascular disease (CVD) in the general population but may not comprehensively reflect phosphorus homeostasis. Whether urine phosphorus/creatinine ratio (UPi/UCr, a marker of intestinal absorption) or urine fractional excretion of phosphorus (FePi, a marker of urinary phosphorus handling) is associated with risk of mortality or CVD is uncertain.
Study Design
Prospective observational study.
Setting and Participants
1,325 community-dwelling men aged ≥65 years.
Serum phosphorus, UPi/UCr, and FePi.
All-cause and CVD death.
Mean age was 74±6 years, eGFR was 75±16 ml/min/1.73m2, and serum phosphorus was 3.2±0.4 mg/dL. During 9.3 years median follow-up, there were 364 deaths (120 CVD deaths). After adjustment for demographics, CVD risk factors, and kidney function, the risks of all-cause death in the highest quartiles of serum phosphorus (≥3.6 mg/dL), UPi/UCr, and FePi were 1.63 (95% CI 1.23-2.17), 1.22 (95% CI 0.90-1.65), and 0.88 (95% CI 0.64-1.23), respectively. Results were similar for CVD death. Results were also similar irrespective of eGFR above or below 60 ml/min/1.73m2.
Older, all male cohort. Few had advanced CKD. Specimens were collected in the morning after an overnight fast.
In community-living older men, higher serum phosphorus is associated with all-cause and CVD death. In contrast, UPi/UCr and FePi were not. These findings do not support using UPi/UCr or FePi as adjuvant measures to predict risk of mortality or CVD in the general population.
PMCID: PMC3815620  PMID: 23261120
Phosphorus; urine phosphorus; mortality; cardiovascular disease; kidney disease; geriatrics
14.  Association between Non-Alcoholic Liver Disease and Chronic Kidney Disease: An Ultrasound Analysis from NHANES 1988–1994 
American journal of nephrology  2012;36(5):466-471.
Background/ Aims
Non-alcoholic fatty liver disease (NAFLD) has been proposed to contribute to chronic kidney disease (CKD) independently of traditional cardiometabolic risk factors. We hypothesized that NAFLD is associated with CKD and that greater severity of NAFLD is associated with higher odds of CKD.
A cross-sectional analysis of 11,469 adults who participated in the National Health and Nutrition Examination Survey 1988–1994. NAFLD was defined by ultrasonographic detection of steatosis in the absence of other liver diseases. CKD was defined as an estimated glomerular filtration rate of ≤60 mL/min/1.73 m2 or the presence of albuminuria in subjects with an estimated glomerular filtration rate of >60 mL/min/1.73 m2.
2,891 (25.4%) patients in the cohort had CKD. The prevalence of NAFLD was higher in individuals with CKD compared to those without CKD (42.2% vs. 34.5%, p<0.0001). NAFLD was associated with CKD in unadjusted logistic regression analysis (odds ratio 1.47, 95% confidence interval 1.29–1.67, p<0.0001). Adjustment for demographics and components of metabolic syndrome attenuated this relationship (odds ratio 1.04, 95% confidence interval 0.88–1.23, p=0.64). Moderate and severe NAFLD on ultrasound were increasingly associated with prevalent CKD in unadjusted analysis but not after adjustment for metabolic syndrome components.
After adjusting for features of metabolic syndrome, ultrasound-diagnosed NAFLD is not associated with prevalent CKD among US adults. Aggressive public health efforts are needed to prevent and treat metabolic syndrome.
PMCID: PMC3563287  PMID: 23128368
chronic kidney disease; nonalcoholic fatty liver disease; NHANES
15.  Comparison of Two Creatinine-Based Estimating Equations in Predicting All-Cause and Cardiovascular Mortality in Patients With Type 2 Diabetes 
Diabetes Care  2012;35(11):2347-2353.
To compare the performance of two glomerular filtration rate (GFR)-estimating equations in predicting the risk of all-cause and cardiovascular mortality in type 2 diabetic patients.
We followed 2,823 type 2 diabetic outpatients for a period of 6 years for the occurrence of all-cause and cardiovascular mortality. GFR was estimated using the four-variable Modification of Diet in Renal Disease (MDRD) study equation and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
At baseline, an estimated GFR (eGFR) <60 mL/min/1.73 m2 was present in 22.0 and 20.2% of patients using the MDRD study equation and the CKD-EPI equation, respectively. A total of 309 patients died during the follow-up (152 patients from cardiovascular causes). Both creatinine-based equations were associated with an increased risk of all-cause and cardiovascular mortality. However, the CKD-EPI equation provided a more accurate risk prediction of mortality than the MDRD study equation. Receiving operating characteristic curves showed that the areas under the curve (AUCs) for all-cause mortality (AUC 0.712 [95% CI 0.682–0.741]) and cardiovascular mortality (0.771 [0.734–0.808]) using eGFRCKD-EPI were significantly greater (P < 0.0001 by the z statistic) than those obtained by using eGFRMDRD (0.679 [0.647–0.711] for all-cause mortality and 0.739 [0.698–0.783] for cardiovascular mortality).
Our findings suggest that the estimation of GFR using the CKD-EPI equation more appropriately stratifies patients with type 2 diabetes according to the risk of all-cause and cardiovascular mortality compared with the MDRD study equation.
PMCID: PMC3476924  PMID: 22837367
16.  Associations of Plasma 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D Concentrations With Death and Progression to Maintenance Dialysis in Patients With Advanced Kidney Disease 
Low vitamin D concentrations are prevalent in chronic kidney disease (CKD) patients. We investigated the relationship between plasma 25-hydroxyvitamin D (25(OH)D) or 1,25-dihydroxyvitamin D (1,25(OH)2D) concentrations with death, cardiovascular events (CVE) and dialysis initiation in patients with advanced CKD. Study Design: The Homocysteine Study was a randomized double-blind trial evaluating the effects of high doses of folic acid on death and chronic dialysis initiation in patients with advanced CKD (stage 4 and 5 not yet on dialysis). 25(OH)D and 1,25(OH)2D concentrations were measured in stored plasma samples obtained 3 months after trial initiation and evaluated at clinically defined cutoffs (<10, 10-30, and >30 ng/mL) and tertiles (< 15, 15-22, and >22 pg/mL), respectively. Cox-proportional hazard models were used to examine the association between vitamin D concentrations and clinical outcomes.
Setting & Participants
1,099 patients with advanced CKD from 36 Veteran Affairs Medical Centers
25(OH)D and 1,25(OH)2D concentrations
Death, CVE and time to initiation of chronic dialysis.
After a median follow-up period of 2.9 years, 41% (n=453) died, while 56% (n=615) initiated dialysis. Mean 25(OH)D and 1,25(OH)2D concentrations were 21±10 ng/mL and 20±11 pg/mL, respectively. After adjustment for potential confounders, the lowest tertile of 1,25(OH)2D was associated with death (HR, 1.33; 95% CI, 1.01-1.74) and initiation of chronic dialysis (HR, 1.78; 95% CI, 1.40-2.26), compared to the highest tertile. The association with death and initiation of dialysis was moderately attenuated after adjustment for plasma fibroblast growth factor-23 (FGF23) concentrations (HRs of lower tertiles of 1.20 [95% CI, 0.91-1.58] and 1.56 [95% CI, 1.23-1.99], respectively, compared to highest tertile). There was no association between 25(OH)D concentrations and outcomes.
Participants were mostly male.
Low plasma 1,25(OH)2D concentrations are associated with death and initiation of chronic dialysis in advanced CKD. Fibroblast growth factor-23 may attentuate this relationship.
PMCID: PMC3439559  PMID: 22621970
17.  Sex Hormones and Serum Phosphorus in Older Men: The Osteoporotic Fractures in Men (MrOs) Study 
Kidney international  2010;78(4):415-422.
Older women have higher phosphorus levels than men. Estradiol causes phosphaturia in rodents. Whether sex hormones associate with phosphorus levels in humans is unknown. In 1,346 community-living older men, we evaluate the cross-sectional association of sex hormones with serum phosphorus, using linear regression with serum phosphorus levels as the dependent variable. Mean age was 76 years, phosphorus was 3.2±0.4mg/dl, and 18% had moderate kidney disease. Each 10pg/ml higher total estradiol associated with 0.05mg/dL lower serum phosphorus levels (95 % CI −0.09 to −0.02; P < 0.01) in a model adjusted for age, race, testosterone, sex hormone binding globulin, calcium, eGFR, intact PTH, 25(OH) vitamin D, body mineral density, and alkaline phosphatase. Results were similar in individuals with or without CKD. Serum testosterone levels were also associated with lower serum phosphorus levels (β per 200ng/dL greater total testosterone = −0.08; 95% CI −0.13 to −0.04; P < 0.001). Results were confirmed in an independent sample of 2,555 older men, and associations were not attenuated when adjusted for fibroblast growth factor-23 levels. Estradiol may induce phosphaturia in humans. Future studies are required to elucidate potential effects of testosterone on phosphorus homeostasis.
PMCID: PMC3787687  PMID: 20531458
Phosphorus; estradiol; testosterone; menopause; sex hormones; kidney disease; cardiovascular disease
18.  Association of Complete Recovery From Acute Kidney Injury With Incident CKD Stage 3 and All-Cause Mortality 
There is a gap of knowledge in the long-term outcomes of patients who have complete recovery of kidney function after an episode of acute kidney injury (AKI). We sought to determine if complete recovery of kidney function after an episode of AKI is associated with development of incident stage 3 chronic kidney disease (CKD) and mortality in patients with normal baseline kidney function.
Retrospective cohort study.
3,809 patients from an integrated healthcare delivery system that had a hospitalization between January 1, 1999 and December 31, 2009 with follow-up through March 31, 2010.
AKI defined by ICD-9 codes and using the Acute Kidney Injury Network (AKIN) definition with complete recovery defined by reduction in serum creatinine to less than 1.10 times the baseline value.
Incident stage 3 CKD persistent for 3 months and all-cause mortality.
After a median follow-up of 2.5 years, incident stage 3 CKD occurred in 15% and 3% of those with and without AKI, respectively, with an unadjusted HR of 5.93 (95% CI, 4.49-7.84) and a HR of 3.82 (95% CI, 2.81-5.19) in propensity score-stratified analyses. Deaths occurred in 35% and 24% of those with and without AKI, respectively, with an unadjusted HR of 1.46 (95% CI, 1.27-1.68). In the propensity score stratified analyses, HR decreased to 1.08 (95% CI, 0.93-1.27).
Measurements of albuminuria were not available.
Complete recovery of kidney function after an episode of AKI in subjects with normal baseline kidney function is associated with an increased risk of development of incident stage 3 CKD but not all-cause mortality.
PMCID: PMC3422603  PMID: 22541737
19.  Fibroblast Growth Factor-23 and Death, Heart Failure, and Cardiovascular Events in Community-Living Individuals: the Cardiovascular Health Study 
To determine the associations of FGF23 with death, HF, and CVD and investigate the influence of CKD in a general community-living population.
FGF23 increases renal phosphorus excretion and inhibits vitamin D activation. In ESRD, high FGF23 levels are associated with mortality. The associations of FGF23 with death, heart failure (HF), and cardiovascular disease (CVD) in teh general population are unknown.
Plasma FGF23 was measured in 3,107 community-living persons ≥ 65 years in 1996–97, and participants were followed through 2008. HF and CVD events were adjudicated by a panel of experts. Associations of FGF23 with each outcome were evaluated using Cox proportional hazards models, and we tested whether associations differed by CKD status.
Both lower eGFR and higher urine ACR were associated with high FGF23 at baseline. During 10.5 years (median) follow-up, there were 1,730 deaths, 697 incident HF events, and 797 incident CVD events. Although high FGF23 concentrations were associated with each outcome in combined analyses, the associations were consistently stronger for those with CKD (P interactions all < 0.006). In the CKD group (n=1,128), the highest FGF23 quartile had adjusted hazards ratios (HR) of 1.87 (1.47, 2.38) for all-cause death, 1.94 (1.32, 2.83) for incident HF, and 1.49 (1.02, 2.18) for incident CVD events compared to the lowest quartile. Corresponding HRs in those without CKD (n=1,979) were 1.29 (1.05, 1.59), 1.37 (0.99, 1.89), and 1.07 (0.79, 1.45).
FGF23, a hormone involved in phosphorous and vitamin D homeostasis, is independently associated with all-cause death and incident HF in community-living older persons. These associations appear stronger in persons with CKD.
PMCID: PMC3396791  PMID: 22703926
Fibroblast growth factor-23; kidney disease; mineral metabolism; cardiovascular disease; heart failure; elderly
20.  C-reactive protein as a predictor of cardiovascular events in elderly patients with chronic kidney disease 
Journal of nephrology  2012;25(5):719-725.
Few studies have evaluated the relationship between high-sensitivity C-reactive protein (hs-CRP) and vascular events in the elderly with chronic kidney disease (CKD).
The relationship of hs-CRP with vascular events was examined according to CKD status in 3166 participants of the Intervention Project on Cerebrovascular Diseases and Dementia in the Community of Ebersberg, Bavaria (INVADE study). CKD was defined as a creatinine clearance <60mL/min estimated by the Cockcroft-Gault formula. hs-CRP was used as a binary variable > or < 2.1mg/l (median value). Vascular events were defined as a composite of myocardial infarction, stroke and vascular death.
After 4 years of follow-up, 204 (6.4%) participants experienced a major cardiovascular event. High hs-CRP levels and CKD at baseline were associated with a greater risk of vascular events. Compared to patients with low hs-CRP/non-CKD, the adjusted HR (95% CI) for vascular events was 1.42 (1.11; 2.21) for low hs-CRP/CKD,1.57 (1.21; 2.34) for high hs-CRP/non-CKD, and 1.93 (1.45; 2.89) for high hs-CRP/CKD.
These results suggest that high CRP provides prognostic information in patients with CKD.
PMCID: PMC3704176  PMID: 22038335
C-reactive protein; inflammation; CKD; cardiovascular disease
21.  Insulin Resistance, Cystatin C, and Mortality Among Older Adults 
Diabetes Care  2012;35(6):1355-1360.
Insulin resistance is a risk factor for cardiovascular and noncardiovascular diseases. Impaired kidney function is linked with insulin resistance and may affect relationships of insulin resistance with health outcomes.
We performed a cohort study of 3,138 Cardiovascular Health Study participants (age ≥65 years) without diabetes. Insulin sensitivity index (ISI) was calculated from fasting and 2-h postload insulin and glucose concentrations. Associations of ISI and fasting insulin concentration with all-cause mortality were tested using Cox proportional hazards models, adjusting for demographic variables, prevalent cardiovascular disease, lifestyle variables, waist circumference, and LDL cholesterol. Subsequent models were additionally adjusted for or stratified by glomerular filtration rate estimated using serum cystatin C (eGFR).
A total of 1,810 participants died during the 14.7-year median follow-up. Compared with the highest quartile of ISI, the lowest quartile (most insulin resistant) was associated with 21% (95% CI 6–41) and 11% (−3 to 29) higher risks of death without and with adjustment for eGFR, respectively. Compared with the lowest quartile of fasting insulin concentration, the highest quartile was associated with 22% (4–43) and 4% (−12 to 22) higher risks of death without and with adjustment for eGFR, respectively. Similar attenuation by eGFR was observed when blood pressure, triglycerides, HDL cholesterol, and C-reactive protein were included in models.
Insulin resistance measured as ISI or fasting insulin concentration is associated with increased risk of death among older adults, adjusting for conventional confounding characteristics. Impaired kidney function may mediate or confound this relationship.
PMCID: PMC3357240  PMID: 22432118
22.  Serum Uric Acid Levels and Incident Chronic Kidney Disease in Patients With Type 2 Diabetes and Preserved Kidney Function 
Diabetes Care  2011;35(1):99-104.
Recent studies have suggested an association between hyperuricemia and adverse renal outcomes in nondiabetic populations. Data on the relationship between hyperuricemia and the risk of incident chronic kidney disease (CKD) in type 2 diabetic patients with normal or near-normal kidney function are lacking. We determined whether baseline serum uric acid levels predict the subsequent development of CKD in patients with type 2 diabetes.
We followed 1,449 type 2 diabetic patients with normal kidney function and without overt proteinuria for 5 years for the occurrence of incident CKD (defined as overt proteinuria or estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2).
During a 5-year follow-up period, 194 (13.4%) patients developed incident CKD. The cumulative incidence of CKD was significantly greater in patients with hyperuricemia than in those without hyperuricemia (29.5 vs. 11.4%, P < 0.001). In univariate logistic regression analysis, the presence of hyperuricemia roughly doubled the risk of developing CKD (odds ratio [OR] 2.55 [95% CI 1.71–3.85], P < 0.001). After adjusting for age, sex, BMI, smoking status, diabetes duration, systolic blood pressure, antihypertensive treatment, insulin therapy, HbA1c, eGFR, and albuminuria, hyperuricemia was associated with an increased risk of incident CKD (adjusted OR 2.10 [1.16–3.76], P < 0.01). In continuous analyses, a 1-SD increment in the serum uric acid level was significantly associated with a 21% increased risk of CKD.
In type 2 diabetic individuals with preserved kidney function, hyperuricemia seems to be an independent risk factor for the development of incident CKD.
PMCID: PMC3241303  PMID: 22028277
23.  Vitamin D, Parathyroid Hormone and Sudden Cardiac Death: Results from the Cardiovascular Health Study 
Hypertension  2011;58(6):1021-1028.
Recent studies have demonstrated greater risks of cardiovascular events and mortality among persons who have lower 25-hydroxyvitamin D (25-OHD) and higher parathyroid hormone (PTH) levels. We sought to evaluate the association between markers of mineral metabolism and sudden cardiac death (SCD) among the 2,312 participants from the Cardiovascular Health Study who were free of clinical cardiovascular disease at baseline. We estimated associations of baseline 25-OHD and PTH concentrations individually and in combination with SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, and kidney function. During a median follow-up of 14 years, there were 73 adjudicated SCD events. The annual incidence of SCD was greater among subjects who had lower 25-OHD concentrations: 2 events per 10,000 for 25-OHD ≥ 20 ng/ml and 4 events per 10,000 for 25-OHD < 20 ng/ml. Similarly, SCD incidence was greater among subjects who had higher PTH concentrations: 2 events per 10,000 for PTH ≤ 65 pg/ml and 4 events per 10,000 for PTH > 65 pg/ml. Multivariate adjustment attenuated associations of 25-OHD and PTH with SCD. Finally, 267 participants (11.7% of the cohort) had high PTH and low 25-OHD concentrations. This combination was associated with a more than 2-fold risk of SCD after adjustment (hazard ratio 2.19, 95% confidence interval 1.17, 4.10, p=0.017) compared to participants with normal levels of PTH and 25-OHD. The combination of lower 25-OHD and higher PTH concentrations appears to be associated independently with SCD risk among older adults without cardiovascular disease.
PMCID: PMC3337033  PMID: 22068871
Sudden cardiac death; Vitamin D; Parathyroid hormone; Elderly; Risk Factors
24.  Relation of Sex and Estrogen Therapy to Serum Fibroblast Growth Factor 23, Serum Phosphorus, and Urine Phosphorus: The Heart and Soul Study 
M[ND1]enopause is associated with urine phosphorus retention, which is mitigated by estrogen therapy. Fibroblast growth factor 23 (FGF-23) is a hormone originating from bone that regulates urine phosphorus excretion. Whether sex or estrogen therapy is associated with different FGF-23 levels is unknown.
Study Design & Setting
Cross-sectional study among ambulatory individuals with prevalent cardiovascular disease.
Sex, and among women, use or non-use of estrogen.
Serum phosphorus, tubular maximum reabsorption of phosphorus indexed to GFR (TMP/GFR), and plasma FGF-23 concentrations.
Among 987 participants, the mean age was 67 ± 11 years, 182 (18%) were female; 46 (25%) were taking estrogen. The mean eGFR was 71 ± 23 (SD) ml/min/1.73m2. Compared to women who were not taking estrogen, both women on estrogen therapy and men had significantly lower serum phosphorus concentrations, lower TMP/GFR (indicating higher urine phosphorus excretion), and lower FGF-23 concentrations with adjustment for age, demographics, and kidney function (P < 0.001 for each). Mean FGF-23 in RU/ml were 68.7 (95% CI, 59.7–79.0) in non estrogen using women, 43.8 (95% CI, 41.2–46.5) in men, and 45.1 (95% CI, 35.2–57.4) in women using estrogen in adjusted analysis (P< 0.001).
The majority of participants were men. Estrogen therapy was not randomly assigned.
Older women who are not taking estrogen have higher FGF-23 levels than either men or women taking estrogen. In the context of prior literature, these data suggest that post-menopausal phosphorus retention may stimulate higher FGF-23 concentrations after menopause.
PMCID: PMC3199317  PMID: 21855188
Menopause; fibroblast growth factor-23; phosphorus; estradiol; sex hormones
25.  The Role of Phosphorus in the Development and Progression of Vascular Calcification 
Vascular calcification is associated with significant cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Factors unique to CKD patients, such as hyperphosphatemia, predispose these patients to early and progressive vascular calcification. Hyperphosphatemia appears to be involved in a number of mechanisms that trigger and advance progression of vascular calcification including (1) transition of vascular smooth muscle cells (VSMC) from a contractile to an osteochondrogenic phenotype and mineralization of VSMC matrix through sodium-dependent phosphate cotransporters; (2) induction of apoptosis of VSMC; (3) inhibition of monocyte/macrophage differentiation into osteoclast-like cells; (4) elevation of fibroblast growth factor 23 levels; and (5) decreases in klotho expression. Whether vascular calcification can be prevented or reversed with strategies aimed at maintaining phosphate homeostasis is currently unknown. The current review discusses these mechanisms in-depth, exploring the interplay among vascular calcification promoters, inhibitors and substrate that affect phosphorus handling leading to vascular calcification in individuals with CKD.
PMCID: PMC3199354  PMID: 21956015

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