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1.  Estimated GFR and Circulating 24,25-Dihydroxyvitamin D3 Concentration: A Participant-Level Analysis of 5 Cohort Studies and Clinical Trials 
Decreased glomerular filtration rate (GFR) leads to reduced production of 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3 (25(OH)D3). Effects of low GFR on vitamin D catabolism are less well understood. We tested associations of estimated GFR (eGFR) with the circulating concentration of 24,25-dihydroxyvitamin D3 (24,25(OH)2D3), the most abundant product of 25(OH)D3 catabolism, across populations with a wide range of GFR.
Study Design
Cross-sectional study.
Setting & Participants
9596 participants in 5 cohort studies and clinical trials: the Diabetes Control and Complications Trial (N=1193), Multi-Ethnic Study of Atherosclerosis (N=6470), Cardiovascular Health Study (N=932), Seattle Kidney Study (N=289), and Hemodialysis Study (N=712).
Circulating 24,25(OH)2D3 concentration.
GFR was estimated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation. Vitamin D metabolites were measured by mass spectrometry.
Circulating 24,25(OH)2D3 concentration was correlated with circulating 25(OH)D3 concentration (Pearson r range, 0.64–0.88). This correlation was weaker with lower eGFR. Moreover, the increment in 24,25(OH)2D3 associated with higher 25(OH)D3 (“slope”) was lower with lower eGFR: 2.06 (95% CI, 2.01–2.10), 1.77 (95% CI, 1.74–1.81), 1.55 (95% CI, 1.48–1.62), 1.17 (95% CI, 1.05–1.29), 0.92 (95% CI, 0.74–1.10), 0.61 (95% CI, 0.22–1.00), and 0.37 (95% CI, 0.35–0.39) ng/mL 24,25(OH)2D3 per 10 ng/mL 25(OH)D3 for eGFR ≥90, 60–89, 45–59, 30–44, 15–29, and <15 mL/min/1.73 m2 and ESRD treated with hemodialysis, respectively. As a result, at a 25(OH)D3 concentration of 20 ng/mL, mean 24,25(OH)2D3 concentration was 2.92 (95% CI, 2.87–2.96), 2.68 (95% CI, 2.64–2.72), 2.35 (95% CI, 2.26–2.45), 1.92 (95% CI, 1.74–2.10), 1.69 (95% CI, 1.43–1.95), 1.14 (95% CI, 0.62–1.66), and 1.04 (95% CI,1.02–1.07) ng/mL for each category, respectively. This interaction was independent of other relevant clinical characteristics. Race, diabetes, urine albumin excretion, and the circulating concentrations of parathyroid hormone and fibroblast growth factor 23 more modestly modified the association of 24,25(OH)2D3 with 25(OH)D3.
Lack of direct pharmacokinetic measurements of vitamin D catabolism.
Lower eGFR is strongly associated with reduced vitamin D catabolism as measured by circulating 24,25(OH)2D3 concentration.
PMCID: PMC4111986  PMID: 24703961
decreased renal function; low estimated glomerular filtration rate; vitamin D catabolism; 1,25-dihydroxyvitamin D3; 25-hydroxyvitamin D3; active vitamin D; chronic kidney disease (CKD); biomarker
2.  Fibroblast Growth Factor-23 and Incident Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS) 
Circulation  2014;130(4):298-307.
Fibroblast growth factor-23 (FGF-23) is a hormone that promotes urinary phosphate excretion and regulates vitamin D metabolism. Circulating FGF-23 concentrations increase markedly in chronic kidney disease and are associated with increased risk of clinical cardiovascular events. FGF-23 may promote atrial fibrillation (AF) by inducing left ventricular hypertrophy and diastolic and left atrial dysfunction.
Methods and Results
We tested associations of circulating FGF-23 concentration with incident AF among 6,398 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and 1,350 participants in the Cardiovascular Health Study (CHS), all free of clinical cardiovascular disease at baseline. Over 7.7 and 8.0 years median follow-up, we observed 291 and 229 incident AF events in MESA and CHS, respectively. In multivariable Cox proportional hazards models, each two-fold higher FGF-23 concentration was associated with a 41% higher risk of incident AF in MESA (HR 1.41 [95% CI 1.13-1.76], p=0.003) and a 30% higher risk of incident AF in CHS (HR 1.30 [95% CI 1.05-1.61], p=0.016), adjusting for potential confounding characteristics including kidney disease. Serum phosphate concentration was significantly associated with incident AF in MESA (HR 1.15 per 0.5 mg/dL [CI 1.02-1.31], p-value=0.023) but not CHS. In MESA, an association of low estimated glomerular filtration rate with incident AF was partially attenuated by adjusting for FGF-23.
Higher circulating FGF-23 concentration is associated with incident AF and may, in part, explain the link between chronic kidney disease and AF.
PMCID: PMC4108550  PMID: 24920722
atrial fibrillation; fibroblast growth factor; mineral; chronic kidney disease
3.  Assessment of Vascular Function in Patients With Chronic Kidney Disease 
Patients with chronic kidney disease (CKD) have significantly increased risk of cardiovascular disease (CVD) compared to the general population, and this is only partially explained by traditional CVD risk factors. Vascular dysfunction is an important non-traditional risk factor, characterized by vascular endothelial dysfunction (most commonly assessed as impaired endothelium-dependent dilation [EDD]) and stiffening of the large elastic arteries. While various techniques exist to assess EDD and large elastic artery stiffness, the most commonly used are brachial artery flow-mediated dilation (FMDBA) and aortic pulse-wave velocity (aPWV), respectively. Both of these noninvasive measures of vascular dysfunction are independent predictors of future cardiovascular events in patients with and without kidney disease. Patients with CKD demonstrate both impaired FMDBA, and increased aPWV. While the exact mechanisms by which vascular dysfunction develops in CKD are incompletely understood, increased oxidative stress and a subsequent reduction in nitric oxide (NO) bioavailability are important contributors. Cellular changes in oxidative stress can be assessed by collecting vascular endothelial cells from the antecubital vein and measuring protein expression of markers of oxidative stress using immunofluorescence. We provide here a discussion of these methods to measure FMDBA, aPWV, and vascular endothelial cell protein expression.
PMCID: PMC4193838  PMID: 24962357
Medicine; Issue 88; chronic kidney disease; endothelial cells; flow-mediated dilation; immunofluorescence; oxidative stress; pulse-wave velocity
4.  Dietary Sodium and Potassium Intake is Not Associated with Elevated Blood Pressure in US Adults with No Prior History of Hypertension 
The relationship between dietary sodium and potassium intake with elevated blood pressure (BP) levels is unclear. We examined the association between dietary sodium and potassium intake and BP levels in 6985 adults 18 years of age or older with no prior history of hypertension who participated in the National Health and Nutrition Examination Survey (2001–2006). After adjustment for age, sex, race, body mass index, diabetes and eGFR, there was no association between higher quartiles of sodium or potassium intake with the risk of a BP >140/90 mmHg or >130/80 mmHg. There was also no relationship between dietary sodium and potassium intake with BP when systolic and diastolic BP were measured as continuous outcomes (p=0.68 and p=0.74, respectively). Furthermore, no association was found between combinations of sodium and potassium intake with elevated BP. In the US adult population without hypertension, increased dietary sodium or low potassium intake was not associated with elevated BP levels.
PMCID: PMC4061250  PMID: 24720647
Dietary; Sodium; Potassium; Blood Pressure; Hypertension
5.  Serum uric acid and insulin sensitivity in adolescents and adults with and without type 1 diabetes 
Decreased insulin sensitivity (IS) exists in type 1 diabetes. Serum uric acid (SUA), whose concentration is related to renal clearance, predicts vascular complications in type 1 diabetes. SUA is also inversely associated with IS in non-diabetics, but has not been examined in type 1 diabetes. We hypothesized SUA would be associated with reduced IS in adolescents and adults with type 1 diabetes.
The cross-sectional and longitudinal associations of SUA with IS was investigated in 254 adolescents with type 1 diabetes and 70 without in the Determinants of Macrovascular Disease in Adolescents with Type 1 Diabetes Study, and in 471 adults with type 1 diabetes and 571 without in the Coronary Artery Calcification in Type 1 diabetes (CACTI) study.
SUA was lower in subjects with type 1 diabetes (p<0.0001), but still remained inversely associated with IS after multivariable adjustments- in adolescents (β±SE: −1.99±0.62, p=0.001, R2=2%) and adults (β±SE:−0.91±0.33, p=0.006, R2=6%) with type 1 diabetes, though less strongly than in non-diabetic controls (adolescents: β±SE: −2.70±1.19, p=0.03, R2=15%, adults: β±SE:−5.99±0.75, p<0.0001, R2=39%).
We demonstrated a significantly weaker relationship between SUA and reduced IS in subjects with type 1 diabetes than non-diabetic controls.
PMCID: PMC4004676  PMID: 24461546
insulin sensitivity; type 1 diabetes; serum uric acid; adolescents and adults
6.  Serum Uric Acid and Hypertension in Adults: a Paradoxical Relationship in Type 1 Diabetes 
Adults with type 1 diabetes have lower serum uric acid levels compared to non-diabetic adults. Little is known about the relationship between serum uric acid and blood pressure in type 1 diabetes and whether it differs from the positive relationship found in non-diabetic adults.
We assessed the cross-sectional and longitudinal relationships over 6-years between serum uric acid and blood pressure in adults with (35±9 years, n=393) and without (38±9 years n=685) T1D in the Coronary Artery Calcification in Type 1 Diabetes study.
In non-diabetic adults, serum uric acid was associated with systolic blood pressure in multivariable-models adjusted for cardiovascular risk-factors. In adults with type 1 diabetes, a negative association was observed between serum uric acid and systolic blood pressure after multivariable-adjustments.
A positive association was observed between serum uric acid and systolic blood pressure in non-diabetic adults. In contrast, an inverse relationship was demonstrated after multivariable-adjustments in type 1 diabetes.
PMCID: PMC3989383  PMID: 24667019
Uric acid; hypertension; type 1 diabetes
7.  Fibroblast Growth Factor 23, the Ankle-Brachial Index, and Incident Peripheral Artery Disease in the Cardiovascular Health Study 
Atherosclerosis  2014;233(1):91-96.
Fibroblast growth factor 23 (FGF23) has emerged as a novel risk factor for mortality and cardiovascular events. Its association with the ankle-brachial index (ABI) and clinical peripheral artery disease (PAD) is less known.
Using data (N=3,143) from the Cardiovascular Health Study (CHS), a cohort of community dwelling adults > 65 years of age, we analyzed the cross sectional association of FGF23 with ABI and its association with incident clinical PAD events during 9.8 years of follow up using multinomial logistic regression and Cox proportional hazards models respectively.
The prevalence of cardiovascular disease (CVD) and traditional risk factors like diabetes, coronary artery disease, and heart failure increased across higher quartiles of FGF23. Compared to those with ABI of 1.1–1.4, FGF23 at baseline was associated with prevalent PAD (ABI<0.9) although this association was attenuated after adjusting for CVD risk factors, and kidney function (OR 0.91, 95% CI 0.76–1.08). FGF23 was not associated with high ABI (>1.4) (OR 1.06, 95% CI 0.75–1.51). Higher FGF23 was associated with incidence of PAD events in unadjusted, demographic adjusted, and CVD risk factor adjusted models (HR 2.26, 95% CI 1.28–3.98; highest versus lowest quartile). The addition of estimated glomerular filtration and urine albumin to creatinine ratio to the model however, attenuated these findings (HR 1.46, 95% CI, 0.79–2.70).
In community dwelling older adults, FGF23 was not associated with baseline low or high ABI or incident PAD events after adjusting for confounding variables. These results suggest that FGF23 may primarily be associated with adverse cardiovascular outcomes through non atherosclerotic mechanisms.
PMCID: PMC3927151  PMID: 24529128
Fibroblast growth factor; peripheral artery disease; ankle-brachial index; chronic kidney disease; cardiovascular disease
8.  Drug-induced reduction in estimated glomerular filtration rate in patients with ALK-positive non-small cell lung cancer treated with the ALK-inhibitor crizotinib 
Cancer  2013;120(5):664-674.
Renal side effects of crizotinib have not been investigated previously.
Estimated Glomerular Filtration Rate (eGFR) was calculated using the CKD-EPI creatinine-based prediction equation during the first 12 weeks of crizotinib and post-crizotinib prior to the introduction of any further systemic therapy.
38 stage IV ALK+ NSCLC patients treated with crizotinib were identified. Mean eGFR fell 23.9% compared to baseline (p<0.0001, 95%CI: 21.3% - 26.6%), with most of the fall occurring within the first 2 weeks of therapy. Clinical history and BUN/creatinine ratios did not suggest prerenal causes. The objective response rate among evaluable patients (n=27) was 41%. Tumor shrinkage was not correlated with changes in eGFR (r = -0.052 (p=0.798)). Among 16 patients with post-crizotinib data, recovery to within 84% of baseline eGFR occurred in all patients. After adjusting for the number of scans with IV contrast and use of known nephrotoxic drugs, whether a patient was on or off crizotinib was significantly associated with changes in eGFR (p<0.0001).
Assessed by the CKI-EPI prediction equation, eGFR is reduced by crizotinib but most patients will recover their eGFR after cessation of therapy. The early onset, size of change, minimal cumulative effect and rapid reversibility raise the possibility that this may be a pharmacological and/or tubular creatinine secretion effect rather than a direct nephrotoxic effect. Increased vigilance with regard to the concomitant use of renally cleared medications or nephrotoxic agents should be considered for patients receiving crizotinib and, when eGFR is reduced, additional renal investigations undertaken.
PMCID: PMC3949169  PMID: 24258622
crizotinib; nonsmall cell lung cancer; anaplastic lymphoma kinase (ALK) gene rearrangements; renal function; kidney injury; glomerular filtration rate (GFR)
9.  Uric acid suppresses 1 alpha hydroxylase in vitro and in vivo 
Metabolism: clinical and experimental  2013;63(1):10.1016/j.metabol.2013.09.018.
Patients with gout have lower calcitriol levels that improve when uric acid is lowered. The mechanism of these observations is unknown. We hypothesized that uric acid inhibits 1- αhydroxylase.
Materials and methods
In vivo, Sprague Dawley rats were randomized to control (n=5), allantoxanamide (n=8), febuxostat (n=5), or allantoxanamide+febuxostat (n=7). Vitamin D, PTH, and 1-αhydroxylase protein were evaluated. In order to directly evaluate the effect of uric acid on 1-αhydroxylase, we conducted a series of dose response and time course experiments in vitro. Nuclear factor κ-B (NFκB) was inhibited pharmacologically. Finally, to evaluate the potential implications of these findings in humans, the association between uric acid and PTH in humans was evaluated in a cross-sectional analysis of data from the NHANES (2003-2006); n= 9773.
1,25(OH)2D and 1-αhydroxylase protein were reduced in hyperuricemic rats and improved with febuxostat treatment. Uric acid suppressed 1-αhydroxylase protein and mRNA expression in proximal tubular cells. This was prevented by NFκB inhibition. In humans, for every 1 mg/dL increase in uric acid, the adjusted odds ratio for an elevated PTH (>65 pg/mL) was 1.21 (95% C.I. 1.14, 1.28; P< 0.0001), 1.15 (95% C.I. 1.08, 1.22; P<0.0001), and 1.16 (95% C.I. 1.03, 1.31; P=0.02) for all subjects, subjects with estimated GFR ≥60, and subjects with estimated GFR <60 mL/min/1.73 m2 respectively.
Hyperuricemia suppresses 1-αhydroxylase leading to lower 1,25(OH)2D and higher PTH in rats. Our results suggest this is mediated by NFκB. The association between uric acid and PTH in NHANES suggests potential implications for human disease.
PMCID: PMC3859721  PMID: 24269076
uric acid; parathyroid hormone; mineral and bone disorders
10.  The association of prevalent kidney stone disease with mortality in U.S. adults: the National Health and Nutrition Examination Survey III, 1988–1994 
American journal of nephrology  2013;37(5):501-506.
Kidney stone disease is associated with hypertension, diabetes, metabolic syndrome, kidney function decline and increased cardiovascular (CV) events. However, its association with all-cause and CV mortality is unclear.
We used The Third National Health and Nutrition Examination Survey, a large US population-based study with mortality data through 2006 determined via linkage to the National Death Index to examine kidney stone disease in relation to all-cause and CV mortality risks.
Among 14,879 men and women over 18 years of age who were eligible for analysis, 683 participants reported a history of kidney stones. There was a total of 3,590 all-cause and 1,608 CV deaths occurred during a median follow up of 14.9 years. Stone formers had a significantly higher risk for all-cause mortality (HR 1.95, 95% CI 1.64–2.33, p<0.0001), and CV mortality (HR 2.05, 95% CI 1.60–2.62, p<0.0001) in unadjusted analyses. However, after multivariate adjustment for age, gender, race and poverty, stone formers no longer had increased risk for all-cause mortality (HR 1.08, 95% CI 0.93–1.26, p=0.3) and CV mortality (HR 1.07, 95% CI 0.84–1.36, p=0.6). Results remain unchanged after further adjustment for other clinical variables including history of hypertension, diabetes, and CV disease.
The increased risk of all-cause and CV mortality in kidney stone formers is likely a reflection of unique demographics and associated co-morbidities. There is no independent association of prevalent kidney stone disease with all-cause and CV mortality.
PMCID: PMC4278430  PMID: 23635714
Mortality; Cardiovascular disease; Kidney stone disease
11.  Higher Fibroblast Growth Factor-23 Concentrations Associate with Left Ventricular Systolic Dysfunction in Dialysis Patients 
Clinical nephrology  2013;80(5):313-321.
The concentration of fibroblast growth factor 23 (FGF-23) is elevated in patients on dialysis. FGF receptors have been implicated in the pathogenesis of left ventricular (LV) hypertrophy. The objective of this study was to examine the associations between high plasma FGF-23 concentration and LV systolic dysfunction.
We tested the hypothesis that high plasma FGF-23 concentration is associated with LV dysfunction in 110 chronic dialysis patients from The Homocysteine Study who had paired echocardiograms performed for clinical indications. C-terminal FGF-23 concentrations were measured in stored plasma samples. Multivariate regression analyses were performed to evaluate the association of FGF-23 concentration with LV dysfunction.
Participants had a mean age of 60 ± 11 years. Median FGF-23 level and mean ejection fraction (EF) at baseline were 4632 (1384–14997) RU/mL and 50 ± 13% respectively. Median follow-up time was 1.9 years. Higher FGF-23 concentration was directly associated with decreases in EF during follow-up. After adjustment for demographics, baseline EF, hypertension, diabetes, cardiovascular disease, body mass index, systolic blood pressure, hemoglobin and markers of mineral metabolism, participants with FGF-23 in the highest tertile had an 8% decrease in EF compared to participants in the lowest tertile (β −8.0, 95% CI −15.5 to −0.53; p=0.04). When FGF-23 was evaluated as a continuous variable, for every log10 increase in FGF-23, EF during follow-up decreased by 6.5% (β −6.5, 95% CI −11.3 to −1.73; p=0.01)
In conclusion, higher FGF-23 concentration is independently associated with LV systolic dysfunction in chronic dialysis patients.
PMCID: PMC4018462  PMID: 23849306
FGF-23; Dialysis patients; LV dysfunction
12.  Early Diabetic Nephropathy 
Diabetes Care  2013;36(11):3678-3683.
Diabetic nephropathy (DN) is a major cause of mortality in type 1 diabetes. Reduced insulin sensitivity is a well-documented component of type 1 diabetes. We hypothesized that baseline insulin sensitivity would predict development of DN over 6 years.
We assessed the relationship between insulin sensitivity at baseline and development of early phenotypes of DN—microalbuminuria (albumin-creatinine ratio [ACR] ≥30 mg/g) and rapid renal function decline (glomerular filtration rate [GFR] loss >3 mL/min/1.73 m2 per year)—with three Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations over 6 years. Subjects with diabetes (n = 449) and without diabetes (n = 565) in the Coronary Artery Calcification in Type 1 Diabetes study had an estimated insulin sensitivity index (ISI) at baseline and 6-year follow-up.
The ISI was lower in subjects with diabetes than in those without diabetes (P < 0.0001). A higher ISI at baseline predicted a lower odds of developing an ACR ≥30 mg/g (odds ratio 0.65 [95% CI 0.49–0.85], P = 0.003) univariately and after adjusting for HbA1c (0.69 [0.51–0.93], P = 0.01). A higher ISI at baseline conferred protection from a rapid decline of GFR as assessed by CKD-EPI cystatin C (0.77 [0.64–0.92], P = 0.004) and remained significant after adjusting for HbA1c and age (0.80 [0.67–0.97], P = 0.02). We found no relation between ISI and rapid GFR decline estimated by CKD-EPI creatinine (P = 0.38) or CKD-EPI combined cystatin C and creatinine (P = 0.50).
Over 6 years, a higher ISI independently predicts a lower odds of developing microalbuminuria and rapid GFR decline as estimated with cystatin C, suggesting a relationship between insulin sensitivity and early phenotypes of DN.
PMCID: PMC3816872  PMID: 24026551
13.  Fibroblast Growth Factor 23, Left Ventricular Mass, and Left Ventricular Hypertrophy in Community-Dwelling Older Adults 
Atherosclerosis  2013;231(1):10.1016/j.atherosclerosis.2013.09.002.
In chronic kidney disease (CKD), high FGF23 concentrations are associated with left ventricular hypertrophy (LVH), cardiovascular events, and death. The associations of FGF23 with left ventricular mass (LVM) and LVH in the general population and the influence of CKD remains uncertain.
C-terminal plasma FGF23 concentrations were measured, and LVM and LVH evaluated by echocardiogram among 2255 individuals ≥65 years in the Cardiovascular Health Study. Linear regression analysis adjusting for demographics, cardiovascular, and kidney related risk factors examined the associations of FGF23 concentrations with LVM. Analyses were stratified by CKD status and adjusted linear and logistic regression analysis explored the associations of FGF23 with LVM and LVH.
Among the entire cohort, higher FGF23 concentrations were associated with greater LVM in adjusted analyses (β=6.71 [95% CI 4.35–9.01] g per doubling of FGF23). 32% (n=624) had CKD (eGFR <60 mL/min/1.73m2 and/or urine albumin-to-creatinine ratio >30 mg/g). Associations were stronger among participants with CKD (p interaction = 0.006): LVM β=9.71 [95% CI 5.86–13.56] g per doubling of FGF23 compared to those without CKD (β=3.44 [95% CI 0.77, 6.11] g per doubling of FGF23). While there was no significant interaction between FGF23 and CKD for LVH (p interaction = 0.25), the OR (1.46 95% CI [1.20–1.77]) in the CKD group was statistically significant and of larger magnitude than the OR for in the no CKD group (1.12 [95% CI 0.97–1.48]).
In a large cohort of older community-dwelling adults, higher FGF23 concentrations were associated with greater LVM and LVH with stronger relationships in participants with CKD.
PMCID: PMC3840534  PMID: 24125420
Left ventricular mass; left ventricular hypertrophy; chronic kidney disease; fibroblast growth factor 23; older adults; cardiovascular disease
14.  Vascular Calcification in End-Stage Renal Disease 
Vascular calcification is highly prevalent in end-stage renal disease (ESRD) and independently predictive of future cardiovascular events and mortality. Calcification can occur in both the intimal and medial layers of vasculature, but medial calcification is the major form in ESRD. Medial calcification increases large elastic artery stiffness and pulse-pressure, promotes left ventricular hypertrophy, reduces perfusion of the coronary arteries, and ultimately promotes increased cardiovascular mortality via increased risk of myocardial infarction and heart failure. It results not from a passive deposition of calcium and phosphate due to increased circulating levels, but rather is an active cell-mediated process involving vascular smooth muscle cells (VSMC) apoptosis and vesicle release, a shift in the balance of inhibitors and promoters of vascular calcification, and VSMC differentiation from a contractile to osteochondrogenic phenotype. This phenotypic shift requires phosphate, as well as the uptake of phosphate by the sodium-dependent phosphate cotransporter PiT-1, which is up-regulated by pro-inflammatory cytokines and the uremic milieu. Further research is needed to determine if targeting these processes can ultimately reduce vascular calcification in this high cardiovascular risk population.
PMCID: PMC3813300  PMID: 24134325
calcium; end-stage renal disease; phosphate; vascular calcification
15.  Impaired Renal Function Further Increases Odds of 6-Year Coronary Artery Calcification Progression in Adults With Type 1 Diabetes 
Diabetes Care  2013;36(9):2607-2614.
To determine whether baseline estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR) independently predict coronary artery calcification (CAC) progression, and to determine how eGFR changes over 6 years in adults with type 1 diabetes compared with nondiabetic adults.
The Coronary Artery Calcification in Type 1 Diabetes study participants (n = 1,066) with complete data for eGFR assessment at baseline and 6 years were included. Three Chronic Kidney Disease Epidemiology Collaboration equations (serum creatinine, cystatin C, and both) were used to estimate eGFR. The association of baseline ACR and eGFR with CAC progression was analyzed using multiple logistic regression.
Increasing categorical baseline ACR (<10, 10–30, and >30 µg/mg) predicted CAC progression in participants with type 1 diabetes (odds ratio [OR], 2.15; 95% CI, 1.50–3.09; 7.19 [3.90–13.26]; and 18.09 [8.48–38.62]), respectively, compared with nondiabetic subjects. Baseline eGFR <60 mL/min/1.73 m2 also predicted CAC progression (OR, 5–7, compared with nondiabetic participants). ORs for CAC progression were higher in women than in men when using the cystatin C–based Chronic Kidney Disease Epidemiology Collaboration equations. Participants with type 1 diabetes had greater eGFR decreases over 6 years than nondiabetic participants using cystatin C–based equations.
Although increasing ACR or decreasing eGFR predicts CAC progression, coronary atherosclerosis progresses faster in people with type 1 diabetes even in the absence of diabetic kidney disease. These findings emphasize the interaction between kidney disease and cardiovascular disease in type 1 diabetes and highlight the public health importance of lowering cardiorenal risk in people with type 1 diabetes.
PMCID: PMC3747879  PMID: 23835686
16.  Blood Pressure Components and Decline in Kidney Function in Community-Living Older Adults: The Cardiovascular Health Study 
American Journal of Hypertension  2013;26(8):1037-1044.
Although hypertension contributes to kidney dysfunction in the general population, the contributions of elevated systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) to kidney function decline in community-dwelling older adults are unknown.
We used linear and logistic regression to examine the separate and combined associations of SBP, DBP, and PP at baseline with kidney function decline among 4,365 older adults in the Cardiovascular Health Study. We used cystatin C to estimate glomerular filtration rate on 3 occasions over 7 years of follow-up. We defined rapid decline ≥ 3ml/min/year.
Average age was 72.2 and mean (standard deviation) SBP, DBP, and PP were 135 (21), 71 (11), and 65 (18) mm Hg, respectively. SBP and PP, rather than DBP, were most significantly associated with kidney function decline. In adjusted linear models, each 10-mm Hg increment in SBP and PP was associated with 0.13ml/min/year (–0.19, –0.08, P < 0.001) and 0.15-ml/min/year faster decline (–0.21, –0.09, P < 0.001), respectively. Each 10-mm Hg increment in DBP was associated with a nonsignificant 0.10-ml/min/year faster decline (95% confidence interval, –0.20, 0.01). In adjusted logistic models, SBP had the strongest associations with rapid decline, with 14% increased hazard of rapid decline (95% confidence interval, 10% to 17%, P < 0.01) per 10mm Hg. In models combining BP components, only SBP consistently had independent associations with rapid decline.
Our findings suggest that elevated BP, particularly SBP, contributes to declining kidney function in older adults.
PMCID: PMC3816322  PMID: 23709568
blood pressure; cystatin C; diastolic blood pressure; elderly; hypertension; kidney function; systolic blood pressure.
17.  Recent advances in the management of hemodialysis patients: a focus on cardiovascular disease 
F1000Prime Reports  2014;6:72.
The number of patients requiring chronic hemodialysis is rapidly growing worldwide. Hemodialysis both greatly reduces quality of life and is associated with extremely high mortality rates. Management of care of patients requiring chronic hemodialysis is complex, and randomized controlled trials aimed at reducing primary outcomes of cardiovascular disease events, mortality, or both in this population have largely been unsuccessful. Topics of major concern in the management of maintenance hemodialysis patients as related to these outcomes include the overall cardiovascular disease burden, blood pressure control, anemia, abnormalities in mineral metabolism, and inflammation. The focus of this review is a discussion of these topics on the basis of current recommendations from major organizations, expert opinion, and the available randomized controlled trials to date. These issues are further complicated by sometimes conflicting observational and randomized controlled trial data. Overall, treatment options for reducing these endpoints in maintenance hemodialysis patients are limited, and future randomized controlled trials are essential to continuing to advance care in this population, with the goal of ultimately improving hard outcomes. Such trials should consider new therapies to better target these factors, additional risk factors that have not been well tested to date, and therapies with new targets, including inflammation.
PMCID: PMC4126528  PMID: 25165571
18.  Endoplasmic Reticulum Stress Effector CCAAT/Enhancer‐binding Protein Homologous Protein (CHOP) Regulates Chronic Kidney Disease–Induced Vascular Calcification 
Cardiovascular diseases such as atherosclerosis and vascular calcification are a major cause of death in patients with chronic kidney disease (CKD). Recently, the long‐awaited results of the Study of Heart and Renal Protection trial were reported. This large randomized clinical trial found that an extensive cholesterol‐lowering therapy through the combination of simvastatin and ezetimibe significantly reduced cardiovascular diseases in a wide range of patients with CKD. However, the mechanism by which this cholesterol‐lowering therapy reduces CKD‐dependent vascular diseases remains elusive. The objective of the present study was to determine the contribution of the oxysterol‐induced pro‐apoptotic transcription factor CCAAT/enhancer‐binding protein homologous protein (CHOP) on the pathogenesis of CKD‐dependent cardiovascular diseases through endoplasmic reticulum stress signaling.
Methods and Results
CKD increased levels of serum oxysterols such as 7‐ketocholesterol in human patients and ApoE−/− mice. Treatment with simvastatin plus ezetimibe strongly reduced levels of serum oxysterols and attenuated CKD‐dependent atherosclerosis, vascular cell death, vascular calcification, and cardiac dysfunction. This therapy also reduced aortic endoplasmic reticulum stress induced by CKD. The short hairpin RNA‐mediated knockdown of CHOP and activating transcription factor‐4 in vascular smooth muscle cells attenuated oxysterol‐induced mineralization, osteogenic differentiation, and endoplasmic reticulum stress. In addition, CHOP deficiency protected ApoE−/− mice from CKD‐dependent vascular calcification, cardiac dysfunction, and vascular cell death.
These data reveal that the cholesterol‐lowering therapy of simvastatin plus ezetimibe attenuates CKD‐dependent vascular diseases through a reduction of oxysterol‐mediated endoplasmic reticulum stress. CHOP plays a crucial role in the pathogenesis of CKD‐dependent vascular calcification.
PMCID: PMC4309099  PMID: 24963104
CHOP; chronic kidney disease; endoplasmic reticulum stress; oxysterol; vascular calcification
19.  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
20.  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
21.  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
22.  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
23.  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
25.  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

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