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1.  Adult height and the risk of cause-specific death and vascular morbidity in 1 million people: individual participant meta-analysis 
Wormser, David | Angelantonio, Emanuele Di | Kaptoge, Stephen | Wood, Angela M | Gao, Pei | Sun, Qi | Walldius, Göran | Selmer, Randi | Verschuren, WM Monique | Bueno-de-Mesquita, H Bas | Engström, Gunnar | Ridker, Paul M | Njølstad, Inger | Iso, Hiroyasu | Holme, Ingar | Giampaoli, Simona | Tunstall-Pedoe, Hugh | Gaziano, J Michael | Brunner, Eric | Kee, Frank | Tosetto, Alberto | Meisinger, Christa | Brenner, Hermann | Ducimetiere, Pierre | Whincup, Peter H | Tipping, Robert W | Ford, Ian | Cremer, Peter | Hofman, Albert | Wilhelmsen, Lars | Clarke, Robert | de Boer, Ian H | Jukema, J Wouter | Ibañez, Alejandro Marín | Lawlor, Debbie A | D'Agostino, Ralph B | Rodriguez, Beatriz | Casiglia, Edoardo | Stehouwer, Coen DA | Simons, Leon A | Nietert, Paul J | Barrett-Connor, Elizabeth | Panagiotakos, Demosthenes B | Björkelund, Cecilia | Strandberg, Timo E | Wassertheil-Smoller, Sylvia | Blazer, Dan G | Meade, Tom W | Welin, Lennart | Svärdsudd, Kurt | Woodward, Mark | Nissinen, Aulikki | Kromhout, Daan | Jørgensen, Torben | Tilvis, Reijo S | Guralnik, Jack M | Rosengren, Annika | Taylor, James O | Kiechl, Stefan | Dagenais, Gilles R | Gerry, F | Fowkes, R | Wallace, Robert B | Khaw, Kay-Tee | Shaffer, Jonathan A | Visser, Marjolein | Kauhanen, Jussi | Salonen, Jukka T | Gallacher, John | Ben-Shlomo, Yoav | Kitamura, Akihiko | Sundström, Johan | Wennberg, Patrik | Kiyohara, Yutaka | Daimon, Makoto | de la Cámara, Agustin Gómez | Cooper, Jackie A | Onat, Altan | Devereux, Richard | Mukamal, Kenneth J | Dankner, Rachel | Knuiman, Matthew W | Crespo, Carlos J | Gansevoort, Ron T | Goldbourt, Uri | Nordestgaard, Børge G | Shaw, Jonathan E | Mussolino, Michael | Nakagawa, Hidaeki | Fletcher, Astrid | Kuller, Lewis H | Gillum, Richard F | Gudnason, Vilmundur | Assmann, Gerd | Wald, Nicholas | Jousilahti, Pekka R | Greenland, Philip | Trevisan, Maurizio | Ulmer, Hanno | Butterworth, Adam S | Folsom, Aaron R | Davey-Smith, George | Hu, Frank B | Danesh, John | Tipping, Robert W | Ford, Charles E | Simpson, Lara M | Walldius, Göran | Jungner, Ingmar | Folsom, Aaron R | Demerath, Ellen W | Franceschini, Nora | Lutsey, Pamela L | Panagiotakos, Demosthenes B | Pitsavos, Christos | Chrysohoou, Christina | Stefanadis, Christodoulos | Shaw, Jonathan E | Atkins, Robert | Zimmet, Paul Z | Barr, Elizabeth LM | Knuiman, Matthew W | Whincup, Peter H | Wannamethee, S Goya | Morris, Richard W | Willeit, Johann | Kiechl, Stefan | Weger, Siegfried | Oberhollenzer, Friedrich | Wald, Nicholas | Ebrahim, Shah | Lawlor, Debbie A | Gallacher, John | Ben-Shlomo, Yoav | Yarnell, John WG | Casiglia, Edoardo | Tikhonoff, Valérie | Greenland, Philip | Shay, Christina M | Garside, Daniel B | Nietert, Paul J | Sutherland, Susan E | Bachman, David L | Keil, Julian E | de Boer, Ian H | Kizer, Jorge R | Psaty, Bruce M | Mukamal, Kenneth J | Nordestgaard, Børge G | Tybjærg-Hansen, Anne | Jensen, Gorm B | Schnohr, Peter | Giampaoli, Simona | Palmieri, Luigi | Panico, Salvatore | Pilotto, Lorenza | Vanuzzo, Diego | de la Cámara, Agustin Gómez | Simons, Leon A | Simons, Judith | McCallum, John | Friedlander, Yechiel | Gerry, F | Fowkes, R | Price, Jackie F | Lee, Amanda J | Taylor, James O | Guralnik, Jack M | Phillips, Caroline L | Wallace, Robert B | Kohout, Frank J | Cornoni-Huntley, Joan C | Guralnik, Jack M | Blazer, Dan G | Guralnik, Jack M | Phillips, Caroline L | Phillips, Caroline L | Guralnik, Jack M | Khaw, Kay-Tee | Wareham, Nicholas J | Brenner, Hermann | Schöttker, Ben | Müller, Heiko | Rothenbacher, Dietrich | Wennberg, Patrik | Jansson, Jan-Håkan | Nissinen, Aulikki | Donfrancesco, Chiara | Giampaoli, Simona | Woodward, Mark | Vartiainen, Erkki | Jousilahti, Pekka R | Harald, Kennet | Salomaa, Veikko | D'Agostino, Ralph B | Vasan, Ramachandran S | Fox, Caroline S | Pencina, Michael J | Daimon, Makoto | Oizumi, Toshihide | Kayama, Takamasa | Kato, Takeo | Bladbjerg, Else-Marie | Jørgensen, Torben | Møller, Lars | Jespersen, Jørgen | Dankner, Rachel | Chetrit, Angela | Lubin, Flora | Svärdsudd, Kurt | Eriksson, Henry | Welin, Lennart | Lappas, Georgios | Rosengren, Annika | Lappas, Georgios | Welin, Lennart | Svärdsudd, Kurt | Eriksson, Henry | Lappas, Georgios | Bengtsson, Calle | Lissner, Lauren | Björkelund, Cecilia | Cremer, Peter | Nagel, Dorothea | Strandberg, Timo E | Salomaa, Veikko | Tilvis, Reijo S | Miettinen, Tatu A | Tilvis, Reijo S | Strandberg, Timo E | Kiyohara, Yutaka | Arima, Hisatomi | Doi, Yasufumi | Ninomiya, Toshiharu | Rodriguez, Beatriz | Dekker, Jacqueline M | Nijpels, Giel | Stehouwer, Coen DA | Hu, Frank B | Sun, Qi | Rimm, Eric B | Willett, Walter C | Iso, Hiroyasu | Kitamura, Akihiko | Yamagishi, Kazumasa | Noda, Hiroyuki | Goldbourt, Uri | Vartiainen, Erkki | Jousilahti, Pekka R | Harald, Kennet | Salomaa, Veikko | Kauhanen, Jussi | Salonen, Jukka T | Kurl, Sudhir | Tuomainen, Tomi-Pekka | Poppelaars, Jan L | Deeg, Dorly JH | Visser, Marjolein | Meade, Tom W | De Stavola, Bianca Lucia | Hedblad, Bo | Nilsson, Peter | Engström, Gunnar | Verschuren, WM Monique | Blokstra, Anneke | de Boer, Ian H | Shea, Steven J | Meisinger, Christa | Thorand, Barbara | Koenig, Wolfgang | Döring, Angela | Verschuren, WM Monique | Blokstra, Anneke | Bueno-de-Mesquita, H Bas | Wilhelmsen, Lars | Rosengren, Annika | Lappas, Georgios | Fletcher, Astrid | Nitsch, Dorothea | Kuller, Lewis H | Grandits, Greg | Tverdal, Aage | Selmer, Randi | Nystad, Wenche | Mussolino, Michael | Gillum, Richard F | Hu, Frank B | Sun, Qi | Manson, JoAnn E | Rimm, Eric B | Hankinson, Susan E | Meade, Tom W | De Stavola, Bianca Lucia | Cooper, Jackie A | Bauer, Kenneth A | Davidson, Karina W | Kirkland, Susan | Shaffer, Jonathan A | Shimbo, Daichi | Kitamura, Akihiko | Iso, Hiroyasu | Sato, Shinichi | Holme, Ingar | Selmer, Randi | Tverdal, Aage | Nystad, Wenche | Nakagawa, Hidaeki | Miura, Katsuyuki | Sakurai, Masaru | Ducimetiere, Pierre | Jouven, Xavier | Bakker, Stephan JL | Gansevoort, Ron T | van der Harst, Pim | Hillege, Hans L | Crespo, Carlos J | Garcia-Palmieri, Mario R | Kee, Frank | Amouyel, Philippe | Arveiler, Dominique | Ferrières, Jean | Schulte, Helmut | Assmann, Gerd | Jukema, J Wouter | de Craen, Anton JM | Sattar, Naveed | Stott, David J | Cantin, Bernard | Lamarche, Benoît | Després, Jean-Pierre | Dagenais, Gilles R | Barrett-Connor, Elizabeth | Bergstrom, Jaclyn | Bettencourt, Richele R | Buisson, Catherine | Gudnason, Vilmundur | Aspelund, Thor | Sigurdsson, Gunnar | Thorsson, Bolli | Trevisan, Maurizio | Hofman, Albert | Ikram, M Arfan | Tiemeier, Henning | Witteman, Jacqueline CM | Tunstall-Pedoe, Hugh | Tavendale, Roger | Lowe, Gordon DO | Woodward, Mark | Devereux, Richard | Yeh, Jeun-Liang | Ali, Tauqeer | Calhoun, Darren | Ben-Shlomo, Yoav | Davey-Smith, George | Onat, Altan | Can, Günay | Nakagawa, Hidaeki | Sakurai, Masaru | Nakamura, Koshi | Morikawa, Yuko | Njølstad, Inger | Mathiesen, Ellisiv B | Løchen, Maja-Lisa | Wilsgaard, Tom | Sundström, Johan | Ingelsson, Erik | Michaëlsson, Karl | Cederholm, Tommy | Gaziano, J Michael | Buring, Julie | Ridker, Paul M | Gaziano, J Michael | Ridker, Paul M | Ulmer, Hanno | Diem, Günter | Concin, Hans | Rodeghiero, Francesco | Tosetto, Alberto | Wassertheil-Smoller, Sylvia | Manson, JoAnn E | Marmot, Michael | Clarke, Robert | Fletcher, Astrid | Brunner, Eric | Shipley, Martin | Kivimaki, Mika | Ridker, Paul M | Buring, Julie | Ford, Ian | Robertson, Michele | Ibañez, Alejandro Marín | Feskens, Edith | Geleijnse, Johanna M | Kromhout, Daan | Walker, Matthew | Watson, Sarah | Alexander, Myriam | Butterworth, Adam S | Angelantonio, Emanuele Di | Franco, Oscar H | Gao, Pei | Gobin, Reeta | Haycock, Philip | Kaptoge, Stephen | Seshasai, Sreenivasa R Kondapally | Lewington, Sarah | Pennells, Lisa | Rapsomaniki, Eleni | Sarwar, Nadeem | Thompson, Alexander | Thompson, Simon G | Walker, Matthew | Watson, Sarah | White, Ian R | Wood, Angela M | Wormser, David | Zhao, Xiaohui | Danesh, John
Background The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.
Methods We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual–participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.
Results For people born between 1900 and 1960, mean adult height increased 0.5–1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96–0.99) for death from any cause, 0.94 (0.93–0.96) for death from vascular causes, 1.04 (1.03–1.06) for death from cancer and 0.92 (0.90–0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12–1.42) for risk of melanoma death to 0.84 (0.80–0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.
Conclusion Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
doi:10.1093/ije/dys086
PMCID: PMC3465767  PMID: 22825588
Height; cardiovascular disease; cancer; cause-specific mortality; epidemiological study; meta-analysis
2.  Estimated GFR and Circulating 24,25-Dihydroxyvitamin D3 Concentration: A Participant-Level Analysis of 5 Cohort Studies and Clinical Trials 
Background
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).
Predictor
eGFR.
Outcome
Circulating 24,25(OH)2D3 concentration.
Measurements
GFR was estimated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation. Vitamin D metabolites were measured by mass spectrometry.
Results
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.
Limitations
Lack of direct pharmacokinetic measurements of vitamin D catabolism.
Conclusions
Lower eGFR is strongly associated with reduced vitamin D catabolism as measured by circulating 24,25(OH)2D3 concentration.
doi:10.1053/j.ajkd.2014.02.015
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
3.  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.
Background
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.
Conclusions
Higher circulating FGF-23 concentration is associated with incident AF and may, in part, explain the link between chronic kidney disease and AF.
doi:10.1161/CIRCULATIONAHA.113.005499
PMCID: PMC4108550  PMID: 24920722
atrial fibrillation; fibroblast growth factor; mineral; chronic kidney disease
4.  25-hydroxyvitamin D and Parathyroid Hormone Levels do not Predict Changes in Carotid Arterial Stiffness: The Multi-Ethnic Study of Atherosclerosis 
Objective
To evaluate the impacts of vitamin D and parathyroid hormone (PTH) on longitudinal changes in arterial stiffness.
Approach and Results
Distensibility coefficient (DC) and Young’s elastic modulus (YEM) of the right common carotid artery were evaluated at baseline and after a mean (standard deviation) of 9.4 (0.5) years in 2,580 MESA participants. Cross-sectional and longitudinal associations were evaluated using multivariable linear regression and analysis of covariance. At baseline, participants were 60.1 (9.4) years old (54% female; 26% Black, 20% Hispanic, 14% Chinese). Mean annualized 25(OH)D was <20 ng/dL in 816 and PTH was >65 pg/dL in 285 participants. In cross-sectional analyses, low 25(OH)D (<20 ng/ml) was not associated with stiffer arteries after adjustment for cardiovascular disease (CVD) risk factors (p>0.4). PTH >65 pg/ml was associated with stiffer arteries after adjustment for CVD risk factors, other than systolic blood pressure (SBP) (DC: β=−2.4×10−4 mmHg−1, p=0.003; YEM: β=166 mmHg, p=0.01), but after adjustment for SBP, these associations no longer were statistically significant. Longitudinal arterial stiffening was associated with older age (p<0.0001), higher SBP (p<0.008), and use of antihypertensive medications (p<0.006), but not with 25(OH)D or PTH (p>0.1).
Conclusions
Carotid arterial stiffness is not associated with low 25(OH)D concentrations. Cross-sectional associations between arterial stiffness and high PTH were attenuated by SBP. After nearly a decade of follow-up, neither baseline PTH nor 25(OH)D concentrations were associated with progression of carotid arterial stiffness.
doi:10.1161/ATVBAHA.113.302605
PMCID: PMC4008121  PMID: 24700125
Arterial stiffness; Cardiovascular disease; Carotid arteries; Parathyroid hormone; Vitamin D; Young’s elastic modulus
5.  Fibroblast Growth Factor-23 and Cardiovascular Disease in the General Population: The Multi-Ethnic Study of Atherosclerosis 
Circulation. Heart failure  2014;7(3):409-417.
Background
Fibroblast growth factor-23 (FGF-23) is a phosphate regulatory hormone that directly stimulates left ventricular hypertrophy in experimental models. The role of FGF-23 in cardiovascular disease development in the general population is unclear. We tested associations of FGF-23 with major subclinical and clinical cardiovascular disease outcomes in a large prospective cohort.
Methods and Results
We evaluated 6,547 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who were initially free of cardiovascular disease. We measured serum FGF-23 using the Kainos immunoassay. The MESA measured left ventricular (LV) mass by magnetic resonance imaging, coronary calcium (CAC) by computed tomography, and carotid intima-medial thickness (IMT) by ultrasound. The MESA adjudicated incident heart failure, coronary heart disease, and stoke by medical record review. After adjustment, the highest FGF-23 quartile was associated with an estimated 2.4 gram greater LV mass (95% CI 0.4, 4.5 greater) and a 26% greater odds of higher CAC scores (95% CI 9% to 46% greater) compared to the lowest quartile. Over 7.5 years follow-up, each 20-pg/mL higher FGF-23 concentration was associated with a 19% greater risk of heart failure (95% CI 3% to 37% greater) and a 14% greater risk of coronary heart disease (95% CI 1% to 28% greater). FGF-23 was not associated with carotid IMT or stroke.
Conclusions
Higher serum FGF-23 concentrations are associated with subclinical cardiac disease and with new heart failure and coronary disease events, but not with carotid IMT or stroke. FGF-23 may be a novel cardiovascular risk factor in the general population.
doi:10.1161/CIRCHEARTFAILURE.113.000952
PMCID: PMC4031265  PMID: 24668259
Fibroblast growth factor-23; FGF-23; left ventricular mass; left ventricular hypertrophy; coronary artery calcium; carotid intima-media thickness; heart failure; coronary heart disease; stroke; cardiovascular disease
6.  Association of 25-hydroxyvitamin D and Parathyroid Hormone with Incident Hypertension: The Multi-Ethnic Study of Atherosclerosis 
Objectives
We investigated whether lower 25-hydroxyvitamin D and higher serum parathyroid hormone concentrations are associated with incident hypertension.
Background
Disturbances in vitamin D metabolism are plausibly related to hypertension.
Methods
The Multi-Ethnic Study of Atherosclerosis is a community-based prospective cohort with baseline measurements obtained between 2000 and 2002. We studied 3,002 men and women free of prevalent cardiovascular disease and hypertension, aged 45–84 years at baseline. Serum 25-hydroxyvitamin D and intact parathyroid hormone were measured from previously frozen baseline samples using liquid chromatography-mass spectroscopy and a 2-site immunoassay, respectively. We used a complementary log-log model with interval censoring to estimate hazard ratios and 95% confidence intervals for 25-hydroxyvitamin D and parathyroid hormone concentrations with incident hypertension through 2010.
Results
During a median follow-up of 9.0 years, 41% of the cohort (n=1,229) developed hypertension. Mean serum 25-hydroxyvitamin D was 26.3±11.2 ng/ml and mean parathyroid hormone was 41.2±17.3 pg/ml. Compared with 25-hydroxyvitamin D ≥30 ng/mL, 25-hydroxyvitamin D <20 ng/ml was associated with a greater hypertension risk 1.28 (1.09–1.50), although the association was attenuated and not statistically significant after adjusting for potential confounders 1.13 (0.96–1.33). Compared with parathyroid hormone <33 pg/ml, parathyroid hormone ≥65 pg/ml was associated with a significantly greater risk of hypertension 1.27 (1.01–1.59), after adjusting for potential confounders.
Conclusions
Lower 25(OH)D concentrations were not associated with a greater risk of incident hypertension. Higher serum PTH concentrations showed a significant, but statistically marginal, relationship to the development of hypertension. These findings will require further confirmation.
doi:10.1016/j.jacc.2014.01.012
PMCID: PMC3999436  PMID: 24480627
vitamin D; parathyroid hormone; incident hypertension; prospective study
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.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1016/j.atherosclerosis.2013.12.015
PMCID: PMC3927151  PMID: 24529128
Fibroblast growth factor; peripheral artery disease; ankle-brachial index; chronic kidney disease; cardiovascular disease
8.  Insulin resistance in CKD: a step closer to effective evaluation and treatment 
Kidney international  2014;86(2):243-245.
Accurate measurements are needed to target insulin resistance in CKD. Among older men with and without moderate CKD, Jia and colleagues compared insulin resistance estimated from glucose and insulin concentrations obtained while fasting or during an oral glucose tolerance test to insulin resistance measured by the gold standard hyperinsulinemic euglycemic clamp and tested associations of each with mortality. These findings move forward the study of insulin resistance in CKD and generate new questions for future work.
doi:10.1038/ki.2014.123
PMCID: PMC4119606  PMID: 25079023
9.  Kidney Disease and Related Findings in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study 
Diabetes Care  2013;37(1):24-30.
OBJECTIVE
Kidney disease manifests clinically as elevated albumin excretion rate (AER), impaired glomerular filtration rate (GFR), or both, and is a cause of substantial morbidity and mortality in type 1 diabetes (T1D). The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study tested whether intensive diabetes therapy (INT) aimed at lowering glucose concentrations as close as safely possible to the normal range reduces the risks of kidney disease and other diabetes complications.
RESEARCH DESIGN AND METHODS
In the DCCT, 1,441 participants with T1D were randomly assigned to INT or conventional diabetes therapy (CON) for a mean duration of 6.5 years. Subsequently, participants have been followed for 18 years in the ongoing observational EDIC. Standardized longitudinal measurements of AER, estimated GFR, and blood pressure were made throughout the DCCT/EDIC.
RESULTS
During the DCCT, INT reduced the risks of incident microalbuminuria (AER ≥40 mg/24 h) and macroalbuminuria (AER ≥300 mg/24 h) by 39% (95% CI 21–52%) and 54% (29–74%), respectively. During EDIC years 1–8, participants previously assigned to DCCT INT continued to experience lower rates of incident microalbuminuria and macroalbuminuria, with risk reductions of 59% (39–73%) and 84% (67–92%), respectively. Beneficial effects of INT on the development of impaired GFR (sustained estimated GFR <60 mL/min/1.73 m2) and hypertension became evident during combined DCCT/EDIC follow-up, with risk reductions of 50% (18–69%) and 20% (6–21%), respectively, compared with CON.
CONCLUSIONS
In the DCCT/EDIC, INT resulted in clinically important, durable reductions in the risks of microalbuminuria, macroalbuminuria, impaired GFR, and hypertension.
doi:10.2337/dc13-2113
PMCID: PMC3867994  PMID: 24356594
10.  Serum Parathyroid Hormone and 25‐Hydroxyvitamin D Concentrations and Risk of Incident Heart Failure: The Multi‐Ethnic Study of Atherosclerosis 
Background
Heart failure (HF) is common and is associated with high mortality. We aimed to determine associations of serum parathyroid hormone (PTH) and 25‐hydroxyvitamin D (25[OH]D) with incident HF and left ventricular mass.
Methods and Results
Among 6459 participants in the community‐based Multi‐Ethnic Study of Atherosclerosis, all of whom were free of prevalent clinical cardiovascular disease, we measured serum concentrations of PTH and 25(OH)D at the baseline examination. In longitudinal analyses, we tested associations of PTH and 25(OH)D with incident HF events, adjudicated by a panel of physicians. In cross‐sectional analyses of a subset of 4763 participants, we tested associations of PTH and 25(OH)D with left ventricular mass, measured by cardiac magnetic resonance imaging at baseline. Multivariable Cox proportional hazard and linear regression models were adjusted for demographics, physical examination measures, comorbidity, kidney function, and other mineral metabolism markers. Mean age was 62 years and 53% of participants were female. There were 180 incident HF events over a median (interquartile range) follow‐up time of 8.46 (7.67 to 8.63) years. Compared with participants with PTH <65 pg/mL, PTH ≥65 pg/mL was associated with a 50% greater risk of incident HF (95% CI: 3% to 210%) and a 5.3 g higher left ventricular mass (95% CI: 2.6, 7.9 g). In contrast, there was no association of 25(OH)D with risk of incident HF or elevated left ventricular mass.
Conclusions
In a racially/ethnically diverse population without prevalent cardiovascular disease, higher serum PTH concentration was associated with increased left ventricular mass and increased risk of incident HF. Further studies should be pursued to determine whether PTH excess may be a modifiable risk factor for HF.
doi:10.1161/JAHA.114.001278
PMCID: PMC4338718  PMID: 25468653
heart failure; hypertrophy; risk factors
11.  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.
Objectives
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.
Methods
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.
Results
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]).
Conclusion
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.
doi:10.1016/j.atherosclerosis.2013.09.002
PMCID: PMC3840534  PMID: 24125420
Left ventricular mass; left ventricular hypertrophy; chronic kidney disease; fibroblast growth factor 23; older adults; cardiovascular disease
12.  Null Association between Abdominal Muscle and Calcified Atherosclerosis in Community-Living Persons Without Clinical Cardiovascular Disease: the Multi-Ethnic Study of Atherosclerosis 
Metabolism: clinical and experimental  2013;62(11):10.1016/j.metabol.2013.06.001.
Objective
Detrimental effects of lean muscle loss have been hypothesized to explain J-shaped relationships of body mass index (BMI) with cardiovascular disease (CVD), yet associations of muscle mass with CVD are largely unknown. We hypothesized that low abdominal lean muscle area would be associated with greater calcified atherosclerosis, independent of other CVD risk factors.
Materials/Methods
We investigated 1020 participants from the Multi-Ethnic Study of Atherosclerosis who were free of clinical CVD. Computed tomography (CT) scans at the 4th and 5th lumbar disk space were used to estimate abdominal lean muscle area. Chest and abdominal CT scans were used to assess coronary artery calcification(CAC), thoracic aortic calcification (TAC), and abdominal aortic calcification (AAC).
Results
The mean age was 64±10 years, 48% were female, and mean BMI was 28±5 kg/m2. In models adjusted for demographics, physical activity, caloric intake, and traditional CVD risk factors, there was no inverse association of abdominal muscle mass with CAC(Prevalence Ratio [PR] 1.02 [95% CI 0.95,1.10]), TAC (PR 1.13 [95%CI 0.92, 1.39]) or AAC (PR 0.99 [95%CI 0.94, 1.04]) prevalence. Similarly, there was no significant inverse relationship between abdominal lean muscle area and CAC, TAC, and AAC severity.
Conclusion
In community-living individuals without clinical CVD, greater abdominal lean muscle area is not associated with less calcified atherosclerosis.
doi:10.1016/j.metabol.2013.06.001
PMCID: PMC3740763  PMID: 23916063
Cardiovascular Disease; atherosclerosis; lean muscle
13.  25-hydroxyvitamin D and parathyroid hormone are not associated with carotid intima-media thickness or plaque in the Multi-Ethnic Study of Atherosclerosis 
Objective
Observational evidence supports independent associations between 25-hydroxyvitamin D (25-OHD), parathyroid hormone (PTH) and cardiovascular risk. A plausible hypothesis for these associations is accelerated development of atherosclerosis.
Approach and Results
We evaluated cross-sectional and longitudinal associations of 25-OHD and PTH with carotid intima-media thickness (IMT) and carotid plaques among 3251 participants free of cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis. 25-OHD and PTH were measured at baseline by mass spectrometry and immunoassay, respectively. All subjects underwent a carotid ultrasound exam at baseline and 9.4 years later (median, range 8–11.1y). Multivariable linear and logistic regressions were used to test associations of 25-OHD and PTH with the extent and the progression of IMT and the prevalence and incidence of carotid plaque. Mean (SD) 25-OHD and PTH were 25.8ng/ml (10.6) and 44.2pg/ml (20.2). No independent associations were found between 25-OHD or PTH and IMT at baseline [increment of 1.9µm (95%CI −5.1 to 8.9) per 10ng/ml lower 25-OHD; increment of 0.8µm (95%CI −3.2 to 4.8) per 10pg/ml higher PTH] or progression of IMT [increment of 2.6µm (95%CI −2.5 to 7.8) per 10ng/ml lower 25-OHD, increment of 1.6µm (95%CI −1.9 to 5.2) per 10pg/ml higher PTH]. No associations were found with the baseline prevalence of carotid plaque or the incidence of new plaques over the study period. We did not observe any interaction by race or ethnicity (White, Chinese, Black and Hispanic).
Conclusions
The consistent lack of association of vitamin D and PTH with carotid IMT and plaque suggests that these hormones may influence cardiovascular risk through pathways not reflected by carotid atherosclerosis.
doi:10.1161/ATVBAHA.113.301781
PMCID: PMC3956469  PMID: 23814117
vitamin D; PTH; mineral metabolism; intima-media thickness; plaque; atherosclerosis; carotid
14.  Influence of Urine Creatinine Concentrations on the Relation of Albumin-Creatinine Ratio With Cardiovascular Disease Events: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Higher urine albumin-creatinine ratio (ACR) is associated with cardiovascular disease (CVD) events, an association that is stronger than that between spot urine albumin on its own and CVD. Urine creatinine is correlated with muscle mass, and low muscle mass is also associated with CVD. Whether low urine creatinine in the denominator of the ACR contributes to the association of ACR with CVD is uncertain.
Study Design
Prospective cohort study.
Setting & Participants
6,770 community-living individuals without CVD.
Predictors
Spot urine albumin, the reciprocal of the urine creatinine concentration (1/UCr), and ACR.
Outcome
Incident CVD events.
Results
During a mean of 7.1 years’ follow-up, 281 CVD events occurred. Geometric means for spot urine creatinine, urine albumin and ACR were 95 ± 2 (SD) mg/dl, 0.7 ± 3.7 mg/dl and 7.0 ± 3.1 mg/g. Adjusted HRs per 2-fold higher increment in each urinary measures with CVD events were similar (1/UCr: 1.07 [95% CI, 0.94-1.22]; urine albumin: 1.08 [95% CI, 1.01-1.14]; and ACR: 1.11 [95% CI, 1.04-1.18]). Urine creatinine was lower in older, female, and low weight individuals. ACR ≥10 mg/g was more strongly associated with CVD events in individuals with low weight (HR for lowest vs. highest tertile: 4.34 vs. 1.97; p for interaction=0.006). Low weight also modified the association of urine albumin with CVD (p for interaction=0.06), but 1/urine creatinine did not (p for interaction=0.9).
Limitations
We lacked 24-hour urine data.
Conclusions
While ACR is more strongly associated with CVD events among persons with low body weight, this association is not driven by differences in spot urine creatinine. Overall, the associations of ACR with CVD events appear to be driven primarily by urine albumin and less by urine creatinine.
doi:10.1053/j.ajkd.2013.05.010
PMCID: PMC3783582  PMID: 23830183
15.  Circulating 25-hydroxyvitamin D and insulin resistance in older adults: The Cardiovascular Health Study 
Metabolism: clinical and experimental  2013;62(12):1788-1794.
Background
Despite extensive study, the role of vitamin D in insulin resistance and secretion remains unclear.
Objective
To examine the cross-sectional and longitudinal relationships between 25-hydroxyvitamin D (25(OH)D) concentrations and indices of insulin resistance and secretion in older adults.
Methods and Results
Among 2134 participants of the Cardiovascular Health Study who were free from cardiovascular disease, we measured serum 25(OH)D concentrations in samples collected in 1992–1993. We examined insulin resistance and secretion using Homeostasis Model Assessment (HOMA) estimates cross-sectionally and among 1469 participants who had repeated HOMA measures four years later (1996–1997). In cross-sectional analysis, each 10 ng/mL increment in 25(OH)D concentration was associated with a 0.09 lower adjusted HOMA-IR [95%CI (−0.17, −0.02), p=0.01]. However, baseline 25(OH)D concentrations were not associated with change in HOMA-IR over 4 years of follow up (p=0.48). 25(OH)D concentrations were not associated with insulin secretion, as determined by HOMA-β, in either cross-sectional or longitudinal analysis.
Conclusions
Circulating 25(OH)D concentrations are associated with lower insulin resistance in cross-sectional but not longitudinal analyses. Whether this reflects residual confounding in cross-sectional analyses or the short-term nature of the relationship between vitamin D and insulin sensitivity will require trials with repeated measures of these factors.
doi:10.1016/j.metabol.2013.07.008
PMCID: PMC4159161  PMID: 23987236
Vitamin D; 25(OH)D; insulin resistance
16.  Association of Obesity and Kidney Function Decline among Non-Diabetic Adults with eGFR > 60 ml/min/1.73m2: Results from the Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Obesity is associated with higher end-stage renal disease incidence, but associations with earlier forms of kidney disease remain incompletely characterized.
Methods
We studied the association of body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) with rapid kidney function decline and incident chronic kidney disease in 4573 non-diabetic adults with eGFR ≥ 60 ml/min/1.73m2 at baseline from longitudinal Multi-Ethnic Study of Atherosclerosis cohort. Kidney function was estimated by creatinine and cystatin C. Multivariate analysis was adjusted for age, race, baseline eGFR, and hypertension.
Results
Mean age was 60 years old, BMI 28 kg/m2, baseline eGFRCr 82 and eGFRCys 95 ml/min/1.73m2. Over 5 years of follow up, 25% experienced rapid decline in renal function by eGFRCr and 22% by eGFRCys. Incident chronic kidney disease (CKD) developed in 3.3% by eGFRCys, 11% by eGFRCr, and 2.4% by both makers. Compared to persons with BMI < 25, overweight (BMI 25 – 30) persons had the lowest risk of rapid decline by eGFRCr (0.84, 0.71 – 0.99). In contrast, higher BMI categories were associated with stepwise higher odds of rapid decline by eGFRCys, but remained significant only when BMI ≥ 35 kg/m2 (1.87, 1.41 – 2.48). Associations of BMI with incident CKD were insignificant after adjustment. Large WC and WHR were associated with increased risk of rapid decline only by eGFRCys, and of incident CKD only when defined by both filtration markers.
Conclusions
Obesity may be a risk factor for kidney function decline, but associations vary by filtration marker used.
PMCID: PMC4157691  PMID: 25210651
Kidney Function Decline; MESA; Obesity; Waist Circumference; Waist-to-Hip Ratio
17.  Parathyroid hormone and arterial dysfunction in the Multi-Ethnic Study of Atherosclerosis 
Clinical endocrinology  2013;79(3):429-436.
Objective
High circulating concentrations of parathyroid hormone (PTH) have been associated with increased risks of hypertension, left ventricular hypertrophy, congestive heart failure, and cardiovascular mortality. Impaired arterial function is a potential mechanism for these associations. We tested whether serum PTH concentration is associated with measures of arterial function.
Design
Cross-sectional study.
Participants
6,545 persons without clinical cardiovascular disease participating in the community-based Multi-Ethnic Study of Atherosclerosis.
Measurements
Brachial artery flow-mediated dilation as well as aortic pulse pressure and arterial pulse parameters derived from Windkessel modeling of the radial pressure waveform.
Results
Higher serum PTH concentration was associated with lower brachial artery flow-mediated dilation (mean difference −0.09% per 10 pg/mL PTH), higher aortic pulse pressure (0.53 mmHg per 10 pg/mL), and reduced Windkessel capacitive index C1 (large artery elasticity, −0.12 ml/mmHg X 10 per 10 pg/mL), adjusting for potential confounding variables (all p-values ≤ 0.001). These relationships were independent of serum calcium concentration, serum 25-hydroxyvitamin D concentration, and estimated glomerular filtration rate and were consistent across relevant participant subgroups. Associations of PTH with aortic pulse pressure and capacitive index C1 were attenuated after adjustment for blood pressure. Serum PTH concentration was not associated with the oscillatory index C2 (small artery elasticity).
Conclusions
Higher serum PTH concentration was associated with impaired endothelial function, increased aortic pulse pressure, and decreased capacitive index C1 in a large, diverse, community-based population. These relationships may help explain previously observed associations of elevated PTH with cardiovascular disease.
doi:10.1111/cen.12163
PMCID: PMC3664253  PMID: 23402353
parathyroid hormone; calcium; vitamin D; arterial function; epidemiology
18.  Vitamin D Bioavailability and Catabolism in Pediatric Chronic Kidney Disease 
Background
Vitamin D-binding protein (DBP) and catabolism have not been examined in childhood chronic kidney disease (CKD).
Methods
Serum vitamin D [25(OH)D, 1,25(OH)2D, 24,25(OH)2D], DBP, intact parathyroid hormone (iPTH), and fibroblast growth factor-23 (FGF23) concentrations were measured in 148 participants with CKD stages 2–5D secondary to congenital anomalies of the kidney/urinary tract (CAKUT), glomerulonephritis (GN), or focal segmental glomerulosclerosis (FSGS). Free and bioavailable 25(OH)D were calculated using total 25(OH)D, albumin and DBP.
Results
All vitamin D metabolites were lower with more advanced CKD (p<0.001) and glomerular diagnoses (p≤0.002). Among non-dialysis participants, DBP was lower in FSGS vs. other diagnoses (FSGS-dialysis interaction p=0.02). Winter season, older age, FSGS and GN, and higher FGF23 were independently associated with lower free and bioavailable 25(OH)D. Black race was associated with lower total 25(OH)D and DBP, but not free or bioavailable 25(OH)D. 24,25(OH)2D was the vitamin D metabolite most strongly associated with iPTH. Lower 25(OH)D, black race, greater CKD severity, and higher iPTH were independently associated with lower 24,25(OH)2D, while higher FGF23 and GN were associated with greater 24,25(OH)2D.
Conclusions
Children with CKD exhibit altered catabolism and concentrations of DBP and free and bioavailable 25(OH)D, and there is an important impact of their underlying disease.
doi:10.1007/s00467-013-2493-9
PMCID: PMC4053210  PMID: 23728936
Vitamin D catabolism; vitamin D-binding protein; glomerular disease; chronic kidney disease; pediatric
19.  Racial Differences in the Association of Serum 25-Hydroxyvitamin D Concentration With Coronary Heart Disease Events 
IMPORTANCE
Low circulating concentrations of 25-hydroxyvitamin D (25[OH]D) have been consistently associated with an increased risk of coronary heart disease (CHD) in white populations. This association has not been rigorously evaluated in other races or ethnicities, in which the distributions of 25(OH)D concentration and possibly other aspects of 25(OH)D metabolism differ.
OBJECTIVE
To examine the association of serum 25(OH)D concentration with risk of CHD in a multiethnic population.
DESIGN, SETTING, AND PARTICIPANTS
We studied 6436 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), recruited from July 2000 through September 2002, who were free of known cardiovascular disease at baseline. We measured baseline serum 25(OH)D concentrations using a mass spectrometry assay calibrated to established standards. We tested associations of 25(OH)D with adjudicated CHD events assessed through May 2012.
MAIN OUTCOME AND MEASURES
Primary outcome measure was time to first adjudicated CHD event, defined as myocardial infarction, angina, cardiac arrest, or CHD death.
RESULTS
During a median follow-up of 8.5 years, 361 participants had an incident CHD event (7.38 events per 1000 person-years). Associations of 25(OH)D with CHD differed by race/ethnicity (P for interaction < .05). After adjustment, lower 25(OH)D concentration was associated with a greater risk of incident CHD among participants who were white (n = 167 events; hazard ratio [HR], 1.26 [95%CI, 1.06–1.49] for each 10-ng/mL decrement in 25(OH)D) or Chinese (HR, 1.67 [95%CI, 1.07–2.61]; n = 27). In contrast, 25(OH)D was not associated with risk of CHD in participants who were black (HR, 0.93 [95%CI, 0.73–1.20]; n = 94) or Hispanic (HR, 1.01 [95%CI, 0.77–1.33]; n = 73).
CONCLUSIONS AND RELEVANCE
Lower serum 25(OH)D concentration was associated with an increased risk of incident CHD events among participants who were white or Chinese but not black or Hispanic. Results evaluating 25(OH)D in ethnically homogeneous populations may not be broadly generalizable to other racial or ethnic groups.
doi:10.1001/jama.2013.7228
PMCID: PMC4150653  PMID: 23839752
20.  Circulating Vitamin D Metabolites and Subclinical Atherosclerosis in Type 1 Diabetes 
Diabetes Care  2013;36(8):2423-2429.
OBJECTIVE
People with type 1 diabetes are at high risk of premature atherosclerosis. Existing evidence suggests that impaired vitamin D metabolism may contribute to the development of atherosclerosis. We tested associations of circulating vitamin D metabolite concentrations with subclinical atherosclerosis among 1,193 participants with type 1 diabetes in the DCCT/EDIC study.
RESEARCH DESIGN AND METHODS
We measured plasma concentrations of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D, and 24,25-dihydroxyvitamin D by mass spectrometry at the end of the DCCT. In a staggered cross-sectional design, we tested associations with coronary artery calcium (CAC), measured by computed tomography a median of 10 years later, and with common and internal carotid intima-media thickness (IMT), measured by B-mode ultrasonography on two occasions a median of 4 years later and a median of 10 years later. We hypothesized that lower concentrations of each vitamin D metabolite would be associated with increased risk of CAC and greater carotid IMT.
RESULTS
At the time metabolites were measured, mean age was 32.4 years and mean duration of diabetes was 7.5 years. The prevalence and severity of CAC tended to be lower—not higher—with lower concentrations of each vitamin D metabolite. For instance, in a fully adjusted multinomial logistic model, a 25 nmol/L lower 25-hydroxyvitamin D was associated with a 0.8-fold decrease in the odds of having higher CAC (95% CI 0.68–0.96, P = 0.01). No vitamin D metabolite was associated with either common or internal mean IMT.
CONCLUSIONS
We did not find evidence linking impaired vitamin D metabolism with increased subclinical atherosclerosis in type 1 diabetes.
doi:10.2337/dc12-2020
PMCID: PMC3714470  PMID: 23530012
21.  Invited Commentary: Quantifying Salt in Urine—A Complex Solution 
American Journal of Epidemiology  2013;177(11):1193-1195.
Reduction of dietary sodium intake has been identified as a priority to reduce the worldwide burden of hypertension and cardiovascular disease. Dietary sodium intake is most precisely ascertained by using timed urine collection. Casual urine sodium measurements are relatively easy to perform, but their relationship to timed urine sodium measurements is unclear. In this issue of the Journal, Brown et al. (Am J Epidemiol. 2013;177(11):1180–1192) report the development and validation of equations to estimate 24-hour urine sodium excretion from casual urine samples. Their study included a large number of participants on 2 continents, a well-collected gold standard, separate discovery and validation samples, and relevant covariates. The resulting equations represent the best available methods to estimate dietary sodium intake from casual urine samples. However, the study is limited by evidence of a suboptimal model fit, restriction to people 20–59 years of age in North America and Europe, and exclusion and adjustment that further limit external validity. In addition, individual-level correlations of estimated and measured 24-hour urine sodium excretion were modest. Properly applied, the results will facilitate tracking of dietary sodium intake within populations over time and identification of communities for which dietary sodium restriction is most likely to be beneficial. Further work is needed to extend estimation to additional populations and improve individual-level assessment.
doi:10.1093/aje/kwt064
PMCID: PMC3664340  PMID: 23673248
cardiovascular disease; diagnostic test; dietary sodium; estimation techniques; hypertension; sodium; urinary sodium
22.  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.
Aims
To examine the effect of combined calcium and vitamin D3 supplementation on bone mineral density (BMD) in patients with chronic kidney disease (CKD).
Methods
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.
Results
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).
Conclusion
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
23.  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.
Background/Aims
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).
Methods
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).
Results
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).
Conclusions
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.
doi:10.1159/000351178
PMCID: PMC3919025  PMID: 23689685
Chronic Kidney Disease; Dietary sodium intake; Dietary potassium intake
24.  Urinary excretion of RAS, BMP, and WNT pathway components in diabetic kidney disease 
Physiological Reports  2014;2(5):e12010.
Abstract
The renin–angiotensin system (RAS), bone morphogenetic protein (BMP), and WNT pathways are involved in pathogenesis of diabetic kidney disease (DKD). This study characterized assays for urinary angiotensinogen (AGT), gremlin‐1, and matrix metalloproteinase 7 (MMP‐7), components of the RAS, BMP, and WNT pathways and examined their excretion in DKD. We measured urine AGT, gremlin‐1, and MMP‐7 in individuals with type 1 diabetes and prevalent DKD (n = 20) or longstanding (n = 61) or new‐onset (n = 10) type 1 diabetes without DKD. These urine proteins were also quantified in type 2 DKD (n = 11) before and after treatment with candesartan. The utilized immunoassays had comparable inter‐ and intra‐assay and intraindividual variation to assays used for urine albumin. Median (IQR) urine AGT concentrations were 226.0 (82.1, 550.3) and 13.0 (7.8, 20.0) μg/g creatinine in type 1 diabetes with and without DKD, respectively (P < 0.001). Median (IQR) urine gremlin‐1 concentrations were 48.6 (14.2, 254.1) and 3.6 (1.7, 5.5) μg/g, respectively (P < 0.001). Median (IQR) urine MMP‐7 concentrations were 6.0 (3.8, 10.5) and 1.0 (0.4, 2.9) μg/g creatinine, respectively (P < 0.001). Treatment with candesartan was associated with a reduction in median (IQR) urine AGT/creatinine from 23.5 (1.6, 105.1) to 2.0 (1.4, 13.7) μg/g, which did not reach statistical significance. Urine gremlin‐1 and MMP‐7 excretion did not decrease with candesartan. In conclusion, DKD is characterized by markedly elevated urine AGT, MMP‐7, and gremlin‐1. AGT decreased in response to RAS inhibition, suggesting that this marker reflects therapeutic response. Urinary components of the RAS, BMP, and WNT pathways may identify risk of DKD and aid development of novel therapeutics.
Urine angiotensinogen, matrix metalloproteinase‐7, and gremlin‐1 concentrations are markedly elevated in people with type 1 diabetes and kidney disease, compared with those with recently diagnosed type 1 diabetes or longstanding type 1 diabetes without kidney disease. Treatment with an inhibitor of the renin–angiotensin system tended to reduce urine angiotensinogen concentration, but not urine matrix metalloproteinase‐7 or gremlin‐1.
doi:10.14814/phy2.12010
PMCID: PMC4098738  PMID: 24793984
BMP pathway; diabetic kidney disease; pathophysiology; renin–angiotensin system; WNT pathway
25.  Impaired Vitamin D Metabolism in CKD 
Seminars in nephrology  2013;33(2):158-168.
Vitamin D metabolism consists of both production and catabolism, which are enzymatically driven and highly regulated. Renal vitamin D metabolism requires filtration and tubular reabsorption of 25-hydroxyvitamin D and is regulated by parathyroid hormone, fibroblast growth factor-23, and 1,25-dihydroxyvitamin D. In CKD, renal production of1,25-dihydroxyvitamin D from 25-hydroxyvitamin D is reduced. In addition, pharmacokinetic studies and epidemiologic studies of 24,25-dihydroxyvitamin D, the most abundant product of 25-hydroxyvitamin D catabolism by CYP24A1, suggest that vitamin D catabolism is also reduced. New insights into the mechanisms and regulation of vitamin D metabolism may lead to novel approaches to assess and treat impaired vitamin D metabolism in CKD.
doi:10.1016/j.semnephrol.2012.12.016
PMCID: PMC3592201  PMID: 23465502

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