Phylloquinone and Vitamin D Status: Associations with Incident Chronic Kidney Disease in the Framingham Offspring Cohort

Harvard University, Cambridge, Massachusetts, United States
American Journal of Nephrology (Impact Factor: 2.67). 06/2012; 36(1):68-77. DOI: 10.1159/000339005
Source: PubMed


Cardiovascular risk factors are associated with the development of chronic kidney disease (CKD), and CKD and vascular disease are etiologically linked. Evidence suggests deficiencies of vitamins D and K may adversely affect the cardiovascular system, but data from longitudinal studies are lacking. We hypothesized that deficiencies of vitamins D and K may be associated with incident CKD and/or incident albuminuria amongst members of the general population.
We analyzed 1,442 Framingham Heart Study participants (mean age 58 years; 50.5% women), free of CKD (eGFR <60 ml/min/1.73 m(2)), with a mean follow-up of 7.8 years in 2005-2008. Incident albuminuria was defined using sex-specific cut-offs of urine albumin-to-creatinine ratio (≥17 mg/g men and ≥25 mg/g women). Baseline log plasma phylloquinone (vitamin K(1)) and 25(OH)D levels, analyzed as continuous variables and by quartile, were related to risk of incident CKD (n = 108) and incident albuminuria (n = 106) using logistic regression models adjusted for standard risk factors.
Participants in the highest phylloquinone quartile (≥1.78 nmol/l) had an increased risk of CKD (multivariable-adjusted OR Q(4) vs. Q(1) 2.39; p = 0.006) and albuminuria at follow-up (multivariable-adjusted OR Q(4) vs. Q(1) 1.95; p = 0.05), whereas no association was observed with continuous phylloquinone levels for either endpoint. Deficiency of 25(OH)D was not associated with incident CKD or albuminuria in either analysis.
Contrary to our hypothesis, higher plasma phylloquinone levels are associated with an increased risk of incident CKD. Whether plasma phylloquinone is a marker for another unmeasured risk factor requires further study. External validation is necessary given the unexpected nature of these results.

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    ABSTRACT: Vitamin D is associated with cardiovascular disease and renal function but the mechanisms are as yet unexplained. Microalbuminuria is associated with a higher risk of kidney function loss, cardiovascular disease, and mortality. Parathyroid hormone is a predictor of cardiovascular mortality and negatively correlated with glomerular filtration rate. We investigated the association between vitamin D status and 5-year changes in urine albumin creatinine ratio (UACR) and parathyroid hormone (PTH). A random sample of 6,784 individuals aged 30-60 years from a general population participated in the Inter99 study in 1999-2001. Vitamin D (serum-25-hydroxyvitamin D) was measured at baseline by high-performance liquid chromatography. UACR and PTH were measured at baseline and follow-up. Increased UACR was defined as UACR >4.0 mg/g reflecting the upper quartile at baseline. We included 4,330 individuals who participated at 5-year follow-up. In multivariable linear regression analysis, a 10-nmol/l higher baseline level of vitamin D was associated with a 5-year decrease in UACR by 0.92 % (95 % confidence interval, CI 0.13, 1.71). In multivariable logistic regression analysis, the odds ratio of developing increased UACR during follow-up was 0.96 (95 % CI 0.92, 0.98) per 10 nmol/l higher baseline vitamin D level. We found a significant inverse cross-sectional (p < 0.0001) but no prospective association (p = 0.6) between baseline vitamin D status and parathyroid hormone. We found low vitamin D status to be a predictor of long-term development of increased UACR. It remains to be proven whether vitamin D deficiency is a causal and reversible factor in the development of albuminuria.
    No preview · Article · Feb 2013 · Endocrine
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    ABSTRACT: BACKGROUND: Low serum 25-hydroxyvitamin D (25[OH]D) levels have been associated with chronic kidney disease in cross-sectional studies. However, this association has not been studied prospectively in a large general population-based cohort. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 6,180 adults 25 years or older participating in the baseline and 5-year follow-up phases of the Australian Diabetes, Obesity and Lifestyle (AusDiab) Study. PREDICTOR: Serum 25(OH)D levels <15 ng/mL were considered deficient. OUTCOMES & MEASUREMENTS: Incident chronic kidney disease was defined as being negative at baseline but positive after 5 years for (1) reduced estimated glomerular filtration rate (eGFR; <60 mL/min/1.72 m(2)) or (2) albuminuria (spot urine albumin-creatinine ratio ≥2.5 mg/mmol [≥22.1 mg/g] for men and ≥3.5 mg/mmol [≥30.9 mg/g] for women). RESULTS: 623 (10.9%) participants were vitamin D deficient, 161 developed incident reduced eGFR, and 222 developed incident albuminuria. In participants with and without vitamin D deficiency, annual age-standardized incidences were 0.92% (95% CI, 0.56%-1.30%) and 0.59% (95% CI, 0.51%-0.68%), respectively, for eGFR <60 mL/min/1.72 m(2) and 1.50% (95% CI, 1.06%-1.95%) and 0.66% (95% CI, 0.56%-0.76%), respectively, for albuminuria. In multivariate regression models, vitamin D deficiency was associated significantly with the 5-year incidence of albuminuria (OR, 1.71; 95% CI, 1.12-2.61; P = 0.01), but not reduced eGFR (OR, 0.93; 95% CI, 0.53-1.66; P = 0.8). LIMITATIONS: The observational nature of the study does not account for unmeasured confounders. Only baseline 25(OH)D level was measured and therefore may not accurately reflect lifetime levels. Differences in baseline characteristics of participants who were included compared with those excluded due to missing data or follow-up may limit the applicability of results to the original AusDiab cohort. CONCLUSIONS: Our prospective cohort study shows that vitamin D deficiency is associated with a higher annual incidence of albuminuria and reduced eGFR and independently predicts the 5-year incidence of albuminuria. These associations warrant further exploration in long-term prospective clinical trials.
    Full-text · Article · Apr 2013 · American Journal of Kidney Diseases
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    ABSTRACT: Vitamin D is essential for bone mineralisation, but a growing body of evidence points at a broader role; vitamin D deficiency has been found to be associated with mortality and several diseases ranging from cardiovascular disease to autoimmune diseases and liver diseases. The evidence is, however, inconclusive and the possible pathways remain unresolved. The aims of the thesis were to investigate the association of vitamin D status to 5-year changes in cardiovascular risk factors such as blood pressure, lipid profile, the metabolic syndrome and urine albumin creatinine ratio (UACR); the association of a known genetic determinant of vitamin D status to cardiovascular risk factors; the association of vitamin D status to the incidence of cardiovascular disease (CVD) and all-cause mortality; and the association of vitamin D status to cause-specific mortality. Data from the 3 population-based studies Monica10 (n = 2,656, 1993-94), Inter99 (n = 6,794, 1999-2001) and Health2006 (n = 3,471, 2006-2008) conducted at the Research Centre for Prevention and Health were used. The studies included questionnaires, physical examinations, and blood tests. Vitamin D status was measured at baseline. Participants were genotyped for the most frequent filaggrin mutations. Registry-based diagnoses and causes of death were obtained from The Danish National Patient Register and the Danish Registry of Causes of Death, respectively. Linear, logistic, Cox and instrumental variable regressions were used to model the associations between vitamin D status and cardiovascular risk factors, disease and mortality. With a 10 year mean follow-up time, we found a significant association between vitamin D status and all-cause mortality with a HR=0.95 (p = 0.005) per 10 nmol/l higher vitamin D level. We found no association between vitamin D status and incidence of ischaemic heart disease or stroke (HR = 1.01, p = 0.442 and HR = 1.00, p = 0.920, respectively). We found a baseline level of vitamin D that was 10 nmol/l higher to be associated with a decrease in triglycerides and very low density lipoprotein cholesterol by 0.52% (p = 0.03) and 0.66% (p = 0.005), respectively. The odds ratios per 10 nmol/l higher baseline vitamin D level were 0.95 (p < 0.05) and 0.94 (p = 0.01) for the development of the metabolic syndrome and hypercholesterolaemia, respectively. There was no association between vitamin D and blood pressure. With filaggrin genotype as an instrumental variable, we found a 23.8% (95% confidence interval, CI: 3.0, 48.6) higher HDL cholesterol level and a 30.5% (95% CI: 0.8, 51.3) lower serum level of triglycerides per doubling of vitamin D. These associations were no longer statistically significant when applying the Bonferroni-adjusted significance level. The remaining lipids showed non-significant changes in a favourable direction. A doubling of vita-min D gave a non-significantly lower odds ratio = 0.26 (95% CI: 0.06, 1.17) of the metabolic syndrome. There were no statistically significant causal effects of vitamin D status on blood pressure or anthropometrics. With a total of 832 deaths and a 10.3 year median follow-up time, we found significant associations between vitamin D status and death caused by respiratory diseases, digestive diseases, and endocrine, nutritional and metabolic diseases with hazard ratios (HRs) 0.26 (ptrend = 0.0042), 0.28 (ptrend = 0.0040), and 0.21 (ptrend = 0.035), respectively, for the fourth vitamin D quartile compared to the first. We found non-significantly lower HRs for death caused by mental and behavioural diseases and diseases of the nervous system, but no association between vitamin D status and death caused by diseases of the circulatory system or neoplasms. We found a baseline level of vitamin D that was 10 nmol/l higher was associated with a small but statistically significant decrease in UACR by 0.92% (p = 0.02), but a non-significantly lower PTH. The odds ratio for an increased UACR were 0.96 (p = 0.0006) per 10 nmol/l higher baseline vitamin D level. Our studies support the idea that vitamin D can affect lipid status in a favourable direction as well as the incidence of metabolic syndrome and increased UACR but neither blood pressure nor anthropometrics. Vitamin D status was inversely associated with mortality, but this was not explained by an association with cardiovascular disease. Rather, the association seemed to be caused by an inverse association with death caused by digestive disease, endocrine, metabolic and nutritional diseases, and respiratory disease. Further studies, e.g. RCTs or Mendelian randomisation studies, are needed to clarify whether low vitamin D status is a causal and reversible factor to prevent disease and mortality.
    No preview · Article · Feb 2015 · Danish Medical Journal
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