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Vitamin D CKD and ESRD

Vitamin D Deficiency is a Significant Health Risk

Vitamin D deficiency is widespread.The prevalence of vitamin D deficiency increases with age, darkness of skin color and progression of poor health.

The clinical review of vitamin D deficiency in CKD & ESRD patients has gained significant attention in the academic press.The most recent focus is upon the extra-renal expression of the 1"-hydroxylase enzyme.

The old concept was that nearly 100% of the conversion of 25(OH)D to calcitriol occurred in the kidney by the 1"-hydroxylase enzyme.   Today we understand that not only does the kidney express the 1"-hydroxylase enzyme, but it is also expressed by many different tissues throughout the body.  This expression, by extra-renal tissues, of the 1"-hydroxylase enzyme suggests that these tissues utilize circulating 25(OH)D in an autocrine/paracrine fashion.  

The following abstracts provide an overview of the association of various disease states and vitamin D deficiency.  It is important to note that 25(OH)D circulates in the serum at levels 1000 fold greater than the active hormone 1,25(OH)2D.  Most tissues of the body need the high circulating levels which suggests that hormonal vitamin D does not work backwards to address true vitamin D (25(OH)D) deficiency. 

Several of the following abstracts address the two most common misconceptions about the use of vitamin D, [25(OH)D] verses hormonal D and its analogues.  The first misconception is that using large doses of vitamin D (cholecalciferol or ergocalciferol) in ESRD patients will cause hypercalcemia.  This is not true.  We know calcitriol is the regulatory hormone for calcium/phosphorus balance and mineral metabolism. However, even in a population with normal kidney function, the conversion of 25(OH)D to 1,25D is highly regulated, partly by serum calcium and phosphorus. Therefore, if there is a tendency to increase calcium there is a negative feedback to decrease conversion in the kidney. In patients with kidney failure there is little conversion due to the underlying kidney disease. 

The second misconception is much more involved, but simply stated, to use hormonal D to treat a vitamin D deficiency is seriously flawed.  Again to simplify, the autocrine requirement for 25(OH)D can not and is not satisfied by providing the hormonal form of D at levels that do not cause serious hypercalcemia. It is possible that in addition to vitamin D replacement, ESRD patients may benefit from hormonal D replacement to help PTH.

In conclusion, the importance of adequate vitamin D levels is significant.  Vitamin D deficiency is widespread in the general public as well as CKD & ESRD.  It is not reasonable to think that one will achieve levels of 25(OH)D >30ng/mL simply by eating well as most foods have minimal vitamin D.  With most of the population experiencing minimal UV-B conversion of 7-dehydrocholesterol to cholecalciferol in the skin, it is no wonder vitamin D deficiency is so severe.  Nutritional supplementation is the appropriate solution.  Current recommendations for vitamin D supplementation range from 1000 IU to more than 5,000 IU per day, with the safe upper limit established at 10,000 IU per day.

Vitamin D in Health and Disease.
Clin J Am Soc Nephrol. 2008 Sep;3(5):1535-41.
Heaney RP
Creighton University, Omaha, NE 68131, USA.

Vitamin D functions in the body through both an endocrine mechanism (regulation of calcium absorption) and an autocrine mechanism (facilitation of gene expression). The former acts through circulating calcitriol, whereas the latter, which accounts for more than 80% of the metabolic utilization of the vitamin each day, produces, uses, and degrades calcitriol exclusively intracellularly. In patients with end-stage kidney disease, the endocrine mechanism is effectively disabled; however, the autocrine mechanism is able to function normally so long as the patient has adequate serum levels of 25(OH)D, on which its function is absolutely dependent. For this reason, calcitriol and its analogs do not constitute adequate replacement in managing vitamin D needs of such patients. Optimal serum 25(OH)D levels are greater than 32 ng/mL (80 nmol/L). The consequences of low 25(OH)D status include increased risk of various chronic diseases, ranging from hypertension to diabetes to cancer. The safest and most economical way to ensure adequate vitamin D status is to use oral dosing of native vitamin D. (Both daily and intermittent regimens work well.) Serum 25(OH)D can be expected to rise by about 1 ng/mL (2.5 nmol/L) for every 100 IU of additional vitamin D each day. Recent data indicate that cholecalciferol (vitamin D3) is substantially more potent than ergocalciferol (vitamin D2) and that the safe upper intake level for vitamin D3 is 10,000 IU/d.

Vitamin D Levels and Early Mortality Among Incident Hemodialysis Patients.
Kidney Int. 2007 Oct;72(8):1004-13.
Wolf M, Shah A, Gutierrez O, Ankers E, Monroy M, Tamez H, Steele D, Chang Y, Camargo CA Jr, Tonelli M, Thadhani R.
Renal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Vitamin D deficiency is associated with cardiovascular disease, the most common cause of mortality in hemodialysis patients. To investigate the relation between blood levels of 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D) with hemodialysis outcomes, we measured baseline vitamin D levels in a cross-sectional analysis of 825 consecutive patients from within a prospective cohort of incident US hemodialysis patients. Of these patients, 78% were considered vitamin D deficient with 18% considered severely deficient. Calcium, phosphorus, and parathyroid hormone levels correlated poorly with 25D and 1,25D concentrations. To test the association between baseline vitamin D levels and 90-day mortality, we selected the next 175 consecutive participants who died within 90 days and compared them to the 750 patients who survived in a nested case-control analysis. While low vitamin D levels were associated with increased mortality, significant interaction was noted between vitamin D levels, subsequent active vitamin D therapy, and survival. Compared to patients with the highest 25D or 1,25D levels who received therapy, untreated deficient patients were at significantly increased risk for early mortality. Our study shows that among incident hemodialysis patients, vitamin D deficiency is common, correlates poorly with other components of mineral metabolism and is associated with increased early mortality.

Prevalence of Vitamin D Deficiency and the Safety and Effectiveness of Monthly Ergocalciferol in Hemodialysis Patients.
Nephron Clin Pract. 2007;105(3):c132-8.
Saab G, Young DO, Gincherman Y, Giles K, Norwood K, Coyne DW
. Chromalloy American Kidney Center and Washington University School of Medicine, Department of Internal Medicine, Renal Division, Saint Louis, MO 65212, USA.

BACKGROUND: Vitamin D deficiency is common in CKD and dialysis patients. Studies suggest a physiologic autocrine and/or paracrine role for 1,25(OH)D produced via 1alpha-hydroxylase in tissues such as vascular smooth muscle, breast, prostate, and bone marrow. Studies have not yet defined the optimal dose and duration of vitamin D necessary to replete and maintain stores in dialysis patients, or whether it is safe or beneficial. METHODS: We performed a review of the prevalence of vitamin D deficiency and the safety and effectiveness of ergocalciferol oral supplementation (vitamin D2, 50,000 IU monthly) given to hemodialysis patients during dialysis May to October 2005 in St. Louis (latitude 38 degrees ). RESULTS: Among the 119-patient cohort present for the entire 6 months, 25(OH)D was (mean +/- SD) 16.9 +/- 8.5 ng/ml, (91% < 30 ng/ml) and increased to 53.6 +/- 16.3 ng/ml (p < 0.001), (95% > 30 ng/ml, and none > 100 ng/ml). Initial versus 6 mo. serum calcium (9.1 +/- 0.56 vs. 9.2 +/- 0.70), phosphorus (5.25 +/- 1.38 vs. 5.11 +/- 1.31), Ca x P, and paricalcitol dose (10.3 +/- 9.6 vs. 11.3 +/- 9.2 mcg/week) were not significantly different. No hypercalcemia could be attributed to supplementation. Mean hemoglobin did not change significantly (11.96 +/- 1.4 vs. 11.69 +/- 1.4, p = 0.124), but most patients experienced a reduced weekly epoetin dose. Epoetin dose decreased in 64% of patients, and increased in 28%. CONCLUSIONS: We conclude that the vast majority of hemodialysis patients are vitamin D-deficient; monthly ergocalciferol 50,000 IU is safe and effective in normalizing serum 25(OH)D levels and may have an epoetin-sparing effect.

Prevalence of Vitamin D [25(OH)D] Deficiency and Effects of Supplementation with Ergocalciferol (vitamin D2) in Stage 5 Chronic Kidney Disease Patients.
Journal of Renal Nutrition 2008 Jul;18(4):375-82.
Blair D, Byham-Gray L, Lewis E, McCaffrey S.
Fresenius Medical Care, Western Massachusetts Kidney Center, Springfield, Massachusetts 01003, USA.

OBJECTIVE: This study investigated the prevalence of vitamin D deficiency, its association with nutrition-related parameters, and the effects of ergocalciferol supplementation in stage 5 chronic kidney disease (CKD). Measures of interest included serum albumin, glycosylated hemoglobin (HgA1c), hemoglobin, phosphorus, corrected calcium, parathyroid hormone (iPTH), equilibrated normalized protein catabolic rate (enPCR), and quality-of life-survey physical component score (SF-36 PCS). DESIGN AND SETTING: This retrospective study was conducted at five dialysis centers in western Massachusetts. Patient records were examined for a 6-month period in 2006, after initiation of a protocol to assess serum 25(OH)D and implement treatment with ergocalciferol if the level of serum 25(OH)D were <40 ng/mL. RESULTS: Over 90% (i.e., 92.4%) of patients had vitamin D levels of less than 40 ng/mL; 80% had vitamin D levels at 31 ng/mL or less. Ergocalciferol supplementation (50,000 IU/week x 24) was associated with significant improvements in serum 25(OH)D from baseline (18.4 +/- 9.0 ng/mL; mean +/- SD) to 6 months (42.0 +/- 24.7 ng/mL) (P < .0005). The level of glycosylated hemoglobin decreased from 6.9% +/- 1.9% at baseline to 6.4% +/- 1.5% at 6 months (P < .0005), while hemoglobin improved from 12.1 +/- 1.6 g/dL to 12.3 +/- 1.4 g/dL (P < .0005). Corrected calcium decreased from 8.7 +/- 0.8 mg/dL to 8.5 +/- 0.9 mg/dL at 6 months (P = .002). Phosphorus and iPTH exhibited a downward trend, though not significantly. Albumin remained stable, while enPCR increased (0.91 +/- 0.23 at baseline, vs. 0.98 +/- 0.32 at 6 months) (P = .01). The SF-36 PCS scores did not differ significantly from baseline (35.4 +/- 11.8) at 6 months (35.0 +/- 11.1). CONCLUSIONS: Vitamin D [25(OH)D] deficiency appears to be widely prevalent in stage 5 CKD. Repletion with ergocalciferol may assist in improving glycemic control in the management of diabetes. Additional research is needed to confirm these results and determine the optimal levels of serum 25(OH)D.

25-Hydroxyvitamin D and Risk of Myocardial Infarction in Men: a Prospective Study.
Arch Intern Med. 2008 Jun 9;168(11):1174-80.
Giovannucci E, Liu Y, Hollis BW, Rimm EB.
Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA.

BACKGROUND: Vitamin D deficiency may be involved in the development of atherosclerosis and coronary heart disease in humans. METHODS: We assessed prospectively whether plasma 25-hydroxyvitamin D (25[OH]D) concentrations are associated with risk of coronary heart disease. A nested case-control study was conducted in 18,225 men in the Health Professionals Follow-up Study; the men were aged 40 to 75 years and were free of diagnosed cardiovascular disease at blood collection. The blood samples were returned between April 1, 1993, and November 30, 1999; 99% were received between April 1, 1993, and November 30, 1995. During 10 years of follow-up, 454 men developed nonfatal myocardial infarction or fatal coronary heart disease. Using risk set sampling, controls (n = 900) were selected in a 2:1 ratio and matched for age, date of blood collection, and smoking status. RESULTS: After adjustment for matched variables, men deficient in 25(OH)D (<or=15 ng/mL [to convert to nanomoles per liter, multiply by 2.496]) were at increased risk for MI compared with those considered to be sufficient in 25(OH)D (>or=30 ng/mL) (relative risk [RR], 2.42; 95% confidence interval [CI], 1.53-3.84; P < .001 for trend). After additional adjustment for family history of myocardial infarction, body mass index, alcohol consumption, physical activity, history of diabetes mellitus and hypertension, ethnicity, region, marine omega-3 intake, low- and high-density lipoprotein cholesterol levels, and triglyceride levels, this relationship remained significant (RR, 2.09; 95% CI, 1.24-3.54; P = .02 for trend). Even men with intermediate 25(OH)D levels were at elevated risk relative to those with sufficient 25(OH)D levels (22.6-29.9 ng/mL: RR, 1.60 [95% CI, 1.10-2.32]; and 15.0-22.5 ng/mL: RR, 1.43 [95% CI, 0.96-2.13], respectively). CONCLUSION: Low levels of 25(OH)D are associated with higher risk of myocardial infarction in a graded manner, even after controlling for factors known to be associated with coronary artery disease.

Daily Oral 25-Hydroxycholecalciferol Supplementation for Vitamin D Deficiency in Haemodialysis Patients: Effects on Mineral Metabolism and Bone Markers.
Nephrol Dial Transplant. 2008 Jun 24.
Jean G, Terrat JC, Vanel T, Hurot JM, Lorriaux C, Mayor B, Chazot C.
Centre de Rein Artificiel, 42 avenue du 8 mai 1945, 69160, Tassin la Demi-lune, France.

BACKGROUND: Vitamin D deficiency is frequently observed in end-stage renal disease (ESRD) patients; however, the effects of vitamin D supplementation have rarely been reported. We aimed to assess the effects of daily 25(OH)D3 supplementation on mineral metabolism, bone markers and Kidney Disease Outcomes Quality Initiative (KDOQI) targets in haemodialysis (HD) patients for a period of 6 months. METHODS: HD patients were included in this study if their serum 25(OH)D level was <75 mmol/L. Oral 25(OH)D3 was administered daily at 10-30 mug/day based on the severity of the deficiency. Characteristics of the patients were compared from the baseline to 6 months on the basis of their response to 25(OH)D3 administration and the patients were divided into three groups. Patients who showed partial response [serum 25(OH)D <75 nmol/L] were placed in group 1, those who showed normal response [serum 25(OH)D ranging from 75 to 150 nmol/L] were placed in group 2 and those who showed excessive response [serum 25(OH)D >150 nmol/L] were placed in group 3. RESULTS: Of the 253 HD patients, 225 (89%) showed vitamin D insufficiency or deficiency, 172 were included in the study and 149 patients completed the study. After 6 months of treatment [mean daily 25(OH)D(3): 16 +/- 5 mug/day], the serum 25(OH)D level increased (30 +/- 19 to 126 +/- 46 nmol/ L, P < 0.001), with 13% of patients in group 1, 57% in group 2 and 30% in group 3. The serum intact parathyroid hormone (iPTH) level decreased (235 +/- 186 to 189 +/- 137 pg/mL, P = 0.05), except in group 1. Bone alkaline phosphatase (BALP) showed a tendency to normalize (23 +/- 16 to 18.3 +/- 11 mug/L, P < 0.05), leading to a decrease in alfacalcidol administration from 66% to 43% (P < 0.05), except in group 1. The KDOQI targets achieved increased significantly for serum calcium (76% to 85%) and phosphate levels (66% to 77%) in all patients. The serum albumin level increased in all groups (34.6 +/- 4 to 36.8 +/- 4 g/L, P < 0.05), without any significant improvement in normalized protein catabolic rate (nPCR) or C-reactive proteins (CRP). CONCLUSION: With a daily dose ranging from 10 to 30 mug, daily oral 25(OH)D3 supplementation corrects most vitamin D deficiencies or insufficiencies in HD patients, without any evident toxicity. The main effects observed included correction of excessive bone turnover, despite less alfacalcidol administration, increase in serum albumin level and increase in the percentage of patients with serum calcium and phosphorus levels within the recommendation of the KDOQI guidelines.

Serum 25-Hydroxyvitamin D Status and Cardiovascular Outcomes in Chronic Peritoneal Dialysis Patients: A 3-y Prospective Cohort Study.
Am J Clin Nutr. 2008 Jun;87(6):1631-8.
Wang AY, Lam CW, Sanderson JE, Wang M, Chan IH, Lui SF, Sea MM, Woo J.
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong.

BACKGROUND: Patients with kidney disease are at high risk of developing 25-hydroxyvitamin D [25(OH)D] deficiency. OBJECTIVE: We studied the association between serum 25(OH)D status and clinical outcomes of chronic peritoneal dialysis patients. DESIGN: We measured serum 25(OH)D concentrations in 230 prevalent peritoneal dialysis patients and then followed these patients prospectively for 3 y or until death. RESULTS: Serum 25(OH)D was deficient or insufficient (ie, <75 nmol/L) in 87% of the patients. Adjusting for clinical and demographic factors, every 1-unit increase in log-transformed serum 25(OH)D was associated with a 44% reduction in the hazard of fatal or nonfatal cardiovascular events (95% CI: 0.35, 0.91; P = 0.018). However, the association was gradually lost when additional adjustment was made in a stepwise fashion for residual glomerular filtration rate (P = 0.078) and echocardiographic measures (P = 0.39). Kaplan-Meier estimates showed a significantly greater fatal or nonfatal cardiovascular event-free survival probability among patients with serum 25(OH)D > 45.7 nmol/L (median) than among patients with concentrations <or= 45.7 nmol/L (P = 0.004). In addition, patients with 25(OH)D > 45.7 nmol/L had a significantly higher cardiovascular event-free survival probability than did patients with 25(OH)D <or= 45.7 nmol/L in the stratified analysis for patients with left ventricular mass index less than the median (P = 0.013) or normal systolic function (P = 0.005). CONCLUSIONS: A lower serum 25(OH)D concentration was associated with an increased risk of cardiovascular events in chronic peritoneal dialysis patients. Furthermore, serum 25(OH)D status appeared to show a differential influence on the cardiovascular outcomes of peritoneal dialysis patients depending on the degree of left ventricular hypertrophy and systolic dysfunction.

Circulating 25-Hydroxyvitamin D Levels Predict Survival in Early-Stage Non-Small-Cell Lung Cancer Patients.
J Clin Oncol. 2007 Feb 10;25(5):479-85.
Zhou W, Heist RS, Liu G, Asomaning K, Neuberg DS, Hollis BW, Wain JC, Lynch TJ, Giovannucci E, Su L, Christiani DC.
Departments of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA.

PURPOSE: Our previous analyses suggested that surgery in the summertime with higher vitamin D intake is associated with improved survival in patients with early-stage non-small-cell lung cancer (NSCLC). We further investigated the results of circulating 25-hydroxyvitamin D (25[OH]D) levels on overall survival (OS) and recurrence-free survival (RFS) in NSCLC patients. PATIENTS AND METHODS: Among 447 patients with early-stage NSCLC, data were analyzed using Cox proportional hazards models, adjusting for age, sex, stage, smoking, and treatment. RESULTS: The median follow-up time was 72 months (range, 0.2 to 141), with 161 recurrences and 234 deaths. For OS, the adjusted hazard ratio (AHR) was 0.74 (95% CI, 0.50 to 1.10; Ptrend = .07) for the highest versus lowest quartile of 25(OH)D levels. Stratified by stage, a strong association was observed among stage IB-IIB patients (AHR, 0.45; 95% CI, 0.24 to 0.82; Ptrend = .002), but not among stage IA patients (AHR, 1.10; 95% CI, 0.62 to 1.96; Ptrend = .53). Similar effects of 25(OH)D levels were observed among the 309 patients with dietary information (AHR, 0.74; 95% CI, 0.46 to 1.17; Ptrend = .19). For the joint effects of 25(OH)D level and vitamin D intake, the combined high 25(OH)D levels and high vitamin D intake (by median) were associated with better survival than the combined low 25(OH)D levels and low vitamin D intake (AHR, 0.64; 95% CI, 0.42 to 0.98; Ptrend = .06). Again, stronger associations were observed among stage IB-IIB than IA patients. Similar effects of 25(OH)D levels and vitamin D intake were observed for RFS. CONCLUSION: Vitamin D may be associated with improved survival of patients with early-stage NSCLC, particularly among stage IB-IIB patients.

Prevalence of Cardiovascular Risk Factors and the Serum Levels of 25-Hydroxyvitamin D in the United States: Data from the Third National Health and Nutrition Examination Survey.
Arch Intern Med. 2007 Jun 11;167(11):1159-65.
Martins D, Wolf M, Pan D, Zadshir A, Tareen N, Thadhani R, Felsenfeld A, Levine B, Mehrotra R, Norris K.
Department of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, Calif., 90262, USA.

BACKGROUND: Results of several epidemiologic and clinical studies have suggested that there is an excess risk of hypertension and diabetes mellitus in persons with suboptimal intake of vitamin D. METHODS: We examined the association between serum levels of 25-hydroxyvitamin D (25[OH]D) and select cardiovascular disease risk factors in US adults. A secondary analysis was performed with data from the Third National Health and Nutrition Examination Survey, a national probability survey conducted by the National Center for Health Statistics between January 1, 1988, and December 31, 1994, with oversampling of persons 60 years and older, non-Hispanic black individuals, and Mexican American individuals. RESULTS: There were 7186 male and 7902 female adults 20 years and older with available data in the Third National Health and Nutrition Examination Survey. The mean 25(OH)D level in the overall sample was 30 ng/mL (75 nmol/L). The 25(OH)D levels were lower in women, elderly persons (>or=60 years), racial/ethnic minorities, and participants with obesity, hypertension, and diabetes mellitus. The adjusted prevalence of hypertension (odds ratio [OR], 1.30), diabetes mellitus (OR, 1.98), obesity (OR, 2.29), and high serum triglyceride levels (OR, 1.47) was significantly higher in the first than in the fourth quartile of serum 25(OH)D levels (P<.001 for all). CONCLUSIONS: Serum 25(OH)D levels are associated with important cardiovascular disease risk factors in US adults. Prospective studies to assess a direct benefit of cholecalciferol (vitamin D) supplementation on cardiovascular disease risk factors are warranted.

Vitamin D Deficiency and Risk of Cardiovascular Disease.
Circulation. 2008 Jan 29;117(4):503-11.
Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, Benjamin EJ, D'Agostino RB, Wolf M, Vasan RS.
Framingham Heart Study, Framingham, Mass, USA.

BACKGROUND: Vitamin D receptors have a broad tissue distribution that includes vascular smooth muscle, endothelium, and cardiomyocytes. A growing body of evidence suggests that vitamin D deficiency may adversely affect the cardiovascular system, but data from longitudinal studies are lacking. METHODS AND RESULTS: We studied 1739 Framingham Offspring Study participants (mean age 59 years; 55% women; all white) without prior cardiovascular disease. Vitamin D status was assessed by measuring 25-dihydroxyvitamin D (25-OH D) levels. Prespecified thresholds were used to characterize varying degrees of 25-OH D deficiency (< 15 ng/mL, < 10 ng/mL). Multivariable Cox regression models were adjusted for conventional risk factors. Overall, 28% of individuals had levels < 15 ng/mL, and 9% had levels < 10 ng/mL. During a mean follow-up of 5.4 years, 120 individuals developed a first cardiovascular event. Individuals with 25-OH D < 15 ng/mL had a multivariable-adjusted hazard ratio of 1.62 (95% confidence interval 1.11 to 2.36, P=0.01) for incident cardiovascular events compared with those with 25-OH D > or = 15 ng/mL. This effect was evident in participants with hypertension (hazard ratio 2.13, 95% confidence interval 1.30 to 3.48) but not in those without hypertension (hazard ratio 1.04, 95% confidence interval 0.55 to 1.96). There was a graded increase in cardiovascular risk across categories of 25-OH D, with multivariable-adjusted hazard ratios of 1.53 (95% confidence interval 1.00 to 2.36) for levels 10 to < 15 ng/mL and 1.80 (95% confidence interval 1.05 to 3.08) for levels < 10 ng/mL (P for linear trend=0.01). Further adjustment for C-reactive protein, physical activity, or vitamin use did not affect the findings. CONCLUSIONS: Vitamin D deficiency is associated with incident cardiovascular disease. Further clinical and experimental studies may be warranted to determine whether correction of vitamin D deficiency could contribute to the prevention of cardiovascular disease.

Serum 25-Hydroxyvitamin D3 Concentrations and Carotid Artery Intima-Media Thickness Among Type 2 Diabetic Patients.
Clin Endocrinol (Oxf). 2006 Nov;65(5):593-7.
Targher G, Bertolini L, Padovani R, Zenari L, Scala L, Cigolini M, Arcaro G.
Division of Internal Medicine, Sacro Cuore Hospital, Negrar (VR), Italy.

OBJECTIVE: To estimate the prevalence of hypovitaminosis D among type 2 diabetic adults and to assess the relationship between hypovitaminosis D and intimal medial thickening (IMT) of the common carotid artery, a marker of preclinical atherosclerosis. DESIGN, PATIENTS AND MEASUREMENTS: We compared winter serum 25-hydroxyvitamin D3 [25(OH)D] concentrations in 390 consecutive type 2 diabetic patients and 390 nondiabetic controls who were comparable for age and sex. Common carotid IMT was measured with ultrasonography only in diabetic patients by a single trained operator blinded to subjects' details. RESULTS: The prevalence of hypovitaminosis D (i.e. 25(OH)D <or= 37.5 nmol/l) was higher in diabetic patients (34.0 vs 16.4%, P < 0.001) than in controls. Among diabetic patients, those with hypovitaminosis D (n = 130) had a marked increase in common carotid IMT (1.10 +/- 0.15 vs 0.87 +/- 0.14 mm, P < 0.001) when compared with their vitamin d-sufficient counterparts (n = 260). These patients also had significantly higher haemoglobin A1c, fibrinogen and C-reactive protein (hs-CRP) concentrations. In multivariate regression analysis, low 25(OH)D concentrations independently predicted carotid IMT (P < 0.001) in people with type 2 diabetes after adjustment for classical risk factors, diabetes duration, HbA1c, calcium, renal function tests, inflammatory markers, use of medications, and presence of the metabolic syndrome (as defined by the Adult Treatment Panel III criteria). CONCLUSIONS: Hypovitaminosis D is highly prevalent in type 2 diabetic adults and is strongly and independently associated with increased carotid IMT. Further investigation into whether vitamin D may play a role in the prevention of atherosclerosis appears to be warranted.

Plasma 25-Hydroxyvitamin D Levels and Risk of Incident Hypertension.
Hypertension. 2007 May;49(5):1063-9.
Forman JP, Giovannucci E, Holmes MD, Bischoff-Ferrari HA, Tworoger SS, Willett WC, Curhan GC.
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Hydroxylation of 25(OH)D to 1,25-dihydroxyvitamin D and signaling through the vitamin D receptor occur in various tissues not traditionally involved in calcium homeostasis. Laboratory studies indicate that 1,25-dihydroxyvitamin D suppresses renin expression and vascular smooth muscle cell proliferation; clinical studies demonstrate an inverse association between ultraviolet radiation, a surrogate marker for vitamin D synthesis, and blood pressure. We prospectively studied the independent association between measured plasma 25-hydroxyvitamin D [25(OH)D] levels and risk of incident hypertension and also the association between predicted plasma 25(OH)D levels and risk of incident hypertension. Two prospective cohort studies including 613 men from the Health Professionals' Follow-Up Study and 1198 women from the Nurses' Health Study with measured 25(OH)D levels were followed for 4 to 8 years. In addition, 2 prospective cohort studies including 38 388 men and 77 531 women with predicted 25(OH)D levels were followed for 16 to 18 years. During 4 years of follow-up, the multivariable relative risk of incident hypertension among men whose measured plasma 25(OH)D levels were <15 ng/mL (ie, vitamin D deficiency) compared with those whose levels were >or=30 ng/mL was 6.13 (95% confidence interval [CI]: 1.00 to 37.8). Among women, the same comparison yielded a relative risk of 2.67 (95% CI: 1.05 to 6.79). The pooled relative risk combining men and women with measured 25(OH)D levels using the random-effects model was 3.18 (95% CI: 1.39 to 7.29). Using predicted 25(OH)D levels in the larger cohorts, the multivariable relative risks comparing the lowest to highest deciles were 2.31 (95% CI: 2.03 to 2.63) in men and 1.57 (95% CI: 1.44 to 1.72) in women. Plasma 25(OH)D levels are inversely associated with risk of incident hypertension.

Vitamin D Supplementation and Total Mortality: a Meta-Analysis of Randomized Controlled Trials.
Arch Intern Med. 2007 Sep 10;167(16):1730-7.
Autier P, Gandini S.
International Agency for Research on Cancer, 150 cours Albert Thomas, F-69372 Lyon, France.

BACKGROUND: Ecological and observational studies suggest that low vitamin D status could be associated with higher mortality from life-threatening conditions including cancer, cardiovascular disease, and diabetes mellitus that account for 60% to 70% of total mortality in high-income countries. We examined the risk of dying from any cause in subjects who participated in randomized trials testing the impact of vitamin D supplementation (ergocalciferol [vitamin D(2)] or cholecalciferol [vitamin D(3)]) on any health condition. METHODS: The literature up to November 2006 was searched without language restriction using the following databases: PubMed, ISI Web of Science (Science Citation Index Expanded), EMBASE, and the Cochrane Library. RESULTS: We identified 18 independent randomized controlled trials, including 57 311 participants. A total of 4777 deaths from any cause occurred during a trial size-adjusted mean of 5.7 years. Daily doses of vitamin D supplements varied from 300 to 2000 IU. The trial size-adjusted mean daily vitamin D dose was 528 IU. In 9 trials, there was a 1.4- to 5.2-fold difference in serum 25-hydroxyvitamin D between the intervention and control groups. The summary relative risk for mortality from any cause was 0.93 (95% confidence interval, 0.87-0.99). There was neither indication for heterogeneity nor indication for publication biases. The summary relative risk did not change according to the addition of calcium supplements in the intervention. CONCLUSIONS: Intake of ordinary doses of vitamin D supplements seems to be associated with decreases in total mortality rates. The relationship between baseline vitamin D status, dose of vitamin D supplements, and total mortality rates remains to be investigated. Population-based, placebo-controlled randomized trials with total mortality as the main end point should be organized for confirming these findings.

Expanding Role for Vitamin D in Chronic Kidney Disease: Importance of Blood 25-OH-D Levels and Extra-Renal 1Alpha-Hydroxylase in the Classical and Nonclassical Actions of 1Alpha,25-Dihydroxyvitamin D(3).
Semin Dial. 2007 Jul-Aug;20(4):316-24.
Jones G.
Departments of Biochemistry and Medicine, Queen's University, Kingston, Ontario, Canada.

Recent advances in the understanding of vitamin D have revolutionized our view of this old nutritional factor and suggested that it has much wider effects on the body than ever believed before. In addition to its well-known effects on calcium/phosphate homeostasis, vitamin D, through its hormonal form, 1alpha,25-dihydroxyvitamin D(3) or calcitriol, is a cell differentiating factor and anti-proliferative agent with actions on a variety of tissues around the body (e.g., skin, muscle, immune system). By influencing gene expression in multiple tissues, calcitriol influences many physiological processes besides calcium/phosphate homeostasis including muscle and keratinocyte differentiation, insulin secretion, blood pressure regulation, and the immune response. The incidence of various diseases including epithelial cancers, multiple sclerosis, muscle weakness as well as bone-related disorders has been correlated with vitamin D deficiency/insufficiency and has led to a re-evaluation of recommended daily intakes both in the normal subject and CKD patient. Critical developments have been the emergence of the value of blood 25-OH-D measurement as a tool in predicting vitamin D-related problems and this has in turn emphasized the importance of the extra-renal version of the 1alpha-hydroxylase, the enzyme responsible for the final step in vitamin D activation. The widespread expression of this extra-renal enzyme supports the view that it exists to boost intracellular concentrations of calcitriol within some target tissues in order to modulate a unique set of genes specifically in those tissues, a process which is therefore dependent upon circulating 25-OH-D. For CKD patients with their tendency to vitamin D substrate insufficiency coupled with their documented loss of the renal 1alpha-hydroxylase in late stages, this new information has profound implications. Physicians must start to manage the vitamin D insufficiency by vitamin D supplements throughout stages 1-5 whilst continuing to provide calcitriol replacement therapy, in the form of calcitriol or its analogs, in stages 3-5.

Vitamin D Levels, Bone Turnover and Bone Mineral Density Show Seasonal Variation in Patients with Chronic Kidney Disease Stage 5.
Nephrology (Carlton). 2007 Feb;12(1):90-4.
Elder GJ.
Centre for Transplant and Renal Research, Westmead Millennium Institute, Sydney, New South Wales, Australia.

AIM: Many patients with chronic kidney disease (CKD) have reduced levels of 25-hydroxyvitamin D (25(OH)D). Although renal conversion of 25(OH)D to calcitriol is reduced or absent in CKD stage 5 (GFR < 15 mL/min per 1.73 m(2) or on dialysis), 25(OH)D may have direct skeletal and non-skeletal paracrine actions. The aim of this study was to assess seasonal variation in levels of 25(OH)D, bone turnover markers and bone mineral density, which would support a direct physiological role for 25(OH)D. METHODS: Vitamin D levels, bone turnover markers and bone mineral density were measured and assessed for seasonal variation in 257 patients about to undergo kidney or kidney pancreas transplantation. RESULTS: The mean age was 43 +/- 11 years; 62% were on haemodialysis, 24% on peritoneal dialysis and 34% had type 1 diabetes. Serum 25(OH)D was less than 50 nmol/L in 39% and lower levels were associated with female sex, diabetes and peritoneal dialysis (P < 0.0001 for each). Levels of 25(OH)D varied by season (P = 0.018; anova) peaking in autumn with a nadir in spring and calcitriol levels followed a similar seasonal trend. Bone mineral denisty Z-scores differed between summer and winter at the lumbar spine (P = 0.009) with a similar trend at the hip. Osteocalcin levels also showed seasonal periodicity (P = 0.0142) and together with alkaline phosphatase were higher in summer than winter. CONCLUSION: In summary, these data suggest direct effects of 25(OH)D on bone parameters in CKD stage 5 and support the need for prospective studies to establish the effect of treatments that increase 25(OH)D levels in all stages of CKD.

The Influence of Serum 25-Hydroxy Vitamin D Levels on Helicobacter Pylori Infections in Patients with End-Stage Renal Failure on Regular Hemodialysis.
Saudi J Kidney Dis Transpl. 2007 Jun;18(2):215-9.
Nasri H, Baradaran A.
Hemodialysis Section, Hajar Medical, Educational and Therapeutic Center, Shahrekord University of Medical Sciences, Shahrekord, Iran.

This study was designed to determine whether the serum levels of 25-OH vitamin D influence the occurrence of infection with Helicobacter Pylori (H.Pylori) in patients on maintenance hemodialysis (HD). The study subjects were patients with end-stage renal disease who were undergoing maintenance dialysis at the hemodialysis section, Hajar Medical, Educational and Therapeutic Center, Shahrekord, Iran. The serum 25-OH vitamin D level and serum H. Pylori specific IgG antibody titers were measured using an enzyme-linked immunosorbent assay (ELISA) method. A total of 36 patients were studied including 21 males and 15 females. The mean age of the study group was 47 (+/- 17) years. The mean level of serum 25-OH vitamin D was 0.5 +/- 18.7 nmol/L (median: 3.5) while the mean value of serum H.Pylori specific IgG antibody titer was 7.7 (+/-9.9) u/ml (median: 2 u/ml). Thus, a significant positive correlation was found between the levels of serum 25-OH vitamin D and serum H. Pylori specific IgG antibody titers (data adjusted for age, urea reduction rate, duration and dose of dialysis) (r=0.36, p=0.043). Our study suggests that vitamin D may positively affect the chronic inflammatory status of dialysis patients and may potentiate the immune response in such patients. Because of this immuno-modulatory effect, vitamin D analogs may offer new means to control the inflammatory status in patients on maintenance dialysis.

Mineral Metabolism and Arterial Functions in End-Stage Renal Disease: Potential Role of 25-Hydroxyvitamin D Deficiency.
J Am Soc Nephrol. 2007 Feb;18(2):613-20.
London GM, Guörin AP, Verbeke FH, Pannier B, Boutouyrie P, Marchais SJ, Mötivier F.
Höpital F.H. Manhös, 8 rue Roger Clavier, 91712 Fleury-Mörogis CEDEX, France.

In ESRD, arterial function is abnormal, characterized by decreased capacitive function (arterial stiffening) and reduced conduit function, shown by diminished flow-mediated dilation (FMD). The pathophysiology of these abnormalities is not clear, and this cross-sectional study analyzed possible relationships among arterial alterations and cardiovascular risk factors, including mineral metabolism parameters, such as serum parathormone, and vitamin D "nutritional" and "hormonal" status by measuring serum 25-hydroxyvitamin D [25(OH)D(3)] and 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] levels. Aortic stiffness (pulse wave velocity), brachial artery (BA) distensibility (echotracking; n = 42), BA FMD (hand-warming; n = 37), and arterial calcification scores (echography and plain x-rays) were measured in 52 stable and uncomplicated patients who were on hemodialysis. 25(OH)D(3) and 1,25(OH)(2)D(3) serum levels were low and weakly correlated (r = 0.365, P < 0.05). After adjustment for BP and age, multivariate analyses indicated that 25(OH)D(3) and 1,25(OH)(2)D(3) were negatively correlated with aortic pulse wave velocity (P < 0.001) and positively correlated with BA distensibility (P < 0.01) and FMD (P < 0.001). Arterial calcification scores were not independently associated with 25(OH)D(3) and 1,25(OH)(2)D(3) serum concentrations. These results suggest that nutritional vitamin D deficiency and low 1,25(OH)(2)D(3) could be associated with arteriosclerosis and endothelial dysfunction in patients who have ESRD and are on hemodialysis.

Cholecalciferol Supplementation Alters Calcitriol-Responsive Monocyte Proteins and Decreases Inflammatory Cytokines in ESRD.
J Am Soc Nephrol. 2010 Feb;21(2):353-61. Epub 2009 Dec 10.
Stubbs JR, Idiculla A, Slusser J, Menard R, Quarles LD.
*The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas

In vitro, monocyte 1alpha-hydroxylase converts 25-hydroxyvitamin D [25(OH)D] to 1,25-dihydroxyvitamin D to regulate local innate immune responses, but whether 25(OH)D repletion affects vitamin D-responsive monocyte pathways in vivo is unknown. Here, we identified seven patients who had 25(OH)D insufficiency and were undergoing long-term hemodialysis and assessed changes after cholecalciferol and paricalcitol therapies in both vitamin D-responsive proteins in circulating monocytes and serum levels of inflammatory cytokines. Cholecalciferol therapy increased serum 25(OH)D levels four-fold, monocyte vitamin D receptor expression three-fold, and 24-hydroxylase expression; therapy decreased monocyte 1alpha-hydroxylase levels. The CD16(+) "inflammatory" monocyte subset responded to 25(OH)D repletion the most, demonstrating the greatest increase in vitamin D receptor expression after cholecalciferol. Cholecalciferol therapy reduced circulating levels of inflammatory cytokines, including IL-8, IL-6, and TNF. These data suggest that nutritional vitamin D therapy has a biologic effect on circulating monocytes and associated inflammatory markers in patients with ESRD.

PMID: 20007751 [PubMed - as supplied by publisher]

Vitamin D as a Novel Nontraditional Risk Factor for Mortality in Hemodialysis Patients.
Ther Apher Dial. 2009 Aug;13(4):268-72.
Pecovnik-Balon B, Jakopin E, Bevc S, Knehtl M, Gorenjak M.
Department of Nephrology, University Clinical Center Maribor, Maribor, Slovenia.

We examined the prevalence of vitamin D deficiency in hemodialysis patients and tested the hypothesis that decreased levels of 25-hydroxyvitamin D (25D) are associated with an increased risk for early all-cause mortality. One hundred and two patients, 57 (56%) men and 45 (44%) women, mean age 60.5 +/- 13.1 years, were included in our study. Serum calcium and phosphorus levels were measured by routine laboratory methods. Parathyroid hormone (PTH) was measured by immunoassay and 25D by enzyme immunoassay. Patients were divided into two groups depending on the serum concentration of 25D: below or above 50 nmol/L. Survival rates were analyzed using the Kaplan-Meier survival curves. The Cox regression model was used to define potential variables effecting all-cause mortality. The mean level of 25D in all patients was 58 +/- 35.6 nmol/L, 52% of patients had 25D levels >50 nmol/L and 48% had levels of 10.5-50 nmol/L. Compared with men, women were more likely to be 25D deficient (67% vs. 37%; P = 0.005). Patients were observed from the date of laboratory measurement until their death or to a maximum of 730 days. Kaplan-Meier survival analysis showed that mortality in patients was significantly higher in the group with 25D levels < or =50 nmol/L (P < 0.033). With Cox multivariable regression modeling, the PTH level (P < 0.029) turned out to be the only predictor of mortality in our patients. Using the definitions recommended in the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines, we found that our hemodialysis patients on average have vitamin D insufficiency. Our results indicate that patients with 25D levels < or =50 nmol/L are associated with higher all-cause early mortality.

PMID: 19695057 [PubMed - indexed for MEDLINE]

Cholecalciferol Supplementation in Hemodialysis Patients: Effects on Mineral Metabolism, Inflammation, and Cardiac Dimension Parameters.
Clin J Am Soc Nephrol. 2010 Mar 4. [Epub ahead of print]
Matias PJ, Jorge C, Ferreira C, Borges M, Aires I, Amaral T, Gil C, Cortez J, Ferreira A. Vila Franca de Xira, Portugal;

BACKGROUND AND OBJECTIVES: Vitamin D deficiency is highly prevalent in chronic kidney disease. The aim of this study was to evaluate the effects of oral cholecalciferol supplementation on mineral metabolism, inflammation, and cardiac dimension parameters in long-term hemodialysis (HD) patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This 1-year prospective study included 158 HD patients. Serum levels of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], intact parathyroid hormone, and plasma brain natriuretic peptide as well as circulating bone metabolism and inflammation parameters were measured before and after supplementation. Baseline 25(OH)D and 1,25(OH)(2)D levels were measured twice (end of winter and of summer, respectively). Therapy with paricalcitol, sevelamer, and darbepoietin was evaluated. RESULTS: There was an increase in serum 25(OH)D and 1,25(OH)(2)D levels after supplementation. Conversely, serum calcium, phosphorus, and intact parathyroid hormone were decreased. There was a reduction in the dosage and in the number of patients who were treated with paricalcitol and sevelamer. Darbepoietin use was also reduced, with no modification of hemoglobin values. Serum albumin increased and C-reactive protein decreased during the study. Brain natriuretic peptide levels and left ventricular mass index were significantly reduced at the end of the supplementation. CONCLUSIONS: Oral cholecalciferol supplementation in HD patients seems to be an easy and cost-effective therapeutic measure. It allows reduction of vitamin D deficiency, better control of mineral metabolism with less use of active vitamin D, attenuation of inflammation, reduced dosing of erythropoiesis-stimulating agents, and possibly improvement of cardiac dysfunction.

PMID: 20203163 [PubMed - as supplied by publisher]

NKF SCM 2011 Poster Session
Effects of Vitamin D Repletion on Hemoglobin and the Dose of an Erythropoiesis Stimulating Agent

Usasiri Srisakul1, Cheryl Gilmartin1, Sanjeev Akkina1, Anna Porter1
1 University of Illinois at Chicago, Illinois

A high incidence of vitamin D [25(OH)D] deficiency, up to 75%, has been reported in patients with end stage renal disease (ESRD) on hemodialysis (HD). Studies postulate that adequate supplementation of 25(OH)D may enhance erythropoiesis by acting synergistically with erythropoietin on erythroid burst-forming units. Clinical studies using cholecalciferol or ergocalciferol for 25(OH)D repletion demonstrated erythropoiesis stimulating agents (ESA) dose reductions with stable hemoglobin (Hgb) levels, suggesting 25(OH)D repletion may have an epoetin-sparing effect. The goal of this retrospective, observational study was to examine the stability of Hgb and doses of darbepoetin (DARB) in HD patients treated with ergocalciferol. A total of 98 patients with baseline serum 25(OH)D levels < 30 ng/mL were included in the study. The ergocalciferol dosing guideline recommended by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative for stage 3 and 4 chronic kidney disease were implemented as dosing guidelines are not yet established for ESRD. Laboratory parameters and DARB doses expressed as the weekly weight-adjusted dose divided by the Hgb level were reported from September 2009 to September 2010. Patients had a mean age of 57 + 15.9 years old; most were male (53%) and African-American (67%). Compliance with ergocalciferol was 64%. The serum 25(OH)D levels increased significantly in the compliant group compared with non/partially-compliant group (p =0.002). A significantly greater percentage of patients (36.5%) in the compliant group achieved 25(OH) D serum levels > 30 ng/mL when compared to 17.1% in non/ partially-compliant group (p = 0.004). There was no significant difference in Hgb levels between groups (p =0.473). The DARB doses were significantly decreased in the compliant group (p = 0.024), but unchanged in the non/partially non-compliant group (p = 0.319). In conclusion, ergocalciferol repletion resulted in improved serum 25(OH) D levels, maintained Hgb levels, and decreased DARB doses. Further studies may be warranted.


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