Clinical Journal of the American Society of Nephrology Moving Points in Nephrology

Introduction to the Second Annual Rostand Vitamin D Symposium

Warnock, D. G., Rostand, S. G. — Thu, 03 Sep 2009 14:47:31 PDT

The role of vitamin D in multiple organ systems is coming into sharp focus with recent advances in the understanding of its mechanisms of actions and interplay with multiple organ systems. Important distinctions between the role of 25-hydroxy metabolites that serve as substrates for subsequent hydroxylase reactions and the class of vitamin D receptor stimulating agents are important in understanding the clinical use of vitamin D in various clinical conditions.

Vitamin D and Parathyroid Hormone in General Populations: Understandings in 2009 and Applications to Chronic Kidney Disease

Johal, M., Levin, A. — Thu, 03 Sep 2009 14:47:31 PDT

Vitamin D is now recognized as an important prohormone in health and disease. Its role in immunoregulation and cardiovascular and bone health has become topical in the lay press and the medical press in the past 5 yr. The target audience for this review includes the interested clinician and researchers. The prevalence of chronic kidney disease in the general population has further increased the interest and perhaps the applicability of findings of population studies. The basic physiology of vitamin D and receptor activation and biologic importance is reviewed, as well as various vitamin D analogues and nomenclature. Issues related to measurement of vitamin D and parathyroid hormone have the potential to complicate the clinical use of these tests and should be understood by all clinicians so as to ensure informed decision making and stimulate interest in participation in clinical trials. The epidemiology of vitamin D deficiency and supplementation in association with health status and disease status is reviewed, and issues related to association versus causation are highlighted. Some recommendations for pragmatic approaches and study design are suggested.

Vitamin D and the Cardiovascular System

Artaza, J. N., Mehrotra, R., Norris, K. C. — Thu, 03 Sep 2009 14:47:31 PDT

Several epidemiologic and clinical studies have suggested that there is a strong association between hypovitaminosis D and cardiovascular disease (CVD). Hypovitaminosis D was reported as a risk factor for increased cardiovascular events among 1739 adult participants in the Framingham Offspring Study. Analysis of more than 13,000 adults in the Third National Health and Nutrition Examination Survey (NHANES III) showed that even though hypovitaminosis D is associated with an increased prevalence of CVD risk factors, its association with all-cause mortality is independent of these risk factors. Importantly, epidemiologic studies suggested that patients who had chronic kidney disease and were treated with activated vitamin D had a survival advantage when compared with those who did not receive treatment with these agents. Mechanistically, emerging data have linked vitamin D administration with improved cardiac function and reduced proteinuria, and hypovitaminosis D is associated with obesity, insulin resistance, and systemic inflammation. Preliminary studies suggested that activated vitamin D inhibits the proliferation of cardiomyoblasts by promoting cell-cycle arrest and enhances the formation of cardiomyotubes without inducing apoptosis. Activated vitamin D has also been shown to attenuate left ventricular dysfunction in animal models and humans. In summary, emerging studies suggest that hypovitaminosis D has emerged as an independent risk factor for all-cause and cardiovascular mortality, reinforcing its importance as a public health problem. There is a need to advance our understanding of the biologic pathways through which vitamin D affects cardiovascular health and to conduct prospective clinical interventions to define precisely the cardioprotective effects of nutritional vitamin D repletion.

Vitamin D, Proteinuria, Diabetic Nephropathy, and Progression of CKD

Agarwal, R. — Thu, 03 Sep 2009 14:47:31 PDT

Although the endocrine effects of vitamin D are widely recognized, somewhat less appreciated is that vitamin D may serve paracrine functions through local activation by 1--hydroxylase and thus maintain immunity, vascular function, cardiomyocyte health, and abrogate inflammation and insulin resistance. In the kidney, vitamin D may be important for maintaining podocyte health, preventing epithelial-to-mesenchymal transformation, and suppressing renin gene expression and inflammation. Replacement with pharmacologic dosages of vitamin D receptor agonists (VDRA) in animal models of kidney disease consistently show reduction in albuminuria, abrogation of glomerulosclerosis, glomerulomegaly, and glomerular inflammation, effects that may be independent of BP and parathyroid hormone, but the effects of VDRA in preventing tubulointerstitial fibrosis and preventing the progression of kidney failure in these animal models are less clear. Emerging evidence in patients with chronic kidney disease (CKD) show that vitamin D can reduce proteinuria or albuminuria even in the presence of angiotensin-converting enzyme inhibition. In addition to reducing proteinuria, VDRA may reduce insulin resistance, BP, and inflammation and preserve podocyte loss providing biologic plausibility to the notion that the use of VDRA may be associated with salubrious outcomes in patients with diabetic nephropathy. Patients with CKD have a very high prevalence of deficiency of 25-hydroxyvitamin D. Whether pharmacologic dosages of vitamin D instead of VDRA in patients with CKD can overcome the paracrine and endocrine functions of this vitamin remains unknown. To demonstrate the putative benefits of native vitamin D and VDRA among patients with CKD, randomized, controlled trials are needed.

Clinical Outcomes with Active versus Nutritional Vitamin D Compounds in Chronic Kidney Disease

Kalantar-Zadeh, K., Kovesdy, C. P. — Thu, 03 Sep 2009 14:47:31 PDT

Increasing confusion exists as to which vitamin D compounds are more appropriate for persons with chronic kidney disease (CKD). Some opinion-based guidelines recommend administration of such nutritional vitamin D agents as ergocalciferol or cholecalciferol as the first therapy in hyperparathyroidism associated with low circulating levels of 25-hydroxy vitamin D (<30 ng/ml) in nondialysis dependent CKD patients. Insufficient to deficient levels of 25-hydroxy vitamin D have been reported in the majority of individuals with CKD, including both nondialysis dependent and maintenance dialysis patients. Epidemiologic studies have almost consistently indicated the survival benefit of active vitamin D agents across all stages of CKD, including among dialysis patients with 25-hydroxy vitamin D deficiency. To date, no large observational or interventional studies have shown any survival advantage of nutritional vitamin D in CKD patients. Several recent (postguideline) small studies have yielded mixed results regarding the potential benefits of ergocalciferol in CKD, including satisfactory to inadequate lowering of PTH level to target ranges, improving response to erythropoietin stimulating agents, and salutary effects on glycemic controls. Compared with nutritional vitamin D agents, active vitamin D compounds appear to more effectively lower the circulating levels of alkaline phosphatase, a conveniently available biomarker associated with increased mortality and coronary artery calcification in CKD patients. The ideal vitamin D therapy for CKD patients should be the one that improves survival irrespective of suggested or imposed target ranges for arbitrary or opinion-based surrogate end points. Randomized controlled trials are needed to verify which agents offer superior survival advantages.