ReviewVitamin D compounds and diabetic nephropathy
Highlights
► Vitamin D therapies have a long history in renal disease. ► New therapeutic targets for vitamin D compounds in this disease likely exist. ► A better understanding of disease development relative to hits on the vitamin D system is needed. ► The best vitamin D treatment regimen requires further study.
Section snippets
History of vitamin D compounds for renal disease
Vitamin D compounds have a lengthy and successful history in renal disease therapy (Table 1). During the middle of the 20th century, vitamin D itself was prescribed to renal patients at pharmacological doses – 50,000–500,000 IU daily [1], [2]. At the time, the understood problems of chronic renal disease were altered calcium homeostasis and bone metabolism and thought to be due to a problem in intestinal uptake of calcium. The discovery that vitamin D must be metabolized to an active form
The pathology of diabetic nephropathy
Renal disease afflicts more than 20 million adults in the US [6]. The predominant cause of end stage renal disease (ESRD) is diabetes with over 40% of the ESRD population comprised of patients suffering from type 1 or 2 diabetes [7]. Clinically, protein loss in the urine (microalbuminuria) has been used as a guide for identification of nephropathy [8]. Decreases in estimated glomerular filtration rates (eGFR) and increases in blood pressure are also used to diagnose nephropathy. Renal biopsies,
The vitamin D signaling pathway in renal disease
Important to this discussion is the recognition that many facets of the vitamin D signaling pathway are perturbed in kidney disease. At present, it is unclear which are causes of the disease and which is a result of the disease. Vitamin D is present naturally in very few foods [13]; however, a number of foods have been fortified and sun exposure produces vitamin D in the skin. Unfortunately, many of the vitamin-D containing foodstuffs are ones that individuals with renal disease should refrain
Possible targets for vitamin D compounds in diabetic nephropathy
A number of possibilities exist for how vitamin D compounds might slow the progression of renal disease in the diabetic population and thereby improve survival: assisting in glucose handling, minimizing renin-angiotensin system (RAS) activation and reducing fibrosis. Unregulated or suboptimal regulation of glucose results in the generation of an excess of glycated proteins, which have been shown to directly impair renal tissue [40], [41]. In addition, glycated hemoglobin levels are linearly
Nonclinical studies of vitamin D compounds and diabetic nephropathy
Several animal models of diabetic nephropathy have been developed and carefully studied relative to the human progression of disease [67], [68]. One model explored further in this laboratory is the nonobese diabetic (NOD) mouse model that spontaneously develops type I diabetes. Within 7 days after the development of hyperglycemia, the mice show signs of proteinuria. However, the animals do not survive much beyond 40 days without insulin therapy and exhibit no striking histological changes in the
Clinical studies of vitamin D and diabetic nephropathy
The addition of vitamin D therapy to a standard regimen of glucose control and RAS inhibition is emerging as a strategy to manage diabetic nephropathy in patients [75]. Results from two clinical trials have provided some initial insight into the benefit of vitamin D therapy in diabetic nephropathy. VITAL was the first study in humans to investigate an active vitamin D analog exclusively in diabetic nephropathy patients [76]. All patients were type 2 diabetics on a stable dose of angiotensin
Ideal therapeutic form of vitamin D
Because the reported incidence of vitamin D deficiency in the CKD population has been reported to be as high as 80%, there has been a lot of discussion regarding the possibility that simple restoration of vitamin D or 25(OH)D3 levels will suffice as a therapy [38], [39]. A better understanding of the temporal perturbations in the vitamin D signaling pathway with respect to disease state will help in deciding on the best treatment regimen. The possibility that 1α-hydroxylase activity is reduced
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