Vitamin D and the Kidney

Abstract

In the course of chronic kidney disease, alterations in vitamin D metabolism contribute to increases in the levels of parathyroid hormone and the development of skeletal disorders, and in addition, may contribute to hypertension, systemic inflammation and cardiovascular risk. In the course of chronic kidney disease, the production of 1,25-dihydroxyvitamin D from the kidney shows a progressive decline due to several factors, which include a reduction in the ability to convert 25-hydroxyvitamin-D to the active hormone, 1,25-dihydroxyvitamin D. The resulting 1,25-dihydroxyvitamin D, as well as 25-hydroxyvitamin D deficiency, correlates strongly with accelerated disease progression and mortality. An understanding of the pathophysiology involved leads to therapeutic strategies to correct these abnormalities, with the ultimate view to improve outcomes for patients with CKD.

Introduction

Alterations in bone and mineral metabolism occur early in the course of chronic kidney disease, and are mainly manifested biochemically by progressive increases in the levels of parathyroid hormone, which leads to skeletal disease and contributes to vascular calcification.¹ There are many factors that contribute to secondary hyperparathyroidism in the setting of chronic kidney disease (CKD), but the central mechanisms involve the abnormalities of phosphate retention and alterations in vitamin D metabolism. Thus, the levels of 1,25-dihydroxyvitamin D decrease progressively as kidney function declines. This reduction in the circulating concentrations of 1,25-dihydroxyvitamin D contribute to the development of secondary hyperparathyroidism.²

Vitamin D Metabolism

Vitamin D can be synthesized in the skin or ingested in the diet and is transported to the liver where it is metabolized into 25-hydroxyvitamin D. This vitamin D metabolite is the main storage form of vitamin D, and subsequently is converted to 1,25-dihydroxy vitamin D in the kidney. This is the major active metabolite of vitamin D and is responsible for the classical effects of vitamin D on calcium-phosphorus metabolism, maintenance of skeletal health, and the regulation of parathyroid function.^3,4 The kidney is not the only site of conversion to 1,25-dihydroxyvitamin D, since the enzyme 1-hydroxylase is known to be present in many tissues.⁵ Thus, 1,25-dihydroxyvitamin D can be made locally in macrophages, osteoblasts, parathyroid cells, mammary tissue, vascular smooth muscle cells, and many tissues, such as the pancreas, prostate, colon, and even the heart. The active synthesis of 1,25-dihydroxyvitamin D at these sites may be important in the regulation of cellular function and may play a role in a variety of non-classical actions of vitamin D.^3,6

Altered Vitamin D Metabolism in Kidney Disease

Several mechanisms contribute to the decreased production of 1,25-dihydroxyvitamin D in the course of chronic kidney disease.⁷ While a marked decrease in renal mass would limit the ability of the kidney to synthesize 1,25-dihyroxy D, this is unlikely to be a major mechanism, since the levels of 1,25-dihydroxyvitamin D begin to fall when renal function is only mildly impaired. A reduction in GFR would limit the delivery of 25-hydroxy vitamin D to the sites of 1-hydroxylase in the kidney and would limit the production of 1,25-dihydroxyvitamin D. Thus, glomerular filtration of 25-hydroxyvitamin D, which circulates bound to vitamin D-binding protein, is filtered at the glomerulus and endocytosed into the proximal tubule by a receptor-mediated mechanism involving megalin.⁸ Once endocytosed, the 25-hydroxyvitamin D can be delivered to the site of the 1-hydroxylase in the mitochondria or returned to the circulation to help maintain the circulating levels of 25-hydroxyvitamin D. Thus, reduction in the levels of 25-hydroxyvitamin vitamin D can result in reduced levels of this metabolite in the glomerular ultrafiltrate and cause a vicious cycle of progressive deterioration in 1,25-dihydroxyvitamin D production.⁸

An additional factor which contributes to a reduction in the levels of 1,25-dihydroxyvitamin D in the course of kidney disease is a progressive increase in the levels of fibroblast growth factor 23 (FGF-23).^9,10 FGF-23 has been shown to directly suppress the activity and expression of 1-hydroxylase, and therefore, this appears to be an important factor, which can limit the ability of the failing kidney to maintain 1,25-vitamin D production.¹⁰ Other factors, such as accumulation of PTH fragments and retention of uremic toxins, may also contribute to the decrease of renal 1-hydroxylase. ¹¹

Therapy of Vitamin D Deficiency in CKD

Since it has been demonstrated that there is a high prevalence of vitamin D insufficiency and deficiency in patients with CKD, the current practice guidelines recommend that the first step in correction of abnormalities in bone and mineral metabolism in these patients would be to correct the levels of 25-hydroxy vitamin D to normal in an effort to facilitate and maintain the production of 1,25-dihydroxyvitamin D.¹² Supplemental vitamin D is available in two forms: ergocalciferol (vitamin D₂) or cholecalciferol (vitamin D₃). Studies in normal subjects show that the administration of vitamin D₃ appears to be more efficacious in raising the level of 25-hydroxyvitamin D.¹³ The mode of administration might also be important. There are limited studies in this regard, but, weekly administration appears to enhance the ability of 25-hydroxyvitamin D degradation more than when daily dosing is utilized.¹⁴

Evaluation of the current practice guidelines to raise 25-dihydroxyvitamin D by the administration of ergocalciferol has shown that the practice guidelines are relatively inefficient in this regard.^15,16 Indeed, in studies by Al Aly et al., 25-hydroxyvitamin D levels could only be incremented in approximately 50 percent of patients with CKD.¹⁵ If, however, 25-hydroxyvitamin D levels can be satisfactory elevated, then PTH levels appear to decline. The reason for the heterogeneous response and relative inability to raise 25-hydroxyvitamin D is unknown at the present time, and is an area of active investigation. Central to this issue is the importance of local production of 1,25-dihydroxyvitamin D, in that if this is an important physiologic function, then it would seem to be imperative to satisfactorily elevate the levels of substrate 25-hydroxyvitamin D. This issue may be particularly important in view of the observations that suggest that administration of active forms of vitamin D in patients on hemodialysis appear to be associated with a survival advantage.^17,18 The mechanism of this apparent survival benefit is unknown, but has been found by many investigators. It appears that this apparent survival benefit is independent of changes in calcium, phosphorus or PTH. All active vitamin D preparations in use, such as paricalcitol, doxercalciferol or calcitriol have been associated with improved patient survival.^{19, 20} This observation also appears to be extended to patients with CKD, where it has been noted that patients who receive active vitamin D sterols appear to have a survival advantage, although no cause and effect has been shown.^{21, 22} These observations have lead to a search for the mechanisms involved, whereby active vitamin D sterols could potentially affect outcomes, and indeed, it has been suggested that vitamin D may be a powerful regulator of the renin angiotensin system, based upon studies in experimental animals. It has also been suggested that active vitamin D sterols may affect the various processes associated with the progression of kidney disease, and so there is some biological plausibility that the vitamin D system may play a role in kidney disease progression ^23–27

Recommendations for Vitamin D Therapy in CKD

Current practice guidelines have provided a reasonable approach to the therapy of disorders of bone and mineral metabolism in patients with CKD. The initial practice guidelines have recently been modified by KDIGO guidelines.¹ The recommendations can be summarized in that they recommend the evaluation of disturbances of bone and mineral metabolism early in the course of CKD, first by measuring PTH, and if this is elevated, then the next step would be to evaluate vitamin D status by the measurements of 25-hydroxyvitamin D. If the levels of 25-hydroxyvitamin D are below 30 ng/ml, efforts should be undertaken to correct this to normal, using various vitamin D preparations. If this is not successful, then therapy with active vitamin D sterols should be considered. Based upon results in experimental animals, it would appear that dietary phosphate restriction should also be undertaken early in the course of CKD, and even the use of phosphate binders might be considered. As kidney disease progresses and glomerular filtration rates (GFRs) fall, it may be that the active metabolites of vitamin D are required to achieve satisfactory control of the abnormalities of bone and mineral metabolism.

It is currently unknown whether it is better to provide 25-hyroxyvitamin D, or if 1,25-dihydroxyvitamin D and other active metabolites are satisfactory to achieve this improved outcome. In this regard, one might consider the observations of Wolf et al., who showed the correlation of 25-hydroxyvitamin D levels with early mortality in patients on dialysis, where the mortality appeared to stratify, according to the levels of 25-hydroxyvitamin D.²⁸ These observations showed that if active vitamin D metabolite was administered, stratification of mortality by 25-hydroxyvitamin D levels was eliminated, suggesting that the active forms of vitamin D are sufficient to mediate this survival benefit. These conclusions are supported by studies in experimental animals, where the active metabolite, 1,25-dihydroxyvitamin D improved left ventricular hypertrophy, and suggests that the heart could be a potential target for the non-classical actions of vitamin D.²⁹

Thus, in-depth research over the past two decades has uncovered many actions of vitamin D which may be important, not only for bone and mineral metabolism, but also which appear to have an impact on patient survival. There is active clinical research ongoing to answer many questions in clinical medicine, including the optimal time to screen for vitamin D deficiency and to consider whether it should be evaluated irrespective of changes in PTH or other abnormalities in bone and mineral metabolism. In addition, there is active research to find more effective treatments for vitamin D deficiency and to investigate potential therapeutic differences between the various vitamin D metabolites. As the field advances and these mechanisms are uncovered, it is possible that these pathways can be exploited to achieve improved outcomes for our patients.

Biography

Kevin J. Martin, MB, BCh, FASN, is a Professor of Internal Medicine, and Director, Division of Nephrology, at Saint Louis University School of Medicine. Esther A. González is also at Saint Louis University School of Medicine.

Contact: martinkj@slu.edu