Vitamin D supplementation in renal disease: Is calcitriol all that is needed?

Abstract

Vitamin D not only plays important roles in mineral metabolism, but also affects the risk of mortality and cardiovascular events. Since the kidney is the main organ that produces 1,25-dihydroxyvitamin D, active vitamin D sterols are widely used in patients with chronic kidney disease (CKD), especially those with secondary hyperparathyroidism. CKD patients also have higher risk of vitamin D deficiency, due to urinary loss associated with proteinuria and possible down-regulation of megalin in the proximal tubular cells. Accordingly, it is reasonable to supplement nutritional vitamin D in CKD patients with vitamin D deficiency. Although still unclear, it has been suggested that local 1α-hydroxylase activity plays more significant roles in CKD patients compared to those with normal kidney function. Future studies should examine whether correction of vitamin D deficiency, administration of active vitamin D, or both, provides survival benefits in patients with CKD.

Key Words::

• Kidney
• hyperparathyroidism
• vitamin D
• phosphorus
• proteinuria

Introduction

Ever since the first report of severe bone disease in a uremic patient by Albright [1], it has been speculated that the kidney plays important roles in mineral metabolism. Such bone diseases were initially called ‘Renal Osteodystrophy’ (ROD) [2], but has currently been renamed as ‘Chronic Kidney Disease-Mineral and Bone Disorder’ (CKD-MBD) [3], which includes vascular calcification as well as bone abnormalities.

Soon after the breakthrough discovery of the fact that the kidney is the exclusively main organ that produces active vitamin D (1,25-dihydroxy vitamin D: 1,25(OH)₂D) from 25-hydroxyvitamin D (25(OH)D) [4], oral active vitamin D sterols such as calcitriol and alfacalcidol, became available in clinical practice for patients with chronic kidney disease (CKD) [5]. Such a rapid process of drug development was in sharp contrast to the time-taking case of erythropoietin.

Nevertheless, the introduction of active vitamin D sterols, or even newer vitamin D receptor activators (VDRAs), has not yet solved all the problems in CKD patients. Meanwhile, significant roles of native vitamin D and its deficiency have recently been revisited in CKD patients.

In this brief review, we would like to summarize and discuss significant roles of vitamin D metabolites used in CKD patients, not only for mineral metabolism, but also for other abnormalities.

Deranged vitamin D metabolism and action in CKD

Hypocalcemia, hyperphosphatemia, and decreased concentration of 1,25(OH)₂D are the major direct stimuli for parathyroid hormone (PTH) secretion in CKD patients [6]. While the first two stimuli develop only in the advanced stages of CKD, serum concentrations of 1,25(OH)₂D begin to decrease along with the decline of kidney function despite the compensation by the action of PTH to stimulate 1a-hydroxylase activity in the residual proximal tubular cells.

Then, what is the main mechanism for the suppression of vitamin D activation, except for the decrease of functioning kidney tissue? Because reduction of dietary phosphorus content, proportional to the reduction of kidney function, prevents increase of PTH and decrease of 1,25(OH)₂D concentrations, it has been suggested that dietary phosphorus load should be another player that determines the activity of 1a-hydroxylase [7,8]. Recent data have further revealed that such a regulation was at least in part mediated by a peptide hormone fibroblast growth factor 23 (FGF23) produced by osteocytes in response to phosphorus load by an unknown pathway [9]. FGF23 induces phosphaturia as PTH, but in contrast suppresses 1a-hydroxylase activity in the kidney. Interestingly, 1,25(OH)₂D not only suppresses secretion of PTH directly, but also stimulates synthesis of FGF23 and thereby indirectly suppresses PTH secretion at least in patients with mild to moderate CKD, since FGF23's receptor complex Klotho-FGF receptor 1 is expressed on the parathyroid.

Considering such pathogenic mechanisms in CKD, it is reasonable to treat them with physiological doses of active vitamin D sterols. Nevertheless, hyperparathyroidism often becomes very severe and refractory to such conventional therapies in dialysis patients, especially those with long vintage. Such a resistance to 1,25(OH)₂D has been shown to be due to the reduction of vitamin D receptor density in parathyroid cells in hyperplastic glands [10]. Part of these refractory patients can be controlled by supra-physiological doses of VDRAs given intravenously; however, the severest patients with nodular hyperplasia, an advanced type of parathyroid hyperplasia, remain uncontrollable even with intravenous VDRA therapy.

Attenuated action of 1,25(OH)₂D due to low serum concentrations and/or to impaired sensitivity has also been postulated in other systems including cardio-vascular organs, suggesting their potential as new therapeutic targets of VDRAs. Although still controversial [11], several observational studies have suggested beneficial effects of VDRA treatment on survival and cardiovascular events in dialysis patients [12,13] even in the presence of higher risk of vascular calcification. Furthermore, in addition to the suppressive effects of VDRAs on the renin synthesis in the kidney [14], amelioration of proteinuria by VDRAs has been demonstrated, possibly through its direct action on the podocytes and its indirect effect of blood pressure lowering [15].

Vitamin D deficiency in CKD

Because of its long half-life, the serum concentration of 25(OH)D has long been used as a marker for vitamin D reserve status. Then, what are the major mechanisms of vitamin D deficiency specific to CKD patients? First mechanism is related to the degree of proteinuria, especially those with diabetic nephropathy [16]. Because of their comparable molecular weights, 25(OH)D bound to vitamin D-binding protein (DBP) is filtered at glomeruli as albumin and lost into the urine. Second mechanism is the failure of reabsorption of 25(OH)D-DBP complex mediated by megalin at proximal tubular cells, which process is downregulated in diabetes [17]. As suggested by clinical course of kidney disease, CKD patients with diabetic nephropathy develops vitamin D deficiency at earlier stages of CKD than in non-diabetic CKD patients. This was also proved in our observational study with CKD stages 3 to 5 patients, in which 84 % patients had 25-hydroxyvitamin D < 75 nmol/L (< 30 μg/L). In these patients, significant determinants of poor vitamin D status included diabetes and severe proteinuria, as well as female gender and high PTH [18,19].

In addition to the studies of normal population, significant associations between serum 25(OH)D concentrations and survival or other important clinical outcomes have been reported in CKD patients [20], even in dialysis patients without residual kidney function [21,22,23]. Precise mechanisms still remain unclear, however, recent data suggest putative roles of extrarenal 1α-hydroxylase activity, such as in osteoblasts, parathyroid glands, endothelial and immune cells [24]. Since CKD patients have high risk of vitamin D deficiency as detailed above, local production of 1,25(OH)₂D might have even more important roles in CKD rather than in those with normal kidney function. In fact, the 1α-hydroxylase activity in the parathyroid cells was reported to be up-regulated in patients with CKD [25]. Given that parathyroid cells express megalin, which is required for the uptake of 25(OH)D, this might explain why ergocalciferol decreases PTH concentrations even in patients with advanced CKD stages including hemodialysis patients, in whom renal 1α-hydroxylase activity is negligible.

Is supplementation of nutritional vitamin D needed in CKD patients?

Despite the absence of high levels of evidences, recent clinical practice guidelines recommend supplementation of nutritional vitamin D in CKD patients. The Kidney Disease Outcomes Quality Initiatives (K/DOQI) guidelines [26] recommend supplementation of ergocalciferol for patients with CKD stages 3 and 4 if the serum concentration of 25(OH)D is < 75 nmol/L (< 30 μg/L) and intact PTH is above the target interval for the stage of CKD, and administration of active vitamin D sterols for patients with CKD stage 5 including those receiving dialysis if intact PTH is > 300 ng/L. More recent global guidelines by the Kidney Disease: Improving Global Outcomes (KDIGO) [27] also recommends supplementation of nutritional vitamin D in cases of vitamin D deficiency, even in those on dialysis.

In recent clinical studies of dialysis patients with vitamin D deficiency, correction of vitamin D status resulted in the reduction in the doses of VDRA, almost free of adverse events [28,29]. It should be noted that the control of PTH was improved by the introduction of cheap native vitamin D therapy, leading to the reduction in dosage of expensive VDRA in these studies. Therefore, from the viewpoint of the cost, nutritional vitamin D therapy is desirable. With regard to the effect of native vitamin D on bone mineralization, ergocalciferol was reported to be very effective for osteomalacia in a hemodialysis patient, which had been refractory to long-time paricalcitol (a VDRA) therapy [30]. This case report strongly suggested a distinct role of native vitamin D therapy, which cannot be replaced by a VDRA.

Besides the effects on mineral metabolism, vitamin D supplementation possibly leads to the improvement of inflammation, nutritional status and cardiac function, as shown in the decrease of C-reactive protein, the increase in albumin, and improvement of echo parameters [29,31]. Further studies are currently under progress, also including CKD patients still not on dialysis. For example, it was found that cholecalciferol supplementation reduced not only the amount of urinary albumin, but also urinary transforming growth factor-beta1 (TGF-β1) concentration in patients with type 2 diabetic nephropathy even on established renin-angiotensin-aldosterone system inhibition [32]. Since TGF-β1 is thought to be a culprit for renal fibrosis, native vitamin D is promising also as a reno-protective agent.

Conclusion

Considering its wide safety window, supplementation of nutritional vitamin D has sufficient rationales in CKD patients with vitamin D deficiency. However, whether both nutritional and active vitamin D should be supplemented in the setting of CKD still remain to be elucidated and further well-designed clinical trials are required [33]. Finally, it is also important to take into account the local differences in the availability and reimbursement policy in 25(OH)D assay and nutritional vitamin D preparation in the indication of nutritional vitamin D administration.

Questions and Answers

JC Souberbielle, France

In terms of observance, I will tell you my experience. At least in dialysis patients, we have tested therapy with vitamin D total of 50,000 U per month professionally administered by a nurse We observed a decrease in PTH but, significantly and most importantly, no increase in serum calcium or phosphate concentrations.

G Jones, Canada

When you combine the treatments, will the patients take more pills? Maybe they don't need more pills because the active analogue may be protected by the vitamin D. Some important studies from Germany support the idea that vitamin D, being given at 1,000 times the amount of analogue, is going to be taking up least 24 hydroxylase, therefore sparing the active analogue, so you may not need so much of it.

JC Souberbielle

Yes, I agree with you. We can start these agents from the early stages of dialysis. Once severe hyperparathyroidism develops, then of course we need it.

G Jones

But don't you think that when you use the two together, you may not need a new generation of active vitamin D compound?

JC Souberbielle

Maybe for a while!

M Hewison, USA

It is interesting that the use of nutritional vitamin D was restricted to a limited number of applications. One suggestion I have heard is the potential to put the nutritional vitamin D in the dialysis fluid or make it part of the dialysis process, so they are actually getting vitamin D via a different route. Would this be realistic? It would be dependent on the type of dialysis being undertaken, but in peritoneal dialysis, I guess vitamin D would dialyse across the peritoneum.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.