Kidney failure – still debating what form of vitamin D to use – April 2016

Kidney vitamin D debate with moderation

Moderator's view: Vitamin D deficiency treatment in advanced chronic kidney disease: a close look at the emperor's clothes

Nephrology Dialysis Transplantation Volume 31, Issue 5Pp. 714-716.
Carmine Zoccali1 and Francesca Mallamaci1,2
1CNR-IFC, Clinical Epidemiology and Pathophysiology of Hypertension and Renal Diseases, Ospedali Riuniti, 89124 Reggio Calabria, Italy
2Nephrology, Hypertension and Renal Transplantation Unit, Ospedali Riuniti, Reggio Calabria, Italy
Correspondence and offprint requests to: Carmine Zoccali; E-mail: carmine.zoccali at tin.it

Two recent vitamin D supplementation (ergocalciferol) trials in stage G5D CKD patients with vitamin D insufficiency showed that this sterol effectively increases serum 25-hydroxyvitamin D [25(OH)D] but fails to modify serum PTH and other clinical outcomes. The Pro side of this polar view emphasizes that the duration of these studies was too short to allow sensible analyses based on a clinical endpoint. Furthermore, he notes that in the second study, the use of active forms of vitamin D, phosphate binders and cinacalcet could have hindered appreciation of the effect of ergocalciferol supplementation per se. The Con side produces an updated meta-analysis showing that inactive vitamin D forms largely fail to reduce serum PTH and affect various relevant endpoints, including muscle strength, functional capacity, quality of life and hospitalization. Studies suggesting an effect of inactive vitamin D forms in advanced CKD are either very small and mainly based on sequential, uncontrolled observations or inherently weak, simple pre/post studies. No biological or clinical evidence exists that 25(OH)D may exert meaningful effects in CKD patients who are being treated with active forms of vitamin D. Careful a etiologic studies based on the omics sciences, i.e. precise pathophysiological profiling of individual CKD patients followed by consequential, well-targeted intervention(s) in the precision medicine scenario, will likely provide a definitive answer to the lingering question of whether inactive vitamin D forms may have biological effects beyond those produced by their proximate metabolite 1,25-dihydroxyvitamin D3.

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Pro: Should we correct vitamin D deficiency/insufficiency in chronic kidney disease patients with inactive forms of vitamin D or just treat them with active vitamin D forms?

Nephrology Dialysis Transplantation Volume 31, Issue 5Pp. 698-705.
David J.A. Goldsmith, david.goldsmith at gstt.nhs.uk
Guy's and St Thomas’ Hospitals, London, UK

Evidence for the usefulness of using vitamin D to treat ‘renal bone disease’ is now nearly six decades old. In regular clinical practice, however, it is more like three decades, at most, that we have routinely been using vitamin D to try to prevent, or reverse, the impact of hyperparathyroidism on the skeleton of patients with chronic kidney disease (CKD). The practice has been in the main to use high doses of synthetic vitamin D compounds, not naturally occurring ones. However, the pharmacological impacts of the different vitamin D species and of their different modes, and styles of administration cannot be assumed to be uniform across the spectrum. It is disappointingly true to say that even in 2016 there is a remarkable paucity of evidence concerning the clinical benefits of vitamin D supplementation to treat vitamin D insufficiency in patients with stage 3b–5 CKD. This is even more so if we consider the non-dialysis population. While there are a number of studies that report the impact of vitamin D supplementation on serum vitamin D concentrations (unsurprisingly, usually reporting an increase), and some variable evidence of parathyroid hormone concentration suppression, there has been much less focus on hard or semi-rigid clinical end point analysis (e.g. fractures, hospitalizations and overall mortality). Now, in 2016, with the practice pattern changes of first widespread clinical use of vitamin D and second widespread supplementation of cholecalciferol or ergocalciferol by patients (alone, or as multivitamins), it is now, in my view, next to impossible to run a placebo-controlled trial over a decent period of time, especially one which involved clinically meaningful (fractures, hospitalisation, parathyroidectomy, death) end-points. In this challenging situation, we need to ask what it is we are trying to achieve here, and how best to balance potential benefits with potential harm.

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Con: Nutritional vitamin D replacement in chronic kidney disease and end-stage renal disease

Nephrology Dialysis Transplantation Volume 31, Issue 5Pp. 706-713.
Rajiv Agarwal1 and Panagiotis I. Georgianos2
1Department of Medicine, Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
2Division of Nephrology and Hypertension1st Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Greece
Correspondence and offprint requests to: Rajiv Agarwal; E-mail: ragarwal at iu.edu

Insufficiency of 25-hydroxyvitamin D [25(OH)D] is highly prevalent among patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD) and is a critical component in the pathogenesis of secondary hyperparathyroidism. Accordingly, current National Kidney Foundation—Kidney Disease Outcomes Quality Initiative and Kidney Disease: Improving Global Outcomes guidelines recommend the correction of hypovitaminosis D through nutritional vitamin D replacement as a first-step therapeutic approach targeting secondary hyperparathyroidism. In this Polar Views debate, we summarize the existing evidence, aiming to defend the position that nutritional vitamin D replacement is not evidence-based and should not be applied to patients with CKD. This position is supported by the following:

• (i) our meta-analysis of randomized controlled trials shows that whereas nutritional vitamin D significantly increases serum 25(OH)D levels relative to placebo, there is no evidence either in predialysis CKD or in ESRD that parathyroid hormone (PTH) is lowered;
• (ii) on the other hand, in randomized head-to-head comparisons, nutritional vitamin D is shown to be inferior to activated vitamin D analogs in reducing PTH levels; (
• iii) nutritional vitamin D is reported to exert minimal to no beneficial actions in a series of surrogate risk factors, including aortic stiffness, left ventricular mass index (LVMI), epoetin utilization and immune function among others; and
• (iv) there is no evidence to support a benefit of nutritional vitamin D on survival and other ‘hard’ clinical outcomes.

Whereas nutritional vitamin D replacement may restore 25(OH)D concentration to near normal, the real target of treating vitamin D insufficiency is to treat secondary hyperparathyroidism, which is untouched by nutritional vitamin D. Furthermore, the pleotropic benefits of nutritional vitamin D remain to be proven. Thus, there is little, if any, benefit of nutritional vitamin D replacement in CKD.