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12 Which Vitamin D Should We Use? Native Vitamin D or Active VDRA Compound? D2 or D3?
Vitamin D and Mortality Risk in Chronic Kidney Disease
Studies capable of demonstrating a positive effect of treatment with vitamin D compounds at the patient level are difficult to undertake if sufficiently robust. Thus virtually all of the available data to hand at the moment fall some way short of being
able to establish clear cut cause and effect in regard to mortality, and also in regard
to specific patient level outcomes that are themselves likely to impact on mortality.
Thus far interventional studies have focused largely on biochemical end points,
although some have examined other surrogates such as mortality and morbid events
that may be closer to the holy grail of patient level outcomes that really matter.
Nevertheless we still lack convincing data from randomized intervention controlled
trials demonstrating that any formulation of vitamin D results in improved patient
level outcomes, although some are planned or are in progress. To be set against this
negative view are the background plausibility as outlined above, and the experimental data and the extensive observational clinical data currently available.
The same limitations apply when it comes to making recommendations in regard
to the indications for vitamin D treatment beyond the classical ones related to bone
and mineral metabolism. This somewhat negative and cautious conclusion that
applies to patients with CKD is close to that drawn by the Institute of Medicine
when making recommendations regarding vitamin D supplementation . That
organisation considered how to ensure that the vitamin D requirements of the general population should be met and concluded that there was sufficiently robust evidence of beneficial effects in relation to classical bone mineral and skeletal
indications to justify current strategies, albeit at slightly higher dose than historically recommended. The Institute of Medicine stopped short of recommending
higher doses such as have been considered in the setting of the pleiotropic actions
of cholecalciferol and also stopped short of routinely recommending treatment with
vitamin D for indications related to infection, autoimmunity or cancer.
For the nephrologist one thing is clear. We need patient level outcome data from
properly designed intervention studies capable of establishing, or refuting, cause and
effect. Less clear is what we should do in the meantime . A pragmatic view, based
on the principle of “do good if you can, provided you do no harm”, is to use active
vitamin D compounds in appropriate pharmacological doses, often supraphysiological, for established indications based on the classical actions of vitamin D on the parathyroids, bone and mineral metabolism. This then leaves two important unanswered
questions. First, should all CKD patients, whether or not manifesting an established
indication, be offered physiological doses of active vitamin D in the hope of reaping
the benefit implied in the results of the many large observational studies already published? Second, should generous supplementation with native vitamin D be offered to
all CKD patients with the aim of supporting widespread extra renal generation of calcitriol and facilitating the putative pleotropic effects of vitamin D that could mitigate
some of the cardiovascular and other attrition faced by these patients (Fig. 24.1)? Such
an approach appears extraordinarily unlikely to do harm and so, for the time being at
least, a cautious and provisional “yes” to both questions appears justified.
Unless contraindicated, default to:
Generous D3 supplementation
to 75 - 150nM
(typically 10,000 – 30,000 units/week)
Physiological replacement of deficient calcitriol
(alfacalcidol/calcitriol 0.125 - 0.25mcg/d)
continue as above
Fig. 24.1 An approach to vitamin D management in CKD. This presumes that the clinician is
willing to make a decision on the basis of likely risk vs. possible, but unproven, benefit. It reflects
widely adopted clinical practice. It is not based on hard evidence or current published guidance
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Vitamin D in Kidney Transplantation
Abstract Renal transplantation restores renal functional mass and corrects metabolic and hormonal disturbances underlying the altered vitamin D metabolism in
chronic kidney disease. As a consequence, concentrations of 1,25 dihydroxyvitamin
D rapidly recover after successful renal transplantation. Remarkably however, concentrations remain often at the lower range in the early posttransplant period despite
the presence of hyperparathyroidism and hypophosphatemia, conditions known to
stimulate increased calcitriol synthesis. Also 25-hydroxyvitamin D concentrations
increase following transplantation but, overall, these increases are modest.
25-hydroxyvitamin D deficiency and insufficiency thus remain very common
among renal transplant recipients. Hypovitaminosis D may contribute to persistent
hyperparathyroidism and posttransplant bone and vascular disease. Limited epidemiological evidence also suggest that hypovitaminosis D may foster malignancies
and infections in renal transplant recipients. Disappointingly, intervention studies
with vitamin D supplementations studies are scanty. They moreover did not yield
unequivocal results. Hard endpoint intervention studies are lacking at all.
Keywords Vitamin D • Renal transplantation • CKD-MBD
For patients with end stage renal disease, kidney transplantation undoubtedly is the
best treatment option. Worldwide, the numbers of transplanted kidneys rise steadily.
In the US alone, more than 17,500 kidneys are transplanted annually. The development of novel immunosuppressive therapies has led to a tremendous increase in the
1-year survival rates of renal allografts . Accordingly, improving the long-term
survival and quality of life for renal transplant recipients has become a major focus
P. Evenepoel, MD
Division of Nephrology, Dialysis and Renal Transplantation, Department of Medicine,
University Hospital Leuven, Leuven, Belgium
© Springer International Publishing Switzerland 2016
P.A. Ureña Torres et al. (eds.), Vitamin D in Chronic Kidney Disease,
of post-transplantation patient care and includes prevention of cardiovascular
complications, diabetes mellitus, infections, cancer, and fractures associated with
bone disease. The increased awareness that vitamin D deficiency, being common
among renal transplant recipients may be involved in the pathogenesis of each of
these complications, fueled interest in posttransplant vitamin D metabolism and
triggered several interventional studies specifically exploring the pivotal benefits of
vitamin D supplementation on bone metabolism and beyond. The present review
aims to present a state of the art on vitamin D metabolism and its association with
non-renal outcomes in kidney transplant recipients.
Vitamin D Metabolism in Health, Chronic Kidney
Disease and Renal Transplantation
Vitamin D Metabolism in Health
Vitamin D is a steroid hormone whose primary function is to regulate calcium
homeostasis and bone mineralization; however, it is increasingly thought to exert
important effects on other tissues such as vascular endothelium and cells of the
immune system. It is a unique vitamin in that it can be sourced from the diet or
synthesized in the skin by ultraviolet B (UVB) sunlight. Most people depend on
solar synthesis of vitamin D to achieve adequate body stores, with dietary vitamin
D normally contributing only 10–20 % of the recommended intake. The formation
of fully active vitamin D out of the prohormones ergocalciferol (vitamin D2) and
cholecalciferol (vitamin D3) requires a further two-step hydroxylation process.
Hepatocytes mediate the first hydroxylation on carbon 25 (by the action of CYP2R1)
to produce 25-hydroxyvitamin D (25(OH)D), also known as calcidiol), which binds
the vitamin D receptor (VDR) with only a modest affinity. The complete activation
of vitamin D requires further hydroxylation on carbon 1 by the enzyme CYP27B1,
resulting in the formation of calcitriol or 1,25 dihydroxyvitamin D (1,25(OH)2D).
This last step takes place mainly in the proximal tubular cells of the kidney. Both
25(OH)D and 1,25(OH)2D undergo catabolism via multiple side chain hydroxylations. Vitamin D catabolism is mediated mainly by renal CYP24A1. Evidence suggests that CYP3A4, i.e. the most abundant cytochrome P450 enzyme in the liver,
may also be involved. The quantitative contribution of CYP3A4 to vitamin D catabolism, compared to CYP24A1, is poorly defined.
Production and catabolism of 1,25(OH)2D by the kidney is tightly regulated
through a complex system of hormones that together maintain calcium and phosphorus homeostasis. These hormones include parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and 1,25(OH)2D itself. While 1,25(OH)2D is
considered the biologically active form of vitamin D, 25(OH)D is the major circulating form and is considered the more reliable measure of vitamin D status.
Vitamin D in Kidney Transplantation
Vitamin D Metabolism in Chronic Kidney Disease
In CKD, 1,25(OH)2D production is reduced owing to alterations in CYP
abundances, CYP activity, and delivery of substrate to CYP enzymes (for review
see ). PTH and FGF23 exert opposite effect on CYP27B1 expression. The net
effect is uncertain, as evidenced by experimental and clinical data. Impaired
delivery of 25(OH)D to CYP27B1 and/or decreased CYP27B1 activity may prove
more important than decreased enzymatic mass in CKD. Circulating 25(OH)D
levels in CKD patients are often low as a result of low sun exposure, decreased
cutaneous synthesis, and limited dietary intake. Moreover, reabsorption of filtered
25(OH)D in the proximal tubule may be impaired in CKD as a consequence of
decreased megalin expression. CKD also disrupts vitamin D catabolism. PTH
suppresses, while FGF23 stimulates CYP24A1 expression and activity. The net
effect remains, as for CYP27B1, incompletely understood. Most recent data suggest that CKD should be considered a state of stagnant vitamin D metabolism
characterized by reduced vitamin D catabolism and turnover in addition to reduced
1,25(OH)2D production. In this paradigm, competing effects of PTH and FGF23
on the expression of CYP27B1 and CYP24A1 either balance each other or are
superseded by a general decrease in vitamin D metabolic function of the kidney,
caused either by impaired uptake of 25(OH)D, diminished metabolic activity of
proximal tubular cells, or a simple reduction in the number of functioning nephrons (for review see ).
Vitamin D Metabolism in Renal Transplant Recipients
Renal transplantation restores, at least partly, renal functional mass and corrects
metabolic and hormonal disturbances underlying the altered vitamin D metabolism
in CKD .
25(OH)D Levels in Renal Transplant Recipients
Following renal transplantation, serum 25(OH)D levels commonly follow a
biphasic pattern characterized by an early decrease followed by a modest recovery
[4–8]. Several mechanisms may be hypothesized to contribute to the early decline
; first, tubular dysfunction (related to ischemia-reperfusion injury) associates
with overload proteinuria which may result in substantial urinary losses of the
Vitamin D- Vitamin D binding protein complex. Second, vitamin D catabolism
may be enhanced in the posttransplant period, due to upregulation of CYP24A1
either by inappropriately high FGF23 levels  or by glucocorticoids .
Despite a slight recovery of 25(OH)D levels later on, 25(OH)D levels remain