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7 Nutritional Vitamin D: Optimal Levels, Required Supplementation Dose and Toxicity
Which Vitamin D in Chronic Kidney Disease
vitamin D receptor , and the higher levels by itself would lead to protective
acceleration of degradation. This could explain the trend toward a smaller relative
increment in serum 25(OH)D when higher doses of vitamin D are given .
FGF23 levels tend to be high in dialysis patients. It has been postulated that FGF23
levels could stimulate 24-hydroxylase activity and explain in part very high prevalence of low 25(OH)D and 1,25(OH)2D levels in dialysis patients. It has been
recently shown that patients with CKD exhibit an decrease ability to increase serum
24,25(OH)2D3 after cholecalciferol therapy, suggesting decreased 24-hydroxylase
activity in CKD . The observed relationship between baseline FGF23 and
increments in 24,25(OH)2D3 further refutes the idea that FGF23 directly contributes to 25(OH)D insufficiency in CKD through stimulation of 24-hydroxylase
In addition to the endocrine effects of the vitamin D axis on bone and mineral
metabolism, studies have demonstrated there is also extrarenal conversion of
25(OH) vitamin D to 1,25(OH)2 vitamin D in multiple cells leading to autocrine
effects. This advance has led to the speculation that CKD patients may also need to
be supplemented with nutritional vitamin D (ergocalciferol or cholecalciferol).
Unfortunately, to date, the majority of interventional studies have focused on biochemical end points. There are no randomized controlled trials demonstrating that
therapy with any formulation of vitamin D results in improved patient level outcomes. Despite the physiologic importance of vitamin D in health and disease, more
research is required to determine which vitamin D derivative is required for optimal
health in CKD patients. Observational studies or even clinical trials in populations
different from the one we are studying may not clearly inform the practicing physician of the correct treatment. Examples of this are hormone replacement therapy in
women or statin use in dialysis patients. The real gold standard for clinical decisionmaking come from randomized clinical trials, conducted in the population we want
to treat and with clinically meaningful end points. Unfortunately, this level of evidence does not exist for vitamin D therapy in CKD. There are no randomized controlled trials demonstrating that therapy with any formulation of vitamin D results
in improved patient level outcomes. Without randomized clinical trials, causation
cannot be inferred from observational studies. Because well designed clinical trials
are expensive, evidence from animal studies, observational studies, and small pilot
randomized trials with surrogate outcomes are needed to evaluate which therapies
have the most potential for success to be tested in definitive clinical trials.
Multiple observational studies suggest an important role of vitamin D in patients
with CKD and ESRD and potentially in the general population. There could be
potentially different roles for nutritional and active vitamin D compounds, having
nutritional vitamin D a preferred role in infections and cancer prevention, whereas
active vitamin D compounds may play more of a role bone disease and mortality.
A.L. Negri et al.
Both nutritional and active vitamin D, eventually activate the same vitamin D receptor; however, nutritional vitamin D has to undergo additional activation in other
body sites distant from the kidney. Active vitamin D has been shown to decrease
albuminuria, blood pressure, and eGFR in patients with diabetic kidney disease.
There are current ongoing studies to test these outcomes with nutritional vitamin D
compounds as well. It is important to mention that there are very few data about
combining therapy with both nutritional and active vitamin D compounds; thus,
caution should be used in clinical practice because of worry about possible vitamin
D intoxication, manifested by hypercalcemia and possibly vascular calcifications.
Many questions remain unanswered. For example, do we need to measure
25(OH)D levels in all CKD patients, or can we replete knowing that of them most
are deficient? Can we combine nutritional and active vitamin D or does this put
patients at increased risk? Does vitamin D has to be replaced in renal transplant
patients and does this affect graft function?
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Use of New Vitamin D Analogs in Chronic
Riccardo Floreani and Mario Cozzolino
Abstract Vitamin D is a common treatment against secondary hyperparathyroidism in renal patients. However, the rationale for the prescription of vitamin D sterols
in chronic kidney disease (CKD) is rapidly increasing due to the coexistence of
growing expectancies close to unsatisfactory evidences, such as the lack of randomized controlled trials (RCTs) proving the superiority of any vitamin D sterol against
placebo on patient-centered outcomes, the scanty clinical data on head-to-head
comparisons between the multiple vitamin D sterols currently available, the absence
of RCTs confirming the crescent expectations on nutritional vitamin D pleiotropic
effects even in CKD patients and the promising effects of vitamin D receptors activators (VDRA) against proteinuria and myocardial hypertrophy in diabetic CKD
cohorts. The present chapter arguments these issues focusing on the opened questions that nephrologists should consider dealing with the prescription and the choice
of a VDRA.
Keywords VDRA • Alfacalcidol • Doxercalciferol • Paricalcitol • Cinacalcet •
Secondary hyperparathyroidism • Albuminuria • Left ventricular hypertrophy • Left
atrial dimension • Bone histology • Bone mineral density • Kidney transplantation
Secondary hyperparathyroidism (SHPT) is recognized as a major complication of
chronic kidney disease (CKD). Over the past decades, nephrologists have been
encouraged to effectively control PTH due to the reported worrisome consequences
R. Floreani, MD
Renal and Dialysis Unit, San Paulo Hospital, Milan, Italy
M. Cozzolino, MD, PhD, FERA (*)
Renal Division, Department of Health Sciences, San Paolo Hospital, University of Milan,
© Springer International Publishing Switzerland 2016
P.A. Ureña Torres et al. (eds.), Vitamin D in Chronic Kidney Disease,
R. Floreani and M. Cozzolino
of SHPT as pruritus, bone pain, severe bone demineralization, skeletal fractures,
brown tumors, severe cardiac hypertrophy, and calciphylaxis. Although repeated
observational data described an independent association between serum PTH levels
and unfavorable outcomes in CKD stage 3–5 as well as in end-stage renal disease
(ESRD) patients, no randomized controlled trial (RCT) has still proven that an
active reduction of PTH values could improve patient-centered outcomes as hospitalizations, cardiovascular events (CVE), CKD progression, and survival.
Furthermore, the optimal targets of PTH levels are still uncertain in CKD as well as
in ESRD cohorts. Thus, Kidney Disease-Improving Global Outcomes (KDIGO)
guidelines provide a low-grade suggestion to maintain serum PTH levels into the
range of normality in CKD 3–5 and between two and nine times the upper limit of
normal range in ESRD.
Active vitamin D receptor activators (VDRA) (Table 30.1) are one of the classic
therapies suggested to achieve those PTH targets. Emerging evidence of several
pleiotropic effects related to the activation of the vitamin D receptor (VDR) is transforming the original world of vitamin D into a more complex scenario and affecting
the use of vitamin D sterols among nephrologists. Different forms of vitamin D
analogs are currently available in several countries, but clinical data on head-to-head
comparisons between them are still scanty. Nonetheless, promising data suggest
some beneficial effects of vitamin D analogs on proteinuria, myocardial hypertrophy in diabetic CKD cohorts, inflammation, and cardio-renal syndromes. Nutritional
vitamin D replenishment is also receiving a growing interest for its potential autocrine-paracrine effects even in CKD patients, although its use is still based on observational rather than RCT data.
Table 30.1 Vitamin D sterols currently available as medical treatments in nephrology field
Nutritional vitamin D
required to activate
All the VDRA reported in the table are considered analogs with the exception of calcitriol, which
corresponds to the natural form of 1,25(OH)2D3
VDRA vitamin D receptor activators, VDR vitamin D receptor
30 Use of New Vitamin D Analogs in Chronic Kidney Disease
Non-dialysis CKD: Effects on Bone Histology and Bone
A multicenter, prospective, double-blind, randomized, placebo-controlled trial was
conducted on 176 non dialysis CKD patients (GFR 15–50 ml/min) with no baseline
clinical, radiographic or biochemical signs of bone disease to test efficacy of a
2 year oral Alfacalcidol treatment (dose range 0.25 μg every other day to 1 μg a day)
on bone histological pattern and quantitative changes in histomorphometric parameters . Oral Alfacalcidol was administered in order to maintain serum calcium
concentration at the upper limit of the normal laboratory reference range; calcium
supplements were allowed (maximum 500 mg a day of elemental calcium), phosphorus restriction and phosphate binders were allowed to keep serum phosphate
below 6.8 mg/dl.
All 176 patients underwent baseline bone biopsy, while only 134 (76 %) received
a second bone biopsy at the end of treatment (n = 124) or after premature withdrawal
because of starting dialysis (n = 10). Reasons for premature withdrawal included
need to start dialysis, default and death, while no patients withdrew for adverse
By definition, all 176 patients had normal serum calcium and alkaline phosphatase at baseline, while serum phosphate levels were high in 50 patients and PTH
levels were high in 72 patients. Prevalence of histological abnormalities was high at
baseline (132/176 patients), with those patients with no subclinical bone disease
having a higher mean GFR. After randomization, no difference in baseline biochemical and bone disease pattern was found between treatment groups, except for
PTH levels (93.6 pg/ml VS 58.2 pg/ml in Alfacalcidol group versus placebo,
Among 134 patients, 72 taking Alfacacidol and 62 taking placebo, whom paired
bone biopsy specimens were available for analysis, 76 % and 73 % respectively had
significant bone abnormalities at baseline. At the end of the study, proportion of
patients with bone disease decreased to 54 % in Alfacacidol group, while it increased
to 82 % in placebo group. When considering only patients with bone abnormalities
at baseline, 42 % of patients receiving Alfacalcidol treatment showed normal bone
histology at the end of the study compared to only 4 % receiving placebo. Among
patients with apparently normal bone at baseline, no difference in bone histology
was found between groups at the end of the study. When compared to placebo,
Alfacalcidol treatment among patients with subclinical bone disease caused a
statistical significant decrease in bone marrow fibrosis, bone turnover (bone resorption and bone formation) and osteomalacia indexes. Four of the six patients in
Aflacalcidol group resolved adynamic bone disease (ABD) by the end of the study
versus two out of the three patients taking placebo; by contrast eight versus four
patients in Alfacalcidol and placebo group respectively developed ABD.
R. Floreani and M. Cozzolino
Mild hypercalcemia occurred in three patients given placebo versus ten patients
given Alfacalcidol, severe hypercalcemia occurred only in one patient taking
Alfacalcidol. Serum phosphate levels increased in both groups in a similar way.
Serum PTH levels rapidly decreased among patients taking Alfacalcidol and then
returned toward baseline levels by 24 month, while progressive increase of serum
PTH levels was observed in placebo group. Serum total alkaline phosphatase levels
showed a similar trend. Serum 25(OH) vitamin D levels were not assessed. There was
a similar decline in glomerular filtration rate (GFR) decline between groups (P = 0.94).
These results strongly support precocious use of Alfacalcidol among CKD
patients in order to improve subclinical bone disease: benefits seem to overwhelm
hazards in terms of developing ABD, hypercalcemia risk and fastening GFR
Results from this study were corroborated by another small prospective double
blind placebo-controlled study which examined the effect of 18-month low dose
Alfacalcidol treatment on bone mineral density (BMD) and markers of bone metabolism in early CKD (GFR 10–60 ml/min) . Starting dose of 0.25 μg a day was
increased in a 3-month period up to a maximum of 0.75 μg a day, while maintaining
ionized serum calcium below 1.35 mmol/l and serum phosphate below 6.2 mg/dl.
BMD was assessed in five sites: lumbar spine, femoral neck, total femur, distal forearm, and total body. ANOVA analysis with BMD as the dependent variable and
treatment and time as independent variables suggested a significant effect of
Alfacalcidol treatment on BMD in the hip, spine and total body sites. During treatment period, only one episode of hypercalcemia occurred among Alfacalcidoltreated subjects, serum phosphate levels were unaffected and a between-group
difference in serum PTH levels was evident from week 3 onward, with lower levels
among Alfacalcidol-treated subjects. Alfacalcidol-treated group showed a significant decrease over time of serum osteocalcin and bone alkaline phosphatase levels
compared to placebo, while no statistical differences was observed in propeptide of
type I collagen (PICP) – a marker of bone formation – and telopeptide of type I collagen (ICTP) – a marker of bone resorption. No difference in GFR decline rate was
also found between groups.
Kidney Transplant Recipients: Effects on Bone Mineral
Bone disease after kidney transplantation is a complex matter with multiple contributing factors, including corticosteroid treatment, duration of prior chronic renal
disease and dialysis, metabolic acidosis, vitamin D insufficiency/deficiency, hyperparathyroidism, hypophosphatemia, diabetes mellitus, etc. A few studies suggest
beneficial effects of Alfacalcidol treatment among kidney transplant recipients.
A randomized study examined the effect of a 12 months course of low dose
Alfacalcidol plus calcium versus calcium supplementation alone in pediatric