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7 Nutritional Vitamin D: Optimal Levels, Required Supplementation Dose and Toxicity

7 Nutritional Vitamin D: Optimal Levels, Required Supplementation Dose and Toxicity

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29



Which Vitamin D in Chronic Kidney Disease



507



vitamin D receptor [99], 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 [103].

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 [104]. 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

activity.



29.8



Conclusions



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.



508



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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102. Sakaki T, Sawada N, Komai K, Ahiozawa S, Yamada S, Yamamoto K, Ohyama Y, Inouye

K. Dual metabolic pathway of 25-hydroxyvitamin D3 catalyzed by human CYP24. Eur

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103. Aloia JF, Patel M, Dimaano R, Li-Ng M, Talwar SA, Mikhail M, Pollack S, Yeh JK. Vitamin

D intake to attain a desired serum 25-hydroxyvitamin D concentration. Am J Clin Nutr.

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104. Stubbs JR, Zhang S, Friedman PA, Nolin TD. Decreased conversion of 25-hydroxyvitamin

D3 to 24,25-dihydroxyvitamin D3 following cholecalciferol therapy in patients with

CKD. Clin J Am Soc Nephrol. 2014;9(11):1965–73.



Chapter 30



Use of New Vitamin D Analogs in Chronic

Kidney Disease

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



30.1



Introduction



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

e-mail: Riccardo.Floreani@unimi.it

M. Cozzolino, MD, PhD, FERA (*)

Renal Division, Department of Health Sciences, San Paolo Hospital, University of Milan,

Milan, Italy

e-mail: mario.cozzolino@unimi.it

© Springer International Publishing Switzerland 2016

P.A. Ureña Torres et al. (eds.), Vitamin D in Chronic Kidney Disease,

DOI 10.1007/978-3-319-32507-1_30



515



R. Floreani and M. Cozzolino



516



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



Vitamin

D2 and

its

analogs

Vitamin

D3 and

its

analogs



Nutritional vitamin D

Hydroxylation

required to

activate VDR

Ergocalciferol

25-hydroxylation

and

1-hydroxylation

Cholecalciferol



Calcifediol



25-hydroxylation

and

1-hydroxylation

1-hydroxylation



VDRA



Paricalcitol

19-nor1,25(OH)2D2

Doxercalciferol

1α(OH)D2

Calcitriol

1,25(OH)2D3

Alfacalcidol 1α(OH)

D3

Oxacalcitriol

22oxa1,25(OH)2D3



Hydroxylation

required to activate

VDR



25-hydroxylation



25-hydroxylation





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



30.2

30.2.1



517



Alfacalcidol

Non-dialysis CKD: Effects on Bone Histology and Bone

Mineral Density



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 [1]. 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

events.

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,

respectively).

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.



518



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

decrease.

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) [2]. 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.



30.2.2



Kidney Transplant Recipients: Effects on Bone Mineral

Density



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



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