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8 Native Vitamin D Supplementation and Vitamin D Analogs in CKD Children

8 Native Vitamin D Supplementation and Vitamin D Analogs in CKD Children

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238



13.9



J. Bacchetta and I.B. Salusky



Native Vitamin D Therapy



In addition to providing a substrate for the formation of calcitriol, thus indirectly

suppressing PTH levels, Ritter et al. identified that 25-D continues to directly suppress PTH synthesis even when parathyroid gland 1 alpha hydroxylase is inhibited,

thus demonstrating a direct effect of 25-D on PTH synthesis, independent of 1,25-D

[58]. Moreover, a recent placebo-controlled randomized trial also demonstrated that

ergocalciferol was able to delay the onset of secondary hyperparathyroidism in

pediatric patients with pre-dialysis CKD [8]. As such, native vitamin D supplementation appears to be a cornerstone of pediatric CKD-MBD management. Although

current international guidelines suggest that increased PTH levels, in face of 25-D

insufficiency/deficiency (<30 ng/ml) be first treated with native vitamin D supplementation, no ‘practical’ guidelines are provided concerning the dose (daily,

monthly, quarterly?) and the type of vitamin D (ergocalciferol or cholecalciferol)

depending on age, body weight, severity of 25-D deficiency and CKD stage. In the

future, clinical trials my focus on this rather simple but critical question.



13.9.1



Vitamin D Analogs



Following 25-D repletion, if hyperparathyroidism is not controlled according to

specific CKD stage, active vitamin D sterols should be initiated to help controlling

serum PTH values. However, one should keep in mind that optimal PTH levels

remain to be defined: indeed, the international KDIGO guidelines recommend PTH

levels two to nine times the upper normal limit in CKD stage V [32], whereas

European pediatric guidelines recommend PTH levels two to three times the upper

normal limit in CKD stage V [59]. This threshold remains discussed, but high PTH

levels are also well known to be associated with anemia, left ventricular hypertrophy

and vascular calcifications; a recent 2013 report from the international pediatric

peritoneal dialysis (PD) registry (IPPN) proposed a PTH target between 100 and

200 pg/ml in children undergoing chronic PD [60], keeping in mind that it can be

difficult to propose guidelines for PTH levels since the assays can have a 30–50 %

variability across the world

In 2010, a Cochrane review emphasized the paucity of long-term data on safety

and efficacy of different active vitamin D sterols for the treatment of pediatric secondary hyperparathyroidism; however, PTH levels have been shown to decrease

similarly with all preparations [61]. Although vitamin D sterols are currently the

mainstay of therapy for elevated PTH levels, over-suppression of PTH levels in

maintenance dialysis children may lead to adynamic bone disease, a condition associated with growth failure and cardiovascular calcifications. Active vitamin D sterols, particularly calcitriol, may also inhibit the growth plate. Taken together, these

data illustrate that active vitamin D sterols exert a positive role in controlling PTH

levels and osteitis fibrosa but, with excessive use, may result in excessive PTH



13



Vitamin D in Children with Chronic Kidney Disease



239



suppression, adynamic bone disease, growth failure, and progressive cardiovascular

calcifications but such suppression of secondary hyperparathyroidism is associated

with progressive rise of FGF23 [1]. Since there are currently no data demonstrating

any differences on the control of secondary hyperparathyroidism or renal osteodystrophy between the various active vitamin D sterols the choice may depend on local

prescription options; and when calcitriol was compared to doxercalciferol similar

control of secondary hyperparathyroidism was obtained but doxercalciferol had a

greater degree of osteoclastic suppression.



13.9.2



Calcimimetics



Calcimimetics have been used in pediatric CKD, but their use remains off-label

[62–64]. As discussed above, recent clinical trials in CKD adults receiving cinacalcet or placebo have shown that cinacalcet significantly decreases FGF23 levels [52].

In the meantime, international pediatric clinical trials on cinacalcet in dialysis are

ongoing, and may change our daily management of pediatric ROD and CKD-MBD

in a near future. Figure 13.1 summarizes the current understanding on phosphate/

calcium metabolism in human physiology, while Fig. 13.2 summarizes the effects

of different CKD-MBD therapies on this complex pathway.



Fig. 13.1 The current understanding of calcium/phosphate metabolism regulation in human physiology. Grey arrows corresponding to an inhibiting effect; Red arrows corresponding to a stimulating effect



J. Bacchetta and I.B. Salusky



240



a



Calcimimetics



Phosphorus



Calcium



FGF 23



PTH



Vitamin D analogs



b



Calcium-free

phosphate binders



1-25 vitamin D



Phosphorus



FGF 23



Calcium-based

phosphate binders



Calcium



PTH



Fig. 13.2 The different effects on calcium, phosphate, FGF23 and PTH levels of the current therapies used for CKD-MBD management. (a) Effects of active vitamin D analogs and calcimimetics.

(b) Effects of calcium-based and calcium-free phosphate binders. Grey arrows corresponding to an

inhibiting effect; Red arrows corresponding to a stimulating effect. It is noteworthy that not all the

Ca-free binders reduce FGF23; for example, lanthanum can reduce FGF23 levels mainly when

used with dietary restriction



13



Vitamin D in Children with Chronic Kidney Disease



13.9.3



241



Vitamin D After Pediatric Renal Transplantation



Vitamin D deficiency remains an important problem after renal transplantation

[65, 66]; in this context, regular vitamin D supplementation may serve as a potentially modifiable factor. Indeed, vitamin D plays an important role for bone quality

after renal transplantation, but it also has critical roles in immunity (through a natural inhibition of the mTor signalling) [67]. In that setting, low 25D levels before

transplantation have also been shown to be associated with an increased risk of

cancer after transplantation whilst low 25(OH)D levels have been linked with an

increased risk of delayed graft function [68, 69].



13.10



Conclusions



Recent research has confirmed that 25(OH)D has plenty of metabolic actions,

including beneficial effects on bone, vessels, inflammation, defense against infection and muscle function, all being frequent conditions in pediatric CKD patients;

however the impact of vitamin D therapy on each of these specific conditions remain

to be defined. Recently, normal 25(OH)D levels have been shown to be associated

with less proteinuria and to attenuate renal failure progression in 167 CKD children

(median GFR 51 mL/min per 1.73 m2) from the ESCAPE trial. In this study, renal

survival increased by 8.2 % per 10 nmol/L increase in 25-D levels, independently of

GFR, proteinuria, blood pressure and FGF23 levels; the threshold for observing

such an effect was 50 nmol/L [70].

Although there are no large randomized controlled trial on the effects on nutritional vitamin D in CKD patients (and especially in children!), and since vitamin D

should be considered as a hormone, it seems prudent to restore sufficient serum

levels. Over dosage is quite uncommon despite extensive administration, and could

be easily monitored by serum calcium and 25(OH)D levels, a routine measure in

pediatric CKD. In the future, international and large clinical trials should provide

not also practical guidelines for 25-D supplementation but also evidence for global

beneficial effects of this non-expensive and well-tolerated drug.

Disclosure of Interest JB: research grants from Amgen, Sandoz, Novartis and Crinex; consulting

fees from Amgen, Genzyme, Otsuka and Pfizer.

IBS: Amgen, OPKO, Abbvie and Sanofi



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Part III



Non-classical Effects of Vitamin D



Chapter 14



Vitamin D and Progression of Renal Failure

Marc De Broe



Abstract In addition to his widely recognized endocrine effects on the calcium,

phosphate, PTH metabolism, vitamin D has many other pleiotropic effects on the

vascular function, blood pressure, proteinuria, insulin resistance, lipid metabolism,

inflammation, immunity which all may play a role in the progression of renal failure.

Angiotensin-converting enzyme inhibitors (ACEi) for renin-angiotensin-aldosterone

system (RAAS) blockade are routinely used to slow CKD progression. Natural vitamin D and active vitamin D analogs may further reduce proteinuria in CKD patients

in addition to these current treatment regimens. The inverse correlation of blood

pressure and vitamin D plasma levels as well as promising data from small intervention studies of vitamin D supplementation provide a rationale for well performed

RCT addressing efficacy and safety of vitamin D in hypertension/cardiovascular

diseases. Unfortunately, up to now three RCT have not been able to support this.

Determination of the optimal vitamin D analogue and its optimal dosage in case

of protection or slowing down the development of vascular calcifications remains to

be investigated in depth in pre-clinical and clinical conditions. Vitamin D supplementation may lead to a small but significant improvement in mortality but did not

appear to prevent the development of diabetes in the largest clinical trial to date.

Effects of Vitamin D on renal fibrosis and slowing down/preventing progressive

renal damage has been investigated thoroughly in vitro, in vivo and in humans but

currently limited to a promising item. The increase in serum creatinine observed

during several studies is not attributable to a decrease of the glomerular filtration

rate but on the increased creatinine generation, an anabolic effect of vitamin

D. Natural vitamin D and active vitamin D preparations are among the few reasonable and evident candidates to be tested in a multicenter, prospective RCT as a

potential protector of the failing kidney in patients with CKD 3 and 4.

Keywords Chronic kidney disease • Proteinuria • Hypertension • Renin

• Angiotensin • Aldosterone • Calcium • Parathyroid hormone • Phosphate • VDR

• Inflammation • FGF23 • Randomized clinical trial (RCT)



M. De Broe, MD, PhD

University Antwerpen, Antwerp, Belgium

e-mail: marc.debroe@uantwerpen.be

© 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_14



249



250



14.1



M. De Broe



Introduction



Patients with progressive chronic kidney disease (CKD) develop phosphate

retention becoming apparent in the serum when CKD stage 3–4 is reached.

Indeed FGF23 is secreted by osteocytes at early stage of renal insufficiency and

because of his potent phosphaturic effect (by decreasing the brush-border abundance of the sodium phosphate (NaPi2a co-transporter channels) is able to control this phosphate retention at least up to estimated glomerular filtration rate

(eGFR) of 50 ml/min/1.73 m2. Concomitantly FGF23 inhibit synthesis of active

vitamin D (calcitriol), inducing a decrease of gastro-intestinal absorption of calcium and hence less inhibitory effect of PTH synthesis at the level of the PTH

gland [1].

Klotho expression, an essential co-factor for the phosphatonin FGF23 signaling, is reduced in the failing kidney also at early stages. This reduced klotho levels

results in relative FGF23 resistance/less effective elevated levels of FGF23 in promoting renal phosphate excretion The decreased synthesis of active vitamin D,

the progressive phosphate retention inducing a relative decrease in ionized calcium (counter ion effect) stimulate PTH synthesis and secretion resulting in the

classical secondary hyperparathyroidism (SHPT) of patients with CKD stage 5

[2].

In 1978, a study published in The Lancet reported 18 patients who had advanced

CKD, and presence of renal osteodystrophy and were treated with either natural

vitamin D3 (4,000 IU/day) or 1,25-dihydroxyvitamin D (1,25(OH)2D; 1 μg/day)

along with 500 mg of calcium after a 6-month observation period [3]. In the group

treated with 1,25(OH)2D, seven of eight patients developed hypercalcemia that

necessitated a reduction in dosage. The percentage fall in creatinine clearance was

greater during treatment than before treatment in all patients who were on

1,25(OH)2D (P < 0.01) and in seven of nine patients on vitamin D3 treatment. The

authors concluded that deterioration of renal function was a major limitation of the

clinical use of 1,25(OH)2D and vitamin D3 in non-dialyzed patients with CKD. Time

and things have changed. Currently vitamin D may be considered as one of the leading substances opening perspectives, never thought of, not only concerning his well

established favorable effects on the bone and mineral metabolism but as having the

potential to slow down the progression of CKD.

The discovery that most tissues and cells in the body have a vitamin D receptor

and that several possess the enzymatic machinery to convert the primary circulating

form of vitamin D, 25-hydroxyvitamin D, to the active form, 1,25-dihydroxyvitamin

D, has opened the way for the currently, discovered many effects of vitamin D in

almost any organ/system of the body.

The pleiotropic effects of vitamin D in CKD have been previously reviewed by

several authors [4–6]. The specific vitamin D related effects on retarding CKD progression is the main issue of this review. In this context the anti-proteinuric antihypertensive, anti-inflammatory and anti-fibrotic effects of vitamin D will be

discussed.



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