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3 Vitamin D and Non-renal Outcomes in Renal Transplant Recipients

3 Vitamin D and Non-renal Outcomes in Renal Transplant Recipients

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428



P. Evenepoel



25.3.2



Vitamin D and Bone Health in Renal Transplant

Recipients



25.3.2.1



Epidemiology of BMD Loss and Fractures in Renal

Transplantation



Patients receiving a kidney transplant experience rapid bone loss [30, 31] and

increased fracture risk [32], especially in the early posttransplant period. On the

long term, BMD either recovers, further deteriorates at a slower pace or stabilizes

[33–36]. Fracture risk in renal transplant recipients is fourfold higher than in healthy

individuals [37–39]. Compared with dialysis patients on the waiting list, the relative

risk of hip fracture in transplant recipients is 34 % higher during the first 6 months

posttransplantation and decreases by ∼1 % each month thereafter [40]. However,

10 years after transplantation, the fracture risk still is twofold higher than in controls

[37]. Although posttransplantation fractures occur both peripherally and centrally,

most studies demonstrate more fractures occurring at peripheral sites. Importantly,

BMD loss and fracture risk is lower in more recent renal transplant cohorts [41].

This decrease may reflect either decreased cumulative steroid exposure, improved

mineral metabolism control, or a combination of both [42–45]. This observation led

some to conclude that the threat of postransplantation bone loss may have come to

an end [46]. Dual-energy x-ray (DXA) is used in the routine to analyze bone mass.

The reliability of DXA in CKD and, by extension, in renal transplantation has long

been questioned [47]. Recent bone biopsy findings [48] and prospective observational data [49–52], however, clearly indicate that DXA may be as valuable in predicting osteoporosis and incident and prevalent fractures in CKD patients (including

renal transplant recipients) as it is in the general population (Fig. 25.3).

25.3.2.2



Risk Factors and Pathophysiology of BMD Loss and Fractures

in Renal Transplant Recipients



The factors contributing to bone loss and increased fracture risks are multiple with

glucocorticoids and hyperparathyroidism being most prominent [3, 53–56].

Glucocorticoids, an integral component of the immunosuppressive regimen in

renal transplantation, are believed to play a major role in compromising bone

strength [57]. Glucocorticoids directly decrease bone formation through increasing apoptosis of osteoblasts and impairing osteogenesis. Glucocorticoids also

directly reduce osteoclast production but, in contrast to the increase of osteoblast

apoptosis, the lifespan of osteoclasts is prolonged. Therefore, with long-term therapy, osteoclast number are usually maintained in the normal range, whereas osteoblasts and bone formation decrease [58]. Glucocorticoids also indirectly decrease

bone formation and mineralization through decreasing intestinal calcium absorption and increasing renal calcium secretion, thereby inducing a negative calcium

balance [59]. The net result of glucocorticoid usage is loss of both cortical and

cancellous bone. Finally, glucocorticoids also trigger osteocyte apoptosis.



25



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Vitamin D in Kidney Transplantation



May attenuate

bone loss



May attenuate

progression of

vascular

calcification



Bone

Disease



Calcification

Vitamin D

posttransplant



Laboratory

Abnormalities



Increases serum Ca

Suppresses serum PTH

Increases serum FGF23

Increases klotho (?)



Increases calciuria



Fig. 25.3 Vitamin D and posttransplant CKD-MBD



Glucocorticoid-induced osteocyte apoptosis could account for the loss of bone

strength that occurs before loss of BMD and the resultant mismatch between bone

quantity and quality in patients with glucocorticoid-related osteoporosis [58]. The

adverse effect of steroids primarily affect the axial (central) skeleton [32, 33, 60,

61]. The observation that fracture risk is substantially higher in renal transplant

recipients than in recipients of other solid organs [62] suggest the involvement of

specific risk factors. Available evidence points to pre-existing (renal) bone disease

and persistent hyperparathyroidism as important culprits [3, 62]. Persistent hyperparathyroidism is common among renal transplant recipients, with reported prevalence rates ranging between 10 % and 66 %. Unique to the transplant setting is the

combination of high PTH levels with low phosphate levels. High PTH and low

phosphate levels have divergent effects on osteoblasts; low phosphate is associated

with increased apoptosis, whereas high PTH is associated with preserved survival

of osteoblasts [63]. Hypophosphatemia may be at least partly responsible for the

uncoupling of bone resorption and formation and explain why low bone turnover

is a frequent observation in renal transplant recipients with persistent hyperparathyroidism [64]. The bone phenotype of persistent hyperparathyroidism may thus

be characterized by low bone volume in combination with either low, normal or

high bone turnover. Most, but not all [30, 33, 42] epidemiological data in renal

transplant populations show a direct association between PTH levels, (cortical)

bone mineral density loss [61, 65, 66], and fracture risk [8, 67, 68]. Even in the

absence of long-term corticosteroids exposure, high PTH levels may accelerate

bone loss [69].



430



P. Evenepoel



Besides glucocorticoids, pre-existing bone disease, and persistent

hyperparathyroidism, older age, female sex [70], white race, deceased kidney donation,

diabetes [70], hypogonadism, metabolic acidosis [71], high FGF23 level [42], increased

time elapsed since transplantation and frequent falls (either related to postural instability, decreased visual acuity, peripheral neuropathy or myopathy) have been identified as

risk factors for posttransplantation bone loss and fractures [32, 39, 55, 57].

Whether vitamin D deficiency, similar to as in the ageing general population

[72] associates with BMD loss and fractures in renal transplant recipients has so far

not been investigated. In combination with a low dietary calcium intake and glucocorticoids, vitamin D deficiency may induce a negative calcium balance, which, in

turn may trigger or accentuate hyperparathyroidism and as such promote (cortical)

bone resorption. Formal calcium balance studies are lacking in renal transplant

recipients, but isotope studies and low 24 h-urinary calcium excretion at least lend

support to the thesis of calcium malabsorption in renal transplant recipients [73].

Vitamin D deficiency, furthermore, may cause muscle weakness and postural instability and thereby increase the risk of falling [72].



25.3.2.3



Implications of Low BMD and Fractures in Renal

Transplant Recipients



Low BMD and fractures confer important risks, not at the least an increased

mortality. Hip fractures are the most devastating; the risk of death is approximately

three times higher for individuals in the year after a hip fracture. In renal transplant

recipients, mortality risk increases by another 60 % [38]. In addition to increased

mortality due to low BMD, there is a detrimental effect on quality of life and a

considerable financial burden.



25.3.2.4



Efficacy of Vitamin D Supplementation in Preserving Bone

Health in Renal Transplant Recipients



Vitamin D supplementation is widely recommended and implemented in the prevention and treatment of both senile and glucocorticoid induced osteoporosis and

fractures [74, 75], whether or not as an adjunct to specific pharmacologic agents and

nonpharmacologic therapies [55]. Current evidence indicates that vitamin D plus

calcium, as opposed to vitamin D alone, may prevent hip or any type of fracture [76,

77]. The need for calcium supplementation in addition to vitamin D is supported by

experimental data showing that under conditions of calcium malabsorption exogenous vitamin D may actually decrease mineralization [78]. Interestingly, individuals

in the older age groups having low baseline vitamin D status and low calcium intake

seem to benefit most from vitamin D and calcium supplementation [72].

Due to the heterogeneity of bone changes after transplantation, osteoporosis

treatment recommendations in the general population, including those related to

vitamin D, may not be transferable to the specialized setting of renal transplantation.



25



Vitamin D in Kidney Transplantation



431



Fortunately, a body of randomized data emerged in recent years specific to the

treatment of bone disease with vitamin D in solid organ transplant recipients, including kidney transplant recipients. Among these studies, several investigated vitamin

D (and calcium) vs. placebo [6, 79–83] or vitamin D and calcium vs calcium [4,

84–86]. Not surprisingly, vitamin D therapy suppresses PTH levels [6, 80, 87].

Vitamin D, conversely increases FGF23, which may explain why phosphorus concentrations tend to decrease in vitamin D treated patients [88]. Most, but not all [6,

81] controlled studies evaluating BMD by DEXA showed higher bone gains in the

active treatment group, both at the lumbar spine and femoral neck. Studies comparing vitamin D to bisphosphonates showed mixed results with some investigators

showing superiority of bisphosphonates [89, 90] and others showing equal efficacy

[43]. Of note, no study was powered to show a reduction in risk for fracture at any

site after transplantation.

Discrepancy between study results can be explained by differences in timing of

intervention, baseline vitamin D status, baseline BMD, treatment regimen (dose,

agent), or vitamin D receptor genotype. The VDR genotype polymorphisms affects

the bone density of renal transplants via its effects on the severity of hyperparathyroidism [67, 91]. It has been suggested that a decreased transcriptional activity or

stability of the VDR mRNA in patients with the bb haplotype could explain the

decreased effects of calcitriol on the parathyroid gland [92]. Type of vitamin D

agent and dose may matter as well [75, 93]. Both native vitamin D and active vitamin D (analogues) have been evaluated, but formal head to head comparisons are

non-existing. A recent meta-analysis of RCTs including organ transplantation studies suggests superiority of active vitamin D (analogues) over native vitamin D [93].

The advantage of administrating active vitamin D (or its analogues) is that potential

disturbances in hepatic and renal vitamin D metabolism do not have to be accounted

for. However, in addition to their higher cost use of active vitamin D (or analogues)

is associated with a higher risk of hypercalcemia and hypercalciuria compared to

native vitamin D supplementation.

The optimal dose to replenish and maintain vitamin D stores are difficult to

define. There is no such “one size fits all” regimen. Factors to be considered include

the magnitude of the deficit and desired velocity of correction. Overall, high doses

may be required, i.e. up to 100,000 IU every 2 weeks to correct vitamin D deficiency, and up to 50,000 IU every 4 weeks to maintain vitamin D sufficiency [15,

87, 94]. A recent meta-analysis indicate that vitamin D3 is more efficacious in raising 25(OH)D concentrations compared to vitamin D2 [95].



25.3.2.5



Safety of Vitamin D Supplementation in Renal

Transplant Recipients



Vitamin D supplementation increases serum calcium levels and calciuria [87, 88].

Hypercalcemia is common in incident renal transplant recipients, even in those not

receiving calcium or vitamin D supplements, with prevalence rates reported in literature varying between 5 and 66 % [13, 20, 96–100]. This wide variation may be



432



P. Evenepoel



explained, at least partly, by case-mix (variable interval since transplantation and

study era) and differences in diagnostic criteria [101]. The pathophysiological

mechanisms underlying the hypercalcemia in renal transplant recipients remain

incompletely understood. PTH mediated calcium release from the bone, renal

calcium retention and/or calcium-sensing receptor downregulation may all be

speculated to be involved [97, 99]. The fear of triggering or aggravating hypercalcemia impedes the widespread implementation of vitamin D and calcium supplementation in the prevention of bone loss in incident renal transplant recipients. This

fear may prove unjustified. Indeed, vitamin D and calcium supplementation may be

hypothezised to be especially beneficial in the setting of persistent hypercalcemic

hyperparathyroidism by reverting the main calcium influx from bone to the gastrointestinal tract. Awaiting additional data confirming or refuting this hypothesis,

clinicians should be less reluctant to initiate vitamin D and calcium in incident

renal transplant recipients and to decrease or stop vitamin D in the advent of mild

hypercalemia.

Besides inducing hypercalcemia, vitamin D may cause a mild decline of measured creatinine clearance. This may related to suppression of PTH [102]. PTH has

vasodilatory effects on pre-glomerular vessels, while efferent arterioles are constricted, presumably secondary to renin release [103]. Alternatively, it may be

related to a reduced tubular secretion of creatinine [104].



25.3.3



Vitamin D and Vascular Calcification in Renal

Transplant Recipients



Cardiovascular (CV) disease is the leading cause of premature death in renal transplant recipients with a 3.5–5 % annual risk of fatal or nonfatal CV events [105].

Vascular calcification burden, and even more so vascular calcification progression

are potent predictors of future cardiovascular events in RTRs [106–108], likewise in

the general population [109] and in CKD patients [110]. Most, but not all clinical

data suggest that vitamin D may confer vascular benefits; a negative association has

been observed between vitamin D level and vascular calcification [111–113], and

pulse wave velocity [114], in CKD patients across stages of disease. Moreover, a

positive and independent association has been observed between 25(OH)D [114,

115] and 1,25(OH)2D [114] level and brachial artery distensability and flowmediated dilation, both in dialysis patients [114] and renal transplant recipients

[115]. Finally, high baseline 25(OH)D levels were associated with attenuated progression of vascular calcification in prevalent renal transplant recipients [116]. In

aggregate, these results support an association between 25(OH)D and 1,25(OH)2D

deficiency and endothelial dysfunction, arteriosclerosis and arterial calcification.

Nevertheless, randomized controlled trials remain mandatory to definitely proof the

benefits of vitamin D treatment on cardiovascular outcomes both in the general

population as in the setting of renal transplantation, especially since intervention

trial in animals yielded discrepant findings [117]. The latter discrepancy most



25



Vitamin D in Kidney Transplantation



433



probably reflects differences in experimental conditions with dose and type of agent

being important variables [118, 119]. The pathophysiological mechanisms underlying the putative beneficial effects of vitamin D on vascular health remain incompletely understood. Experimental evidence indicates that vitamin D may interact at

the vascular tissue level both with Wnt/β-catenin [118], PTH [120], and FGF23/

klotho signaling pathway [121]. Again, findings are dose and agent specific.

Martinez-Moreno et al. for example, demonstrated that procalcifying Wnt signaling

in VSMCs is suppressed by paricalcitol, but activated by calcitriol. Lim et al. demonstrated that calcitriol can restore klotho levels in procalcific environments, thereby

rendering VSMCs again FGF-23 responsive, with proliferation and calcification

inhibitory effects. Of note, similar results were obtained with calcidiol, suggesting

that the VSMC 1α-hydroxylase enzyme is involved in mediating supportive autocrine/paracrine effects in the regulation of klotho [121]. It should be emphasized

that these studies are debated [122] and need confirmation by independent

investigators.



25.3.4



Vitamin D and Non-MBD Effects in Renal Transplant

Recipients



Vitamin D status does not exclusively affect mineral and bone metabolism. Mounting

evidence indicates that hypovitaminosis D may also be involved in the pathogenesis

of oncologic, metabolic, and infectious diseases, all common in renal transplantation. The role of vitamin D in transplant immunology and the relationship between

vitamin D levels, renal transplant rejection, function and survival are discussed elsewhere in this book. Herein, we summarize current evidence on the link between

vitamin D, infections and cancer in renal transplant recipients.



25.3.4.1



Vitamin D and Infections in Renal Transplant Recipients



Vitamin D has emerged as a central player in the immune system, affecting T and B

cells, macrophages and dendritic cells [123]. Contrary to the suppressive effects on

the immune system, vitamin D also has a protective effect against infections. This

was first shown in tuberculosis, where the traditional treatments with sunlight and

cod liver oil, rich in vitamin D, are viewed in a new light after the discovery of antimicrobial peptides induced by vitamin D. The two antimicrobial peptides under the

influence of vitamin D are LL-37 (cathelicidin) and β-defensin [124], which have

activity against several bacteria, as well as viruses [125] and fungi [126].

Epidemiological studies have linked 25(OH)D deficiency to viral as well as bacterial infections in the general population (for review see [127]).

Infections are a common complication among renal transplant recipients. Clinical

data on the association between vitamin D stores and infectious complications in

transplant patients are scare. Severe vitamin D deficiency (25(OH)D3 <10 ng/mL)



434



P. Evenepoel



was observed to be an independent predictor of urinary tract infections after renal

transplantation [128]. In a cohort of 166 patients, who underwent allogeneic hematopoietic stem cell transplantation, low serum levels of 25(OH)D before transplantation significantly correlated to posttransplant cytomegalovirus (CMV) disease.

Studies investigating the association between 25(OH)D deficiency and viral disease

(including polyomavirus associated nephropathy (PVAN) and CMV disease) in

renal transplant recipients have yielded conflicting results [129, 130]. Intervention

studies in renal transplant recipients powered for infectious endpoints are

non-existing.



25.3.4.2



Vitamin D and Cancer in Renal Transplant Recipients



In the past three decades, an increasing body of evidence has emerged on the role of

vitamin D in cell differentiation. The data suggest that vitamin D has a potent antiproliferative action on various cell types, including bone marrow, skin, muscle, and

intestine [131]. Serum level of 25(OH)D has been shown to inversely correlate with

the incidence of various types of cancers (breast, prostate, and colon) in the general

population [132]. The incidence of cancer considerably increases after organ transplantation [133]. Recent data suggest that the rates of cancer in renal transplant

recipients are similar to nontransplanted population who are 20–30 years older

[133]. Elevated cancer risk after transplantation is thought to result from the interplay of several factors including chronic uremic state, cumulative exposure to

immunosuppressive drugs, and viral infections. Studies investigating the association between vitamin D status an incident malignancies in incident renal transplant

recipients so far yielded discrepant findings with some investigators observing an

inverse [134] and others observing no relationship [16].



25.4



Conclusions



Both 25(OH)D and 1,25(OH)2D levels are inappropriately low in a substantial proportion of renal transplant recipients. As in the general population and CKD patients,

low vitamin D levels overall associate with increased mortality, and confer an

increased risk of fractures, infections and malignancy. It should be emphasized that

epidemiological evidence is limited and not universally unequivocal. Intervention

studies with vitamin D supplementation in renal transplant recipients showed higher

bone gains in the active treatment group, both at the lumbar spine and femoral neck.

None of the studies, however, was powered to show a reduction in risk for fracture

(Table 25.1). Awaiting the results of additional studies, native vitamin D supplementation, whether or not guided by 25(OH)D levels, should be considered in renal

transplant recipients.



6



12



12



De Sévaux et al. [4]



Wissing et al. [6]



El-Husseini et al. [83]



Children and adolescents, de

novo RTRs, n = 30



Adult, de novo RTRs, n = 90



Adult, de novo RTRs, n = 111



Population

Adult, de novo RTRs, n = 86



eCa 0,4 g/day







aVit D 0,5 μg/day







aVitD 0,25 μg/day

nVitD 25,000 U/month + eCa

0,4 g/day



Comparator

eCa 0,5 g/day,

12 months



Treatment

aVitD 0,5 μg/2 days, 3 months +

eCa 0,5 g/day, 12 months



Main finding

Better preservation

aBMD total hip; better

control HPT

Better preservation a

BMD lumbar spine

No significant benefit

aBMD; better control

HPT

Increase aBMD at

lumbar spine; better

control HPT



RTR renal transplant recipient, aVitD active vitamin D, nVitD nutritional vitamin D, eCa elementary calcium, HPT hyperparathyroidism, aBMD areal bone

mineral density (by DXA)



Duration (months)

12



Author

Torres et al. [86]



Table 25.1 Comparison of population, duration, and treatment findings among four studies



25

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435



436



P. Evenepoel



Acknowledgements The author thanks D. Vanderschueren, MD, PhD and S. Pauwels, MD for

critical reading of the manuscript.



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3 Vitamin D and Non-renal Outcomes in Renal Transplant Recipients

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