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3 Vitamin D and Non-renal Outcomes in Renal Transplant Recipients
Vitamin D and Bone Health in Renal Transplant
Epidemiology of BMD Loss and Fractures in Renal
Patients receiving a kidney transplant experience rapid bone loss [30, 31] and
increased fracture risk , 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 . However,
10 years after transplantation, the fracture risk still is twofold higher than in controls
. 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 .
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 . 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 . Recent bone biopsy findings  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).
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 . 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 . Glucocorticoids also indirectly decrease
bone formation and mineralization through decreasing intestinal calcium absorption and increasing renal calcium secretion, thereby inducing a negative calcium
balance . The net result of glucocorticoid usage is loss of both cortical and
cancellous bone. Finally, glucocorticoids also trigger osteocyte apoptosis.
Vitamin D in Kidney Transplantation
Increases serum Ca
Suppresses serum PTH
Increases serum FGF23
Increases klotho (?)
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 . 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  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 . 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 . 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 .
Besides glucocorticoids, pre-existing bone disease, and persistent
hyperparathyroidism, older age, female sex , white race, deceased kidney donation,
diabetes , hypogonadism, metabolic acidosis , high FGF23 level , 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
 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 .
Vitamin D deficiency, furthermore, may cause muscle weakness and postural instability and thereby increase the risk of falling .
Implications of Low BMD and Fractures in Renal
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 % . In addition to increased
mortality due to low BMD, there is a detrimental effect on quality of life and a
considerable financial burden.
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 . 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 . 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 .
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.
Vitamin D in Kidney Transplantation
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 . 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
. 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 . 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 .
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 .
Safety of Vitamin D Supplementation in Renal
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
explained, at least partly, by case-mix (variable interval since transplantation and
study era) and differences in diagnostic criteria . 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
Besides inducing hypercalcemia, vitamin D may cause a mild decline of measured creatinine clearance. This may related to suppression of PTH . PTH has
vasodilatory effects on pre-glomerular vessels, while efferent arterioles are constricted, presumably secondary to renin release . Alternatively, it may be
related to a reduced tubular secretion of creatinine .
Vitamin D and Vascular Calcification in Renal
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 .
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  and in CKD patients . 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 , 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  level and brachial artery distensability and flowmediated dilation, both in dialysis patients  and renal transplant recipients
. Finally, high baseline 25(OH)D levels were associated with attenuated progression of vascular calcification in prevalent renal transplant recipients . 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 . The latter discrepancy most
Vitamin D in Kidney Transplantation
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 , PTH , and FGF23/
klotho signaling pathway . 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 . It should be emphasized
that these studies are debated  and need confirmation by independent
Vitamin D and Non-MBD Effects in Renal Transplant
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.
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 . 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 , which have
activity against several bacteria, as well as viruses  and fungi .
Epidemiological studies have linked 25(OH)D deficiency to viral as well as bacterial infections in the general population (for review see ).
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)
was observed to be an independent predictor of urinary tract infections after renal
transplantation . 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
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 . 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 . The incidence of cancer considerably increases after organ transplantation . Recent data suggest that the rates of cancer in renal transplant
recipients are similar to nontransplanted population who are 20–30 years older
. 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  and others observing no relationship .
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
De Sévaux et al. 
Wissing et al. 
El-Husseini et al. 
Children and adolescents, de
novo RTRs, n = 30
Adult, de novo RTRs, n = 90
Adult, de novo RTRs, n = 111
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
eCa 0,5 g/day,
aVitD 0,5 μg/2 days, 3 months +
eCa 0,5 g/day, 12 months
aBMD total hip; better
Better preservation a
BMD lumbar spine
No significant benefit
aBMD; better control
Increase aBMD at
lumbar spine; better
RTR renal transplant recipient, aVitD active vitamin D, nVitD nutritional vitamin D, eCa elementary calcium, HPT hyperparathyroidism, aBMD areal bone
mineral density (by DXA)
Torres et al. 
Table 25.1 Comparison of population, duration, and treatment findings among four studies
Vitamin D in Kidney Transplantation
Acknowledgements The author thanks D. Vanderschueren, MD, PhD and S. Pauwels, MD for
critical reading of the manuscript.
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