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2 Vitamin D Metabolism in Health, Chronic Kidney Disease and Renal Transplantation
Vitamin D in Kidney Transplantation
Vitamin D Metabolism in Chronic Kidney Disease
In CKD, 1,25(OH)2D production is reduced owing to alterations in CYP
abundances, CYP activity, and delivery of substrate to CYP enzymes (for review
see ). PTH and FGF23 exert opposite effect on CYP27B1 expression. The net
effect is uncertain, as evidenced by experimental and clinical data. Impaired
delivery of 25(OH)D to CYP27B1 and/or decreased CYP27B1 activity may prove
more important than decreased enzymatic mass in CKD. Circulating 25(OH)D
levels in CKD patients are often low as a result of low sun exposure, decreased
cutaneous synthesis, and limited dietary intake. Moreover, reabsorption of filtered
25(OH)D in the proximal tubule may be impaired in CKD as a consequence of
decreased megalin expression. CKD also disrupts vitamin D catabolism. PTH
suppresses, while FGF23 stimulates CYP24A1 expression and activity. The net
effect remains, as for CYP27B1, incompletely understood. Most recent data suggest that CKD should be considered a state of stagnant vitamin D metabolism
characterized by reduced vitamin D catabolism and turnover in addition to reduced
1,25(OH)2D production. In this paradigm, competing effects of PTH and FGF23
on the expression of CYP27B1 and CYP24A1 either balance each other or are
superseded by a general decrease in vitamin D metabolic function of the kidney,
caused either by impaired uptake of 25(OH)D, diminished metabolic activity of
proximal tubular cells, or a simple reduction in the number of functioning nephrons (for review see ).
Vitamin D Metabolism in Renal Transplant Recipients
Renal transplantation restores, at least partly, renal functional mass and corrects
metabolic and hormonal disturbances underlying the altered vitamin D metabolism
in CKD .
25(OH)D Levels in Renal Transplant Recipients
Following renal transplantation, serum 25(OH)D levels commonly follow a
biphasic pattern characterized by an early decrease followed by a modest recovery
[4–8]. Several mechanisms may be hypothesized to contribute to the early decline
; first, tubular dysfunction (related to ischemia-reperfusion injury) associates
with overload proteinuria which may result in substantial urinary losses of the
Vitamin D- Vitamin D binding protein complex. Second, vitamin D catabolism
may be enhanced in the posttransplant period, due to upregulation of CYP24A1
either by inappropriately high FGF23 levels  or by glucocorticoids .
Despite a slight recovery of 25(OH)D levels later on, 25(OH)D levels remain
significantly lower compared with controls  and 25(OH)D deficiency and
insufficiency remain very common among renal transplant recipients (see below).
Sun avoidance behavior undoubtedly contributes to the high prevalence of low
25(OH)D levels among renal transplant recipients. Due to increased risk of skin
cancers, renal transplant recipients are routinely advocated to limit sun exposure or
to use sun blockers.
Vitamin D insufficiency, defined by a total 25(OH)D level below 30 ng/mL, is
observed in 75–97 % of the renal transplant recipients [7, 9, 12–17]. Latitude, season, race, gender, comorbidity, diabetes, nutrition, body mass index, and time since
transplantation correlate with serum 25(OH)D levels [15, 17, 18]. In a recent cohort
study, 25(OH)D levels were independently and inversely associated with calcineurin inhibitor (CNI) exposure . This observation argues against a prominent role
of CYP3A4 in the catabolism of 25(OH)D, as CNI are well established competitive
inhibitors of this enzyme.
The increased awareness of the many beneficial pleiotropic (nonskeletal) effects
of 25-hydroxyvitamin D as well as the consistency of observational data showing a
direct association between vitamin D deficiency and poor cardiovascular outcomes
caused a vitamin D hype in recent years , not only in the general population but
also in the transplant community. Supplementation of nutritional vitamin D has
become routine practice in many dialysis and transplant units. As a consequence,
vitamin D deficiency nowadays seems to be less common among renal transplant
candidates and recipients (Evenepoel, unpublished data).
1,25(OH)2D Levels in Renal Transplant Recipients
Serum 1,25(OH)2D levels show a steady increase following successful transplantation [5, 20], parallel to the recovery of renal function. Remarkably however,
concentrations remain often at the lower range in the early posttransplant period
despite the presence of hyperparathyroidism and hypophosphatemia (see below),
conditions known to stimulate increased calcitriol synthesis [5, 6, 21, 22]. Again,
a diminished enzymatic function, perhaps related to redox imbalance being
common in the early posttransplant period, may be involved. By 1 year after transplantation, calcitriol deficiency, defined by 1,25(OH)2D concentrations below
20 ng/L, however is a rare finding, as long as eGFR >30 ml/min per 1.73 m2 .
In a cross-sectional study, low PTH and high FGF23 levels associated with low
calcitriol levels, independent of renal function [14, 23]. This observation confirms
the opposing actions of FGF23 and PTH on CYP27B1 [14, 24]. The CNI cyclosporin increases the synthesis of 1,25(OH)2D in rodents . Clinical studies
exploring the link between cyclosporine exposure and circulating levels of
1,25(OH)2D are lacking. Finally, prospective data show that increments of calcitriol in the early posttransplant period are highest in patients who are able to
maintain their 25(OH)D stores, emphasizing the importance of substrate availability [14, 26] (Fig. 25.1).
Vitamin D in Kidney Transplantation
Vitamin D and Non-renal Outcomes in Renal
Vitamin D and Mortality in Renal Transplant
In agreement with observations in the general population and in CKD patients ,
low 25(OH)D levels in renal transplant recipients were recently shown to associate
with increased (all-cause) mortality . Whether restoring 25(OH)D levels reduces
the risk of mortality, as suggested by a recent meta-analysis of randomized controlled trials , remains to be formally proven (Fig. 25.2).
Fig. 25.1 Time-course of
25(OH)D and 1,25(OH)2D
levels in de novo renal
Time posttransplant (mo)
Fig. 25.2 Vitamin D and 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.