**5. Vitamin D deficiency after kidney transplantation**

Suboptimal 25VD is a commonly detected problem after kidney transplantation (KT) with prevalence above 80% of the kidney transplant recipients (KTRs). As KTRs are CKD patients, all mentioned factors, predisposing to impaired VD metabolism are valid for this cohort of patients, especially considering the fact that more than 50% of the KTRs have GFR<60 ml/min/1.73 m2 . In addition, transplantspecific factors influence VD synthesis: sun exposure avoidance due to the increased risk for skin malignancies, use of sun-protecting cosmetics (limiting further UV exposure), proteinuria after KT (increased loss in urine), higher prevalence of obesity after KT (reduced bioavailability), the presence of new onset diabetes after transplantation (NODAT) (by reducing intestinal absorption), use of steroids (increased 1,25VD catabolism), and calcineurin inhibitors (impaired 25VD liver synthesis) [77, 78]. Similarly to CKD in native kidneys, the VD-associated clinical implications after KT are categorized as post-transplant mineral bone disorder (PTMBD) and VD pleiotropy.

#### **5.1 Post-transplant mineral bone disorder**

Similarly to native kidneys, PTMBD consists of three aspects—biochemical abnormalities, bone involvement, vascular pathology and is associated with higher risk for fractures and death.

### *5.1.1 PTMBD: biochemical abnormalities*

Significant changes occur in the biochemical indicators of calcium-phosphorus metabolism after KT. In the early post-transplant period, the fluctuations in the parameters are more pronounced as the graft function is rapidly changing. Due to the presence of functioning renal tubules and still high levels of PTH and FGF-23, hypophosphatemia and mild hypercalcemia are common. These changes usually normalize within months after KT as graft function stabilizes. Therefore, the current KDIGO guidelines recommend at least weekly testing for calcium and phosphorus immediately after KT [17]. FGF-23 and PTH rapidly decrease; however, PTH may be significantly elevated years after successful KT due to parathyroid cell hypertrophy. VD levels are low in the early post-transplant period; yet, suboptimal levels are very common later after KT [78].

In the late post-transplant period, current guidelines recommend the testing for calcium, phosphorus, PTH, and alkaline phosphatase to be performed according to the magnitude of the abnormalities, rate of progression of post-transplant CKD, and the presence of medical treatment. Practically, the timing is similar to patients with CKD stage 3–5 with native kidneys (see **Table** 2). 25VD should be tested at baseline and repeated testing should be performed according to the initial level and the presence of medical interventions. In our center, 25VD levels are monitored twice annually, taking into consideration its seasonal variations in the general population. Thus, a significant deterioration of VD status in the winter/fall was detected, allowing adequate seasonal supplementation to be initiated.

#### *5.1.2 PTMBD: bone disease*

Post-transplant bone disease is commonly observed after KT and encompasses ROD, osteoporosis, bone fractures, and osteonecrosis. Deterioration in BMD occurs mainly during the first 12 months, though BMD loss persists at lower rates after the first post-transplant year. The etiology is multifactorial: pre-existing CKD-MBD, duration of dialysis and transplantation, poor graft function, hypogonadism, higher rates of diabetes after KT, suboptimal VD levels, and use of immunosuppressive agents. Of these, steroids are of particular importance as their cumulative and mean dose is associated with decreased bone formation and bone density. Some reports indicate that calcineurin inhibitors can rise PTH levels and increase the risk of osteoporosis, but the findings are not uniformly accepted [17, 79].

In KTRs, not only fracture prevalence is significantly increased compared to the general population, but also fracture-associated complications, including mortality, are more common in the post-transplant setting. Major fracture sites are the hip (usually osteoporosis-associated) and the ankle/foot (atypical for osteoporosis), which demonstrate that both ROD and osteoporosis play an important role in bone fragility [80].

The use of DXA–BMD measurement is getting more attention in native CKD, as a growing body of evidence demonstrates that it can predict fracture risk across CKD categories. To date, only one retrospective study, total hip DXA measurement after KT was associated with increased fracture risk. In addition, a recent prospective study had similar findings [81, 82]. Despite the insufficient evidence for KTRs,

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*Vitamin D Deficiency in Renal Disease DOI: http://dx.doi.org/10.5772/intechopen.88928*

*5.1.3 PTMBD: vascular calcifications*

KDIGO suggests the use of BMD testing in all stages of post-transplant CKD in KTRs with high risk for osteoporosis, if the measurement will have effect on treat-

VC is common after KT and is usually associated with pre-transplant uremia. In addition, most studies are semi-quantitative, thus making post-transplant VC progression assessment difficult. However, there are studies demonstrating a stop in progression or even improvement in VC in KTRs [83, 84]. Recognized risk factors for VC after KT are statin use, low 25VD levels, male sex, older age, and higher phosphate levels [85]. The data for the effect of immunosuppressive agents are conflicting. Mycophenolates proved to have protective effects against calcification, especially compared to steroids and calcineurin inhibitors; rapamycin suppressed smooth muscle cell proliferation, whereas everolimus impaired the vasoactive and antithrombotic function of the endothelium [86]. Therefore, more studies are

The graft survival at the tenth year after KT is significantly lower than the survival during the first 12 months. The explanation for these unsatisfactory results is poorer patient survival due to neoplasia, CVD, NODAT, calcineurin toxicity. It could be hypothesized that VD can improve graft and patient survival due to its pleiotropy. However, the trials in KTRs are small in number and in size, thus further

Observational studies linked poor VD status to poorer graft outcomes [86]. Our results also demonstrated that higher VD is associated with lower post-transplant proteinuria [87]. However, interventional studies did not fully support the VD– graft function association. Cholecalciferol supplementation failed to demonstrate renoprotection in prospective study [88]. However, in a recent prospective placebo-

Observational studies demonstrated higher rates of acute rejection in VD deficient KTRs [90]. Unfortunately, interventional studies did not find protective role of cholecalciferol supplementation on rejection prevalence [88]. Therefore, the role of VD in rejection prevention after KT is not fully understood and is under debate.

Infection is a major cause for death after KT. Several recent reports established negative correlation between VD status and infection risk, especially for cytomegalovirus and BK virus infections in KTRs [91, 92]. However, our observational study showed no association between VD status and prevalence of urinary tract infections after KT [93]. Furthermore, the VITA-D study did not establish positive effect of cholecalciferol supplementation on infection risk [88]. A probable explanation for the discrepancies in the studies are the different types of infection evaluated (e.g. in the VITA-D study the total infection risk was assessed). Probably, a more specific

ment. Bone biopsy can be considered to guide treatment [17].

needed in order to evaluate the effect of KT on VC.

**5.2 VD pleiotropy after kidney transplantation**

*5.2.1 VD pleiotropy after KT: proteinuria and renal protection*

controlled study, paricalcitol ameliorated proteinuria in KTRs [89].

research in this sphere is warranted.

*5.2.2 VD pleiotropy after KT: rejection*

*5.2.3 VD pleiotropy after KT: infection*

*Vitamin D Deficiency*

risk for fractures and death.

**5.1 Post-transplant mineral bone disorder**

*5.1.1 PTMBD: biochemical abnormalities*

levels are very common later after KT [78].

*5.1.2 PTMBD: bone disease*

allowing adequate seasonal supplementation to be initiated.

of osteoporosis, but the findings are not uniformly accepted [17, 79].

Similarly to native kidneys, PTMBD consists of three aspects—biochemical abnormalities, bone involvement, vascular pathology and is associated with higher

Significant changes occur in the biochemical indicators of calcium-phosphorus metabolism after KT. In the early post-transplant period, the fluctuations in the parameters are more pronounced as the graft function is rapidly changing. Due to the presence of functioning renal tubules and still high levels of PTH and FGF-23, hypophosphatemia and mild hypercalcemia are common. These changes usually normalize within months after KT as graft function stabilizes. Therefore, the current KDIGO guidelines recommend at least weekly testing for calcium and phosphorus immediately after KT [17]. FGF-23 and PTH rapidly decrease; however, PTH may be significantly elevated years after successful KT due to parathyroid cell hypertrophy. VD levels are low in the early post-transplant period; yet, suboptimal

In the late post-transplant period, current guidelines recommend the testing for calcium, phosphorus, PTH, and alkaline phosphatase to be performed according to the magnitude of the abnormalities, rate of progression of post-transplant CKD, and the presence of medical treatment. Practically, the timing is similar to patients with CKD stage 3–5 with native kidneys (see **Table** 2). 25VD should be tested at baseline and repeated testing should be performed according to the initial level and the presence of medical interventions. In our center, 25VD levels are monitored twice annually, taking into consideration its seasonal variations in the general population. Thus, a significant deterioration of VD status in the winter/fall was detected,

Post-transplant bone disease is commonly observed after KT and encompasses ROD, osteoporosis, bone fractures, and osteonecrosis. Deterioration in BMD occurs mainly during the first 12 months, though BMD loss persists at lower rates after the first post-transplant year. The etiology is multifactorial: pre-existing CKD-MBD, duration of dialysis and transplantation, poor graft function, hypogonadism, higher rates of diabetes after KT, suboptimal VD levels, and use of immunosuppressive agents. Of these, steroids are of particular importance as their cumulative and mean dose is associated with decreased bone formation and bone density. Some reports indicate that calcineurin inhibitors can rise PTH levels and increase the risk

In KTRs, not only fracture prevalence is significantly increased compared to the general population, but also fracture-associated complications, including mortality, are more common in the post-transplant setting. Major fracture sites are the hip (usually osteoporosis-associated) and the ankle/foot (atypical for osteoporosis), which demonstrate that both ROD and osteoporosis play an important role in bone

The use of DXA–BMD measurement is getting more attention in native CKD, as a growing body of evidence demonstrates that it can predict fracture risk across CKD categories. To date, only one retrospective study, total hip DXA measurement after KT was associated with increased fracture risk. In addition, a recent prospective study had similar findings [81, 82]. Despite the insufficient evidence for KTRs,

**258**

fragility [80].

KDIGO suggests the use of BMD testing in all stages of post-transplant CKD in KTRs with high risk for osteoporosis, if the measurement will have effect on treatment. Bone biopsy can be considered to guide treatment [17].
