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

#### **5.1. Impaired vitamin D metabolism after kidney transplantation: prevalence and pathophysiology**

Suboptimal VD levels are commonly detected in kidney transplant recipients (KTRs), with prevalence of VD sufficiency below 20% [69]. Similar findings were detected in our institution in patients with duration of kidney transplantation (KTx) more than 6 months (*n* = 289), [70], **Figure 4**.

**Figure 4.** Prevalence of suboptimal 25-hydroxyvitamin D levels in Bulgarian kidney transplant recipients, *n* = 289. Filipov et al.

During winter-spring fall, during the annual nadir of 25VD, the share of VD sufficient KTRs follow-up in our center dropped to 2.59% [71].

The marked impairment of VD axis after KTx can be explained with transplantation-specific and CKD-related issues. The transplantation-related ones are sun exposure avoidance in order to minimize the risk for skin cancer, immunosuppressive treatment (steroids, calcineurin inhibitors), new onset diabetes after transplantation (NODAT), and higher incidence of obesity after KTx. The CKD-related causes for poor VD status were already outlined. The prevalence of CKD stage 3 and over in our department ranges between 49 and 58% over the last 4 years, which is in accordance with or even better than the results of other centers [72, 73]. **Table 9** summarizes the possible causes of VD insufficiency after KTx with the possible pathophysiological mechanisms involved.

#### **5.2. Vitamin D after kidney transplantation: clinical implications**

There are two basic aspects of vitamin D insufficiency after kidney transplantation—posttransplant mineral bone disease (PTx-MBD) and vitamin D pleiotropy.


Abbreviations: CNI, calcineurin inhibitors; MMF, mycophenolate mofetil; NODAT, new onset diabetes after transplantation.

**Table 9.** Causes for vitamin D insufficiency after kidney transplantation.

#### *5.2.1. Posttransplant mineral bone disease*

**Figure 4.** Prevalence of suboptimal 25-hydroxyvitamin D levels in Bulgarian kidney transplant recipients, *n* = 289. Fili-

During winter-spring fall, during the annual nadir of 25VD, the share of VD sufficient KTRs

The marked impairment of VD axis after KTx can be explained with transplantation-specific and CKD-related issues. The transplantation-related ones are sun exposure avoidance in order to minimize the risk for skin cancer, immunosuppressive treatment (steroids, calcineurin inhibitors), new onset diabetes after transplantation (NODAT), and higher incidence of obesity after KTx. The CKD-related causes for poor VD status were already outlined. The prevalence of CKD stage 3 and over in our department ranges between 49 and 58% over the last 4 years, which is in accordance with or even better than the results of other centers [72, 73]. **Table 9** summarizes the possible causes of VD insufficiency after KTx with the possible pathophysio-

There are two basic aspects of vitamin D insufficiency after kidney transplantation—post-

pov et al.

follow-up in our center dropped to 2.59% [71].

38 A Critical Evaluation of Vitamin D - Clinical Overview

**5.2. Vitamin D after kidney transplantation: clinical implications**

transplant mineral bone disease (PTx-MBD) and vitamin D pleiotropy.

logical mechanisms involved.

After Ktx, PTx-MBD develops at the background of CKD-MBD, and consist of the same three components—biochemical abnormalities, bone pathology, and vascular/soft tissue calcifications. Poor vitamin D status is one of the factors for developing PTx-MBD, together with immunosuppressive therapy, persistent hyperparathyroidism, malnutrition, persistent CKD, hypogonadism, metastatic cancer disease, smoking, duration of dialysis and transplantation, cumulative steroid dose, diabetes, etc.

Biochemical abnormalities. Calcium levels tend to rise and phosphate usually decreases below normal values due to elevated PTH. These parameters should be monitored weekly during the first month posttransplant. PTH starts to decrease after successful KTx, but persistent hyperparathyroidism can be present in up to 43% after the first year [74]. Similar findings (33.69%) were detected in our center, coupled with persistent hypercalcemia or hypophosphatemia. Urine levels of phosphate and calcium were not evaluated routinely in our patients. Vitamin D levels normalize later—around 18 months after KTx [75]. After the early posttransplant period (up to 3 months after transplantation), regular follow-up of the parameters should be based on kidney function and the trends of the values. KDIGO suggested frequency of testing for KTRs similar to the one for pretransplant CKD patients (Table 4). In our center, during the first month calcium and phosphate are monitored once weekly, with gradually decreasing the frequency until the suggested values are reached; 25-hydroxyvitamin D levels are monitored at least twice annually, taking into consideration its seasonal variations.

Bone. Rapid reduction in bone density is widely reported, with faster bone loss during the first months after successful KTx, though reduced bone density loss was reported years after the operation [76]. The factors contributing to posttransplant bone disease were already listed. A major complication is increased fracture risk, associated with increased morbidity and mortality.

Vascular calcification. Assessing the development of soft tissue calcification is difficult due to the high prevalence of vascular calcification in advanced CKD. Only one study demonstrated possible slowing of calcification process after KTx [77]. Therefore, currently there is paucity in scientific data for this problem.

### *5.2.2. Vitamin D pleiotropy after kidney transplantation*

With the advance of transplantology, short-term kidney survival has improved significantly over the last decades. However, long-term graft survival still remains a problem, hardly exceeding 70–80% survival at the 10th year after the operation. The major reasons for late graft loss are death of the patient due to cardiovascular disease (CVD), malignancy, and infection; also, calcineurin toxicity and chronic rejection are also other significant causes. The already mentioned pleiotropic effects of VD were described mostly in the general population or CKD patients. It can be expected that these properties can improve patient- and graft-targeted outcomes.

#### *5.2.2.1. Vitamin D and diabetes mellitus after kidney transplantation (KTx)*

New onset diabetes after transplantation (NODAT) is associated with higher morbidity and mortality after transplantation, and is linked to the use of steroids and calcineurin inhibitors after the operation. Many experimental and animal studies indicate that better vitamin D status is associated to improved insulin secretion and insulin resistance. Several human studies report of inverse correlation between 25VD level and diabetes prevalence [78, 79]. The data after solid organ transplantation are scarce. Our findings do not show any link between 25VD level and glycemic control [80], thus not supporting any association between VD status and glycemia after KT. No interventional studies assessed the effect of VD supplementation or use of calcitriol/VD analogs in solid organ transplantation patients on diabetes prevalence after the procedure [81].

#### *5.2.2.2. Vitamin D and cardiovascular risk after KTx*

The risk for cardiovascular disease (CVD) is increased after transplantation compared to the general population [82]. Low vitamin D levels were associated with arteriosclerosis and endothelial dysfunction in end-stage renal patients [83]. Other studies also reported of increased CVD incidence in poor VD status. A possible explanation may be that VD-receptor activation in the cardiomyocytes suppresses their proliferation. However, the studies after solid organ transplantation are lacking. Furthermore, higher doses of vitamin D may be associated with increased risk for vascular calcifications [84].

#### *5.2.2.3. Vitamin D and malignancy after KTx*

Malignancy is one of the major contributors to patient and graft loss after transplantation, especially in the long run. Several studies reported lower prevalence of different types of neoplasia in subjects with better VD status [85, 86]. The findings were detected in renal transplant patients [87], though the results should be confirmed by prospective studies, as some reports indicate that high 25VD may increase the risk for prostate neoplasia [88].

#### *5.2.2.4. Vitamin D and infection after KTx*

A major complication is increased fracture risk, associated with increased morbidity and

Vascular calcification. Assessing the development of soft tissue calcification is difficult due to the high prevalence of vascular calcification in advanced CKD. Only one study demonstrated possible slowing of calcification process after KTx [77]. Therefore, currently there is paucity in

With the advance of transplantology, short-term kidney survival has improved significantly over the last decades. However, long-term graft survival still remains a problem, hardly exceeding 70–80% survival at the 10th year after the operation. The major reasons for late graft loss are death of the patient due to cardiovascular disease (CVD), malignancy, and infection; also, calcineurin toxicity and chronic rejection are also other significant causes. The already mentioned pleiotropic effects of VD were described mostly in the general population or CKD patients. It can be expected that these properties can improve patient- and graft-targeted

New onset diabetes after transplantation (NODAT) is associated with higher morbidity and mortality after transplantation, and is linked to the use of steroids and calcineurin inhibitors after the operation. Many experimental and animal studies indicate that better vitamin D status is associated to improved insulin secretion and insulin resistance. Several human studies report of inverse correlation between 25VD level and diabetes prevalence [78, 79]. The data after solid organ transplantation are scarce. Our findings do not show any link between 25VD level and glycemic control [80], thus not supporting any association between VD status and glycemia after KT. No interventional studies assessed the effect of VD supplementation or use of calcitriol/VD analogs in solid organ transplantation patients on diabetes prevalence after the

The risk for cardiovascular disease (CVD) is increased after transplantation compared to the general population [82]. Low vitamin D levels were associated with arteriosclerosis and endothelial dysfunction in end-stage renal patients [83]. Other studies also reported of increased CVD incidence in poor VD status. A possible explanation may be that VD-receptor activation in the cardiomyocytes suppresses their proliferation. However, the studies after solid organ transplantation are lacking. Furthermore, higher doses of vitamin D may be

Malignancy is one of the major contributors to patient and graft loss after transplantation, especially in the long run. Several studies reported lower prevalence of different types of

mortality.

outcomes.

procedure [81].

scientific data for this problem.

40 A Critical Evaluation of Vitamin D - Clinical Overview

*5.2.2. Vitamin D pleiotropy after kidney transplantation*

*5.2.2.2. Vitamin D and cardiovascular risk after KTx*

*5.2.2.3. Vitamin D and malignancy after KTx*

associated with increased risk for vascular calcifications [84].

*5.2.2.1. Vitamin D and diabetes mellitus after kidney transplantation (KTx)*

Infections play a key role for mortality and morbidity after transplantation. Experimental studies have shown that macrophages express VD receptor and its activation leads to increased antimicrobial activity of the macrophages [89]. Human studies also report of beneficial effect of better VD status on infection prevalence. However, only one trial has demonstrated inverse correlation between 25VD and infection rate in lung transplant patients [90]. Vitamin D had no influence on urinary tract infection rate in Bulgarian KTRs followed-up in our center [91]. Therefore, further studies are needed to evaluate the association between VD and infection after transplantation.

#### *5.2.2.5. Vitamin D and rejection after KTx*

Rejection episodes are still a matter of concern and linked to reduced graft survival. On the other hand, long-term immunosuppression contributes to serious adverse events. Higher 25VD was related to lower rejection incidence in KTRs [92]. Experimental reports indicate that calcitriol suppresses T-cell activity and proliferation, as well as B-lymphocyte proliferation, IgG secretion, and major histocompatibility complex class II expression [93–95]. In two small prospective studies, calcitriol treatment was found to have significant immunomodulatory effect [96, 97]. However, the trials in transplant patients are small and single centered, and further research is needed.

#### *5.2.2.6. Vitamin D and renoprotection after KTx*

The effect of VD on renal protection has been described earlier in this chapter together with the possible mechanisms and experimental data supporting them. In the setting of renal transplantation, low VD was associated with higher proteinuria [98]. In addition, calcitriol therapy was found beneficial for renal graft function [99]. However, in a small prospective study by Courbebaisse et al. biopsy findings were compared between cholecalciferol-treated KTRs and KTRs without supplementation. The findings did not demonstrate significant difference in terms of interstitial fibrosis and tubular atrophy [100]. Due to the small number of trials and their small size conclusions cannot be drawn.

#### *5.2.2.7. Vitamin D and mortality after KTx*

Better VD status was associated with lower mortality in the general population and CKD patients, including patients on hemodialysis [98–100]. However, there are no data in terms of mortality in patients after renal transplantation.

In summary, the data for VD pleiotropy after renal transplantation are relatively scarce, originate from single-center studies, and usually with small number of patients. Therefore, further studies including prospective interventional ones are needed.

#### **5.3. Vitamin D treatment after KTx**

The influence of vitamin D treatment after KTx was mainly assessed for its effect on biochemical abnormalities in calcium phosphorus metabolism. The data about the effect on fracture risk, bone density, and pleiotropy are still insufficient. Guidelines are available only for the first posttransplant year. The data for the treatment after the first year are insufficient [21].

## *5.3.1. Native vitamin D (cholecalciferol/ergocalciferol)*

Cholecalciferol supplementation effectively suppressed PTH in renal transplant patients [101]. A meta-analysis performed by KDIGO showed improved bone density in patients with cholecalciferol-/ercalciferol-treated KTRs versus KTRs without VD supplementation [21]. The suggested cholecalciferol dose corresponds with the recommended dose for the general population [21]. As no data are present for patient-targeted endpoints such as fracture risk, no guidelines are available for this issue. Similarly, no specific recommendations can be given for VD pleiotropy. However, there are two large randomized trials assessing cholecalciferol supplementation in KTRs and its effect on renal graft function, NODAT incidence, infection risk, cancer prevalence, and mortality after KTx [82].

#### *5.3.2. Calcitriol/vitamin D analogs*

Treatment with calcitriol/VDAs in renal transplant patients with CKD stages 3T–5T is based on the same principles as in patients with CKD stages 3-5 (GFR below 60 ml/min). The reason for accepting the same approach is the paucity of RCTs in KTRs treated with calcitriol/VDAs [21]. However, certain considerations should be taken into account. The most important one is the high prevalence of persistent hyperparathyroidism and hypercalcemia after KTx. If the PTH levels do not resolve parathyroidectomy should be considered in these cases. As already mentioned, further research is needed in terms of pleiotropic effects of calcitriol/VDA treatment in KTRs.

#### *5.3.3. Treatment monitoring in transplant recipients*

Similarly to pretransplant CKD stages, monitoring calcium, phosphate, PTH, bone AP, and 25 hydroxyvitamin D depends on the renal function, the trend in biochemical abnormalities, and the intervention performed. Still, certain frequencies are suggested (**Table 4**) after the first 3 months posttransplant.
