**4. Vitamin D treatment in renal disease**

The major directions in treating CKD-MBD are reducing phosphate levels, controlling PTH, and treatment of bone changes with bisphosphonates and other medications. Vitamin D preparations are used mainly in suppression of secondary hyperparathyroidism.

#### **4.1. Vitamin D preparations**

There are three types of vitamin D preparations used in CKD patients: native cholecalciferol/ ergocalciferol, which is the form of vitamin D prior to hydroxylation in the liver and kidneys; calcitriol, which is the active form of vitamin D (dihydroxyvitamin D, 1,25VD) and vitamin D analogs. Vitamin D analogs are artificially synthesized molecules, aiming at reducing the side effects of calcitriol—hypercalcemia and hyperphosphatemia—while preserving its ability to suppress PTH. By changing the original structure of calcitriol modified affinity for VDR and vitamin D responding elements in the nucleus is created [53]. The most widely used analogs are doxercalciferol, paricalcitol, alfacalcidol, falecalcitriol, and 22-oxacalcitriol (maxacalcitol).

#### *4.1.1. Cholecalciferol/ergocalciferol (nutritional vitamin D)*

Cholecalciferol is the parent vitamin D, synthesized in the skin, known also as vitamin D3. Ergocalciferol is known as vitamin D2, and is detected in certain vegetable foods, whereas vitamin D is found in fish oils and other foods of animal origin. Both vitamin D3 and vitamin D2 have equal biological activity.

Low 25VD levels are widely detected in CKD. In patients with CKD stages 3–5 not on dialysis supplementation with cholecalciferol/ergocalciferol is suggested as initial treatment of secondary hyperparathyroidism, as well as calcium supplementation and controlling phosphate levels [21]. Different dosing regimens have been suggested. In a study by Kooienga et al., 800 IU cholecalciferol with calcium supplementation was found effective in improving vitamin status and lowering PTH levels in elderly women with different GFR categories. However, it was impossible to differentiate the effect of vitamin D from that of calcium [54]. In another study, vitamin D2 supplementation according to the National Kidney Foundation - Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) protocol effectively suppressed PTH and improved 25VD level [55].

#### *4.1.2. Calcitriol and vitamin D analogs (VDAs)*

*3.2.4. Soft tissue and vascular calcifications*

34 A Critical Evaluation of Vitamin D - Clinical Overview

**3.3. Pleiotropic effects in CKD patients**

**4. Vitamin D treatment in renal disease**

*4.1.1. Cholecalciferol/ergocalciferol (nutritional vitamin D)*

**4.1. Vitamin D preparations**

osteogenic transformation [50].

Soft tissue calcification is the third component of the diagnosis of CKD-related mineral bone disease and is more prevalent in CKD patients compared to the general population [49]. The most dangerous locations of extraskeletal calcification are the vasculature and the heart, increasing the risk for cardiovascular event. In renal disease, the pathogenesis of the deposits is not only passive deposition of calcium and phosphate, but also involves active cellular

Poorer VD status is associated with a broad spectrum of nonskeletal clinical effects, probably due to the widely spread VDR and the presence of nonrenal 1-α hydroxylase. As already mentioned, VD is linked to renin-angiotensin aldosterone system suppression, renal protection, antiproteinuric effects, improved diabetes control, and reduced cancer risk. Pleiotropic effects were detected in CKD patients too—treatment with VD and vitamin D analogs in patients with renal disease led to reduced proteinuria; similar findings were reported in patients with diabetic nephropathy with a relatively low risk for hypercalcemia [51, 52]. However, the studies dealing with CKD patients are relatively few, compared to those reporting VD pleiotropy in the general population. Furthermore, no clear-cut data is present what VD treatment dose and target levels are needed to achieve the extraskeletal effects.

The major directions in treating CKD-MBD are reducing phosphate levels, controlling PTH, and treatment of bone changes with bisphosphonates and other medications. Vitamin D

There are three types of vitamin D preparations used in CKD patients: native cholecalciferol/ ergocalciferol, which is the form of vitamin D prior to hydroxylation in the liver and kidneys; calcitriol, which is the active form of vitamin D (dihydroxyvitamin D, 1,25VD) and vitamin D analogs. Vitamin D analogs are artificially synthesized molecules, aiming at reducing the side effects of calcitriol—hypercalcemia and hyperphosphatemia—while preserving its ability to suppress PTH. By changing the original structure of calcitriol modified affinity for VDR and vitamin D responding elements in the nucleus is created [53]. The most widely used analogs are doxercalciferol, paricalcitol, alfacalcidol, falecalcitriol, and 22-oxacalcitriol (maxacalcitol).

Cholecalciferol is the parent vitamin D, synthesized in the skin, known also as vitamin D3. Ergocalciferol is known as vitamin D2, and is detected in certain vegetable foods, whereas

preparations are used mainly in suppression of secondary hyperparathyroidism.

Treatment with calcitriol and VDAs is preserved for more advanced stages of secondary hyperparathyroidism, in cases with optimal 25VD level (above 75 nmol/l) with progressively rising or persistently high PTH and in patients on dialysis [21, 56]. The KDIGO group on CKD-MBD assessed the effect of the treatment on these four groups of indicators: patient-centered indicators—mortality, morbidity, and cardiovascular/cerebrovascular events; vascular calcifications; bone histology; and biochemical endpoints—PTH, calcium, phosphate, and BAP levels. In order to present the issue more clearly, we will present the data for predialysis patients and patients on dialysis.

#### *4.1.2.1. Patients with CKD stages 3–5, not on dialysis*

Patient-centered endpoints. There are several studies suffering from serious methodological limitations. Thus, no clear-cut can be made for this group of indicators.

Vascular calcifications. No study assessed the effect of cacitriol/VDA on vascular calcifications.

Bone morphology. Nordal and Dahl reported of improved histology in patients with osteitis fibrosa when treated with calcitriol. However, adynamic bone disease was not discussed in the paper, which is a major limitation of the study [57]. Hamdy et al. reported of improved findings in patients with osteitis fibrosa in cases treated with alfacalcidol versus placebo. In the treated group higher incidence of AD was detected [58].

Biochemical endpoints. Treatment with calcitriol, doxercalciferol, paricalcitol, and alfacalcidol effectively reduced PTH levels in renal patients [57–60] versus placebo. Similar findings were reported for BAP [54, 55]. Calcium significantly increased in the treated group with alfacalcidol and calcitriol, whereas paricalcitol and doxercalciferol therapy was associated with upward trend for calcium and calcium-phosphorus product. No difference between active and placebo arms was detected for hyperphosphatemia in doxercalciferol and paricalcitol trials [59, 60].

#### *4.1.2.2. Patients on dialysis*

In this patients group, the suggested target level of PTH is 2–9 times the upper normal limit for the assay [21]. The KDIGO group recommends that calcitriol or VDA treatment initiation and monitoring should be based on PTH, calcium, and phosphate level.

Patient-centered endpoints. Currently, no randomized controlled trials (RCT) have assessed the benefit from calcitriol/VDA treatment on mortality and other patient-centered indicators in dialysis patients. There are several observational trials with conflicting results. Treatment with calcitriol/VDA led to lower mortality compared to patients without treatment; use of paricalcitol and doxercalciferol was found superior to calcitriol in hemodialysis patients, with no difference detected between the two types of VDA [61]. Another study also reported superiority of paricalcitol over calcitriol [62]. However, these findings were not confirmed by the Dialysis Outcomes and Practice Patterns Study (DOPPS) analysis in 2009 [63]. Definitely, RCT are needed to evaluate the effect of calcitriol/VDA treatment on mortality.

Vascular calcification. Currently, there are not sufficient trials performed with endpoint soft tissue calcification; therefore, no recommendations have been formed [21].

Bone morphology. In two interventional studies, treatment with calcitriol versus placebo was assessed both in adults and children. Calcitriol significantly improved bone morphology in cases with osteitis fibrosa, but was associated with lower bone turnover and increased risk for AD [64, 65].

Biochemical endpoints. Treatment with VDA and calcitriol significantly reduced PTH and BAP in dialysis patients [64]. VDA were equivalent or superior to calcitriol in reducing PTH, with lower incidence of hypercalcemia and hyperphosphatemia [66]. Comparing the route of administration, the reports are conflicting. A meta-analysis reported of superiority of intravenous over oral vitamin D treatment [67]. Once the higher doses of intravenous vitamin D were removed, there were no differences in PTH suppression [68].

#### **4.2. Monitoring vitamin D therapy**

The major indicators for the effect of treatment are PTH and BAP, whereas calcium and phosphate are used mainly for assessing the risk for adverse events.

#### *4.2.1. Patients with CKD stages 3–5, not on dialysis*

In this group of patients, the target PTH value is not known. As already mentioned, in cases of elevated PTH, calcium, phosphate, and 25VD levels should be corrected first. If these measures fail VDA/calcitriol may be initiated. In these cases, calcium and phosphate levels follow-up is indicated. According to NKF-KDOQI guidelines, serum levels of calcium and phosphorus should be monitored at least every month after initiation of therapy for the first 3 months, then every 3 months thereafter. Plasma PTH levels should be measured at least every 3 months for 6 months, and every 3 months thereafter [56]. If trends for hypercalcemia and hyperphosphatemia occur dose of VDA/calcitriol should be adjusted or stopped.

#### *4.2.2. Patients on dialysis*

*4.1.2.2. Patients on dialysis*

36 A Critical Evaluation of Vitamin D - Clinical Overview

AD [64, 65].

In this patients group, the suggested target level of PTH is 2–9 times the upper normal limit for the assay [21]. The KDIGO group recommends that calcitriol or VDA treatment initiation

Patient-centered endpoints. Currently, no randomized controlled trials (RCT) have assessed the benefit from calcitriol/VDA treatment on mortality and other patient-centered indicators in dialysis patients. There are several observational trials with conflicting results. Treatment with calcitriol/VDA led to lower mortality compared to patients without treatment; use of paricalcitol and doxercalciferol was found superior to calcitriol in hemodialysis patients, with no difference detected between the two types of VDA [61]. Another study also reported superiority of paricalcitol over calcitriol [62]. However, these findings were not confirmed by the Dialysis Outcomes and Practice Patterns Study (DOPPS) analysis in 2009 [63]. Definitely,

Vascular calcification. Currently, there are not sufficient trials performed with endpoint soft

Bone morphology. In two interventional studies, treatment with calcitriol versus placebo was assessed both in adults and children. Calcitriol significantly improved bone morphology in cases with osteitis fibrosa, but was associated with lower bone turnover and increased risk for

Biochemical endpoints. Treatment with VDA and calcitriol significantly reduced PTH and BAP in dialysis patients [64]. VDA were equivalent or superior to calcitriol in reducing PTH, with lower incidence of hypercalcemia and hyperphosphatemia [66]. Comparing the route of administration, the reports are conflicting. A meta-analysis reported of superiority of intravenous over oral vitamin D treatment [67]. Once the higher doses of intravenous vitamin D were

The major indicators for the effect of treatment are PTH and BAP, whereas calcium and

In this group of patients, the target PTH value is not known. As already mentioned, in cases of elevated PTH, calcium, phosphate, and 25VD levels should be corrected first. If these measures fail VDA/calcitriol may be initiated. In these cases, calcium and phosphate levels follow-up is indicated. According to NKF-KDOQI guidelines, serum levels of calcium and phosphorus should be monitored at least every month after initiation of therapy for the first 3 months, then every 3 months thereafter. Plasma PTH levels should be measured at least every 3 months for 6 months, and every 3 months thereafter [56]. If trends for hypercalcemia and

hyperphosphatemia occur dose of VDA/calcitriol should be adjusted or stopped.

and monitoring should be based on PTH, calcium, and phosphate level.

RCT are needed to evaluate the effect of calcitriol/VDA treatment on mortality.

tissue calcification; therefore, no recommendations have been formed [21].

removed, there were no differences in PTH suppression [68].

phosphate are used mainly for assessing the risk for adverse events.

**4.2. Monitoring vitamin D therapy**

*4.2.1. Patients with CKD stages 3–5, not on dialysis*

The target PTH values in dialysis patients range between 2 and 9 times the normal values [21]. In cases of rising or persistently high PTH, VDA/calcitriol treatment should be initiated. Treatment choice, however, should take calcium and phosphate level into consideration, as present hypercalcemia and hyperphosphatemia are contraindications for vitamin D sterol treatment. In cases where PTH level drops below the target value, or hypercalcemia/hyperphosphatemia develop, VDA/calcitriol treatment should be stopped or dose should be reduced. A possible frequency for testing calcium, phosphate, and PTH in these patients is suggested by NKF-KDOQI, serum levels of calcium and phosphorus are to be monitored at least every 2 weeks for 1 month and then monthly thereafter. Plasma PTH should be measured monthly for at least 3 months and then every 3 months once target levels of PTH are achieved [56].

### *4.2.3. Adverse effects from vitamin D treatment*

The major problems in using vitamin D preparations (native vitamin D, calcitriol, VD analogs) are oversuppression of PTH, hypercalcemia, and hyperphosphatemia. These laboratory findings are the basis for increased AD in recent years. Therefore, regular control of PTH, serum calcium, and phosphorus levels is warranted as directed by the NKF-KDOQI guidelines. Other adverse possible events are associated with vitamin D toxicity (weakness, metallic taste, weight loss, muscle or bone pain, constipation, nausea, vomiting) and hypercalcemia (nausea, vomiting, loss of appetite, weight loss, constipation, increased thirst or urination, confusion). Other possible complications associated with VD analogs are chills and flu-like symptoms. However, these events are rare—none were detected in our everyday practice with native VD/ calcitriol/VDAs.

#### **4.3. Cost-effectiveness of VD treatment**

Treatment with vitamin D analogs is an expensive issue, especially compared to the price of native vitamin D. Therefore, prior to VDAs and calcitriol, the first steps to be performed in the treatment of secondary hyperparathyroidism is correction of hyperphosphatemia (reduction of oral intake, calcium phosphate binders if applicable), hypocalcemia, and vitamin D insufficiency. If PTH is progressively rising, calcitriol/VDAs can be initiated [21].
