The Role of Paricalcitol in Chronic Kidney Disease


activators when treating SHPT may, therefore, be independent of their PTH-lowering effect.11,16,17


Focusing mainly on paricalcitol, this article discusses the important preclinical and clinical studies that have explored the effects of VDR activator therapy in CKD. Both the classical and non-classical physiological effects (particularly those related to the cardiovascular system) of paricalcitol will be discussed.


Paricalcitol and the Control of Secondary Hyperparathyroidism Deficiency of the Vitamin D Hormonal System and Secondary Hyperparathyroidism


The parathyroid glands play a central role in calcium homeostasis through the release of PTH, a calcitropic agent that regulates serum calcium levels by increasing bone remodelling, renal calcium reabsorption and renal production of 1,25-D. Calcium and vitamin D regulate the activity of the parathyroid gland via the calcium-sensing receptor (CaSR) and the VDR, respectively, which signal the cells to secrete the appropriate amount of PTH. The early increments in FGF23, the consequent decline in 1,25-D serum levels and the reduced VDR expression seen in CKD patients results in the abnormal regulation of the calcium–PTH–vitamin D axis and these patients develop SHPT, which is characterised by parathyroid hyperplasia, persistently elevated PTH levels and systemic mineral and bone abnormalities.6,14,21


Figure 1: Mean Parathyroid Hormone (± Standard Error of the Mean) Following Paricalcitol or Calcitriol Treatment


100 200 300 400 500 600 700 800 900 1000


0


0 2 4 6 8 101214161820 Paricalcitol


Reproduced with permission from Sprague et al., 2003.42


Table 1: Classical and Non-classical Vitamin D Actions Classical Actions


Non-classical Actions


(Bone and Mineral) Intestinal calcium and


phosphate absorption Bone metabolism


Renal calcium reabsorption


SHPT commences early in the course of CKD, possibly as an adaptive mechanism to maintain calcium and phosphate homeostasis, and worsens as kidney function declines.4


Elevated levels of PTH accelerate bone turnover and indirectly promote extraskeletal complications such as vascular and soft tissue calcification.23


levels of PTH are implicated in the high cardiovascular morbidity and mortality observed in CKD.24–26


Therapeutic strategies for SHPT


therefore focus on controlling serum PTH, calcium and phosphate levels within the ranges recommended by national and international clinical practice guidelines.18,19


Suppression of Parathyroid Hormone Levels by Paricalcitol


Vitamin D repletion with inactive forms of native vitamin D2 or D3 (ergocalciferol and cholecalciferol, respectively) or with 25-D increases


serum 25-D and 1,25-D levels in patients with stages 3 and 4 CKD and has been shown to reduce, but frequently it does not normalise, serum PTH levels.27–29


However, this approach is generally considered insufficient for the suppression of PTH in patients with stage 5 CKD. Vitamin D treatment with biologically active VDR activators suppresses PTH in a dose-related fashion in patients with stage 3 to 5 CKD.30–33


These


VDR activators bind to the VDR in parathyroid cells, decreasing PTH synthesis through transcriptional regulation of the PTH gene and inhibiting excessive parathyroid cell proliferation through modulation of cell cycle inhibitors.34


Exogenous calcitriol, the first available VDR


activator, has been used with success in treating SHPT but is associated with hypercalcaemia and hyperphosphataemia.30


These mineral


disturbances are implicated in the development and progression of soft-tissue and vascular calcification and eventual coronary artery disease in haemodialysis patients.25


A growing understanding of the interactions between calcitriol and the VDR led to the development of structurally modified VDR activators


EUROPEAN NEPHROLOGY Parathyroid function regulation (Beyond Bone and Mineral) Renal and cardiovascular protection Inhibition of renin–angiotensin system


Control of adaptive and innate immune system


Reduction of proteinuria Anti-inflammatory and anti-proliferative actions


Furthermore, chronically elevated serum


that retain the direct suppressive effect of calcitriol on the parathyroid gland but that have differential effects on the small intestine and bone, and thus lower calcaemic and phosphataemic activity. Paricalcitol


(19-nor-1α,25 dihydroxyvitamin D2) is a selective VDR activator that is currently available globally for the treatment of SHPT in dialysis patients and in patients with stage 3 and 4 CKD. Structurally,


paricalcitol lacks the exocyclic carbon 19 and has a vitamin D2 side-chain instead of the D3 side-chain of calcitriol.35


These structural


changes are believed to be responsible for the difference in selectivity between paricalcitol and earlier generation non-selective VDR activators, potentially arising from differential interaction with the VDR, from co-activator recruitment or cell/tissue selectivity, or effects at the level of gene expression.35,36


Initial studies in uraemic rats showed that paricalcitol had a wider therapeutic window compared with calcitriol for the suppression of PTH without hypercalcaemia and hyperphosphataemia.37


In addition, a


non-hypercalcaemic dose of paricalcitol was shown to prevent parathyroid gland growth in uraemic rats.38


Results from placebo-controlled clinical trials support the efficacy and tolerability of paricalcitol in CKD patients with SHPT. Martin et al. investigated the efficacy of intravenous paricalcitol in three identical 12-week, randomised, placebo-controlled studies involving 78 haemodialysis patients.39


Patients were treated three times a week


with increasing doses of paricalcitol until a target reduction in PTH of 30 % was achieved. Of the 40 patients receiving paricalcitol, 27 (68 %) reached the goal of a 30 % decrease in serum PTH for four consecutive weeks, compared with three of 38 patients (8 %) receiving placebo (p<0.001). The long-term efficacy of intravenous


83 Time (weeks)


Calcitriol 22 24 26 28 30 32 34


Parathyroid hormone (pg/mL)


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92