Chronic Kidney Disease
The Role of Paricalcitol in Chronic Kidney Disease Jorge B Cannata-Andía1
and Manuel Naves-Díaz2
1. Professor of Medicine; 2. Biologist Registrar, Servicio de Metabolismo Ósco y Mineral, Instituto Sofía de Investigación, REDinREN del ISCIII, Universidad de Oviedo
Abstract
Of the many complications associated with chronic kidney disease (CKD), deficiency in the vitamin D hormonal system is one of the most prominent and well-studied features. Low vitamin D levels (calcidiol and calcitriol) are associated with CKD progression and an increased risk of cardiovascular morbidity and mortality among patients with CKD and end-stage renal disease. The classical physiological function of the vitamin D hormonal system is centred on its role as a mediator of mineral homeostasis and calcitriol deficiency plays a major role in the development of secondary hyperparathyroidism (SHPT). Treatment with vitamin D receptor (VDR) activators such as paricalcitol is the mainstay of SHPT treatment but recent findings from several large observational studies have also suggested that the benefits of VDR activators may extend beyond the parathyroid hormone- (PTH)-lowering effect and could result in direct cardiovascular and survival benefits. Such data are consistent with the pleiotropic effects of the vitamin D hormonal system, including its ‘non-classical’ (non-bone- and mineral-related) physiological effects. Focusing mainly on paricalcitol, this article discusses the important preclinical and clinical studies that have explored the physiological effects (both classical and non-classical) of VDR activator therapy in CKD.
Keywords Vitamin D, chronic kidney disease, paricalcitol, secondary hyperparathyroidism, calcium–phosphate balance, renal fibrosis, proteinuria
Disclosure: Jorge B Cannata-Andía acknowledges research grants related to bone and mineral studies from Instituto de Salud Carlos III, REDinREN, FIS PS09/00415, PI10/00896, FICYT IB09-033, IRSIN-FRIAT, Abbott, Amgen and Shire. Manuel Naves-Díaz has no conflicts of interest to declare. Received: 2 August 2011 Accepted: 10 September 2011 Citation: European Nephrology, 2011;5(2):82–90 Correspondence: Jorge B Cannata-Andía, Servicio de Metabolismo Óseo y Mineral, Instituto Reina Sofía de Investigación, Hospital Central de Asturias, Julián Clavería s/n, 33006 Oviedo, Spain. E:
cannata@hca.es
Support: The publication of this article was funded by Fresenius Medical Care GmbH. The views and opinions expressed are those of the author.
Chronic kidney disease (CKD) is characterised by a progressive loss of renal function and is a frequent prelude to CKD stage 5D. Of the myriad complications associated with CKD, the deficiency in the vitamin D hormonal system is one of the most prominent and well-studied features. As CKD develops there is a progressive increase in fibroblast growth factor 23 (FGF23)1,2
and a reduction in renal mass, with the
consequent progressive decline in the activity of the renal 1α-hydroxylase enzyme, which is critical in converting the inactive
25-hydroxyvitamin D3 (25-D or calcidiol) to the active form, 1α,25-dihydroxyvitamin D3 (1,25-D or calcitriol).3
Serum 1,25-D levels
begin to decline early in the course of CKD and severe deficiency is widely prevalent in patients with advanced CKD and CKD 5D.4–6 Observational studies have shown that low vitamin D levels (25-D and 1,25-D) are associated with CKD progression7
of cardiovascular morbidity and mortality among patients with CKD.8–12
The ‘classical’ physiological role of the hormonal vitamin D system is as a pivotal mediator of bone and mineral homeostasis (see Table 1). 1,25-D binds with high affinity (25-D binds nearly 100 times less avidly) to the vitamin D receptor (VDR)13
and through activity at this receptor
regulates calcium and phosphate serum levels by enhancing their absorption in the intestine, enhancing calcium reabsorption in the kidney tubules, and suppressing the secretion of parathyroid
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hormone (PTH), which is itself a key regulator of mineral metabolism.3,6 Accordingly, 1,25-D deficiency plays a major role in the development of secondary hyperparathyroidism (SHPT), a common and serious complication of CKD that is characterised by persistently elevated PTH levels and bone and mineral abnormalities.14
Treatment with oral or
injectable VDR activators such as exogenous calcitriol, doxercalciferol or newer agents such as paricalcitol suppresses PTH and has been the mainstay of SHPT therapy for many years.15
Importantly,
administration of VDR activators to treat SHPT in patients on dialysis or with stage 3 or 4 CKD has been correlated with improved survival in observational studies.11,16,17
as well as an increased risk
Although current international clinical practice guidelines for CKD limit the administration of VDR activators only to the treatment of SHPT,18,19 VDRs have been identified in over 30 different human tissues. This is a testament to the different actions of the vitamin D hormonal system beyond those associated with bone and mineral homeostasis,3
giving
rise to the so-called ‘non-classical’ actions of vitamin D (see Table 1).20,21
Many of these effects are of relevance to CKD patients, particularly those with CKD 5D: for example, immune response, inflammation, infections, muscle strength, vascular dysfunction and cardiomyopathy are all well documented clinical correlates of vitamin D deficiency in these patients.22
The survival benefit attributed to VDR © TOUCH BRIEFINGS 2011
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