The Uses and Abuses of Vitamin D Compounds in Chronic Kidney Disease– Mineral Bone Disease (CKD–MBD) D.J.A. Goldsmith, MD,* Z.A. Massy, PhD,†,‡ and V. Brandenburg, PhD§
Summary: Vitamin D is of paramount importance to skeletal development, integrity and health. Vitamin D homeostatis is typically deranged in a number of chronic conditions, of which chronic kidney disease is one of the most important. The use of vitamin D based therapy to target secondary hyperparathyroidism is now several decades old, and there is a large body of clinical practice, experience, guidelines and research to underpin this. However, there are many unknowns, of significant clinical relevance. Amongst which is what "species" of vitamin D we should be using, in what patient, and, under what conditions. Sadly, there has been a real dearth of randomised controlled trials, and trials with outputs of clinical relevance, which means our clinical practice has not developed and refined adequately ove the last 4 decades. This article will discuss the vexed but critical questions of which vitamin D therapies might suit which kidney patients, and will high-light the many important clinical questions which urgently require answering. Semin Nephrol 34:660-668 C 2014 Published by Elsevier Inc. Keywords: Vitamin D, hyperparathyroidism, hypercalcemia, LVH
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hronic kidney disease (CKD) has become a modern-day global epidemic as part of a slew of noncommunicable diseases that now egregiously tax the health and health care economies of rich and poor parts of the world alike. This is extremely important because CKD has significant morbidity and mortality implications. The major complications related to CKD include cardiovascular disease, anemia, infectious complications, neuropathy, and abnormalities related to mineral bone metabolism.1 Advanced CKD has many major prognostic implications. Increased all-cause mortality in patients with CKD compared with those without CKD has been described consistently over the past 40 years.2,3 Most of the increase in mortality is attributed to increased cardiovascular events. CKD is characterized by increased cardiovascular risk, partly owing to the increased prevalence of traditional cardiovascular risk factors such as hypertension and diabetes mellitus, and also owing to direct increased cardiovascular risk from nontraditional cardiovascular risk factors such as anemia, malnutrition-inflammation syndrome, retention of uremic toxins, and CKD–mineral and bone disorder *
Renal and Transplantation Department, Guy's and St Thomas' Hospitals, London, United Kingdom. † Division of Nephrology, Ambroise Paré Hospital, Paris Ile de France Ouest University, Paris, France. ‡ INSERM U1088, Amiens, France. § Department of Cardiology and Intensive Care Medicine, RWTH University Hospital Aachen, Aachen, Germany. Financial disclosure and conflict of interest statements: none. Address reprint requests to Professor David Goldsmith, Consultant Nephrologist, Renal Offices, 6th Floor, Borough Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT. E-mail: david. [email protected] 0270-9295/ - see front matter & 2014 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.semnephrol.2014.10.002
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(MBD).4 CKD patients are also at high risk of developing end-stage renal disease (ESRD) and therefore the risks for all-cause, as well as cardiovascular, mortality are even higher for ESRD compared with CKD patients. Patients with advanced CKD and on dialysis invariably suffer from a spectrum of abnormalities in the form of uremic complications, which include, but are not confined to, increased blood pressure, dyslipidemia, anemia, acidosis, and skeletal (mineral and bone) disorders. However, at earlier stages of CKD, the malign import of loss of kidney function is more insidious and subtle. Mineral and bone disorders are very common in CKD and now collectively are referred to as CKD– MBD, even though this constellatory aggregation of abnormalities has been criticized as both illogical and jejune, despite an erudite and logical defense.5 Increasingly, over the past 5 decades, epidemiologic and clinical evidence has accumulated that these abnormalities, singly and especially when taken together, make a major contribution to adverse outcomes for patients.6 These abnormalities begin to appear even in early stages of CKD and make a cardinal contribution to the pathogenesis of renal bone disease as well as to eventual morbi-mortality. Alteration in vitamin D metabolism, also ubiquitous in CKD, is one of the key features of CKD–MBD that has major clinical and research implications.7
CKD–MBD, PATHOPHYSIOLOGY, AND THE CENTRAL ROLE OF VITAMIN D Renal osteodystrophy (previously also referred to as renal rickets, and nowadays inferring the interpretation of bone histologic information) is a bone disease characterized by deranged bone morphology in patients with CKD. It now is considered a component of CKD– MBD. Although renal osteodystrophy typically is seen Seminars in Nephrology, Vol 34, No 6, November 2014, pp 660–668
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in advanced kidney failure, other features of CKD– MBD begin to develop at earlier stages of CKD and contribute to the pathogenesis of renal osteodystrophy.8,9 Alteration in vitamin D metabolism is one of the key features of CKD–MBD that has major clinical and research implications. These alterations include the following: (1) biochemical abnormalities in calcium, phosphorous, parathyroid hormone (PTH), vitamin D, and fibroblast growth factor-23 (FGF-23); (2) changes in bone morphology such as bone volume, bone turnover, and bone mineralization; and (3) calcification of soft tissue and blood vessels. Current understanding of CKD–MBD suggests that calcium, phosphorous, PTH, FGF-23, and vitamin D are the key players in regulating mineral and bone metabolism. These factors are inter-related and their major target organs include parathyroid gland, kidneys, bone, and intestinal tract. Bone abnormalities in CKD include high bone turnover disease related to secondary hyperparathyroidism (referred to as osteitis fibrosa cystica), low turnover disease (referred to as adynamic bone disease), osteomalacia (low turnover disease accompanied by undermineralized bone tissue), and mixed disease, in which features of both high and low bone turnover disease are present.9 However, it now is abundantly clear that the role of bone in a number of different pathophysiologies is highly complex and nuanced, with much being discovered about a number of new pathways and systems that also are deranged in CKD.10 Patients with these bone abnormalities may be asymptomatic or may develop symptoms related to bone pain or fractures. Dialysis-dependent ESRD patients have a more than 3 times increased risk of vertebral and hip fractures compared with the general population even after adjustment for age, sex, and race. Factors related to CKD–MBD, including increased PTH level, vitamin D deficiency, bone remodeling, increased bone fragility, and microstructural deterioration, when added to the increased risk of falls, may explain the increased fracture risk in ESRD patients.11–13 As is now well described in the literature, CKD is characterized by low 25(OH) vitamin D (calcidiol)
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levels, low 1,25(OH)2 vitamin D (calcitriol) levels, as well as vitamin D resistance (depicted in Fig. 1). Key mechanisms for these changes are summarized in Table 1. Alterations related to vitamin D metabolism, hyperphosphatemia, and hypocalcemia lead to increased synthesis and/or secretion of PTH, leading to secondary hyperparathyroidism that sets in as soon as glomerular filtration rate decreases to less than 60 mL/ min. Secretion of FGF-23 from osteocytes is increased in CKD and FGF-23 has been shown to reduce PTH expression via its action through the Klotho-fibroblast growth factor receptor 1c receptor complex.14,15 As early as stage 2 of CKD, serum 25(OH) vitamin D levels begin to decrease. Reduced sun exposure, impaired skin synthesis of cholecalciferol caused by renal disease, hyperpigmentation seen in late CKD stages, and dietary restrictions that commonly are given to CKD patients contribute to the high prevalence of vitamin D deficiency. In addition, uremia impairs intestinal absorption of dietary and supplemental vitamin D, and in CKD patients with severe proteinuria there are high urinary losses of vitamin D binding protein (DBP) leading to increased renal loss of vitamin D metabolites.7 In addition to the various reasons for calcidiol deficiency in CKD patients described earlier, CKD also is marked by calcitriol deficiency. The availability of renal 1-α hydroxylase, a key enzyme involved in the production of calcitriol from calcidiol, is reduced as the renal mass reduces. Renal 1-α hydroxylase is highly dependent on substrate calcidiol in patients with CKD, and reduced availability of calcidiol substrate has an important role in calcitriol deficiency in CKD patients. In addition, there are a number of factors that are responsible for down-regulation of renal 1-α hydroxylase in CKD. These include hyperphosphatemia, FGF23, acidosis, hyperuricemia, and uremia. Although the enzyme 1-α hydroxylase also is present in extrarenal tissues, the effects of CKD on this enzyme in these locations are unclear (although it is likely to be implicated). Expression of the renal tubular receptor megalin, which normally is responsible for uptake of
Table 1. Reasons for Abnormal Vitamin D Physiology in CKD Calcidiol deficiency Reduced sun exposure, reduced skin synthesis, reduced ingestion of foods rich in vitamin D Loss of DBP with proteinuria Calcitriol deficiency Reduced calcidiol availability, reduced renal 1-ahydroxylase availability, down-regulation of renal 1-α hydroxylase from hyperphosphatemia and FGF-23, reduced endocytotic uptake by megalin Increased degradation of calcitriol by PTH and FGF-23 Calcitriol resistance Loss of VDR in parathyroid glands, impaired binding of active vitamin D to VDR and impaired binding of vitamin D–VDR complex to the VDR element
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the calcidiol–DBP complex from the glomerular filtrate, is reduced in CKD, and reduced filtration of the calcidiol–DBP complex in the setting of reduced glomerular filtration rate further limits its delivery and uptake by renal tubular receptors. Furthermore, secondary hyperparathyroidism and increased FGF-23 lead to degradation of 25(OH) vitamin D by promoting the enzyme 24-hydroxylase to form 24,25-dihydroxy vitamin D. CKD also is characterized by vitamin D resistance because there is a progressive loss of vitamin D receptor (VDR) in the parathyroid glands.16–19 Studies of the association between serum PTH, 25 (OH) vitamin D, bone morphology, bone mineral density, and bone fractures in CKD and/or ESRD are surprisingly limited in number and size. This is notably well reviewed by Garrett et al.20 In a retrospective study of 104 patients on maintenance hemodialysis 104 patients (61 men, 43 women; mean age, 52.9 ⫾ 11.7 y) who were not on any vitamin D supplements underwent a transiliac bone biopsy for histologic, histomorphometric, and histodynamic evaluation. Patients with serum 25 (OH) vitamin D levels of 15 ng/mL-1 or less had a lower bone formation rate and trabecular mineralization surface independent of PTH and calcitriol levels, indicating the important role that 25 (OH) vitamin D has in bone health in ESRD patients. In another study examining the inter-relationship between fracture and vitamin D status in 130 patients on maintenance hemodialysis, patients with fractures had significantly lower 25(OH) vitamin D levels compared with patients without fractures, and lower vitamin D levels were associated independently with increased fracture risk in a multivariable analysis (odds ratio, 11.22). The same investigators also described low 25 (OH) vitamin D levels associated with reduced bone mineral bone density in maintenance hemodialysis patients. In another crosssectional study, lower 25 (OH) vitamin D levels also have been shown to be associated with increased subperiosteal resorption and also with reduced bone mineral density at the wrist and lumbar spine in ESRD patients (see Garrett et al20 for details regarding these different studies).
THERAPEUTIC USE OF VITAMIN D IN CKD Vitamin D compounds in the setting of renal disease have been reported as early as the 1950s. In one such study bone matrix mineralization, evaluated by histomorphometry, increased in patients receiving 25(OH) vitamin D, whereas it did not change significantly in patients receiving calcitriol. However, this study was not a randomized trial and thus had limitations on its internal validity. The field has moved forward since then and multiple randomized trials have been conducted to examine the role of active vitamin D compounds as well as nutritional vitamin D
D.J.A. Goldsmith, Z.A. Massy, and V. Brandenburg
supplements in CKD and ESRD. Many of these trials were not designed specifically to evaluate patientcentered skeletal outcomes and had multiple methodologic limitations including small sample size and a short follow-up evaluation.21–24 Palmer et al25,26 examined the evidence from randomized controlled trials regarding the efficacy of vitamin D compounds in CKD and ESRD patients in a number of surprisingly repetitive meta-analyses. These investigators conducted a comprehensive literature search and included trials that investigated different vitamin D compounds including calcitriol, alfacalcidol, doxerecalciferol, maxacalcitol, paricalcitol, and falecalcitriol. They noted significant variations in PTHlowering effects of vitamin D compounds, with newer vitamin D compounds (doxerecalciferol, maxacalcitol, paricalcitol, and falecalcitriol) significantly lowering PTH (mean reduction, 98 pg/mL-1) compared with placebo (3 studies, 163 patients), but no significant PTH reduction was noted with established vitamin D compounds such as calcitriol, alfacalcidol (6 studies, 187 patients). In this meta-analysis, established vitamin D compounds were associated with an increased serum calcium level (mean increase, 0.2 mg/dL-l) and serum phosphorous level (mean increase, 0.46 mg/dL-1). However, most studies had inadequate power and insufficient follow-up evaluation to ascertain these outcomes appropriately. In this regard, as in so many others, a meta-analysis simply is not a better analysis. In other recent systematic reviews and meta-analyses, investigators identified 5 randomized trials evaluating nutritional vitamin D supplements (ergocalciferol or cholecalciferol) in CKD and ESRD.27,28 In the pooled analyses of randomized trials, there was a significant increase in serum 25(OH) vitamin D levels (mean difference, 14 ng/mL-1) and an associated decrease in PTH levels (mean decrease, 31.5 pg/mL-1) with nutritional vitamin D supplements compared with placebo. A low incidence of mild and reversible hypercalcemia (up to 3%) and hyperphosphatemia (up to 7%) were reported with nutritional vitamin D supplements. However, none of the studies reported patientcentered outcomes related to bone fractures, bone pain, or parathyroidectomy, and most trials were of low to moderate quality.
WHAT IS THE BEST WAY TO INCREASE SERUM VITAMIN D CONCENTRATIONS? A recent review summarized the different approaches that can be taken in theory to increasing plasma 25 (OH)D concentrations. The interested reader is directed earnestly to this encyclopedic publication by Leckstroem et al.7 At the moment, there is no uniform dietary recommendation for vitamin D intake in
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healthy adults around the world, either in good health or for those with CKD. The population is assumed to obtain sufficient vitamin D through sun exposure, but this has been proven not to be the case because, for at least 6 months of the year, there can be no ultraviolet (UV) B–driven skin synthesis of vitamin D in the United Kingdom and at higher latitudes. Indeed, there is mounting evidence to suggest that some of the current guidelines are in need of re-evaluation. Ways to affect vitamin D repletion include eating naturally vitamin D–rich food (eg, fish, meat, offal, dairy) to obtain cholecalciferol. In certain geographic regions (eg, the Arctic Circle), the Inuit or the Sami races have special diets that provide much more vitamin D, both ergocalciferol (plant-derived) and cholecalciferol (animal-derived). Repletion also can be achieved through intake of specifically fortified food (eg, fortified milk, cheese, yogurt, bread, cereal), or through exposure to sunlight/UVB radiation, such as sunbathing, solar beds, sunshine holidays, UV cabinets, or lamps (phototherapy). If the previous approaches are not suitable or possible, it also is feasible to use oral tablets, intramuscular injections, or, rarely, intravenous bolus injections of vitamin D. Dietary Supplements Vitamin D can be ingested through diet, fortified or not, but depending on a person’s choice of food, and the scarcity of vitamin D–containing foods, reliance on food intake is unlikely to be sufficient on its own. It would be useful only in selected populations. Oral Vitamin D Supplements Oral supplementation benefits from being simple, safe, and cheap but, of course, similar to dietary supplementation, relies on adequate intestinal absorption. Studies have shown that in certain instances oral doses of up to 5000 IU/d might be needed to reach serum concentrations of more than 75 nmol/L. There are several variants of oral native (nonsynthesized) vitamin D available to be used for vitamin D supplementation. Vitamin D2 and D3 are the currently recommended compounds, with vitamin D3 often being favored because it is cheap, effective, and safe, but research is ongoing into other semisynthetic or synthetic VDR activator options such as calcidiol, calcitriol, 1α-calcidiol, paricalcitol, and doxercalciferol. These drugs, however, are expensive and not likely to be warranted or practical for public health measures. There are relatively few head-to-head comparisons to review. It is important to note that these vitamin D analogues might not necessarily be interchangeable, and any situation with impaired
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conversion (eg, enzymatic loss) might preclude the usual choices. UVB: Natural Sunlight or Lamps Currently, sensible sun exposure is recommended in a healthy adult population, and UVB exposure might be the natural choice, but it carries the risk of sunburn and is associated with skin cancer if high doses are to be obtained through normal skin exposure. Although some reports have suggested that vitamin D may protect against melanoma adequately, to replete an individual’s vitamin D status might mandate unrealistically long UVB exposure times, especially for people with darker skin. A study found that brief exposure of approximately 20% of the body surface to sunlight could be equivalent to oral supplementation of only 200 IU of vitamin D3. Sun exposure over the whole body, enough to cause mild erythema, has been shown to be able to increase 25(OH)D serum concentrations as much as long-term oral supplementation of 10,000 IU/d of vitamin D3. The long times needed and the inherent risks a UVB burn carries obviously raises some challenges, and the fact that in higher latitudes UVB-driven, skin-derived production of vitamin D is negligible between October and March, all are factors that militate against this otherwise cheap method. The use of UVB light sources (lamps or cabinets restricted typically to a 311-nm wavelength) recently was revisited and may hold promise, especially for locations at high latitudes. In fact, recent research has shown that short courses of narrow-band UVB exposure can increase 25(OH)D concentrations in subjects already receiving oral supplementation. It also should be noted that UV light itself can generate nitric oxide in the skin, and has a number of immune-modulatory effects that appear to be independent of vitamin D–related mechanisms. Other Approaches to Supplementation: Intramuscular or Boluses Intermittent oral doses or intramuscular injections, such as 40,000 IU/mo, or an intermittent bolus injection with a very large dose (eg, 500,000 IU every 6–12 mo) have been used in certain circumstances (eg, to effect very rapid repletion), or if compliance is questioned. The dosing intervals used vary between studies and range from daily to every 6 months. It currently is unclear which dosing interval is optimal, and how to combine this with initial bolus doses (if indeed any are used); most regimens have proven to be effective for repletion and maintenance of adequate concentrations. However, there have been some concerns about the impact of super-large IM boluses on fall frequency in older adults. Naturally, these bolus-based approaches are not suitable for a public health interventional measure.
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NEW SYNTHETIC VITAMIN D COMPOUNDS: HAS THE LABORATORY PROMISE BEEN TRANSLATED INTO TANGIBLE CLINICAL GAINS? Nonselective VDR activators (VDRAs) such as calcitriol and alfacalcidol have been used successfully in the treatment of secondary hyperparathyroidism (SHPT) in dialysis patients for decades (as discussed earlier). Despite their beneficial effects on the control of serum PTH levels, their use has been limited by intolerance (ie, induction of biochemical hypercalcemia and hyperphosphatemia), especially if combined with calciumcontaining phosphate binders. Although this is potentially undesirable, and usually requires therapeutic regimen changes, which is inconvenient to both the physician and patient alike, it is not always definitely clinically associated with morbi-mortality.
SELECTIVE VDRA Because vitamin D can promote the increase of serum calcium and phosphorus levels, there are concerns about the possible side effects of vitamin D preparations. Hyperphosphatemia and hypercalcemia have been shown to promote calcification of the vasculature, myocardium, and cardiac valves. Vascular calcification and calcification of arteriolar media are the main pathophysiological features of cardiovascular disease in the kidney disease population. Vascular calcification currently is accepted as an actively regulated process similar to bone formation, with changes in the phenotype of vascular smooth muscle cells resulting in osteoblast-like cells that produce calcificationregulating proteins. This process of vascular calcification
was not correlated with vitamin D alone. Indeed, in animals, vitamin D excess would not induce calcification if serum phosphate level was controlled, and it seems that ambient serum phosphorus has a pivotal role in the promotion of vascular calcification in a vitamin D– administration environment (Fig. 1).29–32 Several new vitamin D analogs have been developed for the treatment of secondary hyperparathyroidism (Fig. 2), and were designed to try to reduce the risk of hypercalcemia and hyperphosphatemia. The third generation of vitamin D analogs comprises a group of 1- and 25-hydroxylated vitamin D compounds with structural modifications (19-nor-1,25-dihydroxyvitamin D2 or paricalcitol), which have, so it is claimed, fewer calcemic and less phosphatemic effects when compared with calcitriol. Vitamin D analogs have different effects on nuclear VDRs compared with the actions of calcitriol, through different response elements in various target genes. Experimental work has shown that for similar serum concentrations of calcium and phosphate, paricalcitol produces less vascular calcification than does calcitriol, suggesting differential effects at the cellular level.33,34 Such new vitamin D analogues, because of the unique properties of nuclear VDRs, are named selective vitamin D–receptor activation agents. The term selective means that the molecule acts mostly on the parathyroid gland, more so than on intestine and bone, resulting in lower serum calcium and phosphorus blood concentrations. Such selective VDR activation agents are reported to have anti-inflammatory and antithrombotic effects, and could inhibit vascular smooth muscle cell proliferation, the renin-angiotensin system, and
Figure 1. Role of vitamin D in the development of secondary hyperparathyroidism in CKD.
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Figure 2. Different types of vitamin D compounds. SHPT, secondary hyperparathyroidism.
vascular calcification and stiffening, and could cause left-ventricular hypertrophy to regress.35,36
EXPERIMENTAL DATA TO SUGGEST RELEVANT BIOLOGICAL DIFFERENCES IN VITAMIN D METABOLITES Compared with calcitriol, paricalcitol reduces PTH, however, with significantly fewer episodes of hypercalcemia in hemodialysis patients. Reduced episodes of hypercalcemia among patients who received paricalcitol compared with calcitriol could be explained owing to reduced stimulation of intestinal calcium transport proteins. Calcitriol in uremic rats fed with a high-phosphorus diet enhances intestinal calcium absorption because calcitriol promotes calbindin expression, whereas paricalcitol does not. There are also data on lower absorption rates of calcium and phosphorus among patients receiving paricalcitol, compared with calcitriol.37–39 In rat models of gentamicin-induced renal injury, paricalcitol prevented up-regulated inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interferonγ), nuclear factor-κB and phosphorylated extracellular regulated kinase 1/2 expression, and adhesion molecules (monocyte chemoattractant protein-1, intercellular adhesion molecule-1, vascular cell adhesion molecule-1), and it also reversed the transforming growth factor-β1– induced epithelial-to-mesenchymal transition process and extracellular matrix accumulation.40,41 Antifibrotic effects of paricalcitol were reported by Meems et al42 in an animal model: paricalcitol reduced
myocardial fibrosis and preserved diastolic left ventricular function owing to pressure overload associated with reduced fibrosis. A similar study showed the protective effect of enalapril and paricalcitol, alone or in combination, on cardiac oxidative stress in uremic rats.43 A combination of enalapril and paricalcitol reduced glomerulosclerosis, proteinuria, and inflammation— when measured as monocyte chemoattractant protein-1 in uremic rats—via suppression of transforming growth factor-β1 and Smad2.44 Kong et al45 examined the effects of losartan, paricalcitol, doxercalciferol, a combination of losartan and paricalcitol, or a combination of losartan and doxercalciferol, on the development of left ventricular hypertrophy. Echocardiography showed a 65% to 80% reduction in left ventricular wall thickness with losartan, paricalcitol, or doxercalciferol monotherapy, and almost complete prevention of left ventricular hypertrophy with the combination therapies. Renal and cardiac renin expression were increased markedly in losartan-treated animals, but nearly normalized with combination therapy. These data showed that vitamin D analogues had potent antihypertrophic activity, partly by suppressing renin in the kidney and heart. Mizobuchi et al showed that paricalcitol, in contrast to calcitriol and doxercalciferol, had no effect on the serum calcium-phosphate product or the aortic calcium content in uremic rats. A higher dose of paricalcitol still had no effect, but decreasing doxercalciferol levels did not increase the calcium-phosphate product; rather, it increased the aortic calcium content, suggesting independent paricalcitol-mediated mechanisms for protection from vascular calcification.46–48
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Cardús et al49 tested the effects of calcitriol and paricalcitol on vascular smooth muscle cell calcification in an animal end-stage renal disease model, and concluded that calcitriol, but not paricalcitol, increased calcification of vascular smooth muscle cells, independently of the levels of calcium and phosphate.
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Although the results from the earlier-described animal experiments may be interesting to some, there is no evidence yet available that such processes are relevant to hard end points in CKD and dialysis patients. Because therapies with calcitriol and vitamin D analogues have been associated with reduced mortality in CKD patients, although never once shown in a randomized controlled trial setting, particularly in those suffering from secondary hyperparathyroidism different investigators have tried to switch to selective VDRA, usually as paricalcitol, in calcitriol-resistant patients. The reader is invited to compare and contrast these studies, which show contradictory findings.50–55
and there does seem to be some additional antiproteinuric effect achievable, even in fully renin-angiotensinaldosterone system–inhibited patients. The long-term safety of this intervention is not yet known but surely would benefit from being tested in a randomized controlled trial. Despite plenty of observational data on the association of vitamin D with decreased cardiovascularrelated morbidity and mortality, Paricalcitol Capsule Benefits in Renal Failure-Induced Cardiac Morbidity, a randomized controlled trial on a group of 227 patients with chronic kidney disease with mild-to-moderate left ventricular hypertrophy and preserved left-ventricular ejection fraction, could not show the influence of 48 weeks of paricalcitol therapy on the left ventricular mass index or on Doppler measures of diastolic dysfunction.58,59 The similarly conceived and recently reported Effect of paricalcitol on left ventricular mass and function in CKD (the OPERA trial)60 did not find a left ventricular mass difference for the chronic administration of paricalcitol to patients with CKD stages 3 to 5. Therefore, with first the Paricalcitol Capsule Benefits in Renal Failure-Induced Cardiac Morbidity study and now the OPERA trial, the fat lady has indeed finished singing, at least her first act.
PARICALCITOL IN CLINICAL USE AND TRIALS
CONCLUSIONS
Despite some animal models, and small imperfect studies of human participants, there are only a few human randomized trials that might clarify the influence of selective VDR activation on the cardiovascular system in chronic kidney and/or chronic heart failure patients. Paricalcitol appears to block the reninangiotensin-aldosterone system, and could have an effect on proteinuria via the suppression of β-catenin– mediated gene transcription and the prevention of podocyte dysfunction. In the VITamin D and OmegA-3 TriaL,56 a randomized clinical trial, paricalcitol showed the additional effect of decreasing albuminuria in patients with diabetic nephropathy. The study enrolled 281 patients being treated with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. The antiproteinuric effect was stronger when sodium dietary intake was higher. This renal protective effect seemed to be associated with renin transcription suppression, together with an antifibrotic and antiproliferative effect, and possibly with lower blood pressure in the paricalcitol group. These antiproteinuric effects were correlated with paricalcitol, and returned to baseline values upon paricalcitol withdrawal. Because albuminuria is a surrogate end point, further clinical data are needed to establish the potential effects of selective VDR activation on hard end point markers in chronic renal disease. The antiproteinuric effect of vitamin D compounds (mainly paricalcitol) recently was reviewed nicely57
There is no doubt that vitamin D is pivotal to good health in CKD. Deficiency of, and resistance to, vitamin D, are common in CKD, and thus constitute a major part of the skeletal consequences of chronic uremia. The use of vitamin D replacement therapies, a decades-old practice, is both sagacious and salutary. If the practice is now decades old, then so are some of the compounds still in regular clinical therapeutic use, with well-recognized limitations, drawbacks, and toxicities. In the experimental or animal model setting it is relatively easy to engineer differences between different vitamin D compounds in terms of cytoprotection or fibrosis/vascular calcification. However, it is naive if not dangerously misleading to assume that these findings are of relevance to the long-term administration of these drugs to patients with CKD. The value of nutritional vitamin D repletion has been underinvestigated, and thus underexplored, in CKD. Although weaker than VDRAs (in terms of PTH-suppressing effects), it also is associated with fewer problems of hypercalcemia and hyperphosphatemia. Much more clinical and research work is needed to elucidate whether formal repletion at an early stage of CKD using cholecalciferol or ergocalciferol can prevent the renal, cardiac, and skeletal complications associated with CKD. VDRAs clearly have an established place in targeting increased PTH and in particular high-turnover bone disease and osteomalacia.
CLINICAL DATA TO SUGGEST RELEVANT BIOLOGICAL DIFFERENCES IN VITAMIN D METABOLITES
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It is a shock, even in a field as derelict and destitute of evidence as nephrology, that 50 years into the era of regular renal replacement therapy, there has never been a suitable series of outcome trials to show what vitamin D species we should use, at what point, in which patients, and using what marker of therapeutic success. Sole reliance on serum PTH concentrations to guide the initiation and titration of vitamin D therapy is both foolish and unsatisfactory, and it should be to the lasting shame of guideline groups that this simplistic approach has been promulgated relentlessly. This has been a huge impediment to the conduct of proper clinical studies, which we now are unlikely to see in 2014.
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treatment, and outcomes of hip fracture in older patients initiating dialysis in the United States. Clin J Am Soc Nephrol. 2013;8:1336-42. Gutierrez OM. Fibroblast growth factor 23 and disordered vitamin D metabolism in chronic kidney disease: updating the "trade-off" hypothesis. Clin J Am Soc Nephrol. 2010;5: 1710-6. Galitzer H, Ben-Dov IZ, Silver J, Naveh-Many T. Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease. Kidney Int. 2010;77:211-8. Mawer EB, Taylor CM, Backhouse J, Lumb GA, Stanbury SW. Failure of formation of 1,25-dihydroxycholecalciferol in chronic renal insufficiency. Lancet. 1973;1:626-8. Ishimura E, Nishizawa Y, Inaba M, Matsumoto N, Emoto M, Kawagishi T. Serum levels of 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, and 25-hydroxyvitamin D in nondialyzed patients with chronic renal failure. Kidney Int. 1999;55:1019-27. Kawashima H, Kraut JA, Kurokawa K. Metabolic acidosis suppresses 25-hydroxyvitamin in D3-1alpha-hydroxylase in the rat kidney. Distinct site and mechanism of action. J Clin Invest. 1982;70:135-40. Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol. 2005;16:2205-15. Garrett G, Sardiwal S, Lamb EJ, Goldsmith DJ. PTH - a particularly tricky hormone: why measure it at all in kidney patients? Clin J Am Soc Nephrol. 2013;8:299-312. Stanbury SW. Azotaemic renal osteodystrophy. Br Med Bull. 1957;13:57-60. Fournier A, Bordier P, Gueris J, Sebert JL, Marie P, Ferriere C, et al. Comparison of 1 alpha-hydroxycholecalciferol and 25hydroxycholecalciferol in the treatment of renal osteodystrophy: greater effect of 25-hydroxycholecalciferol on bone mineralization. Kidney Int. 1979;15:196-204. Hamdy NA, Kanis JA, Beneton MN, Brown CB, Juttmann JR, Jordans JG, et al. Effect of alfacalcidol on natural course of renal bone disease in mild to moderate renal failure. BMJ. 1995;310:358-63. Baker LR, Muir JW, Sharman VL, Abrams SM, Greenwood RN, Cattell WR, et al. Controlled trial of calcitriol in hemodialysis patients. Clin Nephrol. 1986;26:185-91. Palmer SC, McGregor DO, Craig JC, Elder G, Macaskill P, Strippoli GF, et al. Vitamin D compounds for people with chronic kidney disease requiring dialysis. Cochrane Database Syst Rev. 2009;4:770-65. Palmer SC, McGregor DO, Macaskill P, Craig JC, Elder GJ, Strippoli GF. Meta-analysis: vitamin D compounds in chronic kidney disease. Ann Intern Med. 2007;147:840-53. Moorthi RN, Kandula P, Moe SM. Optimal vitamin D, calcitriol, and vitamin D analogue replacement in chronic kidney disease: to D or not to D: that is the question. Curr Opin Nephrol Hypertens. 2011;20:354-9. Kandula P, Dobre M, Schold JD, Schreiber MJ Jr, Mehrotra R, Navaneethan SD. Vitamin D supplementation in chronic kidney disease: a systematic review and meta-analysis of observational studies and randomized controlled trials. Clin J Am Soc Nephrol. 2011;6:50-62. Liabeuf S, Okazaki H, Desjardins L, Fliser D, Goldsmith D, Covic A, et al. Vascular calcification in chronic kidney disease: are biomarkers useful for probing the pathobiology and the health risks of this process in the clinical scenario? Nephrol Dial Transplant. 2014;29:1275-84. Leonard O, Spaak J, Goldsmith D. Regression of vascular calcification in chronic kidney disease - feasible or fantasy? a
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D.J.A. Goldsmith, Z.A. Massy, and V. Brandenburg review of the clinical evidence. Br J Clin Pharmacol. 2013;76:560-72. Donate-Correa J, Dominguez-Pimentel V, Muros-de-Fuentes M, Mora-Fernandez C, Martin-Nunez E, Cazana-Perez V, et al. Beneficial effects of selective vitamin D receptor activation by paricalcitol in chronic kidney disease. Curr Drug Targets. 2014;15:703-9. Somjen D, Kulesza U, Sharon O, Knoll E, Stern N. New vitamin D less-calcemic analog affect human bone cell line and cultured vascular smooth muscle cells similar to other less-calcemic analogs. J Steroid Biochem Mol Biol. 2014;140:1-6. Martínez-Moreno JM, Muñoz-Castañeda JR, Herencia C, Oca AM, Estepa JC, Canalejo R, et al. In vascular smooth muscle cells paricalcitol prevents phosphate-induced Wnt/β-catenin activation. Am J Physiol Renal Physiol. 2012;303:F1136-44. Cozzolino M, Stucchi A, Rizzo MA, Soldati L, Cusi D, Ciceri P, et al. Vitamin D receptor activation and prevention of arterial ageing. Nutr Metab Cardiovasc Dis. 2012;22:547-52. Covic A, Voroneanu L, Goldsmith D. The effects of vitamin D therapy on left ventricular structure and function - are these the underlying explanations for improved CKD patient survival? Nephron Clin Pract. 2010;116:c187-95. Panizo S, Barrio-Vázquez S, Naves-Díaz M, Carrillo-López N, Rodríguez I, Fernández-Vázquez A, et al. Vitamin D receptor activation, left ventricular hypertrophy and myocardial fibrosis. Nephrol Dial Transplant. 2013;28:2735-44. Lund RJ, Andress DL, Amdahl M, Williams LA, Heaney RP. Differential effects of paricalcitol and calcitriol on intestinal calcium absorption in hemodialysis patients. Am J Nephrol. 2010;31:165-70. Tentori F, Hunt WC, Stidley CA, Rohrscheib MR, Bedrick EJ, Meyer KB, et al, Medical Directors of Dialysis Clinic Inc. Mortality risk among hemodialysis patients receiving different vitamin D analogs. Kidney Int. 2006;70:1858-65. Sprague SM, Llach F, Amdahl M, Taccetta C, Batlle D. Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. Kidney Int. 2003;63:1483-90. Suh SH, Lee KE, Park JW, Kim IJ, Kim O, Kim CS, et al. Antiapoptotic effect of paricalcitol in gentamicin-induced kidney injury. Korean J Physiol Pharmacol. 2013;17:435-40. Park JW, Bae EH, Kim IJ, Ma SK, Choi C, Lee J, et al. Renoprotective effects of paricalcitol on gentamicin-induced kidney injury in rats. Am J Physiol Renal Physiol. 2010;298: F301-F313. Meems LM, Cannon MV, Mahmud H, Voors AA, van Gilst WH, Silljé HH, et al. The vitamin D receptor activator paricalcitol prevents fibrosis and diastolic dysfunction in a murine model of pressure overload. J Steroid Biochem Mol Biol. 2012;132:282-9. Finch JL, Suarez EB, Husain K, Ferder L, Cardema MC, Glenn DJ, et al. Effect of combining an ACE inhibitor and a VDR activator on glomerulosclerosis, proteinuria, and renal oxidative stress in uremic rats. Am J Physiol Renal Physiol. 2012;302: F141-F149. Sanchez-Niño MD, Bozic M, Córdoba-Lanús E, Valcheva P, Gracia O, Ibarz M, et al. Beyond proteinuria: VDR activation
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reduces renal inflammation in experimental diabetic nephropathy. Am J Physiol Renal Physiol. 2012;302:F647-57. Kong J, Kim GH, Wei M, Sun T, Li G, Liu SQ, et al. Therapeutic effects of vitamin D analogues on cardiac hypertrophy in spontaneously hypertensive rats. Am J Pathol. 2010;177:622-31. Husain K, Ferder L, Mizobuchi M, Finch J, Slatopolsky E. Combination therapy with paricalcitol and enalapril ameliorates cardiac oxidative injury in uremic rats. Am J Nephrol. 2009;29:465-72. Mizobuchi M, Finch JL, Martin DR, Slatopolsky E. Differential effects of vitamin D receptor activators on vascular calcification in uremic rats. Kidney Int. 2007;72:709-15. Mizobuchi M, Nakamura H, Tokumoto M, Finch J, Morrissey J, Liapis H, et al. Myocardial effects of VDR activators in renal failure. J Steroid Biochem Mol Biol. 2010;121:188-92. Cardús A, Panizo S, Parisi E, Fernandez E, Valdivielso JM. Differential effects of vitamin D analogs on vascular calcification. J Bone Miner Res. 2007;22:860-6. Zheng Z, Shi H, Jia J, Li D, Lin S. Vitamin D supplementation and mortality risk in chronic kidney disease: a meta-analysis of 20 observational studies. BMC Nephrol. 2013;14:199. Miller JE, Molnar MZ, Kovesdy CP, Zaritsky JJ, Streja E, Fellat IO, et al. Administered paricalcitol dose and survival in hemodialysis patients: a marginal structural model analysis. Pharmacoepidemiol Drug Saf. 2012;21:1232-9. Hansen D. A randomised clinical study of alfacalcidol and paricalcitol. Dan Med J. 2012;59:B4400. Cheng J, Zhang W, Zhang X, Li X, Chen J. Efficacy and safety of paricalcitol therapy for chronic kidney disease: a metaanalysis. Clin J Am Soc Nephrol. 2012;7:391-400. Hansen D, Brandi L, Rasmussen K. Treatment of secondary hyperparathyroidism in haemodialysis patients: a randomised clinical trial comparing paricalcitol and alfacalcidol. BMC Nephrol. 2009;10:28. Kalantar-Zadeh K. Survival differences between activated injectable vitamin D2 and D3 analogs. Kidney Int. 2007; 71:827. de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella T, et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet. 2010;376:1543-51. de Borst MH, Hajhosseiny R, Tamez H, Wenger J, Thadhani R, Goldsmith DJ. Active vitamin D treatment for reduction of residual proteinuria: a systematic review. J Am Soc Nephrol. 2013;24:1863-71. Tamez H, Zoccali C, Packham D, Wenger J, Bhan I, Appelbaum E, et al. Vitamin D reduces left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease. Am Heart J. 2012;164:902-9. Thadhani R, Appelbaum E, Pritchett Y, Chang Y, Wenger J, Tamez H, et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. JAMA. 2012;307:674-84. Wang AY, Fang F, Chan J, Wen YY, Qing S, Chan IH, et al. Effect of paricalcitol on left ventricular mass and function in CKD—the OPERA trial. J Am Soc Nephrol. 2014;25:175-86.
Summary: Vitamin D is of paramount importance to skeletal development, integrity and health. Vitamin D homeostatis is typically deranged in a number of chronic conditions, of which chronic kidney disease is one of the most important. The use of vitamin D based therapy to target secondary hyperparathyroidism is now several decades old, and there is a large body of clinical practice, experience, guidelines and research to underpin this. However, there are many unknowns, of significant clinical relevance. Amongst which is what "species" of vitamin D we should be using, in what patient, and, under what conditions. Sadly, there has been a real dearth of randomised controlled trials, and trials with outputs of clinical relevance, which means our clinical practice has not developed and refined adequately ove the last 4 decades. This article will discuss the vexed but critical questions of which vitamin D therapies might suit which kidney patients, and will high-light the many important clinical questions which urgently require answering. Semin Nephrol 34:660-668 C 2014 Published by Elsevier Inc. Keywords: Vitamin D, hyperparathyroidism, hypercalcemia, LVH
C
hronic kidney disease (CKD) has become a modern-day global epidemic as part of a slew of noncommunicable diseases that now egregiously tax the health and health care economies of rich and poor parts of the world alike. This is extremely important because CKD has significant morbidity and mortality implications. The major complications related to CKD include cardiovascular disease, anemia, infectious complications, neuropathy, and abnormalities related to mineral bone metabolism.1 Advanced CKD has many major prognostic implications. Increased all-cause mortality in patients with CKD compared with those without CKD has been described consistently over the past 40 years.2,3 Most of the increase in mortality is attributed to increased cardiovascular events. CKD is characterized by increased cardiovascular risk, partly owing to the increased prevalence of traditional cardiovascular risk factors such as hypertension and diabetes mellitus, and also owing to direct increased cardiovascular risk from nontraditional cardiovascular risk factors such as anemia, malnutrition-inflammation syndrome, retention of uremic toxins, and CKD–mineral and bone disorder *
Renal and Transplantation Department, Guy's and St Thomas' Hospitals, London, United Kingdom. † Division of Nephrology, Ambroise Paré Hospital, Paris Ile de France Ouest University, Paris, France. ‡ INSERM U1088, Amiens, France. § Department of Cardiology and Intensive Care Medicine, RWTH University Hospital Aachen, Aachen, Germany. Financial disclosure and conflict of interest statements: none. Address reprint requests to Professor David Goldsmith, Consultant Nephrologist, Renal Offices, 6th Floor, Borough Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT. E-mail: david. [email protected] 0270-9295/ - see front matter & 2014 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.semnephrol.2014.10.002
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(MBD).4 CKD patients are also at high risk of developing end-stage renal disease (ESRD) and therefore the risks for all-cause, as well as cardiovascular, mortality are even higher for ESRD compared with CKD patients. Patients with advanced CKD and on dialysis invariably suffer from a spectrum of abnormalities in the form of uremic complications, which include, but are not confined to, increased blood pressure, dyslipidemia, anemia, acidosis, and skeletal (mineral and bone) disorders. However, at earlier stages of CKD, the malign import of loss of kidney function is more insidious and subtle. Mineral and bone disorders are very common in CKD and now collectively are referred to as CKD– MBD, even though this constellatory aggregation of abnormalities has been criticized as both illogical and jejune, despite an erudite and logical defense.5 Increasingly, over the past 5 decades, epidemiologic and clinical evidence has accumulated that these abnormalities, singly and especially when taken together, make a major contribution to adverse outcomes for patients.6 These abnormalities begin to appear even in early stages of CKD and make a cardinal contribution to the pathogenesis of renal bone disease as well as to eventual morbi-mortality. Alteration in vitamin D metabolism, also ubiquitous in CKD, is one of the key features of CKD–MBD that has major clinical and research implications.7
CKD–MBD, PATHOPHYSIOLOGY, AND THE CENTRAL ROLE OF VITAMIN D Renal osteodystrophy (previously also referred to as renal rickets, and nowadays inferring the interpretation of bone histologic information) is a bone disease characterized by deranged bone morphology in patients with CKD. It now is considered a component of CKD– MBD. Although renal osteodystrophy typically is seen Seminars in Nephrology, Vol 34, No 6, November 2014, pp 660–668
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in advanced kidney failure, other features of CKD– MBD begin to develop at earlier stages of CKD and contribute to the pathogenesis of renal osteodystrophy.8,9 Alteration in vitamin D metabolism is one of the key features of CKD–MBD that has major clinical and research implications. These alterations include the following: (1) biochemical abnormalities in calcium, phosphorous, parathyroid hormone (PTH), vitamin D, and fibroblast growth factor-23 (FGF-23); (2) changes in bone morphology such as bone volume, bone turnover, and bone mineralization; and (3) calcification of soft tissue and blood vessels. Current understanding of CKD–MBD suggests that calcium, phosphorous, PTH, FGF-23, and vitamin D are the key players in regulating mineral and bone metabolism. These factors are inter-related and their major target organs include parathyroid gland, kidneys, bone, and intestinal tract. Bone abnormalities in CKD include high bone turnover disease related to secondary hyperparathyroidism (referred to as osteitis fibrosa cystica), low turnover disease (referred to as adynamic bone disease), osteomalacia (low turnover disease accompanied by undermineralized bone tissue), and mixed disease, in which features of both high and low bone turnover disease are present.9 However, it now is abundantly clear that the role of bone in a number of different pathophysiologies is highly complex and nuanced, with much being discovered about a number of new pathways and systems that also are deranged in CKD.10 Patients with these bone abnormalities may be asymptomatic or may develop symptoms related to bone pain or fractures. Dialysis-dependent ESRD patients have a more than 3 times increased risk of vertebral and hip fractures compared with the general population even after adjustment for age, sex, and race. Factors related to CKD–MBD, including increased PTH level, vitamin D deficiency, bone remodeling, increased bone fragility, and microstructural deterioration, when added to the increased risk of falls, may explain the increased fracture risk in ESRD patients.11–13 As is now well described in the literature, CKD is characterized by low 25(OH) vitamin D (calcidiol)
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levels, low 1,25(OH)2 vitamin D (calcitriol) levels, as well as vitamin D resistance (depicted in Fig. 1). Key mechanisms for these changes are summarized in Table 1. Alterations related to vitamin D metabolism, hyperphosphatemia, and hypocalcemia lead to increased synthesis and/or secretion of PTH, leading to secondary hyperparathyroidism that sets in as soon as glomerular filtration rate decreases to less than 60 mL/ min. Secretion of FGF-23 from osteocytes is increased in CKD and FGF-23 has been shown to reduce PTH expression via its action through the Klotho-fibroblast growth factor receptor 1c receptor complex.14,15 As early as stage 2 of CKD, serum 25(OH) vitamin D levels begin to decrease. Reduced sun exposure, impaired skin synthesis of cholecalciferol caused by renal disease, hyperpigmentation seen in late CKD stages, and dietary restrictions that commonly are given to CKD patients contribute to the high prevalence of vitamin D deficiency. In addition, uremia impairs intestinal absorption of dietary and supplemental vitamin D, and in CKD patients with severe proteinuria there are high urinary losses of vitamin D binding protein (DBP) leading to increased renal loss of vitamin D metabolites.7 In addition to the various reasons for calcidiol deficiency in CKD patients described earlier, CKD also is marked by calcitriol deficiency. The availability of renal 1-α hydroxylase, a key enzyme involved in the production of calcitriol from calcidiol, is reduced as the renal mass reduces. Renal 1-α hydroxylase is highly dependent on substrate calcidiol in patients with CKD, and reduced availability of calcidiol substrate has an important role in calcitriol deficiency in CKD patients. In addition, there are a number of factors that are responsible for down-regulation of renal 1-α hydroxylase in CKD. These include hyperphosphatemia, FGF23, acidosis, hyperuricemia, and uremia. Although the enzyme 1-α hydroxylase also is present in extrarenal tissues, the effects of CKD on this enzyme in these locations are unclear (although it is likely to be implicated). Expression of the renal tubular receptor megalin, which normally is responsible for uptake of
Table 1. Reasons for Abnormal Vitamin D Physiology in CKD Calcidiol deficiency Reduced sun exposure, reduced skin synthesis, reduced ingestion of foods rich in vitamin D Loss of DBP with proteinuria Calcitriol deficiency Reduced calcidiol availability, reduced renal 1-ahydroxylase availability, down-regulation of renal 1-α hydroxylase from hyperphosphatemia and FGF-23, reduced endocytotic uptake by megalin Increased degradation of calcitriol by PTH and FGF-23 Calcitriol resistance Loss of VDR in parathyroid glands, impaired binding of active vitamin D to VDR and impaired binding of vitamin D–VDR complex to the VDR element
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the calcidiol–DBP complex from the glomerular filtrate, is reduced in CKD, and reduced filtration of the calcidiol–DBP complex in the setting of reduced glomerular filtration rate further limits its delivery and uptake by renal tubular receptors. Furthermore, secondary hyperparathyroidism and increased FGF-23 lead to degradation of 25(OH) vitamin D by promoting the enzyme 24-hydroxylase to form 24,25-dihydroxy vitamin D. CKD also is characterized by vitamin D resistance because there is a progressive loss of vitamin D receptor (VDR) in the parathyroid glands.16–19 Studies of the association between serum PTH, 25 (OH) vitamin D, bone morphology, bone mineral density, and bone fractures in CKD and/or ESRD are surprisingly limited in number and size. This is notably well reviewed by Garrett et al.20 In a retrospective study of 104 patients on maintenance hemodialysis 104 patients (61 men, 43 women; mean age, 52.9 ⫾ 11.7 y) who were not on any vitamin D supplements underwent a transiliac bone biopsy for histologic, histomorphometric, and histodynamic evaluation. Patients with serum 25 (OH) vitamin D levels of 15 ng/mL-1 or less had a lower bone formation rate and trabecular mineralization surface independent of PTH and calcitriol levels, indicating the important role that 25 (OH) vitamin D has in bone health in ESRD patients. In another study examining the inter-relationship between fracture and vitamin D status in 130 patients on maintenance hemodialysis, patients with fractures had significantly lower 25(OH) vitamin D levels compared with patients without fractures, and lower vitamin D levels were associated independently with increased fracture risk in a multivariable analysis (odds ratio, 11.22). The same investigators also described low 25 (OH) vitamin D levels associated with reduced bone mineral bone density in maintenance hemodialysis patients. In another crosssectional study, lower 25 (OH) vitamin D levels also have been shown to be associated with increased subperiosteal resorption and also with reduced bone mineral density at the wrist and lumbar spine in ESRD patients (see Garrett et al20 for details regarding these different studies).
THERAPEUTIC USE OF VITAMIN D IN CKD Vitamin D compounds in the setting of renal disease have been reported as early as the 1950s. In one such study bone matrix mineralization, evaluated by histomorphometry, increased in patients receiving 25(OH) vitamin D, whereas it did not change significantly in patients receiving calcitriol. However, this study was not a randomized trial and thus had limitations on its internal validity. The field has moved forward since then and multiple randomized trials have been conducted to examine the role of active vitamin D compounds as well as nutritional vitamin D
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supplements in CKD and ESRD. Many of these trials were not designed specifically to evaluate patientcentered skeletal outcomes and had multiple methodologic limitations including small sample size and a short follow-up evaluation.21–24 Palmer et al25,26 examined the evidence from randomized controlled trials regarding the efficacy of vitamin D compounds in CKD and ESRD patients in a number of surprisingly repetitive meta-analyses. These investigators conducted a comprehensive literature search and included trials that investigated different vitamin D compounds including calcitriol, alfacalcidol, doxerecalciferol, maxacalcitol, paricalcitol, and falecalcitriol. They noted significant variations in PTHlowering effects of vitamin D compounds, with newer vitamin D compounds (doxerecalciferol, maxacalcitol, paricalcitol, and falecalcitriol) significantly lowering PTH (mean reduction, 98 pg/mL-1) compared with placebo (3 studies, 163 patients), but no significant PTH reduction was noted with established vitamin D compounds such as calcitriol, alfacalcidol (6 studies, 187 patients). In this meta-analysis, established vitamin D compounds were associated with an increased serum calcium level (mean increase, 0.2 mg/dL-l) and serum phosphorous level (mean increase, 0.46 mg/dL-1). However, most studies had inadequate power and insufficient follow-up evaluation to ascertain these outcomes appropriately. In this regard, as in so many others, a meta-analysis simply is not a better analysis. In other recent systematic reviews and meta-analyses, investigators identified 5 randomized trials evaluating nutritional vitamin D supplements (ergocalciferol or cholecalciferol) in CKD and ESRD.27,28 In the pooled analyses of randomized trials, there was a significant increase in serum 25(OH) vitamin D levels (mean difference, 14 ng/mL-1) and an associated decrease in PTH levels (mean decrease, 31.5 pg/mL-1) with nutritional vitamin D supplements compared with placebo. A low incidence of mild and reversible hypercalcemia (up to 3%) and hyperphosphatemia (up to 7%) were reported with nutritional vitamin D supplements. However, none of the studies reported patientcentered outcomes related to bone fractures, bone pain, or parathyroidectomy, and most trials were of low to moderate quality.
WHAT IS THE BEST WAY TO INCREASE SERUM VITAMIN D CONCENTRATIONS? A recent review summarized the different approaches that can be taken in theory to increasing plasma 25 (OH)D concentrations. The interested reader is directed earnestly to this encyclopedic publication by Leckstroem et al.7 At the moment, there is no uniform dietary recommendation for vitamin D intake in
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healthy adults around the world, either in good health or for those with CKD. The population is assumed to obtain sufficient vitamin D through sun exposure, but this has been proven not to be the case because, for at least 6 months of the year, there can be no ultraviolet (UV) B–driven skin synthesis of vitamin D in the United Kingdom and at higher latitudes. Indeed, there is mounting evidence to suggest that some of the current guidelines are in need of re-evaluation. Ways to affect vitamin D repletion include eating naturally vitamin D–rich food (eg, fish, meat, offal, dairy) to obtain cholecalciferol. In certain geographic regions (eg, the Arctic Circle), the Inuit or the Sami races have special diets that provide much more vitamin D, both ergocalciferol (plant-derived) and cholecalciferol (animal-derived). Repletion also can be achieved through intake of specifically fortified food (eg, fortified milk, cheese, yogurt, bread, cereal), or through exposure to sunlight/UVB radiation, such as sunbathing, solar beds, sunshine holidays, UV cabinets, or lamps (phototherapy). If the previous approaches are not suitable or possible, it also is feasible to use oral tablets, intramuscular injections, or, rarely, intravenous bolus injections of vitamin D. Dietary Supplements Vitamin D can be ingested through diet, fortified or not, but depending on a person’s choice of food, and the scarcity of vitamin D–containing foods, reliance on food intake is unlikely to be sufficient on its own. It would be useful only in selected populations. Oral Vitamin D Supplements Oral supplementation benefits from being simple, safe, and cheap but, of course, similar to dietary supplementation, relies on adequate intestinal absorption. Studies have shown that in certain instances oral doses of up to 5000 IU/d might be needed to reach serum concentrations of more than 75 nmol/L. There are several variants of oral native (nonsynthesized) vitamin D available to be used for vitamin D supplementation. Vitamin D2 and D3 are the currently recommended compounds, with vitamin D3 often being favored because it is cheap, effective, and safe, but research is ongoing into other semisynthetic or synthetic VDR activator options such as calcidiol, calcitriol, 1α-calcidiol, paricalcitol, and doxercalciferol. These drugs, however, are expensive and not likely to be warranted or practical for public health measures. There are relatively few head-to-head comparisons to review. It is important to note that these vitamin D analogues might not necessarily be interchangeable, and any situation with impaired
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conversion (eg, enzymatic loss) might preclude the usual choices. UVB: Natural Sunlight or Lamps Currently, sensible sun exposure is recommended in a healthy adult population, and UVB exposure might be the natural choice, but it carries the risk of sunburn and is associated with skin cancer if high doses are to be obtained through normal skin exposure. Although some reports have suggested that vitamin D may protect against melanoma adequately, to replete an individual’s vitamin D status might mandate unrealistically long UVB exposure times, especially for people with darker skin. A study found that brief exposure of approximately 20% of the body surface to sunlight could be equivalent to oral supplementation of only 200 IU of vitamin D3. Sun exposure over the whole body, enough to cause mild erythema, has been shown to be able to increase 25(OH)D serum concentrations as much as long-term oral supplementation of 10,000 IU/d of vitamin D3. The long times needed and the inherent risks a UVB burn carries obviously raises some challenges, and the fact that in higher latitudes UVB-driven, skin-derived production of vitamin D is negligible between October and March, all are factors that militate against this otherwise cheap method. The use of UVB light sources (lamps or cabinets restricted typically to a 311-nm wavelength) recently was revisited and may hold promise, especially for locations at high latitudes. In fact, recent research has shown that short courses of narrow-band UVB exposure can increase 25(OH)D concentrations in subjects already receiving oral supplementation. It also should be noted that UV light itself can generate nitric oxide in the skin, and has a number of immune-modulatory effects that appear to be independent of vitamin D–related mechanisms. Other Approaches to Supplementation: Intramuscular or Boluses Intermittent oral doses or intramuscular injections, such as 40,000 IU/mo, or an intermittent bolus injection with a very large dose (eg, 500,000 IU every 6–12 mo) have been used in certain circumstances (eg, to effect very rapid repletion), or if compliance is questioned. The dosing intervals used vary between studies and range from daily to every 6 months. It currently is unclear which dosing interval is optimal, and how to combine this with initial bolus doses (if indeed any are used); most regimens have proven to be effective for repletion and maintenance of adequate concentrations. However, there have been some concerns about the impact of super-large IM boluses on fall frequency in older adults. Naturally, these bolus-based approaches are not suitable for a public health interventional measure.
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NEW SYNTHETIC VITAMIN D COMPOUNDS: HAS THE LABORATORY PROMISE BEEN TRANSLATED INTO TANGIBLE CLINICAL GAINS? Nonselective VDR activators (VDRAs) such as calcitriol and alfacalcidol have been used successfully in the treatment of secondary hyperparathyroidism (SHPT) in dialysis patients for decades (as discussed earlier). Despite their beneficial effects on the control of serum PTH levels, their use has been limited by intolerance (ie, induction of biochemical hypercalcemia and hyperphosphatemia), especially if combined with calciumcontaining phosphate binders. Although this is potentially undesirable, and usually requires therapeutic regimen changes, which is inconvenient to both the physician and patient alike, it is not always definitely clinically associated with morbi-mortality.
SELECTIVE VDRA Because vitamin D can promote the increase of serum calcium and phosphorus levels, there are concerns about the possible side effects of vitamin D preparations. Hyperphosphatemia and hypercalcemia have been shown to promote calcification of the vasculature, myocardium, and cardiac valves. Vascular calcification and calcification of arteriolar media are the main pathophysiological features of cardiovascular disease in the kidney disease population. Vascular calcification currently is accepted as an actively regulated process similar to bone formation, with changes in the phenotype of vascular smooth muscle cells resulting in osteoblast-like cells that produce calcificationregulating proteins. This process of vascular calcification
was not correlated with vitamin D alone. Indeed, in animals, vitamin D excess would not induce calcification if serum phosphate level was controlled, and it seems that ambient serum phosphorus has a pivotal role in the promotion of vascular calcification in a vitamin D– administration environment (Fig. 1).29–32 Several new vitamin D analogs have been developed for the treatment of secondary hyperparathyroidism (Fig. 2), and were designed to try to reduce the risk of hypercalcemia and hyperphosphatemia. The third generation of vitamin D analogs comprises a group of 1- and 25-hydroxylated vitamin D compounds with structural modifications (19-nor-1,25-dihydroxyvitamin D2 or paricalcitol), which have, so it is claimed, fewer calcemic and less phosphatemic effects when compared with calcitriol. Vitamin D analogs have different effects on nuclear VDRs compared with the actions of calcitriol, through different response elements in various target genes. Experimental work has shown that for similar serum concentrations of calcium and phosphate, paricalcitol produces less vascular calcification than does calcitriol, suggesting differential effects at the cellular level.33,34 Such new vitamin D analogues, because of the unique properties of nuclear VDRs, are named selective vitamin D–receptor activation agents. The term selective means that the molecule acts mostly on the parathyroid gland, more so than on intestine and bone, resulting in lower serum calcium and phosphorus blood concentrations. Such selective VDR activation agents are reported to have anti-inflammatory and antithrombotic effects, and could inhibit vascular smooth muscle cell proliferation, the renin-angiotensin system, and
Figure 1. Role of vitamin D in the development of secondary hyperparathyroidism in CKD.
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Figure 2. Different types of vitamin D compounds. SHPT, secondary hyperparathyroidism.
vascular calcification and stiffening, and could cause left-ventricular hypertrophy to regress.35,36
EXPERIMENTAL DATA TO SUGGEST RELEVANT BIOLOGICAL DIFFERENCES IN VITAMIN D METABOLITES Compared with calcitriol, paricalcitol reduces PTH, however, with significantly fewer episodes of hypercalcemia in hemodialysis patients. Reduced episodes of hypercalcemia among patients who received paricalcitol compared with calcitriol could be explained owing to reduced stimulation of intestinal calcium transport proteins. Calcitriol in uremic rats fed with a high-phosphorus diet enhances intestinal calcium absorption because calcitriol promotes calbindin expression, whereas paricalcitol does not. There are also data on lower absorption rates of calcium and phosphorus among patients receiving paricalcitol, compared with calcitriol.37–39 In rat models of gentamicin-induced renal injury, paricalcitol prevented up-regulated inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interferonγ), nuclear factor-κB and phosphorylated extracellular regulated kinase 1/2 expression, and adhesion molecules (monocyte chemoattractant protein-1, intercellular adhesion molecule-1, vascular cell adhesion molecule-1), and it also reversed the transforming growth factor-β1– induced epithelial-to-mesenchymal transition process and extracellular matrix accumulation.40,41 Antifibrotic effects of paricalcitol were reported by Meems et al42 in an animal model: paricalcitol reduced
myocardial fibrosis and preserved diastolic left ventricular function owing to pressure overload associated with reduced fibrosis. A similar study showed the protective effect of enalapril and paricalcitol, alone or in combination, on cardiac oxidative stress in uremic rats.43 A combination of enalapril and paricalcitol reduced glomerulosclerosis, proteinuria, and inflammation— when measured as monocyte chemoattractant protein-1 in uremic rats—via suppression of transforming growth factor-β1 and Smad2.44 Kong et al45 examined the effects of losartan, paricalcitol, doxercalciferol, a combination of losartan and paricalcitol, or a combination of losartan and doxercalciferol, on the development of left ventricular hypertrophy. Echocardiography showed a 65% to 80% reduction in left ventricular wall thickness with losartan, paricalcitol, or doxercalciferol monotherapy, and almost complete prevention of left ventricular hypertrophy with the combination therapies. Renal and cardiac renin expression were increased markedly in losartan-treated animals, but nearly normalized with combination therapy. These data showed that vitamin D analogues had potent antihypertrophic activity, partly by suppressing renin in the kidney and heart. Mizobuchi et al showed that paricalcitol, in contrast to calcitriol and doxercalciferol, had no effect on the serum calcium-phosphate product or the aortic calcium content in uremic rats. A higher dose of paricalcitol still had no effect, but decreasing doxercalciferol levels did not increase the calcium-phosphate product; rather, it increased the aortic calcium content, suggesting independent paricalcitol-mediated mechanisms for protection from vascular calcification.46–48
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Cardús et al49 tested the effects of calcitriol and paricalcitol on vascular smooth muscle cell calcification in an animal end-stage renal disease model, and concluded that calcitriol, but not paricalcitol, increased calcification of vascular smooth muscle cells, independently of the levels of calcium and phosphate.
D.J.A. Goldsmith, Z.A. Massy, and V. Brandenburg
Although the results from the earlier-described animal experiments may be interesting to some, there is no evidence yet available that such processes are relevant to hard end points in CKD and dialysis patients. Because therapies with calcitriol and vitamin D analogues have been associated with reduced mortality in CKD patients, although never once shown in a randomized controlled trial setting, particularly in those suffering from secondary hyperparathyroidism different investigators have tried to switch to selective VDRA, usually as paricalcitol, in calcitriol-resistant patients. The reader is invited to compare and contrast these studies, which show contradictory findings.50–55
and there does seem to be some additional antiproteinuric effect achievable, even in fully renin-angiotensinaldosterone system–inhibited patients. The long-term safety of this intervention is not yet known but surely would benefit from being tested in a randomized controlled trial. Despite plenty of observational data on the association of vitamin D with decreased cardiovascularrelated morbidity and mortality, Paricalcitol Capsule Benefits in Renal Failure-Induced Cardiac Morbidity, a randomized controlled trial on a group of 227 patients with chronic kidney disease with mild-to-moderate left ventricular hypertrophy and preserved left-ventricular ejection fraction, could not show the influence of 48 weeks of paricalcitol therapy on the left ventricular mass index or on Doppler measures of diastolic dysfunction.58,59 The similarly conceived and recently reported Effect of paricalcitol on left ventricular mass and function in CKD (the OPERA trial)60 did not find a left ventricular mass difference for the chronic administration of paricalcitol to patients with CKD stages 3 to 5. Therefore, with first the Paricalcitol Capsule Benefits in Renal Failure-Induced Cardiac Morbidity study and now the OPERA trial, the fat lady has indeed finished singing, at least her first act.
PARICALCITOL IN CLINICAL USE AND TRIALS
CONCLUSIONS
Despite some animal models, and small imperfect studies of human participants, there are only a few human randomized trials that might clarify the influence of selective VDR activation on the cardiovascular system in chronic kidney and/or chronic heart failure patients. Paricalcitol appears to block the reninangiotensin-aldosterone system, and could have an effect on proteinuria via the suppression of β-catenin– mediated gene transcription and the prevention of podocyte dysfunction. In the VITamin D and OmegA-3 TriaL,56 a randomized clinical trial, paricalcitol showed the additional effect of decreasing albuminuria in patients with diabetic nephropathy. The study enrolled 281 patients being treated with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. The antiproteinuric effect was stronger when sodium dietary intake was higher. This renal protective effect seemed to be associated with renin transcription suppression, together with an antifibrotic and antiproliferative effect, and possibly with lower blood pressure in the paricalcitol group. These antiproteinuric effects were correlated with paricalcitol, and returned to baseline values upon paricalcitol withdrawal. Because albuminuria is a surrogate end point, further clinical data are needed to establish the potential effects of selective VDR activation on hard end point markers in chronic renal disease. The antiproteinuric effect of vitamin D compounds (mainly paricalcitol) recently was reviewed nicely57
There is no doubt that vitamin D is pivotal to good health in CKD. Deficiency of, and resistance to, vitamin D, are common in CKD, and thus constitute a major part of the skeletal consequences of chronic uremia. The use of vitamin D replacement therapies, a decades-old practice, is both sagacious and salutary. If the practice is now decades old, then so are some of the compounds still in regular clinical therapeutic use, with well-recognized limitations, drawbacks, and toxicities. In the experimental or animal model setting it is relatively easy to engineer differences between different vitamin D compounds in terms of cytoprotection or fibrosis/vascular calcification. However, it is naive if not dangerously misleading to assume that these findings are of relevance to the long-term administration of these drugs to patients with CKD. The value of nutritional vitamin D repletion has been underinvestigated, and thus underexplored, in CKD. Although weaker than VDRAs (in terms of PTH-suppressing effects), it also is associated with fewer problems of hypercalcemia and hyperphosphatemia. Much more clinical and research work is needed to elucidate whether formal repletion at an early stage of CKD using cholecalciferol or ergocalciferol can prevent the renal, cardiac, and skeletal complications associated with CKD. VDRAs clearly have an established place in targeting increased PTH and in particular high-turnover bone disease and osteomalacia.
CLINICAL DATA TO SUGGEST RELEVANT BIOLOGICAL DIFFERENCES IN VITAMIN D METABOLITES
Vitamin D compounds in CKD–MBD
It is a shock, even in a field as derelict and destitute of evidence as nephrology, that 50 years into the era of regular renal replacement therapy, there has never been a suitable series of outcome trials to show what vitamin D species we should use, at what point, in which patients, and using what marker of therapeutic success. Sole reliance on serum PTH concentrations to guide the initiation and titration of vitamin D therapy is both foolish and unsatisfactory, and it should be to the lasting shame of guideline groups that this simplistic approach has been promulgated relentlessly. This has been a huge impediment to the conduct of proper clinical studies, which we now are unlikely to see in 2014.
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