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Vitamin D compounds in chronic kidney disease: change may be needed for good!
1 Department of Medicine, University of Otago, Christchurch, New Zealand 2 Mario Negri Sud, Italy
Over the last half a century, we have come to appreciate the importance of vitamin D prescription for people with renal disease. Vitamin D and its analogues have profoundly altered the natural history of deforming ‘renal rickets’. Observational studies have found significant associations between use of vitamin D compounds and improved survival [1,2]. We have now become convinced by clinical and experimental evidence that the abnormalities of calcium, phosphorus and parathyroid hormone observed in chronic kidney disease are associated with increased mortality [3–5]. Some of these abnormalities may be affected by treatment with vitamin D compounds. Our guidelines [6] have therefore reflected the need to target improvement of biochemical targets, including parathyroid hormone, phosphorus and calcium, which implies use of both pharmacological (vitamin D and its analogues, calcimimetics and phosphate binders) and non-pharmacological strategies (long-hours dialysis and dietary restriction). The management of bone disease/secondary hyperparathyroidism by targeting tight near-to-normal levels of these biochemical markers is now standard practice and well reflected by policy in clinical nephrology [7,8] and primary care [9]. Prescriptions of vitamin D compounds, as well as other agents for management of renal bone disease, have escalated and our annual outpatient vitamin D expenditure alone has risen from $5 million in 1992 to $400 million in 2005 for Medicare in the USA [10]. Are we done with this matter? Is progress an issue of finding additional effective agents, or is it refining performances of existing agents for improving biochemical targets of bone disease in chronic kidney disease (which is the main focus of ongoing clinical research in this area)? Or do we still need to prove that existing and newer agents are effective for improving survival of our patients?
That vitamin D compounds suppress circulating parathyroid hormone levels has been identified in clinical studies, but evidence also demonstrates that these compounds may increase serum calcium and phosphorus. Such elevations of calcium and phosphorus are identified, again in observational studies, as correlates and predictors of increased all-cause and cardiovascular mortality/morbidity, possibly through upregulation of vascular calcification [11]. This means that although there is a broad acceptance of vitamin D compounds and other therapies for bone disease in chronic kidney disease, considerable uncertainty persists particularly relating to the potential harms of these agents and, more importantly, whether vitamin D compounds really have an effect on important clinical outcomes, outside altering the levels of biochemical markers [12,13]. It is surprising that the uncertainty and ongoing debate over vitamin D use in chronic kidney disease still relies on uncontrolled data (which advocate a survival advantage) and few randomized trials that show efficacy only for correction of bone or serum abnormalities, and not for mortality, cardiovascular events and fractures.
In December 2007, we reported a meta-analysis of existing randomized, controlled trials (RCTs) for vitamin D compounds in chronic kidney disease [14]. The meta-analysis included 76 RCTs, enrolling over 3500 patients. The major finding was that insufficient randomized evidence was available to determine the effect of vitamin D compounds on mortality and clinical outcomes in all stages of chronic kidney disease. Existing data were lacking to support the widespread belief that control of secondary hyperparathyroidism in chronic kidney disease by vitamin D compounds is beneficial to patients; we and others have also reported similar findings for other drugs which are used in secondary hyperparathyroidism, but that are only proven to influence biochemical and not patient-level end points in this condition [12,13]. It is also noteworthy that even the most recent trials, which have compared newer synthetic vitamin D analogues with established vitamin D compounds (calcitriol or alphacalcidol) or placebo, have not assessed comparative equivalence or superiority between agents for major patient-level end points.
In our systematic review, newer vitamin D analogues (paricalcitol, maxicalcitol, falecalcitriol and doxercalciferol) suppressed parathyroid hormone levels by 
11 pmol/l when directly compared with placebo at the expense of increasing serum phosphorus levels by 0.13 mmol/l [0.40 mg/ dl] [95% confidence interval, 0.03–0.23 mmol/l (0.09– 0.72 mg/dl)], but not serum calcium. Established vitamin D compounds, in an analysis of 20 studies with nearly 1000 patients, showed no consistent reduction in parathyroid hormone levels although the point estimate was consistent with parathyroid hormone suppression by 17 pmol/l (95% confidence interval, –36.32 –2.00 pmol/l). Treatment with established vitamin D compounds in these trials was associated with increases in both serum calcium and phosphorus. Our conclusion was that there is an inconsistent effect of established vitamin D compounds on parathyroid hormone levels, which makes clinical use of these agents difficult, likely because of balancing increasing treatment doses with increased hypercalcaemia and hyperphosphataemia. This is not the same as stating that vitamin D compounds are ineffective, but rather that they have unproven efficacy relative to important clinical end points. No conclusions could be drawn by the review for overall treatment effects when directly comparing calcitriol and alfacalcidol with newer vitamin D analogues, as these trials were few and small, and showed no differences for biochemical outcomes between treatment groups.
The responses of many clinicians and researchers to the key findings of this meta-analysis have been varied. An accompanying editorial to the meta-analysis in the Annals of Internal Medicine, by Marcello Tonelli, acknowledged limitations of the analysis [15]. None of the studies included in the meta-analysis were either powered, or designed to evaluate ‘clinically relevant outcomes, such as mortality or hospitalization’. Second, and important, the primary finding of the meta-analysis was discordant with a ‘compelling body of experimental and observational data that support the hypothesis that vitamin D supplementation generally (and injectable vitamin D analogues, specifically) may improve outcomes for patients with chronic kidney disease’. Despite these aspects underlined by Tonelli, he supports the major conclusion of the systematic review that the evidence for vitamin D compounds in chronic kidney disease is weak. A large and clinically important effect for vitamin D compounds, either beneficial or harmful, remains indeterminate in available controlled trials. The case for policy reassessment and research performance in this area is strong.
On 5 January 2008 the British Medical Journal published a brief commentary on the meta-analysis and editorial [16], which wrote, regarding hard patient-level end points, that ‘few trials bothered to look, relying instead on surrogate markers of bone metabolism’, and concluded that ‘large placebo controlled trials with hard clinical end points are justified and must be done’. A review in the Lancet in February 2008 of activated vitamin D sterols in chronic kidney disease [17] importantly observed that clinical effects of vitamin D compounds are necessarily pleiotropic and incompletely understood, because of gene transcription by vitamin D in diverse tissues, via activation of vitamin D receptors. It is precisely this uncertain effect of vitamin D compounds on multiple receptor pathways that may confer the advantage seen with vitamin D treatment in observational studies, and that we conclude needs confirmation by randomized controlled trials.
The invited editorial comment by Drs Olgaard and Lewin reviews the recent meta-analysis for today's Journal. They reiterate that chronic kidney disease is necessarily a state of 1,25 hydroxy-vitamin D deficiency, and that such a deficiency left untreated will lead to severe bone and skeletal deformity, as shown by the natural history of secondary hyperparathyroidism before treatment was widely available. We, as any clinician would, believe that for this reason use of vitamin D compounds in chronic kidney disease may be essential. The crucial question remains, however, how to best use these agents in chronic kidney disease to maximize the potential benefits without causing harm, and not whether they should be used at all. The authors of today's editorial note that ‘most nephrologists should today be aware of the narrow therapeutic window of active vitamin D compounds, aware of the risk of inducing hypercalcaemia and hyperphosphataemia and of oversuppression of PTH levels’. This is consistent with the assertion that using vitamin D therapy is difficult, through balancing the need for suppression of parathyroid hormone on the one hand, and minimizing hypercalcaemia and hyperphosphataemia on the other. It is these opposing and challenging clinical effects of vitamin D compounds that make them difficult to use, and which are likely to explain why our meta-analysis did not find a consistent effect for alfacalcidol and calcitriol over placebo for the reduction of parathyroid hormone. We request trials to examine our current treatment algorithms on important patient end points, ensuring that vitamin D replacement is beneficial, and not at the expense of increased mortality. This demand for evidence of patient-level benefits prior to policy, the ‘trials for policy’ concept, is becoming increasingly recognized in the medical community [18].
A repeated criticism of meta-analysis is that data are combined from trials with important clinical and methodological differences [19]. Indeed, today's editorial raises the clinical concern that the meta-analysis combined trials, including some patients with severe secondary hyperparathyroidism, a subgroup with resistance to the actions of vitamin D, which may lead to a conclusion that vitamin D is less effective and associated with higher toxicity than may be found for the whole population with chronic kidney disease overall. The authors suggest that ‘it is not correct just to group these different patient categories together and it is not clinically correct or relevant to draw conclusions from such an analysis’. This raises the important philosophical and scientific issue of whether overall findings of clinical trials and meta-analyses are the appropriate outcome to apply to individuals (‘lumping’), or whether it is better to try to match the characteristics of particular patients to characteristics of subgroups within trials or meta-analyses (‘splitting’). The generalizability and usefulness of meta-analyses, however, are increased considerably if the individual trials cover different patient populations, settings and concomitant routine care, and significant results may be lost through lack of power if trials in a meta-analysis are divided into a number of subgroups. And independent of this, whether from a meta-analysis or from individual randomized trials, evidence is still lacking on the ability of vitamin D and related compounds to affect hard, patient-level endpoints in chronic kidney disease.
Our meta-analysis did include trials enrolling some patients with severe hyperparathyroidism, who may demonstrate resistance to vitamin D therapy and the inclusion of such patients may contribute to some of the adverse effects of vitamin D compounds on biochemical outcomes in the analysis. A formal metaregression analysis of the 29 placebo-controlled trials included in the review was used to determine whether any particular patient, intervention or trial characteristic modified the biochemical outcomes of the meta-analysis, and found none. In particular, no significant effect modification of vitamin D therapy on biochemical outcomes was seen when baseline trial parathyroid hormone levels were assessed as a covariate in meta-regression analysis. Olgaard and Lewin conclude, as we also do, that despite any limitations of the analyses the ‘important conclusions’ remain that effects of vitamin D compounds on clinically important outcomes are largely unknown.
Their editorial refutes the well-known example of erythropoietin-stimulating agent (ESA) use, confirmed by meta-analysis as associated with increased mortality [20], as being a cautionary tale for reliance on surrogate outcomes in trials, instead of hard end points, as in the current debate for vitamin D compounds. They suggest that ‘studies on the optimal haemoglobin targets focused however on the dosage levels of erythropoietin and did not at all question the use of erythropoietin to chronic kidney disease patients, therefore the comparison with the meta-analysis on the use of vitamin D is not very relevant’. We disagree. The conclusion from the vitamin D meta-analysis is a call for adequate research to determine efficacy and optimal dose of vitamin D for each stage of kidney disease, and controlled studies to identify biochemical targets that should be achieved by vitamin D treatment to impact mortality, cardiac and cerebrovascular events among other patient-relevant end points. So far, on the basis of existing published controlled trials, there are insufficient data to know the answers to these questions for vitamin D compounds.
While therapeutic replacement of a deficient hormone, to improve health and outcomes, seems instinctively safe and appropriate, the literature contains examples where this approach may be harmful (e.g. oestrogen plus progestin after menopause [21], brain natriuretic peptide in heart failure [22]). Indeed, some observers of the very recent debate on the safety of very tight blood glucose control in type 2 diabetes have suggested the excess mortality in the highly intensive treatment group of the Action to Control Cardiovascular Risk (ACCORD) trial [23], may be linked to higher doses of injected insulin, by means of adverse cellular effects we are yet to understand [24]. Similarly, this situation has occurred with epoetins, following strong interest in administration of these agents for targeting progressively higher haemoglobin levels.
The role of clinicians and scientists is to prove that our current strategies for vitamin D therapy in chronic kidney disease are safe and effective. We might want to go beyond being satisfied with partial correction of parathyroid hormone levels for our patients and show that treatment leads to improved clinical outcomes, including skeletal pain, hospitalization, parathyroidectomy and very important mortality and cardiac-cerebrovascular outcomes. Conducting ongoing trials of vitamin D compounds to demonstrate parathyroid hormone suppression uses scarce resources and leads to more rapid results, but will not takes us much forward. We might become strategic about expenditure on future research and decide what the most important questions are to be answered about vitamin D use in chronic kidney disease. We would contend that the priority is to refute the possible harm caused by vitamin D therapy, in RCTs and powering them appropriately to determine treatment effects on mortality. Alternatively, a trial of target levels of either phosphorus or parathyroid hormone regardless of therapeutic intervention could be conducted to determine whether it is the biochemical target, and not the intervention, that really matters. This may be commercially unattractive, such that it may require funding by public agencies. Until these things have happened, we need to acknowledge the significant uncertainty around management of mineral and bone disorder in chronic kidney disease. Undoubtedly, in our view, this provides the momentum for further large-scale research.
Conflict of interest statement. None declared.
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