AJKDBlog Interviews Editor Timothy Yau (@Maximal_Change) talked with Wing-Chi Gigi Yeung about her systematic review recently published in AJKD evaluating the effects of vitamin D therapy on mortality, cardiovascular, bone, and kidney outcomes in adults with CKD.
Dr Gigi Yeung is a nephrologist at Wollongong Hospital in Sydney, Australia. She is currently doing a PhD at the University of New South Wales on CKD-MBD.
AJKDBlog: Vitamin D has been one of the most studied medications for kidney, cardiac, vascular, and bone disease. There have even been studies looking at outcomes in malignancy and infection, and as a result is one of the most polarizing medications in healthcare. Before we even jump into the study itself, can you give a big picture overview on Vitamin D and its uses in patients with kidney disease?
Sure! Not surprisingly, Vitamin D deficiency is common in patients with chronic kidney disease (CKD). As kidney function declines, the conversion of 25(OH)D into 1,25(OH)2D also decreases. This then leads to development of secondary hyperparathyroidism and Chronic Kidney Disease Mineral Bone Disorder (CKD-MBD). Vascular calcification and abnormalities in mineral metabolism, which are features of CKD-MBD, are thought to contribute to arterial stiffness, left ventricular hypertrophy and increased mortality in CKD patients. So the rationale for prescribing vitamin D therapy in patients with kidney disease goes beyond just bone health.
Nutritional vitamin D, such as cholecalciferol, is commonly prescribed for 25(OH)D deficiency. This is a Grade 2C recommendation in the 2017 KDIGO guidelines, but there is little evidence for this. Calcitriol and other vitamin D analogues tend to be used for patients with severe hyperparathyroidism in more advanced CKD stage 4-5. There is an ungraded recommendation for this in the 2017 KDIGO guidelines.
AJKDBlog: Your study references both the 2017 KDIGO Clinical Practice Guidelines and a prior meta-analysis of Vitamin D therapy. How does your recent paper differ from this prior meta-analysis with regards to outcomes?
It has been 15 years since the previous meta-analysis of vitamin D therapy in CKD was published. The original review included 76 studies (60 in patients with non-dialysis CKD and 16 in patients with dialysis-dependent CKD). The patient-level outcomes examined included all-cause mortality, fracture, parathyroidectomy and bone pain. The study conclusion was that vitamin D compounds suppress PTH, but the beneficial effects on patient-level outcomes were unproven. At the time in 2007, there were no studies that had been designed to examine the effect of vitamin D therapy on cardiovascular endpoints or mortality.
Since then, many new studies have been performed, including some larger trials which examined mortality and cardiovascular outcomes. We included 128 randomized controlled trials in our updated meta-analysis. Compared to the prior meta-analysis, we examined multiple additional outcomes including cardiovascular mortality, MACE, hospitalization, blood pressure, pulse wave velocity, left ventricular mass, bone mineral density (BMD), progression to kidney failure, proteinuria, eGFR, and bone turnover markers.
AJKDBlog: In reviewing Vitamin D trials for the meta-analysis, did you differentiate trials that treated patients with 25-OH Vit D and active 1, 25-OH Vit D analogues such as calcitriol? Similarly, there are many Vitamin D studies looking at a variety of doses, formulations, frequencies, and routes of administration – how did you categorize all of the different studies?
In contrast to the previous meta-analyses on vitamin D in CKD, we divided the trials based on the specific vitamin D intervention used. Nutritional vitamin D compounds are those that require further renal hydroxylation (e.g. cholecalciferol) and active compounds are those that do not require renal hydroxylation (e.g. calcitriol). We also separately categorized trials that compared the same vitamin D compound in a different dose, route or frequency, as well as those comparing vitamin D to calcium or cinacalcet. The number of these studies was small.
AJKDBlog: What were the big takeaways from your results? There were over a hundred trials, over 10,00 participants, and numerous endpoints. Did Vitamin D therapy have any effect on the endpoints you chose?
The biggest takeaway from the results is that vitamin D compounds, both nutritional or active, unfortunately appear to have little or no effect on all-cause mortality in patients with CKD. Compared to placebo, active vitamin D compounds significantly increase the risk of hypercalcemia by more than 2-fold, whereas nutritional vitamin D does not. The effect of vitamin D therapy on fractures, cardiovascular and kidney outcomes remain uncertain.
Interestingly, there were two small trials in patients with non-dialysis CKD which showed active vitamin D compounds increased bone mineral density (BMD) compared to placebo. This is certainly not a new concept. Eldecalcitol, an active vitamin D compound, has been approved for treatment of osteoporosis in Japan since 2011. Several RCTs have shown that eldecalcitol reduces incidence of vertebral fractures and increases BMD compared to placebo and alfacalcidol. Given the important role that vitamin D plays in the pathogenesis of CKD-MBD, adequately powered RCTs are needed to evaluate the effect of active vitamin D compounds on fractures and BMD in patients with CKD.
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AJKDBlog: Although not as meaningful as endpoints like mortality and GFR, what were the effects of Vitamin D on biochemical markers such as serum calcium, phosphorus, and PTH?
Like the prior meta-analysis, we found that vitamin D compounds (both active and nutritional) significantly reduce serum PTH compared to placebo. Active vitamin D increases serum calcium and probably increases serum phosphate compared to placebo, but not nutritional vitamin D.
AJKDBlog: It’s challenging to generalize a treatment like Vitamin D for all patients with kidney disease, but did this meta-analysis alter the findings from the 2007 trial? Has more data in this field led to a practice changing conclusion? And what lies ahead for future Vitamin D trials for them to be clinically meaningful?
Observational studies have suggested an association between vitamin D deficiency and mortality in patients with CKD. However, 25(OH)D levels are influenced by many factors such as nutritional intake and sun exposure, which are potential confounders. Since the previous meta-analysis published in 2007, there have been a few larger trials examining clinical outcomes. Our updated meta-analysis found moderate certainty evidence that vitamin D supplementation does not have any effect on all-cause mortality.
Many of the older studies included in our meta-analysis were of low quality and mainly focused on biochemical outcomes. Looking ahead, we need further high-quality vitamin D trials which focus on clinically meaningful outcomes including fractures, BMD, as well as cardiovascular and kidney endpoints.
To view Yeung et al, please visit AJKD.org.
Title: Vitamin D Therapy in Adults With CKD: A Systematic Review and Meta-analysis
Authors: Wing-Chi G. Yeung, Suetonia C. Palmer, Giovanni F.M. Strippoli, Carmel M. Hawley, Nigel D. Toussaint, Sunil V. Badve
DOI: 10.1053/j.ajkd.2023.04.003
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- Source: https://ajkdblog.org/2023/12/06/vitamin-d-and-kidney-disease-an-interview/