Vitamin D Deficiency and Treatment Versus Risk of Infection in End-Stage Renal Disease Patients Under Dialysis

A Systematic Review and Meta-analysis

Guobin Su; Zhuangzhu Liu; Xindong Qin; Xu Hong; Xusheng Liu; Zehuai Wen; Bengt Lindholm; Juan-Jesus Carrero; David W Johnson; Nele Brusselaers; Cecilia Stålsby Lundborg

Disclosures

Nephrol Dial Transplant. 2019;34(1):146-156. 

In This Article

Discussion

This meta-analysis, based on 17 studies of patients receiving long-term dialysis, showed that the risk of infection-related outcomes was lower in patients with higher serum levels of 25(OH)D. Furthermore, the use of vitamin D, particularly VDRA, was also associated with a lower risk of infection-related outcomes in this population.

Our observations are in line with the evidence from general population studies, suggesting an independent association between low serum concentrations of 25(OH)D and susceptibility to infection, as well as a potentially protective effect of vitamin D against infections.[7,40] In contrast, previous systematic reviews of either vitamin D status or use of vitamin D treatment in dialysis populations have not focused on infection-related outcomes but have instead focused on all-cause mortality[20] in relation to vitamin D status or all-cause mortality,[17,18,21] cardiovascular outcomes (CVD-related mortality,[17,18,21] vascular calcification[17]), bone-related outcomes (fracture,[17] bone pain,[17] bone histomorphometry[17]) and laboratory-related outcomes {parathyroid hormone (PTH),[17,19] serum phosphorus,[17,19] serum calcium[17,19] and serum alkaline phosphatase[17]} in relation to the use of vitamin D (supplementation or VDRA).

Vitamin D has been shown to play an important role in maintaining normal immune function and crosstalk between the innate and adaptive immune systems, which are essential in infection prevention.[41] In innate immunity, vitamin D promotes the production of cathelicidin and β-defensin 2, enhances the capacity for autophagy via toll-like receptor activation and influences complement concentrations.[42] In adaptive immunity, vitamin D suppresses the maturation of dendritic cells and weakens antigen presentation.[41] These pathways provide a biologically plausible mechanism underpinning the observed association between higher serum 25(OH)D levels or the use of vitamin D with a lower risk of infection. This association is consistent in PD patients but not in HD patients. It should be noted that studies in PD patients only evaluated PD-related peritonitis, not other infections, while HD studies explored all types of infection-related outcomes. It remains a question whether specific mechanisms of vitamin D action may differ between different dialysis populations. We found that VDRA but not nutritional supplements were associated with a lower risk of infection. This discrepancy might be related to differences in power (only two studies of nutritional vitamin D supplements) or outcome ascertainment (infection was not the primary outcome). It is still unclear whether nutritional vitamin D supplementation has an effect on infections. Other RCTs in non-dialysis populations report inconsistent findings.[14,43] This discrepancy of associations with vitamin D supplements might be related to genetic variation in vitamin D metabolism or signalling, which may in turn modify the infection prevention effects of vitamin D.[44] Since 1,25-dihydroxyvitamin D [1,25(OH)2D], not 25(OH)D, is a direct inducer of antimicrobial peptide gene expression,[45,46] it is also conceivable that nutritional vitamin D supplements may exert less of an effect on infections than VDRA, owing to reduced delivery of 25(OH)D to the renal proximal tubule and subsequent decreased 1α-hydroxylation in the setting of reduced glomerular filtration rate in dialysis patients.[42]

The Kidney Disease: Improving Global Outcomes CKD-mineral and bone disorder (CKD-MBD) guidelines currently only advocate the use of vitamin D to treat CKD-MBD when intact PTH levels exceed nine times the upper normal limit and do not consider infection-related outcomes.[47] Similarly, the International Society for Peritoneal Dialysis guidelines cite the absence of VDRA as a modifiable risk factor for peritonitis but advise that prospective randomized studies are needed before further recommendations can be made.[48] The results from this systematic review and meta-analysis reinforce the hypothesis that achieving higher serum 25(OH)D concentrations and/or prescribing VDRA may lower the risk of infection in dialysis patients. For guideline developers, these results should motivate calls for further RCTs. For dialysis patients and clinicians, our results suggesting that the use of VDRA may be beneficial for reducing infection risk may influence clinical practice. For researchers, the observed associations of this meta-analysis provide sufficient justification for the design and conduct of an adequately powered RCT examining the effect of vitamin D supplementation on infection-related outcomes in patients with ESKD who receive chronic dialysis.

Our study has a number of strengths. We performed comprehensive searches using not only English databases such as PubMed and Embase, but also Chinese databases such as CNKI and CMB to capture as many relevant studies as possible. Our study focused on both the status of vitamin D [25(OH)D] and the use of vitamin D (both nutritional supplementation and VDRA), thereby allowing a comprehensive investigation of the association of vitamin D with infection-related outcomes.

We also acknowledge a number of limitations that need to be considered when interpreting our findings:

  1. Our analysis plan selected the most adjusted RR presented in the studies, which may have resulted in outcome reporting bias despite representing the most conservative risk estimation.

  2. Considering that our meta-analysis was mostly based on observational studies, except for two RCTs exploring nutritional vitamin D supplementation, our data cannot prove causality and residual or unmeasured confounding could not be eliminated.

  3. We found overall high heterogeneity in our estimates. Heterogeneity may be attributed in part to the different study designs and differences with regard to patient characteristics (e.g. diabetes prevalence, mean dialysis vintages, sex distribution, mean age and mode of dialysis), intervention type (nutrient supplementation or VDRA), 25(OH)D measurement method and concentration of vitamin D levels to define deficiency, different follow-up periods, study quality and sample size. However, we were unable to perform all of these subgroup analyses owing to the limited data available and lack of access to the original, individual patient data.

  4. Although the tests for publication bias were insignificant, the possibility of publication bias could not be confidently excluded.

In conclusion, lower serum levels of 25(OH)D and the use of vitamin D, particularly VDRA, were each associated with a lower risk of composite infection in patients with ESKD receiving chronic dialysis. An adequately powered RCT examining the effect of vitamin D supplements on infection-related outcomes in such patients is both important and justified.

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