Vitamin D and chronic kidney disease: cardiovascular and metabolic risk

Petchey, William George (2011). Vitamin D and chronic kidney disease: cardiovascular and metabolic risk PhD Thesis, School of Medicine, The University of Queensland.

       
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Author Petchey, William George
Thesis Title Vitamin D and chronic kidney disease: cardiovascular and metabolic risk
School, Centre or Institute School of Medicine
Institution The University of Queensland
Publication date 2011-11
Thesis type PhD Thesis
Supervisor Nicole Isbel
Carmel Hawley
Johannes Prins
Total pages 283
Total colour pages 4
Total black and white pages 279
Language eng
Subjects 110201 Cardiology (incl. Cardiovascular Diseases)
110312 Nephrology and Urology
110107 Metabolic Medicine
Formatted abstract Patients with chronic kidney disease (CKD) have cardiovascular event rates far in excess of the healthy population. Traditional risk factor modification appears unable to abate this and as such, novel mechanisms in the uraemic milieu have been postulated.

Hypovitaminosis D is highly prevalent in the CKD population, the predisposing factors for which are multiple; decreased sun exposure, impaired metabolism (further manipulated by drugs commonly used in this cohort); decreased renal activation and vitamin D receptor number, and increased loss of active metabolites. Epidemiological data has suggested that lower vitamin D status is associated with worse cardiovascular outcomes and thus, vitamin D has been proposed to be a linking intermediate associating elevated morbidity and mortality with uraemia.

Mechanistically, vitamin D has been shown to beneficially affect multiple facets of cardiovascular risk, namely; insulin resistance, inflammation, cardiovascular structure and function, proteinuria, renin-angiotensin over-activity, and aerobic metabolism. Unfortunately, most of this data arises from the basic science literature, some from observational studies and uncontrolled trials in the dialysis population, and even less from patients with pre-dialysis CKD. This thesis aims to add knowledge regarding the clinical relationship between vitamin D and cardiovascular risk in this latter group.

This thesis demonstrates that despite a higher UV climate in Queensland, Australia, significant vitamin D insufficiency exists in the CKD population, and despite relatively higher circulating 25-hydroxyvitamin D (25(OH)D), bone-mineral parameters progress in a detrimental manner with advancing CKD in a classical fashion.

In terms of cardiovascular structure and function, it appears that in moderate CKD there is a beneficial association between vascular calcification, cardiac structure and systolic function with 1,25-dihydroxyvitamin D (1,25(OH)2D), but not 25(OH)D, independent of known confounders. We hypothesise that this may represent receptor activation that is reflective of the circulating hormone at a stage of renal impairment when the kidney is still the predominant source, and 1,25(OH)2D is acting in an endocrine fashion.

Conversely, aerobic metabolism and markers of glycaemic control appear independently related to circulating 25(OH)D concentrations. If there is a true causal relationship, it may be that vitamin D substrate availability is more important to metabolic processes, with 1,25(OH)2D production and vitamin D receptor activation controlled at the autocrine or paracrine level. Given the cellular importance of these processes, this level of homeostatic control seems feasible.

To test this hypothesis, an intervention trial was performed supplementing vitamin D3 to patients with CKD stage 3 - 4 for 6 months, to assess whether this could ameliorate the insulin resistance observed in CKD. Despite its safety and relative efficacy, raising 25(OH)D to supra-sufficient concentrations did not change insulin resistance, adiponectin levels, the metabolic flexibility of the individual, or alter inflammatory burden.

Thus it would appear that despite the cross-sectional relationship between 25(OH)D and markers of metabolic health, a simple ‘cause and effect’ relationship could not be demonstrated. Therefore the assertion that vitamin D is a modifiable cardiovascular risk factor cannot be supported by this thesis. However, it may be that given the relative sufficiency of 25(OH)D in the study population with serum concentrations thought optimal for bone health, these concentrations may also be optimal for metabolic health, but the positive role of vitamin D in these processes is overshadowed by other competing adverse uraemic processes. Whether there is a benefit in supplementation of individuals who are profoundly vitamin D deficient to begin with, or a differential effect with the use of active vitamin D compounds in pre-dialysis CKD should be the subject of future work.
Keyword Calcitriol
Cardiovascular diseases
Cholecalciferol
Chronic renal insufficiency
Deficiency
Insulin resistance
Metabolism
Randomized controlled trial
Vitamin D

 
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