Invited commentary from Dr. Sairah Sharif

It is appreciated that CKD leads to reduced production of active 1,25-dihydroxyvitamin D3 (1,25(OH)D3). However the effects of estimated glomerular filtration rate (eGFR) on vitamin D catabolism are not well known. In earlier studies it has been shown that CKD is characterized by reduced vitamin D catabolism. A recent study in AJKD by Boer et al was conducted to test the association between eGFR and vitamin D metabolites, specifically 24,25(OH)2D3, over a wide range of eGFRs from 5 cohort studies and clinical trials. Their hypothesis was that lower eGFR leads to reduced vitamin D catabolism, and the increase of 24,25 (OH)2D3 for any given increase of 25(OH)D3 would progressively decrease with drop in eGFR.

Over 9500 participants across 5 cohort studies were evaluated. These were the Diabetes Control and Complications Trial (DCCT), the Multi-Ethnic Study of Atherosclerosis (MESA), the Cardiovascular Health Study (CHS), the Seattle Kidney Study (SKS), and the Hemodialysis (HEMO) Study. In all the studies, males and females were equally represented except SKS where females were 17% of the total. The parathyroid hormone (PTH) levels were highest in the HEMO Study and eGFR was highest in the DCCT patients.

Within each cohort there was a positive correlation between 24,25(OH)2D3 with 25(OH)D3, and the relationship was strongest in the cohorts with higher eGFR in DCCT and MESA (r=0.88 and r=0.84) compared to CHS and SKS (r=0.78 and r=0.64). Pooling data from all 5 studies showed that the slope of increase in 24,25(OH)2D3 with increase in 25(OH)D3 reduced with lower eGFR (see figure).

Fig 4, de Boer et al AJKD, © National Kidney Foundation.

The increase in 24,25(OH)2D3 with increased 25(OH)D3 was highest in DCCT and MESA. Unadjusted as well as adjusted mean 24,25(OH)2D3 concentrations were significantly lower at concentration of 20ng/ml 25(OH)D3 at lower eGFRs. Higher PTH was associated with significantly lower mean 24,25(OH)2D3 at 25(OH)D3 concentration of 20ng/ml in SKS, but not in MESA or CHS. FGF23 was associated with significantly higher slope and higher mean 24,25(OH)2D3 at 25(OH)D3 concentration of 20 ng/mL.

This study shows that CKD is a state of retarded vitamin D metabolism – reduced production and reduced catabolism. One reason could be reduced activity of CYP24A1 by renal and extra renal cells. In CKD there is reduction of tubular delivery of 25(OH)D3, impaired luminal uptake by megalin and cubilin, and perhaps impaired CYP24A1 function. Furthermore, FGF23 stimulates and PTH inhibits transcription of CYP24A1, leading to higher and lower levels of 24,25(OH)2D3, respectively. The association of 24,25(OH)2D3 was strongest with eGFR suggesting that the transcription is not the most important regulator of vitamin D catabolism.

This study has important strengths such as using diverse cohorts to enhance external validity, encompassing the full range of eGFRs, and assessing a large number of novel 24,25(OH)2D3 metabolites. It has some limitations including cross sectional design, not taking into account temporal changes of 24,25(OH)2D3, and inclusion of interfering analytes. However the concentration of analytes was low compared with specific 24,25(OH)2D3, and the sum value of interfering analytes and 24,25(OH)2D3 correlated strongly with 24,25(OH)2D3.

Overall, this study by Boer et al provides an interesting argument that although we continue to measure PTH and 25(OH)D3 to guide the need for activated vitamin D therapy, these markers may not best represent actual 1,25(OH)2D3 status. It raises important questions. What are the additional catabolic pathways of 25(OH)D3, and how does CKD affect them? Can use of vitamin D metabolites such as 24,25(OH)2D3 assess vitamin D interventions in CKD? Further studies are needed to answer these questions.

Sairah Sharif
Nephrology Fellow at Winthrop Hospital, Mineola, New York

To view the article abstract or full-text (subscription required), please visit AJKD.org.