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Recommendations Summary

CKD: Micronutrients: Vitamin D Supplementation (2020)

Click here to see the explanation of recommendation ratings (Strong, Fair, Weak, Consensus, Insufficient Evidence) and labels (Imperative or Conditional). To see more detail on the evidence from which the following recommendations were drawn, use the hyperlinks in the Supporting Evidence Section below.


  • Recommendation(s)

    CKD: Vitamin D Supplementation for Vitamin D Deficiency and Insufficiency, CKD 1-5D

    In adults with CKD 1-5D (2C), we suggest prescribing Vitamin D supplementation in the form of cholecalciferol or ergocalciferol to correct 25(OH)D deficiency/insufficiency.

    Rating: Weak
    Conditional

    CKD: Vitamin D Supplementation with Proteinuria

    In adults with CKD 1-5 with nephrotic-range proteinuria, it is reasonable to consider supplementation of cholecalciferol, ergocalciferol or other safe and effective 25(OH)D precursors (OPINION).

    Rating: Consensus
    Conditional

    CKD: Vitamin D Supplementation for Vitamin D Deficiency and Insufficiency, CKD Post-Transplant

    In adults with CKD posttransplantation,  we suggest prescribing Vitamin D supplementation in the form of cholecalciferol or ergocalciferol to correct 25(OH)D deficiency/insufficiency (OPINION).

    Rating: Consensus
    Conditional

    • Risks/Harms of Implementing This Recommendation

      There is no recommendation of safe dose of cholecalciferol or ergocalciferol supplementation to prevent for toxicity or adverse effects such as hypercalcemia or hyperphosphatemia in CKD.
       

    • Conditions of Application

      Special Discussions
      There are potential benefits of vitamin D supplementation (cholecalciferol or ergocalciferol) in CKD. A systematic review with meta-analysis of observational and randomized studies showed a significant decline in PTH levels with cholecalciferol or ergocalciferol supplementation in patients who are non-dialyzed, on hemodialysis or peritoneal dialysis, and renal transplant recipients (Kandula et al 2011) However, whether such improvements translate into clinically significant outcomes is yet to be determined.

      Cross-sectional analysis of Third National Health and Nutrition Examination Survey (NHANES III) showed progressively higher prevalence of albuminuria with decreasing 25(OH)D levels (de Boer et al 2007). In a prospective cohort study vitamin D deficiency was associated with a higher incidence of albuminuria (Damasiewicz et al 2013). There are limited randomized clinical trials investigating  the effect of cholecalciferol or calcifediol on proteinuria in CKD and the results are not clear with both positive and null results (Susantitaphong et al 2017,  Levin et al 2017).

      Implementation Considerations

      • The optimal serum 25(OH)D concentration for patients with CKD and the concentration at which patients with CKD are considered deficient/insufficient is not well defined but is generally considered to be the same as in the general population, although there is no absolute consensus about the definition of vitamin D sufficiency. For most experts, vitamin D insufficiency is defined as a serum 25(OH)D level between 20–29 ng/mL, deficiency is considered as 25(OH)D levels of less than 20 ng/mL and sufficiency serum 25(OH)D equal or greater than 30 ng/mL (Holick et al 2011).
      • Both the Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease Improving Global Outcomes (KDIGO) experts recommend checking and supplementing low serum 25(OH)D levels in CKD and dialysis patients. In the most recent update of the KDIGO guidelines on bone mineral disorder, it is suggested based on low quality evidence that patients with CKD stage 1–5D have 25(OH)D levels measured, and repeated testing should be individualized according to baseline values and interventions. However, there was no clear suggestion on how frequently 25(OH)D levels should be reviewed.
      • With respect to vitamin D supplementation, current guidelines suggest that patients with CKD stages 1–5D and vitamin D insufficiency/deficiency should receive supplementation using the same strategies recommended for the general population. However, even for the general population, the optimal dosage of supplementation varies among the main guidelines. It has been recommended 1000–2000 IU/d  of cholecalciferol for vitamin D repletion for the general population. However, KDOQI acknowledges that patients with CKD may require a more aggressive therapeutic plan. 
      • There is also a debate regarding which form of vitamin D should be used, ergocalciferol or cholecalciferol. In the general population there appears to be some advantage of using cholecalciferol over ergocalciferol. PMID 22552031 Since in CKD there is no clear evidence about the superiority of chocalciferol, clinicians should use the form commercially available in the context of their clinical practice.
      • The tolerable upper intake levels (UL) proposed by the Institute of Medicine (IOM) for the general population is 4, 000 IU/day. (IOM, Dietary Reference Intakes for Calcium and Vitamin D, 2011)  There is no recommendation of safe dose of cholecalciferol or ergocalciferol supplementation to prevent for toxicity or adverse effects such as hypercalcemia or hyperphosphatemia in CKD. However, periodically measurement of serum calcium and phosphorus should be considered especially for patients who are on calcium-containing phosphate binders and/or on vitamin D active analogs.

    • Potential Costs Associated with Application

      The cost of nutrition supplements should be considered before recommending to a patient.

    • Recommendation Narrative

      Vitamin D2 (ergocalciferol) and Vitamin D3 (cholecalciferol) are recognized as a pro-hormones and comprise a group of fat-soluble secosteroids. A unique aspect of vitamin D as a nutrient is that it can be synthesized by the human body through the action of sunlight. These dual sources of vitamin D (diet and sunlight) make it challenging to develop dietary reference intake values (IOM, Dietary Reference Intakes for Calcium and Vitamin D, 2011). The classic actions of vitamin D are the regulation of calcium and phosphorus homeostasis contributing to bone health. More recently, there has been a growing interest in the potential pleiotropic actions of vitamin D on immune, cardiovascular and neurological systems and on antineoplastic activity since extra-renal organs possess the enzymatic capacity to convert 25 (OH)D to 1, 25(OH)2D (Holick 2007)

      Insufficiency/deficiency of vitamin D, assessed by serum concentration of calcidiol [25(OH)D], has been found to be common in the general population and even more prevalent in patients with CKD/ESRD (LaClair et al 2005,  Wolf et al 2007,  Taskapan et al 2006).

      A number of factors or conditions are implicated in suboptimal vitamin D status in patients with CKD, including aging, diabetes mellitus, obesity, reduced sun exposure, loss of urinary/dialysate vitamin D binding protein (DBP), impaired tubular 25(OH) reabsorption and dietary restrictions (Cuppari et al 2008,  Caravaca-Fontan et al 2016,  Takemoto et al 2003,  Barreto Silva et al 2017,  Caravaco-fontan et al 2016). Considering the elevated prevalence of vitamin D deficiency/insufficiency in CKD/ESRD and the potential benefits of restoring the vitamin D status the K/DOQI and KDIGO Clinical Practice Guidelines for CKD-MBD have proposed ergocalciferol or cholecalciferol supplementation.

      Due to the complex nature of vitamin D, the present guideline is focused on the effect of vitamin D supplementation, in the forms of cholecalciferol and ergocalciferol, on vitamin D insufficiency/deficiency in patients with CKD and not on outcomes related to CKD-MBD or other clinical disturbances.  Supplementation of prehormone and activated forms of vitamin D, calcidiol and calcitriol, were not included in this guideline.

      Vitamin D Levels and Deficiency
      Despite differences in dosing regimens and vitamin D status at baseline, supplementation was effective in increasing 25(OH)D serum concentration in 14 RCTs, including in the form of ergocalciferol (Bhan et al and Miskulin et al) and cholecalciferol (Alvarez et al 2012 and 2013,  Armas et al 2012,  Chandra et al 2008,  Hewitt et al 2013,  Marckmann et al 2012,  Meireles et al 2016,  Massart et al 2014,  Seibert et al 2013,  Delanaye et al 2013,  Mager et al 2016 and Tokmak et al 2008). This effect was demonstrated in HD patients (8 studies), HD and PD patients combined (1 study), stages 1-4 CKD patients (4 studies) and in 1 study with any CKD participants. Five studies reported that ergocalciferol using doses 50, 000 IU/week and dose dependent on status (Bhan and Miskulin) and cholecalciferol in doses ranging from 25, 000-50, 000 IU/week (Massart et al, Alvarez et al and Delanaye et al) improved vitamin D status.  There were significant effects noted after three months of supplementation. However, there was no difference in vitamin D deficiency status between non-dialyzed groups receiving two different dosing regimens (Mager et al).

      A meta-analysis was conducted to determine odds of vitamin D sufficiency according to vitamin D supplementation, which included Bhan, et al. (each group compared to the placebo group), Delanaye et al, Massart et al, and Alvarez et al 2012. Participants that were supplemented with vitamin D had an OR (95% CI) of 9.31 (3.38, 24.7) (p<0.001) of being vitamin D sufficient (defined as either >30 or 32 ng/mL), though there was moderate heterogeneity in the data (I2=51.84; p=0.08). Additionally, data from eight studies were pooled to determine mean difference (95% CI) in vitamin D levels according to vitamin D supplementation. There was a mean increase of 21.06 (17.46, 24.66) ng/mL in the vitamin D supplemented groups compared to the placebo groups, but heterogeneity was moderate (I2=67.3%; p=0.003), so results should be interpreted with caution.

      Calcium and Phosphorus Levels
      In adults with chronic kidney disease, twelve studies examined the effect of vitamin D intake on biomarkers and/or health outcomes (Alvarez et al 2012,  Armas et al 2012,  Bhan et al 2015, Chandra et al 2008,  Dalanaye et al 2013,  Marckmann et al 2012,  Massart et al 2014,  Meireles et al 2016, Miskulin et al 2016 and Seibert et al 2013, Khajehdehi et al 2000 and Mager et al 2016). Moderate quality evidence demonstrated no effect of vitamin D supplementation on calcium or phosphorus levels.

      In predominantly vitamin D deficient participants, there was no effect of ergocalciferol supplementation on effect of calcium levels (Bhan et al and Miskulin et al) in doses of 50, 000 IU/week or /month or in individualized doses. The effect of cholecalciferol on calcium levels was unclear with seven studies finding no effect on calcium levels and three studies determining supplementation increased calcium levels. In Massart et al., there was no effect of 25, 000 IU weekly cholecalciferol on proportion of HD participants reaching target levels at 3 months. There was no clear pattern of effect according to participant population, deficiency status or vitamin D dosage. In pooled analysis of four studies in which data could be combined (Delanaye et al 2013, Miskulin 2016, Khajehdehi 2000, Seibert et al 2013), there was no effect of vitamin D supplementation on calcium levels [MD (95% CI): 0.07 (-0.18, 0.31) mg/dL].

      Vitamin D supplementation had no effect on phosphorus levels with ergocalciferol supplementation (2 studies with doses of 50, 000 IU/week or /month or in individualized doses) or cholecalciferol doses ranging from 50, 0000 IU/day to 50, 000 IU/month (10 studies). In pooled analysis of five RCTs (Delanaye et al 2013, Khajehdehi et al 2000, Miskulin et al 2016, Seibert et al 2013, Meireles et al 2016), there was no effect of vitamin D supplementation on phosphorus levels [MD (95% CI): -0.15 (-0.44, 0.15)  (mg/dL)].

    • Recommendation Strength Rationale

      The evidence supporting the recommendations for vitamin D supplementation are based on Grade III /Grade C evidence as well as Consensus/expert opinion. 

    • Minority Opinions

      Consensus reached.