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Recommendations Summary

CKD: Micronutrients: Vitamin C 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 C Supplementation

    In adults with CKD 1-5D or posttransplantation who are at risk of Vitamin C deficiency it is reasonable to consider supplementation to meet the recommended intake of at least 90 mg/d for men and 75 mg/d for women (OPINION).

    Rating: Consensus
    Conditional

    • Risks/Harms of Implementing This Recommendation

      Toxicity is a possible concern for excessive vitamin C supplementation.

    • Conditions of Application

      Special Discussions
      Current nutritional requirements or Recommended Dietary Intake of vitamin C for individuals with CKD stages 1-5D and post-transplant are not known and are based on those from the general population. The prevalence of vitamin C deficiency may vary according to the stage of CKD and dialysis modality. Toxicity is a possible concern for excessive vitamin C supplementation.

      The above findings do not however preclude the importance of assessing for vitamin C supplementation or when to discontinuing supplementation. Ongoing monitoring of overall food intake and nutrition status is required to assess for vitamin C deficiency. An individualized approach to evaluation and monitoring of vitamin C status is ideally accomplished by the nephrology care team that includes Nephrologist, Nurse Practitioner, Physician Assistant, and RDN.

      Implementation Considerations

      • Initiation and cessation of vitamin C supplementation as well as supplementation dose should take into account of the subject’s nutritional status, dietary intake, co-morbid conditions and dialysis modality.
      • Suggested vitamin intake should be based on recommendations for the general population (ex: Recommended Dietary Allowance) unless there are specific considerations requiring modification.

      Monitoring and Evaluation
      Higher doses of Vitamin C supplementation (500 mg daily) have been shown to increase serum oxalate levels. Vitamin C is a potent physiologic antioxidant. Lipid metabolism may be affected by vitamin C supplementation and patients receiving vitamin C supplementation should have lipid fractions monitored. Vitamin C also affects immune function, and carnitine metabolism. Patients with any malabsorption or diseases of an inflammatory nature may be more prone to having lower plasma vitamin C levels than the general population. Therefore, supplementation dose should take into consideration of medical history, co-morbid conditions, and concomitant medications. Measurement of serum oxalate levels may be considered in patients prescribed high doses of vitamin C and/or who are susceptible to calcium oxalate stone formation.

    • Potential Costs Associated with Application

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

    • Recommendation Narrative

      There are currently a lack of studies identifying daily vitamin C requirements for individuals with CKD, including those on dialysis and post-transplant. Amount of daily intake and optimal serum levels of vitamin C required to maintain nutritional health, reverse deficiency, and to avoid toxicity are unclear.  Studies included for this current review evaluated the effect of vitamin C supplementation on nutritional status, inflammation, anthropometrics, micronutrient levels, electrolytes levels, fluid status, serum uric acid levels, lipid levels, morbidity events, quality of life, mortality and hospitalizations. Limited data from a very small number of studies prohibit definitive evidence-based conclusions for all the above surrogate and hard outcomes. Therefore, Committee members suggest that individualized decision-making is the best clinical approach to determine if vitamin C supplementation, or termination of supplementation, is required for adults with CKD stages 1-5, non-dialyzed, on dialysis and post-transplant.

      Nine studies examined the effect of vitamin C on nutrition-related outcomes in the CKD population, including five RCTs (Abdollahazard et al 2007,  Fumeron et al 2005,  Singer et al 2011,  Biniaz et al 2013,  Khajehdehi et al 2000),  one randomized crossover trial (Zhang et al 2013) and three comparative studies (Canavese et al 2005,  De vriese et al 2007,  Ono et al 1989) All studies examined MHD patients. Two studies (Canavese et al and Singer et al) also included PD patients and those with eGFR <20mL/min.

      QOL (Quality of Life), Mortality, and Hospitalizations
      In adults with CKD, one RCT (250 mg oral ascorbic acid 3x/week for 3 months) (Singer et al 2008) and one comparative study (Ono 1989) (500 mg oral vitamin C/day for 2 years) measured the effect of vitamin C supplementation, compared to either a placebo or control, on hard outcomes, including all-cause mortality, Quality of Life or hospitalizations events.

      Singer et al reported no changes in symptom, cognitive, or nausea sub-scales of the KDQOL-SF in either the vitamin C supplemented or placebo groups in MHD/PD participants. QOL was the primary outcome of interest. Approximately 40% of participants were vitamin C deficient at baseline. In a comparative study by Ono et al., there were no differences in mortality rates or hospitalization events between vitamin C supplemented and non-supplemented periods in MHD participants. Mortality was a primary outcome measure. Baseline vitamin C status was not reported. 

      In summary, Vitamin C supplementation did not affect QOL, Mortality or hospitalizations in MHD patients, but evidence was extremely limited. Evidence based recommendations for the use of vitamin C in this patient population for these endpoints could not be provided.

      Nutritional Status Parameters: serum Albumin, Pre-albumin, Transferrin, and Protein Nitrogen Appearance
      Three studies examined the effect of vitamin C supplementation on nutritional status in MHD participants: one RCT (Fumeron et al 2005),  one  randomized crossover trial (Zhang et al 2013),  and one  comparative study (De Vriese et al 2008). . However, nutritional status was not the primary outcome of interest. In Zhang et al, all patients were vitamin C-deficient at baseline,  while in DeVriese, et al. 44% of participants were deficient at baseline. In Fumeron et al, vitamin C deficiency status at baseline was unclear.  All outcomes were reported as quantitative values but were not compared to a reference standard. Supplementation dosage and duration ranged from 750 mg/week for 2 months to 1500 mg/week for 3 months.

      All three studies reported no effect of supplementation on albumin levels, as did pooled analysis of two of the RCTs. Zhang et al.  measured the effect of vitamin C supplementation on pre-albumin levels in a randomized crossover trial with MHD participants. While one supplemented group experienced an increase in pre-albumin levels after three months of supplementation with 200 mg vitamin C, pre-albumin levels did not change in the other group after the same intervention. Therefore, the effect of vitamin C supplementation on pre-albumin levels is unclear. Fumeron, et al. supplemented MHD participants with 750 mg/week of vitamin C for 2 months.  There were no significant changes in transferrin levels in either group. De Vriese et al measured nPNA (nPCR) in a NRCT and found no effect of vitamin C supplementation on nPNA (nPCR) following supplementation with 360mg/week or 1500mg/ week for 9 months in MHD patients.

      CRP Levels
      Three studies examined the effect of oral vitamin C supplementation on CRP levels in MHD participants (Fumeron et al 2005,  Zhang et al 2013,  De Vriese et al 2008) and found no significant effects compared to placebo or control groups, but evidence was limited.

      Vitamin C Levels/Deficiency
      Four RCTs (Abdollahzad et al 2009,  Fumeron et al 2005,  Singer et al 2011,  Zhang et al 2013) and two comparative studies (De Vriese et al 2008,  Ono et al 1989). examined the effect of Vitamin C supplementation in doses ranging from 360-3500 mg/week and duration ranging from 3 months to 2 years. In summary, oral vitamin C supplementation increased serum vitamin C levels in MHD patients and decreased the proportion of participants who were vitamin C deficient/insufficient (cut-offs were 11.44 and 23.0 µmol/L). However, in pooled analysis of three RCTS, the increase in vitamin C levels may not be clinically significant. The quality of evidence in this regard remains low. Other CKD populations such as non-dialysis CKD 1-5, PD and post-transplant participants remain poorly studied.

      These studies did not analyze the effects of vitamin C supplementation on optimal dosing or thresholds for toxicity.  The potential for toxicity was acknowledged with dosage ranges maintained at 200-250 mg daily or three times weekly in most studies. The study by Ono that dosed MHD patients with daily 500 mg oral Vitamin C daily for 2 years reported an aggravation of hyperoxalemia (Ono et al 1989). De-Vriese et al had subjects dosed as 360 mg per week for 0-3 months followed by 1500mg/week dosing x 3-6 months and then no supplementations for 6-9 months in MHD patients. This study reported an increase in plasma malondialdehyde (De Vriese et al 2008). Supplementation with vitamin C increased the low levels but there is a potential risk of toxicity that requires monitoring.

      Lipid Levels: Total Cholesterol, Triglycerides, LDL, HDL-C, LDL:HDL Ratio
      In summary, the results of three trials (Abdollahzad et al 2009,  Khajehdehi et al 2001,  De Vriese et al 2008),  demonstrated that vitamin C supplementation of 125-200 mg/d for 3 months may decrease total cholesterol and LDL cholesterol levels, but there was no effect on triglyceride or HDL cholesterol levels. Vitamin C supplementation of 125-200 mg/day decreased LDL:HDL  ratio or prevented the increase seen in the placebo group.

      There were several limitations to this evidence including a small number of studies, small sample sizes and low evidence quality. It is important to note that the study by Khajehdehi, et al included supplementing patients with potentially toxic doses of ergocalciferol, 50, 000 IU daily x 3 months (Khajehdehi et al 2011). The impact of this amount of vitamin D on study outcome parameters, if any, cannot be ascertained.

      Treatment of anemia with vitamin C supplementation was beyond the scope of this guideline.

    • Recommendation Strength Rationale

      The recommendation regarding vitamin C supplementation is based on Consensus/expert opinion. 

    • Minority Opinions

      Consensus reached.