CKD: Micronutrients: Folic Acid and Vitamin B12 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.
CKD: Folic Acid Supplementation for Hyperhomocysteinemia
In adults with CKD 3-5D or posttransplantation who have hyperhomocysteinemia associated with kidney disease, we recommend not to routinely supplementing folate with or without B-complex since there is no evidence demonstrating reduction in adverse cardiovascular outcomes (1A).
CKD: Folic Acid Supplementation for Folic Acid Deficiency and Insufficiency, CKD 1-5 and Dialysis
In adults with CKD 1-5D, we suggest prescribing folate, Vitamin B12 and/or B-complex supplement to correct for folate or Vitamin B12 deficiency/insufficiency, based on clinical signs and symptoms (B2).
CKD: Folic Acid Supplementation for Folic Acid Deficiency and Insufficiency, CKD Post-Transplant
In adults with CKD posttransplantation, we suggest prescribing folate, Vitamin B12 and/or B-complex supplement to correct for folate or Vitamin B12 deficiency/insufficiency based on clinical signs and symptoms (OPINION).
Risks/Harms of Implementing This Recommendation
Excessive folate intake inhibits zinc absorption in the gut by forming a complex with zinc in the intestinal lumen. High intake of folic acid may mask signs of pernicious anemia leading to undetected progression of neurological disease.
Conditions of Application
Folate status is most often assessed through measurement of folate levels in the plasma, serum, or red blood cells. Serum or plasma folate levels reflect recent dietary intake, so deficiency must be diagnosed by repeated measures of serum or plasma folate. In contrast, RBC folate levels are more reflective of folate tissue status than serum folate and represent vitamin status at the time the RBC was synthesized (i.e. longer-term folate status). Usually, RBC folate concentrations diminish after about 4 months of low folate intake reflecting the 120-day life span of RBC in healthy individuals. In patients with CKD such concentrations often decrease more rapidly reflecting the shorter RBC life span in CKD. Excessive folate intake inhibits zinc absorption in the gut by forming a complex with zinc in the intestinal lumen.
High intake of folic acid may mask signs of pernicious anemia leading to undetected progression of neurological disease. Based on the 2015 USRDS annual report, more than 2/3 (38.9%) of the patients who are on dialysis are 65 years or older. Older people have a higher risk of impaired gastrointestinal function. Since absorption of vitamin B12 is dependent on Intrinsic Factor and normal gut function and since the latter is often at least partially impaired in older individuals, assessment of serum vitamin B12 may be necessary if folate supplementation is considered.
Serum homocysteine levels, vitamin B12 and folate levels monitoring may be considered for patients who take certain medications such as methotrexate, nitrous oxide, 6-azaridine, phenytoin, carbamazepine, oral contraceptives, and excessive alcohol intake that can interfere with folate absorption.
- Vitamin B deficiencies may be identified by clinical signs and symptoms. Assessment of serum vitamin B12 should be considered if folate supplementation is administered.
- High folic acid intake may mask signs of pernicious anemia and undetected progression of neurological disease, and thus levels of folate and vitamin B12 should be monitored if folate is being supplemented.
- Suggested vitamin intake should be based on recommendations for the general population (ex: Recommended Dietary Allowance) unless there are specific considerations requiring modification.
- Individualization of therapy, including supplementation dosage, is essential to the management of any comorbid condition.
- Individualization should include patient age since adults over 50 years may have increased needs due to the prevalence of athrophic gastritis in this population.
Monitoring and Evaluation
Serum/plasma/RBC folate level, serum vitamin B12 should be assessed as appropriate
Potential Costs Associated with Application
The cost of nutrition supplements should be considered before recommending them to a patient.
Folic acid is involved in the synthesis of several amino acids, including serine, glycine, methionine, and histidine. Folic acid can be provided by dietary sources as well as over-the-counter nutritional supplements. Over-the-counter supplements come in various forms, such as folic acid, methyl folate (also known as L-methyl folate, L-5-methyl folate or MTHF), and folinic acid, among others. Folic acid’s primary mechanism of action is its role as a one-carbon donor. Folic acid is reduced to methyl folate which helps transfer single methyl groups in various metabolic reactions in the body. Folic acid also plays a role in the functioning of the nervous system, in DNA synthesis and in cell division. Food sources rich in folic acid include green leafy vegetables, fruits, yeast, and liver. Even though intake of food naturally rich in folic acid is limited in patients with CKD due to their high potassium content, folic acid deficiency among this patient population seems to be rare. This is especially true since 1996, when folic acid fortification of enriched cereal grain products was mandated in the United States and Canada. Because folate, vitamin B12 and vitamin B6 assist in the conversion of homocysteine to methionine (and therefore reduce serum homocysteine levels), they have received considerable attention as a putative treatment for cardiovascular disease in patients with CKD.
Mortality, Cardiovascular Outcomes and Vascular Function
Four RCTs did not show any effect of folic acid when taken with vitamins B6 and B12 on hard outcomes, including all-cause mortality and/or cardiovascular events in patients with stage 5 CKD, on MHD or PD, and post-transplant (Jamison et al 2007, Bostom et al 2011, Heinz et al 2012, Mann et al 2008). Folic acid and other B-vitamin supplementation ranged from 2.5-40 mg/d folic acid, 1.4-100 mg/d B6, 150 µg/week- 2 mg/d B12 for a duration of 2-5 years.
Folic acid (alone) intake of 1 to 5 mg/day for 4 to 40 weeks showed no effect on flow mediated dilation (van Guldener et al 1998 and Thambyrajah et al 2000). Additionally, folic acid supplementation did not alter the risk of cardiovascular outcomes in four RCTs (Righetti et al 2013, Wrone et al 2004, Vianna et al 2007 and Zoungas et al 2006). The 4 RCTs included patients with CKD, stage 5 non-dialyzed and on PD and MHD. The folic acid supplementation dose ranged from 1-15 mg/day and supplementation duration ranged from 1-3.6 years in these studies.
Supplementation with folic acid in combination with other B-vitamins did not improve total cholesterol levels, intima media thickness (IMT) or BP in MHD patients. Doses ranged from 5 mg to 15 mg folic folic acid and a B-complex vitamin for 3 to 6 months (Chang et al 2007 and Tungkasereerak et al 2006).
One RCT examined the effect of folic acid supplementation on CKD progression (Xu et al 2016). In a sub-study of a larger primary stroke prevention trial including 15, 104 participants with CKD Stage 3 diagnosed with hypertension and taking the angiotensin converting enzyme inhibitor enalapril being randomized to receive 0.8 mg/day of folic acid or placebo for a median of 4.4 years. Compared to the group receiving enalapril and placebo, the enalapril + folic acid group significantly reduced the adjusted risk of CKD progression (Hazard Ratio (95% CI): 0.45 (0.27, 0.76); p=0.003), which was the sub-study’s primary outcome. The limitation of this study was that a placebo alone group (without enalapril) was not included.
Two other RCTs showed no effect of supplementation with folic acid with vitamins B6 and B12 on the risk of dialysis initiation/kidney failure in participants with stages 3-5 chronic kidney disease and those post-transplant (Jamison et al 2007 and Bostom et al 2011) .
Serum Homocysteine Levels
Fourteen studies examined the effect of folic acid supplementation alone on plasma homocysteine levels (Alvares et al 2007, Bernasconi et al 2006, Nafar et al 2009, Sunder-Plassmann et al 2000, Thambyrajah et al 2000, Vianna et al 2007, Wrone et al 2004, Xu et al 2016, Zoungas et al 2006, De Vecchi et al 2001, McGregor et al 2000, Ossareh et al 2009, Righetti et al 2013 and van Guldener et al 1998). Participants included were those with CKD, non-dialyzed (4 studies), on MHD (10 studies) and PD (4 studies), and post-transplant (1 study). In the ten RCTs, folic acid supplements ranged from 0.8-60 mg/day and duration varied from 4 weeks to 4.4 years in patients of various stages of CKD. All but one study (Tamadon et al 2011) concluded that folic acid supplementation significantly decreased homocysteine levels.
Thirteen RCTs examined the effect of supplementation with folate and other B-vitamins on homocysteine levels (Chang et al 2007, Azadibakhsh et al 2009, Chiu et al, Trimarchi et al 2002, Tamadon et al 2011, Bostom et al 1995, Bostom et al 2011, Jamison et al 2007, Heinz et al 2012, Mann et al 2008, Gonin et al 2003, Nakhoul et al 2004 and Tungkasereerak et al 2006). Serum homocysteine level was a primary outcome of interest in eight studies. Twelve out of 13 studies found that folic acid with other B vitamin supplementation decreased homocysteine levels in participants with CKD Stages 3-5, on MHD, PD and post-transplant. Supplementation doses in these studies ranged from 2.5-40 mg/d folic acid (one study utilized 3 mg IV folinic acid/week), 1 µg/d oral to 1000 mg/week IV B12, and 1.4-100 mg B6 and supplementation duration ranged from 8 weeks to 5 years.
CRP and IL-6 Levels
Daily oral folic acid (5 mg) with a B-complex vitamin for 3 months was associated with a decrease in CRP, but not IL-6, levels in a RCT that included 121 patients on MHD (Chang et al 2007).
Folic acid and B12 Levels
Six RCTs reported that supplementation of folic acid alone increased serum folic acid levels in participants with stages 3-5 CKD and those on MHD and PD (Sunder-Plassmann et al, Thambyrajah et al, Xu et al, Zoungas et al, De Vecchi et al and McGregor et al). When folic acid with vitamins B6 and B12 were provided, it is worth noting that serum folic acid level increased with a daily intake of 5 mg for 3 months, or a daily intake of 2.5 mg for a longer time frame. When folic acid with B6 and B12 was provided (Mann et al) to patients on MHD, serum folic acid significantly increased with an intake of 2.5 mg after 2 years of supplementation as compared to the control group. In Chiu, et al., a supplementation of 3 mg folinic acid weekly via IV for 3 months did not result in a significant increase in serum folic acid levels in participants with stage 3 – 5 CKD or were on MHD and PD.
Of the ten studies that examined the effect of supplementation of folic acid with B-complex, nine found a significant increase in serum folic acid levels (Chang et al 2007, Azadibakhsh et al 2009, Trimarchi et al 2002, Bostom et al 1995, Jamison et al 2007; Heinz et al 2012, Mann et al 2008, Gonin et al 2003 and Tungkasereerak et al 2006). Doses ranged from 2.5-60 mg folic acid and study duration ranged from 4 weeks to 5 years.
Recommendation Strength Rationale
The evidence supporting the recommendation on folic acid and vitamin B12 supplementation is based on Grades I and II/Grades A and B evidence. The recommendation supplementation for people with CKD, post-transplant was based on Consensus/expert opinion.
- Risks/Harms of Implementing This Recommendation
The recommendations were created from the evidence analysis on the following questions. To see detail of the evidence analysis, click the blue hyperlinks below (recommendations rated consensus will not have supporting evidence linked).
What is the effect of folate supplementation on cardiovascular disease outcomes in adults with CKD 1-5D and post-transplant?
What is the effect of folate supplementation on intima media thickening in adults with CKD 1-5D and post-transplant?
What is the effect of folate supplementation on endothelium-dependent flow mediated dilation in adults with CKD 1-5D and post-transplant?
What is the effect of folate supplementation on folate levels in adults with CKD 1-5D and post-transplant?
What is the effect of supplementation with folate combined with other B vitamins on all-cause and cardiovascular-related mortality in adults with CKD 1-5D and post-transplant?
What is the effect of supplementation with folate combined with other B vitamins on cardiovascular disease events in adults with CKD 1-5D and post-transplant?
What is the effect of supplementation with folate combined with other B vitamins on folate and vitamin B12 levels in adults with CKD 1-5D and post-transplant?
What is the effect of folate supplementation on homocysteine levels in adults with CKD 1-5D and post-transplant?
What is the effect of supplementation with folate combined with other B vitamins on homocysteine levels in adults with CKD 1-5D and post-transplant?
What is the effect of folate supplementation on mortality in adults with CKD 1-5D and post-transplant?
What is the effect of folate supplementation on end stage renal disease in adults with CKD 1-5D and post-transplant?
What is the effect of folate supplementation on eGFR in adults with CKD 1-5D and post-transplant?
What is the effect of supplementation with folate combined with other B vitamins on kidney failure/dialysis initiation in adults with CKD 1-5D and post-transplant?
What is the effect of supplementation with folate combined with other B vitamins on blood pressure and intima media thickening in adults with CKD 1-5D and post-transplant?
What is the effect of supplementation with folate combined with other B vitamins on total cholesterol in adults with CKD 1-5D and post-transplant?
What is the effect of supplementation with folate combined with other B vitamins on inflammatory markers in adults with CKD 1-5D and post-transplant?
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Vianna A, Mocelin A, Matsuo T, Morais-Filho D, Largura A, Delfino V, Soares A, Matni A. Uremic hyperhomocysteinemia: a randomized trial of folate treatment for the prevention of cardiovascular events. Hemodialysis International. International Symposium on Home Hemodialysis 2007; 11:210-216
Wrone E, Hornberger J, Zehnder J, McCann L, Coplon N, Fortmann S. Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease. Journal of the American Society of Nephrology 2004; 15:420-6
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van Guldener C, Janssen M, Lambert J, ter Wee P, Jakobs C, Donker A, Stehouwer C. No change in impaired endothelial function after long-term folic acid therapy of hyperhomocysteinaemia in haemodialysis patients. Nephrology, Dialysis, Transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 1998; 13:106-12
Alvares Delfino V, de Andrade Vianna A, Mocelin A, Barbosa D, Mise R, Matsuo T. Folic acid therapy reduces plasma homocysteine levels and improves plasma antioxidant capacity in hemodialysis patients. Nutrition (Burbank, Los Angeles County, Calif.) 2007; 23:242-7
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De Vecchi A, Patrosso C, Novembrino C, Finazzi S, Colucci P, De Franceschi M, Fasano M, Bamonti-Catena F. Folate supplementation in peritoneal dialysis patients with normal erythrocyte folate: effect on plasma homocysteine. Nephron 2001; 89:297-302
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Ossareh S, Shayan-Moghaddam H, Salimi A, Asgari M, Farrokhi F. Different doses of oral folic acid for homocysteine-lowering therapy in patients on hemodialysis: a randomized controlled trial. Iranian Journal of Kidney Diseases 2009; 3:227-33
Sunder-Plassmann G, Födinger M, Buchmayer H, Papagiannopoulos M, Wojcik J, Kletzmayr J, Enzenberger B, Janata O, Winkelmayer W, Paul G, Auinger M, Barnas U, Hörl W. Effect of high dose folic acid therapy on hyperhomocysteinemia in hemodialysis patients: results of the Vienna multicenter study. Journal of the American Society of Nephrology 2000; 11:1106-16
Xu X, Qin X, Li Y, Sun D, Wang J, Liang M, Wang B, Huo Y, Hou F. Efficacy of Folic Acid Therapy on the Progression of Chronic Kidney Disease: The Renal Substudy of the China Stroke Primary Prevention Trial. JAMA Internal Medicine 2016; 176:1443-1450
Bostom A, Carpenter M, Kusek J, Levey A, Hunsicker L, Pfeffer M, Selhub J, Jacques P, Cole E, Gravens-Mueller L, House A, Kew C, McKenney J, Pacheco-Silva A, Pesavento T, Pirsch J, Smith S, Solomon S, Weir M. Homocysteine-lowering and cardiovascular disease outcomes in kidney transplant recipients: primary results from the Folic Acid for Vascular Outcome Reduction in Transplantation trial. Circulation 2011; 123:1763-70
Heinz J, Kropf S, Domröse U, Westphal S, Borucki K, Luley C, Neumann K, Dierkes J. B vitamins and the risk of total mortality and cardiovascular disease in end-stage renal disease: results of a randomized controlled trial. Circulation 2010; 121:1432-8
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Mann J, Sheridan P, McQueen M, Held C, Arnold J, Fodor G, Yusuf S, Lonn E. Homocysteine lowering with folic acid and B vitamins in people with chronic kidney disease--results of the renal Hope-2 study. Nephrology, Dialysis, Transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 2008; 23:645-53
Azadibakhsh N, Hosseini R, Atabak S, Nateghiyan N, Golestan B, Rad A. Efficacy of folate and vitamin B12 in lowering homocysteine concentrations in hemodialysis patients. Saudi Journal of Kidney Diseases and Transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia 2009; 20:779-88
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Chang T, Chou K, Tseng C, Chung H, Fang H, Hung Y, Wu M, Tzeng H, Lind C, Lu K. Effects of folic acid and vitamin B complex on serum C-reactive protein and albumin levels in stable hemodialysis patients. Current Medical Research and Opinion 2007; 23:1879-86
Chiu Y, Chang J, Hwang S, Tsai J, Chen H. Pharmacological dose of vitamin B12 is as effective as low-dose folinic acid in correcting hyperhomocysteinemia of hemodialysis patients. Renal Failure 2009; 31:278-83
Gonin J, Nguyen H, Gonin R, Sarna A, Michels A, Masri-Imad F, Bommareddy G, Chassaing C, Wainer I, Loya A, Cary D, Barker L, Assefi A, Greenspan R, Mahoney D, Wilcox C. Controlled trials of very high dose folic acid, vitamins B12 and B6, intravenous folinic acid and serine for treatment of hyperhomocysteinemia in ESRD. Journal of Nephrology 2003; 16:522-34
Nakhoul F, Abassi Z, Plawner M, Khankin E, Ramadan R, Lanir N, Brenner B, Green J. Comparative study of response to treatment with supraphysiologic doses of B-vitamins in hyperhomocysteinemic hemodialysis patients. The Israel Medical Association Journal 2004; 6:213-7
Tamadon M, Jamshidi L, Soliemani A, Ghorbani R, Malek F, Malek M. Effect of different doses of folic acid on serum homocysteine level in patients on hemodialysis. Iranian Journal of Kidney Diseases 2011; 5:93-6
Trimarchi H, Schiel A, Freixas E, Díaz M. Randomized trial of methylcobalamin and folate effects on homocysteine in hemodialysis patients. Nephron 2002; 91:58-63
Tungkasereerak P, Ong-ajyooth L, Chaiyasoot W, Ong-ajyooth S, Leowattana W, Vasuvattakul S, Vareesangthip K, Shayakul C, Chanchairujira T, Sritippayawan S. Effect of short-term folate and vitamin B supplementation on blood homocysteine level and carotid artery wall thickness in chronic hemodialysis patients. Journal of the Medical Association of Thailand - Chotmaihet thangphaet 2006; 89:1187-93
References not graded in Academy of Nutrition and Dietetics Evidence Analysis Process
No additional references.