Vitamin B12 deficiency in dialysis patients: risk factors, diagnosis, complications, and treatment: A comprehensive review

Table 1 A summary of the different diagnostic methods for vitamin B12 deficiency in end-stage kidney disease patients, their utility, and cut-off criteria

Diagnostic method	Use in ESKD	Cut-off criteria for deficiency
Serum vitamin B12 level	Often used as a first-line screening test; limited use due to false normal and inactive analogues (functional deficiency)	< 200 pg/mL; levels < 100 pg/mL have 90% specificity for identifying clinically evident deficiency
Methylmalonic acid	More sensitive in ESKD; elevated due to kidney dysfunction	> 0.4 μmol/L
Homocysteine	Elevated in ESKD; affected by vitamin B12 and folate status	> 15 μmol/L
Holotranscobalamin (active-B12)	Promising but requires more research for ESKD specific cut-offs	< 50 μmol/L
Neutrophil hypersegmentation	Rarely used; not sensitive for mild deficiency	Presence of > 5% neutrophils with ≥ 5 lobes
Macrocytosis (MCV)	May be present but not specific; affected by other factors in ESKD	MCV > 100 fL

MCV: Mean corpuscular volume; ESKD: End-stage kidney disease.

Table 2 Summarizes the studies on vitamin B12 supplementation in dialysis patients (provides a comparison of the different treatment modalities and their effect on homocysteine, methylmalonic acid, and vitamin B12 levels)

Ref.	Endpoint	Treatment	Results
Azadibakshsh et al[94]	Effect of high dose oral folic acid and vitamin B12 on homocysteine levels	High dose oral folic acid (15 mg/day) + vitamin B12 (1 mg/day)	Significant reduction in total homocysteine levels by 30% with a desirable effect on serum folic acid and vitamin B12 levels
Elian and Hoffer[95]	Effect of hydroxocobalamin on plasma total homocysteine and methylmalonic acid levels	1 mg hydroxocobalamin subcutaneously per week after hemodialysis vs standard treatment (oral folic acid + pyridoxine + vitamin B12)	32% reduction in plasma total homocysteine and 19% reduction in methylmalonic acid levels
Papadakis et al[97]	Effect of oral vs intravenous vitamin B12 with oral folic acid on homocysteine levels	Oral folic acid (1 mg/day) + oral vitamin B12 (600 μg) vs oral folic acid (1 mg/day) + 1mg intravenous vitamin B12	Significant reduction in total homocysteine levels with intravenous treatment compared to oral treatment
Chiu et al[98]	Effect of intravenous vitamin B12 alone vs intravenous low-dose folic acid alone vs combination of both on homocysteine levels	1 mg intravenous vitamin B12 weekly after hemodialysis vs 3 mg intravenous folic acid weekly vs combination of both	Intravenous vitamin B12 alone is as effective as intravenous low-dose folic acid in lowering homocysteine levels with the combination of both having a greater effect
Koyama et al[99]	Effect of high dose oral folic acid vs intravenous methylcobalamin vs combination of both on homocysteine levels	High dose oral folic acid (15 mg/day) vs 500 mg intravenous methylcobalamin after each hemodialysis vs combination of both	Similar efficacy of both treatments in reducing homocysteine levels, with greater effect in combination
Kaplan et al[100]	Effect of parenteral vitamin B12 alone on homocysteine levels	Three parenteral injections of 1 mg vitamin B12 given at 4-week intervals	Significant reduction in homocysteine levels and increase in serum B12 levels
Arnadottir and Hultberg[105]	Effect of oral vitamin B12 on homocysteine levels and vitamin B12 levels	2 mg oral vitamin B12 3 times a week (after each dialysis session) for 6 weeks vs no treatment	Significant increase in serum vitamin B12 levels in treated group with no significant reduction in homocysteine levels compared to control group
Polkinghorne et al[88]	Effect of intramuscular vitamin B12 on homocysteine levels and vitamin B12 levels	1 mg intramuscular vitamin B12 monthly for 3 months vs 1 mL saline placebo injection	Significant increase in serum vitamin B12 levels in treated group with no significant reduction in homocysteine levels compared to placebo group
Hoffer et al[106]	Comparison of different intravenous cyanocobalamin dosage regimens on plasma homocysteine	1 mg intravenous cyanocobalamin post-dialysis every 28, 14, and 7 days + routine oral vitamin B	7- or 14-day intervals had a similar effect on reducing homocysteine concentrations, with 7-day regimen increasing serum B12 the most
Hoffer et al[107]	Effect of different formulations of vitamin B12 on serum homocysteine and vitamin B12 levels	1 mg intravenous hydroxocobalamin weekly for 8 weeks followed by cyanocobalamin for 8 weeks vs 1 mg intravenous cyanocobalamin weekly for 8 weeks followed by hydroxocobalamin for 8 weeks	Hydroxocobalamin increased serum vitamin B12 concentrations 40-fold compared to cyanocobalamin which increased them only 10-fold, but both treatments reduced plasma homocysteine concentrations similarly by 33%
Dierkes et al[108]	Effect of vitamin B12 in patients with low baseline serum levels (< 180 pmol/L) on homocysteine and methylmalonic acid levels	1 mg intravenous cyanocobalamin weekly for 4 weeks	Reduction in plasma total homocysteine and methylmalonic acid levels by 35% and 48%, respectively