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Functional vitamin B12 deficiency in renal insufficiency

Vitamin B12 deficiency is very common in patients with renal disorders. These patients show raised serum concentrations of MMA and tHcy that can be corrected with B12 substitution, which indicates a deficiency before starting treatment. In contrast to this, normal or high normal plasma concentrations of total B12 or holoTC were reported in renal patients. The likely cause is a disrupted cellular absorption of holoTC, which results in intracellular B12 deficiency and raised metabolites. Studies have shown that patients with renal disorders may have higher concentrations of holoTC, which seems to contradict B12 deficiency (1). 

Diagnosing B12 deficiency in renal patients remains a challenge. This is because renal insufficiency causes elevation of MMA and tHcy. However, low serum concentrations of B12 or holoTC are uncommon in patients with renal insufficiency (2). Renal patients show significant metabolic improvements (reduction of MMA) after treatment with B12 (3). A reduction of the MMA serum concentration by more than 200 nmol/L after B12 injection confirms a pre-treatment deficiency. Since patients with renal disorders may have raised MMA concentrations that are not associated with B12 deficiency, vitamin B12 deficiency can be determined only by lowering of MMA (3). The reasons for elevated serum B12 (total B12 and holoTC) in renal patients are not known. An abnormal distribution of holoTC, a disturbed receptor activity for renal TC uptake and the possibility that TC is functionally altered by renal failure are possible explanations for accumulation of B12 in serum of renal patients.

Chronic hemodialysis patients are a group of high risk for B12 deficiency. Dialysis patients have a negligible residual renal function. Therefore, holoTC is neither filtered nor reabsorbed in the proximal tubule. This could participate in the retention of holoTC in blood. Additionally, the short half-life of holoTC in serum and the accumulation of this portion in renal failure might suggest an increment in the rate of its synthesis. In our investigations we observed higher concentrations of holoTC in patients on hemodialysis than in control subjects (median holoTC 100 vs. 61 pmol/L), and the distribution of serum concentrations of holoTC was shifted towards a higher range compared with a group of age-matched subjects with normal renal function (2). By contrast, serum concentrations of MMA were severely elevated in dialysis patients (median MMA 987 nmol/L), and were associated with high serum concentrations of holoTC However, it is not known how much of the MMA elevation comes from B12 deficiency and how much comes from renal insufficiency. Furthermore, intervention studies on renal patients demonstrated that supra-physiological doses of B12 significantly reduce serum MMA and normalize tHcy. Thus, serum B12 levels within the reference range in renal patients are not likely to ensure B12 delivery into the cells.


1.     Obeid R, Kuhlmann M, Kirsch CM, Herrmann W. Cellular uptake of vitamin B12 in patients with chronic renal failure. Nephron Clin Pract 2005;99:c42-c48.
2.     Herrmann W, Obeid R, Schorr H, Geisel J. The usefulness of holotranscobalamin in predicting vitamin B12 status in different clinical settings. Curr Drug Metab 2005;6:47-53.
3.     Obeid R, Kuhlmann MK, Kohler H, Herrmann W. Response of homocysteine, cystathionine, and methylmalonic acid to vitamin treatment in dialysis patients. Clin Chem 2005;51:196-201.