Vitamin B12 Handling by the Kidney, a Major Site of B12 Traffic: Normal and Abnormal Physiology.
Authors: Hazin Hesham , Neelakantappa Kotresha , Ramasahayam Lakshmi , Abdel-Maksoud Ahmed , Fogel Josua , Moestrup Søren Kragh , Carmel Ralph 
Published: April 2020

Abstract
Background : The kidney is a major site of daily vitamin B12 (B12) processing. It filters transcobalamin (TC) II-bound B12 (holoTCII; the transport protein that delivers its B12 to all cells) and reabsorbs holoTCII in the proximal tubule via megalin, a multiligand receptor for TCII. The process, its quantitation, and the roles of TCI and TCII are still poorly characterized in normal subjects or in renal failure, in which serum B12 levels often rise. It is assumed that this rise in serum B12 reflects decreased renal clearance, but little is known about the details. The fractional excretion (FE) has not been measured but would be expected to approach zero for an essential vitamin, denoting a 100% tubular reabsorption. We characterized the tubular reabsorption and urinary excretion of B12 and holoTCII, as well as quantitating the distribution of serum B12 among its TC carriers (because B12 does not circulate unbound) in normal subjects and patients with acute kidney injury (AKI).
Methods: Serum and 24-hour urine B12 (Roche assay) and holoTC II (Axis-Shield assay) were measured directly in 10 AKI patients and 10 control subjects. AKI was diagnosed by a recent increase in BUN/creatinine 3 times their baseline; glomerular filtration rate (GFR) was 12 ± 9 ml/min. Normal subjects were selected who had no renal co-morbidities and had a normal BUN/creatinine and glomerular filtration rate (GFR = 95 ± 36). Holo-nonTCII, which is identical to holoTCI in serum but whose nature is still undefined in urine, was calculated by subtracting holoTCII from (total) B12. FE, a measure of the filtered amount that is not reabsorbed, was calculated for B12, holoTCII, and holo-nonTCII. Group data were compared using ANOVA, with log transformation for skewed distributions. Correlation coefficients were calculated by Spearman rank test.
Results: Serum total B12 (p&lt;0.001), holo-TC II levels (p=0.005), and serum holoTCI levels (p&lt;0.005) were significantly increased in AKI (see Table). Consonant with the importance of tubular reabsorption of B12, reabsorption fell and FE of B12 increased 4.4- fold in AKI (p&lt;0.001), and FE of holoTCII increased 3.2-fold (p=0.007). Nevertheless, the 24-hour excretion of B12 and holo-TCII did not change significantly from normal in AKI, presumably because reduced GFR counterbalanced the decreased tubular reabsorption and increased FE. Serum, urine, and FE findings for holo-nonTCII, whose levels exceeded holoTCII in both serum and urine, resembled those for total B12 and holoTCII (Table). Moreover, relatively less B12 was found as holoTCII in urine in AKI than in control subjects (11.7% ± 7.2 vs. 20.2% ± 6.4; p=0.012) and more was found as holo-nonTCII; these ratios did not differ in AKI serum, however.
B12 AKI Serum (pmol/l) 1611±1153* Urine (pmol/24hr) 115±88 Fractional Excretion (%) 0.70±0.35* Controls 369±100 75±32 0.15±0.08 * p &lt;0.001 ** p≤0.005 ▴ p=0.007 TCII AKI 232±148** 13±16 0.50±0.39▴ Controls 100±76 14±8 0.15±0.10 NonTCII AKI 1378±1128** 102±81 1.13±1.33* Controls 269±100 60±26 0.19±0.14
Conclusion:
The patients with AKI revealed an approximately fourfold increase in FE of B12, holoTCII, and holo-nonTCII (possibly TCI) compared with controls. This indicates a dramatic loss of tubular reabsorption, consistent with the tubular necrosis of AKI. Although there is no significant difference in the 24-hour urinary output of B12 and the TCs, our data show that urinary B12 excretion is neither increased nor decreased in AKI. Presumably, this reflects in part, a balance between reduced glomerular filtration and reduced tubular reabsorption. The diminished reabsorption of B12 and holoTCII probably arises from disruption of uptake by tubular megalin, which requires further documentation. One net result of the previous events is a rise in serum B12, holoTCII and non-holoTCII in AKI. The serum B12 elevation has been described in the past and is particularly striking in this study, as is the new observation of TC I (non-holoTCII). It is presumed to reflect the loss of normal glomerular filtration, as discussed, but the possibility of contributions from extrarenal sources and events must also be considered.