Vitamin B7 (biotin)BackgroundDiscovered by Kögl in 1948, B7 is a cofactor responsible for carbon transfer in several carboxylase reactions [31]. Gross deficiency states are rare, as a large but variable proportion of B7 absorbed by humans is produced by alimentary tract bacteria [31]. Egg white contains a glycoprotein, avidin, that tenaciously binds B7; excessive consumption of egg white (more than 20 a day) can lead to frank clinical deficiency, called egg-white disease, and characterized by scaly dermatitis and skin dryness, atrophy of lingual papillae, graying of mucous membranes, depression, lassitude, and muscle pain [31]. Other studies of experimental B7 deficiency in humans have identified seborrhoeic dermatitis as the cardinal manifestation [52].Dietary sources include yeast, liver, egg yolk, tomato, soybeans, rice, and bran [31].Plasma B7 levels are not a sensitive indicator of deficiency. Plasma B7 was in the normal range in half of patients fed raw egg white to induce deficiency and in some cases of overt deficiency [53]. In the general population, urinary excretion of B7 and B7 metabolites is thought a more reliable indicator of sufficiency [53].Toxicity appears to be low, with no syndrome reported [31, 54]. Excess B7 is excreted in the urine in patients with normal renal function and those with low glomerular filtration rate not on dialysis [55].General PopulationThe RDA varies from 20 to 35 mcg/day for adolescents and adults: 20 mcg for an adolescent male, and somewhat higher recommendations with increasing age, pregnancy, and lactation [37]. There are few reports of frank deficiency syndromes and to our knowledge, no large-scale epidemiologic assessment of the effect of lower vs. higher levels on clinically important outcomes.A few studies have reported beneficial effects on glucose metabolism, atherogenic markers, and coronary risk factors in people with type 2 diabetes (given in conjunction with chromium) [56-58]. Little work appears to have been conducted on patient-important outcomes. Two small RCTs, one in women with alopecia and one in infants with seborrhoeic dermatitis (both negative) have been conducted [52, 59].People with Low Glomerular Filtration Rate & End-Stage Renal DiseaseIn a comparative study of patients with and without chronic kidney disease, normal controls and patients with renal transplants ingested 37 (SD 12) mcg of B7 daily, compared with 30 (SD 9) mcg in people with low GFR not on dialysis and 19 (SD 5) mcg in unsupplemented patients on dialysis.In prevalent patients on low-flux or high-flux HD, almost all patients had values in the normal or high range (Table 3) [2, 60]; 70% of patients had values above 1000 ng/l, which would be highly unusual in the general population. Patients on HD for longer than 5 years had levels that were higher than those on of more recent vintage (mean: 1642 vs. 1274 ng/l, p < 0.01), and anuric patients had higher values than patients with residual renal function (mean: 1581 vs. 1116, p < 0.01) [2]. In a different study, these factors were not examined, but plasma B7 concentrations were not associated with duration or frequency of dialysis, high-flux vs. low-flux dialysis, Qb, smoking, body mass index, or age [55].As neurologic disease is not part of the described deficiency syndrome and because we now know that levels of B7 are not low in patients on dialysis, it is hard to understand the finding, in 1985, of dramatic clinical improvement in an uncontrolled trial of B7 10 mg daily given to nine patients who had developed dementia or peripheral neuropathy while on dialysis [54].SummaryGiven the large proportion of B7 derived from intestinal flora, the documented high levels of B7 in unsupplemented dialysis patients, the extreme rareness of clinical syndromes associated with B7 deficiency, it seems unlikely that B7 supplementation in dialysis patients would be useful. However, all studies addressed sufficiency by assaying B7 concentrations in blood, which are known not to be sensitive indicators of deficiency; furthermore, no toxicity has been described. Perhaps this rationale explains the large amounts of B7 found in some dialysis supplements (e.g., Replavite at 300 mcg/day contains 10 times the RDA for adults).Vitamin B9 (folic acid, folate)BackgroundFolate is derived from polyglutamates in food which are deconjugated in the upper jejunum and actively transported across mucosal epithelia [61]. Folate circulates as 5-methyltetrahydrofolate, which is further demethylated to tetrahydrofolate in a reaction, catalyzed by B12, which requires homocysteine as a methyl acceptor (leading to methionine generation). Tetrahydrofolate is responsible for one-carbon transfer reactions in the body, most notably in the reactions needed for DNA synthesis. The cardinal clinical manifestation of frank deficiency is megaloblastic anemia [61].Green leafy vegetables, whole grains, yeast, and liver are particularly rich in folate, particularly when raw or not heavily processed [31, 62]. Intestinal bacteria also synthesize folate [64]. The RDA is given as dietary folate equivalents (DFE; 1 DFE = 1 μg food folate = 0.6 μg of folate from fortified food or as a supplement consumed with food = 0.5 μg of a supplement taken on an empty stomach) and is 300–600 mcg/day for adolescents and adults, with the higher end of that range recommended for pregnant and lactating women, and older people [37]. In many countries, flour and bread are fortified with folate as a public health measure, and many breakfast cereals are also fortified with 25–100% of the RDA per serving [62]. This resulted in a decrease from 4.9% to 1.9% in the proportion of the people in the general population who were frankly deficient [64].Folate stores are low, so deficiency can occur 21–28 days of severe dietary deficiency [63]. Red cell folate, rather than plasma folate, is thought the better reflection of tissue stores, and is the recommended blood measurement for the assessment of folate status [65].Toxicity appears to be low, and no syndrome associated with excess consumption has been described [63]. Very high doses (in excess of 1000 mcg/day) can correct the anemia associated with B12 deficiency and lead to delay in diagnosis [66], and folate supplementation can precipitate neurologic deterioration in B12-deficient patients [61, 66].General PopulationIn the general population, frank deficiency of folate leads to megaloblastic anemia. This is most commonly due to inadequate intake such as occurs in anorexia nervosa, malabsorption, or alcoholism; or increased demand, as in hyperthyroidism, pregnancy or lactation [63].Neural Tube DefectsFolate deficiency is associated with fetal neural tube defects (including spina bifida). Following recognition that many people had diets inadequate in folate and that the benefits of folate supplementation would be greatest preconception and in the first month of pregnancy, the US Food and Drugs Administration issued a regulation, effective 1998, that all enriched cereals (included flour and products of flour) should be fortified with 140 mcg of folate per 100 g (in addition to the iron, thiamine, riboflavin and niacin already added to these products) [64], and Canada soon followed suit [67]. Follow-up indicates that food fortification has been among the most successful public health programs in reducing the rates of neural tube defects in the United States and Canada [68] and a number of reports show reduction in the incidence of neural tube defects by 20–78% [69].Cardiovascular DiseaseFolate is also required for one-carbon transfer in homocysteine metabolism. Higher levels of folate intake are associated with lower levels of homocysteine in general populations, but the relationship is not linear and seems to plateau at around dietary intake of 300 mg/day [70]. Whether folate intake is associated with vascular disease is still controversial [71]. Randomized trials have usually included the other B vitamins involved in homocysteine pathways (B6 and B12) and are discussed in the section on B12 and summarized in Table 4.Cognitive FunctionA Cochrane review of a limited number of studies found no benefit of folate supplementation, with or without B12, on cognitive function for prophylaxis in unselected elderly people or for treatment in people with cognitive decline [72]. Three RCTs of 247 people provided limited support for the idea that folate might be a useful adjunct in the treatment of depression [73].People with Low Glomerular Filtration Rate & End-Stage Renal DiseaseMean predialysis serum folate concentrations were in the normal range in all 36 patients studied on high-flux thrice weekly hemodialysis, although dialytic losses documented in this study were thought likely to be clinically important (Table 3), and 3/36 (9%) had levels suggestive of deficiency [1]. However, RBC folate concentrations were normal in all patients in this study [1]. This study was conducted in Canada around the time that mandatory food fortification came into effect. Two other studies of 50–60 unsupplemented patients on HD found that 10% had folate or RBC folate below the lower limit of normal [74, 75], while none of 34 patients on CAPD had folate deficiency [74]. These studies were conducted in Korea [74] where plasma folate levels in the general population are higher than in other countries without mandatory fortification [76], likely because of relatively high content of leafy green vegetables in the diet, and in France [75], where recommendations rather than regulations govern the addition of folate to cereal. This probably has not led to clinically important increases in folate consumption, judged by the lack of effect on the rates of neural tube defects in France) [77].Importance of Assessment of RBC Folate rather than Serum FolateAssessment of folate status in patients on dialysis may be particularly liable to error if plasma rather than RBC folate is measured: in one of these studies, estimating folate stores by plasma folate rather than RBC folate would have led to 3% of CAPD and 72% of HD patients being thought folate-deficient, rather than 0% and 10%, respectively [74]. Discordance between serum and RBC folate was also noted in a study from Canada in 2000 [1]. Patients on HD consistently have lower RBC folate that those on CAPD [74, 78].Extended Hours DialysisExtended hours dialysis did not have an impact on serum levels of folate in 52 HD patients, 38% of whom were taking a multivitamin [17].SevelamerIn one small pre–post study, sevelamer use was associated with a decrease in serum folate levels (5.5 vs. 4.79 ng/ml, p < 0.05) and an increase in homocysteine levels (51 vs. 68 nmol/ml) [79].SummaryWhile some experts have recommended that folate supplementation is not necessary in patients on HD, findings of 10% of prevalent patients with levels in the range associated with deficiency call this recommendation into question. The countries' policy on folate fortification may be relevant, as at least 2 of the 3 studies available were conducted in populations that were not exposed to mandatory cereal supplementation. Fortification is in effect in Canada, United States, Chile, and Australia [69], but not in any European countries [80]. However, no documentation of adequate folate stores in countries that practice fortification has appeared, and toxicity and costs are low, so perhaps the most reasonable approach until further evidence is developed is fortification with small quantities (perhaps 2–7 mg/week). Use of large doses, usually in conjunction with other B vitamins, appears to lower homocysteine, but not to prevent cardiovascular events and cannot be recommended.
Water soluble vitamins (summary)
Vitamin B2 (Riboflavin), Vitamin B3 (Niacin = nicotinic acid; niacinamide = nicotinamide)
Vitamin B7 (biotin), Vitamin B9 (folic acid, folate)
Clase, C. M., Ki, V. and Holden, R. M. (2013), Water-Soluble Vitamins in People with Low Glomerular Filtration Rate or On Dialysis: A Review. Seminars in Dialysis, 26: 546–567. doi: 10.1111/sdi.12099
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