Vitamin B5 (Pantothenic acid)BackgroundPantothenic acid is essential to the synthesis of coenzyme-A as well as in the synthesis and metabolism of proteins, carbohydrates, and fats.General PopulationPantothenic acid is found in nearly all food sources and thus deficiency states are poorly defined and exceedingly rare. Toxicity is presumed to be unlikely and there is no UL of intake defined for this vitamin [4].People with low Glomerular Filtration Rate & End-Stage Renal DiseasePantothenic acid levels were measured in the 1960s in hemodialysis and peritoneal dialysis patients and were reported as normal [30].SummaryThere is no recommendation to supplement patients with low GFR or ESRD with this vitamin and, based on the available evidence, it is likely not indicated.Vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride)BackgroundVitamin B6 is a water-soluble vitamin named by Szent-György in 1934, who discovered a substance that prevented dermatitis acrodynia in rats [31]. The human deficiency syndrome is characterized by seborrhoeic skin lesions, microcytic and hypochromic anemia, weakness, irritability, nervousness, and insomnia [32]. The vitamin exists in several different forms (pyridoxine, pyridoxal and pyridoxamine); the supplementary form most often given is pyridoxine. All are converted to the active form pyridoxal 5-phosphate (PLP). Vitamin B6 is a cofactor for reactions such as transamination, decarboxylation, dehydratase, and side chain cleavage reactions for at least 140 distinct enzymes, and is implicated in pathways as diverse as red blood cell synthesis, homocysteine metabolism, macronutrient metabolism, histamine synthesis, and gene expression [32]. Some forms of vitamin B6 also appear to protect against glycation or carbonylation reactions [33, 34].PLP is also a component of two enzymes that metabolize homocysteine, by transulfuration, to cysteine [35]: deficiency of B6 leads to hyperhomocysteinemia [36], which is associated with thrombosis and atherosclerosis.Dietary sources of B6 include fortified cereals, organ meats, fortified soy-based meat substitutes, yeast, nuts, beans, avocados, and bananas [31, 37].Most reports of toxicity, in the form of peripheral neuropathy, have occurred in the context of intakes of >600 mg daily, although reports of toxicity in people taking 300–500 mg have appeared [38].General PopulationBecause B6, B12, and folate intersect at the homocysteine pathway [35], and homocysteinemia is a graded risk factor for atherosclerosis [39], trials of combinations of these vitamins have been conducted in the general population in the hope of reducing the risk of cardiovascular disease. In general, these trials have been negative: we summarize them in the section on B12 use in the general population, below.CognitionA Cochrane review of a limited number of studies found no evidence that B6 has beneficial effects on mood or on cognition [40].People with low glomerular filtration rate & end-stage renal diseaseDietary Intake and LevelsIn 36 unsupplemented patients on high-flux thrice weekly hemodialysis, PLP levels were low in 56% and in the low normal range in a further 38%, with clinically important dialytic losses documented (Table 3) [1]. PLP levels fell when patients who were receiving B6 10 mg daily were changed from low-flux to high-flux dialysis, but were still judged to be sufficient by the investigators (Table 3) [41]. From their primary data and a review of previous literature of supplemented and unsupplemented patients, the authors concluded that 10 mg/day supplementation was likely adequate, even for patients undergoing high-flux hemodialysis [41]. In patients on high-flux hemodialysis who had not previously received supplementation, mean values were grossly deficient at 1.6 ± SD 1.3 mcg/l [2]. B6 12–17 mg/day normalized PLP and one of two measures of PLP-sufficiency at the red cell level: the other measure required the much higher dose of 43–64 mg/day for normalization [2].In a study of 11 unsupplemented patients on peritoneal dialysis, mean dietary intake was 50% and 59% on the RDA on two separate occasions, and were correlated with protein intake [42]. In this study, despite normal plasma B6 levels in all patients, PLP levels were low (<40 nmol/l) in all patients. PLP was not correlated with dietary intake. In another study of patients on PD who received B6 5–20 mg daily supplementation, B6 levels were in the normal range and higher than those of controls; losses in dialysate were small (Table 3) [43]. PLP was not measured in this study.In unselected prevalent patients on PD, who had not been receiving supplements, all of whom had been found to be PLP-deficient (levels <40 nmol/l) at baseline, supplementation of 5 mg daily normalized PLP levels in 8 of 11 patients, and the remaining 3 normalized during a more prolonged period of supplementation at a dose of 10 mg [42].In contrast to their levels of other water-soluble vitamins, patients on extended hours dialysis had higher levels of PLP than patients on conventional dialysis (23 vs. 11 mg/ml, p = 0.03), perhaps because dialysis losses were offset by higher dietary intake of this nutrient [17]. In this study, none of the patients on extended-hours dialysis, but 35% of patients on conventional dialysis, had levels considered deficient. Patients were taking a multivitamin containing 0.7 mg pyridoxine daily.Higher levels of supplementation of B6 may be required at times of erythropoietin-driven red cell synthesis. Erythrocyte B6 levels fell after the initiation of erythropoietin despite supplements of 5 mg of pyridoxine daily, but were normalized by 3 months of further treatment with pyridoxine 20 mg daily [44].Dissociation between B6 and PLP LevelsBecause most studies have measured either B6 [43, 45, 46] or PLP [1, 2, 17, 41], but not both, we do not know if the finding of marked discrepancy between PLP and B6 levels observed in one small study of patients on peritoneal dialysis is reproducible. In this study, none of 11 patients were deficient by B6 and all were found deficient by PLP [42]. The investigators speculated that uremic patients might have specific problems with synthesis or PLP from B6 or with excess degradation, perhaps by circulating alkaline phosphatase [42].Biochemical and Surrogate OutcomesVitamin B6 is a cofactor for the production of glycine from glyoxalate, reducing the availability of glyoxalate as a substrate for degradation into oxalate [47]. Vitamin B6 supplementation lowered oxalate levels in a small study of patients on peritoneal dialysis who were receiving ascorbate supplementation [48]. The clinical utility of this approach has not been further studied.Coadministration of thiamine and pyridoxine did not affect blood levels of advanced glycation end products or markers of oxidative stress in patients on HD [49]. However, in uremic rats treated with peritoneal dialysis, pyridoxamine improved structural and functional abnormalities thought to be induced by advanced glycation end products or by carbonyl stress [35, 36].Peripheral NeuropathyPLP levels correlated with symptoms of peripheral neuropathy in elderly unsupplemented patients on PD, and improved in 8 of 12 most symptomatic patients after 1 month's treatment with 30 mg daily [50]. In a blinded randomized trial of 26 patients on high-flux HD who had peripheral neuropathy, B6 50 mg/day compared with B12 500 mg/day resulted in improvement in peripheral neuropathy scores (effect shown graphically, p < 0.05, effect size not reported) [45].Cardiovascular Disease and ThrombosisInadequate B6 leads to hyperhomocysteinemia; genetic hyperhomocysteinemia is associated with venous thrombosis and arterial atherosclerosis; patients with low glomerular filtration rate or on dialysis have very high levels of homocysteine, and are at high risk for both thrombosis and atherosclerosis [51]. Because of these connections, it has been hypothesized that hyperhomocysteinemia accounts for some of the excess cardiovascular risk associated with low kidney function, and that lowering homocysteine levels with B6, B12, and folate, especially in high-dose combination, might ameliorate this risk. Randomized trials of multiple B vitamins in the treatment of hyperhomocysteinemia in patients on dialysis have been conducted and are largely disappointing; results are summarized in detail in the section on B12, below, and in Table 4.SummaryThe recommended dose has varied between none, 10 mg, and 300 mg/day [42]. Levels of PLP in patients on either HD or PD have been very low in most, but not all, studies, suggesting that some supplementation is warranted. In high-flux hemodialysis, some regard 10 mg daily as adequate supplementation, but other data suggest that somewhat higher doses of 12–17 mg daily are needed to normalize PLP. In peritoneal dialysis, 10 mg appears to be adequate for all patients, based on one small study [42]. However, studies have been conducted in prevalent patients who may have become deficient over some time, and it is possible that lower doses would be needed if started earlier in the course of kidney disease or at the initiation of dialysis.
Water soluble vitamins (summary)
Vitamin B2 (Riboflavin), Vitamin B3 (Niacin = nicotinic acid; niacinamide = nicotinamide)
Vitamin B5 (Pantothenic acid), Vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride)
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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