> ## Content Index > Fetch the complete content index at: https://www.foodconsumer.org/llms.txt > Use this file to discover other available public pages before exploring further. # Vitamin C in People with Low Glomerular Filtration Rate & End-Stage Renal Disease - URL: https://www.foodconsumer.org/vitamin_c_1109131026/ - Published: 2013-11-09T23:26:00.000Z - Updated: 2026-09-15T08:32:37.000Z - Description: Background on vitamin C: most animals make their own, but humans, guinea pigs and some birds must eat it. The piece recounts naval surgeon Joseph Lind's 1753 shipboard experiment, in which two sailors given oranges and a lemon recovered from scurvy while controls did not. - Author: Food Consumer - Tags: Vitamins, Nutrition, #vivvo-import Vitamin C Background Vitamin C (ascorbic acid) is a water-soluble vitamin produced from metabolism of glucose. Only the l enantiomer has biologic activity. Most animals possess the enzyme (l-gulonolactone oxidase: GULO) required for its synthesis, so that they do not require exogenous dietary ascorbic acid: for these animals, ascorbic acid is not a vitamin \[133\]. Loss of the enzyme appears to have occurred at more than one point in evolution; some primates, including humans, guinea pigs and capybara, and some passerine birds require dietary vitamin C. The frank deficiency syndrome of scurvy has a unique place in the history of clinical medicine. In 1753, the British naval surgeon (ship's doctor) Joseph Lind described in five paragraphs of his 358-page treatise his nonrandomized controlled experiment on sailors with scurvy (n = 2 per group) that is often credited as the first description of a controlled clinical trial \[134\]. Scurvy, the clinical syndrome resulting from vitamin C deficiency, is characterized by gum disease, tooth loss, skin rash, corkscrew hairs (poikilocytosis), and fatigue. In Lind's time, it was a life-threatening disease that commonly reduced crews on long sea voyages by more than 50%, resulting from the consumption of a ship's diet devoid of fresh vegetables. The two seamen who received two oranges and a lemon daily for 6 days recovered, one to the point of return to duty and the other to the capacity of nurse for the other afflicted men; controls remained poor or deteriorated. The serendipitous discovery, in the search for animal models of beriberi, that guinea pigs developed scurvy in response to vitamin C deficiency led to a reliable animal model and facilitated the identification of the anti-scorbutic substance in citrus fruits. A number of critical roles for vitamin C have been identified: it is a cofactor in pathways for collagen synthesis, explaining many of the clinical manifestations of scurvy. It is a potent antioxidant, perhaps the most quantitatively important free radical scavenger in blood \[135\]. Dietary Sources and RDA Usual dietary sources are citrus fruits, but some green vegetables such as broccoli and spinach are rich in vitamin C. Usual dietary intake on a western diet is around the RDA, which was increased in 2000 to 60 to 90 mg/day for men and 75 to 90 mg/day for women \[136, 137\]. As for vitamin D, the difference between required and optimal is controversial. Nonhuman primates who also lack the GULO enzyme required for vitamin C de novo synthesis typically consume 2–6 g of vitamin C daily; wild fruits and new shoots are particularly rich sources. Animals that possess GULO synthesize much larger quantities that the RDA also: for example, goats synthesize 13 g daily and can triple this in times of stress. For this reason, some scientists, most notably Nobel Laureate Linus Pauling, have advocated for daily intakes of 1–2 g/day, sometimes referred to as megadosing \[138\]. The American Medical Association/Nutrition Advisory Group recommends 100 mg/day in total parenteral nutrition. A typical dialysis vitamin such as Replavite contains 100 mg \[136\]. Absorption and Bioavailability Vitamin C is absorbed actively and passively, and is highly bioavailable, with 75–90% absorbed in a typical diet. Absorption may fall to as low as 16% in people who are vitamin C-replete who have high intakes \[139\]. Excretion and Metabolism In people with normal renal function, excess ingested vitamin C is rapidly excreted in the urine \[31\]. Some is also metabolized to oxalate, leading to concerns that supplements, especially megadoses, may lead to kidney stones. However, the initial studies reporting very large increases in urinary oxalate used heat in the analytic process that may have converted urinary vitamin C to oxalic acid. Subsequent studies avoiding this problem have shown more modest increases in oxalate, within the normal range, and the possibility that this too resulted from artefactual conversion from vitamin C in vitro remains \[38\]. In people whose GFR is low, there is also the concern that the calcium oxalate saturation threshold may be exceeded in blood leading to systemic oxalosis and vascular calcification \[140\]. Toxicity Other than these concerns about oxalate accumulation or stones, it appears that vitamin C itself is, at least acutely, very safe \[31\]. General Population In keeping with theory about antioxidant properties, cohort data consistently show a strong relationship between low vitamin C levels, cardiovascular death and death from all causes (summarized in \[135\]). The cut-point beyond which risk of events decreases appears to be around levels of 40–50 mmol/l \[141\]. Observational data relating use or dose of supplemental vitamin C to outcomes are not, to our knowledge, available. However, the Medical Research Council/British Heart Foundation Heart Protection Study randomized 20,536 adults to antioxidant vitamins (vitamin C 250 mg daily, vitamin E 600 mg daily, carotene 20 mg daily) or placebo and found no difference between groups in cardiovascular or all-cause mortality (rate ratio cardiovascular death 1.04; death from all causes 1.04) \[142\]. While megadose vitamins have been implicated in kidney stones or renal oxalosis in individual cases, some authorities feel that these data do not stand up to critical review and that harm from doses of 1–2 g/day in people without preexisting low GFR or kidney stones has not been well documented (summarized in \[38, 140\]). In critical illness, blood levels appear to fall rapidly and recovered only after days on high-dose supplementation (more than 1000 mg/day) \[143\]. In these patients, high urinary losses were seen with high-dose supplementation, in the face of plasma levels that remained extremely low for several days after the initiation of supplements. Common Cold A Cochrane meta-analysis of 29 RCTs of 11,306 people suggests that while prophylaxis with high-dose vitamin C (defined as more that 200 mg/day for the purpose of the review) does not affect the incidence of colds (RR 0.97, 95% CI 0.94–1.00), it does reduce severity and duration \[144\]. Taking vitamin C after the onset of a cold had no effect on either severity or duration. In a planned subgroup analysis of five RCTs of 598 people engaged in extreme activity or working in extreme cold, a protective effect on the incidence of colds was noted (RR 0.48, 95% CI 0.35–0.64). Interesting although these findings are, these doses should not be used in people with low GFR or people on dialysis outside studies, because of the risks of oxalosis, discussed in detail below. Iron Absorption By preventing the formation of insoluble and unabsorbable iron compounds and by promoting the conversion from ferric to ferrous iron (which is more readily absorbed), vitamin C increases the absorption of dietary and supplemental iron in the gut by up to 60% \[145\]. People with Low Glomerular Filtration Rate & End-Stage Renal Disease Dietary Intake and Levels In a cross-sectional study of patients with low GFR, vitamin C levels were positively associated with GFR, suggesting that either spontaneous or prescribed dietary restrictions limits adequate intake in people with advanced chronic kidney disease \[145\]. Many vitamin-C-rich foods are also high in potassium, which may lead to their restriction in patients with advanced renal failure and in those on dialysis. Another cross-sectional study estimated dietary intake from dietary records at 94 mg/day in patients with low GFR and 66 mg/day in patients on dialysis \[146\]. In cross-sectional studies, 15% of patients on HD had levels <10 mcmol/l \[147\], and 12% of patients on PD had levels below 2 mg/l \[148\], generally considered below the scorbutic threshold. Supplementation appears to improve the situation, but not in all patients: an Australian study of patients on PD found 44% of unsupplemented patients and 17% of patients receiving around 100 mg daily had vitamin C levels less than 2 mg/l \[149\]. In addition to low dietary intake, the dialysis procedure also contributes to deficiency: removal of this water-soluble nonprotein-bound small molecule has been estimated at mean 66 mg per HD session \[150\] and 29 mg per PD exchange \[43\]. In PD, transport status was not predictive of levels \[149\]. Oral or intravenous vitamin C supplementation increases levels. For example, in patients on PD 100 mg daily for 4 weeks increased levels by 45% \[151\], and in another study, when patients on PD whose initial level was less than 4 mg/l were treated for 12 months with a multivitamin containing 120 mg vitamin C, levels rose from 1.7 (IQR 1.2–2.2) mg/l to 22.5 (IQR 16.7–32.9) mg/l \[149\]. Because of the nonspecific nature of many of the symptoms of vitamin C deficiency (fatigue, weakness, poor connective tissue, mental disturbances, anemia), it is possible that subclinical or unrecognized vitamin C deficiency contributes to the disturbances as part of the uremic syndrome in people with low GFR or people on dialysis. As in the general population, lower vitamin C levels in patients on dialysis predict fatal and nonfatal major cardiac outcomes: adjusted hazard ratios were 3.90 (95% CI 1.42–10.67; p = 0.008) and 3.03 (95% CI 1.03–8.92; p = 0.044) for the lower (<32 mcmol/l and middle (32–60 mcmol/l) thirds compared with people in the upper third (>60 mcmol/l) \[135\]. To the best of our knowledge, no trials of the effects of vitamin C supplementation in dialysis patients on cardiovascular events or death from all causes have been conducted or are planned \[152\]. Secondary Hyperoxaluria and Oxalosis Oxalate is a product of metabolism of vitamin C and though dialyzable, accumulates in patients on dialysis \[153\]. High levels of oxalate are seen in patients on peritoneal dialysis (33.1 ± 9.3 mcmol/l) and hemodialysis (40.3 ± 9.8 mcmol/l) \[153\]: levels are similar to those seen in type 1 primary hyperoxaluria \[47, 149, 153\], an inborn error of metabolism associated with clinically important damage to the heart, vessels, joints, and muscles. In a 1985 study of seven patients, a strong correlation between vitamin C levels and oxalate levels was observed \[154\]. Long-term intravenous supplemental vitamin C in moderate doses of 250–500 mg weekly led to increases in plasma oxalate levels that exceeded the supersaturation threshold for calcium oxalate in some patients \[140\]. We do not know to what extent hyperoxalemia contributes to morbidity in patients with low GFR, but the possibility of vascular and tissue damage from calcium oxalate precipitation means that large or even moderate doses cannot be recommended without caution. Further work is needed in this area. Functional Iron Deficiency and Erythropoietin Hyporesponsiveness Functional iron deficiency, defined as a low transferrin saturation with normal or high ferritin levels (>100 mcg/l), is thought to result when iron stores are adequate, but iron cannot be released from storage forms for hematopoiesis. The clinical syndrome is one of persistent anemia and erythropoietin hyporesponsiveness. Vitamin C, acting as a reducing agent, mobilizes iron from storage sites and also plays a direct role in the integration of iron into the heme moiety \[155\]. A 2007 meta-analysis identified six trials of 327 patients treated with intravenous or oral vitamin C in doses of 200–500 mg once to three times weekly \[155\]. Random-effect models were without important statistical heterogeneity and identified a rise in hemoglobin (9 g/l, 95% CI 0.5–1.2 g/l), fall in erythropoietin requirements (−17 units/kg/week, 95% CI –26 to –8 units/kg/week), and rise in transferrin saturation, without change in ferritin concentration. This suggests a potential role for larger doses of vitamin C in anemia management. However, this conclusion is qualified by the variable quality of the original studies. Furthermore, there were no measures of oxalate, adverse effect reporting was suboptimal, and the sample sizes and duration of studies were insufficient to detect possible increases in patient-important outcomes such as cardiovascular events (from calcium oxalate precipitation). Randomized trials of vitamin C in dialysis patients have either examined the effects on blood levels of vitamin C and its metabolites or have focused on anemia outcomes. Blood levels rise predictably in HD and PD patients with oral or parenteral supplements; however, in patients on HD, supplementation with 500 mg weekly for a year led to a rise in oxalate level that was associated with around 40% of patients exceeding the saturation threshold for calcium oxalate product in blood \[140\]. No clinical adverse events were noted. Extended Hours Dialysis Vitamin C levels were lower in patients on extended hours hemodialysis (0.30 vs. 1.14 mg/dl, p < 0.001) with 7/26 patients (27%) in the extended hours group having levels less than 0.18 mg/dl and 16/26 (73%) having levels less than the lower limit of normal (0.48 mg/dl) \[17\], compared with no patients in the conventional group. There was wide interindividual variation in vitamin C dose in this study; all patients received a multivitamin with 45 mg vitamin C, but a third of patients took additional vitamin C; mean dose in these patients was 151 mg/day. B6 to Lower Oxalate In a pre–post study of seven patients, vitamin B6 administration was temporally associated with a decline in serum oxalate levels in ascorbic acid-supplemented patients \[48\]. B6 is a cofactor for glyoxalate conversion to glycine, reducing the substrate available for degradation into oxalate \[47\]. To our knowledge, whether this might be clinically useful has not been further evaluated. Multiple Pathways Novel mechanistic insights into vitamin C in patients on dialysis are being elucidated. For example, high-dose vitamin C was shown to ameliorate dialysis-associated blood reactive oxygen species and total antioxidant score, decrease peroxidation of plasma lipid and red cell membranes, reduce hemolysis and levels of proinflammatory cytokines \[156\]. Vitamin C administration also leads to shifts in several polypeptides identified in proteomic analysis from abnormal expression levels observed in patients on dialysis toward the expression levels seen in normal controls \[157\]. Finally, in a randomized trial of vitamin C in patients with renal transplants, some, but not all, indices of vasomotor function were improved when assessed by intravascular ultrasound \[158\]. Treatment of Cramps One trial compares the use of oral vitamin C 250 mg daily, vitamin E 400 mg daily, both, or placebo in the treatment of cramps, and showed a reduction of 61%, 54% and 97%, respectively, for the active treatment, compared with 7% for placebo \[159\]. However, the concerns that cardiovascular events from systemic calcium oxalate deposition might increase, as discussed above, apply when considering whether to use vitamin C for this indication also. Treatment of Iron Overload In a small randomized trial of patients on hemodialysis with iron overload secondary to intravenous iron, vitamin C 200 mg iv three times weekly improved erythropoietin responsiveness more than desferrioxamine or controls, but did not lead to increases in iron loss or mobilization compared with either group \[160\]. Ongoing Studies In hemodialysis patients, trials of vitamin C to reduce hyperpigmentation, and to alleviate restless legs syndrome, are ongoing \[152\]. One trial in patients with chronic kidney disease will examine antioxidant properties by comparing vitamin C with N-acetylcysteine for prevention of contrast nephrotoxicity \[152\]. Summary Vitamin C deficiency is prevalent in unsupplemented patients on dialysis, with perhaps 10% having severe deficiency, below the scorbutic threshold. It is also possible that most dialysis patients, or even most humans, eating a typical western diet, have intakes and levels that are far from optimal. Pending rigorous randomized trials in dialysis patients, powered to examine cardiovascular and infectious outcomes and the possibility of harm from calcium oxalate, it seems reasonable to administer low-dose vitamin C supplementation, perhaps 60–100 mg daily, to patients on hemodialysis, and to consider the diagnosis of vitamin C deficiency in patients whose anemia or fatigue is disproportionate to their known comorbidities, in patients on extended-hours hemodialysis treatments, and in those who have difficulty in maintaining a balanced diet within the restrictions imposed by dialysis. Short-term use of parenteral vitamin C can be considered for patients with functional iron deficiency, but strong evidence of the efficacy of this approach is lacking, and there are no long-term safety data. Multivitamin Supplements In patients on dialysis, the evidence summarized above suggests that supplementation with low doses, similar to the RDAs, for at least some of the B vitamins (in particular B1, B6, B9 \[folic acid\] and B12) and for vitamin C is warranted, although no randomized trials have been performed. Vitamins formulated for patients on dialysis tend to include these vitamins in doses that seem reasonable \[161, 162\]. We are not aware of strong reasons to choose one over another. Because of the factors associated with advanced chronic kidney disease that lead to poor intake, at least one agency recommends the use of a vitamin B and C multivitamin in patients with low GFR, not on dialysis, who have poor eating habits, are consuming less than 50% of meals or fewer than 1500 kcal/day, or who have appetite changes, food aversions, or weight loss \[162\]. We believe general multivitamin tablets should be avoided, at least in patients on dialysis. They tend to contain somewhat lower doses of B vitamins, which might not adequately cover needs. They often contain doses of vitamin C in excess of those recommended for people on dialysis. They contain vitamin A, which is unnecessary and may lead to toxicity. Finally, general multivitamin tablets contain vitamin D, often in doses lower than public health recommendations for the general population. The effects of nutritional vitamin D supplementation in patients with very low GFR and patients on dialysis are currently unclear \[163\]. When supplementation of nutritional vitamin D to patients on dialysis is desired, we believe, it is likely safer to prescribe this separately so that its pharmacologic effects can be taken into account in the interpretation of calcium, phosphate, and parathyroid hormone values. [Water soluble vitamins (summary)](https://www.foodconsumer.org/water%5Fsoluble%5Fvitamin%5Ffor%5Fpeople%5Fon%5Fdialysis%5F1109130915/) [Vitamin B1 (thiamine)](https://www.foodconsumer.org/vitamin%5Fb1%5Fthiamine%5F1109131004/) [Vitamin B2 (Riboflavin), Vitamin B3 (Niacin = nicotinic acid; niacinamide = nicotinamide)](https://www.foodconsumer.org/vitamin%5Fb2%5Fb3%5F1109131007/) [Vitamin B5 (Pantothenic acid), Vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride)](https://www.foodconsumer.org/vitamin%5Fb5%5Fand%5Fb7%5F1109131012/) [Vitamin B7 (biotin), Vitamin B9 (folic acid, folate)](https://www.foodconsumer.org/vitamins%5Fb7%5Fb9%5F1109131018/) [Vitamin B12](https://www.foodconsumer.org/vitamin%5Fb12%5F1109131023/) Vitamin C *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*