Renal Vitamins

Thiamin (B1), Riboflavin (B2), Pantothenic Acid (B5) 

Studies vary regarding thiamin, with some recommending no supplementation to others recommending 1.5 mg/day.2, 3, 4 There may be an increased need for thiamine in chronic ambulatory peritoneal dialysis (CAPD) patients, possibly due to the glucose content of the dialysis solution.5 Riboflavin is similar to thiamin in that studies vary from no recommended supplementation to supplementation of 1.7 mg/day.4, 6 While research has been published on thiamin and riboflavin using amounts above 1.5 mg/day and 1.7 mg/day, respectively, there is no evidence of beneficial effects using larger doses with the possible exception of thiamine in CAPD patients. Information is limited regarding pantothenic acid in dialysis patients, so recommendations are generally 10 mg/day.4

Niacin (B3) 

Niacin can refer to either nicotinic acid or nicotinamide (niacinamide), even though they have different pharmacological uses. Niacin as nicotinic acid is sometimes used as a treatment for dyslipidemia.7 Nicotinamide does not work for treating dyslipidemia, but Takahashi et al looked at suppression of hyperphosphatemia using this form.8 The study used nicotinamide daily for 12 weeks and the starting dose was 500 mg/day with the mean dose being 1080 mg/day. Although it was successful, there are some concerns regarding the results. The study only lasted 12 weeks while using large doses. Nicotinamide does not cause the flushing associated with nicotinic acid, but there have been reports of elevated liver tests and liver damage when used in extremely high doses.9 While nicotinamide may potentially offer another treatment option for hyperphosphatemia, further research should be done before routinely recommending doses above the standard 20 mg/day.

Folic Acid, Cobalamin (B12), Pyridoxine (B6) 

Folic acid, cobalamin, and pyridoxine are important for development of red blood cells as well as homocysteine pathways.10, 11 Hyperhomocysteinemia is common and may affect as many as 85%-94% of dialysis patients.12 Areas of concern for folic acid supplementation include antagonism of antifolate medications and masking of pernicious anemia.13 Folic acid doses of 5-30 mg have been linked with interference of anticonvulsant drugs such as diphenylhydantoin, which is used to treat epilepsy.13 The pernicious anemia masking effect is unlikely in doses up to 1 mg/day but will occur at 5 mg/day.13 It is unknown where the cut-off for partial to full masking falls in the 1-5 mg/day range. If supplementing folic acid above 1 mg/day, make sure the patient has either been evaluated for pernicious anemia or is receiving enough cobalamin to negate any masking effect. As pernicious anemia can be treated with supplementation of 1000 mcg cobalamin, this should be enough to prevent any masking effects.14 In diabetic neuropathy, improvement was noted in numbness, loss of sensation, and muscle cramps when methylcobalamin was supplemented at 500 mcg 3 times daily for 4 months.15 Atrophic gastritis and certain medications can increase the risk of cobalamin deficiency due to decreased acid secretion. However, the decrease in acid does not affect cobalamin found in fortified foods and supplements.16

High-flux/high-efficiency dialysis increases the clearance of pyridoxine.12 Pyridoxine deficiency can contribute to symptoms of peripheral neuropathy.17 In one study, 56% of unsupplemented patients receiving high-efficiency dialysis were deficient in this vitamin.11 Supplementation of pyridoxine can interfere with the effectiveness of levodopa, used to treat Parkinson’s Disease, although this effect is negated if carbidopa is administered along with the levodopa. Supplementation of pyridoxine should contain at least 10 mg/day, whereas those patients receiving high-flux/high-efficiency dialysis may need more than 15-20 mg/day.4, 10, 18

Biotin 

Biotin has been studied in HD patients in regard to both diabetes and neurologic disorders. Two studies of interest used 10 mg/day with 9 patients and 50 mg postdialysis with 11 patients.19, 20 The results help support the beneficial effects of biotin treatment for both diabetes mellitus and uremic neurologic disorders. For routine supplementation, 300 mcg is recommended.4 If treating for restless legs and other uremic neurologic disorders, 10-20 mg/day may be used.21 Biotin is considered safe in doses up to 200 mg/day and it may take 1-3 months of treatment for symptoms to show improvement.21

Vitamin C 

Vitamin C works as an antioxidant by being an electron donor.22 Vitamin E’s antioxidant function depends upon Vitamin C, which regenerates alpha-tocopherol and thus allows maintenance of Vitamin E in its nonradical form. Plasma vitamin C levels are lower in HD patients and are subject to increased oxidation rates during dialysis sessions.23 Vitamin C can be metabolized to oxalate and deposition of oxalate crystals in tissues may be a concern.4, 24 While plasma oxalate in HD and peritoneal dialysis (PD) patients have been found to be greater than in normal subjects, the causes are unknown.25 Oxalate is removed at a higher rate from HD patients versus control subjects, which leads to one conclusion that the increased levels are not due to a poor removal process but possibly increased oxalate synthesis or gastrointestinal absorption.25 The issue is further clouded by the difficulty in interpreting and comparing studies dealing with Vitamin C and oxalate. Depending on how the samples were handled, oxalate levels could be falsely elevated due to conversion of ascorbic acid to oxalate during the analysis phase.4, 24, 26 For instance, in CAPD, the fluid has a dwell time that allows oxalate generation from ascorbate to occur in the peritoneum, which will affect any measurements of oxalate removal or clearance.26 Conversions occurring after samples are drawn may explain a major part of the discrepancy between some earlier studies and those more recently completed.26 The issue of adverse effects associated with long-term supplementation of doses above 60-100 mg/day is unclear. For some, the possible risk of larger doses may be outweighed by the antioxidant and wound healing benefits of this vitamin. Vitamin C is further discussed in the Vitamin E section because of the integral relationship between these two antioxidants.

Vitamin A 

Vitamin A is important because of its role in vision, growth, and the immune system.27 The most common sign of deficiency is night blindness, whereas toxicity manifests as liver damage, bone abnormalities and joint pain, alopecia, headaches, and vomiting.28 Signs of toxicity of special note for dialysis patients also include anemia, hypertriglyceridemia, and hypercalcemia. It is believed that the hypercalcemia is caused by an increase in osteolytic activity.29 Often patients not receiving Vitamin A supplements will still have increased levels of serum retinol in relation to those without renal disease.4 To complicate matters, Aguilera et al studied PD patients and found elevated plasma retinol in combination with intracellular and clinical signs of hypovitaminosis A, which they hypothesized may be due to disorders with vitamin/carrier complexes.30 These disorders could lead to a mobilization of select vitamins from pool and target cells thereby increasing blood levels while at the same time depleting intracellular levels. This may affect not only Vitamin A but Vitamin E as well.

Vitamin E 

Miller et al published a meta-analysis that found supplementation of Vitamin E above 400 IU/day was associated with increased mortality.31 The results need to be viewed with caution though, because there was a lack of consistency between the studies reviewed. Variances between studies involved such things as the form of Vitamin E used, Vitamin E treatment alone versus in combination with other vitamins or minerals, and dosages ranging from 16.5 IU/day to 2000 IU/day.

Khajehdehi et al looked at supplementation of Vitamins E and C for the treatment of cramping in HD patients.32 The study lasted 8 weeks and used 400 mg (∼600 IU) Vitamin E and 250 mg Vitamin C. What they found was that using Vitamin E or Vitamin C alone helped with cramps, but combination treatment with both vitamins worked the best. Vitamin C supplementation may be associated with increased oxalate production, as discussed earlier, but no side effects such as increased urinary stone formation were seen in this trial. The authors concluded that short-term treatment with the combination of both Vitamin E and Vitamin C was safe and successful for treating HD-related cramps but that the safety of long-term treatment was unknown.32

Oxidative stress, which is frequently found in dialysis patients, has been proposed as one contributor to shortened red blood cell (RBC) survival.33 RBC levels of Vitamin E can be decreased even when serum levels are within normal range, which is of special concern for erythropoietin treatment.33 Cristol et al supplemented patients with 500 mg/daily (∼750 IU) of Vitamin E for 6 months and found that erythropoietin needs were reduced by 20%-30%, as compared to initial doses, while still maintaining target hemoglobin levels.33 The authors suggest that the decrease in erythropoietin needs may have been due to Vitamin E’s antioxidant properties. Vitamin E was chosen over Vitamin C as the antioxidant used due to concerns regarding oxalate production, but supplementation with Vitamin C may have produced similar results. It was suggested that supplementation of an antioxidant should occur in HD patients.33 Yonova et al also recommend treatment of oxidative stress in all dialysis patients with more aggressive treatment aimed at those on HD versus PD.34

Vitamins D and K 

Vitamin K usually does not need to be supplemented in dialysis patients. An exception may be if the patient has been receiving chronic antibiotic treatment since antibiotics can deplete the beneficial bacteria of the intestinal tract. If a patient has been treated chronically with antibiotics and has an unexplained elevation of prothrombin time, Vitamin K should be evaluated.4 Care should be taken for those patients receiving coumadin or aspirin since they are Vitamin K antagonists. Vitamin D can no longer be converted to its active form by the kidney, so the presence of its inactive form in an oral vitamin supplement is unnecessary.

Zinc and Copper 

Zinc is used in over 300 enzymes as well as being involved in the immune system.35 Signs of deficiency include blunting of taste and smell, anorexia, skin changes, hair loss, diarrhea, negative nitrogen balance, immune dysfunction, and glucose intolerance.19, 36 Studies involving trace elements such as zinc and copper are difficult because serum and sometimes erythrocyte or tissue levels do not always reflect the true status and a deficiency can still be present.36 Depletion studies suggest that alterations in immune response occur before plasma reductions become evident.35

There is a positive correlation between protein catabolic rate (PCR) and serum zinc concentration.37 Atkin-Thor et al found that zinc supplementation resulted in taste acuity improvement in 95% of patients, improved appetites, and an increase in average caloric intake of 675 kcal/day.38 Chevalier et al also had similar results in that patients supplemented with 50 mg/day of elemental zinc showed an increased intake of 297 kcal/day.39 Zinc and copper are not lost during dialysis, which suggests that decreased levels are most likely due to causes other than dialysis itself.40 Zinc intakes of 50 mg/day will affect copper indexes such as Cu/Zn-superoxide dismutase.35 Because copper also plays a role in the immune system, it is important to be cautious with long-term zinc supplementation.35 Only a few cases of acute poisoning have been reported after ingestion of 4-8 g of zinc and are characterized by nausea, vomiting, diarrhea, fever, and lethargy.35

Selenium 

Selenium acts in conjunction with Vitamin E to protect cell membranes against oxidative damage.41 Signs of deficiency include muscle weakness, myalgia, and congestive heart failure.41 Much of the interest in selenium relates to its role as an antioxidant. Dialysis patients often have low antioxidant levels and show evidence of oxidative stress including increased lipid peroxidation.42 Bonomini et al supplemented selenium at levels of 500 mcg 3 times per week for 3 months and then at 200 mcg 3 times per week for the following 3 months with no apparent side effects.43 The authors concluded that chronic uremic patients could benefit from moderate and safe selenium supplementation.

Lesser Known Supplements of Interest 

More recent supplements of interest include CoQ10 and L-Carnitine. CoQ10 is an antioxidant that helps regenerate alpha-tocopherol. Decreased levels are found in multiple disease states.44

L-Carnitine therapy has been associated with suppression of inflammation with reduced c-reactive protein (CRP) concentrations and increased serum albumin, transferrin, blood hemoglobin, and body mass index (BMI).45 Some nephrologists and dietitians are already recommending CoQ10 and L-Carnitine, so expect to hear more about them in the future.