The Use of Vitamin C as an Adjuvant Therapy to Recombinant Human Erythropoietin in Patients with End-Stage Renal Disease

Sehsuvar Ertürk, M.D.

Department of Nephrology, Ankara University Medical School.
Ankara, Turkey

erturk@medicine.ankara.edu.tr

Introduction:

Research over the last 25 years has resulted in a favoring of the concept of insufficient synthesis and secretion of erythropoietin as a major cause of anemia of chronic kidney disease.¹ Indeed, recombinant human erythropoietin (rhEPO) has revolutionized the management of anemia in patients with end-stage renal disease (ESRD).^1-4 However, there is wide variability in effective doses of rhEPO and there are even many reports of resistance to rhEPO.¹ The common causes for inadequate response to rhEPO are iron deficiency, inflammation, malnutrition, hyperparathyroidism, aluminum intoxication, and deficiency of vitamin B12 or folate.^5-9 After the exclusion of these common factors, other probable causes including genetic factors, use of ACE inhibitors, malignancy, and vitamin C-deficiency should also be considered.^9-13

Recently, several studies have searched for adjuvant therapies to rhEPO to provide greater clinical benefits and to make this treatment more cost-effective^13-20 The current article focuses on the rationale, benefits, and the limitations of the use of vitamin C in the management of anemia in patients with ESRD.

Rationale

Vitamin C status in ESRD Patients

Chronic hemodialysis patients generally have lower plasma vitamin C levels than healthy subjects,²¹ possibly caused by the loss of vitamin C during dialysis, increased consumption, or inadequate dietary intake.^22,23 It was reported that 1,000 to 1,500 mg/week or 150 to 200 mg/d of vitamin C could normalize the plasma levels in the majority of patients. More recently, Mydlik et al²⁴ reported that 60 mg/d vitamin C replacement prevented vitamin C deficiency in hemodialysis patients without leading to further increase of plasma oxalate levels.

Probable Mechanisms for a Better Response to rhEPO

Beneficial effects of vitamin C in the management of anemia have been reported not only in vitamin C-deficient patients, but also in patients with normal baseline vitamin levels.²⁵ Furthermore, plasma vitamin levels have been reported to rise in a similar manner in both responsive and non-responsive patients.²⁶ Therefore, mechanisms other than the correction of vitamin C-deficiency state should be considered. Although not definitely proven, the probable mechanisms may be related to anti-oxidant properties of vitamin C, and to its effects on iron metabolism or endogenous erythropoietin synthesis. Since vitamin C is one of the most important antioxidants existing in plasma, another possible mechanism for a better response to rhEPO may be increased erythrocyte lifespan via both the prevention of hemoglobin denaturation and erythrocyte membrane lipid peroxidation^27,28 Vitamin C increases intestinal iron absorption and induces iron mobilization from inert tissue stores, including reticuloendothelial system, and may improve iron availability. It has also a role in the enzymatic incorporation of iron into protophorphyrin for heme synthesis.^29-31. In addition, most intervention studies found a rise of transferrin saturation and/or a decrease in ferritin level in response to vitamin C.^19,20,26,32It has been suggested, therefore, that beneficial effect of vitamin C is related to its effects on iron metabolism. Finally, vitamin C, when administrated with the antioxidant vitamins A and E, was shown to lead to an increase in erythropoietin production of isolated serum-free perfused rat kidneys.³³ However, this effect was suggested to be a consequence of the protection of cells from oxidative damage as vitamin C alone did not increase erythropoietin production in hepatoma cell cultures.

Clinical Studies

In a small pioneer study, Gastaldello et al.²⁵ showed the beneficial effect of intravenous vitamin C in four iron-overloaded hemodialysis patients, whereas no effect on hematocrit was achieved in seven patients with normal iron status. In that study, dose of intravenous vitamin C was defined as 1,000 mg/wk and study duration was three months. Tarng and Huang reported a significant increase in hematocrit levels together with a 20% reduction in rhEPO dose under 8-week duration of 300 mg thrice-weekly intravenous vitamin C.³⁴ In both studies, beneficial effects of vitamin C paralleled a significant rise in transferrin saturation.

In another study, Tarng et al. administrated 300 mg of vitamin C intravenously after each hemodialysis session for 8 weeks in 37 hyperferritinemic patients (i.e., ferritin > 500 g/L).²⁶ They found the response rate was approximately 50%, and the predictors of the response were transferrin saturation < 25% and erythrocyte zinc protophorphyrin > 105 mol/mol heme (indicating insufficient iron incorporation into heme).

In a prospective, randomized, crossover study, Giancaspro et al. evaluated 27 hemodialysis patients with functional iron deficiency.³² They found that all the patients administrated 500 mg of intravenous vitamin C three times a week for 3 months had significant increases in both hemoglobin and transferrin saturation. The authors also reported that both hemoglobin and transferrin saturation declined after cessation of vitamin C therapy. Sezer et al.¹⁹ also reported a significant increase in hemoglobin and decrease in dose of rhEPO in 36 hemodialysis patients whose ferritin level > 500 g/L with an 8-week duration of 1g/wk vitamin C treatment. More recently, in a prospective, randomized, crossover study, our group demonstrated that approximately 65% of hemodialysis patients responded to 6-month duration of 1,500 mg/wk of intravenous vitamin C treatment with almost a 2-g/dL increase in hemoglobin level, together with a 2,500-IU/wk (30%) reduction in EPO dose.²⁰ Interestingly, the number of responder patients, increase in hemoglobin levels, and decrease in EPO doses were not different in patients with a ferritin level greater or less than 800 g/L. The clinical studies on the effects of parenteral vitamin C in hemodialysis patients are summarized in Table 1. Finally, a four-week duration of low-dose oral vitamin C treatment was also shown to lead to a significant increase in hemoglobin in hemodialysis patients²⁴

Limitations

Long-term high doses of vitamin C treatment might be a potential risk for the development of secondary oxalosis in ESRD patients. Shah et al³⁵ reported 19% increase in plasma oxalate levels after 4 weeks of 100 m/d oral vitamin C in peritoneal dialysis patients. Ono also found high oxalate levels after 500 mg/d of oral vitamin C supplementation of longer than 6 months, and suggested that hyperoxalemia is aggravated by long duration of vitamin C supplementation in hemodialysis patients.³⁶ Although plasma oxalate levels were not assessed in many interventional studies mentioned above, Tarng et al.²⁶ showed no significant increase in oxalate levels with intravenous vitamin C treatment of 300 mg thrice weekly. Nevertheless, caution is warranted when using long-term vitamin C treatment in hemodialysis patients.

Another probable limitation for the use of vitamin C to achieve a better anemia control in hemodialysis patients is the lack of any proven mechanisms for the beneficial effects. It is also unclear whether it is related to baseline plasma vitamin C levels. Furthermore, there is currently no consensus on the use of vitamin C in patients with normal iron status.

Conclusion

After the exclusion of the common causes of hypo-responsiveness, intravenous vitamin C replacement may be used as an adjuvant therapy to rhEPO in hemodialysis patients, particularly in those with functional iron deficiency. Future larger-sized interventional studies, however, are needed to prove its safety and to find out the mechanisms of its beneficial effects.

References:

1. Eschbach JW, Varma A, Stivelman JC: Is it time for a paradigm shift? Is erythropoietin deficiency still the main cause of renal anemia? Nephrol Dial Transplant 17 (Suppl 5):2-7, 2002.
2. Eschbach JW: The anemia of chronic renal failure: Pathophysiology and the effects of recombinant erythropoietin. Kidney Int 35:134-148, 1989.
3. Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM: Effect of human erythropoietin derived from recombinant DNA on the anemia of patients maintained by chronic hemodialysis. Lancet 2:1175-1178, 1986.
4. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW: Correction of the anemia of end-stage renal disease with recombinant human erythropoietin: Results of a combined phase I and II clinical trial. N Engl J Med 316:73-78, 1987.
5. Adamson JW, Eschbach JW: Management of the anemia of chronic renal failure with recombinant human erythropoietin. Q J Med New Series 73:1093-1101, 1989.
6. Kaiser L, Schwartz KA: Aluminum induced anemia. Am J Kidney Dis 6:348-352, 1985.
7. Potasman I, Better OS: The role of secondary hyperparathyroidism in the anemia of chronic renal failure. Nephron 33:229-231, 1983.
8. Hampers CL, Streiff R, Nathan DG, Snyder D, Merrill JP: Megaloblastic hematopoiesis in uremia and in patients on long-term hemodialysis. N Engl J Med 276:551-554, 1967.
9. National Kidney Foundation: K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease, 2000.Am J Kidney Dis 37 (Suppl 1):S182-S238, 2001.
10. Ertürk S, Kutlay S, Karabulut HG, et al: The impact of vitamin D receptor genotype on the management of anemia in hemodialysis patients. Am J Kidney Dis 40:816-823, 2002.
11. Ertürk S, Ates K, Duman N, Karatan O, Erbay B, Ertug E: Unresponsiveness to recombinant human erythropoietin in haemodialysis patients: Possible implications of angiotensin-converting enzyme inhibitors. Nephrol Dial Tranplant 11: 396-397, 1996.
12. Ertürk S, Nergizoglu G, Ates K, et al: The impact of withdrawing ACE inhibitors on erythropoietin responsiveness and left ventricular hypertrophy in haemodialysis patients. Nephrol Dial Transplant 14: 1912-1916, 1999.
13. Hörl WH: Is there a role for adjuvant therapy in patients being treated with epoetin? Nephrol Dial Transplant 14 (Suppl 2):S50-S60, 1999.
14. Labonia WD: L-Carnitine effects on anemia in hemodialyzed patients treated with erythropoietin. Am J Kidney Dis 26:757-764, 1995.
15. Kooistra MP, Struyvenberg A, van Es A: The response to recombinant human erythropoietin in patients with the anemia of end-stage renal disease is correlated with serum carnitine levels. Nephron 57:127-128, 1991.
16. Berard E, Iordache A: Effects of low doses of Lcarnitine on the response to recombinant human erythropoietin in hemodialyzed children: About two cases. Nephron 62:368-369, 1992.
17. Berns JS, Rudnick MR, Cohen RM: A controlled trial of recombinant human erythropoietin and nandrolone decanoate in the treatment of anemia in patients on chronic hemodialysis. Clin Nephrol 37:264-267, 1992.
18. Ballal SH, Domato DT, Polack DC, Marciulonis P, Martin KJ: Androgens potentiate the effects of erythropoietin in the treatment of anemia of end-stage renal disease. Am J Kidney Dis 17:29-33, 1991.
19. Sezer S, Ozdemir FN, Yakupoglu U, Arat Z, Turan M, Haberal M: Intravenous ascorbic acid administration for erythropoietin-hyporesponsive anemia in iron overloaded hemodialysis patients. Artif Organs 26:366-370, 2002.
20. Keven K, Kutlay S, Nergizoglu G, Ertürk S: Randomized, crossover study of the effect of vitamin C on EPO response in hemodialysis patients. Am J Kidney Dis 41:1233-1239, 2003.
21. Descombes E, Hanck AB, Fellay G: Water soluble vitamins in chronic hemodialysis patients and need for supplementation. Kidney Int 43:1319-1328, 1993.
22. Sullivan JF, Eisenstein AB: Ascorbic acid depletion in patients undergoing chronic hemodialysis. Am J Clin Nutr 23:1339-1346, 1970.
23. Pönka A, Kuhlback B: Serum ascorbic acid in patients undergoing chronic hemodialysis. Acta Med Scand 213:305-307, 1983.
24. Mydlik M, Derzsiova K, Boldizsar J, Hribikova M, Petrovicova J: Oral use of iron with vitamin C in hemodialyzed patients. J Ren Nutr 13:47-51, 2003.
25. Gastaldello K, Vereerstraeten A, Nzame Nze T, Vanherweghem L, Tielemans C: Resistance to erythropoietin in iron overloaded hemodialysis patients can be overcome by ascorbic acid administration. Nephrol Dial Transplant 10 (Suppl 6):S44-S47, 1995.
26. Tarng DC,Wei YH, Huang TP, Kuo BIT: Intravenous ascorbic acid as an adjuvant therapy for recombinant erythropoietin in hemodialysis patients with hyperferritinemia. Kidney Int 55:2477-2486, 1999.
27. Rosenmund A, Binswanger U, Straub PW: Oxidative injury to eryhrocytes, cell rigidity, and splenic hemolysis in hemodialyzed uremic patients. Ann Intern Med 82:460-465, 1975.
28. Candan F, Gültekin F, Candan F: Effect of vitamin C and zinc on osmotic fragility and lipid peroxidation in zinc-deficient haemodialysis patients. Cell Biochem Funct 20:95-98, 2002.
29. Banerjee S, Chakrabarty AS: Utilization of iron by scorbutic guinea pigs. Blood 25:839-844, 1965.
30. Bridges KR, Hoffman KE: The effects of ascorbic acid on the intracellular metabolism of iron and ferritin. J Biol Chem 261:14273-14277, 1986.
31. Lipschitz DA, Bothwell TH, Seftel HC,Wapnick AA, Charlton RW: The role of ascorbic acid in the metabolism of storage iron. Br J Haematol 20:155-163, 1971.
32. Giancaspro V, Nuzziello M, Pallotta G, Sacchetti A, Petrarulo F: Intravenous ascorbic acid in hemodialysis patients with functional iron deficiency: A clinical trial. J Nephrol 13:444-449, 2000.
33. Jelkmann W, Pagel H, Hellwig T, Fandrey J: Effects of antioxidant vitamins on renal and hepatic erythropoietin production. Kidney Int 51:497-501, 1997.
34. Tarng DC, Huang TP: A parallel, comparative study of intravenous iron versus intravenous ascorbic acid for erythropoietin hyporesponsive anemia in hemodialysis patients with iron overload. Nephrol Dial Transplant 13:2867-2872, 1998.
35. Shah GM, Ross EA, Sabo A, Pichon M, Bhagavan H, Reynolds RD: Ascorbic acid supplements in patients receiving chronic peritoneal dialysis. Am J Kidney Dis 18:84-90, 1991.
36. Ono K: Secondary hyperoxalemia caused by vitamin C supplementation in regular hemodialysis patients. Clin Nephrol 26: 239-243, 1986.