Feeding the Patient on Dialysis with Wounds to Heal

Retinoic acid, a form of vitamin A, mediates the DNA transcription of several growth factors essential to the wound healing process (Wicke, Halliday, Allen, & Roche, 2000). Vitamin A also assists with collagen crosslinking and re-epithelization. In renal failure vitamin A metabolism changes as retinol binding protein (RBP), the carrier for vitamin A or retinol, is no longer degraded by the kidney. Normally serum retinol rises as binding sites increase, however, inflammatory states such as wound healing can also depress RBP. Osteolytic activity with hypercalcemia may occur if available binding sites are exceeded with the use of supplemental vitamin A (Farrington, Miller, Varghese, Baillod, & Moorhhead, 1981; Fishbane, Frei, Finger, Dressler, & Silbiger, 1995). No vitamin A other than that provided in diet should be given unless the usual intake is less than two-thirds of the Dietary Reference Intake (DRI) (Chazot & Kopple, 1997), or the serum retinol:serum RBP ratio is less than 0.4 (Cundy, Earnshaw, Heynen, & Kanis, 1983). Then, vitamin A should be supplemented at the level of the DRI, 900 mcg per day for 7 to 10 days (Chazot & Kopple, 1997).

Vitamin C
The hydroxylation of prolyl and lysyl hydrolases in collagen crosslinking during wound healing is vitamin C dependent. Doses of 1000 to 2000 mg of vitamin C per day are frequently given to support this activity, however, the recommendation for the patient on dialysis is not to exceed 150 mg (Costello, Sadovnic, & Cottingham 1991). Most renal vitamins supply 60 to 100 mg of vitamin C.
The dose of vitamin C in renal vitamins was established to correct for dialysis losses and limit oxalate generation. Vitamin C is an oxalate precursor that is excreted in the urine with normal renal function but is retained in the dialysis patient, increasing the likelihood of soft tissue calcification (Ono, 1986; Pru, Eaton, & Kjellstrand, 1985). The short-term risk of calcification with higher doses of vitamin C must be weighed against the needs of wound healing.

Although usually considered an antioxidant, vitamin C also has pro-oxidant activity that presents another issue with its use in dialysis patients. When provided at high doses, vitamin C will penetrate the ferritin molecule. Iron is then reduced to its ferrous state and lost as free or redox iron into the serum (Herbert, Shaw, & Jayatileke, 1995). This has been used in EPO blockade with 300 mg or more of vitamin C given intravenously during dialysis (Gastadello, Vereerstraeten, Nzame-Nze, Vanherweghem, & Tielemens, 1995; Tarng & Huang, 1998). Iron is freed with an improvement in hematocrit, but a rise in oxidative stress parameters has also been noted. Vitamin E provided orally or incorporated into the dialyzer membrane can alleviate oxidative stress in the dialysis patient receiving IV iron (Handelman, 2003;  Roob et al., 2000). Perhaps a more appropriate dose of vitamin C is 250 mg to support wound healing while adding 200 to 400 IU of vitamin E to control for oxidative stress effects.

Zinc
Cellular immunity is dependent on zinc and essential to wound infection control. Metallothionein is a zinc-binding protein produced on wound edges as a zinc reservoir to support the synthesis of the over 200 zinc-dependent enzymes within the wound matrix (Lansdowne, 2002, Ravanti & Kahari, 2000). With an abundance of zinc-containing enzymes in wound fluid, it can be expected that high drainage wounds incur significant zinc losses.Those dialysis patients with high output ostomies and/or enterocutaneous fistulas will incur zinc losses in addition to that from wound drainage.

Zinc is greater than 90% protein bound in the serum, primarily to albumin. Therefore, serum zinc is not a good indicator of zinc status when inflammatory conditions such as wounds are present (Galloway, McMillan & Sattar, 2000). A better measure is an assessment of dietary intake in conjunction with the consideration to any wound and/or gastrointestinal losses. Most high protein foods are good sources of zinc so if protein intake has been poor, then zinc status is likely poor. Zinc sulfate provides 50 mg of elemental zinc in 220 mg and should be provided for 2 to 3 weeks for repletion then returning to an intake in the DRI range of 8 to 11 mg/day.

Arginine
In stress, such as wound healing, the amino acid arginine becomes semi-essential with demand out running supply (Witte & Barbul, 2003). Arginine is not directly a building block in tissue synthesis but rather a precursor. Via nitric oxide synthase and arginase, arginine is metabolized to nitric oxide, polyamines, and proline which facilitate wound healing (Frank, Kampfer, Wetzler, & Pfeilschifter, 2002).

Dietary intake is the primary source of arginine, amounting to 5 to 6 grams per day in a well-tolerated diet. The intestinal-renal axis, the only route for de novo arginine synthesis, is lost in dialysis dependency worsening the potential arginine deficit. However, hyperkalemia has been noted in the patient on dialysis with intakes of 30 grams or more of arginine per day (Zaloga, Siddiqui, Terry, & Marik, 2004). A safe dose achieved from diet and arginine-enhanced oral or enteral feedings appears to be about 20 grams per day in the patient on dialysis. The available arginine-enhanced products also contain supplemental vitamin A and C that needs to be accounted for in the cumulative intake of these vitamins.

Calories and Protein
The nitrogen needs of wound healing can be met with a protein intake of 1.2 to 2.0 grams per day. Higher protein intakes should be used for more serious stage 3 and 4 wounds. Current dialysis technology can provide the clearance to match the potential urea generation from a higher protein intake. An adequate energy intake in the range of 30 to 35 kcal/kg will also provide protein-sparing effect and promote positive nitrogen balance (Kopple, 2001).

Achieving a sufficient intake of calories and protein may require more than one feeding route. When the dietary intake consumed fails to meet calorie and protein needs, supplemental enteral feedings may be indicated. Persistent gastrointestinal symptoms such as vomiting and/or diarrhea that do not respond to pharmaceutical and/or diet intervention may require parenteral nutrition.

Conclusion
Wounds can be a debilitating, lifestyle limiting morbidity for the patient on dialysis. Treatment requires attention to nutrition, pressure relief, and infection control. Failure to address one or more of these three areas will result in chronic, nonhealing wounds. However, the expertise in these areas is available from the patient’s dialysis team and should be used to heal and rehabilitate the patient.

References
AChazot, C. & Kopple, J. (1997). Vitamin metabolism and requirements in renal disease and renal failure. In Kopple, J. & Massry, S.G. (Eds.), Nutritional management of renal disease.  Baltimore, MD: Williams and Wilkens.

Costello, J.F., Sadovnic, M.J. & Cottingham, E.M. (1991). Plasma oxalate levels rise in hemodialysis patients despite increased oxalate removal. Journal of the American Society of Nephrology, 1, 1289- 1298.

Cundy, T., Earnshaw, M., Heynen, G., & Kanis, J.A. (1983). Vitamin A and hyperparathyroid bone disease in uremia. American Journal of Clinical Nutrition, 38, 914-920.

Farrington, K., Miller, P., Varghese, Z., Baillod, R.A., & Moorhead, J.F. (1981). Vitamin A toxicity and hypercalcemia in chronic renal failure. British Medical Journal, 282, 1999-2002.

Fishbane, S., Frei, G.L., Finger, M., Dressler, R., & Silbiger, S. (1995). Hypervitaminosis A in two healthy hemodialysis patients. American Journal of Kidney Disease, 25, 346-349.

Galloway, P., McMillian, D.C., & Sattar, N. (2000). Effect of inflammatory response on trace element and vitamin status. Annals of Clinical Biochemistry, 37, 289-297.

Gastadello, K., Vereerstraeten, A., Nzame-Nze, T., Vanherweghem, J.L., & Tielemans, C. (1995). Resistance to erythropoietin in iron-overloaded hemodialysis patients can be overcome by asacorbic acid administration. Nephrology Dialysis Transplantation, 10, 44-47.

Handelman, G.J. (2003). Current studies on oxidant stress in dialysis. Blood Purification, 21, 46-51.

Herbert, V., Shaw, S., & Jayatileke, E. (1995). Vitamin C driven free radical generation from iron. Journal of Nutrition, 126, 1213-1218.

Lansdown, A.B. (2002). Metallothioneins: Potential therapeutic agents aids for wound healing in the skin. Wound Repair and Regeneration, 10, 130-132.

Ono, K. (1986). Secondary hyperoxalemia caused by vitamin C supplementation in regular hemodialysis patients. Clinical Nephrology, 26, 239-243.

Pru, C., Eaton, J. & Kjellstrand, C. (1985). Vitamin C and hyperoxalemia in chronic hemodialysis patients. Nephron, 39, 112-116.

Raventi, L. & Kahari, V.M. (2000). Matrix metalloproteinases in wound repair, International Journal of Molecular Medicine, 6, 391-407.

Roob, J.M., Khoschsorur, G., Tiran, A., Horina, J.H., Holzer, H., & Winkelhofer-Roob, B.M. (2000). Vitamin E attenuates oxidative stress induced by intravenous iron in patients on hemodialysis. Journal of the American Society Nephrology, 11, 539-49.

Tarng, D.C., & Huang, T.P. (1998). A parelllel, comparative study of intravenous iron versus intravenous ascorbic acid for erythropoietin-hyporesponsive anemia in hemodialysis patients with iron overload. Nephrology Dialysis Transplantation, 13, 2867-2872.

Wicke, C., Halliday, B., Allen, D., & Roche, N.S. (2000). Effects of steroids on wound healing. Archives of Surgery, 135, 1265-1270.

Witte, M.B., & Barbul, A. (2003). Arginine physiology and its implication for wound healing. Wound Repair and Regeneration, 11, 419-423.

Zaloga, G.P., Siddiqui, R., Terry, C., & Marik, P.E. (2004). Arginine: Mediator or modulator of sepsis. Nutrition in Clinical Practice, 19, 201-219.