Trace Elements and Vitamins

Joel D. Kopple

TRACE ELEMENTS

Overview

The body burden and tissue concentrations of many trace elements are altered in chronic kidney disease (CKD) and kidney failure. Various factors contribute to these alterations: many trace elements are excreted primarily by the kidney, and with renal failure they may accumulate. Secondly, elements such as iron, zinc, and copper, which are protein bound, may be lost in excessive quantities with urinary protein losses as in the nephrotic syndrome. Excessive uptake or losses of trace elements may also occur during dialysis therapy depending on their relative concentrations in plasma and dialysate and the degree of binding to protein or red cells. Hemodialysis of copper, strontium, zinc, and lead should be minimal because they are largely bound to plasma proteins or red cells. Table 10-1 shows commonly recognized abnormalities in trace elements in patients with chronic renal failure.

Hemodialysis or hemodiafiltration (MHD) may remove some trace elements if the dialysate concentrations are sufficiently low (e.g., bromide, iodine, lithium, rubidium, cesium, and zinc). Because many trace elements are bound avidly to serum proteins, they may be taken up by blood against a concentration gradient when present in even small quantities in dialysate. In fact, therapeutic doses of trace elements may be administered through dialysis, as has been done for zinc. These observations provide part of the rationale for the intensive purification of dialysate used for maintenance dialysis patients. Besides changes in removal, inhalation could result in increased intake of certain trace elements as may occur in people exposed to certain industrial processes, fertilizers, insecticides, herbicides, or burning of fossil fuels.

Protein-energy wasting can be associated with lowered serum concentrations of proteins that bind trace elements to decrease the serum levels of elements including zinc, manganese, and nickel. Occupational exposure or pica can increase the burden of some trace elements. The effect of the altered dietary intake of the patient with CKD on body pools of trace elements is unknown. Oral and, for maintenance dialysis patients, intravenous iron supplements are commonly provided for patients with renal failure.

Assessment of the trace element burden in patients with renal failure is often difficult because the serum concentrations of binding proteins may be decreased, thereby lowering serum trace element levels, or the binding characteristics of these proteins may be altered in renal failure as well. Also, red cell concentrations of trace elements may not reflect levels in other tissues. In general,
supplements of trace elements should be undertaken with caution, because impaired urinary excretion and the poor dialysance of trace elements, because of protein binding, increases the risk of overdosage. Dietary requirements for trace elements have not been defined for patients with CKD because of the difficulties in conducting the studies to determine nutritional requirements plus the problems of identifying sensitive and reliable methods of determining deficiency of trace elements.

Table 10-1. Commonly recognized abnormalities in trace elements and vitamins in patients with chronic renal failure^*

Micronutrient	Effect of Chronic Renal Failure^†
Zinc	Serum^‡^↓-N; RBC^↑ leukocyte^↓ in CRF and HD; N in CPD
Selenium	Serum^↓ in CRF, HD, and CPD
Iron	Serum^↓-N; tissue^↓ in CRF, HD, and CPD
Aluminum	Serum N-^↑ in CRF; serum and tissue^↓ in HD and CPD
Copper	Serum N-^↑ in CRF and HD, N in CPD; RBC^↓-N
Thiamin	Serum^↓-N in CRF, HD, and CPD
Riboflavin	Serum^↓-N in CRF, HD, and CPD
Pyridoxine	Serum^↓-N in CRF, HD, and CPD; RBC^↓ in CRF and HD
Cobalamin	Serum^↑ in CRF; serum N in HD and CPD
Folic acid	Serum^↓-N and RBC N-^↑ in CRF, HD, and CPD
Ascorbic acid	Serum^↓-N in CRF, HD, and CPD
Vitamin A	Serum^↑ in CRF, HD, and CPD
Vitamin E	Serum^↓-N-^↑ in CRF, HD, and CPD; RBC^↓ in HD and CPD
^*Refers to persons with CRF who are not receiving trace element or vitamin supplements. ^†Serum levels of many trace elements and vitamins may be reduced in the nephrotic syndrome because of increased urinary losses and low serum levels of binding proteins. ^‡Values ascribed to serum refer to serum or plasma. ^↓, decreased compared to normal values; ^↑, increased compared with normal values; CPD, chronic peritoneal dialysis; CRF, chronic renal failure; HD, maintenance hemodialysis;.
N, not different from normal values; RBC, erythrocytes.

Iron

Iron deficiency is common, particularly in patients receiving hemodialysis (Table 10-2). Because intestinal iron absorption can be impaired, because there are often blood losses from the intestinal tract and from blood drawing, and because blood may be sequestered in the hemodialyzer, iron deficiency is occurs frequently. Also, iron may bind to the dialyzer membrane while the erythropoietin-induced rise in hemoglobin concentrations may deplete the body’s iron supply. Not only do iron requirements increase during the time between initiation of erythropoietin therapy and
the rise in hemoglobin but also higher serum iron levels are associated with a greater response to erythropoietin. Some researchers recommend that, in general, patients undergoing MHD or chronic peritoneal dialysis (CPD) should maintain serum transferrin saturation (TSAT) at 30% to 50% and serum ferritin at about 400 to 800 ng/mL.

Table 10-2. Factors leading to iron deficiency in patients with chronic renal failure or patients receiving maintenance dialysis

•	Increased demand for iron during erythropoiesis stimulated by rhEPO
•	Decreased iron uptake by intestinal mucosal cells
•	Gastrointestinal tract blood loss which may be clinically apparent or occult
•	Massive proteinuria
•	Blood retention in hemodialyzer and blood lines at end of hemodialysis
•	Blood drawing for testing
•	Accidental blood loss from vascular access tubing, grafts, and fistulae
•	Menstruation
rhEPO, recombinant human erythropoietin.

Although some patients receiving maintenance dialysis can maintain these iron values with oral iron supplements, many patients will require parenteral iron therapy. Oral ferrous sulfate, 300 mg three times per day, one-half hour after meals should be tried, but some patients will develop anorexia, nausea, constipation, or abdominal pain; these individuals sometimes will tolerate other iron compound, including ferrous fumarate, gluconate, or lactate. The levels sought include TSAT at 30% to 50% and serum ferritin levels of 400 to 800 ng/mL, and if these are not achieved with oral iron, the patient can be treated with intravenous iron (intramuscular injections cause pain and staining of skin, so intravenous iron, given as ferrous gluconate, ferrous sucrose, or iron dextran is generally the preferred method of administration). Iron dextran has a slightly greater risk of anaphylactic reactions, from 0.6% to 0.7%, and 31 deaths have been reported from anaphylactic reactions to iron dextran between 1976 and 1996 in the United States. Consequently, many physicians prefer to use other iron salts. Although rare, iron overload can be treated by simply halting intake or by removal using deferoxamine (see below) or by injections of erythropoietin along with repeated phlebotomy. Recommendations for iron therapy in patients receiving erythropoietin treatment are given in Chapter 11.

Aluminum

In patients with stage 5 CKD or those receiving maintenance dialysis, increased aluminum has been implicated as a cause of a progressive dementia syndrome (particularly in patients receiving MHD), osteomalacia, weakness of the proximal muscles of the
limbs, impaired immune function, and anemia. Although contamination of dialysate with aluminum previously was the major source of aluminum toxicity, current methods of water treatment have removed virtually all aluminum from the dialysates. Instead, ingestion of aluminum binders of phosphate is probably the major cause of the excess burden of aluminum, and aluminum binders are now used sparingly if at all. Increased body burden and toxicity of iron or aluminum in patients receiving MHD or CAPD may be reduced simply by eliminating intake or by infusion of deferoxamine (a dialyzable chelator of divalent cations). Care must be taken with the latter method because deferoxamine can promote loss of iron as well as certain serious infections, particularly mucormycosis.

Zinc

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