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testosterone [ 1371. Androgen-treated female rats exhibit definite renal hypertrophy which closely parallels an increase in red cell mass [ 1381. It has also been shown that the ribonucleic acid of the mouse kidhey is decreased by castration and increased by the administration of androgens [ 1391. In man, because of the extrarenal source of erythropoietin, the presehce of kidneys does not seem essential for androgens to stimulate erythropoiesis. Significant erythrapoietic response has been achieved after androgen therapy in nephrectomized patients undergoing long-term hemodialysis [ 126,129]. It has been suggested, however, that these patients might show an even greater erythropoietic response if one of the kidneys were still present. The renotrophic action of androgens seems to depend, as for target organs such as prostate, on the presence of specific cytoplasmic androgen receptor proteins [ 1401. 5&H steroids have been reported to stimulate hemoglobin synthesis only by their direct cellular action without stimulating erythropoletin production [ 1411443. Other studies using thymidine suicide technics have yet uncovered another cellular effect of testosterone and some of its metaboiites; namely, the triggering of colony-forming units into cell cycles [ 1451. More recent investigations measuring the colonyforming ability of erythroid cells in vitro not only have cohfirmed the direct cellular action of most @-H steroids, but have also further shown that some of the 5a-H metabolites may exert similar direct action on erythroid elements [ 146,147]. Although the erythropoietic effect of unsaturated and tne 5a-H compounds in vivo has been well documented, studies evaluating the role of 5P-H metabolites in enhancing erythropoiesis in vivo have yielded conflicting results [143,144,148]. The Side Effects of Androgenic-Anabolic Hormones. The administration of androgens in dosage used to en-
hance erythropoiesis has definite side effects. Some degree of masculinization occurs in all children and women receiving large doses of androgens regardless of the preparation used. Flushing of the skin and acne appear usually two to three months after the initiation of androgen therapy. Deepening and hoarseness of the voice follow these dermal changes. In children before puberty, changes of external genitalia and growth of pubic hair occur one to three months after therapy. In females of menstruating age, amenorrhea and moderate enlargement of the clitoris develop. Changes in libido in both sexes have also been observed. It is known that prolonged administration of large doses of androgens to children increases the rate of the skeletal maturation. However, no serious growth retardation or roenfgenologic evidence of accelerated bone maturation‘has been noted in children treated with anabolic-androgenic steroids. Treatment with 17a-alkylated androgens may cause considerable disturbance to liver function. The abnormality ranges from an increase in sulfobromophthalein retention elevation in serum transaminase to a frank picture of cholestasis. This abnormality is, however, often reversible; Other complications such as significant weight gain as a result of water retention and elevation of plasma triglycerate levels have also been noted. In addition td’their hemopoietic effect, androgens are protein anabolic steroids that result in an appreciable nitrogen retention and thereby in a decrease in the formation of intoxicating protein breakdown products. As a result, sudden withdrawal of these hormones in uremic patients may markedly increase azotemia. A significant increase in erythrocyte 2,3diphosphoglycerate after androgen administration has been observed in man and in laboratory animals [ 1221. It is well known that this organic phosphate facilitates the unloading of oxygen from hemoglobin into the tissues by decreasing the oxygen affinity for hemoglobin.
Nutritional Supplements in Renal Failure KURT H. STENZEL, M.D., Rogosin Kidney Center, The New York Hospital-Cornell
A variety of nutritional supplements are often prescribed for patients with renal disease because of the frequency of wasting syndromes, the frequency of various vitamin and mineral deficiencies, and the necessity for limiting protein intake. These additives include caloric, vitamin, mineral and amino acid supplements. Precise nutritional requirements in patients with renal disease are not known. Requirements for normal people have been determined largely by short-term balance
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studies. The efficacy of nutritional supplements depends not only on over-all balance, but also on the particular metabolic pathways used to maintain that balance. For instance, external balance of a particular nutrient may be maintained in uremia by very different mechanisms than in health. Nutritional supplements, to be effective, must first be absorbed and then metabolized in a fashion that promotes normal tissue function. Gastrointestinal disease is common in uremia and may prevent adequate
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absorption of nutrients. Pathways of intermediary metabolism may be altered by retention of metabolites, leading to unusual and possibly energy-consuming pathways of nutrient utilization. Disturbances in hormone function that occur in uremia can also be expected to alter utilization of nutrients. Energy-containing nutrients are metabolized in three major steps. First, ingested food is digested, and the products of digestion are absorbed and transported to the tissues. Second, absorbed glucose, glycerol, fatty acids and amino acids may be incorporated into cellular biomolecules (anabolism) or undergo further degregation (catabolism) to small intermediates such as acetyl coenzyme A (acetyl-CoA). The third step includes complete oxidation of acetyl groups with release of four pairs of electrons that are utilized to generate ATP. The energy stored in ATP is then used for biologic workmechanical, transport or biosynthetic [ 1491. Recommended caloric intake for healthy men is 34 to 45 kilo calories (kcal) per kilogram per day; and for women, 3 1 to 36 kcal/kg/day [ 1501. Several factors complicate the determination of adequate caloric intake in patients with renal disease, and especially in those undergoing dialysis. Ideal weight is sometimes difficult to evaluate. Patients may be overhydrated or may have lost muscle mass that should be replenished. Uremia, infection and the stress of surgery for shunts and fistulas may all increase catabolism and, consequently, caloric requirements. Some nutrients may be lost during dialysis, thus increasing requirements. Kopple [1511 has recommended a minimal caloric intake of 35 kcal/kg of ideal body weight per day; and, of course, this should be increased in patients who are wasted, malnourished or subjected to any stress that might increase energy requirements. Several high-caloric, low-protein, lowelectrolyte supplements are available [ 15 11. Unfortunately, many patients find such supplements unpalatable, and if high-caloric foods can be included in a varied diet, they are better tolerated and lead to a better result. Vitamin deficiencies may arise in several ways. Water-soluble vitamins are lost during dialysis. Sullivan et al. [ 1521 documented that borderline vitamin C deficiencies may occur in dialyzed patients if vitamin C is not supplemented. This probably results from a combination of losses during dialysis and avoiding foods that are high in vitamin C, since many of these are also high in potassium. The actual quantities of water-soluble vitamins lost during dialysis are probably no greater than those lost in the urine when kidney function is normal. Evidence has been presented that there is a circulating inhibitor of vitamin B6 in uremia that necessitates larger than normal doses of this vitamin [ 1531. Because of losses during dialysis and the frequency of restricted diets and poor appetites in patients with renal disease,
vitamin supplements are recommended. These can simply be given as multiple vitamins, assuring that at least 10 mg/day of vitamin B6 is included. The major mineral supplements that are used are calcium and iron. Calcium has been discussed by the previous essayists. There has been some concern that iron may not be absorbed efficiently in uremic patients. Certainly, anemia is almost universal in patients with renal disease; but, as Dr. Shahidi has pointed out, the major defect is probably a lack of erythropoietin. Nevertheless, iron deficiency has been frequently documented in dialyzed patients. Several recent studies have indicated that iron absorption is, indeed, normal in dialyzed patients [ 1541. However, these studies are made in carefully controlled clinical research settings. Several factors may contribute to poor iron absorption in the day to day treatment of patients undergoing dialysis. Some patients have a high gastric pH that impedes iron absorption. The concomitant ingestion of bicarbonate or antacids and the ingestion of iron pills with meals to reduce gastric irritability may both contribute to poor iron absorption. Finally, the actual loss of blood and consequently iron during dialysis may be underestimated by the dialysis team. Because of the frequent occurrence of wasting syndromes, protein nutrition is of paramount interest to nephrologists. Decreasing protein intake clearly improves uremic symptoms. Keto acid analogues of essential amino acids and essential amino acids themselves as elemental diets have been recommended. Now that dialysis is widespread, however, there is less need for extreme dietary restriction. Nevertheless, interest in amino acid supplementation has continued in three major areas. Acute renal failure following trauma or surgery continues to present severe problems, and hyperalimentation with essential amino acids has been shown to be beneficial [ 1551. Several workers, especially in Europe, have suggested that patients with chronic uremia treated with dialysis benefit by supplementation with essential amino acis [ 1561. Heidland and Kult [ 1571 have demonstrated an increase in body weight, total serum protein, serum albumin, transferin and various complement components after supplementation of chronic dialysis patients with free amino acids. A third area of interest is the metabolic handling of amino acids in uremia. Studies have shown that phenylalanine metabolism is deranged, with a decreased conversion of phenylalanine to tyrosine [ 1581. There is a decreased protein binding of tryptophan in uremia that might affect metabolism of this amino acid [ 159). Multiple defects in fasting plasma amino acids have been described; the most usual alteration is a decrease in essential amino acids as opposed to nonessential amino acids. Kopple et al. ] 1601, however,
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demonstrated that many of these abnormalities could be duplicated in normal subjects by simply restricting protein intake. We studied first-pass metabolism and total body clearance of essential amino acids in a group of patients whose condition was stabilized during long-term dialysis and who were ingesting 60 to 70 g of protein per day and compared these data with those in normal subjects [ 1611. First-pass metabolism is quite variable in both the normal subjects and those with uremia. However, significant differences were seen in total body clearance rates. The branched-chain amino acids especially had a decreased total metabolic clearance rate. Renal clearances could not account for these differences, since they were negligible in both the normal subjects and the uremic patients. One patient was undergoing daily dialysis to lessen a peripheral neuropathy, and the metabolic clearance rate in this patient more closely approximated that in normal subjects than that in the group undergoing intermittent dialysis. Total body clearance of phenylalanine remained abnormal even in this patient. We gave relatively small doses of amino acids (approximately 10 g), and these were not enough to cause significant alterations in blood glucose or immunoreactive insulin levels. Garber [162] has dem-
onstrated that elevated PTH levels increase muscle protein breakdown, and vitamin D deficiency decreases the synthesis of muscle protein. PTH also increases hepatic gluconeogenesis. Our findings of a decreased total metabolic clearance rate might be put into a hypothetical scheme for the biochemical basis of muscle wasting in uremia. Vitamin D deficiency decreases muscle protein synthesis and perhaps leads to delayed clearance of branched-chain amino acids from plasma; PTH meanwhile increases skeletal protein breakdown and increases hepatic gluconeogenesis; and uremic toxins themselves may interfere *with amino acid transport. Studies are now underway to test the various aspects of this hypothesis. The glucose-alanine cycle has been well described [ 1631, and it may well be that PTH and vitamin D abnormalities are one of the primary reasons for muscle wasting in uremia. For a nutritional supplement to be effective, it must be absorbed, transported throughout the body and utilized in effective ways. In uremia, utilization of nutrients may be abnormal, so simply giving patients excessive nutrients may not be successful in reversing wasting syndromes. The pathogenesis of wasting must be established for each person and therapy directed at the basic abnormality.
REFERENCES 1. 2.
7.
8.
9. 10.
11.
550
Cheigh JS: Drug administration in renal failure. Am J Med 62: 555,1977. Szeto HH, lnturrisi CE, Houde RW, et al.: The accumulation of normeperidine, an active metabolite of meperidine, In patients with renal failure or cancer. Ann Intern Med (in press) Szeto HH, lnturrisi CE: Simultaneous determination of meperidine and normeperidine in biofluids. J Chromatogr 125: 503, 1976. Klotz U, Mcl-forse TS. Wilkinson GR, et al.: The effect of cirrhosis on the disposition and elimination of meperidine in man. Clin Pharmacol Ther 16: 667, 1974. McHorse TS, Wilkinson GR, Johnson RF, et al.: Effect of acute viral hepatitis in man on the disposition and elimination of meperidine. Gastroenterology 68: 775, 1975. Miller JW, Anderson HH: The effect of Ndemethylation on certain pharmacologic actions of morphine, codeine, and meperidine in the mouse. J Pharmacol Exp Ther 112: 19 1, 1954. Deneau GA, Nakai K: The toxicity of meperidine in the monkey as influenced by its rate of absorption. Bulletin, Drug Addiction and Narcotics, App. 6, 2460, 1961. Gilbert PE, Martin WR: The antagonism of the convulsant effects of heroin, d-propoxyphene, meperidine, normeperidine and thebaine by naloxone in mice. J Pharmacol Exp Ther 192: 538, 1975. lntunisi CE: Disposition of narcotics and narcotic antagonists. Ann NY Acad Sci 281: 273. 1976. Kreek MJ, Gutjahr CL, Bowen DV, et al.: Fecal excretion of methadone and its metabolites. A major pathway of elimination in man. Proceedings of the Third National Drug Abuse Conference (in press). Reidenberg MM: Renal Function and Drug Action, Philadel-
April 1977
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12.
13.
14. 15.
16.
17.
18.
19.
20.
21.
phia, W. B. Saunders, 1971. Lindner A, Charra B, Sherrard DJ, et al.: Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 290: 697, 1974. Evans GH, Shand DG: Disposition of propranolol. V. Drug accumulation and steady-state concentrations during chronic oral administration in man. Clin Pharmacol Ther 14: 487, 1973. Shand DG, Nukolls EM, Oates JA: Plasma propranolol levels in adults. Clin Pharmacol Ther 11: 112, 1970. Briggs WA, Lowenthal DT, Cirksena W, et al.: Propranolol in hypertensive dialysis patients: efficacy and compliance. Clin Pharmacol Ther 18: 606, 1975. Cotham RH, Shand D: Spuriously low plasma propranolol concentrations resulting from blood collection methods. Clin Pharmacol Ther 18: 535, 1975. Lowenthal DT, Briggs WA, Gibson TP, et al.: Pharmacokinetics of oral propranolol in chronic renal disease. Clin Pharmacol Ther 18: 761, 1974. Bianchetti G, Graziani G, Brancaccio D, et al.: Pharmacokinetics and effects of propranolol in terminal uraemic patients and in patients undergoing regular dialysis treatment. Clin Pharmacokin 1: 373, 1976. Lowenthal DT, Mutterperl R: Pharmacokinetics of oral propranolol. II. The effects of chronic dosing and protein binding (abstract). Clin Pharmacol Ther 19: 111, 1976. Lichter M, Black M, Arias IM: The metabolism of antipyrine in patients with chronic renal failure. J Pharmacol Exp Ther 187: 612, 1973. Reidenberg MM, Ddar-Cederlof I, von Bahr C, et al.: Protein binding of diphenylhydantoin and desmethylimipramine in plasma from patients with poor renal function. N Engl J Med 285: 264, 1971.
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22.
23.
24.
25.
26. 27.
28.
29.
30.
31.
32.
33.
34.
35.
36. 37. 38.
39. 40.
41.
42. 43.
44.
Reidenberg MM, Lowenthal DT, Briggs WA, et al.: Pentobarbital elimination in patients with poor renal function. Clin Pharmacol Ther 20: 67, 1976. Gerhardt RE, Knouss RF, Thyrum PT. et al.: Quinidine excretion in aciduria and alkaluria. Ann Intern Med 71: 927, 1969. Kessler KM, Lowenthal DT, Warner H, et al.: Unimpaired quinidine elimination in patients with poor renal function or congestive heart failure. N Engl J Med 290: 706, 1974. Bellett S, Roman LR, Boza A: Relation between serum quinidine levels and renal function: studies in normal subjects and patients with congestive failure and renal insufficiency. Am J Cardiol 27: 368, 1971. Lowenthal DT. Drayer D, Reidenberg MM: Unpublished observations. Galeazzi RL, Sheiner LB, Lockwood T, et al.: The renal elimination of procainamide. Clin Pharmacol Ther 19: 55, 1976. Gibson TP, Matusik EJ, Briggs WA: N-acetylprocainamide levels in patients with end-stage renal failure. Clin Pharmacol Ther 19: 206, 1976. Drayer DE, Lowenthal DT, Woosley RL, et al.: Accumulation of N-acetylprocainamide (NAPA), an active metabolite of procaine amide in patients with poor renal function (abstract). Program of 9th Annual Meeting of the American Society of Nephrology, Washington, D.C., 1976. Gibson TP, Lowenthal DT, Nelson HA, et al.: Elimination of procainamide in end-stage renal failure. Clin Pharmacol Ther 17: 321, 1975. Drayer D, Reidenberg MM, Sevy RW: N-acetylprocainamide: an active rnetabolite of procaine amide. Proc Sot Exp Biol 146: 358, 19.74. Elson J, Strong JM, Lee WK, et al.: Antiarrhythmic potency of n-acetylprocainamide. Clin Pharmacol Ther 17: 134, 1975. Collinsworth KA. Kalman SM. Harrison DC: The clinical pharmacology of lidocaine as an antiarrhythmic drug. Circulation 50: 1217, 1974. Thomson PD. Melmon KL, Richardson JA, et al.: Lidocaine pharmacokinetics in advanced heat-l failure, liver disease and renal failure in humans. Ann Intern Med 78: 499, 1973. Williams RL, Blaschke TF, Meffin PJ, et al.: Influence of viral hepatitis on the disposition of two compounds with high hepatic clearance: lidocaine and indocyanine green. Clin Pharmacol Ther 20: 290, 1976. Boyes RN, Scott DB, Jebson PJ, et al.: Pharmacokinetics of lidocaine in man. Clin Pharmacol Ther 12: 105, 197 1. Bryan FA: National Dialysis Registry: Final Report, Research Triangle Institute, Research Triangle Park, N.J., 1976. Linder A, Charra B. Sherrard DJ, et al.: Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 290: 697, 1974. Lazarus JM, Hampers CL, Merrill JP: Hypertension in chronic renal failure. Arch Intern Med 133: 1059, 1974. Dathran JRE, Goodwin FJ: The relationship between body fluid compartment volume, renin and blood pressure on chronic renal failure. Clin Sci 42: 29, 1972. Weideman P, Maxwell MM, Lupu AN, et al.: Plasma renin activity and blood pressure in terminal renal failure. N Engl J Med 285: 757, 1971. Vertes V, Cangiano JL, Berman LB, et al.: Hypertension in end-stage renal disease. N Engl J Med 280: 978, 197 1. Schonberg SM, Stone RA, Kirshner N, et al.: Plasma dopamine-@-hydroxylase: a possible aid in the study and evaluation of hypertension. Science 183: 523, 1974. White RP, Sealey J, Reidenberg M, et al: Mechanisms of blood pressure control in anephrics: plasma renin and dopamine-&hydroxylase activity. Trans Am Sot Artif
45.
46.
47.
48.
49.
50.
51.
52. 53. 54.
55. 56. 57.
58.
59. 60.
61. 62. 63. 64. 65.
66. 67.
68. 69.
April 1977
Intern Organs 22: 420, 1976. Kelly MR. Cutler RE, Christopher TG, et al.: Pharmacokinetics of furosemide in normal subjects and anephric patients. Clin Res 21: 470, 1973. Pillay VKG, Schwartz FD, Aimi K, et al.: Transient and permanent deafness following treatment with ethacrynic acid in renal failure. Lancet 1: 77, 1969. Laragh JH: Vasoconstriction volume analysis for understanding and treating hypertension: the use of renin and aldosterone profiles. Am J Med 55: 261, 1973. Brunner MR, Gavras, M, Laragh JH, et al.: Angiotensin II blockade in man by sar’-alas-angiotensin II for understanding and treatment of high blood pressure. Lancet 2: 1045, 1973, Gavras M, Brunner HR, Laragh JH, et al.: An angiotensinconverting enzyme inhibitor to identify and treat vasoconstrictor and volume factors in hypertensive patients. N Engl J Med 291: 817, 1974. Case DB, Wallace JM, Keim HJ, et al.: Estimating renin participation in hypertension: superiority of converting enzyme inhibitors over saralasin. Am J Med 61: 790, 1976. Hollifield JW, Sherman K, VanderZuagg R, et al.: Proposed mechanisms of propranolol’s antihypertensive effect. N Engl J Med 295: 68, 1976. Davies R, Slater JDM: Is the adrenergic control of renin release dominant in man? Lancet 2: 594, 1976. Holland OB, Kaplan NM: Propranolol in the treatment of hypertension. N Engl J Med 294: 936, 1976. Myhre E, Brodwell EK, Stenback 0, et al.: Plasma turnover of methyldopa in advanced renal failure. Acta Med Stand 191: 343, 1972. Onesti G. Schwartz AB, Kim KE: Antihypertensive effect of clonidine. Circ Res 2 (suppl): 53, 1971. Reidenberg MM, Drayer D, DeMarco AL, et al.: Hydralazine elimination in man. Clin Pharmacol Ther 14: 970. 1973. Gottlieb TB, Thomas RC, Chidsey CA: Pharmacokinetic studies of minoxidil. Clin Pharmacol Ther 13: 436, 1972. O’Malley K, Velasco M, Pruitt A, et al.: Decreased plasma protein binding of diazoxide in uremia. Clin Pharmacol Ther 18: 53, 1975. Koch-Weser J: Drug therapy: diazoxide. N Engl J Med 294: 1271, 1976. Guiha NH, Limas CJ, Franciosa JA, et al.: Treatment of refractory heart failure with sodium nitroprusside (abstract). Circulation 46 (suppl 2): 105, 1972. Kennedy AC: Men of Parts. Philos Trans R Philos Sot Glasgow 10: 3, 1973. Abel JJ. Rowntree LG, Turner BB: J Pharmacol Exp Ther 5: 275, 1913. Kolff WJ, Berk HTJ: Artificial kidney: dialyzer with great area. Acta Med Stand 117: 121, 1944. Merrill JP: Clinical application of an artificial kidney. Bull N Engl Med Ctr 11: 111, 1949. Quinton W, Dillard D. Scribner BH: Cannulation of blood vessels for prolonged hemodialysis. Trans Am Sot Artif Intern Organs 6: 104, 1960. Friedman EA: Sorbents in the management of uremia. Am J Med 60: 614, 1976. Giordano C, Esposito R, Randazzo G: Oxystarch as a gastrointestinal sorbent in uremia. Uremia (Kluthe R, Berlyne G, Burton 8, eds), Stuttgart, Georg Thieme Verlag, 1972, p 231. Giordano C: Digestible adsorbents in renal failure. Proc Strathclyde Bioengineering Sem II (in press). Friedman EA, Fastook J, Beyer MM, et al.: Potassium and nitrogen binding in the human gut by ingested oxidized starch (OS). Trans Am Sot Artif Intern Organs 20: 161, 1974.
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70.
7 1.
72.
73. 74.
75.
76.
77.
78.
79. 80.
81.
82. 83.
84.
85.
86.
87.
88.
89.
90.
552
Friedman EA. Laungani GB, Beyer MM: Life prolongation in nephrectomized rats fed oxidized starch and charcoal. Kidney Int 7 (suppl 3): 377, 1975. Saltzman MJ, Beyer MM, Friedman EA: Mechanism of life prolongation in nephrectomized rats treated with oxidized starch and charcoal. Kidney Int 10 (suppl 7): 343, 1976. Saltzman MI, Delano BG, Frank WM. et al.: Control of uremic hyperlipidemia (HL) by activated charcoal (AC) and oxidized starch (OS) (abstract). Program of the 9th Annual Meeting of the American Society of Nephrology, Washington, D.C., 1976. Yatzidis H: Recherches sur I’epuration extra renale a I’akfe de charbon actif. Nephron 1: 310. 1964. Friedman EA, Saltzman MJ, Beyer MM, et al.: Combined oxystarch-charcoal trial in uremia; sorbent-induced reduction in serum cholesterol. Kidney Int 10 (suppl7): 273, 1976. Goldenhersh KK, Huang W, Mason NS, et al.: Effect of microencapsulation on competitive adsorption in intestinal fluids. Kidney Int 10 (suppl 7): 251, 1976. Sparks RE, Gupta DVS, Mason NS: Adsorbtion of barbiturates from buffers, blood and intestinal fluids. Strachclyde Sem on Artif Organs II (in press). Alfrey AC, LeGendre GR, Kaehny WD: The dialysis encephalopathy syndrome possible aluminum intoxication. N Engl J Med 294: 184, 1976. Pierides AM, Ward MK, Kerr DNS: Hemodialysis encephalopathy: possible role of phosphate depletion. Lancet 1: 1234, 1976. Omdahl JL, DeLuca HF: Regulation of vitamin D metabolism and function. Physiol Rev 53: 327, 1973. Norman AW, Henry H: 1,25-Dihydroxycholecalciferol-a hormonally active form of vitamin 0s. Ret Prog Horm Res 30: 431, 1974. Norman AW: The hormone-like action of 1,25-(OH)*cholecalciferol (a metabolite of the fat-soluble vitamin D) in the intestine. Vitam Horm 32: 325, 1974. DeLuca HF: The kidney as an endocrine organ involved in the function of vitamin D. Am J Med 58: 39. 1975. Dent CC, Richens A, Rowe DJF, et al.: Osteomalacia with long-term anticonvulsant therapy in epilepsy. Br Med J 4: 69, 1970. Hunter J, Maxwell JD, Stewart DA, et al.: Altered calcium metabolism in epileptic children on anticonvulsants. Br Med J 4: 202, 1971. Hahn TJ, Hendin BA, Scharp CR, et al.: Effect of chronic anticonvulsant therapy on serum 25hydroxycalciferol levels in adults. N Engl J Med 287: 900, 1972. Stamp TCB, Round JM, Rowe DJF, et al.: Plasma levels and therapeutic effect of 25hydroxychofecalciferol in epileptic patients taking anticonvulsant drugs. Br Med J 4: 9, 1972. Caspary WF, Hesch RD, Matte R, et al.: Intestinal calcium absorption in epileptics under anticonvulsant therapy. Vitamin D and Problems Related to Uremic Bone Disease (Norman AW, Schaeffer K, Grigoleit HG. et al.. eds), Berlin, de Gruyter, 1975, p 737. Brickman AS, Coburn JW, Norman AW: Action of 1,25dihydroxycholecalciferol, a potent kidney-produced metabolite of vitamin Ds in uremic man. N Engl J Med 287: 891, 1972. Brickman AS, Coburn JW, Massry SG, ef al.: 1,25-Dihydroxyvitamin Ds in normal man and patients with renal failure. Ann Intern Med 80: 161, 1974. Chalmers TM, Davie MW, Hunter JO, et al.: 1-Alpha-hydroxycholecalciferol as a substitute for the kidney hormone, 1,25dihydroxycholecalciferol in chronic renal failure. Lancet 2: 696, 1973.
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Volume 62
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101. 102.
103.
104.
105.
106.
107.
108.
109.
Brickman AS, Coburn JW, Friedman GR, et al.: Comparison of effects of la-hydroxy-vitamin 0s and 1,25dihydroxyvitamin Ds in man. J Clin Invest 57: 1540. 1976. Bar A, Wasserman RH: Duodenal calcium binding protein in the chick: a new bioassay for vitamin D. J Nutr 104: 1202,1974. Haussler MR. Zerwekh JE, Hesse RH, et al.: Biological activity of la-hydroxycholecalciferol, a synthetic analog of the hormonal form of vitamin Ds. Proc Natl Acad Sci USA 70: 2248, 1973. Hibberd KA, Norman AW: Comparative biological effects of vitamin Ds and 0s and dihydrotachysterols and dihydrotachysterols in the chick. Biochem Pharmacol 18: 2347, 1969. Stanbury SW: Bony complications of renal disease, chap 26. Renal Disease (Black DAK, ed), Philadelphia, F. A. Davis, 1967. E&wood JB, Bordier PJ, Clarkson EM, et al.: The contrasting effects on bone histology of vitamin D and of calcium carbonate in the osteomalacia of chronic renal failure. Clin Sci 47: 23, 1974. Verberckmoes R, Bouillon R, Krempien B: Osteodystrophy of dialyzed patients treated with vitamin D. Proc Eur Dial Transplant Assoc 10: 216, 1973. David DS: Mineral and bone homeostasis in renal failure: pathophysiology and management, chap 1. Calcium Metabolism in Renal Failure and Nephrolithiasis (David DS, ed), New York, John Wiley (in press). Kaye M, Chatterjee G, Cohen GF, et al.: Arrest of hyperparathyroid bone disease with dihydrotachysterol in patients undergoing chronic hemodialysis. Ann Intern Med 73: 225, 1970. Hill AVL, Alvarez-Ude F, Pierides AM, et al.: The effects of calcium carbonate, aluminum hydroxide and dihydrotachysterol on hemodialysis bone disease. Vitamin D and Problems Related to Uremic Bone Disease (Norman AW, Schaeffer K. Grigoleit HG, et al., eds), Berlin, de Gruyter, 1975, p 643. Hallick RB, DeLuca HF: Metabolites of dihydrotachysterols in target tissues. J Biol Chem 247: 91. 1972. Gray RW, Orndahl JL, Ghazarian JG, et al.: 25hydroxycholecalciferol-l-hydroxylase: subcellular location and properties. J Biol Chem 247: 7528, 1972. DeLuca HF: The kidney as an endocrine organ for the production of 1,25dihydroxyvitamin Ds. a calcium-mobilizing hormone. N Engl J Med 289: 359, 1973. Davie MWJ, Chalmers TM, Hunter JO, et al.: l-alpha.‘rydroxycholecalciferol in chronic renal failure: studies of the effect of oral doses. Ann Intern Med 84: 281, 1976. Peacock M, Gallagher JC, Nordin BEC: Action of la-hydroxy vitamin Ds on calcium absorption and bone resorption in man. Lancet 1: 385, 1974. Naik RB, Gosling P, Price CP, et al.: Whole-body in-vivo neutron activation analysis in assessing treatment of renal osteodystrophy with 1-alpha-hydroxycholecalciferol. Br Med J 2: 79, 1976. Peacock M, Nordin BEC, Gallagher JC, et al.: Action of la-hydroxy vitamin Ds in man. Vitamin D and Problems Related to Uremic Bone Disease (Norman AW, Schaeffer K. Grigoleit HG, et al., eds), Berlin, de Gruyter, 1975, p 611. Zerwekh HE, Brumbaugh PF, Haussler DH. et al.: la-hydroxyvitamin Ds, an analog of vitamin D which apparently acts by metabolism to lLu.25dihydroxyvitamin 0s. Biochemistry 13: 4097, 1974. Pierides AM, Ellis HA, Ward M, et al.: Barbiturate and anticonvulsant treatment in relation to osteomalacia with hemodialysis and renal transplantation. Br Mad J 1: 190, 1976.
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110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122. 123. 124.
125.
126.
127.
128.
129.
130.
Pierides AM, Kerr DNS, Ellis HA, et al.: la-hydroxycholecalciferol in hemodialysis renal osteodystrophy: adverse effects of anticonvulsant therapy. Clin Nephrol 5: 189, 1976. Coburn JW, Brickman AS, Hartenbower DL: Clinical disorders of calcium metabolism in relation to vitamin D. Vitamin D and Problems Related to Uremic Bone Disease (Norman AW, Schaeffer K, Grigoleit HG, et al., eds), Berlin, de Gruyter. 1975, p 219. Catto GRD, MacLeod M, Pelt B, et al.: la-hydroxycholecalciferol: a treatment of renal bone disease. Br Med J 1: 12, 1975. Rutherford WE, Blondin J, Hruska K, et al.: Effect of 25 hydroxycholecalciferol on calcium absorption in chronic renal disease. Kidney Int 8: 320, 1975. Bordier PJ, Marie PJ, Arnaud CD: Evolution of renal osteodystrophy: correlation of bone histomorphometry and serum mineral and immunoreactive parathyroid hormone values before and after treatment with calcium carbonate or 25hydroxycholecalciferol. Kidney Int (suppl 2) p 102, 1975. Teitelbaum SL, Bone JM, Stein PM, et al.: Calcifediol in chronic renal insufficiency: skeletal response. JAMA 235: 164, 1976. Steele TH, Tyson IB: Use of a rapid external counting tracer technique for assessing calcium absorption in advanced renal disease. Clin Dial Transpl Forum 1: 136, 1971. Brickman AS, Coburn JW, Massty SG: 1,25 dihydroxy-vitamin D3 in normal man and patients with renal failure. Ann Intern Med 80: 161, 1974. Henderson RG, Russell RGG, Ledingham JGG, et al.: Effects of 1,25_dihydroxycholecalciferol on calcium absorption, muscle weakness, and bone disease in chronic renal failure. Lancet 1: 379, 1974. Bordier PJ, Tun Chot S, Eastwood JB, et al.: Lack of histological evidence of vitamin D abnormality in the bones of anephric patients. Clin Sci 44: 33, 1973. Jubiz W, Haussler MR, Tolman KG, et al.: Plasma 1.25 dihydroxyvitamin D levels in patients on anticonvulsant drugs. Clin Res 24: 255A, 1976. Rasmussen H, Bordier P: The Physiological and Cellular Basis of Metabolic Bone Disease, Baltimore, Williams & Wilkins, 1974. Shahidi NT: Androgens and erythropoiesis. N Engl J Med 289: 72, 1973. Fried W: Use of androgens in hematologic disease. Postgrad Med 55: 155, 1974. Richardson JR Jr, Weinstein MB: Erythropoietic response of dialyzed patients to testosterone administration. Ann Intern Med 73: 403, 1970. Shaldon S, Koch KM, Oppermann F, et al.: Testosterone therapy for anaemia in maintenance dialysis. Br Med J 3: 212,197l. Eschbach JW, Adamson JW: Improvement in the anemia of chronic renal failure with fluoxymasterone. Ann Intern Med 78: 527, 1973. Lindholm DD, Fisher JW, Vieira JA, et al.: Clinical effects of oral fluoxymesterone in patients with dialysis-controlled uremia. Trans Am Sot Artif Intern Organs 19: 475, 1973. Fried W. Jonasson 0, Lang G, et al.: The hematologic effect of androgen in uremic patients: study of pack cell volume and erythropoietin responses. Ann Intern Med 79: 823, 1973. Hendler ED, Goffinet JA, Ross S, et al.: Controlled study of androgen therapy in anemia of patients on maintenance hemodialysis. N Engl J Med 291: 1046, 1974. McCredie KB: Oxymetholone in refractory anaemia. Br J Haematol 17: 265, 1969.
131.
132.
133.
134. 135. 136.
137. 138.
139.
140.
141.
142.
143.
144.
145. 146.
147.
148. 149. 150. 151.
152. 153.
154. 155.
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Davies M, Muckle TJ, Cassells-Smith A, et al.: Oxymetholone in the treatment of anaemia in chronic renal failure. Br J Urol 44: 387, 1972. Baulieu EE: The action of hormone metabolites: a new concept in endrocrinology (a review on the metabolism and the activity of testosterone). Ann Clin Res 2: 246, 1970. Naets J-P, Wittek M: Etude du mecanisme d’action des androgenes sur I’erythropoiese. C R Acad Sci [D] (Paris) 259: 3371, 1964. Gurney CW, Fried W: Further studies on the erythropoietic effect of androgens. J Lab Clin Med 65: 775, 1965. Mirand EA, Gordon AS, Wenig J: Mechanism of testosterone action in erythropoiesis. Nature (Lond) 206: 270, 1965. Fried W, Kilbridge T: Effect of testosterone and of cobalt on erythropoietin production by anephric rats. J Lab Clin Med 74: 623, 1969. Gordon AS, Mirand EA, Wenig J, et al.: Androgen actions on erythropoiesis. Ann NY Acad Sci 149: 318, 1968. Nathan DG, Gardner FH: Effects of large doses of androgen on rodent erythropoiesis and body composition. Blood 26: 411, 1965. Kochakian CD, Nishida M, Hirone T: Ribosomes of mouse kidney: regulation by androgens. Am J Physiol 217: 383, 1969. Attardi B, Ohno S: Cytosol androgen receptor from kidney of normal and testicular feminized (Tfm) mice. Cell 2: 205, 1974. Levere RD, Kappas A, Granick S: Stimulation of hemoglobin synthesis in chick blastoderms by certain 5 @androstane and 5 p pregnane steroids. Proc Natl Acad Sci USA 58: 985, 1967. Necheles TF, Rai US: Studies on the control of hemoglobin synthesis: the in vitro stimulating effect of a 5&H steroid metabolite on heme formation in human bone marrow cells. Blood 34: 380, 1969. Gorshein D, Gardner FH: Erythropoietic activity of steroid metabolites in mice. Proc Natl Acad Sci USA 65: 564, 1970. Gordon AS, Zanjani ED, Levere RD, et al.: Stimulation of mammalian erythropoiesis by 5&H steroid metabolites. Proc Natl Acad Sci USA 65: 919, 1970. Byron JW: Effect of steroids on the cycling of haemopoietic stem cells. Nature (Lond) 228: 1204. 1970. Singer JW, Samuels Al. Adamson JW: Steroids and hematopoiesis. I. The effect of steroids on in vitro erythroid coloy growth: structure/activity relationships. J Cell Physiol 88: 127, 1976. Singer JW, Adamson JW: Steroids and hematopoiesis. II: The effect of steroids on in vitro erythroid colony growth: evidence for different target cells for different classes of steroids. J Cell Physiol 88: 135, 1976. Fisher JW, Samuels Al, Malgor LA: Androgens and erythropoiesis. Isr J Med Sci 7: 892, 1971. Scrimshaw NS, Young VR: The requirements of human nutrition. Sci Am 235: 51, 1976. Galloway DH: Recommended dietary allowances for protein and energy 1973. J Am Diet Assoc 64: 157, 1974. Kopple JD: Dietary requirements. Clinical Aspects of Uremia and Dialysis (Massty SG, Sellers AL, eds), Springfield, Ill., Charles C Thomas, 1976, p 453. Sullivan JF, Eisenstein AB: Ascorbic acid depletion during hemodialysis. JAMA 220: 1697, 1972. Dobbelstein H. Korner WF, Mempel W, et al.: Vitamin B6 deficiency in uremia and its implications for the depression of immune responses. Kidney Int 5: 233, 1974. Merrill RH, Tasch R: Iron absorption in hemodialyzed patients. Trans Am Sot Artif Intern Organs 22: 69, 1976. Abel RM, Beck CH Jr, Alcott WM, et al.: Improved survival
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157.
158.
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from acute renal failure after treatment with intravenous essential L-amino acids and glucose. N Engl J Med 288: 695, 1973. Nome LO, Bergstrom J: Treatment of chronic uremic patients with protein poor diet and oral supply of essential amino acids. II. Clin Nephrol 3: 195, 1975. Heidland A, Kult J: Long term effects of essential amino acids supplementation in patients on regular dialysis treatment. Clin Nephrol 3: 234, 1975. Young GA, Parsons FM: Impairment of phenylalanine hydroxylation in chronic renal insufficiency. Clin Sci Molec Med 45: 69. 1973.
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159. 160.
161.
162. 163.
Gulyassy PF, DeTorrenti A: Tryptophan metabolism in uremia. Kidney Int suppl 7, p 311, 1975. Kopple JD, Swendseid MD: Protein and amino acid metabolism in patients undergoing maintenance hemodialysis. Kidney Int Suppl 2, p 64, 1975. Chami J, Reidenberg M, Wellner D, et al.: Essential amino acid metabolism in maintenance dialysis patients. Trans Am Sot Artif Intern Organs 22: 168, 1976. Garber AJ: Abnormalities of carbohydrate metabolism in chronic uremia. Proc 9th Ann Conract Conf, p 5, 1976. Felig P. Pozefsky T, Marl& E, Cahill GF Jr: Alanine: key role in gluconeogenesis. Science 167: 1003, 1970.
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testosterone [ 1371. Androgen-treated female rats exhibit definite renal hypertrophy which closely parallels an increase in red cell mass [ 1381. It has also been shown that the ribonucleic acid of the mouse kidhey is decreased by castration and increased by the administration of androgens [ 1391. In man, because of the extrarenal source of erythropoietin, the presehce of kidneys does not seem essential for androgens to stimulate erythropoiesis. Significant erythrapoietic response has been achieved after androgen therapy in nephrectomized patients undergoing long-term hemodialysis [ 126,129]. It has been suggested, however, that these patients might show an even greater erythropoietic response if one of the kidneys were still present. The renotrophic action of androgens seems to depend, as for target organs such as prostate, on the presence of specific cytoplasmic androgen receptor proteins [ 1401. 5&H steroids have been reported to stimulate hemoglobin synthesis only by their direct cellular action without stimulating erythropoletin production [ 1411443. Other studies using thymidine suicide technics have yet uncovered another cellular effect of testosterone and some of its metaboiites; namely, the triggering of colony-forming units into cell cycles [ 1451. More recent investigations measuring the colonyforming ability of erythroid cells in vitro not only have cohfirmed the direct cellular action of most @-H steroids, but have also further shown that some of the 5a-H metabolites may exert similar direct action on erythroid elements [ 146,147]. Although the erythropoietic effect of unsaturated and tne 5a-H compounds in vivo has been well documented, studies evaluating the role of 5P-H metabolites in enhancing erythropoiesis in vivo have yielded conflicting results [143,144,148]. The Side Effects of Androgenic-Anabolic Hormones. The administration of androgens in dosage used to en-
hance erythropoiesis has definite side effects. Some degree of masculinization occurs in all children and women receiving large doses of androgens regardless of the preparation used. Flushing of the skin and acne appear usually two to three months after the initiation of androgen therapy. Deepening and hoarseness of the voice follow these dermal changes. In children before puberty, changes of external genitalia and growth of pubic hair occur one to three months after therapy. In females of menstruating age, amenorrhea and moderate enlargement of the clitoris develop. Changes in libido in both sexes have also been observed. It is known that prolonged administration of large doses of androgens to children increases the rate of the skeletal maturation. However, no serious growth retardation or roenfgenologic evidence of accelerated bone maturation‘has been noted in children treated with anabolic-androgenic steroids. Treatment with 17a-alkylated androgens may cause considerable disturbance to liver function. The abnormality ranges from an increase in sulfobromophthalein retention elevation in serum transaminase to a frank picture of cholestasis. This abnormality is, however, often reversible; Other complications such as significant weight gain as a result of water retention and elevation of plasma triglycerate levels have also been noted. In addition td’their hemopoietic effect, androgens are protein anabolic steroids that result in an appreciable nitrogen retention and thereby in a decrease in the formation of intoxicating protein breakdown products. As a result, sudden withdrawal of these hormones in uremic patients may markedly increase azotemia. A significant increase in erythrocyte 2,3diphosphoglycerate after androgen administration has been observed in man and in laboratory animals [ 1221. It is well known that this organic phosphate facilitates the unloading of oxygen from hemoglobin into the tissues by decreasing the oxygen affinity for hemoglobin.
Nutritional Supplements in Renal Failure KURT H. STENZEL, M.D., Rogosin Kidney Center, The New York Hospital-Cornell
A variety of nutritional supplements are often prescribed for patients with renal disease because of the frequency of wasting syndromes, the frequency of various vitamin and mineral deficiencies, and the necessity for limiting protein intake. These additives include caloric, vitamin, mineral and amino acid supplements. Precise nutritional requirements in patients with renal disease are not known. Requirements for normal people have been determined largely by short-term balance
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studies. The efficacy of nutritional supplements depends not only on over-all balance, but also on the particular metabolic pathways used to maintain that balance. For instance, external balance of a particular nutrient may be maintained in uremia by very different mechanisms than in health. Nutritional supplements, to be effective, must first be absorbed and then metabolized in a fashion that promotes normal tissue function. Gastrointestinal disease is common in uremia and may prevent adequate
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absorption of nutrients. Pathways of intermediary metabolism may be altered by retention of metabolites, leading to unusual and possibly energy-consuming pathways of nutrient utilization. Disturbances in hormone function that occur in uremia can also be expected to alter utilization of nutrients. Energy-containing nutrients are metabolized in three major steps. First, ingested food is digested, and the products of digestion are absorbed and transported to the tissues. Second, absorbed glucose, glycerol, fatty acids and amino acids may be incorporated into cellular biomolecules (anabolism) or undergo further degregation (catabolism) to small intermediates such as acetyl coenzyme A (acetyl-CoA). The third step includes complete oxidation of acetyl groups with release of four pairs of electrons that are utilized to generate ATP. The energy stored in ATP is then used for biologic workmechanical, transport or biosynthetic [ 1491. Recommended caloric intake for healthy men is 34 to 45 kilo calories (kcal) per kilogram per day; and for women, 3 1 to 36 kcal/kg/day [ 1501. Several factors complicate the determination of adequate caloric intake in patients with renal disease, and especially in those undergoing dialysis. Ideal weight is sometimes difficult to evaluate. Patients may be overhydrated or may have lost muscle mass that should be replenished. Uremia, infection and the stress of surgery for shunts and fistulas may all increase catabolism and, consequently, caloric requirements. Some nutrients may be lost during dialysis, thus increasing requirements. Kopple [1511 has recommended a minimal caloric intake of 35 kcal/kg of ideal body weight per day; and, of course, this should be increased in patients who are wasted, malnourished or subjected to any stress that might increase energy requirements. Several high-caloric, low-protein, lowelectrolyte supplements are available [ 15 11. Unfortunately, many patients find such supplements unpalatable, and if high-caloric foods can be included in a varied diet, they are better tolerated and lead to a better result. Vitamin deficiencies may arise in several ways. Water-soluble vitamins are lost during dialysis. Sullivan et al. [ 1521 documented that borderline vitamin C deficiencies may occur in dialyzed patients if vitamin C is not supplemented. This probably results from a combination of losses during dialysis and avoiding foods that are high in vitamin C, since many of these are also high in potassium. The actual quantities of water-soluble vitamins lost during dialysis are probably no greater than those lost in the urine when kidney function is normal. Evidence has been presented that there is a circulating inhibitor of vitamin B6 in uremia that necessitates larger than normal doses of this vitamin [ 1531. Because of losses during dialysis and the frequency of restricted diets and poor appetites in patients with renal disease,
vitamin supplements are recommended. These can simply be given as multiple vitamins, assuring that at least 10 mg/day of vitamin B6 is included. The major mineral supplements that are used are calcium and iron. Calcium has been discussed by the previous essayists. There has been some concern that iron may not be absorbed efficiently in uremic patients. Certainly, anemia is almost universal in patients with renal disease; but, as Dr. Shahidi has pointed out, the major defect is probably a lack of erythropoietin. Nevertheless, iron deficiency has been frequently documented in dialyzed patients. Several recent studies have indicated that iron absorption is, indeed, normal in dialyzed patients [ 1541. However, these studies are made in carefully controlled clinical research settings. Several factors may contribute to poor iron absorption in the day to day treatment of patients undergoing dialysis. Some patients have a high gastric pH that impedes iron absorption. The concomitant ingestion of bicarbonate or antacids and the ingestion of iron pills with meals to reduce gastric irritability may both contribute to poor iron absorption. Finally, the actual loss of blood and consequently iron during dialysis may be underestimated by the dialysis team. Because of the frequent occurrence of wasting syndromes, protein nutrition is of paramount interest to nephrologists. Decreasing protein intake clearly improves uremic symptoms. Keto acid analogues of essential amino acids and essential amino acids themselves as elemental diets have been recommended. Now that dialysis is widespread, however, there is less need for extreme dietary restriction. Nevertheless, interest in amino acid supplementation has continued in three major areas. Acute renal failure following trauma or surgery continues to present severe problems, and hyperalimentation with essential amino acids has been shown to be beneficial [ 1551. Several workers, especially in Europe, have suggested that patients with chronic uremia treated with dialysis benefit by supplementation with essential amino acis [ 1561. Heidland and Kult [ 1571 have demonstrated an increase in body weight, total serum protein, serum albumin, transferin and various complement components after supplementation of chronic dialysis patients with free amino acids. A third area of interest is the metabolic handling of amino acids in uremia. Studies have shown that phenylalanine metabolism is deranged, with a decreased conversion of phenylalanine to tyrosine [ 1581. There is a decreased protein binding of tryptophan in uremia that might affect metabolism of this amino acid [ 159). Multiple defects in fasting plasma amino acids have been described; the most usual alteration is a decrease in essential amino acids as opposed to nonessential amino acids. Kopple et al. ] 1601, however,
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demonstrated that many of these abnormalities could be duplicated in normal subjects by simply restricting protein intake. We studied first-pass metabolism and total body clearance of essential amino acids in a group of patients whose condition was stabilized during long-term dialysis and who were ingesting 60 to 70 g of protein per day and compared these data with those in normal subjects [ 1611. First-pass metabolism is quite variable in both the normal subjects and those with uremia. However, significant differences were seen in total body clearance rates. The branched-chain amino acids especially had a decreased total metabolic clearance rate. Renal clearances could not account for these differences, since they were negligible in both the normal subjects and the uremic patients. One patient was undergoing daily dialysis to lessen a peripheral neuropathy, and the metabolic clearance rate in this patient more closely approximated that in normal subjects than that in the group undergoing intermittent dialysis. Total body clearance of phenylalanine remained abnormal even in this patient. We gave relatively small doses of amino acids (approximately 10 g), and these were not enough to cause significant alterations in blood glucose or immunoreactive insulin levels. Garber [162] has dem-
onstrated that elevated PTH levels increase muscle protein breakdown, and vitamin D deficiency decreases the synthesis of muscle protein. PTH also increases hepatic gluconeogenesis. Our findings of a decreased total metabolic clearance rate might be put into a hypothetical scheme for the biochemical basis of muscle wasting in uremia. Vitamin D deficiency decreases muscle protein synthesis and perhaps leads to delayed clearance of branched-chain amino acids from plasma; PTH meanwhile increases skeletal protein breakdown and increases hepatic gluconeogenesis; and uremic toxins themselves may interfere *with amino acid transport. Studies are now underway to test the various aspects of this hypothesis. The glucose-alanine cycle has been well described [ 1631, and it may well be that PTH and vitamin D abnormalities are one of the primary reasons for muscle wasting in uremia. For a nutritional supplement to be effective, it must be absorbed, transported throughout the body and utilized in effective ways. In uremia, utilization of nutrients may be abnormal, so simply giving patients excessive nutrients may not be successful in reversing wasting syndromes. The pathogenesis of wasting must be established for each person and therapy directed at the basic abnormality.
REFERENCES 1. 2.
7.
8.
9. 10.
11.
550
Cheigh JS: Drug administration in renal failure. Am J Med 62: 555,1977. Szeto HH, lnturrisi CE, Houde RW, et al.: The accumulation of normeperidine, an active metabolite of meperidine, In patients with renal failure or cancer. Ann Intern Med (in press) Szeto HH, lnturrisi CE: Simultaneous determination of meperidine and normeperidine in biofluids. J Chromatogr 125: 503, 1976. Klotz U, Mcl-forse TS. Wilkinson GR, et al.: The effect of cirrhosis on the disposition and elimination of meperidine in man. Clin Pharmacol Ther 16: 667, 1974. McHorse TS, Wilkinson GR, Johnson RF, et al.: Effect of acute viral hepatitis in man on the disposition and elimination of meperidine. Gastroenterology 68: 775, 1975. Miller JW, Anderson HH: The effect of Ndemethylation on certain pharmacologic actions of morphine, codeine, and meperidine in the mouse. J Pharmacol Exp Ther 112: 19 1, 1954. Deneau GA, Nakai K: The toxicity of meperidine in the monkey as influenced by its rate of absorption. Bulletin, Drug Addiction and Narcotics, App. 6, 2460, 1961. Gilbert PE, Martin WR: The antagonism of the convulsant effects of heroin, d-propoxyphene, meperidine, normeperidine and thebaine by naloxone in mice. J Pharmacol Exp Ther 192: 538, 1975. lntunisi CE: Disposition of narcotics and narcotic antagonists. Ann NY Acad Sci 281: 273. 1976. Kreek MJ, Gutjahr CL, Bowen DV, et al.: Fecal excretion of methadone and its metabolites. A major pathway of elimination in man. Proceedings of the Third National Drug Abuse Conference (in press). Reidenberg MM: Renal Function and Drug Action, Philadel-
April 1977
The American Journal of Medlclne
Volume 62
12.
13.
14. 15.
16.
17.
18.
19.
20.
21.
phia, W. B. Saunders, 1971. Lindner A, Charra B, Sherrard DJ, et al.: Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 290: 697, 1974. Evans GH, Shand DG: Disposition of propranolol. V. Drug accumulation and steady-state concentrations during chronic oral administration in man. Clin Pharmacol Ther 14: 487, 1973. Shand DG, Nukolls EM, Oates JA: Plasma propranolol levels in adults. Clin Pharmacol Ther 11: 112, 1970. Briggs WA, Lowenthal DT, Cirksena W, et al.: Propranolol in hypertensive dialysis patients: efficacy and compliance. Clin Pharmacol Ther 18: 606, 1975. Cotham RH, Shand D: Spuriously low plasma propranolol concentrations resulting from blood collection methods. Clin Pharmacol Ther 18: 535, 1975. Lowenthal DT, Briggs WA, Gibson TP, et al.: Pharmacokinetics of oral propranolol in chronic renal disease. Clin Pharmacol Ther 18: 761, 1974. Bianchetti G, Graziani G, Brancaccio D, et al.: Pharmacokinetics and effects of propranolol in terminal uraemic patients and in patients undergoing regular dialysis treatment. Clin Pharmacokin 1: 373, 1976. Lowenthal DT, Mutterperl R: Pharmacokinetics of oral propranolol. II. The effects of chronic dosing and protein binding (abstract). Clin Pharmacol Ther 19: 111, 1976. Lichter M, Black M, Arias IM: The metabolism of antipyrine in patients with chronic renal failure. J Pharmacol Exp Ther 187: 612, 1973. Reidenberg MM, Ddar-Cederlof I, von Bahr C, et al.: Protein binding of diphenylhydantoin and desmethylimipramine in plasma from patients with poor renal function. N Engl J Med 285: 264, 1971.
COMBsINED SEMINAR ON THE USE OF DRUGS IN RENAL FAILURE
22.
23.
24.
25.
26. 27.
28.
29.
30.
31.
32.
33.
34.
35.
36. 37. 38.
39. 40.
41.
42. 43.
44.
Reidenberg MM, Lowenthal DT, Briggs WA, et al.: Pentobarbital elimination in patients with poor renal function. Clin Pharmacol Ther 20: 67, 1976. Gerhardt RE, Knouss RF, Thyrum PT. et al.: Quinidine excretion in aciduria and alkaluria. Ann Intern Med 71: 927, 1969. Kessler KM, Lowenthal DT, Warner H, et al.: Unimpaired quinidine elimination in patients with poor renal function or congestive heart failure. N Engl J Med 290: 706, 1974. Bellett S, Roman LR, Boza A: Relation between serum quinidine levels and renal function: studies in normal subjects and patients with congestive failure and renal insufficiency. Am J Cardiol 27: 368, 1971. Lowenthal DT. Drayer D, Reidenberg MM: Unpublished observations. Galeazzi RL, Sheiner LB, Lockwood T, et al.: The renal elimination of procainamide. Clin Pharmacol Ther 19: 55, 1976. Gibson TP, Matusik EJ, Briggs WA: N-acetylprocainamide levels in patients with end-stage renal failure. Clin Pharmacol Ther 19: 206, 1976. Drayer DE, Lowenthal DT, Woosley RL, et al.: Accumulation of N-acetylprocainamide (NAPA), an active metabolite of procaine amide in patients with poor renal function (abstract). Program of 9th Annual Meeting of the American Society of Nephrology, Washington, D.C., 1976. Gibson TP, Lowenthal DT, Nelson HA, et al.: Elimination of procainamide in end-stage renal failure. Clin Pharmacol Ther 17: 321, 1975. Drayer D, Reidenberg MM, Sevy RW: N-acetylprocainamide: an active rnetabolite of procaine amide. Proc Sot Exp Biol 146: 358, 19.74. Elson J, Strong JM, Lee WK, et al.: Antiarrhythmic potency of n-acetylprocainamide. Clin Pharmacol Ther 17: 134, 1975. Collinsworth KA. Kalman SM. Harrison DC: The clinical pharmacology of lidocaine as an antiarrhythmic drug. Circulation 50: 1217, 1974. Thomson PD. Melmon KL, Richardson JA, et al.: Lidocaine pharmacokinetics in advanced heat-l failure, liver disease and renal failure in humans. Ann Intern Med 78: 499, 1973. Williams RL, Blaschke TF, Meffin PJ, et al.: Influence of viral hepatitis on the disposition of two compounds with high hepatic clearance: lidocaine and indocyanine green. Clin Pharmacol Ther 20: 290, 1976. Boyes RN, Scott DB, Jebson PJ, et al.: Pharmacokinetics of lidocaine in man. Clin Pharmacol Ther 12: 105, 197 1. Bryan FA: National Dialysis Registry: Final Report, Research Triangle Institute, Research Triangle Park, N.J., 1976. Linder A, Charra B. Sherrard DJ, et al.: Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 290: 697, 1974. Lazarus JM, Hampers CL, Merrill JP: Hypertension in chronic renal failure. Arch Intern Med 133: 1059, 1974. Dathran JRE, Goodwin FJ: The relationship between body fluid compartment volume, renin and blood pressure on chronic renal failure. Clin Sci 42: 29, 1972. Weideman P, Maxwell MM, Lupu AN, et al.: Plasma renin activity and blood pressure in terminal renal failure. N Engl J Med 285: 757, 1971. Vertes V, Cangiano JL, Berman LB, et al.: Hypertension in end-stage renal disease. N Engl J Med 280: 978, 197 1. Schonberg SM, Stone RA, Kirshner N, et al.: Plasma dopamine-@-hydroxylase: a possible aid in the study and evaluation of hypertension. Science 183: 523, 1974. White RP, Sealey J, Reidenberg M, et al: Mechanisms of blood pressure control in anephrics: plasma renin and dopamine-&hydroxylase activity. Trans Am Sot Artif
45.
46.
47.
48.
49.
50.
51.
52. 53. 54.
55. 56. 57.
58.
59. 60.
61. 62. 63. 64. 65.
66. 67.
68. 69.
April 1977
Intern Organs 22: 420, 1976. Kelly MR. Cutler RE, Christopher TG, et al.: Pharmacokinetics of furosemide in normal subjects and anephric patients. Clin Res 21: 470, 1973. Pillay VKG, Schwartz FD, Aimi K, et al.: Transient and permanent deafness following treatment with ethacrynic acid in renal failure. Lancet 1: 77, 1969. Laragh JH: Vasoconstriction volume analysis for understanding and treating hypertension: the use of renin and aldosterone profiles. Am J Med 55: 261, 1973. Brunner MR, Gavras, M, Laragh JH, et al.: Angiotensin II blockade in man by sar’-alas-angiotensin II for understanding and treatment of high blood pressure. Lancet 2: 1045, 1973, Gavras M, Brunner HR, Laragh JH, et al.: An angiotensinconverting enzyme inhibitor to identify and treat vasoconstrictor and volume factors in hypertensive patients. N Engl J Med 291: 817, 1974. Case DB, Wallace JM, Keim HJ, et al.: Estimating renin participation in hypertension: superiority of converting enzyme inhibitors over saralasin. Am J Med 61: 790, 1976. Hollifield JW, Sherman K, VanderZuagg R, et al.: Proposed mechanisms of propranolol’s antihypertensive effect. N Engl J Med 295: 68, 1976. Davies R, Slater JDM: Is the adrenergic control of renin release dominant in man? Lancet 2: 594, 1976. Holland OB, Kaplan NM: Propranolol in the treatment of hypertension. N Engl J Med 294: 936, 1976. Myhre E, Brodwell EK, Stenback 0, et al.: Plasma turnover of methyldopa in advanced renal failure. Acta Med Stand 191: 343, 1972. Onesti G. Schwartz AB, Kim KE: Antihypertensive effect of clonidine. Circ Res 2 (suppl): 53, 1971. Reidenberg MM, Drayer D, DeMarco AL, et al.: Hydralazine elimination in man. Clin Pharmacol Ther 14: 970. 1973. Gottlieb TB, Thomas RC, Chidsey CA: Pharmacokinetic studies of minoxidil. Clin Pharmacol Ther 13: 436, 1972. O’Malley K, Velasco M, Pruitt A, et al.: Decreased plasma protein binding of diazoxide in uremia. Clin Pharmacol Ther 18: 53, 1975. Koch-Weser J: Drug therapy: diazoxide. N Engl J Med 294: 1271, 1976. Guiha NH, Limas CJ, Franciosa JA, et al.: Treatment of refractory heart failure with sodium nitroprusside (abstract). Circulation 46 (suppl 2): 105, 1972. Kennedy AC: Men of Parts. Philos Trans R Philos Sot Glasgow 10: 3, 1973. Abel JJ. Rowntree LG, Turner BB: J Pharmacol Exp Ther 5: 275, 1913. Kolff WJ, Berk HTJ: Artificial kidney: dialyzer with great area. Acta Med Stand 117: 121, 1944. Merrill JP: Clinical application of an artificial kidney. Bull N Engl Med Ctr 11: 111, 1949. Quinton W, Dillard D. Scribner BH: Cannulation of blood vessels for prolonged hemodialysis. Trans Am Sot Artif Intern Organs 6: 104, 1960. Friedman EA: Sorbents in the management of uremia. Am J Med 60: 614, 1976. Giordano C, Esposito R, Randazzo G: Oxystarch as a gastrointestinal sorbent in uremia. Uremia (Kluthe R, Berlyne G, Burton 8, eds), Stuttgart, Georg Thieme Verlag, 1972, p 231. Giordano C: Digestible adsorbents in renal failure. Proc Strathclyde Bioengineering Sem II (in press). Friedman EA, Fastook J, Beyer MM, et al.: Potassium and nitrogen binding in the human gut by ingested oxidized starch (OS). Trans Am Sot Artif Intern Organs 20: 161, 1974.
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70.
7 1.
72.
73. 74.
75.
76.
77.
78.
79. 80.
81.
82. 83.
84.
85.
86.
87.
88.
89.
90.
552
Friedman EA. Laungani GB, Beyer MM: Life prolongation in nephrectomized rats fed oxidized starch and charcoal. Kidney Int 7 (suppl 3): 377, 1975. Saltzman MJ, Beyer MM, Friedman EA: Mechanism of life prolongation in nephrectomized rats treated with oxidized starch and charcoal. Kidney Int 10 (suppl 7): 343, 1976. Saltzman MI, Delano BG, Frank WM. et al.: Control of uremic hyperlipidemia (HL) by activated charcoal (AC) and oxidized starch (OS) (abstract). Program of the 9th Annual Meeting of the American Society of Nephrology, Washington, D.C., 1976. Yatzidis H: Recherches sur I’epuration extra renale a I’akfe de charbon actif. Nephron 1: 310. 1964. Friedman EA, Saltzman MJ, Beyer MM, et al.: Combined oxystarch-charcoal trial in uremia; sorbent-induced reduction in serum cholesterol. Kidney Int 10 (suppl7): 273, 1976. Goldenhersh KK, Huang W, Mason NS, et al.: Effect of microencapsulation on competitive adsorption in intestinal fluids. Kidney Int 10 (suppl 7): 251, 1976. Sparks RE, Gupta DVS, Mason NS: Adsorbtion of barbiturates from buffers, blood and intestinal fluids. Strachclyde Sem on Artif Organs II (in press). Alfrey AC, LeGendre GR, Kaehny WD: The dialysis encephalopathy syndrome possible aluminum intoxication. N Engl J Med 294: 184, 1976. Pierides AM, Ward MK, Kerr DNS: Hemodialysis encephalopathy: possible role of phosphate depletion. Lancet 1: 1234, 1976. Omdahl JL, DeLuca HF: Regulation of vitamin D metabolism and function. Physiol Rev 53: 327, 1973. Norman AW, Henry H: 1,25-Dihydroxycholecalciferol-a hormonally active form of vitamin 0s. Ret Prog Horm Res 30: 431, 1974. Norman AW: The hormone-like action of 1,25-(OH)*cholecalciferol (a metabolite of the fat-soluble vitamin D) in the intestine. Vitam Horm 32: 325, 1974. DeLuca HF: The kidney as an endocrine organ involved in the function of vitamin D. Am J Med 58: 39. 1975. Dent CC, Richens A, Rowe DJF, et al.: Osteomalacia with long-term anticonvulsant therapy in epilepsy. Br Med J 4: 69, 1970. Hunter J, Maxwell JD, Stewart DA, et al.: Altered calcium metabolism in epileptic children on anticonvulsants. Br Med J 4: 202, 1971. Hahn TJ, Hendin BA, Scharp CR, et al.: Effect of chronic anticonvulsant therapy on serum 25hydroxycalciferol levels in adults. N Engl J Med 287: 900, 1972. Stamp TCB, Round JM, Rowe DJF, et al.: Plasma levels and therapeutic effect of 25hydroxychofecalciferol in epileptic patients taking anticonvulsant drugs. Br Med J 4: 9, 1972. Caspary WF, Hesch RD, Matte R, et al.: Intestinal calcium absorption in epileptics under anticonvulsant therapy. Vitamin D and Problems Related to Uremic Bone Disease (Norman AW, Schaeffer K, Grigoleit HG. et al.. eds), Berlin, de Gruyter, 1975, p 737. Brickman AS, Coburn JW, Norman AW: Action of 1,25dihydroxycholecalciferol, a potent kidney-produced metabolite of vitamin Ds in uremic man. N Engl J Med 287: 891, 1972. Brickman AS, Coburn JW, Massry SG, ef al.: 1,25-Dihydroxyvitamin Ds in normal man and patients with renal failure. Ann Intern Med 80: 161, 1974. Chalmers TM, Davie MW, Hunter JO, et al.: 1-Alpha-hydroxycholecalciferol as a substitute for the kidney hormone, 1,25dihydroxycholecalciferol in chronic renal failure. Lancet 2: 696, 1973.
April 1977
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Journal of Medlclne
Volume 62
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101. 102.
103.
104.
105.
106.
107.
108.
109.
Brickman AS, Coburn JW, Friedman GR, et al.: Comparison of effects of la-hydroxy-vitamin 0s and 1,25dihydroxyvitamin Ds in man. J Clin Invest 57: 1540. 1976. Bar A, Wasserman RH: Duodenal calcium binding protein in the chick: a new bioassay for vitamin D. J Nutr 104: 1202,1974. Haussler MR. Zerwekh JE, Hesse RH, et al.: Biological activity of la-hydroxycholecalciferol, a synthetic analog of the hormonal form of vitamin Ds. Proc Natl Acad Sci USA 70: 2248, 1973. Hibberd KA, Norman AW: Comparative biological effects of vitamin Ds and 0s and dihydrotachysterols and dihydrotachysterols in the chick. Biochem Pharmacol 18: 2347, 1969. Stanbury SW: Bony complications of renal disease, chap 26. Renal Disease (Black DAK, ed), Philadelphia, F. A. Davis, 1967. E&wood JB, Bordier PJ, Clarkson EM, et al.: The contrasting effects on bone histology of vitamin D and of calcium carbonate in the osteomalacia of chronic renal failure. Clin Sci 47: 23, 1974. Verberckmoes R, Bouillon R, Krempien B: Osteodystrophy of dialyzed patients treated with vitamin D. Proc Eur Dial Transplant Assoc 10: 216, 1973. David DS: Mineral and bone homeostasis in renal failure: pathophysiology and management, chap 1. Calcium Metabolism in Renal Failure and Nephrolithiasis (David DS, ed), New York, John Wiley (in press). Kaye M, Chatterjee G, Cohen GF, et al.: Arrest of hyperparathyroid bone disease with dihydrotachysterol in patients undergoing chronic hemodialysis. Ann Intern Med 73: 225, 1970. Hill AVL, Alvarez-Ude F, Pierides AM, et al.: The effects of calcium carbonate, aluminum hydroxide and dihydrotachysterol on hemodialysis bone disease. Vitamin D and Problems Related to Uremic Bone Disease (Norman AW, Schaeffer K. Grigoleit HG, et al., eds), Berlin, de Gruyter, 1975, p 643. Hallick RB, DeLuca HF: Metabolites of dihydrotachysterols in target tissues. J Biol Chem 247: 91. 1972. Gray RW, Orndahl JL, Ghazarian JG, et al.: 25hydroxycholecalciferol-l-hydroxylase: subcellular location and properties. J Biol Chem 247: 7528, 1972. DeLuca HF: The kidney as an endocrine organ for the production of 1,25dihydroxyvitamin Ds. a calcium-mobilizing hormone. N Engl J Med 289: 359, 1973. Davie MWJ, Chalmers TM, Hunter JO, et al.: l-alpha.‘rydroxycholecalciferol in chronic renal failure: studies of the effect of oral doses. Ann Intern Med 84: 281, 1976. Peacock M, Gallagher JC, Nordin BEC: Action of la-hydroxy vitamin Ds on calcium absorption and bone resorption in man. Lancet 1: 385, 1974. Naik RB, Gosling P, Price CP, et al.: Whole-body in-vivo neutron activation analysis in assessing treatment of renal osteodystrophy with 1-alpha-hydroxycholecalciferol. Br Med J 2: 79, 1976. Peacock M, Nordin BEC, Gallagher JC, et al.: Action of la-hydroxy vitamin Ds in man. Vitamin D and Problems Related to Uremic Bone Disease (Norman AW, Schaeffer K. Grigoleit HG, et al., eds), Berlin, de Gruyter, 1975, p 611. Zerwekh HE, Brumbaugh PF, Haussler DH. et al.: la-hydroxyvitamin Ds, an analog of vitamin D which apparently acts by metabolism to lLu.25dihydroxyvitamin 0s. Biochemistry 13: 4097, 1974. Pierides AM, Ellis HA, Ward M, et al.: Barbiturate and anticonvulsant treatment in relation to osteomalacia with hemodialysis and renal transplantation. Br Mad J 1: 190, 1976.
COMBINED SEMINAR ON THE USE OF DRUGS IN RENAL FAILURE
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122. 123. 124.
125.
126.
127.
128.
129.
130.
Pierides AM, Kerr DNS, Ellis HA, et al.: la-hydroxycholecalciferol in hemodialysis renal osteodystrophy: adverse effects of anticonvulsant therapy. Clin Nephrol 5: 189, 1976. Coburn JW, Brickman AS, Hartenbower DL: Clinical disorders of calcium metabolism in relation to vitamin D. Vitamin D and Problems Related to Uremic Bone Disease (Norman AW, Schaeffer K, Grigoleit HG, et al., eds), Berlin, de Gruyter. 1975, p 219. Catto GRD, MacLeod M, Pelt B, et al.: la-hydroxycholecalciferol: a treatment of renal bone disease. Br Med J 1: 12, 1975. Rutherford WE, Blondin J, Hruska K, et al.: Effect of 25 hydroxycholecalciferol on calcium absorption in chronic renal disease. Kidney Int 8: 320, 1975. Bordier PJ, Marie PJ, Arnaud CD: Evolution of renal osteodystrophy: correlation of bone histomorphometry and serum mineral and immunoreactive parathyroid hormone values before and after treatment with calcium carbonate or 25hydroxycholecalciferol. Kidney Int (suppl 2) p 102, 1975. Teitelbaum SL, Bone JM, Stein PM, et al.: Calcifediol in chronic renal insufficiency: skeletal response. JAMA 235: 164, 1976. Steele TH, Tyson IB: Use of a rapid external counting tracer technique for assessing calcium absorption in advanced renal disease. Clin Dial Transpl Forum 1: 136, 1971. Brickman AS, Coburn JW, Massty SG: 1,25 dihydroxy-vitamin D3 in normal man and patients with renal failure. Ann Intern Med 80: 161, 1974. Henderson RG, Russell RGG, Ledingham JGG, et al.: Effects of 1,25_dihydroxycholecalciferol on calcium absorption, muscle weakness, and bone disease in chronic renal failure. Lancet 1: 379, 1974. Bordier PJ, Tun Chot S, Eastwood JB, et al.: Lack of histological evidence of vitamin D abnormality in the bones of anephric patients. Clin Sci 44: 33, 1973. Jubiz W, Haussler MR, Tolman KG, et al.: Plasma 1.25 dihydroxyvitamin D levels in patients on anticonvulsant drugs. Clin Res 24: 255A, 1976. Rasmussen H, Bordier P: The Physiological and Cellular Basis of Metabolic Bone Disease, Baltimore, Williams & Wilkins, 1974. Shahidi NT: Androgens and erythropoiesis. N Engl J Med 289: 72, 1973. Fried W: Use of androgens in hematologic disease. Postgrad Med 55: 155, 1974. Richardson JR Jr, Weinstein MB: Erythropoietic response of dialyzed patients to testosterone administration. Ann Intern Med 73: 403, 1970. Shaldon S, Koch KM, Oppermann F, et al.: Testosterone therapy for anaemia in maintenance dialysis. Br Med J 3: 212,197l. Eschbach JW, Adamson JW: Improvement in the anemia of chronic renal failure with fluoxymasterone. Ann Intern Med 78: 527, 1973. Lindholm DD, Fisher JW, Vieira JA, et al.: Clinical effects of oral fluoxymesterone in patients with dialysis-controlled uremia. Trans Am Sot Artif Intern Organs 19: 475, 1973. Fried W. Jonasson 0, Lang G, et al.: The hematologic effect of androgen in uremic patients: study of pack cell volume and erythropoietin responses. Ann Intern Med 79: 823, 1973. Hendler ED, Goffinet JA, Ross S, et al.: Controlled study of androgen therapy in anemia of patients on maintenance hemodialysis. N Engl J Med 291: 1046, 1974. McCredie KB: Oxymetholone in refractory anaemia. Br J Haematol 17: 265, 1969.
131.
132.
133.
134. 135. 136.
137. 138.
139.
140.
141.
142.
143.
144.
145. 146.
147.
148. 149. 150. 151.
152. 153.
154. 155.
April 1977
Davies M, Muckle TJ, Cassells-Smith A, et al.: Oxymetholone in the treatment of anaemia in chronic renal failure. Br J Urol 44: 387, 1972. Baulieu EE: The action of hormone metabolites: a new concept in endrocrinology (a review on the metabolism and the activity of testosterone). Ann Clin Res 2: 246, 1970. Naets J-P, Wittek M: Etude du mecanisme d’action des androgenes sur I’erythropoiese. C R Acad Sci [D] (Paris) 259: 3371, 1964. Gurney CW, Fried W: Further studies on the erythropoietic effect of androgens. J Lab Clin Med 65: 775, 1965. Mirand EA, Gordon AS, Wenig J: Mechanism of testosterone action in erythropoiesis. Nature (Lond) 206: 270, 1965. Fried W, Kilbridge T: Effect of testosterone and of cobalt on erythropoietin production by anephric rats. J Lab Clin Med 74: 623, 1969. Gordon AS, Mirand EA, Wenig J, et al.: Androgen actions on erythropoiesis. Ann NY Acad Sci 149: 318, 1968. Nathan DG, Gardner FH: Effects of large doses of androgen on rodent erythropoiesis and body composition. Blood 26: 411, 1965. Kochakian CD, Nishida M, Hirone T: Ribosomes of mouse kidney: regulation by androgens. Am J Physiol 217: 383, 1969. Attardi B, Ohno S: Cytosol androgen receptor from kidney of normal and testicular feminized (Tfm) mice. Cell 2: 205, 1974. Levere RD, Kappas A, Granick S: Stimulation of hemoglobin synthesis in chick blastoderms by certain 5 @androstane and 5 p pregnane steroids. Proc Natl Acad Sci USA 58: 985, 1967. Necheles TF, Rai US: Studies on the control of hemoglobin synthesis: the in vitro stimulating effect of a 5&H steroid metabolite on heme formation in human bone marrow cells. Blood 34: 380, 1969. Gorshein D, Gardner FH: Erythropoietic activity of steroid metabolites in mice. Proc Natl Acad Sci USA 65: 564, 1970. Gordon AS, Zanjani ED, Levere RD, et al.: Stimulation of mammalian erythropoiesis by 5&H steroid metabolites. Proc Natl Acad Sci USA 65: 919, 1970. Byron JW: Effect of steroids on the cycling of haemopoietic stem cells. Nature (Lond) 228: 1204. 1970. Singer JW, Samuels Al. Adamson JW: Steroids and hematopoiesis. I. The effect of steroids on in vitro erythroid coloy growth: structure/activity relationships. J Cell Physiol 88: 127, 1976. Singer JW, Adamson JW: Steroids and hematopoiesis. II: The effect of steroids on in vitro erythroid colony growth: evidence for different target cells for different classes of steroids. J Cell Physiol 88: 135, 1976. Fisher JW, Samuels Al, Malgor LA: Androgens and erythropoiesis. Isr J Med Sci 7: 892, 1971. Scrimshaw NS, Young VR: The requirements of human nutrition. Sci Am 235: 51, 1976. Galloway DH: Recommended dietary allowances for protein and energy 1973. J Am Diet Assoc 64: 157, 1974. Kopple JD: Dietary requirements. Clinical Aspects of Uremia and Dialysis (Massty SG, Sellers AL, eds), Springfield, Ill., Charles C Thomas, 1976, p 453. Sullivan JF, Eisenstein AB: Ascorbic acid depletion during hemodialysis. JAMA 220: 1697, 1972. Dobbelstein H. Korner WF, Mempel W, et al.: Vitamin B6 deficiency in uremia and its implications for the depression of immune responses. Kidney Int 5: 233, 1974. Merrill RH, Tasch R: Iron absorption in hemodialyzed patients. Trans Am Sot Artif Intern Organs 22: 69, 1976. Abel RM, Beck CH Jr, Alcott WM, et al.: Improved survival
The American Journal of Medicine
Volume 62
553
COMBINED SEMINAR ON THE USE OF DRUGS IN RENAL FAILURE
156.
157.
158.
554
from acute renal failure after treatment with intravenous essential L-amino acids and glucose. N Engl J Med 288: 695, 1973. Nome LO, Bergstrom J: Treatment of chronic uremic patients with protein poor diet and oral supply of essential amino acids. II. Clin Nephrol 3: 195, 1975. Heidland A, Kult J: Long term effects of essential amino acids supplementation in patients on regular dialysis treatment. Clin Nephrol 3: 234, 1975. Young GA, Parsons FM: Impairment of phenylalanine hydroxylation in chronic renal insufficiency. Clin Sci Molec Med 45: 69. 1973.
April 1977
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Journal of Medicine
Volume 62
159. 160.
161.
162. 163.
Gulyassy PF, DeTorrenti A: Tryptophan metabolism in uremia. Kidney Int suppl 7, p 311, 1975. Kopple JD, Swendseid MD: Protein and amino acid metabolism in patients undergoing maintenance hemodialysis. Kidney Int Suppl 2, p 64, 1975. Chami J, Reidenberg M, Wellner D, et al.: Essential amino acid metabolism in maintenance dialysis patients. Trans Am Sot Artif Intern Organs 22: 168, 1976. Garber AJ: Abnormalities of carbohydrate metabolism in chronic uremia. Proc 9th Ann Conract Conf, p 5, 1976. Felig P. Pozefsky T, Marl& E, Cahill GF Jr: Alanine: key role in gluconeogenesis. Science 167: 1003, 1970.
