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Chronic Renal Insufficiency
Symposium on Pediatric Nephrology
Chronic Renal Insufficiency Peter R. Lewy, M.D.*, and John K. Hurley, M.D.t
In health, the functional capacities of the normal kidneys permit maintenance of body homeostasis in the presence of wide variations in the need for excretion or conservation of the many constituents under their control,55 and provide ample reserve for periods of stress. As renal mass is diminished, by congenital maldevelopment or by acquired disease processes, the limits of homeostatic tolerance are progressively reduced. When this results in detectable abnormalities in the body content or concentrations of the various components regulated by the kidneys, renal insufficiency can be said to exist. This occurs when renal function is reduced below 25 to 30 per cent of normal, as reflected clinically by a creatinine clearance of 30 to 40 ml1min/1. 73 m 2 • At this point definite elevations in the serum concentrations of urea (> 20 mg per 100 ml) and creatinine (> 1.5 mg per 100 ml) are noted. It is important to recognize that the normal limits of serum creatinine concentration are much lower for infants and small children (- 0.3 to 0.8 mg per 100 ml) than for larger children and adults (- 0.7 to 1.5 mg per 100 ml). With progressive decline in renal function a variety of adaptive responses occur. Most are highly effective in maintaining normal body composition despite marked reductions in renal mass, to as low as 5 to 15 per cent of normal, but may have adverse effects on other bodily functions. The concept of "trade off" is suggested by Bricker et al. H • 12 The most clearly defined example of this "trade off," the manner in which phosphorus balance is maintained by the failing kidney, is fully described elsewhere in this symposium. Although chronic dialysis is necessary to sustain the patient with severe renal insufficiency, several manifestations of more moderate renal impairment respond favorably to careful medical management. These include abnormalities of salt and water metabolism, hyperkalemia, acidosis, anemia, azotemia and uremia, and growth failure.
SALT AND WATER REGULATION In chronic renal insufficiency the decreased glomerular filtration reduces the amount of salt and water potentially available for excretion. *Assistant Professor of Pediatrics, Northwestern University Medical School; Head, Division of Nephrology, The Children's Memorial Hospital, Chicago, Illinois
t Assistant Professor of Pediatrics, Northwestern University Medical School; Attending Nephrologist, The Children's Memorial Hospital, Chicago, Illinois
Pediatric Clinics of North America-Vol. 23, No.4, November 1976
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However, compensatory physiologic and hormonal mechanisms,12 as well as the increased osmotic load provided by retained urea and other wastes, generally provide for the excretion of sodium and water in amounts comparable to normal individuals. The limits of homeostatic tolerance are reduced, however, so that unusually large loads of salt and water may not be readily excreted. Conversely, mechanisms for the conservation of salt and water are often damaged by the disease process and/or rendered relatively ineffective by virtue of the markedly increased volume of filtrate which must be processed by each remnant nephron. Undue restriction of salt and water may thus lead to volume depletion and further reduction of glomerular filtration. Unless demanded by specific aspects of the clinical situation, such as seVere hypertension or pulmonary congestion, free selection of salt and water is generally permissible and desirable in patients with mild or moderate renal insufficiency. Three patterns of abnormality of salt and water homeostasis are relatively characteristic of specific underlying renal disease. Many infants and small children with congenitally dysplastic kidneys or with urinary obstructive disease tend to excrete large volumes of dilute urine low in sodium content. Overall renal function is generally only moderately impaired, with serum creatinine in the range of 1. 5 to 4.0 mg per 100 ml and B UN in the range of 25 to 60 mg per 100 ml. The situation may mimic nephrogenic diabetes insipidus, and is due to maldevelopment of, or damage to, the renal medullary concentrating mechanism. The large volumes of urine these children excrete as infants may not be obvious because babies are generally assumed to "wet" frequently. Such infants are noted to have an affinity for water and may cry until water is provided, even after a formula or milk feeding. These infants are at particular risk from severe dehydration when they may be unwilling to take fluids or unable to retain them, such as in the event of illness. They are at risk in the hospital where water is not routinely provided at frequent intervals. Prolonged periods of "nothing by mouth" preoperatively are similarly hazardous. Infants and small children suspected of having renal dysplasia must be carefully monitored for state of hydration with daily weights and accurate measurement of intake and output. From the data obtained, adequate fluid reg'imens may be prescribed. Manipulations of dietary sodium are rarely needed. Hypertension is uncommon in these children. The second pattern, salt and water retention associated with chronic glomerulonephritis, is presumed to result from greater reduction of glomerular filtration than of tubular reabsorption, causing a glomerulotubular imbalance. Consequences of fluid retention include peripheral edema, hypertension, congestive failure, and pulmonary edema. In addition, marked proteinuria in many patients with nephritis leads to nephrotic (noncongestive) edema. Urine volume is generally "normal," with urine sodium in the range of20 to 60 mEqlliter and a fixed specific gravity of 1.010. In the older age range and in the absence of obvious edema, water intake is perhaps best governed by the child's own thirst mechanisms. Sodium restriction in the range of 1 to 3 gm/day is helpful in limiting edema and ameliorating hypertension. Antihypertensive agents are recommended for blood pressures greater than 135 mm Hg systolic, 95 diastolic. 9 Diuretics, particularly furosemide, are useful in the management of edema and hypertension, though doses as large as 4 to 10
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mg/kg/day may be necessary in moderate to severe renal insufficiency.43 The third pattern of abnormal salt and water regulation is that of salt wasting which is seen in some patients with chronic pyelonephritis or hydronephrosis and normal blood pressure, as well as in patients with nephronophthisis (medullary cystic disease). These patients lose large amounts of urine high in sodium content (60 to 120 mEqlliter) and may obligatorily excrete 12 to 25 gm of salt in 3 to 6 or more liters of urine per day. The defect in sodium reabsorption is primarily in the distal nephron, and the salt wasting is accompanied by inability to concentrate or to dilute the urine. Salt ingestion is spontaneously high in these patients. Sodium restriction by intent or by omission (as in the hospitalized patient) can lead rapidly to severe hyponatremic dehydration and must be avoided. For proper fluid management, knowledge of the patient's usual urinary volume and sodium content is mandatory. In end-stage renal disease the markedly reduced glomerular filtration is inadequate to permit complete excretion ofloads of sodium and water in the amounts ingested by normal individuals. Retention of salt and water then leads to edema and vascular congestion, often with resultant hypertension, pulmonary edema, and cardiac failure. These complications may be prevented by restriction of water intake to equal insensible water losses (basal losses 30 mllkg/day in infants up to 1 year of age, 20 mllkglday to a maximum of 400 to 500 ml in older children) plus measured urinary and nonurinary losses. Sodium intake should be restricted to equal measured urinary losses plus any other measurable losses. When problems in such fluid management become severe, especially in association with various other manifestations of severe renal disease, peritoneal dialysis or hemodialysis may be the treatment of choice.
HYPERKALEMIA Hyperkalemia is an infrequent occurrence in patients with chronic renal insufficiency. The chronically diseased kidney has the ability to adapt to the task of eliminating potassium by increasing its excretion per nephron as much as 600 per cent.44 This adaptation occurs with such precision that daily variations in the dietary potassium load usually do not cause significant variations in the serum potassium. Thus it is not necessary to restrict the dietary potassium for a patient with chronic renal failure, until the glomerular filtration rate has been reduced to extremely low levels. However, patients with renal insufficiency do not excrete potassium loads in a normal manner30 and a longer period of time is required for the diseased kidney to rid the body of excess potassium. An unusual load of potassium presented acutely to the patient with renal insufficiency may result in dangerous hyperkalemia. Ingestion of a potassium salt (during diuretic therapy), hemolysis, acidosis, volume depletion, or a catabolic state induced by fever may overwhelm the ability of the impaired kidney to excrete potassium. 48 If the hyperkalemia is not severe, treatment may be directed at the cause of the elevation. Discontinuation of potassium supplements, elimination of foods high in potassium, or correction of dehydration may be enough to reverse the problem. If the plasma concentration rises above
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6.5 mEq/liter and there are abnormalities on the electrocardiogram (peaked T waves, abnormal rhythm), the situation is urgent and immediate steps must be taken to promote the transfer of potassium into cells, thereby lowering the plasma' concentration. There are several means of accomplishing this goal: 1. NaHC0 3 (8.4 per cent solution) may be given intravenously rapidly. This will cause K+ to enter cells in exchange for H+. A dose of 3 cc/kg will provide a short-term effect (5 to 15 minutes) and other measures must then be undertaken. 2. Glucose and insulin will also cause K+ to enter cells. Insulin is given at 0.5 unit/kg and glucose at 3 gm per unit of insulin. Both the insulin and the glucose may be given by drip infusion or by injection over 10 minutes. Blood sugar must be monitored frequently (glucose oxidase strips are helpful) since hypoglycemia may be induced. 3. Calcium gluconate (10 per cent solution) may be given by slow (5 min) intravenous injection at a dose of 0.5 cc/kg. Pulse rate must be monitored because bradycardia may result from too rapid an infusion rate. Calcium does not cause K+ to enter cells but it does decrease the cardiotoxic effect of K+ on the myocardium. If an arrhythmia is present as a result of hyperkalemia, intravenous calcium should be given immediately because it is the most rapidly effective agent. 4. Once the serum potassium has been lowered by these measures, an exchange resin may be used to rid the body of the excess K+. Kayexalate (sodium polystyrene sulfonate) will exchange Na+ for K+. The dose is 1 gm/kg and it is mixed 3 to 4 cc/gram resin with sorbitol or 10 per cent dextrose and water. If the resin is given orally, sorbitol is preferred as the diluent since it is not absorbable and will counteract the constipating effect of the resin. Dextrose and water is recommended when the resin is given as an enema. 34 It should be retained for at least 30 minutes. Approximately 1 mEq K+ will be exchanged for each gram of resin. Because 2 to 3 mEq Na+ will be absorbed per gram of resin, a calcium exchange has been recommended for individuals at risk for fluid overload and congestive heart failure. 7 (At present the calcium resin is not available in the United States.) The exchange resin may be given every 3 to 4 hours as needed. 5. Dialysis is the most effective means of eliminating K+ from the body and should be undertaken if the above methods are unsuccessful.
ACIDOSIS One of the primary functions of the kidney is to maintain the body's balance offixed (nonrespiratory) acid. It does this by excreting in the urine a quantity of acid equal to that generated by the metabolic processes. Three aspects of tubular function are involved in the renal regulation of acid-base balance: (1) acidification ofthe urinary buffers; (2) secretion of ammonia; and (3) reabsorption of bicarbonate from the glomerular filtrate. Net acid excretion is an expression of these functions and is used to quantify the kidney's ability to rid the body of acid. It is defined as titratable acidity and ammonium ion production minus bicarbonate loss in the urine. In health the kidney is remarkably adept at maintaining the serum pH within a narrow range (7.35 to 7.45). W.hen renal insufficiency occurs, the kidney'S ability to excrete acid is impaired and metabolic acidosis results. There are two major reasons for this metabolic acidosis: the reduced capacity of the distal tubule to produce ammonia,44 and the bicarbonate "wasting" that can be demonstrated in some patients. 47 The ability of the damaged kidney to acidify the urine by excreting titratable acid appears to be nearly normal. The reduced excretion of ammonium ion seems to be due to a failure of
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ammonia production by the renal tubular cell. Whether this reflects an abnormality in delivery or utilization of glutamine by the damaged kidney, or a quantitative reduction in the number ofnephrons that are capable of producing ammonia is not certain. Ammonia production decreases in proportion to the fall in glomerular filtration rate. 58 The loss of bicarbonate in the urine was recognized by Schwartz et alY when they discovered that some of their patients had increasing amounts of bicarbonate in the urine when efforts were made to raise serum bicarbonate levels to near normal. In a few patients this defect may make a significant contribution to the metabolic acidosis and negate any attempts to correct the acidosis. Many patients with metabolic acidosis resulting from chronic uremia will tolerate it without any symptoms. Usually these are the patients whose serum bicarbonate is greater than 15 mEq/liter. If the acidosis is more severe, it is likely the patient will experience more difficulty. Anorexia or nausea can be induced by acidosis as well as an uncomfortable dyspnea, especially on exertion. More significantly, hyperkalemia is exaggerated by acidosis,13 and a certain amount of bone dissolution will occur as a result of its buffering the retained acid. 35 In young children a lowered serum bicarbonate places them at a risk for profound decompensated acidosis if an additional insult (diarrhea) should occur. It has become our practice to prescribe alkali when the bicarbonate level falls below 15 mEq/liter or sooner if the patient is symptomatic. We prefer to give a solution of sodium citrate (Shohl's solution) since it is well accepted by small children especially when mixed with some beverage. Shohl's solution provides 1 mEq of buffer for each ml of solution. One to two ml per kg of body weight is given in divided doses 3 times each day. The serum bicarbonate is checked to be sure alkalosis has not been induced. The dosage of Shohl's can be increased if the serum bicarbonate does not improve on that schedule. One should consider the possibility of a bicarbonate "wasting" state if no improvement occurs with the increasing amounts of alkali. An alkaline urine in association with a lowered serum bicarbonate level would suggest this. It is important that the serum calcium is examined before and during any therapy with alkali. Tetany and convulsions can be induced if the correction of the acidosis is too rapid. Some investigators have recommended giving a calcium supplement during the alkali therapy or treating the acidosis with calcium carbonate. 4o ANEMIA Anemia is a consistent feature of chronic renal insufficiency. Although there is a correlation between the severity of the anemia and the degree of uremia, there is wide variation in the time of onset and the progression of anemia. 3 The etiology of the renal disease does not seem to be a significant factor in the onset or the extent of the anemia. The anemia of chronic renal disease is a normochromic, normocytic anemia. It is the result of a shortened'red cell lifespan and a decreased rate of red cell production. The decreased lifespan of the red cell in the azotemic patient is due to some extracorpuscular factor in his environment. When red cells
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from azotemic patients are injected into normal individuals, they have a normal lifespan, whereas red cells from normal individuals have a shortened life when infused into azotemic patients. 15 The nature of this extracorpuscular factor(s) has not been defined. Various guanidino compounds have been suggested as the responsible toxin(s). Recently guanidinoproprionic acid has been shown to interfere with red cell G6PD activity. 50 This compound is known to be elevated in uremic plasma. Another significant factor in the anemia of chronic renal insufficiency is decreased red cell production. Although the bone marrow aspirate is normally cellular and the reticulocyte count may be slightly elevated, this response by the azotemic patient is less than is needed and less than occurs in a comparably anemic patient who does not have azotemia. The production failure in the azotemic patient has been attributed to a failure of erythropoietin production by the damaged kidney.37 Erythropoietin is a mucoprotein with a molecular weight of about 65,000 and it stimulates the bone marrow to increase red blood cell production. In individuals who are anemic or hypoxic, erythropoietin levels are elevated, but in anemic patients with chronic renal insufficiency, no such increase occurs. Although erythropoietin is also produced in extrarenal sites,42 these other sources do not seem to contribute significantly to the total erythropoietin production. Additionally the uremic patient is somewhat refractory to the effect of erythropoietin. Administration of erythropoietin to the uremic patient has resulted in a suboptimal response,32 suggesting that the uremic environment is deleterious to the action of erythropoietin. Inhibitors of erythropoiesis have been demonstrated in the plasma of patients with chronic renal failure. 18 Because some patients do improve their red cell mass when placed on chronic hemodialysis, these inhibitors are presumably dialyzable.
Nutritional Anemia Although the anemia of chronic renal insufficiency is normochromic, normocytic, iron deficiency anemia may be superimposed. True iron deficiency anemia may result from an inadequate dietary intake because of the anorexia in many patients with severe renal insufficiency. Blood loss is common in uremic patients, usually from the gastrointestinal tract (uremic gastroenteritis), or from heavy menses. Platelet function is impaired in uremia33 and this abnormality may contribute to blood loss. Evaluation of the serum ion, red blood cell indices, and the peripheral smear are helpful in the recognition of iron deficiency. The diagnosis of iron deficiency anemia in patients with chronic renal disease is best established by the demop.stration of the absence of stainable iron in bone marrow aspirates. Folic acid deficiency is another nutritional anemia that occurs in patients with renal failure. It is usually found in patients on chronic hemodialysis since folate is dialyzable. This type of anemia is characterized by macrocytic red cells and hypersegmented polymorphonuclear leukocytes.
Therapy In every patient with anemia and renal failure, a cause for the anemia other than uremia should be sought. Correction of an iron or folic acid
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deficient state, or the elimination of an infection may improve the anemia substantially. Blood transfusions are not generally needed, since most children will tolerate hemoglobin levels of 4 to 8 gm/IOO ml without significant. symptomatology. We have not had to give transfusions to any child under our care who has chronic renal failure and has not begun chronic dialysis. It is important to keep transfusions to a minimum in any patient with chronic renal failure ifhe is a candidate for transplantation. Sensitization to the leukocytes and transplantation antigens could impair the future success of a graft. Cobalt and androgenic steroids have been shown to increase erythropoietin production 19.24 and it has been suggested that they might increase red cell mass in the uremic patient. Cobalt is a toxic substance and probably acts to increase erythropoietin production by interfering with tissue oxygen utilization. 4 It is therefore questionable whether it results in any net improvement of tissue oxygenation. Androgens increase production of erythropoietin by sensitizing the renal site of its synthesis so that more hormone is produced for any given level of stimulation. 19 The side effects of these compounds (hirsutism, increased libido, hypertension, liver damage) may outweigh the benefits.
UREMIA AND UREMIC TOXINS The uremic syndrome is a complex of signs and symptoms (Table 1) resulting from the retention of nitrogenous waste products from imbalances in the body content and distribution of water and electrolytes, and from abnormalities of hormone functions in consequence of renal failure. 23 Many symptoms have multiple causes. For example, the muscular weakness and twitching of uremia could result from hypocalcemia, hyperkalemia, hypermagnesemia, the maldistribution of sodium, potassium, and water in the intracellular fluid, the effects of motor neuropathy, and/or the effects of toxic nitrogenous wastes on membrane function or energy metabolism. Similarly, uremic bleeding may result from abnormal platelet function,33 capillary fragility resulting from malnutrition, and/or irritation of mucosal or serosal surfaces by uremic toxins. More specific pathophysiologic mechanisms underlying many of the symptoms of
Table 1. Features of Chronic Renal Failure and Uremia Fatigue, lethargy, somnolence, coma Anorexia, nausea, vomiting, hematemesis, gastric ulcers Uremic colitis, diarrhea, melena Pericarditis, myocardiopathy, cardiac failure Pleuritis, pulmonary edema, pulmonary hemorrhage Anemia, thrombasthenia, pUrPura Edema, hypertension Rickets/osteomalacia, osteitis fibrosa, hyperphosphatemia, hypocalcemia, hyperParathyroidism, pruritus Hyperkalemia, metabolic acidosis, hyperuricemia Glucose intolerance Peripheral neuropathy Impaired immunologic competence Retardation of growth and maturation
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uremia are unknown, but interference with proper enzyme functions of various tissues is often presumed. For example, the enzyme transketolase, active in the hexose monophosphate shunt pathway and important in the metabolism of peripheral nerve tissue, is inhibited in uremic patients and in the presence of uremic serum in vitro. 54 This inhibition has been proposed as a factor in the development of uremic neuropathy.54 Transketolase is also active in the normal metabolism of the red blood cell and reduction of its activity may also playa role in the decreased red cell lifespan in uremia. 38 On the basis of observations such as these it has been assumed that certain "uremic toxins" may exist which lead to the development of the uremic syndrome. That some of these presumed toxins are dialyzable, and thus of relatively small molecular size, is suggested by the success of dialytic therapy in the resolution of most uremic symptoms. Urea and/or creatinine were thought to be possible toxins, but the experimental infusion or retention of either of these substances has failed to produce more than trivial symptoms. 29 Moreover, though the symptoms of uremia are generally worse in patients with higher serum concentrations of urea or creatinine, some patients with markedly elevated levels remain asymptomatic, whereas others with relatively low serum concentrations are clearly uremic. The search for specific uremic toxins has led to the identification of a few substances which can produce uremic-like symptoms in normal animals, and which are present in much higher concentrations in renal failure than in health. Most convincing among these are methylguanidine and guanidino succinic acid (GSA). The chronic administration of methylguanidine to dogs has resulted in vomiting, poor appetite, decreased red cell survival, anemia, gastrointestinal ulceration, muscle twitching and hypertonia, decreased motor nerve conduction velocity, and convulsions. 22 The excretion of methylguanidine is increased fourfold in patients with renal failure ,22, 53 indicating an increased production rate in uremia. Experimentally, the concentration of methyl guanidine within many cellular tissues, notably muscle, peripheral nerve, and liver,22 is higher than that of plasma. Since the effect of uremic toxins is likely on enzymatic processes within the cells, such a finding may help explain the erratic correlation between the serum content of these various nitrogenous wastes and the presence of uremic symptoms. 23 Guanidino succinic acid is a by-product of the urea cycle in uremia and has been found to inhibit ADP-induced activation of platelet factor III which promotes platelet adhesiveness. 27 Thus GSA may thereby contribute to the bleeding tendency of uremia. In addition, stimulation of insulin and glucagon secretion by GSA and related compounds may help explain the glucose intolerance characteristic of the uremic state. 16 Other substances which have been investigated as possible uremic toxins are the so-called "middle molecules." Certain symptoms of uremia, notably neuropathy and pericarditis, do not resolve readily with dialysis. This observation led Scribner et al. 49 to suggest the existence of substances with molecular weights in the range of 500 to 5000 daltons which might be acting as uremic toxins. These "middle molecules" would be only poorly dialyzable. Peptide fragments in this range of molecular weights have recently been separated by complex chromatographic
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techniques from the sera of uremic patients 6 , 41 and are absent in normal sera, The quantity of these substances present in uremic plasma can be roughly correlated with the presence of uremic symptoms 41 and the chromatographic peaks disappear promptly after renal transplantation. 6 At present the role of these substances in the pathogenesis of uremia remains uncertain. Finally, a presumed natriuretic hormone may contribute to the uremic syndrome. 12 This hormone, also known as Third Factor,':' acts to decrease proximal renal tubular reabsorption of sodium, and has been suggested as a mechanism by which sodium homeostasis is maintained in renal insufficiency as well as in health. It has been proposed that an excess of this hormone may occur in renal insufficiency10 and cause abnormalities of sodium metabolism in various nonrenal tissues, thus evoking some of the manifestations of uremia. 12
Dietary Management of Uremia Regulation of the diet is the most effective nondialytic method for reducing the quantity of materials requiring renal excretion and must be considered a cornerstone in the management of the patient with chronic renal failure. The goals of dietary management in the patient with chronic renal failure are to: (1) minimize metabolic bone disease; (2) reduce the production of nitrogenous wastes; (3) ensure proper nutrition and foster appropriate physical growth; and (4) minimize the occurrence of fluid and electrolyte imbalances. Attainment of these goals requires considerable skill in dietary manipulations and considerable patient education and cooperation. The assistance of an experienced dietitian is of great value, and should be sought when important dietary manipulations are indicated. PHOSPHORUS RESTRICTION. As discussed in detail elsewhere in this symposium, the reduction of phosphorus intake is one of the first dietary adjustments which are required in the management of secondary hyperparathyroidism. 52 In children this may be accomplished most easily by elimination of milk from the diet. The intake of milk products should also be moderately restricted. This tactic has the virtue of being simple and generally effective. However, since milk is the major source of dietary calcium and of vitamin D, supplemental calcium salts (lactate, gluconate, or carbonate to provide approximately one gram of elemental calcium) and vitamin D must be prescribed. If needed, further reduction of phosphorus absorption may be accomplished with the use of oral aluminum hydroxide (500 to 1000 mg, q.i.d.). PROTEIN RESTRICTION. As renal insufficiency progresses, restriction of dietary protein becomes advisable as a means of reducing the production of the nitrogenous metabolites associated with uremic symptoms. At the same time, sufficient protein must be provided to prevent chronic negative nitrogen balance. The need to provide an adequate diet in the context of protein restriction has stimulated many clinical investigations of protein metabolism in uremia. 20 , 24, 28, 31 Most of the studies have been performed in azotemic adults; similar specific data on the ':'The first two factors known to affect the renal regulation of sodium are glomerular filtration and aldosterone.
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protein requirements of azotemic children are not available in the literature. The symptoms of uremia rarely occur until the blood urea nitrogen exceeds 100 mg/IOO ml. Therefore, dietary protein is generally not reduced until this level of azotemia is reached. In normal adults the minimum daily requirement of protein approximates 0.2 to 0.3 gm/kg/day (equivalent to 35 to 65 gm protein nitrogen/kg/day), provided the protein is of high biological value. The biological value of protein is predicated upon the adequacy of its complement of essential amino acids-those which cannot be synthesized de novo by the body. The amount of essential amino acids available limits the amount of new body protein which can be synthesized. When the essential amino acid present in least supply has been exhausted, further net protein synthesis will cease. Any amino acids, essential or nonessential, which remain are converted to their respective fat or carbohydrate derivatives plus nitrogenous waste products (urea). Protein derived from animal sources (exemplified by egg albumin and casein) are of the highest biological value. The proteins which are best omitted from the uremic diet are therefore those oflow biological value, derived principally from vegetable sources. In uremic adults the curtailment of dietary protein to 20 gm/day (0.3 gm/kg/day) has been associated with negative total body nitrogen balance and ultimately with signs of malnutrition. 31 Such stringent restriction necessitates profound reduction in the variety of foodstuffs which may be taken and has met with considerable difficulties in patient acceptance, especially when the patient is a child. At least in dialyzed patients, the provision of a more liberal diet containing 40 gm of high quality protein results in neutral to slightly positive overall balance and in improved patient cooperation and feelings of well-being without increased symptoms of uremia. 31 In the management of children with severe azotemia, diets containing 1.0 to 2.0 gm/kg/day of protein of high biological value appear to be preferred. 26 The greater need of children for protein to permit growth and the generally satisfactory clinical results of such a regimen appear to warrant a relatively liberal protein intake in many uremic children. As renal failure progresses, uremic symptoms will supervene despite even stringent protein restriction. At this point, regular dialysis is generally the treatment of choice. However, an additional dietary maneuver which remains available increasingly is being tried. Specifically, this concerns the use of balanced mixtures of essential amino acids, with or without an added supplement of carbohydrate and fats, to provide the materials and caloric supply from which new body protein may be synthesized. When such a mixture is taken, the nonessential amino acids are produced by the body, utilizing available urea as a source of amino nitrogen. 20 ,21 Net protein synthesis is thus achieved as reflected by a net positive nitrogen balance. 5 , 25 At the same time the B UN fails because of both the reduced nitrogen intake and the increased utilization of urea nitrogen. Use of such supplements in adults 5 , 25, 36 and in at least one child 2 has permitted reduced dialysis time, and a substantial improvement in nutritional status. A further advantage of such a dietary supplement has been the reduced need for restriction of phosphorus or potassium. This is a result of their incorporation into new cellular tissue.
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Indeed, in some individuals supplementation of phosphorus and potassium has been necessary.36 The essential amino acid mixtures presently available have good patient acceptance. A present disadvantage of the essential amino acid diet from a practical standpoint is the high cost of these preparations. With their increasing use it is anticipated that the cost will be reduced. A more recent adaptation of this same dietary principle has been the use of the alpha-ketoanalogues of the essential amino acids valine, methionine, leucine, isoleucine, and phenylalanine. 56.57 These analogues are aminated in the body to their respective L-amino acids, which are then available for protein synthesis. Their use has been associated with decrease in the rate of appearance of urea nitrogen and a decrease in the BUN. This results from improvement in the efficiency of amino-N reutilization and decrease of its entry into the urea cycle. 57 However, ketoacid therapy may be useful only in a diet low in protein and thus does not allow a more liberal or more palatable dietary regimen. Moreover, it has been claimed that the rate of renal functional deterioration might actually be reduced with the use of these ketoanalogues. 57 CALORIC INTAKE. As important as restriction of dietary protein is the provision of a diet adequate or even abundant in total caloric content to promote the efficiency with which protein is utilized. 28 , 36 Thus in uremic adults on a low protein diet, nitrogen balance was negative when caloric intake was below 45 to 55 cal/kg/day.28 The usual caloric needs of normal adults is 35 cal/kg/day. Similarly, the provision to adult dialysis patients of a high calorie diet (3000 to 4000 callday)in which mostofthe nitrogen was in the form of essential amino acids led to strongly positive N-balance. No such effect was noted in nondialyzed patients on a similar diet consuming only 2600 to 3000 calories/day.36 In children with renal insufficiency, failure to ingest adequate calories appears to be the most important factor responsible for the growth failure which is often so striking. Other factors such as chronic acidosis, metabolic bone disease (renal osteodystrophy), anemia, uremic toxicity, and abnormal hormone function or hormone balance may also contribute to growth defects in these patients,14 The problem of growth in renal failure is reviewed elsewhere in this symposium. It should be noted here, however, that studies both in children 8,51 and in animals 4 , 17,39 are strongly in support of the importance of caloric intake in promoting growth in uremia. Thus Simmons et al. 51 showed that children on hemodialysis who ingested less than 67 per cent of the recommended caloric intake for age, grew at only one third the normal rate, whereas patients with a caloric intake greater than 67 per cent of the recommended daily allowance grew at a normal rate, on the average. Caloric supplementation of the diet resulted in improved growth rates for all five children with previously low intake. The protein intake in all subjects ranged from 1.0 to 2.0 gmlkg/day. Betts and Magrath,8 found that the spontaneous caloric intake was low in 80 per cent of children with renal impairment. The deficit was evenly distributed with regard to protein, fats, and carbohydrates. The growth rate correlated strongly with caloric intake, being normal when intake exceeded 80 per cent of recommended requirements, and falling drastically at intakes below 60 per cent, with cessation of growth below 40
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per cent of normal caloric intake. At the same time, growth velocity was related to residual renal function and declined only after the glomerular filtration rate fell below 25 mllminl1. 73 m 2 • The relationship between glomerular filtration rate and caloric intake was not established. These· observations demonstrate, as Holliday 26 has stated, that growth is possible only after caloric intake is sufficient first to support the metabolic processes required of tissues already present in the body. That is, basal caloric requirements must be fully met before any energy may be diverted to the growth process. In summary, the restriction of dietary protein is effective in reducing or preventing uremic symptoms until renal function becomes severely impaired. Protein restriction need not be introduced until BUN is in the range of 100 to 120 mgl100 ml, when uremic symptoms become increasingly likely. Protein should be of high biological value to be optimally effective. For azotemic children, reduction of protein intake to approximately 1.0 to 1.3 gm/kglday, up to 40 to 50 gm/day, appears most satisfactory, but represents a significant reduction from the usual intake of2 to 4 gmlkglday. The use of mixtures of essential amino acids as a source of dietary nitrogen is also highly effective in limiting nitrogenous wastes and can prevent negative nitrogen balance with a minimum dietary nitrogen load. Provision of a full complement of calories is essential, however, for optimal utilization of dietary protein and is the single most important factor in the prevention of growth retardation in children with significant renal functional impairment.
REFERENCES 1. Adamson, J. W., Eshback, J., and Finch, C. A. : The kidney and erythropOiesis. Am. J. Med., 44:725, 1968. 2. Alexander, E., and Levinsky, N.: An extrarenal mechanism of potassium adaptation. J.C.I., 47:740, 1968. 3. Aronson, A. S., Furst, P., Kuylenstierna, B., et al.: Essential amino acids in the treatment of advanced uremia: Twenty-two months experience in a 5-year-old girl. Pediatrics, 56:538-543, 1975. 4. Barron, A. G., and Barron, E. S. G.: Mechanism of cobalt polycythemia. Effect of ascorbic acid. Proc. Soc. Exper. BioI. Med., 35:407;1936. 5. Bergstrom, J., Furst, P., and Noree, L. 0.: Treatment of chronic uremia patients with protein poor diet and oral supply of essential amino acids. I. Nitrogen balance studies. Clin. Nephrol., 3:187-194,1975. 6. Bergstrom, J., Furst, P., Gordon, A., et al. : Middle molecules in uremia (abstract). Proceedings of Sixth International Congress of Nephrology, Firenze, 1975. 7. Berlyne, G., Janabi, K., and Shaw, A.: Dangers of resonium A in the treatment of hyperkalemia in renal failure. Lancet, 1: 167, 1966. 8. Betts, P. R., and Magrath, G.: Growth pattern and dietary intake of children with chronic renal insufficiency. Brit. Med. J., 1 :189-193, 1974. 9. Blaufox, M. D.: Systemic arterial hypertension in pediatric practice. PEDIAT. CLIN. NORTH AM., 18:577-593,1971. 10. Bourgiognie, J. J., Hwang, K. H., Espinel, C., et al.: A natriuretic factor in the serum of patients with chronic uremia. J. Clin. Invest., 51 :1514, 1972. 11. Bricker, N. S., Klahr, S., Lubowitz, H., et al.: The pathophysiology of renal insufficiency: On the functional transformations in the residual nephrons with advancing disease. PEDIAT. CLIN. NORTH AM., 18:595-611, 1971. 12. Bricker, N. S.: The pathogenesis of the uremic state: The "trade-off hypothesis." New Engl. J. Med., 286:1093-1099,1972. 13. Burnell, J., Villamil, M., Uyeno, B., et al. : Effect in humans of extracellular pH change on the relationship between serum potassium concentration and intracellular potassium. J.C.I., 35:935, 1956. 14. Chantler, C., and Holliday, M. A.: Growth in children with renal disease with particular reference to the effects of caloric malnutrition: A review. Clin. Nephrol, 1 :230-242, 1973.
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15. Chaplin, H., and Mollison, P. H.: Red cell life span in nephritis and in hepatic cirrhosis. Clin. Sci., 12:351, 1953. 16. Cohen, B. D., Handelsman, D. G., and Pai, B. N.: Toxicity arising from the urea cycle. Kidney Int., 7:S285-S287, 1975. 17. Diaz, M., Kleinknecht, C., and Broyer, M.: Growth in experimental renal failure: Role of calorie and amino acid intake. Kidney Int., 8:349-354,1975. 18. Fisher, J. W., Hatch, F. E., Roh, B. L., et al. : Erythropoietin inhibitor in kidney extracts and plasma from anemic uremic human subjects. Blood, 31 :440, 1968. 19. Fried, W., and Gurney, C. W.: The erythropoietic stimulating effects of androgens. Ann. N.Y. Acad. Sci., 149:356, 1968. 20. Giordano, C.: Use of exogenous and endogenous urea for protein synthesis in normal and uremic subjects. J. Lab. Clin. Med., 62:231-245,1963. 21. Giordano, C., DePascale, C., Balestrieri, C., et al.: Incorporation of urea 15N in amino acids of patients with chronic renal failure on low nitrogen diet. Am. J. Clin. Nutr., 21 :394-402, 1968. 22. Giovanetti, S., Balestri, P. L., and Barsotti, G.: Methylguanidine in uremia. Arch. Intern. Med., 131 :709, 1973. 23. Giovannetti, S., and Barsotti, G.: Uremic intoxication. Nephron, 14:123-133, Hl75. 24. Goldwasser, E., Jacobson, L. 0., and Plzak, L.: Studies on erythropoiesis. V. The effect ofcobalt on the production of erythropoietin. Blood, 13 :55, 1958. 25. Heidland, A., and Kult, J.: Long term effects of essential amino acids supplementation in patients on regular dialysis treatment. Clin. NephroI., 3:234-239,1975. 26. Holliday, M. A.: Calorie deficiency in children with uremia: Effect upon growth. Pediatrics, 50:590-597, 1972. 27. Horowitz, H. I., Stein, I. M., Cohen, B. D., et al.: Further studies on the platelet inhibitory effect of guanidino succinic acid and its role in uremic bleeding. Am. J. Med., 49:336345,1970. 28. Hyne, B. E. B., Fowell, E., and Lee, H. A.: The effect of caloric intake on nitrogen balance in chronic renal failure. Clin. Sci., 43:679-688, 1972. 29. Johnson, W. J., Hagge, W. W., Wagoner, R. D., et al.: Toxicity arising from urea. Kidney Int., 7:S288-S293, 1975. 30. Keith, N., and Osterberg, A.: The tolerance for potassium in severe renal insufficiency. A study often cases. J.C.I., 26:773,1947. 31. Kopple, J. D., and Coburn, J. W.: Metabolic studies of low protein diets in uremia. I. NitrQgen and potassium. MediCine, 52:583-595, 1973. 32. Larsen, O. A., Josephson, P., and Lassen, N. A.: Nefrogen anaemi behandlet med erythropoietin. Ugeskr Laeg., 125:435, 1963. 33. Lewis, J. H., Zucker, M. B., and Ferguson, J. H.: Bleeding tendency in uremia. Blood, 11 :1073,1956. 34. Lieberman, E.: Management of acute renal failure in infants and children. Nephron, 11 :193, 1973. 35. Litzow, J., Lemann, J., and Lennon, E.: The effect of treatment of acidosis on calcium balance in patients with chronic azotemic renal disease. J.C.I., 46:280,1967. 36. Llach, F., Franklin, S. S., and Maxwell, M. H.: Dietary management of patients in chronic renal failure. Nephron, 14:401-412, 1975. • 37. Loge, J. P., Lange, R. D .., and Moore, C. V.: Characterization of the anemia associated with chronic renal insufficiency. Am. J. Med., 24:4, 1958. 38. Lonergan, E. T., Semar, M., Sterzel, R. B., et al.: Erythrocyte transketolase activity in dialyzed patients. New Engl. J. Med., 284:1399-1402,1971. 39. MacDonell, R. C., Buzon, M. M., and Holliday, M. A.: Growth failure in uremic rats: The role of calorie deficiency (abstract). Pediat. Res., 7:411, 1973. 40. Makoff, D. L., Gordon, A., Franklin, S. S., et al.: Chronic calcium carbonate therapy in uremia. Arch. Intern. Med., 123:15, 1969. 41. Migone, L., Dall'Aglio, P., and Buzio, C.: Middle molecules in uremic serum, urine and dialysis fluid. Clin. NephroI., 3:82-93, 1975. 42. Mirand, E. A., Murphy, G. P., Steeves, R. A., et al.: Erythropoietin activity in anephric, allotransplanted, unilaterally nephrectomized and intact man. J. Lab. Clin. Med., 73:121,1969. 43. Muth, R. G.: Diuretic properties of furosemide in renal disease. Ann. Intern. Med., 69:249-261, 1968. 44. Palmer, W. W., and Henderson,.L. J.: A study of the several factors of acid excretion in nephritis. Arch. Intern. Med., 16:109, 1915. 45. Richards, P.: Protein metabolism in uremia. Nephron, 14:134-152, 1975. 46. Schultz, R., Taggart, D., Shapiro, H., et al.: On the adaptation in potassium excretion associated with nephron reduction in the dog. J.C.I., 50:1061,1971. 47. Schwartz, W. B., Hall, P. W., Hays, R. M., et aI.: On the mechanism of acidosis in chronic renal disease. J.C.I., 38:39,1959. 48. Schwartz, W., and Kassirer, J.: Medical management of chronic renal failure. Amer. J. Med., 44:786,1968.
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49. Scribner, B. H., Farrell, P. C., Milutinovic, J., et al.: Evolution of the middle molecule hypothesis. In Villareal, H. (ed.): Proceedings of Fifth International Congress of Nephrology, Basel, Karger, 1974, pp. 190-199. 50. Shainkin, R., Giatt, Y., and Berlyne, G.: The presence and toxicity of guanidino-propionic acid in uremia. Kidney Int., 7:S-302, 1975. 51. Simmons, J. M., Wilson, C. J., Potter, D. E., et al.: Calorie intake and linear growth of children on hemodialysis. New EngI. J. Med., 285:653-655, 1971. 52. Slatopolsky, E., and Bricker, N. S.: The role of phosphorus restriction in the prevention of secondary hyperparathyroidism in chronic renal disease. Kidney Internat., 4:141-145, 1973. 53. Stein, I. M., Perez, G., Johnson, R., et al.: Serum levels and urinary excretion of methylguanidine in renal failure. J. Lab. Clin. Med., 77:1020-1024, 1971. 54. Stenzel, R. B., Semar, M., Lonergan, E. T., et aI.: Relationship of nervous tissue transketolase to the neuropathy in chronic uremia. J. Clin. Invest., 50:2295-2304, 1971. 55. Talbot, N. B., Crawford, J. D., and Butler, A. M.: Homeostatic limits to safe parental fluid therapy. New Engl. J. Med., 248:1100, 1953. 56. Walser, M., Coulter, A. W., Dighe, S., et aI.: The effect of keto analogues of essential amino acids in severe chronic uremia. J. Clin. Invest., 52:678-690, 1973. 57. Walser, M.: Ketoacids in the treatment of uremia. Clin. NephroI., 3:180-186, 1975. 58. Wrong, 0., and Davies, H. E. F.: Excretion of acid in renal disease. Quart. J. Med., 28:259, 1959. Children's Memorial Hospital 2300 Children's Plaza Chicago, Illinois 60614
Chronic Renal Insufficiency Peter R. Lewy, M.D.*, and John K. Hurley, M.D.t
In health, the functional capacities of the normal kidneys permit maintenance of body homeostasis in the presence of wide variations in the need for excretion or conservation of the many constituents under their control,55 and provide ample reserve for periods of stress. As renal mass is diminished, by congenital maldevelopment or by acquired disease processes, the limits of homeostatic tolerance are progressively reduced. When this results in detectable abnormalities in the body content or concentrations of the various components regulated by the kidneys, renal insufficiency can be said to exist. This occurs when renal function is reduced below 25 to 30 per cent of normal, as reflected clinically by a creatinine clearance of 30 to 40 ml1min/1. 73 m 2 • At this point definite elevations in the serum concentrations of urea (> 20 mg per 100 ml) and creatinine (> 1.5 mg per 100 ml) are noted. It is important to recognize that the normal limits of serum creatinine concentration are much lower for infants and small children (- 0.3 to 0.8 mg per 100 ml) than for larger children and adults (- 0.7 to 1.5 mg per 100 ml). With progressive decline in renal function a variety of adaptive responses occur. Most are highly effective in maintaining normal body composition despite marked reductions in renal mass, to as low as 5 to 15 per cent of normal, but may have adverse effects on other bodily functions. The concept of "trade off" is suggested by Bricker et al. H • 12 The most clearly defined example of this "trade off," the manner in which phosphorus balance is maintained by the failing kidney, is fully described elsewhere in this symposium. Although chronic dialysis is necessary to sustain the patient with severe renal insufficiency, several manifestations of more moderate renal impairment respond favorably to careful medical management. These include abnormalities of salt and water metabolism, hyperkalemia, acidosis, anemia, azotemia and uremia, and growth failure.
SALT AND WATER REGULATION In chronic renal insufficiency the decreased glomerular filtration reduces the amount of salt and water potentially available for excretion. *Assistant Professor of Pediatrics, Northwestern University Medical School; Head, Division of Nephrology, The Children's Memorial Hospital, Chicago, Illinois
t Assistant Professor of Pediatrics, Northwestern University Medical School; Attending Nephrologist, The Children's Memorial Hospital, Chicago, Illinois
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However, compensatory physiologic and hormonal mechanisms,12 as well as the increased osmotic load provided by retained urea and other wastes, generally provide for the excretion of sodium and water in amounts comparable to normal individuals. The limits of homeostatic tolerance are reduced, however, so that unusually large loads of salt and water may not be readily excreted. Conversely, mechanisms for the conservation of salt and water are often damaged by the disease process and/or rendered relatively ineffective by virtue of the markedly increased volume of filtrate which must be processed by each remnant nephron. Undue restriction of salt and water may thus lead to volume depletion and further reduction of glomerular filtration. Unless demanded by specific aspects of the clinical situation, such as seVere hypertension or pulmonary congestion, free selection of salt and water is generally permissible and desirable in patients with mild or moderate renal insufficiency. Three patterns of abnormality of salt and water homeostasis are relatively characteristic of specific underlying renal disease. Many infants and small children with congenitally dysplastic kidneys or with urinary obstructive disease tend to excrete large volumes of dilute urine low in sodium content. Overall renal function is generally only moderately impaired, with serum creatinine in the range of 1. 5 to 4.0 mg per 100 ml and B UN in the range of 25 to 60 mg per 100 ml. The situation may mimic nephrogenic diabetes insipidus, and is due to maldevelopment of, or damage to, the renal medullary concentrating mechanism. The large volumes of urine these children excrete as infants may not be obvious because babies are generally assumed to "wet" frequently. Such infants are noted to have an affinity for water and may cry until water is provided, even after a formula or milk feeding. These infants are at particular risk from severe dehydration when they may be unwilling to take fluids or unable to retain them, such as in the event of illness. They are at risk in the hospital where water is not routinely provided at frequent intervals. Prolonged periods of "nothing by mouth" preoperatively are similarly hazardous. Infants and small children suspected of having renal dysplasia must be carefully monitored for state of hydration with daily weights and accurate measurement of intake and output. From the data obtained, adequate fluid reg'imens may be prescribed. Manipulations of dietary sodium are rarely needed. Hypertension is uncommon in these children. The second pattern, salt and water retention associated with chronic glomerulonephritis, is presumed to result from greater reduction of glomerular filtration than of tubular reabsorption, causing a glomerulotubular imbalance. Consequences of fluid retention include peripheral edema, hypertension, congestive failure, and pulmonary edema. In addition, marked proteinuria in many patients with nephritis leads to nephrotic (noncongestive) edema. Urine volume is generally "normal," with urine sodium in the range of20 to 60 mEqlliter and a fixed specific gravity of 1.010. In the older age range and in the absence of obvious edema, water intake is perhaps best governed by the child's own thirst mechanisms. Sodium restriction in the range of 1 to 3 gm/day is helpful in limiting edema and ameliorating hypertension. Antihypertensive agents are recommended for blood pressures greater than 135 mm Hg systolic, 95 diastolic. 9 Diuretics, particularly furosemide, are useful in the management of edema and hypertension, though doses as large as 4 to 10
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mg/kg/day may be necessary in moderate to severe renal insufficiency.43 The third pattern of abnormal salt and water regulation is that of salt wasting which is seen in some patients with chronic pyelonephritis or hydronephrosis and normal blood pressure, as well as in patients with nephronophthisis (medullary cystic disease). These patients lose large amounts of urine high in sodium content (60 to 120 mEqlliter) and may obligatorily excrete 12 to 25 gm of salt in 3 to 6 or more liters of urine per day. The defect in sodium reabsorption is primarily in the distal nephron, and the salt wasting is accompanied by inability to concentrate or to dilute the urine. Salt ingestion is spontaneously high in these patients. Sodium restriction by intent or by omission (as in the hospitalized patient) can lead rapidly to severe hyponatremic dehydration and must be avoided. For proper fluid management, knowledge of the patient's usual urinary volume and sodium content is mandatory. In end-stage renal disease the markedly reduced glomerular filtration is inadequate to permit complete excretion ofloads of sodium and water in the amounts ingested by normal individuals. Retention of salt and water then leads to edema and vascular congestion, often with resultant hypertension, pulmonary edema, and cardiac failure. These complications may be prevented by restriction of water intake to equal insensible water losses (basal losses 30 mllkg/day in infants up to 1 year of age, 20 mllkglday to a maximum of 400 to 500 ml in older children) plus measured urinary and nonurinary losses. Sodium intake should be restricted to equal measured urinary losses plus any other measurable losses. When problems in such fluid management become severe, especially in association with various other manifestations of severe renal disease, peritoneal dialysis or hemodialysis may be the treatment of choice.
HYPERKALEMIA Hyperkalemia is an infrequent occurrence in patients with chronic renal insufficiency. The chronically diseased kidney has the ability to adapt to the task of eliminating potassium by increasing its excretion per nephron as much as 600 per cent.44 This adaptation occurs with such precision that daily variations in the dietary potassium load usually do not cause significant variations in the serum potassium. Thus it is not necessary to restrict the dietary potassium for a patient with chronic renal failure, until the glomerular filtration rate has been reduced to extremely low levels. However, patients with renal insufficiency do not excrete potassium loads in a normal manner30 and a longer period of time is required for the diseased kidney to rid the body of excess potassium. An unusual load of potassium presented acutely to the patient with renal insufficiency may result in dangerous hyperkalemia. Ingestion of a potassium salt (during diuretic therapy), hemolysis, acidosis, volume depletion, or a catabolic state induced by fever may overwhelm the ability of the impaired kidney to excrete potassium. 48 If the hyperkalemia is not severe, treatment may be directed at the cause of the elevation. Discontinuation of potassium supplements, elimination of foods high in potassium, or correction of dehydration may be enough to reverse the problem. If the plasma concentration rises above
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6.5 mEq/liter and there are abnormalities on the electrocardiogram (peaked T waves, abnormal rhythm), the situation is urgent and immediate steps must be taken to promote the transfer of potassium into cells, thereby lowering the plasma' concentration. There are several means of accomplishing this goal: 1. NaHC0 3 (8.4 per cent solution) may be given intravenously rapidly. This will cause K+ to enter cells in exchange for H+. A dose of 3 cc/kg will provide a short-term effect (5 to 15 minutes) and other measures must then be undertaken. 2. Glucose and insulin will also cause K+ to enter cells. Insulin is given at 0.5 unit/kg and glucose at 3 gm per unit of insulin. Both the insulin and the glucose may be given by drip infusion or by injection over 10 minutes. Blood sugar must be monitored frequently (glucose oxidase strips are helpful) since hypoglycemia may be induced. 3. Calcium gluconate (10 per cent solution) may be given by slow (5 min) intravenous injection at a dose of 0.5 cc/kg. Pulse rate must be monitored because bradycardia may result from too rapid an infusion rate. Calcium does not cause K+ to enter cells but it does decrease the cardiotoxic effect of K+ on the myocardium. If an arrhythmia is present as a result of hyperkalemia, intravenous calcium should be given immediately because it is the most rapidly effective agent. 4. Once the serum potassium has been lowered by these measures, an exchange resin may be used to rid the body of the excess K+. Kayexalate (sodium polystyrene sulfonate) will exchange Na+ for K+. The dose is 1 gm/kg and it is mixed 3 to 4 cc/gram resin with sorbitol or 10 per cent dextrose and water. If the resin is given orally, sorbitol is preferred as the diluent since it is not absorbable and will counteract the constipating effect of the resin. Dextrose and water is recommended when the resin is given as an enema. 34 It should be retained for at least 30 minutes. Approximately 1 mEq K+ will be exchanged for each gram of resin. Because 2 to 3 mEq Na+ will be absorbed per gram of resin, a calcium exchange has been recommended for individuals at risk for fluid overload and congestive heart failure. 7 (At present the calcium resin is not available in the United States.) The exchange resin may be given every 3 to 4 hours as needed. 5. Dialysis is the most effective means of eliminating K+ from the body and should be undertaken if the above methods are unsuccessful.
ACIDOSIS One of the primary functions of the kidney is to maintain the body's balance offixed (nonrespiratory) acid. It does this by excreting in the urine a quantity of acid equal to that generated by the metabolic processes. Three aspects of tubular function are involved in the renal regulation of acid-base balance: (1) acidification ofthe urinary buffers; (2) secretion of ammonia; and (3) reabsorption of bicarbonate from the glomerular filtrate. Net acid excretion is an expression of these functions and is used to quantify the kidney's ability to rid the body of acid. It is defined as titratable acidity and ammonium ion production minus bicarbonate loss in the urine. In health the kidney is remarkably adept at maintaining the serum pH within a narrow range (7.35 to 7.45). W.hen renal insufficiency occurs, the kidney'S ability to excrete acid is impaired and metabolic acidosis results. There are two major reasons for this metabolic acidosis: the reduced capacity of the distal tubule to produce ammonia,44 and the bicarbonate "wasting" that can be demonstrated in some patients. 47 The ability of the damaged kidney to acidify the urine by excreting titratable acid appears to be nearly normal. The reduced excretion of ammonium ion seems to be due to a failure of
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ammonia production by the renal tubular cell. Whether this reflects an abnormality in delivery or utilization of glutamine by the damaged kidney, or a quantitative reduction in the number ofnephrons that are capable of producing ammonia is not certain. Ammonia production decreases in proportion to the fall in glomerular filtration rate. 58 The loss of bicarbonate in the urine was recognized by Schwartz et alY when they discovered that some of their patients had increasing amounts of bicarbonate in the urine when efforts were made to raise serum bicarbonate levels to near normal. In a few patients this defect may make a significant contribution to the metabolic acidosis and negate any attempts to correct the acidosis. Many patients with metabolic acidosis resulting from chronic uremia will tolerate it without any symptoms. Usually these are the patients whose serum bicarbonate is greater than 15 mEq/liter. If the acidosis is more severe, it is likely the patient will experience more difficulty. Anorexia or nausea can be induced by acidosis as well as an uncomfortable dyspnea, especially on exertion. More significantly, hyperkalemia is exaggerated by acidosis,13 and a certain amount of bone dissolution will occur as a result of its buffering the retained acid. 35 In young children a lowered serum bicarbonate places them at a risk for profound decompensated acidosis if an additional insult (diarrhea) should occur. It has become our practice to prescribe alkali when the bicarbonate level falls below 15 mEq/liter or sooner if the patient is symptomatic. We prefer to give a solution of sodium citrate (Shohl's solution) since it is well accepted by small children especially when mixed with some beverage. Shohl's solution provides 1 mEq of buffer for each ml of solution. One to two ml per kg of body weight is given in divided doses 3 times each day. The serum bicarbonate is checked to be sure alkalosis has not been induced. The dosage of Shohl's can be increased if the serum bicarbonate does not improve on that schedule. One should consider the possibility of a bicarbonate "wasting" state if no improvement occurs with the increasing amounts of alkali. An alkaline urine in association with a lowered serum bicarbonate level would suggest this. It is important that the serum calcium is examined before and during any therapy with alkali. Tetany and convulsions can be induced if the correction of the acidosis is too rapid. Some investigators have recommended giving a calcium supplement during the alkali therapy or treating the acidosis with calcium carbonate. 4o ANEMIA Anemia is a consistent feature of chronic renal insufficiency. Although there is a correlation between the severity of the anemia and the degree of uremia, there is wide variation in the time of onset and the progression of anemia. 3 The etiology of the renal disease does not seem to be a significant factor in the onset or the extent of the anemia. The anemia of chronic renal disease is a normochromic, normocytic anemia. It is the result of a shortened'red cell lifespan and a decreased rate of red cell production. The decreased lifespan of the red cell in the azotemic patient is due to some extracorpuscular factor in his environment. When red cells
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from azotemic patients are injected into normal individuals, they have a normal lifespan, whereas red cells from normal individuals have a shortened life when infused into azotemic patients. 15 The nature of this extracorpuscular factor(s) has not been defined. Various guanidino compounds have been suggested as the responsible toxin(s). Recently guanidinoproprionic acid has been shown to interfere with red cell G6PD activity. 50 This compound is known to be elevated in uremic plasma. Another significant factor in the anemia of chronic renal insufficiency is decreased red cell production. Although the bone marrow aspirate is normally cellular and the reticulocyte count may be slightly elevated, this response by the azotemic patient is less than is needed and less than occurs in a comparably anemic patient who does not have azotemia. The production failure in the azotemic patient has been attributed to a failure of erythropoietin production by the damaged kidney.37 Erythropoietin is a mucoprotein with a molecular weight of about 65,000 and it stimulates the bone marrow to increase red blood cell production. In individuals who are anemic or hypoxic, erythropoietin levels are elevated, but in anemic patients with chronic renal insufficiency, no such increase occurs. Although erythropoietin is also produced in extrarenal sites,42 these other sources do not seem to contribute significantly to the total erythropoietin production. Additionally the uremic patient is somewhat refractory to the effect of erythropoietin. Administration of erythropoietin to the uremic patient has resulted in a suboptimal response,32 suggesting that the uremic environment is deleterious to the action of erythropoietin. Inhibitors of erythropoiesis have been demonstrated in the plasma of patients with chronic renal failure. 18 Because some patients do improve their red cell mass when placed on chronic hemodialysis, these inhibitors are presumably dialyzable.
Nutritional Anemia Although the anemia of chronic renal insufficiency is normochromic, normocytic, iron deficiency anemia may be superimposed. True iron deficiency anemia may result from an inadequate dietary intake because of the anorexia in many patients with severe renal insufficiency. Blood loss is common in uremic patients, usually from the gastrointestinal tract (uremic gastroenteritis), or from heavy menses. Platelet function is impaired in uremia33 and this abnormality may contribute to blood loss. Evaluation of the serum ion, red blood cell indices, and the peripheral smear are helpful in the recognition of iron deficiency. The diagnosis of iron deficiency anemia in patients with chronic renal disease is best established by the demop.stration of the absence of stainable iron in bone marrow aspirates. Folic acid deficiency is another nutritional anemia that occurs in patients with renal failure. It is usually found in patients on chronic hemodialysis since folate is dialyzable. This type of anemia is characterized by macrocytic red cells and hypersegmented polymorphonuclear leukocytes.
Therapy In every patient with anemia and renal failure, a cause for the anemia other than uremia should be sought. Correction of an iron or folic acid
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deficient state, or the elimination of an infection may improve the anemia substantially. Blood transfusions are not generally needed, since most children will tolerate hemoglobin levels of 4 to 8 gm/IOO ml without significant. symptomatology. We have not had to give transfusions to any child under our care who has chronic renal failure and has not begun chronic dialysis. It is important to keep transfusions to a minimum in any patient with chronic renal failure ifhe is a candidate for transplantation. Sensitization to the leukocytes and transplantation antigens could impair the future success of a graft. Cobalt and androgenic steroids have been shown to increase erythropoietin production 19.24 and it has been suggested that they might increase red cell mass in the uremic patient. Cobalt is a toxic substance and probably acts to increase erythropoietin production by interfering with tissue oxygen utilization. 4 It is therefore questionable whether it results in any net improvement of tissue oxygenation. Androgens increase production of erythropoietin by sensitizing the renal site of its synthesis so that more hormone is produced for any given level of stimulation. 19 The side effects of these compounds (hirsutism, increased libido, hypertension, liver damage) may outweigh the benefits.
UREMIA AND UREMIC TOXINS The uremic syndrome is a complex of signs and symptoms (Table 1) resulting from the retention of nitrogenous waste products from imbalances in the body content and distribution of water and electrolytes, and from abnormalities of hormone functions in consequence of renal failure. 23 Many symptoms have multiple causes. For example, the muscular weakness and twitching of uremia could result from hypocalcemia, hyperkalemia, hypermagnesemia, the maldistribution of sodium, potassium, and water in the intracellular fluid, the effects of motor neuropathy, and/or the effects of toxic nitrogenous wastes on membrane function or energy metabolism. Similarly, uremic bleeding may result from abnormal platelet function,33 capillary fragility resulting from malnutrition, and/or irritation of mucosal or serosal surfaces by uremic toxins. More specific pathophysiologic mechanisms underlying many of the symptoms of
Table 1. Features of Chronic Renal Failure and Uremia Fatigue, lethargy, somnolence, coma Anorexia, nausea, vomiting, hematemesis, gastric ulcers Uremic colitis, diarrhea, melena Pericarditis, myocardiopathy, cardiac failure Pleuritis, pulmonary edema, pulmonary hemorrhage Anemia, thrombasthenia, pUrPura Edema, hypertension Rickets/osteomalacia, osteitis fibrosa, hyperphosphatemia, hypocalcemia, hyperParathyroidism, pruritus Hyperkalemia, metabolic acidosis, hyperuricemia Glucose intolerance Peripheral neuropathy Impaired immunologic competence Retardation of growth and maturation
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uremia are unknown, but interference with proper enzyme functions of various tissues is often presumed. For example, the enzyme transketolase, active in the hexose monophosphate shunt pathway and important in the metabolism of peripheral nerve tissue, is inhibited in uremic patients and in the presence of uremic serum in vitro. 54 This inhibition has been proposed as a factor in the development of uremic neuropathy.54 Transketolase is also active in the normal metabolism of the red blood cell and reduction of its activity may also playa role in the decreased red cell lifespan in uremia. 38 On the basis of observations such as these it has been assumed that certain "uremic toxins" may exist which lead to the development of the uremic syndrome. That some of these presumed toxins are dialyzable, and thus of relatively small molecular size, is suggested by the success of dialytic therapy in the resolution of most uremic symptoms. Urea and/or creatinine were thought to be possible toxins, but the experimental infusion or retention of either of these substances has failed to produce more than trivial symptoms. 29 Moreover, though the symptoms of uremia are generally worse in patients with higher serum concentrations of urea or creatinine, some patients with markedly elevated levels remain asymptomatic, whereas others with relatively low serum concentrations are clearly uremic. The search for specific uremic toxins has led to the identification of a few substances which can produce uremic-like symptoms in normal animals, and which are present in much higher concentrations in renal failure than in health. Most convincing among these are methylguanidine and guanidino succinic acid (GSA). The chronic administration of methylguanidine to dogs has resulted in vomiting, poor appetite, decreased red cell survival, anemia, gastrointestinal ulceration, muscle twitching and hypertonia, decreased motor nerve conduction velocity, and convulsions. 22 The excretion of methylguanidine is increased fourfold in patients with renal failure ,22, 53 indicating an increased production rate in uremia. Experimentally, the concentration of methyl guanidine within many cellular tissues, notably muscle, peripheral nerve, and liver,22 is higher than that of plasma. Since the effect of uremic toxins is likely on enzymatic processes within the cells, such a finding may help explain the erratic correlation between the serum content of these various nitrogenous wastes and the presence of uremic symptoms. 23 Guanidino succinic acid is a by-product of the urea cycle in uremia and has been found to inhibit ADP-induced activation of platelet factor III which promotes platelet adhesiveness. 27 Thus GSA may thereby contribute to the bleeding tendency of uremia. In addition, stimulation of insulin and glucagon secretion by GSA and related compounds may help explain the glucose intolerance characteristic of the uremic state. 16 Other substances which have been investigated as possible uremic toxins are the so-called "middle molecules." Certain symptoms of uremia, notably neuropathy and pericarditis, do not resolve readily with dialysis. This observation led Scribner et al. 49 to suggest the existence of substances with molecular weights in the range of 500 to 5000 daltons which might be acting as uremic toxins. These "middle molecules" would be only poorly dialyzable. Peptide fragments in this range of molecular weights have recently been separated by complex chromatographic
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techniques from the sera of uremic patients 6 , 41 and are absent in normal sera, The quantity of these substances present in uremic plasma can be roughly correlated with the presence of uremic symptoms 41 and the chromatographic peaks disappear promptly after renal transplantation. 6 At present the role of these substances in the pathogenesis of uremia remains uncertain. Finally, a presumed natriuretic hormone may contribute to the uremic syndrome. 12 This hormone, also known as Third Factor,':' acts to decrease proximal renal tubular reabsorption of sodium, and has been suggested as a mechanism by which sodium homeostasis is maintained in renal insufficiency as well as in health. It has been proposed that an excess of this hormone may occur in renal insufficiency10 and cause abnormalities of sodium metabolism in various nonrenal tissues, thus evoking some of the manifestations of uremia. 12
Dietary Management of Uremia Regulation of the diet is the most effective nondialytic method for reducing the quantity of materials requiring renal excretion and must be considered a cornerstone in the management of the patient with chronic renal failure. The goals of dietary management in the patient with chronic renal failure are to: (1) minimize metabolic bone disease; (2) reduce the production of nitrogenous wastes; (3) ensure proper nutrition and foster appropriate physical growth; and (4) minimize the occurrence of fluid and electrolyte imbalances. Attainment of these goals requires considerable skill in dietary manipulations and considerable patient education and cooperation. The assistance of an experienced dietitian is of great value, and should be sought when important dietary manipulations are indicated. PHOSPHORUS RESTRICTION. As discussed in detail elsewhere in this symposium, the reduction of phosphorus intake is one of the first dietary adjustments which are required in the management of secondary hyperparathyroidism. 52 In children this may be accomplished most easily by elimination of milk from the diet. The intake of milk products should also be moderately restricted. This tactic has the virtue of being simple and generally effective. However, since milk is the major source of dietary calcium and of vitamin D, supplemental calcium salts (lactate, gluconate, or carbonate to provide approximately one gram of elemental calcium) and vitamin D must be prescribed. If needed, further reduction of phosphorus absorption may be accomplished with the use of oral aluminum hydroxide (500 to 1000 mg, q.i.d.). PROTEIN RESTRICTION. As renal insufficiency progresses, restriction of dietary protein becomes advisable as a means of reducing the production of the nitrogenous metabolites associated with uremic symptoms. At the same time, sufficient protein must be provided to prevent chronic negative nitrogen balance. The need to provide an adequate diet in the context of protein restriction has stimulated many clinical investigations of protein metabolism in uremia. 20 , 24, 28, 31 Most of the studies have been performed in azotemic adults; similar specific data on the ':'The first two factors known to affect the renal regulation of sodium are glomerular filtration and aldosterone.
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protein requirements of azotemic children are not available in the literature. The symptoms of uremia rarely occur until the blood urea nitrogen exceeds 100 mg/IOO ml. Therefore, dietary protein is generally not reduced until this level of azotemia is reached. In normal adults the minimum daily requirement of protein approximates 0.2 to 0.3 gm/kg/day (equivalent to 35 to 65 gm protein nitrogen/kg/day), provided the protein is of high biological value. The biological value of protein is predicated upon the adequacy of its complement of essential amino acids-those which cannot be synthesized de novo by the body. The amount of essential amino acids available limits the amount of new body protein which can be synthesized. When the essential amino acid present in least supply has been exhausted, further net protein synthesis will cease. Any amino acids, essential or nonessential, which remain are converted to their respective fat or carbohydrate derivatives plus nitrogenous waste products (urea). Protein derived from animal sources (exemplified by egg albumin and casein) are of the highest biological value. The proteins which are best omitted from the uremic diet are therefore those oflow biological value, derived principally from vegetable sources. In uremic adults the curtailment of dietary protein to 20 gm/day (0.3 gm/kg/day) has been associated with negative total body nitrogen balance and ultimately with signs of malnutrition. 31 Such stringent restriction necessitates profound reduction in the variety of foodstuffs which may be taken and has met with considerable difficulties in patient acceptance, especially when the patient is a child. At least in dialyzed patients, the provision of a more liberal diet containing 40 gm of high quality protein results in neutral to slightly positive overall balance and in improved patient cooperation and feelings of well-being without increased symptoms of uremia. 31 In the management of children with severe azotemia, diets containing 1.0 to 2.0 gm/kg/day of protein of high biological value appear to be preferred. 26 The greater need of children for protein to permit growth and the generally satisfactory clinical results of such a regimen appear to warrant a relatively liberal protein intake in many uremic children. As renal failure progresses, uremic symptoms will supervene despite even stringent protein restriction. At this point, regular dialysis is generally the treatment of choice. However, an additional dietary maneuver which remains available increasingly is being tried. Specifically, this concerns the use of balanced mixtures of essential amino acids, with or without an added supplement of carbohydrate and fats, to provide the materials and caloric supply from which new body protein may be synthesized. When such a mixture is taken, the nonessential amino acids are produced by the body, utilizing available urea as a source of amino nitrogen. 20 ,21 Net protein synthesis is thus achieved as reflected by a net positive nitrogen balance. 5 , 25 At the same time the B UN fails because of both the reduced nitrogen intake and the increased utilization of urea nitrogen. Use of such supplements in adults 5 , 25, 36 and in at least one child 2 has permitted reduced dialysis time, and a substantial improvement in nutritional status. A further advantage of such a dietary supplement has been the reduced need for restriction of phosphorus or potassium. This is a result of their incorporation into new cellular tissue.
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Indeed, in some individuals supplementation of phosphorus and potassium has been necessary.36 The essential amino acid mixtures presently available have good patient acceptance. A present disadvantage of the essential amino acid diet from a practical standpoint is the high cost of these preparations. With their increasing use it is anticipated that the cost will be reduced. A more recent adaptation of this same dietary principle has been the use of the alpha-ketoanalogues of the essential amino acids valine, methionine, leucine, isoleucine, and phenylalanine. 56.57 These analogues are aminated in the body to their respective L-amino acids, which are then available for protein synthesis. Their use has been associated with decrease in the rate of appearance of urea nitrogen and a decrease in the BUN. This results from improvement in the efficiency of amino-N reutilization and decrease of its entry into the urea cycle. 57 However, ketoacid therapy may be useful only in a diet low in protein and thus does not allow a more liberal or more palatable dietary regimen. Moreover, it has been claimed that the rate of renal functional deterioration might actually be reduced with the use of these ketoanalogues. 57 CALORIC INTAKE. As important as restriction of dietary protein is the provision of a diet adequate or even abundant in total caloric content to promote the efficiency with which protein is utilized. 28 , 36 Thus in uremic adults on a low protein diet, nitrogen balance was negative when caloric intake was below 45 to 55 cal/kg/day.28 The usual caloric needs of normal adults is 35 cal/kg/day. Similarly, the provision to adult dialysis patients of a high calorie diet (3000 to 4000 callday)in which mostofthe nitrogen was in the form of essential amino acids led to strongly positive N-balance. No such effect was noted in nondialyzed patients on a similar diet consuming only 2600 to 3000 calories/day.36 In children with renal insufficiency, failure to ingest adequate calories appears to be the most important factor responsible for the growth failure which is often so striking. Other factors such as chronic acidosis, metabolic bone disease (renal osteodystrophy), anemia, uremic toxicity, and abnormal hormone function or hormone balance may also contribute to growth defects in these patients,14 The problem of growth in renal failure is reviewed elsewhere in this symposium. It should be noted here, however, that studies both in children 8,51 and in animals 4 , 17,39 are strongly in support of the importance of caloric intake in promoting growth in uremia. Thus Simmons et al. 51 showed that children on hemodialysis who ingested less than 67 per cent of the recommended caloric intake for age, grew at only one third the normal rate, whereas patients with a caloric intake greater than 67 per cent of the recommended daily allowance grew at a normal rate, on the average. Caloric supplementation of the diet resulted in improved growth rates for all five children with previously low intake. The protein intake in all subjects ranged from 1.0 to 2.0 gmlkg/day. Betts and Magrath,8 found that the spontaneous caloric intake was low in 80 per cent of children with renal impairment. The deficit was evenly distributed with regard to protein, fats, and carbohydrates. The growth rate correlated strongly with caloric intake, being normal when intake exceeded 80 per cent of recommended requirements, and falling drastically at intakes below 60 per cent, with cessation of growth below 40
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per cent of normal caloric intake. At the same time, growth velocity was related to residual renal function and declined only after the glomerular filtration rate fell below 25 mllminl1. 73 m 2 • The relationship between glomerular filtration rate and caloric intake was not established. These· observations demonstrate, as Holliday 26 has stated, that growth is possible only after caloric intake is sufficient first to support the metabolic processes required of tissues already present in the body. That is, basal caloric requirements must be fully met before any energy may be diverted to the growth process. In summary, the restriction of dietary protein is effective in reducing or preventing uremic symptoms until renal function becomes severely impaired. Protein restriction need not be introduced until BUN is in the range of 100 to 120 mgl100 ml, when uremic symptoms become increasingly likely. Protein should be of high biological value to be optimally effective. For azotemic children, reduction of protein intake to approximately 1.0 to 1.3 gm/kglday, up to 40 to 50 gm/day, appears most satisfactory, but represents a significant reduction from the usual intake of2 to 4 gmlkglday. The use of mixtures of essential amino acids as a source of dietary nitrogen is also highly effective in limiting nitrogenous wastes and can prevent negative nitrogen balance with a minimum dietary nitrogen load. Provision of a full complement of calories is essential, however, for optimal utilization of dietary protein and is the single most important factor in the prevention of growth retardation in children with significant renal functional impairment.
REFERENCES 1. Adamson, J. W., Eshback, J., and Finch, C. A. : The kidney and erythropOiesis. Am. J. Med., 44:725, 1968. 2. Alexander, E., and Levinsky, N.: An extrarenal mechanism of potassium adaptation. J.C.I., 47:740, 1968. 3. Aronson, A. S., Furst, P., Kuylenstierna, B., et al.: Essential amino acids in the treatment of advanced uremia: Twenty-two months experience in a 5-year-old girl. Pediatrics, 56:538-543, 1975. 4. Barron, A. G., and Barron, E. S. G.: Mechanism of cobalt polycythemia. Effect of ascorbic acid. Proc. Soc. Exper. BioI. Med., 35:407;1936. 5. Bergstrom, J., Furst, P., and Noree, L. 0.: Treatment of chronic uremia patients with protein poor diet and oral supply of essential amino acids. I. Nitrogen balance studies. Clin. Nephrol., 3:187-194,1975. 6. Bergstrom, J., Furst, P., Gordon, A., et al. : Middle molecules in uremia (abstract). Proceedings of Sixth International Congress of Nephrology, Firenze, 1975. 7. Berlyne, G., Janabi, K., and Shaw, A.: Dangers of resonium A in the treatment of hyperkalemia in renal failure. Lancet, 1: 167, 1966. 8. Betts, P. R., and Magrath, G.: Growth pattern and dietary intake of children with chronic renal insufficiency. Brit. Med. J., 1 :189-193, 1974. 9. Blaufox, M. D.: Systemic arterial hypertension in pediatric practice. PEDIAT. CLIN. NORTH AM., 18:577-593,1971. 10. Bourgiognie, J. J., Hwang, K. H., Espinel, C., et al.: A natriuretic factor in the serum of patients with chronic uremia. J. Clin. Invest., 51 :1514, 1972. 11. Bricker, N. S., Klahr, S., Lubowitz, H., et al.: The pathophysiology of renal insufficiency: On the functional transformations in the residual nephrons with advancing disease. PEDIAT. CLIN. NORTH AM., 18:595-611, 1971. 12. Bricker, N. S.: The pathogenesis of the uremic state: The "trade-off hypothesis." New Engl. J. Med., 286:1093-1099,1972. 13. Burnell, J., Villamil, M., Uyeno, B., et al. : Effect in humans of extracellular pH change on the relationship between serum potassium concentration and intracellular potassium. J.C.I., 35:935, 1956. 14. Chantler, C., and Holliday, M. A.: Growth in children with renal disease with particular reference to the effects of caloric malnutrition: A review. Clin. Nephrol, 1 :230-242, 1973.
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15. Chaplin, H., and Mollison, P. H.: Red cell life span in nephritis and in hepatic cirrhosis. Clin. Sci., 12:351, 1953. 16. Cohen, B. D., Handelsman, D. G., and Pai, B. N.: Toxicity arising from the urea cycle. Kidney Int., 7:S285-S287, 1975. 17. Diaz, M., Kleinknecht, C., and Broyer, M.: Growth in experimental renal failure: Role of calorie and amino acid intake. Kidney Int., 8:349-354,1975. 18. Fisher, J. W., Hatch, F. E., Roh, B. L., et al. : Erythropoietin inhibitor in kidney extracts and plasma from anemic uremic human subjects. Blood, 31 :440, 1968. 19. Fried, W., and Gurney, C. W.: The erythropoietic stimulating effects of androgens. Ann. N.Y. Acad. Sci., 149:356, 1968. 20. Giordano, C.: Use of exogenous and endogenous urea for protein synthesis in normal and uremic subjects. J. Lab. Clin. Med., 62:231-245,1963. 21. Giordano, C., DePascale, C., Balestrieri, C., et al.: Incorporation of urea 15N in amino acids of patients with chronic renal failure on low nitrogen diet. Am. J. Clin. Nutr., 21 :394-402, 1968. 22. Giovanetti, S., Balestri, P. L., and Barsotti, G.: Methylguanidine in uremia. Arch. Intern. Med., 131 :709, 1973. 23. Giovannetti, S., and Barsotti, G.: Uremic intoxication. Nephron, 14:123-133, Hl75. 24. Goldwasser, E., Jacobson, L. 0., and Plzak, L.: Studies on erythropoiesis. V. The effect ofcobalt on the production of erythropoietin. Blood, 13 :55, 1958. 25. Heidland, A., and Kult, J.: Long term effects of essential amino acids supplementation in patients on regular dialysis treatment. Clin. NephroI., 3:234-239,1975. 26. Holliday, M. A.: Calorie deficiency in children with uremia: Effect upon growth. Pediatrics, 50:590-597, 1972. 27. Horowitz, H. I., Stein, I. M., Cohen, B. D., et al.: Further studies on the platelet inhibitory effect of guanidino succinic acid and its role in uremic bleeding. Am. J. Med., 49:336345,1970. 28. Hyne, B. E. B., Fowell, E., and Lee, H. A.: The effect of caloric intake on nitrogen balance in chronic renal failure. Clin. Sci., 43:679-688, 1972. 29. Johnson, W. J., Hagge, W. W., Wagoner, R. D., et al.: Toxicity arising from urea. Kidney Int., 7:S288-S293, 1975. 30. Keith, N., and Osterberg, A.: The tolerance for potassium in severe renal insufficiency. A study often cases. J.C.I., 26:773,1947. 31. Kopple, J. D., and Coburn, J. W.: Metabolic studies of low protein diets in uremia. I. NitrQgen and potassium. MediCine, 52:583-595, 1973. 32. Larsen, O. A., Josephson, P., and Lassen, N. A.: Nefrogen anaemi behandlet med erythropoietin. Ugeskr Laeg., 125:435, 1963. 33. Lewis, J. H., Zucker, M. B., and Ferguson, J. H.: Bleeding tendency in uremia. Blood, 11 :1073,1956. 34. Lieberman, E.: Management of acute renal failure in infants and children. Nephron, 11 :193, 1973. 35. Litzow, J., Lemann, J., and Lennon, E.: The effect of treatment of acidosis on calcium balance in patients with chronic azotemic renal disease. J.C.I., 46:280,1967. 36. Llach, F., Franklin, S. S., and Maxwell, M. H.: Dietary management of patients in chronic renal failure. Nephron, 14:401-412, 1975. • 37. Loge, J. P., Lange, R. D .., and Moore, C. V.: Characterization of the anemia associated with chronic renal insufficiency. Am. J. Med., 24:4, 1958. 38. Lonergan, E. T., Semar, M., Sterzel, R. B., et al.: Erythrocyte transketolase activity in dialyzed patients. New Engl. J. Med., 284:1399-1402,1971. 39. MacDonell, R. C., Buzon, M. M., and Holliday, M. A.: Growth failure in uremic rats: The role of calorie deficiency (abstract). Pediat. Res., 7:411, 1973. 40. Makoff, D. L., Gordon, A., Franklin, S. S., et al.: Chronic calcium carbonate therapy in uremia. Arch. Intern. Med., 123:15, 1969. 41. Migone, L., Dall'Aglio, P., and Buzio, C.: Middle molecules in uremic serum, urine and dialysis fluid. Clin. NephroI., 3:82-93, 1975. 42. Mirand, E. A., Murphy, G. P., Steeves, R. A., et al.: Erythropoietin activity in anephric, allotransplanted, unilaterally nephrectomized and intact man. J. Lab. Clin. Med., 73:121,1969. 43. Muth, R. G.: Diuretic properties of furosemide in renal disease. Ann. Intern. Med., 69:249-261, 1968. 44. Palmer, W. W., and Henderson,.L. J.: A study of the several factors of acid excretion in nephritis. Arch. Intern. Med., 16:109, 1915. 45. Richards, P.: Protein metabolism in uremia. Nephron, 14:134-152, 1975. 46. Schultz, R., Taggart, D., Shapiro, H., et al.: On the adaptation in potassium excretion associated with nephron reduction in the dog. J.C.I., 50:1061,1971. 47. Schwartz, W. B., Hall, P. W., Hays, R. M., et aI.: On the mechanism of acidosis in chronic renal disease. J.C.I., 38:39,1959. 48. Schwartz, W., and Kassirer, J.: Medical management of chronic renal failure. Amer. J. Med., 44:786,1968.
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49. Scribner, B. H., Farrell, P. C., Milutinovic, J., et al.: Evolution of the middle molecule hypothesis. In Villareal, H. (ed.): Proceedings of Fifth International Congress of Nephrology, Basel, Karger, 1974, pp. 190-199. 50. Shainkin, R., Giatt, Y., and Berlyne, G.: The presence and toxicity of guanidino-propionic acid in uremia. Kidney Int., 7:S-302, 1975. 51. Simmons, J. M., Wilson, C. J., Potter, D. E., et al.: Calorie intake and linear growth of children on hemodialysis. New EngI. J. Med., 285:653-655, 1971. 52. Slatopolsky, E., and Bricker, N. S.: The role of phosphorus restriction in the prevention of secondary hyperparathyroidism in chronic renal disease. Kidney Internat., 4:141-145, 1973. 53. Stein, I. M., Perez, G., Johnson, R., et al.: Serum levels and urinary excretion of methylguanidine in renal failure. J. Lab. Clin. Med., 77:1020-1024, 1971. 54. Stenzel, R. B., Semar, M., Lonergan, E. T., et aI.: Relationship of nervous tissue transketolase to the neuropathy in chronic uremia. J. Clin. Invest., 50:2295-2304, 1971. 55. Talbot, N. B., Crawford, J. D., and Butler, A. M.: Homeostatic limits to safe parental fluid therapy. New Engl. J. Med., 248:1100, 1953. 56. Walser, M., Coulter, A. W., Dighe, S., et aI.: The effect of keto analogues of essential amino acids in severe chronic uremia. J. Clin. Invest., 52:678-690, 1973. 57. Walser, M.: Ketoacids in the treatment of uremia. Clin. NephroI., 3:180-186, 1975. 58. Wrong, 0., and Davies, H. E. F.: Excretion of acid in renal disease. Quart. J. Med., 28:259, 1959. Children's Memorial Hospital 2300 Children's Plaza Chicago, Illinois 60614