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The role of nutrition in the growth retardation of children with chronic renal failure undergoing maintenance… Rothney, Linda Mary 1978

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THE ROLE OF NUTRITION IN THE GROWTH RETARDATION OF CHILDREN WITH CHRONIC RENAL FAILURE UNDERGOING MAINTENANCE DIALYSIS by LINDA MARY ROTHNEY B.S.H. (HON.), Acadia University, 1974 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES School of Home Economics Div i s i o n of Human Nut r i t i o n We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA June 19 78 © Linda Mary Rothney, 19 78 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the Head of my Department or by his representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of Hocne Economics ) th'^ 'sioo o-C \Woaf\ lOu4vci-i6o The University of Brit ish Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 Date A^L- cT, i ABSTRACT Growth f a i l u r e i s a major problem i n children with chronic renal f a i l u r e (CRF). A number of factors have been suggested as explanations for t h i s impaired growth including renal osteodys-trophy, age of onset of chronic renal f a i l u r e , degree of azotemia and n u t r i t i o n a l status. As children with CRF are frequently un-able to maintain s u f f i c i e n t nutrient intakes for optimal growth, the n u t r i t i o n a l status of these individuals must obviously have a major, i f as yet poorly understood, role i n the observed growth f a i l u r e . Therefore, a n u t r i t i o n a l , physical and biochem-i c a l study was. conducted to assess the n u t r i t i o n a l status of seven,children undergoing maintenance hemodialysis. To evaluate the adequacy of dietary intake, fourteen day food records were obtained from each of the participants and average nutrient intakes were compared to the recommended d a i l y nutrient intake of the Canadian Dietary Standard (CDS) (1975). To assess the physical status of the children,'height, height v e l o c i t y , weight, per cent body f a t , and bone age were determined. As abnormalities of taste s e n s i t i v i t y are known to influence dietary patterns, s a l i v a r y flow rates, s a l i v a r y urea concentrations, and taste detection and recognition thresholds for sweet, sour, s a l t and b i t t e r were determined pre and post d i a l y s i s . Biochemical investigations included the determination of pre and post d i a l y s i s plasma amino acid concentrations following a standardized fast of f i v e hours, and the q u a n t i f i c a t i o n of the amounts of amino acids l o s t into dialysate during a complete hemodialysis treatment. The mean c a l o r i c intake of 54% ±11 of the CDS i s inadequate for optimal growth. The mean protein intake was 1.09 ±.16 grams of protein per kilogram of body weight. The f i r s t and second l i m i t i n g amino acids were h i s t i d i n e and threonine, respectively. N u t r i t i o n a l d e f i c i e n c i e s of certa i n water soluble vitamins ( r i b o f l a v i n , n i a c i n and pyridoxine) existed for some of the children. The mean zinc, magnesium and copper intakes were 45% ±8, 51% ±19 and 54% ±32 of the CDS, respectively. Growth (as measured by body height and weight) was found to be retarded one to two standard deviations from normal i n the children studied. Per cent body fat estimations were within normal l i m i t s , but bone age was frequently below chronological age. Taste s e n s i t i v i t y was impaired as shown by elevated pre d i a l y s i s sweet and b i t t e r recognition thresholds (p<.01). This reduced taste acuity was improved post d i a l y s i s (p<.005), but did not reach normal values. Pre and post d i a l y s i s , s a l i v a r y flow rates were reduced (p<.0005) and s a l i v a r y urea concentra-tions elevated (p<.0005) when compared to normal. Pre d i a l y s i s , plasma concentrations of taurine, a-amino-butyric acid, valine, cystine, leucine, tyrosine and tryptophan were decreased from normal l e v e l s (p<.025), and aspartic acid, proline, glycine, c i t r u l l i n e , ornithine, h i s t i d i n e , arginine, asparagine, 3-methylhistidine and hydroxyproline were elevated above normal (p<.005). The presence of s u b c l i n i c a l protein c a l o r i e malnutrition (PCM) was indicated by a depressed plasma ess e n t i a l to nonessential amino acid r a t i o , a depressed plasma valine to glycine r a t i o , and an elevated plasma phenylalanine to tyrosine r a t i o as compared to normal. The detection of 3-methylhistidine and hydroxyproline i n plasma provides addi-t i o n a l indications of PCM. The mean amount of t o t a l amino acid l o s t into dialysate was 4.7 ±.9 grams. H i s t i d i n e , threonine, lysine and valine were the ess e n t i a l amino acids l o s t i n the largest amounts. In conclusion, growth i s retarded i n children with CRF and may be due to the accumulation of metabolic end products which depress appetite and/or delay the natural rate of growth events Suboptimal nutriture, as evidenced by the presence of PCM, i s a major factor i n the growth retardation of these i n d i v i d u a l s . I V TABLE OF CONTENTS Page ABSTRACT i TABLE OF CONTENTS i v LIST OF TABLES v i ACKNOWLEDGEMENTS v i i i SECTION 1. REVIEW OF LITERATURE 1.1 Introduction 1 1.2 Growth Diagnosis and Measurement 2 1.3 Etiology of Growth Fa i l u r e i n Children with Chronic Renal F a i l u r e 4 1.4 Calorie Intake and Growth 5 1.5 Protein and Amino Acid Metabolism i n Uremia 9 1.6 Vitamin Nutriti o n i n Uremia 17 1.7 Mineral Metabolism i n Uremia 19 1.8 Dietary Treatment of Chronic Renal F a i l u r e 20 1.9 Etiology of Hypogeusia and Disgeusia i n Chronic Renal F a i l u r e 22 2. INTRODUCTION 29 3. MATERIALS AND METHODS 3.1 Study Participants 32 3.2 Anthropometric Measurements 36 3.3 Dietary Records, Food Collections and Analysis 37 3.4 C o l l e c t i o n and Analysis of Blood Samples 40. 3.5 C o l l e c t i o n and Analysis of Dialysate 43 3.6 Assessment of Taste S e n s i t i v i t y 43 4. RESULTS 4.1 Anthropometric Data 46 4.2 Dietary Data 46 4.3 Biochemical Data 53 4.4 Dialysate Data 65 4.5 Taste S e n s i t i v i t y Data 68 5. DISCUSSION 5.1 Anthropometry 79 5.2 N u t r i t i o n a l Status 80 5.3 Plasma Amino Acids 86 5.4 Losses of Amino Acids into Dialysate 9 2 5.5 Hypogeusia and Disgeusia i n Uremia 94 6. CONCLUSIONS 9 8 BIBLIOGRAPHY 101 V Page APPENDICES A. Consent Form 113 B. Approval of Study 114 C. Sample Set of Instructions 115 D. Sample Calendar Describing Study Period 117 E. Sample Food Intake Record Sheet 118 F. Sample A c t i v i t y Record Sheet 119 G. Sample Taste Testing Response Sheet 120 H. Normal Taste Thresholds for Sweet (Sucrose), Sour (Hydrochloric Acid), Salt (Sodium Chloride) and B i t t e r (Quinine Sulfate) Reported i n the Literature 121 v i LIST OF TABLES Page Table I A description of the study p a r t i c i p a n t s . 33 II Composition of the standard dialysate. 34 III Details of each subject's dietary r e s t r i c t i o n s and n u t r i t i o n a l supplements. 35 IV L i s t of dietary constituents included i n computer ca l c u l a t i o n of food intakes. 39 V L i s t of laboratory analyses performed on venous blood samples pre and post d i a l y s i s . 42 VI Per cent concentrations of taste t e s t i n g solutions. 45 VII Results of anthropometric measurements of seven uremic children. 47 VIII Average nutrient intakes of seven uremic children for fourteen day food record period. I. 48 IX Average nutrient intakes of seven, uremic children for fourteen day food record period. I I . 49 X Per cent of t o t a l c a l o r i e s contributed to the d i e t by protein, fat and carbohydrate over the fourteen day food record period. 51 XI Average chemical scores and most l i m i t i n g amino acids of diets consumed during a fourteen day period by seven uremic children. 52 XII Comparison of the dietary protein and amino acids as given by food table calculations and chemical analyses. 54 XIII Comparison of pre d i a l y s i s plasma amino acids i n s i x children with CRF with normal values given i n the l i t e r a t u r e for individuals of the same age group. 56 XIV Comparison of post d i a l y s i s plasma amino acids i n s i x children with CRF with normal, values given i n the l i t e r a t u r e for individuals of the same age group. 57 XV S i g n i f i c a n t changes i n plasma amino acids before and af t e r a hemodialysis treatment i n s i x children with CRF. 59 XVI Pre and post d i a l y s i s plasma valine/glycine, phenyl-alanine/tyrosine and essential/nonessential amino acid r a t i o s i n s ix -uremic children. 60 v i i Table XVII Page XVIII XIX XX XXI XXII XXIII XXIV" XXV XXVI XXVII XXVIII XXIX Pearson Product-Moment Correlation C o e f f i c i e n t : Test of c o r r e l a t i o n between cert a i n plasma amino acid concentrations and selected dietary constituents, blood urea concentration, or plasma creatinine concentration. Pearson Product-Moment Correlation C o e f f i c i e n t : Test of c o r r e l a t i o n between dietary amino acid chemical score and blood c i t r u l l i n e , urea, creatinine, ornithine or arginine concentration. Results of biochemical analyses of blood pre and post d i a l y s i s . Free amino acids present i n dialysate of seven uremic children at the termination of a d i a l y s i s treatment. Total amino acids, e s s e n t i a l and nonessential, l o s t into dialysate during a complete hemodialysis treatment for each of seven uremic subjects. Colony counts of microorganisms i s o l a t e d from dialysate at the termination of d i a l y s i s . Comparison of pre and post d i a l y s i s stimulated parotid s a l i v a flow rate i n seven uremic children with normal values given i n the l i t e r a t u r e . Saliva urea concentrations pre and post d i a l y s i s i n seven uremic children. Sweet detection and recognition thresholds i n seven uremic children before and after d i a l y s i s . S a l t detection and recognition thresholds i n seven uremic children before and afte r d i a l y s i s . Sour detection and recognition thresholds i n seven uremic children before and afte r d i a l y s i s . B i t t e r detection and recognition thresholds i n seven uremic children before and a f t e r d i a l y s i s . Pearson Product-Moment Correlation C o e f f i c i e n t : Test of c o r r e l a t i o n between taste thresholds and blood urea nitrogen, s a l i v a urea, and serum alk a l i n e phosphatase. 61 62 63-64 66 67 69 70 71 73" l-'k 75 76 77 ACKNOWLEDGEMENTS I wish to express my sincere thanks to those people who have helped make thi s thesis a r e a l i t y , To Dr. David S. Lirenman for the constructive support, gentle humour, i n q u i s i t i v e approach and concern for his patients that spurred me on during my career as a c l i n i c a l researcher, To Dr. Derek Applegarth and his side kick, S t e l l a , for thei r enlightened technical assistance, To the s t a f f of the renal unit for always managing to accommodate "the n u t r i t i o n study" with a smile, To Drs. Nancy Schwartz and Patrick Stapleton for serving as committee members, To Mr. Lewis James and Dr. Thomas Abernathy for t h e i r s t a t i s t i c a l genius and a b i l i t y to coerce the computer to s p i l l out r e s u l t s , To the National Research Council of Canada for pouring f i n a n c i a l aid into an undeveloped resource, And to those seven children for playing "every game i n the book", but always l e t t i n g me win i n the end. REVIEW OF LITERATURE 1.1 Introduction Growth f a i l u r e i s one of the major problems encountered i n the management of uremic children treated with d i a l y s i s . A pre-occupation with the underlying disease and the sustained e f f o r t required to maintain children on d i a l y s i s i n a tolerable state of health, make i t a l l too easy to accept growth f a i l u r e as an inev i t a b l e consequence of renal i n s u f f i c i e n c y . Growth i s a complicated process which,, i n spite of recent intensive i n v e s t i -gation, i s s t i l l incompletely understood. Equally, the metaboli consequences of CRF are complex and poorly delineated. When one asks questions about the effects of a poorly understood disease state upon a complicated process, the answers are inev i t a b l y incomplete. The fact that growth f a i l u r e i n children with CRF i s an immediate and pressing dilemma was shown by Scharer et a l in 19 76. They measured body height i n 2 50 boys and 22 4 g i r l s at the s t a r t of hemodialysis, or at the time of the f i r s t trans-plant, and found that 40% of the children f e l l below the t h i r d percentile for height. Growth v e l o c i t i e s less than three c e n t i -meters per year (this represents less than the t h i r d percentile for growth v e l o c i t y before puberty) were found i n 62% of the boys and 72% of the g i r l s . Due to small body s i z e , the intake of potassium, sodium-and nitrogen must be more rigorously controlled i n the c h i l d than i n the adult on d i a l y s i s . The dietary r e s t r i c t i o n s im-posed on such children are combined with the malaise, anorexia and attendant emotional disturbance caused by t h e i r condition 2. and i t s treatment. The end r e s u l t i s the inadequate consumption of s u f f i c i e n t c a l o r i e s and other nutrients to support growth. The n u t r i t i o n a l status of children with CRF must obviously have a major, i f as yet poorly understood, role i n the observed growth,retardation. The ensuing review w i l l present some of the information available on the assessment of growth and some of the nonnutri-t i o n a l factors that have been implicated i n the.etiology of growth f a i l u r e i n uremic children. The n u t r i t i o n a l factors to be considered include: the nature of the c a l o r i c requirements for growth i n uremia; the alterations of protein and amino acid metabolism i n CRF; the implications of vitamin and mineral nutriture' i n uremics; and the current dietary recommendations for children undergoing maintenance d i a l y s i s . A short.discus-sion on the po t e n t i a l causes and consequences of hypogeusia and dysgeusia i n uremia w i l l conclude t h i s review. 1.2 Growth Diagnosis and Measurement Normal growth, i n i t s inception, maintenance, and termina-t i o n , depends upon an orderly sequence of genetic, c o n s t i t u t i o n a l , environmental, n u t r i t i o n a l , and endocrine influences. Children are very s e n s i t i v e about t h e i r size and shape, e s p e c i a l l y during adolescence when even the most normal boy and g i r l experience some anxiety about the outcome of the pubertal metamorphosis. In evaluating the growth status of a given c h i l d , his measurements, both absolute and derived, must be compared with suitable norms. Growth retardation generally refers to short-ness of stature or retarded sReie t a l growth. However, abnormal 3. s k e l e t a l growth i s associated with disturbances of other systems, e s p e c i a l l y muscle mass, and with changes i n body composition (for example, f a t and e x t r a c e l l u l a r volume). In severe chronic renal f a i l u r e loss of weight i s due to a reduction i n body fat and fat-free s o l i d s . The lean body mass forms an increased proportion of body weight. Body water i s increased largely due to an. excess of e x t r a c e l l u l a r f l u i d , and, i n t r a c e l l u l a r f l u i d i s reduced r e l a t i v e to standard weight i n the majority of uremic patients (Coles, 1972). These changes of body water may inval i d a t e the use of body weight as an i n d i -cator of growth i n children with CRF. However, the use of body weight and appropriate s k i n f o l d measurements together may present a more accurate description of body composition (Holliday, 1975, and Durnin and Rahaman, 1967). The relationship between body density and s k i n f o l d thickness at four s i t e s (biceps, t r i c e p s , subscapular, and supra-iliac) i s s u f f i c i e n t l y uniform (r = -.80) that regression equations can be used to calculate body fat i n adolescents (Durnin and Rahaman, 1967, and Durnin and Womersley, 1974). Body composition assessment has played an important role i n the evaluation of growth, maturation, n u t r i t i o n and physical performance (Lohman et a l . , 1975, and Cureton et a l . , 1975). Growth rates vary at d i f f e r e n t times of the year and i t i s d i f f i c u l t to assess growth performance.satisfactorily i n periods less than one year (Bayer and Bayley, 1976). Height i s best measured with a stadiometer. Height increments, or height v e l o c i t y , are d i f f i c u l t to compare when growth i s retarded or puberty i s beginning. Assessment of height over the age of eleven years must take into account the stage of puberty the c h i l d has reached (Tanner and Whitehouse, 1976). This i s p a r t i c u l a r l y important i n children with CRF i n whom puberty i s often delayed. Often, i t i s more r e a l i s t i c to compare the height v e l o c i t y of uremic children to that projected for normal ch i l d r e of the same height rather than the same age (Chantler and Holliday, 1973). Bone age (BA) i s also useful i n predicting height pote n t i a l when sk e l e t a l growth i s slow. A single x-ray of one hand and wrist can provide the basis for a c r i t i c a l evaluation of matur-ation to which other indices, analyses and predictions can be meaningfully related (Bayer and Bayley, 1976). The l e f t hand i s customarily chosen as i t i s less subject to environmental influences. Normal standards for hand and wrist (Greulich and Pyle, 1959) ex i s t for assessment and comparison. The knee i s a second choice for radiographic analyses, and i s useful as an additional area for appraisal. By i t s e l f , the knee i s a less r e l i a b l e indicator of s k e l e t a l maturity than i s the hand-wrist combination. About two-thirds of the population of healthy children have a BA no more than one year above or below t h e i r chronological age (CA). A retardation of three or more years i s considered grossly abnormal (Bayer and Bayley, 19 76, and Broyer et a l . , 1974). 1.3 Etiology of Growth Fa i l u r e i n CRF The metabolic consequences of renal disease are extensive and a number of factors have been implicated i n growth f a i l u r e . These include: a. Age of onset of CRF (Betts and Magrath, 19 74) b. Renal osteodystrophy (Lirenman et a l . , 1968) 5. c. Anemia (Penington and Kincaid-Smith, 1971) d. Chronic infections (Uttley et a l . , 1972) e. Degree of azotemia (Berlyne et a l . , 1968) f. Acidosis (West and Smith, 1956 and Nash, 1972) g. Hypertension (Caliguini et a l . , 1963) h. Urinary concentrating defect (West and Smith, 1956) with r e s u l t i n g hyposthenuria and hypernatremia (Uttley et a l . , 1972), albuminuria (Bianchi et a l . , 1975), and depletions of body sodium (West and Smith, 1956 and Cooke et a l . , 1960), phosphate (Harrison et a l . , 1966), magnesium ( E l l i o t t and Cheek, 1968), potassium (Cheek and West, 1956), and zinc (Halsted and Smith, 19 70) i . Endocrine disorders including elevated levels of c i r c u l a t i n g growth hormone (Wright et a l . , 1968), glucocorticosteroids (Feldman and Singer, 1974), i n s u l i n (Lowrie et a l . , 1970), and decreased l e v e l s of somatomedin (Saenger et a l . , 1974), and thyroid hormones (Dandona et a l . , 1977). N u t r i t i o n a l status has also been indicated as a f f e c t i n g the growth c h a r a c t e r i s t i c s of uremic children (Berlyne et a l . , 1968, Betts and Magrath, 19 74, Broyer et a l . , 1974, Chantler and H o l l i -day, 1973, Counahan et a l . , 1976, Delaporte et a l . , 1976, Holliday, 1975, Lewy and New, 1975, and Simmons et a l . , 1971). I t should be noted that a l l of the aforementioned factors have been implicated i n the growth retardation of uremic children, but no one factor has been designated as more important than any of the others. 1.4 Calorie Intake and Growth Cal o r i c intake i n healthy people i s regulated by appetite 6 . to approximate c a l o r i e e x p enditure. C a l o r i e expenditure i s the sum o f c a l o r i e s r e q u i r e d f o r b a s a l metabolic r a t e (BMR), p h y s i c a l a c t i v i t y , thermal r e g u l a t i o n , and, i n c h i l d r e n , growth. C a l o r i e i n t a k e i n c r e a s e s w i t h the growth of body s i z e , but the i n c r e a s e i s not p r o p o r t i o n a l to body weight. T h i s d i f f e r e n c e i s due to the c h i l d having a high e r BMR per kilo g r a m , g e n e r a l l y a h i g h e r l e v e l o f p h y s i c a l a c t i v i t y , and a c a l o r i e requirement f o r growth, as compared to the a d u l t . The g r e a t e r c a l o r i e requirement of the c h i l d r e s u l t s i n a p r o p o r t i o n a t e l y l a r g e r consumption of p r o t e i n , s a l t and other e l e c t r o l y t e s (Wilson e t a l . , 1973). Kidney f u n c t i o n i s g r e a t e r d u r i n g growth ( H o l l i d a y , 1972), and, hence, the normal c h i l d , as compared to the normal a d u l t , maintains the same l e v e l of plasma urea and the same r e l a t i v e e x c r e t i o n o f e l e c t r o l y t e s . The range of t o l e r a n c e f o r p r o t e i n , s a l t and other d i e t a r y c o n s t i t u e n t s i s g r e a t l y c o n t r a c t e d i n the c h i l d w i t h CRF. T h i s r e d u c t i o n i n t o l e r a n c e f r e q u e n t l y n e c e s s i t a t e s the d i e t a r y r e s t r i c t i o n o f these n u t r i e n t s w i t h a r e s u l t a n t r e d u c t i o n i n c a l o r i e i n t a k e . Since c a l o r i e d e f i c i e n c y i s a s s o c i a t e d w i t h growth r e t a r d a t i o n , the development of c a l o r i c d e f i c i e n c y i n the c h i l d w i l l a f f e c t growth. This i s a l s o e v i d e n t i n o v e r t c a l o r i e m a l n u t r i t i o n where s k e l e t a l growth i s g r e a t l y slowed (height f o r age i s reduced), muscle mass i s sm a l l (weight f o r h e i g h t i s low), and body f a t minimal. While the r e s u l t o f c a l o r i e d e f i c i e n c y upon growth i s c l e a r , the mechanism by which c a l o r i e d e f i c i e n c y a f f e c t s growth remains obscure. The c a l o r i c c o s t o f growth f o r the h e a l t h y c h i l d i s estimated a t about 10% of t o t a l c a l o r i e i n t a k e , but i n recovery from m a l n u t r i t i o n , the c o s t i s 7. predicted to be much larger (Ashworth et a l . , 1968) . Uremia i n children i s often attended by the symptoms of c a l o r i e malnutri-tio n , namely, apathy, low l e v e l of physical a c t i v i t y , intolerance to cold, low weight for height, and short stature (height may be more than two standard deviations (2 SD) below normal height for age), (Holliday, 1972). I t appears that although growth accounts for only a small proportion of ingested c a l o r i e s , the energy requirements for BMR take p r i o r i t y , and only those ca l o r i e s not required for basal metabolism are available for a c t i v i t y and growth. Experimental evidence exists that c a l o r i c i n s u f f i c i e n c y i s a growth l i m i t i n g factor i n renal disease. Rats rendered uremic by 5/6 nephrectomy gain less weight and consume fewer c a l o r i e s than control r a t s . When matched for body weight and c a l o r i e intake with controls, the uremic rats are s t i l l noted to have a poorer rate of weight gain. This indicates that the c a l o r i c cost of growth i s higher i n uremic animals (Chantler et a l . , 19 74). Lowering the degree of uremia by lowering the protein content of the d i e t from a s u r f e i t (40%) to a minimum adequate l e v e l (.15%) did not a f f e c t growth. Calorie supplementation by gavage with corn o i l (equal to a 25% supplement) accelerates growth i n uremic r a t s . However, the growth i s not equal to that of control nonuremic rats (MacDonnell et a l . , 1973). These experimental re s u l t s have provided evidence that c a l o r i e s are l i m i t i n g to growth i n uremic r a t s . Providing extra c a l o r i e s increased the growth rate i n the uremic r a t s , but did not restore i t to normal. 8. The n u t r i t i o n of children on chronic hemodialysis has been studied (Simmons et a l . , 1971). Five uremic children with c a l o r i c intakes less than 67% of the recommended dietary allow-ance (RDA) had a mean li n e a r growth rate of 34% of normal. Ten uremic children with c a l o r i c intakes greater than 67% of the RDA had a mean li n e a r growth rate of 117% of normal. Calorie supplements were offered to the f i v e children with poor growth and low intakes, and i n the four children subsequently measured, growth was accelerated (Simmons et a l . , 1971). These authors measured growth over three month periods only and did not state the season of the year i n which the study was undertaken. This lack of procedural standardization may invalidate the results obtained, as growth rates vary at d i f f e r e n t times of the year and i t i s d i f f i c u l t to assess growth performance s a t i s -f a c t o r i l y i n periods less than one year (Bayer and Bayley, 1976). In a recent study, (Counahan et a l . , 1976) the c a l o r i c intakes of sixteen uremic children seemed adequate when expressed as per cent RDA for height age (HA), but suboptimal when expressed i n r e l a t i o n to chronological age (CA). C l i n i c a l signs of mal-n u t r i t i o n were not present, but growth retardation and delayed bone maturation frequently were. As pointed out by the authors, given the existence of chronic s u b c l i n i c a l malnutrition and the other constraints of uremia, the energy requirements for catch-up growth (Ashworth et a l . , 1968) are l i k e l y greatly increased (Counahan et a l . , 1976). Three to eight grams of amino acids are removed from the body during a hemodialysis treatment (Kopple et a l . , 1973). There i s a loss of approximately sixteen grams (range of 8 to 9, 3 3 grams) of glucose from the body for every d i a l y s i s of four hours (Novarini et a l . , 1974). The removal of these c a l o r i f i c substances from body c i r c u l a t i o n by d i a l y s i s imposes an addi-t i o n a l s t r a i n on the c a l o r i c requirements for growth. 1.5 Protein and Amino Acid Metabolism i n Uremia Although many of the minutiae of protein and amino acid metabolism are known, l i t t l e i s known about the co-ordination and integration of these d e t a i l s . Thus, i t i s not surprising that the knowledge of protein and amino acid metabolism i n uremia i s scattered and incomplete. Amino Acids The most frequently reported abnormalities of amino acid metabolism i n uremia have been decreases of most plasma essen-t i a l amino acids (E), and increases of most plasma nonessential amino acids (N). The exceptions usually being, the elevation of two E, methionine and phenylalanine, and the depression of one N and one E, tyrosine and h i s t i d i n e , respectively. The re-s u l t i s a depressed E/N r a t i o and an elevated phenylalanine/ tyrosine CPhe/Tyr) r a t i o (Feldman and Singer, 1974). Many c o n f l i c t i n g reports occur i n the l i t e r a t u r e concerning the alterations of plasma amino acids i n patients with CRF (Condon and Astoor, 1971, Counahan et a l . , 1976, Kopple and Swendseid, 1974, Rubini and Gordon, 1968, Schaeffer et a l . , 1975, and Young et a l . , 1975) . The described differences i n plasma amino acids of uremics may be attributed to a number of factors. F i r s t , adult males show higher values for a l l amino acids, except threonine, serine and glycine, than do adult females. Second, the age of the subject effects c h a r a c t e r i s t i c plasma amino acid concentrations although within two age groups (ages six to eighteen, and ages eighteen to twenty-seven) there i s homogeneity of the reported values (Armstrong and Stave, 19 7 3 I ) . A t h i r d factor that influences the plasma amino acid p r o f i l e i s the l e v e l of protein i n the d i e t (MacLean et a l . , 1976, Swend-seid et a l . , 1966, and Whitehead and Dean, 1964), as well as, the uremic state i t s e l f and d i a l y s i s (McGale et a l . , 1972). The d i f f e r e n t methods and machines employed i n the analysis of amino acid concentrations w i l l vary i n t h e i r s e n s i t i v i t y . a n d accuracy (Armstrong and Stave, 19 73 I ) . The length of f a s t before sampling affects plasma amino acid l e v e l s and most hospitals require the patient to have fasted "overnight" before the blood sample i s drawn. F i n a l l y , i t i s also desirable to l i m i t the possible i n t e r f e r i n g e f f e c t s of diurnal variations i n plasma amino acids (Wurtman.et a l . , 1968). In spite of the many factors known to influence the measure-ment of plasma amino acid concentration, a number of abnormalities of amino acid metabolism have been described i n patients with CRF. There i s apparently an impaired conversion of phenylalanine to tyrosine due to a blockage of 4-phenylalanine hydroxylase. The depressed tyrosine/phenylalanine r a t i o of uremia has been reported a consequence of abnormal metabolism, not of amino acid malnutri-ti o n (Kopple et a l . , 1972, L e t t e r i and Scipione, 1974, and Young and Parsons, 197 3). Due to a decreased binding of tryptophan to albumin, fas t i n g plasma tryptophan levels are 40% of normal, and thi s appears to be the l i m i t i n g amino acid for protein synthesis i n the l i v e r , leukocytes, and brain (Gulyassy et a l . , 1972). There are increased plasma concentrations of free and bound hydroxy-prolin e , presumably because of enhanced release from c a r t i l a g e and bone matrix, and decreased urinary excretion (Prockop and K i v i r i k k o , 19 67). The excretion of 1- and 3-methylhistidine i s decreased i n CRF, and t h i s i s the cause of t h e i r elevated con-centrations i n uremic plasma (Gulyassy et a l . , 19 70, and Condon and Astoor, 1971). As well, increased 3-methylhistidine levels are associated with muscle wasting i n patients with CRF (Condon and Astoor, 19 71). The reason for elevated plasma cystine con-centration i n CRF i s not known, but i t does not appear to be due to n u t r i t i o n a l factors (Gulyassy et a l . , 1970, and McGale et a l . 1972). The l e v e l of plasma h i s t i d i n e i s c h a r a c t e r i s t i c a l l y reduced, more so i n dialyzed than nondialyzed uremic indiv i d u a l s In spite of a h i s t i d i n e intake of 1 to 2 grams d a i l y , d i a l y s i s patients show more d e f i n i t e signs of h i s t i d i n e deficiency than CRF patients with only 0.4 grams h i s t i d i n e intake per day. Di-alyzed patients experience losses of h i s t i d i n e into dialysate (approximately 0.3 grams per d i a l y s i s ) . As well, h i s t i d i n e metabolism may be more severely impaired i n dialyzed than i n nondialyzed uremics (Jontofsohn et a l . , 1974). Kopple and Swendseid (19 75) provided evidence that h i s t i d i n e metabolism i s similar i n normal and uremic subjects, but the patients with CRF studied were not undergoing d i a l y s i s . H i s t i d i n e appears to be a l i m i t i n g factor of protein metabolism i n dialyzed patients as shown i n the r i s e i n serum t r a n s f e r r i n i n these patients follow-ing h i s t i d i n e supplementation (Jontofsohn et a l . , 1974). Trans-f e r r i n i s a sensitive parameter of protein n u t r i t i o n (Ingenbleek et a l . , 1975). The inadequacy of dietary h i s t i d i n e has been associated with the f a i l u r e of normal erythropoeisis (Kopple and Swendseid, 19 75). Urea retention may retard the enzymatic reactions which lead to urea production with the subsequent accumulation of arginine, c i t r u l l i n e , ornithine, and aspartic acid (Giordano et a l . , 1975). The abnormal amino acid p r o f i l e i n CRF i s , at least i n part, due to dietary d e f i c i e n c i e s or imbalances of amino acids. Similar amino acid p r o f i l e s have been reported i n patients with kwashiorkor, as well as normal individuals maintained on low protein diets (Whitehead and Dean, 1964, Swendseid, et a l . , 1966, and MacLean et a l . , 1976) . The plasma valine concentration i s p a r t i c u l a r l y sensitive to low protein intakes, and i s commonly reduced i n CRF. The glycine l e v e l i s usually normal, or i n -creased, under these same conditions. The valine/glycine (Val/ Gly) r a t i o has therefore been used as an indicator of n u t r i t i o n a l status. A reduced Val/Gly r a t i o may be interpreted as i n d i c a t i v e of malnutrition, i n spite of the fact that the r a t i o i s independ-ently affected by uremia i t s e l f (Kopple and Swendseid, 1975). A normal E/N r a t i o may be achieved i n patients with CRF by feeding them a d i e t adequate i n protein content. There i s no conclusive evidence that a decreased E/N r a t i o i n plasma i s undesirable per se (Kopple et a l . , 1973). However, v u l n e r a b i l i t y to disease i s increased when dietary nutrients are "imbalanced". This concept i s pertinent to dietary amino acids. A quantitative r e l a t i o n s h i p between the dietary intake of a given amino acid and i t s plasma concentration has been established. An increased dietary intake of a single amino acid usually produces an elevation of i t s plasma concentration (Swendseid et a l . , 1962). The curve r e l a t i n g the response of the plasma concentration of an amino acid to changes i n dietary intake i s sigmoidal i n slope. This means the plasma l e v e l may remain unchanged as dietary intake i s increased from low values, u n t i l the dietary intake exceeds the requirement. Then the plasma concentration may increase sharply and proportionately to intake (Zimmerman and Scott, 1965). However, i n short term studies, a l i n e a r c o r r e l a t i o n between intake and plasma concentration has been described for a number of amino acids, including lysine and h i s t i d i n e (McLaughlan and Illman, 1967) . Restorative changes of plasma amino acid levels occur rapidly (Giordano et a l . , 1975). A dietary amino acid imbalance i s a circumstance i n which catabolism i s enhanced due to a d i e t which contains an excess of an e s s e n t i a l amino acid other than the one which i s present i n the most l i m i t i n g amounts for growth. Experimental dietary amino acid imbalance i n rats can be induced e a s i l y when low protein diets are ingested (Harper et a l . , 1970), and low protein diets are frequently prescribed i n the n u t r i t i o n a l management of CRF. Many dietary amino acid imbalances have been described and the adverse effects observed include de-pressions of food intake and growth, and, i n some studies, development of f a t t y l i v e r s (Harper et a l . , 1970). Giordano et a l . (1975) found that h i s t i d i n e concentration i s low, and arginine, ornithine and c i t r u l l i n e concentrations are elevated i n uremic plasma. The same study demonstrated that arginine and h i s t i d i n e supplementation i n patients with CRF was associated with adverse e f f e c t s on threonine and phenylalanine l e v e l s , the plasma concentrations of which were decreased following arginine loading, whereas the converse was noted during h i s t i d i n e supple-mentation. As we l l , aspartic acid levels were elevated and leucine l e v e l s were depressed a f t e r h i s t i d i n e and arginine supplementation, respectively. Lysine supplementation was accompanied by a s i g n i f i c a n t diminution of plasma concentrations of.arginine and leucine. Similar findings were not observed i n normal subjects. The authors showed reciprocal i n h i b i t i o n s of arginine, h i s t i d i n e , lysine and ornithine, and concluded that an increase or decrease of one. or more of.these basic amino acids within the body pool may be followed by an increased or decreased requirement of one or more, of the remaining amino acids (Giordano et a l . , 19 75). Arginine i s unique among the urea cycle intermed-iates i n i t s biosynthetic r o l e s , not only in.protein synthesis v i a arginyl RNA, but also i n the synthesis of creatine. Arginine i s the most potent of the amino acids for the stimulation of i n s u l i n and the predominant tissue source of guanidino compounds (Swendseid et a l . , 19 75). It i s i n t e r e s t i n g to speculate that i n children with CRF the e f f e c t of day to day fluctuations of d i e t -ary amino acids on the plasma concentrations of amino acids may be. related to t h e i r observed reduced food intakes and retarded growth rates. The plasma E/N r a t i o of patients undergoing maintenance d i a l y s i s i s s l i g h t l y lower than that of uremic subjects ingesting 60 gram protein d i e t s , even though the former ingest somewhat larger quantities of protein. This may r e f l e c t the losses of free and bound amino acids during d i a l y s i s , and may suggest a higher dietary protein requirement for the patient undergoing maintenance hemodialysis CKopple et a l . , 1973). The quantitative 15. losses of amino acids into dialysate has been reviewed (Kopple et a l . , 19 73) and the amounts range from the 3 to 8 grams of amino acids per d i a l y s i s . Total amino acid losses reported were similar despite a variety of standard dialyzers being u t i l i z e d (Giordano et a l . , 1975, McGale et a l . , 1972, and Rubini and Gordon, 1968). The f r a c t i o n of amino acids l o s t during d i a l y s i s i s derived from c e l l u l a r pools of free or bound amino acids, or from proteins that are rapidly turning over. Aviram et a l . (1971) reported the e s s e n t i a l amino acids l o s t into dialysate i n the largest amounts were valine, l y s i n e , threonine, phenylalanine and methionine. Later research showed approximately one-third of the free amino acids removed by hemodialysis to be e s s e n t i a l ones. The most abundant free amino acids i n dialysate were asparagine, glutamine and glycine (Kopple et a l . , 1973). The presence of glucose i n dialysate may have a sparing e f f e c t on plasma amino acid concentrations, but the mechanism for t h i s i s not known. Glucose may enhance the c e l l u l a r uptake and decrease the plasma lev e l s of amino acids (Counahan et a l . , 1976, and Munro, 19 64). The addition of glucose to dialysate may lower plasma levels of free amino acids, and lessen the amount l o s t i n dialysate (Kopple et a l . , 1973). The ingestion of food during d i a l y s i s causes a moderate increase i n the losses of amino acids, but most of the ingested protein i s retained. A patient may e a s i l y replenish the free amino acids removed by hemodialysis by eating a d i e t adequate i n protein, c a l o r i e s and other nutrients (Kopple et a l . , 1973). The aggravation of pre d i a l y s i s plasma amino acid imbalances by hemodialysis remains to be studied. Proteins A few discrete abnormalities of protein metabolism have been i d e n t i f i e d i n advanced c h r o n i c r e n a l f a i l u r e , and the over-a l l d i s t u r b a n c e may be profound. A p e r s i s t e n t n e g a t i v e n i t r o g e n balance occurs i n i n d i v i d u a l s w i t h CRF, and may be due to i n s u f f i c i e n t n i t r o g e n and energy i n t a k e , poor a b s o r p t i o n , and/or a chemical i n t e r f e r e n c e w i t h p r o t e i n metabolism (Richards, 19 75) . N i t r o g e n balance i n uremic p a t i e n t s on s i m i l a r n i t r o g e n i n t a k e s improves w i t h i n c r e a s i n g c a l o r i c i n t a k e i n the range o f 35 to 55 k c a l / k g body weight (Hyne e t a l . , 1972). Serum albumin, a crude index of p r o t e i n c a l o r i e m a l n u t r i t i o n , i s o c c a s i o n a l l y depressed i n uremic p a t i e n t s (Feldman and S i n g e r , 19 74). There i s an impaired s y n t h e s i s and d e g r a d a t i o n of serum albumin, as w e l l as a s h i f t o f albumin from the e x t r a v a s c u l a r to the i n t r a -v a s c u l a r space. These a b n o r m a l i t i e s are found i n m a l n u t r i t i o n , and can be produced by prolonged an o r e x i a and vomiting, and by p r o t e i n r e s t r i c t e d d i e t s i n CRF p a t i e n t s (Feldman and S i n g e r , 1974). However, a more r e c e n t study demonstrated t h a t the prolonged use of low p r o t e i n d i e t s does not appear r e s p o n s i b l e f o r the albumin d e p l e t i o n o f uremics ( B i a n c h i e t a l . , 19 75). A l t e r e d immunoglobulin s y n t h e s i s may c o n t r i b u t e to the uremic's i n c r e a s e d s u s c e p t i b i l i t y t o i n f e c t i o n , and p r o t e i n r e s t r i c t i o n may c o n t r i b u t e to t h i s by i m p a i r i n g t h e " l e u k o c y t e response, lymphocyte f u n c t i o n , and s y n t h e s i s o f complement p r o t e i n s (Richards, 1975). Serum t r a n s f e r r i n (comprising about 25% of the serum g - g l o b u l i n f r a c t i o n ) may be a more s e n s i t i v e and r e l i a b l e b i o c h e m i c a l index of p r o t e i n - c a l o r i e m a l n u t r i t i o n i n uremic i n -d i v i d u a l s . T r a n s f e r r i n l e v e l s are e q u a l l y depressed i n d i a l y z e d and n o n d i a l y z e d p a t i e n t s , and may r e f l e c t s u b c l i n i c a l p r o t e i n -c a l o r i e m a l n u t r i t i o n i f i t e x i s t s (Young and Parsons, 1970). In summary, chronic d i a l y s i s may stress the impaired pro-t e i n homeostasis of uremic patients, although c a r e f u l attention to dietary protein intake can minimize i t s impact. The low serum t r a n s f e r r i n levels and abnormal amino acid p r o f i l e that p e r s i s t i n dialyzed patients may mean that a precarious state of mild protein deficiency exists. 1.6 Vitamin N u t r i t i o n i n Uremia The complexities of determining the optimal dietary intake of vitamins are further obscured i n CRF because both the meta-b o l i c a c t i v i t y and the metabolic fate of certain vitamins may be altered. The current knowledge of blood concentrations of vitamins i n uremic adults has been thoroughly reviewed (Feldman and Singer, 1974, and Kopple and Swendseid, 1975). L i t t l e i s known about the c i r c u l a t i n g levels and dietary requirements of vitamins i n children with CRF. Vitamin n u t r i t i o n i n these individuals may be of p a r t i c u l a r importance i n view of t h e i r impaired growth (West and Smith, 1956). Factors which promote a vitamin deficiency in CRF are low dietary intake; altered absorption, metabolism or excretion; and losses during hemo-d i a l y s i s . The intake of water soluble vitamins i s often decreased i n CRF, and at least small quantities are removed by hemodialysis. The water soluble vitamins function as co-enzymes and, as such, are.involved i n energy and protein metabolism. Optimal water soluble vitamin n u t r i t u r e i s therefore e s s e n t i a l for the growing i n d i v i d u a l . While no c l i n i c a l evidence of vitamin d e f i c i e n c i e s has been found i n uremic patients, a dietary supplement of t h i a m i n , n i a c i n , r i b o f l a v i n , p a n t o t h e n i c a c i d and b i o t i n , - e q u i v -a l e n t t o the CDS f o r normal s u b j e c t s i s recommended. Evidence i s s t r o n g e r f o r the need f o r d i e t a r y supplements o f f o l i c a c i d , p y r i d o x i n e , and a s c o r b i c a c i d . Low serum f o l a t e l e v e l s o c c u r i n both d i a l y z e d and n o n d i a l y z e d p a t i e n t s , and supplements o f 1 to 5 m i l l i g r a m s d a i l y are recommended (Skoutakis et a l . , 1975). There i s a p r o g r e s s i v e f a l l i n plasma and l e u k o c y t e concentra-t i o n s of Vitamin C d u r i n g h e m o d i a l y s i s . Suboptimal ascorbate l e v e l s may be i n s t r u m e n t a l i n the anemia o f CRF ( S u l l i v a n and E i s e n s t e i n , 1970) and supplements o f 100 t o 500 m i l l i g r a m s d a i l y are recommended (Feldman and S i n g e r , 1974). Based on p y r i d o x a l phosphate-stimulated e r y t h r o c y t e g l u t a m a t e - o x a l a c e t i c t r a n s -aminase a c t i v i t y , r e c e n t data i n d i c a t e t h a t n e a r l y 70% o f p a t i e n t s w i t h advanced r e n a l f a i l u r e have a marked p y r i d o x i n e d e f i c i e n c y ( D o b b e l s t e i n e t a l . , 19 74). The m e t a b o l i c r a m i f i c a -t i o n s o f these f i n d i n g s are e x t e n s i v e . The plasma amino a c i d p r o f i l e s o f Vitamin Bg d e f i c i e n t animals and p a t i e n t s w i t h CRF are s i m i l a r . Vitamin Bg co-enzymes p l a y a v i t a l r o l e i n every aspect o f amino a c i d u t i l i z a t i o n and a d e f i c i e n c y impairs the s y n t h e s i s , i n t e r c o n v e r s i o n , c a t a b o l i s m and c e l l u l a r uptake of amino a c i d s . The need f o r Vitamin Bg i s p a r t i c u l a r l y c r i t i c a l i f amino a c i d i n t a k e i s l i m i t e d ( W i l l i a m s , 1964). The p y r i d o x i n e requirement o f uremic i n d i v i d u a l s i s not known (Kopple and Swendseid, 1975). Serum V i t a m i n B 1 2 l e v e l s are reduced i n both d i a l y z e d and n o n d i a l y z e d p a t i e n t s w i t h CRF. T h i s phenomenon does not appear t o be due t o inadequate d i e t a r y Vitamin B^2 O R malabsorption. Serum cobalamin c o n c e n t r a t i o n s and nerve con-d u c t i o n v e l o c i t i e s show a s i g n i f i c a n t c o r r e l a t i o n i n uremic 19. i n d i v i d u a l s , and both are improved when pharmacological doses of Vitamin B^2 a r e administered parenterally (Rostand, 1976). The excessive consumption of fat soluble vitamins should be avoided since there i s the p o s s i b i l i t y that increased tissue concentrations of cert a i n vitamins may be tox i c . At,present, there does not appear to be any need to provide supplements of Vitamins A, E, or K to patients with,CRF (Kopple and Swendseid, 1975). Mega doses of Vitamin D (75,000-150,000 IU) are i n d i c a -ted i n uremic children symptomatic of rickets and secondary hyperparathyroidism (Lirenman et a l . , 1968, and H i l l and Stan-bury, 19 75) . In view of the e s s e n t i a l i t y of vitamins and the ubiquity of their actions, the adequacy of vitamin nutriture i n CRF should be' assessed i n d e t a i l . 1.7 Mineral Metabolism i n Uremia The deficiency or excess of dietary minerals may produce a variety of disease states. Disorders of mineral metabolism may be responsible for some of the c l i n i c a l and biochemical disturb-ances of CRF. A number of trace elements such as vanadium, s i l i c a , f l u o r i d e , selenium, chromium, n i c k e l , cobalt, molybdenum, strontium, rubidium, bromine, and aluminum are lar g e l y excreted by renal mechanisms (Underwood, 19 71) , and consequently may tend to accumulate i n the uremic state. A second group of elements including zinc, copper, t i n , i r o n , mercury are not normally dependent.on the kidney for t h e i r excretion. The d i a l y s i s procedure, and the use of tap water without pretreat-ment, could expose the dialyzed patient to a variety of trace element contaminates, thereby, increasing the body burden of those elements. In addition, some trace elements could also be removed by d i a l y s i s and deplete body stores (Alfrey et a l . , 1975). A number of trace element abnormalities have been de-scribed i n uremia, but the c l i n i c a l importance of these a l t e r -ations has yet to be defined. Depressed serum zinc levels have been reported i n patients with CRF (Halsted and Smith, 1970), and may be a r e f l e c t i o n of n u t r i t i o n a l status (Grupe et a l . , 1975). The role of zinc deficiency i n growth f a i l u r e , delayed sexual maturation, hypogeusia, and impaired wound healing i s well documented (Prasad, 1966). The results of a preliminary investigation of trace element abnormalities i n children with CRF showed that serum calcium i s subnormal, but i s higher i n children s t a b i l i z e d on d i a l y s i s than i n nondialyzed children; plasma magnesium i s normal i n both dialyzed and nondialyzed uremic children; serum iron f a l l s progressively i n dialyzed patients despite iron supplementation; and serum copper l e v e l s r i s e from subnormal to normal when children are s t a b i l i z e d on d i a l y s i s (Grupe et al.. , 1975) . The implication of altered mineral metabolism on the growth performance of children with CRF remains to be studied. 1.8 Dietary Treatment of CRF Most nonsurgical"conditions i n the realm of renal disease are not amenable to permanent cure. Thus, medical therapy aims at prolonged control of the disorder and amelioration of the systemic abnormalities which r e s u l t from disturbed kidney function. Diet i s a part of the long range control program i n renal f a i l u r e . Diet i s not s t a t i c , rather, as the c l i n i c a l s i t u a t i o n changes with d i f f e r e n t stages of the disease, dietary-adjustments become necessary (Burton, 1974). With progressive deterioration we are faced with starving the c h i l d or poisoning him. The decision must be made to transplant, c h r o n i c a l l y hemodialyze or permit the disease to progress to i t s natural conclusion. Children are l i k e l y candidates for the d i a l y s i s -transplant route. Therefore, e f f o r t s must be made to maintain them i n the best medical condition possible, not only to encour-age normal growth and development, but also to avoid cachexia which would make them u n f i t for the a c t i v i t i e s of d a i l y l i v i n g , or transplantation. A protein intake of 0.5 to 1 g/kg body weight per day i s recommended for the c h i l d i n end stage renal f a i l u r e , as i n d i -cated by c l i n i c a l symptoms and growth. Seventy to 75% of t h i s should be protein of high b i o l o g i c a l value (Chan, 1973, and Kofranji et a l . , 1970). The presence of hemodialysis and in f e c t i o n , or other catabolic states w i l l increase the protein requirement (Chan, 1973, and David et a l . , 1972). I t i s recommended that the uremic infant consume 150 kcal/kg body weight per day. After one year of age, 100 kcal/kg body weight per day i s indicated (Chantler and Holliday, 19 73). The absolute minimum c a l o r i c intake should be 35 kcal/kg body weight per day (Blainey and Chamberlain, 19 71). The supplementary vitamin re-quirements i n CRF have been discussed (see Section 1.6). The alterations of mineral requirements for patients with CRF remain to be elucidated. Intakes of minerals should approximate the CDS (Dietary Standard for Canada, 19 75). The elevated plasma t r i g l y c e r i d e and cholesterol concentrations of patients with CRF (Kaye et a l . , 197 3) do not appear to be due to the dietary intake of fat (Bagdade, 1975). At the present time, the incorporation of extra fat int o the diet remains an excellent form of c a l o r i c supplementation i n growth retarded uremic children. 1.9 Etiology of Hypogeusia and Disgeusia i n CRF Abnormalities of taste have been noted throughout the h i s -tory of mankind. These pathological states have not stimulated the development of.a formal d i s c i p l i n e comparable to ophthamology or otology. This i s perhaps due to the fact that, i n the past, the anorexia of many chronically i l l patients has been viewed as in t r a c t a b l e , and consequently, has been ignored. As a r e s u l t , the evolution of a systematic body of knowledge allowing insight into the basic physiology of taste remains incomplete. Taste abnormalities are associated with certain disease states and commonly used medications (Carson and Gormican, 1976). Strong, acceptance and rejecti o n responses to s p e c i f i c tastes ' influence dietary patterns. The c h i l d with CRF presents a number of problems to those concerned with the conservative management of his/her condition. As previously mentioned, one of these problems i s the need for a continued intake of s u f f i c i e n t nutrients i n the proper pro-portions for optimal growth. Taste acuity i s of p a r t i c u l a r importance i n this regard because of i t s close association with eating habits. Alterations of taste s e n s i t i v i t y could possibly play a role i n the noted f a i l u r e of uremic children to maintain adequate nutrient intakes. The metabolic consequences of CRF could then be viewed as d i r e c t l y a f f e c t i n g taste acuity and im-p l i c a t e d i n the i n a b i l i t y to maintain appropriate intakes. The physical experience of taste i s a complex composite of various sensations acting on the brain (Ganong, 1975). The four basic modalities of taste as found i n man are sweet, s a l t , sour and b i t t e r . The s i t e s s e n s i t i v e to the compounds that man can taste are located i n the taste buds. Although taste buds are s t r u c t u r a l l y very s i m i l a r , they vary as to the kind and number of taste s t i m u l i they respond to, the type of p a p i l l a e i n which they are housed, the form and degree of nerve innervention (Ganong, 1975), and the enzymatic compositions of t h e i r membranes (Trefz, 1972). A l l of these variables appear instrumental i n the f i n a l taste that i s perceived. The a b i l i t y of humans to d i s t i n g u i s h i n t e n s i t i e s of a substance i s crude. A 30% change i n the concentration of a substance i s necessary before any i n t e n s i t y difference can be detected (Ganong, 1975). In general, taste s e n s i t i v i t y i s related to the s o l u b i l i t y of a compound in s a l i v a (Strother, 1974, and Ganong, 1975). The r e s t i n g and p a r a f f i n stimulated s a l i v a secre-tion rates are 0.04±0.036 ml/min (Shannon and I s b e l l , 1962) and 0.7*0.1 ml/min (Hawkins and Zipkin, 196.4), respectively. A decreased s a l i v a r y flow rate results i n a generalized decrease i n taste s e n s i t i v i t y (Strother, 1974). The presence of abnormally high concentrations of such things as iodides and urea i n s a l i v a , may r e s u l t i n the abnormal perception of tastes (Snapper, 1967). The urea concentration of p a r a f f i n stimulated s a l i v a i s 8.8 mg/ 100 ml (Updegraff and Lewis, 1924). The resting parotid s a l i v a iodide concentration i s 6.46 ug/100 ml, and t h i s i s a function of c i r c u l a t i n g plasma iodide (Harden et a l . , 1965). To investigate taste acuity two types of taste threshold are usually measured: the detection threshold and the recog-. n i t i o n threshold. A detection threshold i s defined as the lowest concentration of a test substance that the patient can i d e n t i f y as being d i f f e r e n t from water. A recognition threshold i s defined as the lowest concentration of a t e s t substance that the patient can i d e n t i f y as being e i t h e r s a l t y , b i t t e r , sweet or sour,. (Kelty and Mayer, 1971) . Certain factors have been implicated i n abetting the pro-cess of taste s e n s i t i v i t y a l t e r a t i o n . A number of. these taste abnormalities are associated with altered metabolic states, n u t r i t i o n a l d e f i c i e n c i e s , drug therapies, age, sex or smoking. Patients with pseudohypoparathyroidism (PHP) exhibit increased detection and recognition thresholds for sour and b i t t e r , although thresholds for s a l t and sweet are within normal l i m i t s (Henkin, 1967). The c h a r a c t e r i s t i c a l l y altered metabolic state of PHP includes elevated serum phosphorous, parathyroid hormone, and alkaline phosphatase, and decreased serum calcium. This pattern i s also observed in uremic individuals with second-ary hyperparathyroidism (Mazzaferri, 1974), although for d i f f e r -ent reasons. I t may be that uremic patients with secondary hyperparathyroidism experience a s i m i l a r decrease i n b i t t e r and sour s e n s i t i v i t y . Treatment of patients with PHP to correct t h e i r hyperphosphatemia and/or hypocalcemia does not a l t e r t h e i r taste thresholds (Henkin, 19 67). No explanation exists for the decreased sour and b i t t e r s e n s i t i v i t y i n PHP. I t i s i n t e r e s t i n g to note that alkaline phosphatase i s e s p e c i a l l y active i n s a l t and sweet modalities (Trefz, 19 72) and elevated serum alkaline phosphatase may account for the normal thresholds of these two tastes, observed i n PHP (Trefz, 19 72) . Carbohydrate active steroids appear to function i n taste detection s e n s i t i v i t y , but t h e i r mechanism of action i s not known. Patients with Addison's Disease and nonsalt losing con-genital adrenal hyperplasia e x h i b i t thresholds more than one hundred times: below normal for each of the four taste modalities (Henkin,.1967). Associated with the normal circadian v a r i a t i o n i n endogenous s t e r o i d hormone, production i s a circadian v a r i a -t i o n i n taste. Between s i x and seven i n the morning, when plasma C o r t i s o l i s highest, taste detection s e n s i t i v i t y i s lowest; and between seven and nine i n the evening, when plasma C o r t i s o l concentration i s lowest, taste detection s e n s i t i v i t y i s highest (Mazzaferri, 19 74). Carbohydrate active steroids influence neural transmission by i n h i b i t i n g catacholamine-o-methyl trans-ferase, an enzyme which inactivates catacholamine hormones and transmitters at t h e i r - s i t e s of action (Mountcastle, 1974). An increase i n nerve conduction v e l o c i t y has been demonstrated i n patients with Addison's Disease (Henkin et a l . , 1966). Steroid hormones may influence the detection and integration of taste producing s t i m u l i by c o n t r o l l i n g the speed and pattern of neural transmission. Patients with CRF frequently e x h i b i t elevated plasma C o r t i s o l s and decreased nerve conduction v e l o c i t i e s (Bindeballe et a l . , 1973). A decreased s e n s i t i v i t y for the four taste modalities might.be expected i n these i n d i v i d u a l s . Hormones other than s t e r o i d hormones have been reported to a l t e r taste s e n s i t i v i t y . A decrease i n sweet and sour sensi-t i v i t y has been observed i n patients with diabetes (Weiss Val-branca and Pascucc, 1965). This a l t e r a t i o n can not be correlated with high blood sugar lev e l s (Schelling et a l . , 1965), but the prolonged use o f i n s u l i n has been suggested as a cause (Fogan, 1971). Glucose intolerance exists i n over 50% of uremic patients. The best,established mechanism for t h i s occurrence i s peripheral i n s u l i n antagonism, manifested by elevated fasting i n s u l i n l e v e l s and normal fasting glucose levels (Feldman and Singer, 1974). Elevated C o r t i s o l i n h i b i t s peripheral glucose u t i l i z a t i o n (Mount-ca s t l e , 19 74). Uremic patients with a prolonged elevation of i n -s u l i n levels may experience decreased sweet and sour s e n s i t i v i t y . Recent evidence demonstrated that long term hemodialysis may be a cause of biochemical hypothyroidism. Hemodialyzed patients exhibit a p r o l o n g e d A c h i l l e s tendon r e f l e x time, a decreased serum thyroxine and protein bound iodine, and an increased serum inorganic iodide (Dandona et a l . , 1977). (The e f f e c t of sub-c l i n i c a l hypothyroidism on the growth of uremic children has yet to be defined.) A raised s a l i v a iodide concentration and altered taste acuity may consequently be expected. Of i n t e r e s t i s the,fact that thyroid hormones are responsible for stimulat-ing the hepatic i n a c t i v a t i o n of C o r t i s o l . Biochemical hypothy-roidism may explain the prolonged h a l f l i f e (Feldman and Singer, 1974) and elevated c i r c u l a t i n g levels (Bindeballe et a l . , 1973) of C o r t i s o l i n uremic patients. N u t r i t i o n a l d e f i c i e n c i e s can cause taste abnormalities. Idiopathic hypogeusia has been reported i n patients with sub-c l i n i c a l p ellegra. Niacin supplementation ameliorates t h i s 27. condition, and i f the disease i s long standing, zinc sulfate administration i s a useful adjunct (Green, 1971). The enzymes NAD diaphorase and NADP diaphorase, phosphate cleavage enzymes, show a c t i v i t y i n a l l four taste sensing areas (Trefz, 1972). Subjects p a r t i c i p a t i n g i n a two year experimental Vitamin A deficiency study demonstrated decreased taste and smell acuity, and impaired dark adaptation. Supplementation with Vitamin A corrected a l l of these pathologies (Hodges, 19 71) . Lower than normal leve l s of zinc i n serum, hair and s a l i v a i n man have been associated with anorexia and hypogeusia (Halsted et a l . , 19 72, Henkin et a l . , 1975, Prasad, 1966, and Sandstead et a l . , 1967). Zinc deficiency i s common i n hospital patients (Sullivan et a l . , 1969) and has been documented i n a multitude of conditions, including uremia (Halsted and Smith, 1970). Serum zinc f a l l s r a p i d l y a f t e r the administration of glucocorticoids and these steroids impair wound healing, a zinc dependent progress. The carbohydrate steroids appear to function i n the balance of the body zinc stores (Larson, 1975). Thus, there may be a r e l a t i o n -ship between the elevated C o r t i s o l levels (Bindeballe et a l . , 1973), hypozincemia (Halsted and Smith, 1970) and decreased taste acuity (Burge, i n press) of uremia. These n u t r i t i o n a l problems may be rare, but they can occur i n the hospitalized or chr o n i c a l l y i l l patient, whose intake may be below his needs due to anorexia, malabsorption and/or special treatments (for example, the leaching of nutrients during d i a l y s i s ) . Certain medications, commonly administered to uremics, may decrease food intake and/or a l t e r taste acuity by: - causing anorexia, nausea, vomiting and headache ( f o r example, c e r t a i n intravenous i r o n supplements, potassium removing i o n exchange r e s i n s , and a n t i m i c r o b i a l agents) - p r e c i p i t a t i n g the dry mouth syndrome and so decreasing the amount of s a l i v a a v a i l a b l e f o r the s o l u t i o n of t a s t e producing compounds (for example, c e r t a i n a n t i h i s t a m i n e s and a n t i -e p i l e p t i c s ) - causing a b i t t e r t a s t e i n the mouth (f o r example, c e r t a i n a n t i h i s t a m i n e s and sedatives) - l e a v i n g a bad a f t e r t a s t e ( f o r example, c e r t a i n v i t a m i n preparations) ( S t r o t h e r , 1974 and Osol, 1975). Although a c e r t a i n number of t a s t e a b n o r m a l i t i e s are a s s o c i a t e d w i t h age and sex, no s i g n i f i c a n t a g e - r e l a t e d , or s e x - r e l a t e d , d i f f e r e n c e s i n t a s t e s e n s i t i v i t y are observed between the ages of 16 and 55 years. While smoking does, a f f e c t the t a s t e a c u i t y of older i n d i v i d u a l s , the t a s t e s e n s i t i v i t y of smokers^ rs (greater than 20 c i g a r e t t e s per day) i n the 16 to 24 year o l d group does not d i f f e r (Kaplan e t a l . , 1965) from non-smokers In summary, a number of f a c t o r s may a f f e c t t a s t e s e n s i t i -v i t y i n uremic c h i l d r e n and they may be of endocrine, n u t r i t i -onal and/or pharmaceutical o r i g i n s . INTRODUCTION In the normal c h i l d , endocrine, n u t r i t i o n a l , and genetic influences blend together to determine ultimate height and weight. CRF occurs in. approximately three to four children per m i l l i o n population per year. One of the major complications of CRF in ped i a t r i c patients i s the impairment or interruption of normal growth processes. This growth disturbance received l i t t l e attention u n t i l the advent of successful treatment with hemo-d i a l y s i s and transplantation. Consequently, more undergrown children with renal disease are surviving into adult l i f e . Growth f a i l u r e i n children with renal f a i l u r e has been attributed to a number of factors. These include undernutrition (Berlyne et a l . , 1968, Betts and Magrath, 1974, Broyer et a l . , 1974, Chantler and Holliday, 1973, Counahan et a l . , 1976, Dela-porte et a l . , 19 76, Holliday, 19 75, Lewy and New, 19 75, and Simmons et a l . , 1971), renal osteodystrophy (Lirenman et a l . , 196 8) , chronic acidosis (Nash, 19 72 , and West and Smith, 1956) , age of onset of CRF (Betts and Magrath, 1974), anemia (Penington and Kincaid-Smith, 1971), chronic infections (Uttley et a l . , 1972), degree of azotemia (Berlyne et a l . , 1968), hypertension (Caliguini et a l . , 1963), various urinary concentrating defects (West and Smith, 1956) and a number of endocrine disorders (Feldman and Singer, 1974, Lowrie et a l . , 1970, Dandona et a l . , 1977, and Wright et a l . , 1968). The importance of dietary management for patients with renal f a i l u r e has been appreciated since the time of Richard Bright (1936), but i t remained for Giordano (1963) and Giovan-e t t i and Maggiore (196 4) to put i t on a r a t i o n a l basis with the use of e s s e n t i a l amino acids. These I t a l i a n nephrologists pub-lished a series of papers i n the early 1960's pointing out that feeding uremic patients t h e i r d a i l y requirements of e s s e n t i a l amino acids along with adequate c a l o r i e s , minerals, and vitamins lowered blood urea nitrogen l e v e l and led to p o s i t i v e nitrogen balance. The c l i n i c a l and biochemical improvements were a t t r i -buted to the u t i l i z a t i o n of endogenous urea i n combination with exogenous e s s e n t i a l amino acids i n the biosynthesis of nonessen-t i a l amino acids. Recently dietary protein regimes have been relaxed somewhat with the r e a l i z a t i o n s that amino acids are l o s t into dialysate (Kopple et a l . , 1973) and that a d i e t with a balance of e s s e n t i a l and nonessential amino acids r e s u l t s i n a more e f f i c i e n t synthesis of tissue protein (Kofranji et a l . , 1970). Inadequate c a l o r i e intake has frequently been described i n children with CRF and strongly associated with t h e i r slowed growth rates (Holliday, 1975, and Simmons et a l . , 1971). Re-ports of e s s e n t i a l nutrient losses into dialysate (Novarini et a l . , 1974, Kopple et a l . , 1973, and Feldman and Singer, 1974) further complicates the nutrient requirements for growth of uremic children. The n u t r i t i o n a l status of children with chronic renal f a i l u r e must obviously have a major, i f as yet poorly under-stood, role i n the observed growth f a i l u r e . A n u t r i t i o n a l , biochemical and physical study was conducted to assess the n u t r i t i o n a l status of seven children undergoing maintenance hemodialysis considering the following assumptions: 1. Growth retardation i n children with CRF i s due to suboptiirtal nutrient intakes. 2. Intakes of nutrients below the CDS are due to anorexia r e s u l t i n g from c i r c u l a t i n g uremic toxins and imbalances of plasma amino acids which may depress appetite and a l t e r taste acuity. 3. Imbalances of plasma amino acids are due to imbalances of dietary amino acids, losses of plasma amino acids into dialysate, and the build-up of urea cycle end products. To evaluate the adequacy of dietary intake, 14 day records of food intake were coll e c t e d and analyzed using food composi-ti o n tables. The data were compared to the CDS 1s, for CA, BA and HAd In addition, food c o l l e c t i o n s representing a 24 hour consumption period were obtained, and t o t a l protein and amino acid compositions were derived by d i r e c t analysis and from food tables. To assess the physical status of the children, height, height v e l o c i t y , weight, per cent body f a t and bone age were determined. In addition, pre and-post d i a l y s i s taste recogni-t i o n and detection thresholds for sweet, s a l t , sour and b i t t e r were measured. Saliva flow rates and s a l i v a urea concentrations were also determined before and a f t e r d i a l y s i s . To evaluate the biochemical protein and.amino acid status of the seven uremic children, pre and post d i a l y s i s plasma amino acid levels were determined following a standardized fast of fiv e hours duration. In addition, dialysates were c o l l e c t e d during complete hemodialysis treatments and analyzed for amino acid concentrations. MATERIALS AND. METHODS 3.1 Study Participants Seven children, four boys and three g i r l s , with a mean age of 16.99 years (range 14.84 to 20.58 years) who had been on regular hemodialysis in a hospital renal unit for more than s i x months (range 0.87 to 4.54 years) were studied (Table I ) . One (M.E.) had Pseudomonas pyocyaneus, Pseudomonas vulgaris, and Proteus r e t t g e r i growing i n urine taken from his i l e a l conduit, and two ( C S . and D.T.) demonstrated r a d i o l o g i c a l and biochemical evidence of secondary hyperparathyroidism at the time of the i n -vestigation. The others were free of systemic disease, and a l l were c l i n i c a l l y stable when studied. The children were accus-tomed to i n d i v i d u a l i z e d d i a l y s i s times, three using Western-Gear K i i l d i a l y z e r s , and four using P e d i a t r i c Gambro dialyzers (Table I ) . A Standard glucose-free dialysate was employed for a l l children, except one. (D.T.) whose bath was made potassium-free (Table I I ) . Each c h i l d and/or his guardian had received person-a l i z e d dietary instructions and supportive follow-up r e i n f o r c e -ments by the renal unit d i e t i t i a n . The d e t a i l s of each c h i l d ' s dietary r e s t r i c t i o n s and n u t r i t i o n a l supplements are given on Table I I I . The children had been following these dietary regimes for periods greater than six months. Signed informed consent (Appendix A) for p a r t i c i p a t i o n in the study was obtained from the children and t h e i r guardians i n accordance with the rules set out by the Committee on Research Involving Human Subjects at the University of B r i t i s h Columbia. The study was duly approved by said committee (Appendix B). TABLE I. A description of the study participants. Subject Renal Disease Sex Chrono-l o g i c a l Age (years) Age of Diagnosis of CRF (years) Age of D i a l y s i s Commence-ment (yrs) Duration of D i a l y s i s (years) Type of Dialyzer Some D e t a i l s of D i a l y s i s Urine Output (ml/24 hours)^ M.E. B i l a t e r a l Hydro-ureter Nephrosis Secondary to Prune B e l l y M 3 16.65 at b i r t h 15.78 0.87 c Western Gear K i i l F i s t u l a , Standard Dialysate, 2X/wk,e Overnight, 10 hrs. each 500 D.O. F a m i l i a l Juvenile Nephronophthisis Fb 15.06 8.68 12.68 2.38 Western Gear K i i l F i s t u l a , Standard Dialysate, 2X/wk, Overnight, 8 hrs. each None D.T. F a m i l i a l Juvenile Nephronophthisis M 20.58 12.42 16.04 4.54 P e d i a t r i c ^ Gambro Leg Shunt, No Potassium Dialysate, 3X/wk, Overnight, 6 hrs. each None C S . F a m i l i a l Juvenile Nephronophthisis F 17.38 4.86 15.68 1.70 Pe d i a t r i c Gambro F i s t u l a , Standard Dialysate, 2X/wk, Evenings, 7 hrs. each None R.J. Chronic Glomerulonephritis F 14.84 11.9 12.27 2.57 Western Gear K i i l F i s t u l a , Standard Dialysate, 3X/wk, Overnight, 10 hrs. each <50 CM. Congenital Obstructive Uropathy M 15.93 4.31 12.58 3.35 Pe d i a t r i c Gambro F i s t u l a , Standard Dialysate, 2X/wk Overnight, 6 hrs. each 1300 G.C. Congenital Obstructive Uropathy and CRF C rx /-»-n rloviT -f- /~i M 18.47 0.7 15.51 2.96 Pe d i a t r i c Gambro F i s t u l a , Standard Dialysate, 2X/wk, Overnight, 7 hrs. each None u t ^ u n u a i y L.\j - — — 1 -•• i Nonfunctioning Ectopic Right P e l v i c Kidney, and Hypoplastic L e f t Kidney. ^Vi. - male d T F - female 'Pediatric Gambro Dialyzer e2X/wk - two times a week "Western Gear K i i l Dialyzer Gambro Incorporated, Northbrook, ILL., USA ^length of each hemodialysis treatment g approximate urine output per day TABLE I I . Composition of the standard dialysate. Compound Concentration (mEq/l) Actual Amounts (g.) Sodium chloride 95 2138 Sodium acetate 40 1262.8 in Potassium chloride* Calcium chloride 1.0 3.0 28.7 84. 9 385 I > of tap water Magnesium chloride 1.0 39.1 *omitted from D.T.'s bath TABLE I I I . Details of each sub jeet !-s dietary r e s t r i c t i o n s and n u t r i t i o n a l supplements. Subject D i e t as Ordered by P h y s i c i a n D i e t Recommended to Subject by D i e t i t i a n C a l o r i c Supplements A d d i t i o n a l N u t r i t i o n a l Supplements C a l o r i e s (kcal) P r o t e i n (R.) Fat (g.) Carbohydrate (g.) M.E. 50g P r o t e i n 50mEq Potassium 2580 51 72 432 Cal-Power 4 oz Gluconol 4 oz Vitamin D 100,000 I.U. o.d.a M u l t i v i t e s 1 t a b l e t o.d. F o l i c A c i d 5 mg. o.d. Ferrous Gluconate 1 t a b l e t t . i . d . b Calcium Sandoz 45 ml. o.d. D.O. 50g P r o t e i n 50mEq Potassium 1250 cc F l u i d 2537 51 93 374 Gluconol 7 oz Vitamin D 50-100,000 I.U. o.d. M u l t i v i t e s 1 t a b l e t o.d. F o l i c A c i d 5 mg. o.d. D.T. 50g P r o t e i n 60mEq Potassium 33mEq Sodium 1500 cc F l u i d 1754 56 70 224 None Vitamin D 150,000 I.U. o.d. M u l t i v i t e s 1 t a b l e t o.d. F o l i c A c i d 5 mg. o.d. Imferon 150 mg. q l m c C S . P r o t e i n "In moderation" 2275 53 78 340 Hycal 4 oz Vitamin D 50,000 I.U. o.d. M u l t i v i t e s 1 t a b l e t o.d. F o l i c A c i d 5 mg. o.d. Imferon 150 mg. qlm R.J. 50g P r o t e i n 50mEq Potassium 35mEq Sodium 1250 cc F l u i d 2480 52 83 380 Cal-Power 10 oz Vitamin D 50,000 I.U. o.d. Imferon 150 mg. qlm CM. None ( r e n a l u n i t uses 70g p r o t e i n as guide when i n h o s p i t a l ) 2645 71 85 400 None Vitamin D 100,000 I.U. o.d. Beminal Forte 1 t a b l e t o.d. w i t h C F o l i c A c i d 2.5 mg o.d. C C None ( r e n a l u n i t uses 60g p r o t e i n as guide when i n h o s p i t a l ) 1623 59 67 196 None Vitamin D 100,000 I.U. o.d. F l u o r i d e 4 g t t s . ^ o.d. M u l t i v i t e s Calcium Sandoz 1000 mg. b . i . d . e Imferon 150 mg. qlm o.d. - every day g t t s . - drops t . i . d . - three times a day e b . i . d . - twice a day glm - once a month 3.2 Anthropometric Measurements Height was measured with a wall stadiometer. Previous height measurements were obtained from hospital records. Growth v e l o c i t i e s for the year preceding the study days were determined by the method of Tanner and Whitehouse (1976) with respect to the chronological age (GVCA), height age (GVHA), and bone age (GVBA), as shown by the following equation (Saenger et a l . , 1974): GVBA (%) = observed growth v e l o c i t y per year , . -(GVCA) growth v e l o c i t y expected for BA (CA or HA) x (GVHA) Weight was measured with balance scales, the children wear-ing only l i g h t underclothing. Weight was calculated as the average of post d i a l y s i s weights during the month preceding the study day. Skinfold thickness was measured at four s i t e s (biceps, t r i -ceps, s u p r a - i l i a c , and subscapular). Per cent body f a t was calculated according to the method of Durnin Womersley (19 74) as follows: 1. Sum of the four s k i n f o l d measurements (biceps, t r i c e p s , subscapular, supra-iliac) = x 2. Body Density = 1.1533-0.0643 (log x) 3. Per Cent Body Fat = -,4,9^J_ - 4.5 x 100 • density Bone age was assessed by independent observers using radio-graphs of the hand-wrist and knee, and the method of Greulich and Pyle (1959). Determination of s k e l e t a l age involves two ser-ies of standard radiographic films, one for each sex, arranged i n increasing order of maturity. B r i e f l y , t h i s i s a simple matching procedure i n which the patient's hand and wrist i s compared with the standard plates i n twenty-nine c r i t i c a l areas u n t i l one plate i s found which best approximates that of the patient (Greulich and Pyle, 19 59). Each child's a c t i v i t y l e v e l was. assessed employing standard a c t i v i t y patterns (Dietary Standard for Canada, 19 75, and Durnin and Passmore, 1967) and a c t i v i t y records kept by each subject on three days (including, one d i a l y s i s day, one nondialysis day, and one weekend day). The Dietary Standard for Canada (1975) describes four a c t i v i t y patterns (A, B, C and D) based on the. number of hours per day spent i n r e s t i n g metabolism, i n s i t t i n g o standing s t i l l , i n l i g h t a c t i v i t y , and i n more rigorous a c t i v i t y . Using the rates of energy expenditure, as given by the. Dietary  Standard for Canada (1975) for these.different types of a c t i v i -t i e s , one can estimate energy requirements. 3.3 Dietary Records, Food Collections and Analysis Approximately two weeks p r i o r to his/her study day, each chi1d re ce ived: 1. A folder containing: a set of instructions (Appendix C), a calender depicting his/her study period (Appendix D), fourteen sheets for recording two 7 day food intakes (Appendix E), three sheets for recording a c t i v i t i e s on each of a d i a l y s i s , nondial-y s i s and weekend.day (Appendix F). 2. A set of food scales for weighing a l l foods, consumed over, the two week period. 3. A p l a s t i c food bucket for c o l l e c t i n g a food sample equivalent to the subject's intake during the 24 hours preceding the study day (from breakfast on the pre study day to the f i v e a.m. snack on the study day, i n c l u s i v e ) . The procedures for carrying out the above a c t i v i t i e s were ca r e f u l l y explained to the subjects (or, a parent, as i n the case of D.O.), and reviewed again several days l a t e r . This ensured that the subjects understood the a c t i v i t i e s and records required of them. Dietary Records and Analysis The dietary data (each day of the fourteen day dietary rec-ord; the contents of the food bucket; a 24-hour dietary r e c a l l to check the record for the food bucket and to check the. seventh day of the fourteen day food record; and the food consumed while on d i a l y s i s the day of the study) was coded and analyzed by com-puter employing standard food composition tables (Food Values of  Portions Commonly Used, 1970, Amino Acid Content of Foods, 1970, and Food Composition Table for Use i n East Asia, 1972). The dietary constituents considered i n these calculations are shown on Table IV. The average nutrient intake over the fourteen day period was determined for each c h i l d and compared to those intakes recommended for normal children (Dietary Standard  for Canada, 19 75) with respect to the CA, HA and BA of the c h i l d . The results were expressed as per cent of the RDA. Coll e c t i o n of Food Sample and Chemical Analysis Clean p l a s t i c buckets were used to c o l l e c t the food sample equivalent to each subject's intake during the 2 4 hours preced-ing the study day (from breakfast on the day before the study day to the f i v e a.m. snack, i n c l u s i v e ) . The food buckets were kept in a freezer during the food sample c o l l e c t i o n . The subjects were instructed to weigh and record the amounts of food placed i n the food buckets. On the study day 2 4-hour dietary r e c a l l s were done TABLE IV. L i s t of dietary constituents included in computer ca l c u l a t i o n of food intakes 3. Constituent Units Constituent Units Calories kcal Isoleucine (ile) mg. Protein grams (g.) Leucine (leu) mg. Calcium milligrams (mg.) Lysine (lys) mg. Iron mg. Methionine (met) mg. Vitamin A International Units (I.U.) Cystine (cys) mg. Vitamin E I.U. Total Sulfur Amino Acids mg. Thiamin mg. Phenylalanine (phe) mg. Riboflavin mg. Valine (val) mg. Niacin mg. Histidine (his) mg. Ascorbic Acid mg. Tyrosine (tyr) mg. Total Fat g- Arginine (arg) mg. Saturated Fat g- Alanine (ala) mg. Monounsaturated Fat g- Aspartic Acid (asp) mg. Polyunsaturated Fat g. Glutamic Acid (glu) mg. Carbohydrate g- Glycine (gly) mg. Tryptophan (trp) mg. Proline (pro) mg. Threonine (thr) mg. Serine (ser) mg. Values obtained were for grams of t o t a l food to assess the v a l i d i t y of these records. Four study participants (M.E, D.O., R.J. and CM.) agreed to do the food c o l l e c t i o n on two occasions. After c o l l e c t i o n , each food sample was homogenized for two minutes i n a Waring Blender. The homogenates were immediately frozen at -20°C and then freeze-dried to constant weight i n a Thermovac Freeze-Dryer a. The freeze-dried samples were stored i n s t e r i l e a i r t i g h t p l a s t i c bags. Aliquots were analyzed for amino acids with a Technicon Automatic Amino Acid Analyzer* 3, by the Technicon operating procedure, and t o t a l nitrogen by a microkjel-dahl procedure (A.O.A.C., 1970). The mean value of each amino acid obtained from the chemical analysis was compared, using the Student's t Test, to the mean value of each amino acid obtained from the food table c a l c u l a t i o n of the amino acid content. Operating procedures and d e t a i l s of buffers including sample buffer are described i n Technicon Technical Publication No. TA1-0233-10, 1971. 3 . 4 C o l l e c t i o n and'Analysis of Blood Samples. On the day of the study each subject was awakened at 4:30 a.m. and given a snack, usually a piece of toast with butter and honey and 24 0 ml. of homogenized milk. The subjects were instructed not to eat or drink anything, except water, from that time u n t i l after the onset of hemodialysis l a t e r that morning. The study day had been arranged so that an i n t e r d i a l y t i c period of 48 hours had been experienced by a l l subjects. Immediately aThermovac Freeze-Dryer, Thermovac Industrial Corp., Copaigue, NY Technicon TSM Model Amino Acid Analyzer, Tarrytown, NY p r i o r to d i a l y s i s , blood samples were coll e c t e d without s t a s i s in the resting state from the venous side of the arteriovenous f i s t u l a , or shunt, into heparinized, or nonheparinized, tubes as indicated by the analysis to be done. Plasma amino acids were determined using a Durham B-120 Automatic Amino Acid Analyzer. Other biochemical tests were performed as l i s t e d on Table V. Subjects were permitted to eat during d i a l y s i s , but observed a minimum f i v e hour fast p r i o r to the c o l l e c t i o n of post d i a l y s i s blood samples. These c o l l e c t i o n s were carried out i n a similar manner as the pre d i a l y s i s c o l l e c t i o n s , and the same analyses performed (except for t r a n s f e r r i n which was determined pre d i a l -y s i s only). Using ten and one-half hours as the base l i n e f a s t , (Armstrong and Stave, 197 3 I) , there are no appreciable changes i n plasma amino acid concentrations u n t i l two to f i v e hours l a t e r when taurine, glutamic acid and cystine become elevated, and ... there i s a reduction of a l l other amino acids to 78%-98% of i n i t -i a l values. The e f f e c t of drinking milk (6 ml/kg body weight), after a f a s t , i s undetectable two hours l a t e r . High concentra-tions of methionine, valine, isoleucine, leucine, phenylalanine and lysine are indicators of an inadequate fast (Armstrong and Stave, 1973 I ) . In view of the above evidence and the undesir-able e f f e c t of r e s t r i c t i n g c a l o r i c intake that a day time t r a d i t i o n a l twelve hour fas t would have precipitated, a fast of f i v e to eleven hours before sampling appears appropriate. The r e s u l t s of amino acid concentrations were compared to normal values reported i n the l i t e r a t u r e (Armstrong and Stave, 1973 II) using the Student's t Test. S i m i l a r l y , the pre d i a l y s i s cl Vacutainer tubes, Becton, Dickeson, and Co., Canada, Limited TABLE V. L i s t o f l a b o r a t o r y analyses performed on venous b l o o d samples pre and post d i a l y s i s . A n a l y s i s Range of Normal Reference Sodium 134-143 m E q / £ . a Henry, 1964 (p.346) Potassium 4.0-5.5 mEq/Jl. Henry, 1964 (p.351) C h l o r i d e 95-105 mEq/l. Henry, 1964 (p.403) Bicarbonate 18-26 mEq/£. Nat e l s o n , 1971 (p.220) Calcium 8.5-10.5 mg.%b D i e h l and E l l i n g h o e , 1956 Phosphorus 3.5-8.5 mg.% Fis k e and Sctubbarow, 19 25 Urea 8.0-20 mg.% Gentzkow and Mason, 1942 U r i c A c i d 3.0-5.5 mg.% Caraway, 1955 C r e a t i n i n e 0.7-1.2 mg.% a d u l t 0.5-1.0 mg.% a d u l t male female Henry, 1964 (p.292) Glucose© 80-110 mg.% Natelson, 1971 (p. 355) A l k a l i n e Phosphatase 6-30 K.A. u n i t s King and Wootton, 1959 (P- 83) T r a n s f e r r i n 338±45 mg.% Henry, 1964 (p.392) Osmolality.y 295±6 mOsm. Natelson, 1971 (p. 778) "Hemoglobin 13-18 g.%e a d u l t 11-16 g.% a d u l t male female Henry, 1964 (p.740) T o t a l P r o t e i n s 6.0-8.5 g.% King and Wootton, 19 59 (P. 57) Serum P r o t e i n E l e c t r o p h o r e s i s Henry, 1964 (p.216) Albumin 3.5-5.5 g.% Oil 0.2-0.4 g.% a 2 0.5-0.9 g.% 3 0.6-1.1 g. % Y 0.7-1. 7 g. % amEq/£. - m i l l i e q u i v a l e n t s per l i t e r t>mg. % - m i l l i g r a m s per 100 m i l l i l i t e r s ( milligrams per cent) CK.A. u n i t s - King-Armstrong u n i t s dmOsm. - m i l l i o s m o l e s e g . % - grams per 100 m i l l i l i t e r s (grams per cent) plasma amino acid levels were compared to the post d i a l y s i s l e v e l s . 3.5 C o l l e c t i o n and Analysis of Dialysate On the day of the study, dialysate was c o l l e c t e d i n a large clean tank during a complete hemodialysis treatment. Sodium thy-mol was added to the tank at a concentration of one c r y s t a l per l i t e r . The dialysate was mixed continuously during the c o l l e c t i o n , and, at the termination of d i a l y s i s , an aliquot of dialysate was taken and analyzed for amino acids with a Durham B-120 Automatic Amino Acid Analyzer. B a c t e r i a l counts were also determined at the end of the c o l l e c t i o n . 3.6 Assessment of Taste S e n s i t i v i t y Subjects were instructed not to eat, drink or smoke within the hour preceding the taste testing'sessions. Before and a f t e r d i a l y s i s , a Curby suction cup was f i t t e d over the o r i f i c e of the right parotid gland and a timed sample of p a r a f f i n stimulated parotid s a l i v a was co l l e c t e d . The stimulated s a l i v a flow rate was determined by the method of Blair-West et a l . (19 67). The subjects were instructed to chew p a r a f f i n to stimulate s a l i v a secretion. S a l i v a was c o l l e c t e d i n two consecutive f i f t e e n minute periods and the second sample was analyzed for urea by the modified method of Gentzkow and Mason 3 (1942). Taste detection and recognition thresholds were determined, pre and post d i a l y s i s , using a paired comparison forced choice method (Kelty and Mayer, 1971). The s e n s i t i v i t i e s of sweet, sour, s a l t and b i t t e r modalities were assessed using solutions aAs described in the. Sigma Technical B u l l e t i n No. 14 (1974). Sigma Chemical Company, Saint Louis, Missouri, U.S.A. of sucrose, hydrochloric acid, sodium chloride, and quinine s u l -fate, respectively. The solutions were presented to the. subjects i n the aforementioned order. Details of the concentrations of the solutions are given i n Table VI, and a sample of the sheets employed for recording responses are shown i n Appendix G. The pre and post d i a l y s i s thresholds were compared to normal values reported i n the l i t e r a t u r e (Appendix H) by the Student's t Test. The Wald-Wolfowitz Runs Test (19 4 0) was employed to determine i f the•thresholds d i f f e r e d pre and post d i a l y s i s . This nonpara-metric s t a t i s t i c a l t e s t tests the hypothesis that when data taken from two populations i s placed i n ranked sequence, t h e i r means, variances and d i s t r i b u t i o n s are s i m i l a r (Wald and Wolfowitz, 1940). Five subjects (D.O., D.T., R.J.., C.S. and G.C.) agreed to a retest s i x months afte r the f i r s t taste s e n s i t i v i t y assessment described above. In order to eliminate the p o s s i b i l i t y that a learned response had influenced the thresholds obtained a f t e r d i a l y s i s , the retest was scheduled so that each i n d i v i d u a l tasted the s o l -utions post d i a l y s i s f i r s t and then pre d i a l y s i s three to seven days l a t e r . TABLE VI. Per cent eoficentrations of taste testing s o l u t i o n s . 3 Tube No. Hydrochloric Sodium Quinine Sucrose Acid Chloride Sulfate (Sweet) (Sour) (Salt) (Bitter) 1 .013 .00005 .001 .000028 2 .025 . 0001 . .002 .000056 3 .05 .0002 .004 .00011 4 . 1 .0003 .009 . 00023 5 .2 .0007 .018 .00045 6 . 4 .0014 .04 .0009 7 . 8 .0027 .07 .0018 8 1.6 .0055 .14 .0036 9 3. 3 .011 .28 .007 10 6.6 .022 .56 .014 11 13.1 .044 1.12 .03 Each solution series (sweet, to the subjects in i d e n t i c a l sour, s a l t , randomized or b i t t e r ) order. was presented RESULTS 4.1 Anthropometric Data • The data obtained from height, weight, and s k i n f o l d measure-ments of the seven children are presented i n Table VII. Height was retarded more than one standard deviation from the mean normal (>1 SD) i n a l l cases, and >2 SD i n some (D.O., D.T., C S . and G.C.). A l l children, except one (R.J.) had experienced l i n e a r increments during the year preceding the study. Growth v e l o c i t y expressed as the per cent of that expected for BA, HA, (or an average of the two), appears a more r e a l i s t i c i n d i c a t i o n of the patient's progress, than when considered with respect to CA. BA was appropriate for CA i n three cases (C.S., R.J. and CM.) , but for the re s t , f e l l two or more years behind CA. BA was consis-tently greater than HA. Per cent body f a t measurements were found to be normal i n a l l cases except one (D.T.). This individual's body fat estimation f e l l >1 SD below the mean given by Durnin and Rahaman, 19 67. The subjects maintained a sedentary a c t i v i t y pattern ( A c t i v i t y Pattern D as given by the Dietary Standard for  Canada, 1975) on each of the d i a l y s i s , nondialysis and weekend days considered. 4.2 Dietary Data The average of each subject's nutrient intake for the four-teen day food record, period i s presented i n Table VIII and expressed as per cent of the CDS. for CA, BA and HA. The average intake.of those nutrients for which the SD.S does not change with age are depicted i n Table IX. The average c a l o r i c contribution to the diet by protein, f a t , and carbohydrate i s presented i n TABLE VII. Results of anthropometric measurements of seven uremic children. Subject Height (cm) Weight a (kg) Bone Age (BA) Chrono-l o g i c a l Age (CA) Height Age (HA) b GVCA (%) GVBA° (%) GVHAd' (%) Height V e l o c i t y (cm/yr) Body F a t e Weight (%) A c t i v i t y Pattern M.E. 157.2 (>1SD) 48.2 14.5 16.65 12.0 233 39 175 3.5 16 f D D.O. 138.9 (>2SD) 29.0 11.0 15.06 10.0 185 37 40 2.4 21 D D.T. 138.3 (>2SD) 37.8 13.0 20.58 9.75 No growth expected for age. 6 7 0.4 8 D C S . 146.0 (>2SD) 39.8 17.0 17.38 11.3 240 240 16 1.2 20.5 D R.J. 153.5 (>1SD) 41.1 14.5 14.84 11.75 No growth No growth No growth 0 24 D CM. 160.1 (>1SD) 46.1 15.5 15.93 13.5 540 203 98 8.1 18 D G.C. 155.3 (>2SD) 40.7 16.5 18.47 13.25 4900 980 65 4.9 13 D ^Weight - average of dry weight measurements recorded f o r one month p r i o r to the t e s t day. cGVCA - growth v e l o c i t y expressed as per cent of that expected f or CA. dGVBA - growth v e l o c i t y expressed as per cent of that expected f o r BA. gGVHA - growth v e l o c i t y expressed as per cent of that expected f o r HA. fBody Fat Weight - expressed as per cent of average of dry weight records for one month preceding t e s t day. A c t i v i t y Pattern D (Dietary Standard f o r Canada, 1975) TABLE VIII. Average nutrient intakes of seven uremic children for fourteen day food record period. I. ^ ^ ^ N u t r i ent C a l o r i e s e P r o t e i n a Calcium e Phosphorus a Irone Magnesium^ Sub j ect~"---^^ l a 2 b 3 C 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 M.E. 57 65 49 83 87 109 121 101 135 62 51 68 946 1018 1204 38 45 65 D.O. 54 52 52 67 73 73 30 24 24 55 44 44 142 180 180 38 48 48 D.T. 45 48 61 79 85 133 59 39 67 87 58 99 213 164 213 46 55 92 C S . 73 73 67 116 116 126 59 59 41 120 120 84 207 207 309 92 92 115 R.J. 63 63 41 86 86 92 35 35 28 66 66 53 85 85 108 43 43 54 CM. 49 57 57 91 94 94 55 46 46 74 62 62 79 89 89 56 67 67 G.C 39 39 45 96 96 100 259 259 129 85 85 71 1221 1221 1315 43 43 52 """""^-^Nutr ient Z i n c a Vitamin A e Vitamin E a Thiamin e Ribof la\ N i a c i n e Sub j ect 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 M.E. 37 44 55 189 189 272 1275 1416 1821 94 107 125 53 62 71 77 85 96 D.O. 39 43 43 270 309 309 1384 1384 1384 129 129 129 71 71 71 72 72 72 D.T. 50 50 72 229 229 324 713 713 1069 110 118 150 80 85 111 68 71 96 C S . 48 48 59 291 291 291 1520 1520 1303 135 135 135 97 97 80 131 131 113 R.J. 39 39 44 86 86 86 684 684 684 59 59 59 79 79 79 54 54 54 CM. 43 52 52 73 73 73 2707 3008 3008 2545 2545 2545 940 940 940 316 316 316 G.C. 58 58 70 222 222 222 537 597 597 94 94 107 73 73 86 66 66 73 1 - Average of fourteen day food intake expressed as per cent CDS for CA. c2 - Average of fourteen day food intake expressed as per cent C D S for BA. d 3 - Average of fourteen day food intake expressed as per cent CDS for HA. - Indicates intakes c a l c u l a t e d from food only. - Indicates intakes c a l c u l a t e d from food and supplements. TABLE IX. Average nutrient intakes of seven uremic children for fourteen day food record period. II. " ~ ^ \ N u t r i e n t a Sub j ect ^ ^ ^ ^ ^ c Vitamin D c Vitamin C Pyridoxine F o l i c A c i d d Cobalamin b Copper Sodium6 Potassium^ M.E. 25100 223 50 250 100 54 292 594 D.O. 188500 243 67 500 100 40 240 457 D.T. 25100 25 50 250 100 55 442 662 C S . 12600 557 20 250 100 76 476 946 R.J. 12600 233 No Supplement No Supplement No Supplement 38 205 553 CM. 25100 1094 250 125 333 57 386 687 G.C. 25100 270 50 No Supplement 100 106 294 689 Average of fourteen day intakes expressed as per cent CDS. Indicates intake calculated from food only. ^Indicates intake calculated from food and supplements. Indicates intake calculated from supplements only. Requirement based on minimal sodium loss i n adults per day (15 mEq) minus obligatory . renal losses (10 mEq) per day plus the d a i l y requirement f or growth (1 mEq). Requirement based on minimal potassium loss i n adults per day (30 mEq) minus obligatory renal losses per day (10 mEq) plus the d a i l y requirement f or growth (1 mEq). Table X, i n a d d i t i o n t o the average p r o t e i n and c a l o r i e i n t a k e per k i l o g r a m of body weight. The average amino a c i d p a t t e r n o f the d i e t s as compared t o the r e f e r e n c e amino a c i d p a t t e r n of the FAO/WHO (19 73) i s d e s c r i b e d i n Table XI. Despite the p r e s c r i p t i o n o f c a l o r i c supplements, the c a l o r i e i n t a k e s of a l l s u b j e c t s were found t o be d r a s t i c a l l y suboptimal. The mean c a l o r i c i n t a k e s were 54.3% ±11.4, 57.6% ±10.0, and 53.1% ±9.1 of normal f o r CA, BA and HA, r e s p e c t i v e l y . The mean c a l o r i c i n t a k e p e r k i l o g r a m of body weight was 31.2 ±5.5 k c a l . The aver-age p r o t e i n i n t a k e s were suboptimal i n most cases when expressed as per cent CDS f o r CA, BA and HA. However, i n view of the mean i n t a k e of 1.09 ±.16 grams of p r o t e i n per k i l o g r a m body weight (Table X) and the high chemical scores given by the d i e t a r y amino a c i d composition, mean 85.7 ±5.3 (Table X I ) , these p r o t e i n i n -takes are co n s i d e r e d adequateaforfuremic individuacLs^ifcThe most l i m i t i n g d i e t a r y amino a c i d s were c o n s i s t e n t l y the s u l f u r -c o n t a i n i n g amino a c i d s ( c y s t i n e and methionine) and t h r e o n i n e . A d i e t a r y imbalance of amino a c i d s was e v i d e n t (Table X I ) . A l l d i e t s showed e x c e s s i v e amounts o f p h e n y l a l a n i n e and t y r o s i n e , mean 22 5.7% ±49 o f the amino a c i d p a t t e r n recommended by the FAO/ WHO, 1973. The i n t a k e s o f f a t s o l u b l e v i t a m i n s , a s c o r b a t e , t h i a m i n and f o l a t e were more than adequate i n most cases. D e f i c i e n c i e s o f c e r t a i n water s o l u b l e v i t a m i n s , namely, r i b o f l a v i n , n i a c i n and p y r i d o x i n e , e x i s t e d f o r some o f the s u b j e c t s . Of the minerals c o n s i d e r e d , z i n c , magnesium and copper i n -takes were very low. The mean z i n c i n t a k e s were 44.9% ±7.6, 49.4% ±10.1 and 56.4% ±11.5 of the CDS f o r normal i n d i v i d u a l s f o r TABLE X. Per cent of t o t a l c a l o r i e s c o n t r i b u t e d to the d i e t by-p r o t e i n , f a t and carbohydrate over the f o u r t e e n day food r e c o r d p e r i o d . Subject P r o t e i n F a t Carbohydrate g P r o t e i n / k g Body Weight kca l / k g Body Weight M.E. 15 41 45 0.93 25.5 D.O. 13 38 49 1.0 30.6 D.T. 13 35 52 1.16 35.3 C S . 13 39 48 1.28 38.6 R.J. 15 35 49 0.9 22.9 CM. 12 44 44 1.08 34.3 G.C 16 40 44 1.28 30.9 TABLE XI. Average chemical scores and most l i m i t i n g amino acids of diets consumed during a fourteen day period by seven uremic children. Subject Chemical Score 1st L i m i t i n g Amino A c i d 2nd L i m i t i n g Amino A c i d 3rd L i m i t i n g Amino A c i d Amino A c i d i n Excess M.E. 79 S u l f u r C o n t a i n i n g Amino A c i d s Threonine Tryptophan P h e n y l a l a n i n e and T y r o s i n e D.O. 91 S u l f u r C o n t a i n i n g Amino A c i d s Threonine None Ph e n y l a l a n i n e and T y r o s i n e D.T. 89 S u l f u r C o n t a i n i n g Amino A c i d s Threonine None Phe n y l a l a n i n e and T y r o s i n e C S . 86 S u l f u r C o n t a i n i n g Amino A c i d s Threonine None Phe n y l a l a n i n e and T y r o s i n e R.J. 92 Threonine S u l f u r C o n t a i n i n g Amino A c i d s None Ph e n y l a l a n i n e and T y r o s i n e C M. 79 S u l f u r C o n t a i n i n g Amino A c i d s S u l f u r C o n t a i n i n g Amino A c i d s Threonine P h e n y l a l a n i n e and T y r o s i n e G.C. 84 S u l f u r C o n t a i n i n g Amino A c i d s Threonine None Phe n y l a l a n i n e and T y r o s i n e CA, BA and HA, respectively. The mean copper intake, for which there exists only one CDS for a l l age groups, was 53.7% ±32.0 of the CDS for normal ind i v i d u a l s . The mean c a l o r i c contributions to the die t by protein, f a t and carbohydrate over the fourteen day periods were 13.9% ±1.46, 38.9% ±3.24 and 47.3% ±3.03, respectively of t o t a l c a l o r i e s . These re s u l t s r e f l e c t the consumption pattern observed i n Canada, namely, 11% protein, 41% f a t and 49% carbohydrate of t o t a l c a l o r i e s (Dietary Standard for Canada, 1975). The r e s u l t s of the dietary r e c a l l s correlated highly with the food records kept by the subjects (the average of the co r r e l a t i o n c o e f f i c i e n t s for the various nutrients was .9155). The mean values obtained from the protein and amino acid com-position of eleven food samples as compared to the mean values ob-tained from the computerized food table c a l c u l a t i o n are presented in Table XII. The food table c a l c u l a t i o n was found to provide an accurate estimation of dietary protein and amino acids for the group. Only the mean isoleucine, cystine, and valine values were s i g n i f i c a n t l y d i f f e r e n t (p<.05), and i n a l l cases the food table c a l c u l a t i o n overestimated the chemical analysis. When considering i n d i v i d u a l intakes, large discrepancies existed between the amino acid values given by the food composition tables and those given by the chemical analysis. This v a r i a t i o n i s l i k e l y due to the d i f -ferent types of amino acid analyzers used i n the preparation of the food composition tables and the d i f f e r e n t methods of hydrolysis used i n preparing samples for amino acid analysis. 4.3 Biochemical Data Comparisons of the mean pre and post d i a l y s i s plasma amino TABLE X I I . Comparison of the d i e t a r y p r o t e i n and amino a c i d s as gi v e n by food t a b l e c a l c u l a t i o n s and chemical a n a l y s e s . N u t r i e n t Food Table P r o t e i n and Amino C a l c u l a t i o n A c i d A n a l y s i s P° T o t a l P r o t e i n 3 18.56±6.13 16.55±4.66 NS d Threonine* 3 681.67±254.26 719.28±160.46 NS I s o l e u c i n e 976.64±383.61 683.13±156.40 <.05 e L y s i n e 1128.33+407.48 1135.'62±340.65 NS Methionine 519.99±413.09 587.35±919.84 NS C y s t i n e 266.23±99.11 181.11±63.80 <.05 Phe n y l a l a n i n e 894.78±341.51 690.24±204.72 NS V a l i n e 1071.47±413.85 723.45±277.04 <.05 H i s t i d i n e 467.39±177.69 580.49±207.56 NS T y r o s i n e 650.89±267.41 506.61±154.01 NS A r g i n i n e 856.23±318.54 857.72+201.56 NS A l a n i n e 670.91±258.92 621.05±205.79 NS A s p a r t i c A c i d 1276.34±470.72 1260.92±353.68 NS Glutamine and 3417.5±1400.0 Glutamic A c i d 3716.0±674.57 NS G l y c i n e 649.92±304.43 697.06+165.63 NS P r o l i n e 1178.46±572.29 1280.8±344.33 NS Seri n e 725.90±444.04 826.76±180.45 NS Leucine 1470.62±566.18 1218.55±276.52 NS ^ P r o t e i n v a l u e s are expressed i n grams. Amino a c i d v a l u e s are expressed i n m i l l i g r a m s , p r o b a b i l i t y by Student's t T e s t . N o n s i g n i f i c a n t P r o b a b i l i t y i s l e s s than .05. acid concentrations of six subjects with normal values reported in the l i t e r a t u r e CArmstrong and Stave, 1973 II) are given i n Tables XIII and XIV. Pre d i a l y s i s , there was no evidence of an inadequate fas t i n six subjects as there were no s i g n i f i c a n t differences (NS) of mean methionine, isoleucine, l y s i n e , and phenylalanine lev e l s from normal, and leucine (p<.025) and valine (p<.0005) le v e l s were s i g n i f i c a n t l y decreased. Elevations of these amino acids are ind i c a t i v e of an inadequate fas t (Armstrong and Stave, 1973 I I ) . Consequently, M.E.'s re s u l t s had to be elim-inated as he demonstrated elevated phenylalanine, methionine, isoleucine, leucine, l y s i n e , and h i s t i d i n e concentrations post d i a l y s i s (lysine concentration having increased during d i a l y s i s ) . M.E. fasted only 4-1/4 hours prior to the post d i a l y s i s blood sampling. Pre d i a l y s i s , taurine (p<.0005), a-amino-butyric acid (p<.0005), valine (p<.0005), cystine (p<.0005), leucine (p<.025), tyrosine (p<.0005) and tryptophan (p<.0005) were s i g n i f i c a n t l y decreased from normal. Increases from normal were evident for aspartic acid (p<.0005), proline (p<.0005), c i t r u l l i n e (p<.0005), glycine (p<.0005), ornithine (p<.005), h i s t i d i n e (p<.0005), aspar-agine (p<.001), and arginine (p<.005). In addition, g-alanine, g-amino-butyric acid, 1-methylhistidine and 3-methylhistidine, not normally present i n appreciable amounts, were detected and elevat-ed above normal. Post d i a l y s i s , there were s i g n i f i c a n t decreases of taurine, a-amino-butyric acid, valine, threonine, cystine, serine, methionine, alanine, tyrosine, l y s i n e , tryptophan, ( a l l with p<...0005) , and arginine (p<.025). Only aspartic acid (p<.0005), asparagine (p<.0005), c i t r u l l i n e (p<.005) and glycine (p<.02 5) were elevated above normal i n post d i a l y s i s plasma. The TABLE XIII. Comparison of pre d i a l y s i s plasma amino acids i n six children with CRF with normal values given i n the l i t e r a t u r e for individuals of the same age-group. Amino Acid Patients Normals Change Observed P r o b a b i l i t y N Mean ym/ml SD N Mean ym/ml SD Taurine 6 .0525 .014 134 .109 .063 D a <.0005 Hydroxyproline 6 .0822 .128 127 .023 .012 NS Aspartic Acid 6 .0603 .035 76 .006 .004 I b <.0005 Threonine 6 .1477 .060 136 .139 .032 NS Serine 6 .1073 .032 136 .124 .027 NS Asparagine 6 .1443 .035 135 .048 .007 I <.001 Proline 6 .5098 .270 135 .187 .058 I <.0005 Glutamic Acid 6 .1538 .183 133 .036 .014 NS C i t r u l l i n e 6 .1287 .052 135 .035 .008 I <.0005 Glycine 6 .5032 .137 136 .232 .036 I <.0005 Alanine 6 .3830 .112 136 .361 .088 NS a-Amino-Butyric Acid 6 .0082 .009 134 .023 .007 D <.0005 Valine 6 .1620 .030 8.5 .223 .031 D <.0005 Cystine 6 .0630 .021 81 .093 .019 D <.0005 Methionine 6 .0268 .006 135 .0268 .006 NS Isoleucine 6 .0663 .010 136 .067 .013 NS Leucine 6 .0988 .032 136 .127 .021 D <.025 Tyrosine 6 .0443 .015 135 .067 .011 D <.0005 Phenylalanine 6 .0702 .022 136 .058 .008 NS 3-Alanine 6 .0037 .006 Not normally present B-Amino-Isobutyric Ac i d 6 .0075 .018 Not normally present Ornithine 6 .0833 .026 127 .049 .014 I <.005 Lysine 6 .1518 .040 134 .170 .028 NS 1-Methylhistidine 6 .0498 .090 Not normally present H i s t i d i n e 6 .1330 .024 134 .085 .010 I <.0005 3-Methylhistidine 6 .0242 .020 Not normally present Tryptophan 6 .0078 .009 126 .055 .012 D <.0005 Arginine 6 .1322 .035 130 .089 .020 I <.005 D-decrease I-increase TABLE XIV. Comparison of post dialysis-plasma amino, acids i n six children with CRF with normal values given i n the l i t e r a t u r e for individuals of the same age group. Amino Acid Patients Normals Change Observed P r o b a b i l i t y N Mean ym/ml SD N Mean ym/ml SD Taurine 6 .0458 .013 134 . .109 .063 D a <.0005 Hydroxyproline 6 .0315 .050 127 .023 .012 NS Aspartic Acid 6 .0193 .007 76 .006 .004 i b <.0005 Threonine 6 .0902 .018 136 .139 .032 D <.0005 Serine 6 .0712 .027 136 .124 .027 D <.0005 Asparagine 6 .1032 .029 135 .048 .007 I <.0005 Proline 6 .3247 .211 135 .187 .058 NS Glutamic Acid 6 .1183 .124 133 .036 .014 NS C i t r u l l i n e 6 .0528 .015 135 .035 .008 I <.005 Glycine 6 .2712 .048 136 .232 .036 I <.025 Alanine 6 .1800 .093 136 .361 .088 D <.0005 a-Amino-Butyric Acid 6 .0023 .006 134 .023 .007 D <.0005 Valine 6 .1352 .022 85 .223 .031 D <.0005 Cystine 6 .0425 .018 81 .093 .019 D <-0005 Methionine 6 .0155 .004 135 .0268 .006 D <.0005 Isoleucine 6 .0737 .030 136 .067 .013 NS Leucine 6 .0868 .054 136 .127 .021 <.05 Tyrosine 6 .0323 .013 135 .067 .011 D <.0005 Phenylalanine 6 .0588 .011 136 .058 .008 NS 3-Alanine 6 Not detected Not normally present B-Amino-Isobutyric Acid 6 .0012 .003 Not normally present Ornithine 6 .0483 .016 127 .049 .014 NS Lysine 6 .0882 .022 134 .170 .028 D <.0005 1-Methylhistidine 6 .0222 .035 Not normally present H i s t i d i n e 6 .0930 .016 134 .085 .010 NS 3-Methylhistidine 6 .0075 .011 Not normally present Tryptophan 6 .0123 .018 126 .055 .012 D <.0005 Arginine 6 .0742 .016 130 .089 .020 D <.025 D-decrease I-mcrease pre and post mean .plasma amino acid lev e l s of the six subjects were compared by the Student's t Test. The amino acids which were found to be s i g n i f i c a n t l y altered by hemodialysis, and the d i r e c -tion of the observed change are presented i n Table XV. The i n d i -vidual and mean valine/glycine, phenylalanine/tyrosine, and E/N ra t i o s before and afte r d i a l y s i s are presented i n Table XVI. The results of the Pearson Product-Moment Test of Correlation between certain pre d i a l y s i s plasma amino acid concentrations and dietary constituents are presented i n Table XVII. There as an inverse li n e a r r e l a t i o n s h i p between plasma c i t r u l l i n e concentration and protein, f a t , carbohydrate and c a l o r i c intakes (p<.05). There was a d i r e c t l i n e a r r elationship between plasma 3-methylhistidine l e v e l and dietary f a t , carbohydrate and c a l o r i c intakes (p<.01) Table XVII). Plasma glycine, alanine, and possibly arginine con-centrations are d i r e c t l y related to blood urea nitrogen lev e l s (Table XVII). The Val/Gly r a t i o tends to vary inversely with blood urea nitrogen (Table XVII). There i s a d i r e c t l i n e a r re-latio n s h i p between plasma c i t r u l l i n e concentration and the chemi-ca l score of dietary protein intake (p<.05) (Table XVIII). There appears to be an inverse l i n e a r r e l a t i o n s h i p between chemical score and each of arginine, ornithine, urea and creatinine (Table XVIII). The plasma Phe/Tyr r a t i o before d i a l y s i s correlated highly with the average Phe/Tyr r a t i o calculated from the fourteen day food intake record (r. = +.87, p<.02). The r e s u l t s of additional laboratory tests done on blood samples are presented i n Table XIX. The mean, pre arid post d i a l -y s i s , blood sodium, potassium, bicarbonate, chloride, calcium, phosphorous, glucose, t o t a l proteins, albumin, alpha 2 globulin, TABLE XV. S i g n i f i c a n t changes i n plasma amino a c i d s before and a f t e r a hemodialysis treatment i n s i x c h i l d r e n w i t h CRF. Amino Acid Change Observed b P r o b a b i l i t y Aspartic Acid D a <.01 Threonine D <.02 Serine D <.025 C i t r u l l i n e D <.005 Glycine D <.005 Alanine D <.005 Valine D <.05 Cystine D <.05 Ornithine D <.01 Lysine D <.005-H i s t i d i n e D <.005 3-Methylhistidine D <.05 Arginine D <.005 Asparagine D <.025 D-decreased a f t e r d i a l y s i s Student's t Test TABLE XVI. Pre and post dialysis plasma valine/glycine, phenylalanine/ tyrosine and essential/nonessential- amino acid ratios in six uremic children. Subject Valine/Glyc ine Phenylalanine/Tyrosine E/N -Pre a P o s t b Pre Post Pre Post D.O. .257 .616 1.28 1.92 .592 1.289 D.T. .232 .439 3.06 1.52 .422 .691 C S . .258 .453 1.57 3.85 .402 .518 R.J. .710 .440 1.59 1.67 .510 .481 CM. .322 .549 1.58 1.68 .510 .716 G.C. .379 .530 1.04 1.71 .472 .497 Mean .360 .505 1.69 2.058 .485 .699 ±SD ±.180 ±.072 ±.708 ±.887 .069 ±.306 Pre d i a l y s i s Post d i a l y s i s TABLE XVII. Pearson Product-Moment Correlation C o e f f i c i e n t : Test of cor r e l a t i o n between c e r t a i n plasma amino acid concentrations and selected dietary constituents, blood urea concentration, or plasma creatinine concentration. Amino Acid(s) Considered Dietary Protein Dietary Fat Dietary Carbohydrate Dietary Calories Urea Creatinine r a pb r P r P r P r P r P Glycine + .18 NS + .33 NS + .40 NS + .37 NS + 86 < .01 + .34 NS Valine + 14 NS - .22 NS - .45 NS - .31 NS + .13 NS + .45 NS Val/Gly - 23 NS - .50 NS - .60 NS - •5:5' NS - .76 NS -.28 NS C i t r u l l i n e - 85 <.05 - .86 < .05 - .88 <.02 - .91 <.02 - 41 NS -.26 NS Alanine + 59 NS + 41 NS + .37 NS + .42 NS + 80 < .02 -.40 NS 3-Methylhistidine + 46 NS + 95 < .01 + .93 <.01 + .93 <.01 + 14 NS .15 NS Arginine + 11 NS - 12 NS - 03 NS - .06 NS + 79 NS .51 NS Correlation coefficient Probability TABLE XVIII. Pearson Product-Moment Correlation C o e f f i c i e n t : Test of correlation between dietary amino acid chemical score and blood c i t r u l l i n e , urea, creatinine, ornithine or arginine concentration. C i t r u l l i n e Urea Creatinine Ornithine Arginine r a p b r P r p r p r p Chemical Score +.76 <.05 -.53 NS -.52 NS -.51 NS -.65 NS Cor r e l a t i o n c o e f f i c i e n t 'Probability TABLE XIX. Results of biochemical analyses Of blood pre and post dialysis. (For normal value refer to Table V) Subject Soc _ (mEc lium I/A) e Potas (mE >sium. i q/SL) ^icarfc (mEc >onate [/£) Chloride (mEq/Ji) Calcium mg% f Phosphorus mg% ' BUNC mg% Uric Acid mg% Creatinin mg% e BSa mg% P r e a Post b Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post M.E. 142 136 3.9 3.0 19 24.8 103 97 10.3 10.3 3.3 3.7 75 30 8.9 3.8 15.9 7.8 83 79 D.O. 136 141 4.2 2.2 20.5 21 98 95 Not done 9.5 Not done 3.0 69 3 7.5 1.3 11.1 2.3 92 88 D.T. 135 142 6.5 3.6 21.5 24.4 Not done 10.1 9.8 7.2 6.0 78 28 7.5 3.0 9.6 3.2 81 62 C S . 137 137 6.2 3.3 20.5 19.2 96 92 9.8 10.0 6.5 Not done 74 18 7.4 2.3 10.8 3.5 94 69 R.J. 138 137 4.9 3.1 27.2 21 102 92 9.1 9.8 5.1 4.2 84 19 8.0 1.8 11.4 4.6 80 52 CM. 143 136 5.6 3.1 19.5 23.4 Not done 9.0 Not done 9.4 Not done 60 23 5.9 Not done 10.5 5.6 98 93 CM. , 143 134 5.3 2.8 15.1 21.6 109 97 8.6 9.7 10.1 7.1 79 32 6.0 2.8 13.2 6.6 94 74 G.C. 143 140 4.6 3.2 21 25.6 99 94 9.2 10.6 9.6 5.6 68 19 7.8 1.9 14.1 6.2 Not done 101 j_Pre d i a l y s i s sample Post d i a l y s i s sample ^BUN - Blood urea nitrogen BS - Blood sugar ^mEq/i - m i l l i e q u i v a l e n t s per l i t e r mg.% - milligrams per 100 m i l l i l i t e r s (milligrams per cent) % - grams .per 100 m i l l i l i t e r s (grams per cent) A. units - King-Armstrong units mOsm. - milliosmoles TABLE XIX. R e s u l t s of b i o c h e m i c a l analyses of blood pre and post d i a l y s i s , (continued) Subject Total Proteins (g%)9 Albumin (g%) Alpha 1 Globulin (g%) Alpha 2 Globulin (g%) Beta Globulin (g%) Gamma Globulin (g%) Hemo-globin (g%) Osmol-a l i t y _ (mOsm)1 A l k a l i n e Phosphatase [K.A.Units )h Trans-f e r r i n mg% Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre P6st Pre Post Pre M.E. 6.0 6.0 4.3 4.8 0.1 0.1 0.5 0.4 0.5 0.4 0.5 0.3 4.8 4.5 322 289 19 18 Not done D.O. 5.7 5.5 4.1 4.0 0.1 0.1 0.4 0.5 0.6 0.5 0.5 0.4 4.3 4.1 296 280 19 28 Not done D.T. 5.6 5.9 3.5 3.6 0.1 0.2 0.7 0.8 0.6 0.6 0.7 0.7 5.3 5.3 Not done 66 42 Not done C S . 6.7 7.1 4.2 4.3 0.2 0.2 0.6 0.7 0.6 0.7 1.1 1.3 5.6 5.1 308 272 56 44 235 R.J. 6.0 6.0 3.7 4.2 0.2 0.1 0.5 0.3 0.7 0.5 1.0 0.8 4.8 4.7 313 276 10 9 235 CM. 6.9 7.3 4.6 4.9 0.2 0.2 0.8 0.9 0.7 0.8 0.6 0.5 Not. done 302 264 20 Not dc me CM. 6.5 6.1 4.7 4-5 0.1 0.1 0.7 0.7 0.6 0.5 0.4 0.3 7.4 7.6 307 276 20 Not dc >ne G.C. 7.4 7.0 4.7 4.0 0.1 0.1 0.7 0.7 0.7 0.6 1.2 1.0 6.3 6.0 329 284 9 7 189 beta globulin, gamma globulin, and al k a l i n e phosphatase measure-ments were within normal l i m i t s . Pre d i a l y s i s blood urea nitrogen u r i c acid and creatinine concentrations were elevated above normal values due to decreased urinary excretion of these compounds. The mean blood urea nitrogen, u r i c acid and creatinine concentrations were 73.4 mg% ±7.5 (normal, 8.0-20 mg%) (Gentzkow and Mason, 1942) 7.4 mg% ±1.0 (normal, 3.0-5.5 mg%) (Caraway, 1955) and 12.1 mg% ±2 (normal, 0.5-1.2 mg%) (Henry, 1964), respectively. Post d i a l y s i s only creatinine remained elevated above normal (mean, 5.3 mg% ±2). The r e s u l t s of the serum protein electrophoresis demonstrated that the mean pre and post d i a l y s i s alpha 1 globulin concentrations (both with mean, 0.13 g% ±0.5) were decreased when compared to the normal values of 0.2-0.4 g% (Henry, 1964). The mean, pre and post d i a l y s i s , hemoglobin concentrations (5.1 g% ±1.1 and 5.3 g% ±1.2, respectively) were also reduced from the normal l e v e l s of 11-18 g% (Henry, 1964). The mean pre d i a l y s i s serum osmolality (311 mOsm ±11.4) was elevated compared to the normal l e v e l of 2 95 mOsm ±6 (Natelson, 1971). Post d i a l y s i s , the mean serum osmolality (277.3 mOsm ±8.1) was reduced when compared to normal. Serum t r a n s f e r r i n was measured i n three patients and was found to be depressed compared to normal (see Table V, page 42 and Table XIX, page 64). 4.4 Dialysate Data The mean amounts of free amino acids l o s t into dialysate during a complete hemodialysis treatment for seven subjects are given i n Table XX. Table XXI presents the t o t a l amino acids l o s t by each i n d i v i d u a l and the per .cent of the t o t a l which were essen-t i a l and nonessential. The ess e n t i a l amino acids accounted for TABLE XX. Free amino acids i n dialysate of seven uremic children at the termination of a d i a l y s i s treatment. Amino Acid Amount (um/ml) N E s s e n t i a l h Threonine .009 (±.004) a Valine .006 (±.005) 6 Methionine Trace 7 Isoleucine .004 (.006, .002) 2 Leucine .008 (±.005) 3 Tyrosine .002 (±.001) 6 Phenylalanine .004 (±.001) 7 Lysine .004 (±.002) 7 H i s t i d i n e .028 (±.003) 7 Tryptophan Trace/Not Detected 7 Cystine .004 (.003, .005) 2 Nonessential Asp a r t i c Acid .002 (±.0008) 7 Serine .007 (±.004) 7 Pr o l i n e Trace/Not Detected 7 Asparagine .012 (±:.009) 4 Glutamic Acid .007 (±.003) 7 C i t r u l l i n e .003 (±.002) 4 Glycine .028 (±.011) 7 Alanine .018 (±.014) 7 a-Amino-Butyric Acid Trace 7 Ornithine .004 (±.0009) 7 1-Methylhistidine Trace 7 3-Methylhistidine Trace 7 Arginine .005 (±.0004) 6 3-Alanine Not Detected 7 (3-Amino-Isobutyric Acid Not Detected 2 Taurine .003 (±.001) 3 Hydroxyproline Not Detected 7 Mean ± standard deviation; when n was 2, mean and i n d i v i d u a l values are given. 'The number of amino acids used f or c a l c u l a t i n g the mean i s not constant because some amino acids f o r c e r t a i n i n d i v i d u a l s separated poorly, were present i n only trace amounts or were not detected. TABLE XXI. T o t a l amino a c i d s , e s s e n t i a l and n o n e s s e n t i a l , l o s t i n t o d i a l y s a t e d u r i n g a complete hemodialysis treatment f o r each of seven uremic c h i l d r e n . Subject T o t a l (g) E N B a A b Total E(g) % T o t a l 0 Total N(g) % T o t a l c M.E. 5.52 5.32 2.55 47.9 2.77 52.1 D.O. 4.57 4.29 2.57 59.1 1.71 39.9 D.T. 4.16 3.94 2.20 55.8 1.74 44.2 C S . 3.64 3.30 2.01 60.9 1.29 39.1 R.J. 3.66 3.39 1.65 48.7 1.74 51.3 CM. 5.13 4.74 2.69 56.8 2.05 43.2 G.C 6.05 5.56 2.58 46.4 2.98 53.6 Mean 4.67 4.36 2.32 53.7 2.04 46. 3 ±SD ±.93 ±.89 :±.38 ±5.9 ±.61 ±6.0 B-Includes the amino acids, h i s t i d i n e , isoleucine, leucine, l y s i n e , methionine, phenylalanine, threonine, tyrosine, v a l i n e , glycine, serine, asparagine, cystine, alanine, arginine, aspartic acid, glutamic a c i d , c i t r u l l i n e , ornithine, taurine, and 1-methylhistidine. A-Includes a l l of the amino acids i n B except c i t r u l l i n e , taurine, ornithine, and 1-methylhistidine. '% Total-E and N expressed as per cent of A. 53.7% ±5.9 of the t o t a l amino acids l o s t . There was no evident rela t i o n s h i p between the amounts of amino acids present i n the dialysate and the pre d i a l y s i s plasma l e v e l s , the amounts eaten during d i a l y s i s , or the molecular weights of the amino acids. A mean 4.67 ±.93 grams of t o t a l amino acids were l o s t into dialysate (range, 3.64-6.05 grams). There was a l o t of i n d i v i d u a l v a r i a t i o n i n the b a c t e r i a l counts of the dialysate at the end of the c o l l e c t i o n as shown in Table XXII, but only a few microorganisms were i s o l a t e d . Tables XXI and XXII show that the individuals with the highest dialysate microbial counts had the highest amino acid losses. It i s not known i f the high microbial concentrations resulted from the n u t r i -tious amino acid media, or i f the high amino acid concentrations resulted from the microbial proteolysis of amino acid conjugates present in the dialysate. The microbial counts did not vary di- . r e c t l y with the amounts of amine acids l o s t . In any event, the addition of sodium thymol to dialysate at a concentration of one c r y s t a l per l i t e r does not appear to be e f f e c t i v e for i n h i b i t i n g microbial growth. 4.5 Taste S e n s i t i v i t y Data Table XXIII shows that the stimulated parotid s a l i v a flow rate was reduced before and a f t e r d i a l y s i s (p<.0005) when compared to normal values reported i n the l i t e r a t u r e (Hawkins and Zipkin, 1964). The mean flow rates, pre and post d i a l y s i s , were .046±.04 ml/min and .063±.06 ml/min, respectively. Pre d i a l y s i s a l l s a l i v a urea concentrations (Table XXIV) were elevated (p<.0005) compared to the normal l e v e l (mean, 8.8 mg%; range, 0-14.3 mg%) (Updegraff and Lewis, 1924). Saliva urea concentrations correlated strongly with TABLE XXII. Colony counts of microorganisms isol a t e d from dialysate at the termination of d i a l y s i s . Subject Microorganisms Isolated Number per M i l l i l i t e r of Dialysate M.E. Pseudomonas pyocyaneus <75,000 D.O. Mainly Enterobacter sp. »100,000 Pseudomonas pyocyaneus >100,000! D.T. Pseudomonas pyocyaneus <1,000 C S . Pseudomonas pyocyaneus 5,000 Other Pseudomonas sp. 30,000 R.J. Mixed coliforms (mainly Acinetobacter sp.) >100,000 Pseudomonas pyrocyanus <1,000 CM. Mainly Acinetobacter an t i t r a t u s >100,000 Pseudomonas aeruginosa 100,000 G.C. Pseudomonas aeruginosa Other Pseudomonas sp. 71,000 (total) TABLE XXIII. Comparison of pre and post d i a l y s i s stimulated parotid s a l i v a flow rate i n seven uremic children with normal values given in the l i t e r a t u r e . S a l i v a Flow Rate (ml/min) .Subject- Pre d i a l y s i s Post d i a l y s i s Normal^ M.E .267 .06 D.O. .04 e D.T. .15 .06 C S . .03 .015 R.J. .267 .056 CM. .006 .186 G.C .04 .003 Mean .046 .063 .07 ± SD ±.04 ±.06 ±.54 N C 7 6 29 P d <.0005 <.0005 m i l l i l i t e r s , per minute Hawkins and Zipkins, 1964 jnumber p r o b a b i l i t y 'omitted due to inaccuracy of measurement TABLE XXIV. Saliva urea concentrations pre and post d i a l y s i s i n seven uremic children. S a l i v a Urea Concentration (mg%) .Subject Pre d i a l y s i s Post d i a l y s i s M.E. 44 11 D.O. 59 13 D.T. 61 31 C S . 63 20 R.J. 71 25 CM. 72 25 G.C. 67 15 milligrams per 100 m i l l i l i t e r s (milligrams per cent) blood urea l e v e l s (r = .9347, p<.0005) pre and post d i a l y s i s (for blood urea l e v e l s refer to Table XIX, pages 63-64). The detection and recognition thresholds of each i n d i v i d u a l , pre and post d i a l -y s i s , and on retest are presented i n Tables XXV, XXVI, XXVII and XXVIII, for each of sweet, sour, s a l t and b i t t e r , respectively. Sweet detection threshold was within normal l i m i t s pre d i a l y s i s but was improved over normal post d i a l y s i s (p<.0005). Sweet recognition threshold was impaired pre and post d i a l y s i s (p<.005). B i t t e r detection thresholds were normal throughout the assessment but the recognition thresholds were increased before d i a l y s i s . Salt recognition and pre d i a l y s i s detection thresholds were normal, but the detection thresholds were s i g n i f i c a n t l y decreased from normal (p<.0005), both before and after d i a l y s i s . Retesting of taste s e n s i t i v i t y thresholds confirmed the f i n d -ings of the i n i t i a l t e s t i n g . It should be noted that for the retest an i n t e r d i a l y t i c period of 48 hours was not possible i n a l l cases, and t h i s may have influenced retest taste thresholds. The r e s u l t s of the Wald-Wolfowitz Runs Test (Wald and Wolf-owitz, 194 0) show that the pre d i a l y s i s detection and recognition thresholds for sweet, s a l t and sour are s i g n i f i c a n t l y d i f f e r e n t from those obtained post d i a l y s i s (p<.05). Results of the Pearson Product-Moment Test of Correlation between the detection and recognition thresholds for each of ..the four modalities, be-fore and after d i a l y s i s , and each of blood urea nitrogen, s a l i v a urea concentration and serum al k a l i n e phosphatase are presented i n Table XXIX. Sweet recognition and b i t t e r detection thresholds appear related to blood urea nitrogen concentrations (r = .5617, p<.05, and r = .7157, p<.01, re s p e c t i v e l y ) . B i t t e r detection TABLE XXV. Sweet d e t e c t i o n and r e c o g n i t i o n t h r e s h o l d s i n uremic c h i l d r e n before and a f t e r d i a l y s i s . DETECTION SUBJECT RECOGNITION I n i t i a l Assessment Retest I n i t i a l Assessment Retest Before^ After"? Before"? A f t e r f Before^ After9 Before*? A f t e r f 1.20 a .04 - - M.E. 6.6 .1 - -.60 .30 .30 .04 D.O. .8 .4 . .8 .8 .60 .02 1.2 .04 D.T. 3.3 .4 3.3 .4 9.85e .30 .30 .01 C S . 13. l e .4 1.6 .2 .02 .02 .4 .02 R.J. 13.1 6.6 13.1 1.6 .30 .15 - - CM. 1.6 .8 - -.30 .04 .30 .15 G.C .8 .4 .8 .4 .503 .124 .50 .052 Mean 2.45 1.3 3.9 .68 ±.405 ±.128 ±.39 ±.056 ±SD ±3.83 ±2.3 ±5.2 ±.56 NS <.0005 NS <.0005 Pr o b a b i l i t y NS <.005 NS NS N* I C N I Change Observed N D d N N Before - pre d i a l y s i s •After - post d i a l y s i s per cent concentration of taste solution N - none 'I - increased s e n s i t i v i t y from normal TD - decreased s e n s i t i v i t y from normal /values omitted from c a l c u l a t i o n s t e s t done i n the morning before 9:00 a.m. f t e s t done i n the evening a f t e r 7:30 p.m. TABLE XXVI. Salt detection and recognition thresholds in uremic children before and after d i a l y s i s . DETECTION • SUBJECT RECOGNITION I n i t i a l A| sessment Retest I n i t i a l Assessment Retest Before A f t e r g Before g A f t e r 1 Before 1 A f t e r g Before^ A f t e r 1 .055 a .0135 - - M.E. .56 .28 - -.0065 .003 .0065 .0065 D.O. .14 .04 .14 .14 .055 .105 .055 .105 D.T. .28 .56 .28 .56 .105 .0065 .055 .002 C S . .14 .14 .14 .14 .029 .0065 .105 .0135 R.J. .14 .14 .28 .28 .029 .0135 - - CM. .07 .07 - -.029 .0065 .029 .003 G.C. .28 .14 .04 .009 .044 .022 .050 .026 Mean .23 .20 .18 .23 ±.032 ±.037 ±.037 ±.04 ±SD ±.17 ±.18 ±.10 ±.21 NS <.01 NS <.05 P r o b a b i l i t y NS NS NS NS N b • I C N I Change Observed N N N N Before - pre d i a l y s i s A f t e r - post d i a l y s i s per cent concentration of taste solution i N - None pL" - increased s e n s i t i v i t y from normal D - decreased s e n s i t i v i t y from normal lvalues omitted from c a l c u l a t i o n s t e s t done i n the morning before 9:00 a.m. t e s t done i n the evening a f t e r 7:30 p.m. TABLE: XXVII. Sour detection and recognition thresholds i n uremic children before and after d i a l y s i s . DETECTION RECOGNITION I n i t i a l Assessment Retest SUBJECT I n i t i a l Assessment Retest Before^ After? Before? A f t e r f Before^ After? Before? A f t e r f .0002 a .0001 - - M.E. .0014 .0007 - -.00105 .00205 .00205 .00105 D.O. .0055 .0027 .0055 .0055 .0005 .00105 .0005 .0005 D.T. .044 .044 .044 .0055 .0041 .0005 .004 .00008 C S . .011 .0014 .044 .0014 .0005 .00008 .0007 .00008 R.J. .0055 .0003 .044 .0055 .00205 .00205 - - CM. .0055 .0055 - -.0002 .0001 .008 .0005 G.C. .0027 .0014 .011 .0007 .00123 .0008 .003 .0004 Mean .0108 .008 .03 .004 ±.00142 ±.0009 ±.003 ±.0004 ±SD ±.015 ±.016 ±.02 ±.002 <.0005 <.0005 NS <.0005 Pro b a b i l i t y NS NS <.0005 <.005 I c I N b I -hange Observed N N D<a I Before - pre d i a l y s i s A f t e r - post d i a l y s i s per cent concentration of taste so l u t i o n |N - none |I - increased s e n s i t i v i t y from normal D - decreased s e n s i t i v i t y from normal yalues omitted from c a l c u l a t i o n s t e s t done i n the morning before 9:00 a.m. t e s t done i n the evening a f t e r 7:30 p.m. TABLE XXVIII. B i t t e r detection and recognition thresholds i n uremic children before and after d i a l y s i s . DETECTION SUBJECT RECOGNITION I n i t i a l .Assessment Retest I n i t i a l .Assessment Retest Before 1 A f t e r 9 Before 9 A f t e r ' Before''" A f t e r 9 Before 9 r A f t e r .0034 a .000083 - - M.E. .00045 .00045 - -.000675 .00034 .03 .01 D.O. .0009 .0009 .03 .014 .00135 .00034 .000083 .000028 D.T. .0018 .0018 .0009 .00023 .000675 .0017 .00135 .000675 C S . .0036 .0009 .007 .0036 .00135 .00017 .00045 .00034 R.J. .0018 .00023 .0009 .00034 .01 .000083 - - CM. .014 .0018 - -.00135 .00034 .00034 .00017 G.C. .0018 .0018 .00045 .0018 .002 .0002 .006 .002 Mean .0035 .0011 .0079 .004 ±.003 ±.0001 ±.013 ±.004 ±SD ±.,005 ±.0007 ±.0127 ±..006 NS NS NS NS Pro b a b i l i t y NS <.005 d D NS NS N b N N N Chanqe Observed N N N Before - pre d i a l y s i s A f t e r - post d i a l y s i s per cent concentration of taste solution N - none | l - increased s e n s i t i v i t y from normal D - decreased s e n s i t i v i t y from normal [values omitted from c a l c u l a t i o n s t e s t done i n the morning before 9:00.a.m. f t e s t done i n the evening a f t e r 7:30 p.m. TABLE XXIX. Pearson Product-Moment Correlation C o e f f i c i e n t : Test of c o r r e l a t i o n between taste thresholds and blood urea nitrogen, s a l i v a urea, and serum alkaline phosphatase. Threshold Considered Blood Urea Nitrogen a b r p S a l i v a r Urea P Alk a l i n e r Phosphatase P c Sweet D .4956 NS .3119 NS .2318 NS d Sweet R .5617 <.05 .4851 NS -.2385 NS Sour D .0796 NS .2329 NS .4679 NS Sour R .1740 NS .1991 NS .6756 <.01 S a l t D .4170 NS . 3707 NS .5086 NS Sa l t R .2381 NS .0644 NS .5994 <.02 B i t t e r D .7157 <.01 .8642 <.001 .1438 NS B i t t e r R .2141 NS .4767 NS .0173 NS c o r r e l a t i o n c o e f f i c i e n t 'probability 'D-detection threshold ^R-recognition threshold thresholds correlate highly with s a l i v a urea concentrations (r = .8642, p<.001). Sour and s a l t recognition thresholds appear to be related to serum al k a l i n e phosphatase (r = .6756, p<.01, and r = .5994, p<.02, re s p e c t i v e l y ) . There were no s i g n i f i c a n t correlations between any of the eight thresholds measured and the average fourteen day intake of zinc, n i a c i n , copper or c a l o r i e s . The average dietary magnesium intake appeared related to sour and s a l t detection thresholds pre d i a l y s i s (r = .97, p<.001, and r = .78, p<.05, re s p e c t i v e l y ) . However, dietary magnesium intake was low (mean, 50%±19 of the CDS) and there i s no apparent reason why magnesium should a f f e c t sour and s a l t detection thresholds. DISCUSSION 5 .1 Anthropometry, , Retardation of growth i s common i n chronic renal disease and depends on many factors (see Section 1.3), some of which can be i d e n t i f i e d and corrected with r e s u l t i n g improvement in. growth. Most reports of hemodialyzed children describe severe st a t u r a l growth retardation (Betts and McGrath, 1974, Broyer et a l . , 1974, Chantler and Holliday, 1973, Counahan et a l . , 1976, and Lewy and New, 19 75). The age of onset of chronic renal i n s u f f i c i e n c y appears to a f f e c t growth performance. An onset of CRF i n infancy i s more l i k e l y to have an adverse e f f e c t on growth than i t s development i n l a t e r childhood (Betts and McGrath, 1974). The data presented i n t h i s study showed that l i n e a r growth was retarded >:1 SD from normal i n a l l subjects and >2 SD in some. This retarded growth may be due to the accumulation of certain metabolic end products that severely depress the natural sequence of growth events. Total body fat estimations were within normal l i m i t s for a l l of the children studied except one. In view of the inadequate dietary intakes of most of the subjects, s k i n f o l d measurements are not good indicators of n u t r i t i o n a l status i n uremic children. Growth had occurred i n a l l subjects, except one (R.J.) i n the year preceding the study day. Growth v e l o c i t y expressed as the per cent of that expected for e i t h e r bone age or height age appears to be a r e a l i s t i c parameter for evaluating the growth performance of uremic ch-ildren. 5.2 N u t r i t i o n a l Status The problem of undernutrition in children with CRF i s currently receiving much attention. Recent studies have empha-sized the e t i o l o g i c role which undernutrition may play i n growth retardation (Betts and McGrath, 1974, Broyer et a l . , 1974, Chantler and Holliday, 19 73, Holliday, 19 75, Lewy and New, 19 75, and West and Smith, 1956). Betts and McGrath (1974) demonstrated that the energy and protein intake of children with chronic renal i n s u f f i c i e n c y was less than that recommended for normal children of the same age or height. They found a highly s i g n i f i c a n t c o r r e l a t i o n between growth v e l o c i t y and energy intake. The authors proposed that normal growth would be expected with an energy intake of above 80% or more of the RDA, whereas cessation of growth would be predicted with an energy intake of 40% or less of the RDA. Simmons et a l . (1971) suggested that an energy i n -take greater than 6 7% of the RDA allows for better than normal li n e a r growth, and that c a l o r i c intakes below t h i s l e v e l r e s u l t in inadequate growth increments. Counahan et a l . (1976) demon-strated that t h e i r subjects had inadequate energy intakes when expressed as per cent of the RDA for CA, but when expressed as per cent of the RDA for HA were adequate. The majority of the children had experienced growth v e l o c i t i e s less than those ex-pected for t h e i r BA. These findings may indicate that nutrient intakes should be evaluated with respect to the RDA for BA (Counahan et a l . , 1976). In the present sudy the mean c a l o r i c intakes of the subjects were d r a s t i c a l l y suboptimal when expressed as per cent of the CDS for CA, BA or HA. This occurred despite the p r e s c r i p t i o n and provision of c a l o r i c supplements. The majority of the c h i l -dren had experienced l i n e a r growth increments during the year preceding the study. None of the c a l o r i c intakes met the recom-mended 80% of the RDA of Betts and McGrath (1974), and only one (C.S.) had an energy intake greater than the 67% of the RDA recommended by Simmons et a l . (1971) for uremic children. No subject had a c a l o r i e intake less than 40% of the RDA. The mean c a l o r i c intake per kilogram of body weight (mean, 31.2±5.5 k c a l / kg) was less than the recommended minimum (35 kcal/kg) (Blainey and Chamberlain, 1971), (35 kcal/kg represents approximately 65% of the RDA). Two children (CM. and C.S.), who were growing at rates appropriate f o r , or better than, that expected for t h e i r BA, had the highest c a l o r i c intakes per kilogram body weight (34.3 and 38.6 kcal/kg, respectively) (these are approximately 67% and 71% of t h e i r CDS's, re s p e c t i v e l y ) . The c h i l d (R.J.) that had experienced no increase i n height during the year pre-ceding the study, had an average intake of 22.9 kcal/kg body weight per day (this i s approximately 44% of her CDS for CA). The average protein intakes of the children were suboptimal when expressed as per cent of the CDS for CA, BA or HA, and when considered from a normal metabolism and growth point of view. However, given the mean intake of 1.09±.16 grams of protein per kilogram body weight, the high chemical score of the protein ingested (mean, 85.7±5.3) based on the reference protein of the FAO/WHO (197 3), and the constraints of the uremic state, the protein intakes described are considered adequate. Evidence exists that protein intake i s not c r i t i c a l i n l i m i t i n g the growth of uremic rats i f the protein content of the d i e t i s at a minimum adequate l e v e l (15%) and the c a l o r i c intake of the uremic rats matches that of normal (nonuremic) rats (MacDonnell et a l . , 1973) . Calor i c i n s u f f i c i e n c y has been shown a growth l i m i t i n g factor i n renal disease (Chantler et a l . , 1974). This suggests that ade-quate c a l o r i e intake i s ess e n t i a l for the optimal u t i l i z a t i o n of dietary protein i n tissue protein synthesis. In the presence of c a l o r i e i n s u f f i c i e n c y the uremic animal uses dietary or tissue protein as an energy source at the expense of growth. The c a l -o r i c cost of growth i s higher i n uremic than nonuremic rats (Chantler et a l . , 1974). Calorie supplementation by gavage accelerates growth i n uremic rats, but the accelerated growth rate i s not equal to that of normal rats (MacDonnell et a l . , 1973) These findings suggest an i n e f f i c i e n t use of c a l o r i e s for growth by the uremic animal. This i s i n t e r e s t i n g i n view of the thyroid disturbances that have been reported i n both dialyzed and non-dialyzed uremic patients, namely, low serum thyroxine and t r i -iodothyronine levels (Dandona et a l . , 1977, and Ramirez et a l . , 19 76). These thyroid hormones are reputed to have a dual action within the c e l l : they appear to have an e f f e c t on nuclear trans-c r i p t i o n concerned with growth and d i f f e r e n t i a t i o n ; and they appear to have an e f f e c t on the mitochondria concerned with energy metabolism and thermogenesis (Sterling, 1975). Both serum thyroxine and triiodothyronine concentrations decrease as renal disease progresses toward end stage renal f a i l u r e (Ramirez et a l . , 1976). Within the f i r s t six months of hemo-d i a l y s i s treatment biochemical hypothyroidism i s improved. After one year, the incidence of abnormalities of thyroid func-tion increases with the duration of hemodialysis (Dandona et a l . , 1977). This biochemical hypothyroidism could e f f e c t an i n e f f i c -ient u t i l i z a t i o n of c a l o r i e s for growth i n uremic children. Subnormal thyroid hormone concentrations are found i n children with protracted protein-calorie malnutrition (Ingenbleek and Beckers, 1975). As neither of the reports on thyroid function i n uremic individuals (Dandona et a l . , 1977, and Ramirez et a l . , 1976) gave d e t a i l s of the n u t r i t i o n a l status of the subjects studied, i t i s d i f f i c u l t to decide i f the biochemical hypothy-roidism described was primarily due to the uremic state or i n -adequate protein and c a l o r i e intakes. Hemodialysis may i n i t i a l l y improve biochemical hypothyroidism by a l l e v i a t i n g the uremic condition. However, chronic hemodialysis l i k e l y aggravates bio-chemical hypothyroidism by a prolonged leaching of thyroid hormones and iodide from the c i r c u l a t i o n . In addition, uremic patients are frequently maintained on dietary s a l t r e s t r i c t i o n s and table s a l t i s the main dietary source of iodide. Biochemical hypothyroidism, whatever the cause ( n u t r i t i o n a l or metabolic) may play an important role i n the retarded growth of children with CRF. The most l i m i t i n g amino acids of the proteins ingested by the subjects were the sulfur-containing amino acids (methionine and cystine) and threonine. Lysine, t o t a l sulfur-containing amino acids, or tryptophan are the amino acids found to be most l i m i t i n g i n most foods and diets (FAO/WHO, 1973). The finding that threonine i s the f i r s t or second l i m i t i n g acid of the children's diets i s of i n t e r e s t i n view of the r e l a t i v e l y large amounts of t h i s amino acid that are l o s t into dialysate (Section 4.4, Table XX). Evidence of a dietary imbalance of amino acids existed for a l l subjects. Phenylalanine and tyrosine levels were high when compared to the reference protein (FAO/WHO, 1973). This may be of significance i n view of the increased plasma phenylalanine to tyrosine r a t i o , and the d i r e c t l i n e a r r e l a t i o n -ship of the plasma Phe/Tyr r a t i o and the average dietary Phe/Tyr r a t i o (r = .87, p<.02) observed i n the present study. An i n -creased Phe/Tyr r a t i o has frequently been described i n CRF (Giordano et a l . , 19 75, Kopple and Swendseid, 19 75, and Young and Parsons, 1973) and this occurrence has been attributed to an im-pairment of phenylalanine hydroxylation to tyrosine (Young and Parsons, 1973). Low plasma tyrosine does not appear to stimulate hepatic phenylalanine hydroxylation. Young and Parsons (1973) found an inverse relationship between the plasma Phe/Tyr and the percentage of esse n t i a l to t o t a l amino acid nitrogen i n the plas-ma suggesting that the impairment of phenylalanine hydroxylation was related to a deficiency of es s e n t i a l amino acids. I t i s well known that protein and c a l o r i e malnourished, nonuremic children exhibit an elevated Phe/Tyr r a t i o and a markedly depressed E/N r a t i o (Arroyave et a l . , 1962). Young and Parsons (1973) showed that, i n v i t r o , uremic plasma does i n h i b i t phenylalanine hydroxy-lase. Their n u t r i t i o n a l studies of sham-operated and p a r t i a l l y nephrectomized rats fed normal (15%) or low (8%) protein diets showed that rats with a moderate degree of renal i n s u f f i c i e n c y fed normal diets had normal plasma tyrosine concentrations and normal l i v e r hydroxylase a c t i v i t y . However, when protein intake was decreased below that required for growth, plasma tyrosine f a l l s as a consequence of decreased synthesis of the hydroxylase enzyme. They concluded that, although some degree of enzyme i n a c t i v a t i o n or i n h i b i t i o n i n severe uremia c o u l d not be e n t i r e l y excluded, d i e t a r y p r o t e i n l e v e l s p l a y an important r o l e i n the plasma Phe/Tyr r a t i o o f CRF (Young and Parsons, 1973). The p r e s -ent study agrees w i t h these f i n d i n g s . Plasma Phe/Tyr r a t i o s were e l e v a t e d and plasma E/N r a t i o s were reduced i n the s u b j e c t s s t u d i e d . A l l c h i l d r e n were i n g e s t i n g inadequate amounts o f pro-t e i n as given by the CDS f o r CA, BA and HA. The high chemical score (mean, 85.7±5.3) when compared to the chemical score o f 76 f o r the t y p i c a l Canadian d i e t ( D i e t a r y Standard f o r Canada, 1975) i s due to a high e r percentage o f e s s e n t i a l amino a c i d s p r e s e n t . A p r o p o r t i o n a l decrease i n n o n e s s e n t i a l amino a c i d s may i n d i c a t e t h a t when t o t a l p r o t e i n i n t a k e i s low, t o t a l t y r o s i n e i n t a k e may be inadequate. T h i s may f u r t h e r aggravate the e l e v a t e d Phe/Tyr r a t i o o f uremia and may suggest t h a t a balance of e s s e n t i a l and • n o n e s s e n t i a l amino a c i d s i n the d i e t s o f p a t i e n t s w i t h CRF i s i n -d i c a t e d . In the pr e s e n t study, the i n t a k e s o f the f a t s o l u b l e v i t a m i n s Vitamin C, thiamin and f o l a t e were adequate, i n most cases. D e f i c i e n c i e s o f c e r t a i n water s o l u b l e v i t a m i n s ( r i b o f l a v i n , n i a c i n , and pyr i d o x i n e ) e x i s t e d f o r some i n d i v i d u a l s . The c h i l d (R.J.) t h a t had experienced no l i n e a r increment d u r i n g the year p r e c e d i n g the study was d e f i c i e n t i n d i e t a r y n i a c i n , r i b o f l a v i n and thiamin, and r e c e i v e d no supplements of p y r i d o x i n e , f o l a t e or cobolamin. The c h i l d (CM.) t h a t experienced the l a r g e s t l i n e a r increment d u r i n g the year p r e c e d i n g the study had been p r e s c r i b e d a supplement t h a t was very high i n a l l o f the water s o l u b l e v i t a m i n s . Both o f these c h i l d r e n (R.J. and CM.) had suboptimal c a l o r i e , p r o t e i n and Vi t a m i n A i n t a k e s . These f i n d i n g s suggest t h a t water s o l u b l e vitamin nutriture i s of importance i n uremic children undergoing maintenance d i a l y s i s . The losses of water soluble vitamins into dialysate may be quite substantial. The dietary intakes of calcium, phosphorous, zinc, magnesium and copper were alarmingly suboptimal, approximately one-half the CDA i n most cases. One c h i l d (CS.) had adequate dietary magnes-ium and another (G.C.) had adequate dietary copper. Mineral supplements are not routinely prescribed for uremic patients. The low mineral intakes of the subjects, possibly aggravated by los s -es into dialysate, may be additional factors i n p r e c i p i t a t i n g t h e i r retarded growth. Mineral supplements may be indicated for uremic children undergoing maintenance d i a l y s i s . 5 . 3 Plasma /Amino Acids The s c i e n t i f i c l i t e r a t u r e contains many c o n f l i c t i n g reports concerning the plasma amino acid a l t e r a t i o n s with CRF. These documented discrepancies are caused by a number of factors i n -cluding: the age and sex of the subjects; the l e v e l of dietary protein; the time of sampling aft e r the l a s t meal; the type of amino acid analyzer employed; the d a i l y diurnal variations of amino acids; the uremic state; and the presence of d i a l y s i s (Armstrong and Stave, 197 3 I ) . One of the objectives of the present study was to minimize the number of these factors present and thereby obtain a more accurate p r o f i l e of plasma amino acid alterations i n uremic patients. A l l of the study participants had bone ages within the six to eighteen years old group, con-sumed an average 43.7 grams of protein d a i l y (range 28.8 to 52.4 grams protein per day) , were undergoing maintenance hemodialysis and had observed a 48 hour i n t e r d i a l y t i c p e r i o d a t the time o f the pre d i a l y s i s blood sampling. A standard f i v e hour f a s t was observed p r i o r t o a l l b l o o d sampling s e s s i o n s . Armstrong and Stave (1973 I) presented evidence t h a t a f a s t o f i n s u f f i c i e n t d u r a t i o n i s demonstrated by e l e v a t i o n s o f plasma methionine, v a l i n e , l e u c i n e , i s o l e u c i n e , p h e n y l a l a n i n e and l y s i n e when com-pared to those c o n c e n t r a t i o n s p r e s e n t a f t e r a base l i n e t e n and one- h a l f hour f a s t . A f a s t of too long a d u r a t i o n i s diagnosed by e l e v a t i o n s of t a u r i n e , glutamic a c i d and c y s t i n e , and depres-s i o n s o f oth e r amino a c i d s t o 78%-98% of i n i t i a l base l i n e v alues (Armstrong and Stave, 1973 I ) . In the p r e s e n t study, plasma methionine, v a l i n e , l e u c i n e , i s o l e u c i n e , p h e n y l a l a n i n e and l y s i n e c o n c e n t r a t i o n s were w i t h i n normal l i m i t s or decreased when compared to normal l e v e l s found i n c h i l d r e n ages s i x through e i g h t e e n (Armstrong and Stave, 1973 I I ) . Taurine and c y s t i n e c o n c e n t r a t i o n s were decreased from normal i n the plasma of the s u b j e c t s s t u d i e d , and glutamic a c i d l e v e l s were w i t h i n normal l i m i t s when compared to normal c h i l d r e n of the same age group. The evidence presented here i n d i c a t e d t h a t the standard f i v e hour f a s t , p r i o r to b l o o d sampling f o r plasma amino a c i d s , was o f an a p p r o p r i a t e d u r a t i o n . Under the c o n d i t i o n s o f the study, pre d i a l y s i s plasma con-c e n t r a t i o n s of t a u r i n e , a-amino-butyric a c i d , v a l i n e , c y s t i n e , l e u c i n e , t y r o s i n e and tryptophan were decreased, and a s p a r t i c ac p r o l i n e , g l y c i n e , c i t r u l l i n e , o r n i t h i n e , h i s t i d i n e , asparagine and a r g i n i n e were i n c r e a s e d when compared to normal. The remain i n g amino a c i d s were prese n t w i t h i n normal l i m i t s (Armstrong and Stave, 19 73 I I ) . Post d i a l y s i s plasma c o n c e n t r a t i o n s o f t a u r i n e a-amino-butyric acid, valine, cystine, leucine, tyrosine, trypto-phan, threonine, serine, methionine, alanine, lysine and arginine were decreased, and only aspartic acid, asparagine, c i t r u l l i n e and glycine remained s i g n i f i c a n t l y elevated. The E/N and Val/Gly r a t i o were found decreased and the Phe/Tyr r a t i o increased. These plasma alterations are highly i n d i c a t i v e of p r o t e i n - c a l o r i e malnutrition (Arroyave et a l . , 1962, and Kopple and Swendseid, 1975). In addition, 3-methylhistidine, an amino acid not present i n normal plasma, was detected i n considerable amounts (mean, 0.024±.02 micromoles per m i l l i l i t e r ) , pre d i a l y s i s . The presence of t h i s amino acid i s i n d i c a t i v e of tissue protein catabolism. S i m i l a r l y hydroxyproline was detected in the pre d i a l y s i s plasma of the uremic children (mean, 0.082±0.128 micromoles per. m i l l i -l i t e r ) and, again, the presence of t h i s amino a c i d . i s explained by protein catabolism and i t s consequent release from ca r t i l a g e and bone matrix. The results of the present study d i f f e r s i g n i f i c a n t l y from those reported by Counahan et a l . (19 76) who also studied plasma amino acids i n children on hemodialysis. Their subjects had a wide range (18-132 grams per day) of protein intakes, a variable 24 to 48 hour i n t e r d i a l y t i c period p r i o r to the study, and observed a fast of fourteen or more hours before blood sampling. These investigators did not report plasma taurine and glutamic acid concentrations, but found that plasma cystine was within normal l i m i t s . These authors showed s i g n i f i c a n t l y decreased concentrations of leucine (<.025), isoleucine (<.0005), meth-ionine (<.0005), phenylalanine (<.005), h i s t i d i n e (<.0005), c i t r u l l i n e (<.05), tyrosine (<.005), ornithine (<.05) and 89. arginine (<.005) when compared to normal (Armstrong and Stave, 1973 I I ) . In view of t h i s , a nonstandardized f a s t of too long duration may have influenced, and possibly invalidated, the re-sults they obtained. Condon and Astoor (19 71) maintained t h e i r subjects on a 25 gram protein d i e t and fasted them overnight be-fore blood sampling for plasma amino acid concentrations. They reported elevated plasma cystine, glutamic acid, aspartic acid, arginine, 3-methylhistidine and "possibly taurine". Plasma con-centrations of a l l other amino acids were found to be moderately decreased or normal. None of these patients had been dialyzed. Again, there i s strong evidence that a fa s t of too long a duration influenced t h e i r r e s u l t s . Rubini and Gordon (1968) obtained three hour post prandial venous blood samples from normal control sub-jects, from nondialyzed uremic patients and from patients under-going maintenance hemodialysis. The plasma free amino acid con-centrations i n nondialyzed uremics were similar to those i n chronically dialyzed patients at the beginning of d i a l y s i s . Several amino acids appeared somewhat reduced below normal; (ala-nine, valine and leucine); conversely, glycine, cystine, ornithine and h i s t i d i n e were somewhat increased above normal. The authors stated that due to a wide range of values i n normal individuals and the large v a r i a t i o n i n i n d i v i d u a l patients i n both dialyzed and nondialyzed groups, these differences were not s i g n i f i c a n t (Rubini and Gordon, 1968) . These nonconclusive findings are l i k e -l y a t tributable to the inadequate fas t of three hours observed by th e i r subjects. Young and Parsons (1975, 1970, 1973) did not report the length of fast p r i o r to blood sampling for plasma amino acid l e v e l s i n normal ind i v i d u a l s , and p e r i t o n e a l l y dialyzed and hemodialyzed patients. If the length of fas t was the same for a l l of t h e i r subjects t h e i r r e s u l t s are l i k e l y meaningful, how-ever comparison with the present study i s not indicated. Kopple and Swendseid (1974) had t h e i r nondialyzed c h r o n i c a l l y uremic subjects observe a twelve hour fas t p r i o r to blood sampling and appeared to have raised cystine and glutamic acid concentrations. Again, i t i s d i f f i c u l t to j u s t i f y comparing the r e s u l t s of the present study with the plasma amino acid l e v e l s of the Kopple and Swendseid (1974) study. In conclusion, the length of fast p r i o r to blood samples may be the major reason for the c o n f l i c t i n g re-ports on plasma amino acid concentrations i n patients with CRF. The elevation of plasma c i t r u l l i n e i n uremic rats i s l i k e l y due to decreased conversion of t h i s compound to arginine by remnant kidney tissue (Swendseid et a l . , 1975). There i s e v i -dence that the arginine produced by the kidney i s a major source of the arginine u t i l i z e d for protein synthesis by tissues other than the l i v e r (Featherston et a l . , 1973). Uremic rats fed an 18% protein d i e t devoid of arginine demonstrate decreased plasma and muscle c i t r u l l i n e concentrations, normal plasma arginine l e v e l s , decreased plasma urea concentrations and elevated kidney arginine synthetase a c t i v i t y (the enzyme which converts c i t r u l -l i n e to arginine) when compared to normal and uremic rats fed an 18% casein d i e t (Swendseid et a l . , 1975). A number of uremic toxins (such as the quanidines and some amines) arise d i r e c t l y from the urea cycle and i t may be possible to reduce t h e i r pro-duction by decreasing the urea cycle a c t i v i t y through the elim-ination of dietary arginine. However, nephrectomized patients or those patients with severely damaged kidney tissue might not be able to compensate for the lack of dietary arginine by i n -creasing kidney arginine synthetase a c t i v i t y . These individuals would have an absolute requirement for exogenous arginine (Swend-seid et a l . , 1975) . These findings are consistent with the present r e s u l t s , i n that plasma c i t r u l l i n e concentration was d i r e c t l y related to the average chemical score (protein quality) over a fourteen day period. There was an inverse rel a t i o n s h i p between the average chemical scores and plasma creatinine, arginine, ornithine and urea concentrations. In the present study pre d i a l y s i s plasma concentrations of c i t r u l l i n e and arginine were elevated above normal. Post d i a l y s i s , plasma c i t r u l l i n e remained elevated, but arginine was decreased when compared to normal values. Similar amounts of c i t r u l l i n e and arginine were detected i n the dialysate at the termination of d i a l y s i s (means, .003±.002 micromoles per m i l l i l i t e r and .005+ .0004 micromoles per m i l l i l e t e r , r e s p e c t i v e l y ) . In view of the magnitude of the decrease i n the mean plasma arginine concentra-t i o n pre and post d i a l y s i s , and the r e l a t i v e l y small mean amount l o s t into dialysate, i t might be proposed that as d i a l y s i s pro-gresses and uremia improves arginine i s made available for tissue uptake i n protein synthesis. The inverse r e l a t i o n s h i p between plasma c i t r u l l i n e concentrations and dietary c a l o r i e s may i n d i -cate a more e f f i c i e n t use of c i t r u l l i n e for arginine and hence protein synthesis with increasing c a l o r i c intake. The uremic state s i g n i f i c a n t l y affects the plasma Val/Gly r a t i o as shown by the d i r e c t r e l a t i o n s h i p between plasma glycine and urea l e v e l s , and the inverse rel a t i o n s h i p between the plasma Val/Gly r a t i o s and urea concentrations. The reason for the apparently strong p o s i t i v e c o r r e l a t i o n between plasma 3-methylhistidine l e v e l and protein, f a t , carbohydrate and c a l o r i e intakes i s not known. 5.4 Losses of Amino Acids into Dialysate The quantitative losses of amino acids into dialysate aver-aged 4.7 grams in the present study. This agrees with other reports that show three to eight grams of amino acids l o s t per d i a l y s i s (Kopple et a l . , 1973). In contrast to the findings of Kopple et a l . (1973) who stated approximately one-third of the amino acids l o s t into dialysate were e s s e n t i a l , t h i s study found the proportion to be higher, namely, one-half of the t o t a l amino acids l o s t . Aviram et a l . (1971) reported the e s s e n t i a l amino acids l o s t into hemodialysate i n the largest amounts were valine, l y s i n e , threonine, phenylalanine and methionine. Later research showed the most abundant free amino acids i n hemodialysate to be asparagine, glutamine and glycine (Kopple et a l . , 1973). The present study o f f e r s d i f f e r e n t findings. The e s s e n t i a l amino acids l o s t i n the greatest amounts during hemodialysis were h i s t i d i n e , threonine, l y s i n e , phenylalanine and valine. The h i s t i d i n e losses were exceedingly large, namely, an average of 1.24 grams d a i l y . H i stidine has been shown to be. an e s s e n t i a l amino acid i n normal and c h r o n i c a l l y uremic man (Kopple and Swendseid, 1975). The c l i n i c a l symptoms of h i s t i d i n e deficiency are fatigue and lack of energy; anorexia and nausea; a sense of depression, sadness and i r r i t a b i l i t y ; loss of memory for recent events and decreased a b i l i t y to think c l e a r l y ; dry, scaly skin eruption and f a i l u r e of normal erythropoesis (Kopple and Swend-seid, 1975). A l l of these symptoms are commonly reported i n uremic patients. In view of the large losses of h i s t i d i n e into dialysate, the dietary h i s t i d i n e requirement for uremics may be much higher than for normal i n d i v i d u a l s . The presence of a dietary e s s e n t i a l amino acid deficiency markedly retards growth in young rats (Munro, 1964). It i s i n t e r e s t i n g that threonine was the es s e n t i a l amino acid l o s t i n the second greatest amounts. As reported e a r l i e r , threonine i s the f i r s t or second, l i m i t i n g amino acid i n the.diets of the study p a r t i c i p a n t s . Hemodialysis may aggravate the threonine status of these uremic children and the p o s s i b i l i t y of a threonine deficiency may exist. A s i m i l a r s i t u a t i o n may e x i s t for the sulfur-containing amino acid, methionine. The nonessential amino acids l o s t i n the. greatest amounts into hemodialysate in the present study were glycine, alanine and glutamic acid. On comparing the quantitative losses of amino acids i n t h i s study with those of Kopple et a l . (1973), the present study showsrgEea.tero'lossesfofhphen^larl.anine, h i s t i d i n e , aspartic acid, glutamic acid, glycine, ornithine, arginine ( a l l with p<.0005), threonine, tyrosine, serine ( a l l with p<.005), lysin e (p<.01), alanine (p<.025), isoleucine and leucine (both' with p<.05). These differences are l i k e l y due to the fact that the subjects i n the present study were permitted to eat on d i a l -y s i s and those i n the Kopple et a l . (19 73) study were not. In some cases hemodialysis corrects elevated plasma amino acid levels by decreasing them to within normal l i m i t s (for example, h i s t i d i n e , p r o l i n e and ornithine). In other instances hemodial-ysi s depresses^plasma amino acid l e v e l s to less than normal concentrations (for example, threonine, serine, methionine, alanine, lysine and arginine). Hemodialysis aggravates the plasma E/N r a t i o by further decreasing i t from normal and im-proves the Val/Gly and Phe/Tyr r a t i o s by increasing them toward normal values. 5.5 Hypogeusia and Disgeusia i n Uremia The sense of taste i s unique among the chemical senses i n that the discrete receptor organs (taste buds) are of nonneural derivation. Taste receptors respond to substances dissolved i n the o r a l f l u i d s bathing them, but the mechanism by which the molecules i n solution i n t e r a c t with the receptor c e l l s i s not well known. There i s evidence that the taste producing sub-stances act on the membranes of the receptor c e l l s , or t h e i r processes, by one of two mechanisms: a. The f i r s t theory of taste perceptions i s based on the hypo-thesis that the receptor hairs ( m i c r o v i l l i ) have a polyelectro-lyt e surface f i l m . The binding of ions to t h i s f i l m causes a d i s t o r t i o n i n the s p a t i a l arrangement of the f i l m with a conse-quent change i n the d i s t r i b u t i o n of charge energy interpreted nervously (Ganong, 19 75) . This theory can be rea d i l y applied to sensations of sour and s a l t , as the compounds that e l i c i t these sensations e x i s t i n solution as ions. The ammonia taste of uremia i s usually as-cribed to elevated s a l i v a NH 3 + from the increased concentration of urea i n gastric juice that i s metabolized by urease present i n the stomach (Snapper, 1967). I t may be expected that post d i a l y s i s the s a l i v a ammonia concentration i s lower, and, as more s a l t and sour binding s i t e s are free, the thresholds for these two modalities would be lower. b. The second theory of taste perception i s based on the hypo-thesis that the taste provoking molecules bind to s p e c i f i c pro-teins i n the taste buds (Guyton, 1976). These proteins are plasma membrane bound and have a cati o n i c charge. Apparently, the binding of sweet (or b i t t e r ) taste producing molecules causes a conformational change i n the protein which i s propor-t i o n a l to the sweetness (or bitterness) of the compound, and, again, interpreted nervously (Dastoli, 1974). There i s no one common feature of the molecular structures of substances that evoke a b i t t e r taste. The presence of amine groups i s perceived as b i t t e r (Strother, 1974). Sweet and b i t t e r sensing proteins may l i e i n close proximity and sweet sensitive proteins can bind b i t t e r t a s t i n g compounds (Birch and Mylvaga-nam, 1976). Therefore, urea would p r e f e r e n t i a l l y bind to a b i t t e r sensing protein, but i n the case of excess amounts urea could also be received by a. sweet sensing protein. The binding of urea by the receptor proteins would make them unavailable to other b i t t e r or sweet stimulating compounds. The presence of abnormally high concentrations of metabolic end products i n blood and/or s a l i v a i s l i k e l y the prime factor responsible for the hypogeusia described i n the present study. B i t t e r and sweet recognition s e n s i t i v i t i e s are impaired pre d i a l -y s i s (p<.01) and, although improved post d i a l y s i s (p<.005), do not reach normal values as reported i n the l i t e r a t u r e (Appendix H). B i t t e r detection thresholds are within normal l i m i t s , before and after d i a l y s i s , but correlate strongly with blood urea nitrogen and s a l i v a urea concentrations. Sweet recognition thresholds also appear related to blood urea l e v e l s . The decrease of c i r c u l a t i n g urea by d i a l y s i s must free some protein receptor s i t e s making them available to taste producing s t i m u l i , and thereby lowering the b i t t e r and sweet thresholds. Perhaps the magnitude o f blood urea concentration change was not great enough or blood and s a l i v a urea concentrations had not equilibrated to bring these thres-holds down to normal, or perhaps other factors were instrumental i n p r e c i p i t a t i n g the p e r s i s t e n t l y elevated thresholds. The pro-t e i n receptor theory i s further supported by the fact that neither s a l t nor sour thresholds correlated with either blood or s a l i v a urea concentrations. The removal of ammonia (which binds to s a l t and sour receptors) by d i a l y s i s may also account for the improved sour and s a l t detection and thresholds observed post d i a l y s i s . The presence of endocrine disturbances may have influenced taste perception in. the individuals studied. Patients with PHP exhibit increased thresholds for sour and b i t t e r , although thres-holds for s a l t and sweet are within normal l i m i t s (Henkin, 1967). Trefz (1972) demonstrated a high concentration of a l k a l i n e phos-phatase i n the b i t t e r sensitive taste buds of adult rhesus mon-keys. B i t t e r recognition was impaired i n the present study, but no r e l a t i o n s h i p existed between serum al k a l i n e phosphatase leve l s and b i t t e r thresholds (the surrounding f l u i d urea concentrations are l i k e l y the more i n f l u e n t i a l i n the a l t e r i n g of b i t t e r sensi-t i v i t y ) . The presence of secondary;hyperparathyroidism may indeed be a factor i n the altered taste acuity of these in d i v i d u a l s , as sour recognition thresholds correlated with serum al k a l i n e phos-phatase levels (p<.01), and the mean s a l t and sweet detection thresholds and the mean s a l t recognition threshold were within normal l i m i t s . The loss of C o r t i s o l into dialysate may be expected to be considerable i n patients with elevated plasma C o r t i s o l levels since transcortin binding capacity i s saturated at about 20 ug of 97. C o r t i s o l per 100 ml and normal d a i l y p r o d u c t i o n i s about 10,000 jig (Bondy, 1974). The s i g n i f i c a n t improvement i n sweet, s a l t and sour d e t e c t i o n t h r e s h o l d s p o s t d i a l y s i s compared to normal may be r e l a t e d to the l o s s o f carbohydrate a c t i v e s t e r o i d s d u r i n g d i a l y s i s , i n a d d i t i o n to the decreased s a l i v a urea and ammonia c o n c e n t r a t i o n s . Sweet and s a l t r e c o g n i t i o n t h r e s h o l d s are impaired pre d i a l -y s i s , as i s sweet r e c o g n i t i o n p o s t d i a l y s i s . These a b n o r m a l i t i e s may be r e l a t e d t o the prolonged e l e v a t e d i n s u l i n l e v e l s commonly found i n uremics (Feldman and S i n g e r , 19 74). A decrease i n sweet and sour s e n s i t i v i t y has been observed i n d i a b e t i c p a t i e n t s (Weiss Valbranca and Pascucc, 1965) and c o r r e l a t e d w i t h the prolonged use of i n s u l i n (Fogan, 1971). The e x i s t e n c e of c e r t a i n n u t r i t i o n a l d e f i c i e n c i e s and medica-t i o n regimes may be a d d i t i o n a l f a c t o r s i n the d i s g e u s i a d e s c r i b e d . L e v e l s of d i e t a r y z i n c and n i a c i n were suboptimal i n the m a j o r i t y of the s u b j e c t s . A l l of the c h i l d r e n had been p r e s c r i b e d one or more of the f o l l o w i n g drugs a t some time: intravenous i r o n , po-tassium removing i o n exchange r e s i n s , a n t i m i c r o b i a l agents, a n t i -h i s t a m i n e s , a n t i e p i l e p t i c s , s e d a t i v e s and/or v i t a m i n s . A l l of these medications are known to a f f e c t t a s t e s e n s i t i v i t y to some degree ( S t r o t h e r , 19 74). The l o s s o f t a s t e a c u i t y may be i n v o l v e d i n the decreased c a l o r i c i n t a k e s observed i n c h i l d r e n undergoing maintenance d i a l -y s i s . As.shown by p o s t d i a l y s i s improvement, t a s t e s e n s i t i v i t y a l t e r a t i o n s may be due to the accumulation of metabolic end pro-ducts d u r i n g the i n t e r d i a l y t i c p e r i o d . Zinc and n i a c i n d e f i c i -e n c i e s , drug t h e r a p i e s and endocrine imbalances may be a d d i t i o n a l f a c t o r s i n the d i s g e u s i a d e s c r i b e d . CONCLUSIONS 1. Growth i s retarded i n children with CRF and may be due to the accumulation of metabolic end products. These abnormal metabolites depress appetite and/or delay the natural rate of growth events. 2. Calorie deficiency plays a major role i n the growth f a i l u r e of uremic children. C a l o r i c i n s u f f i c i e n c y r e s u l t s i n the use of dietary and tissue protein as an energy source at the expense of growth. A syndrome of prote i n - c a l o r i e malnutrition (PCM) i s present i n children with CRF as evidenced by depressed E/N and Val/Gly r a t i o s , elevated Phe/Tyr r a t i o and biochemical hypo-thyroidism. 3. Dietary imbalances of ce r t a i n amino acids depress food i n -take and growth rate. Dietary Phe/Tyr r a t i o s were elevated as compared to the reference protein of the FAO/WHO and d i r e c t l y related to the plasma Phe/Tyr r a t i o s which were elevated above normal. A dietary imbalance of phenylalanine and tyrosine may be a factor i n the observed growth f a i l u r e . 4. Dietary d e f i c i e n c i e s of certa i n e s s e n t i a l amino acids may undesirably a f f e c t growth performance. Inadequate quantities of these constituents at the si t e s of protein synthesis delay the growth process. Sulfur-containing amino acids and threonine were the f i r s t and second l i m i t i n g amino acids of the diets studied. A d d i t i o n a l l y , the amino acids l o s t i n the largest amounts into dialysate were h i s t i d i n e and threonine. A dietary deficiency of threonine and a dietary inadequacy (in view of losses) of h i s t i d i n e , may be a factor i n the growth f a i l u r e described. 5. D i e t a r y d e f i c i e n c i e s o f water s o l u b l e v i t a m i n s may be a d d i -t i o n a l f a c t o r s i n the growth r e t a r d a t i o n o f c h i l d r e n undergoing maintenance d i a l y s i s . 6. Plasma amino a c i d c o n c e n t r a t i o n s should be determined a f t e r a f a s t t h a t i s a minimum of f i v e hours and a maximum of el e v e n hours. 7. In uremia pre d i a l y s i s , the f o l l o w i n g plasma amino a c i d s are s i g n i f i c a n t l y decreased below normal, t a u r i n e , a-amino-butyri a c i d , v a l i n e , c y s t i n e , l e u c i n e , t y r o s i n e and tryptophan. Under the same c o n d i t i o n s , a s p a r t i c a c i d , p r o l i n e , g l y c i n e , c i t r u l l i n e , o r n i t h i n e , h i s t i d i n e , a r g i n i n e , asparagine, 3 - m e t h y l h i s t i d i n e and hy d r o x y p r o l i n e are s i g n i f i c a n t l y e l e v a t e d above normal v a l u e s . The d e t e c t i o n of 3 - m e t h y l h i s t i d i n e and h y d r o x y p r o l i n e i n plasma s i g n i f i e s the breakdown of t i s s u e p r o t e i n s and i s a f u r t h e r i n -d i c a t i o n o f PCM. Abnormal plasma amino a c i d c o n c e n t r a t i o n s depress a p p e t i t e and slow growth r a t e i n r a t s . The plasma amino a c i d a l t e r a t i o n s d e s c r i b e d may be important f a c t o r s i n the growth f a i l u r e of c h i l d r e n w i t h CRF. 8. In uremia post d i a l y s i s , the f o l l o w i n g plasma amino a c i d s are s i g n i f i c a n t l y decreased below normal, t a u r i n e , a-amino-butyri a c i d , v a l i n e , c y s t i n e , l e u c i n e , t y r o s i n e , tryptophan, t h r e o n i n e , s e r i n e , methionine, a l a n i n e , l y s i n e and a r g i n i n e . A s p a r t i c a c i d , asparagine, c i t r u l l i n e and g l y c i n e are the o n l y plasma amino a c i d s t h a t remain s i g n i f i c a n t l y e l e v a t e d above normal post d i a l y -s i s . Inadequate c o n c e n t r a t i o n s o f amino a c i d s a t the s i t e s o f p r o t e i n s y n t h e s i s delay the growth p r o c e s s . A d i e t a r y supplement of threonine may be i n d i c a t e d f o r these uremic c h i l d r e n i n view of the decreased plasma c o n c e n t r a t i o n s post d i a l y s i s , the l a r g e 100. losses during d i a l y s i s and the f a c t that threonine i s a f i r s t or second l i m i t i n g amino acid i n t h e i r d i e t s . Low plasma arginine concentrations and a decreased conversion of c i t r u l l i n e to arginine by kidney tissue may indicate that exogenous arginine i s also required by uremic i n d i v i d u a l s . 9. The importance of adequate dietary c a l o r i e s for optimal protein anabolism i s emphasized by the inverse r e l a t i o n s h i p be-tween plasma c i t r u l l i n e concentration and c a l o r i c intake. With increasing c a l o r i c intake the conversion of c i t r u l l i n e to arginine appears to be more e f f i c i e n t . 10. An average of 4.7 grams of amino acids were l o s t into dialysate. The major losses of e s s e n t i a l amino acids were h i s t i d i n e , threonine, l y s i n e , phenylalanine and v a l i n e . Exogenous h i s t i d i n e supplementation may be indicated i n uremics undergoing regular d i a l y s i s treatments. D i a l y s i s aggravates PCM by further reducing the plasma E/N r a t i o and by leaching c a l o r i f i c sub-stances (glucose and amino acids) from body c i r c u l a t i o n . 11. The decreased taste s e n s i t i v i t y of uremic children may be a factor p r e c i p i t a t i n g t h e i r low c a l o r i c intakes. B i t t e r and sweet recognition thresholds are impaired pre and post d i a l y s i s . B i t t e r detection thresholds correlate strongly with blood urea nitrogen and s a l i v a urea concentrations. The presence of i n -creased amounts of ammonia i n s a l i v a may a f f e c t s a l t and sour thresholds. 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Plasma amino acid pattern of chicks i n r e l a t i o n to length of feeding period. J . Nutr. 91:503-506. APPENDIX A. Consent Form THE ROLE OF NUTRITION IN GROWTH FAILURE IN PATIENTS WITH CHRONIC RENAL FAILURE I, have been informed of the (name) purpose of t h i s study, which i s an attempt to determine what n u t r i t i o n a l factors are important i n promoting s a t i s f a c t o r y growth i n renal f a i l u r e . I agree to p a r t i c i p a t e i n t h i s research project with the understanding that I may withdraw at any time at my request without fear that such a withdrawal might jeopardize my expectations for continued conventional management of my condition. I have also been assured that any information obtained from me w i l l be handled c o n f i d e n t i a l l y at a l l times. Witness Patient Date Witness Patient Date 2. A sample " A c t i v i t y Record Sheet" follows to show you how to keep these records. 3. Please bring these sheets with you to the h o s p i t a l on your Study Day COLLECTION OF FOOD SAMPLES 1. You have been given one food bucket f o r c o l l e c t i n g your food sample on ; . 2. On t h i s day place a duplicate sample of what you eat on that day i n the appropriate bucket and freeze i t . For example, i f you eat 1/2 a grape-f r u i t f o r breakfast, take the sections out of the other 1/2 g r a p e f r u i t and put them i n the freezer bucket. 3. Please bring the food bucket with you to the h o s p i t a l on your Study Day 4. You w i l l be given f i v e d o l l a r s ($5.00) f o r the food you c o l l e c t . In conclusion, you w i l l bring with you to the h o s p i t a l on the following: 1. f i r s t - 7 day -food intake record 2. a c t i v i t y record sheets 3. food bucket containing the frozen food sample. Thank you f o r your cooperation. APPENDIX D. Sample Calendar Describing Study Period Name SUNDAY MONDAY TUESDAY WEDNESDAY THURSDAY FRIDAY SATURDAY 1 2 3 4 b 6 7 8 9 Begin 1st Dietary Record at breakfast 10 A c t i v i t y Record 11 12 13 A c t i v i t y Record 14 A c t i v i t y Record 15 C o l l e c t food sample i n bucket (from breakfast today to snack tomorrow morning) End 1st Diet.Rec. 16 4:30 a.m. snack. Begin 2nd Dietary Record Study Day 17 18 19 20 21 22 End 2nd Dietary Record 23 24 25 26 27 28 29 30 31 118. APPENDIX E. Sample Food Intake Record Sheet Date FOOD INTAKE RECORD SHEET Name TIME FOOD ITEM AMOUNT DO NOT WRITE IN THIS SPACE BREAKFAST A.M. LUNCH P.M. DINNER H.S. 119. APPENDIX F. Sample A c t i v i t y Record Sheet ACTIVITY RECORD SHEET Name Date ACTIVITY LENGTH OF TIME 120. APPENDIX G. Sample Taste T e s t i n g Response Sheet Name TASTE TESTING Date_ Age Time Please answer the f o l l o w i n g q u e s t i o n s b e f o r e you begin t a s t i n g the s o l u t i o n s . 1. Do you have a c o l d ? yes no 2. Do you f e e l i l l ? yes no 3 . Do you smoke? yes no I f yes, how many c i g a r e t t e s per day? I f yes, have you smoked w i t h i n the l a s t h a l f hour? 4. Do you f e e l r e s t e d ? yes no 5. Have you eaten any s p i c y foods yesterday or today? yes no 6. At what time d i d you l a s t have something to eat or d r i n k (except f o r water)? In each p a i r of samples b e f o r e you ( f o r example, IL and IR) one i s water, p l a c e a check ( v / ) i n the space p r o v i d e d f o r the sample which i s not water. I f you can t e l l what the t a s t e i s (for example, sweet, s a l t , sour, or b i t t e r ) w r i t e i t i n the blank to the r i g h t under the word " t a s t e " . SERIES 1,2,3, or 4 L R Taste 1 2 3 4 5 6 7 8 9 10 11 12 APPENDIX H. Normal Taste Thresholds for Sweet (Sucrose), Sour (Hydrochloric Acid), Salt (Sodium Chloride) and B i t t e r (Quinine Sulfate) Reported i n the Literature Sucrose Hydrochloric Acid Sodium Chloride Quinine Sulfate Reference D a Rb D R D R D R .34 .58 .0033 - .058 .175 - - Pffaffman, C. (1967) .41 1.03 .01 .02 .07 .175 - - Henkin, R.I. (1971) .275 .540 .0012 .0022 .032 .071 .000176 .000321 Cooper, R.M. (1959) .56 1.30 .002 .0028 .064 .288 - - Fabian, F.W. (1942) - .75 - - - .127 - - Knowles, D. (1937) - .68 - - - ..234 - - Parker, G.H. (1922) - - - - - .292 - - Blakeslee, A.F. (1931) - .68 - - - .175 - - Crocker, E.C. (1932) - .45 - - - .117 - - King, F. (1937) .34 - .0036 - .117 - - - Ganong, w.F. (1975) .50 - - - - - - - Bailey, E.H.S. (1888) .31 - - - - - - - Berg, H.W.F. (1955) .35 - - - .089 - ' - - Schutz, H.C. (1957) .017 .274 - - - - - - Pangborn, R.M. (1959) .017 .274 - - - - - - Pangborn, R.M. (1963) - - - - - .044 - - Mosel, J.N. (1952) - - - - .016 .087 - - Richter, C P . (1939) .35 .35 - - .065 .160 - - Kelty, M.F. (1971) .41 . - .0015 - .009 - .,000235 - Fischer, R. (1965) ...3233 .628 .0036 .0083 .0577 .162 .0002 .000321 Mean ± Standard ±.1636 ±.317 ±.0033 ±.0101 ±.0345 ±.0795 .00004 ±.0001 Deviation D-detection threshold R-recognition threshold 

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