Nephron 14: 134-152(1975)

Protein Metabolism in Uraemia P eter R ich ar ds St. George’s Hospital and Medical School, Hyde Park Corner, London

Abstract. Protein metabolism in uraemia is reviewed. Very few, Key Words if any, disorders of amino acid metabolism can at present confi­ Protein metabolism dently be attributed to uraemia per se rather than to protein/ Uraemia energy deprivation. Retained urea nitrogen is recycled to the liver Nitrogen reutilization as ammonia; a proportion is reutilized for synthesis of non-essen­ Essential amino acids tial amino acids and, if their carbon skeletons are supplied, for synthesis of essential amino acids. Practical applications of the reutilization of non-amino nitrogen in advanced chronic renal failure are being explored. Nevertheless, uraemic individuals readily become undernourished, and they should receive as much protein as their symptoms will permit.

Introduction Although many minutiae of protein metabolism are known, we know little about the coordination and integration o f these details. Thus, it is not sur­ prising that knowledge o f protein metabolism in uraemia is very incomplete. This review will first consider the few respects in which amino acid metabolism has been found to be disturbed in chronic renal failure. Later the recycling of non-amino nitrogen retained in renal failure will be described, and the extent to which this recycled nitrogen might be reutilized to replace dietary nitrogen will be discussed.

Not only is knowledge of protein metabolism in uraemia fragmentary, but it has been obtained from various species and under different circumstances of

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Disordered Protein Metabolism in Uraemia

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diet, as well as different degrees of severity and duration of renal failure. At this moment it would be premature to attempt to synthesize these disparate findings into a pattern of disordered metabolic activity in uraemic men. At best we can take the available data only as pointers to the derangements which may take place - partly as a result of uraemia and partly as a result of prolonged subnutrition. Often the relative importance of these two factors is not clear. Uraemia has so far only been implicated in the disturbance of the metabolic pathways o f two amino acids: phenylalanine and histidine. Conversion of phenylalanine to tyrosine by phenylalanine hydroxylase is impaired with the result that the tyrosine :phenylalanine ratio in plasma falls [19,30], and phenylpyruvic acid may be detected in the urine [19]. The extent to which this abnormality is primarily an effect of uraemia is uncertain, for a similar defect has been described in protein-energy malnutrition [1,62]. No harmful conse­ quence of impaired oxidation of phenylalanine to tyrosine has been estab­ lished, but the altered metabolism of histidine appears of practical importance. The plasma concentration of histidine is low in uraemia [19,56] as a result of interference with the synthesis of histidine sufficient to make it an essential amino acid, as in infancy [54], Positive nitrogen balance was enhanced when histidine was added to a solution of amino acids given intravenously to uraemic individuals taking a low-protein diet [2,28]. This observation gave reason to the earlier observation that oral administration of histidine to uraemic patients increased the incorporation of I4C-lysine in vitro into their erythro­ cytes [8], F ürst [13] has confirmed that histidine is an essential amino acid for at least some individuals with chronic uraemia by showing that they failed to incorporate 15N into histidine separated from muscle and plasma protein, whereas 15N was recovered from histidine similarly prepared from post­ operative patients and healthy individuals. Histidine might become an essential dietary requirement in uraemia, either because of impaired ability to synthesize its carbon skeleton, imidazole-pyruvic acid, or because of inability to transaminate this ketoacid. Transamination o f the ketoacid appears normal, for imidazole-pyruvic acid replaced histidine satisfactorily in the diet of one individual with advanced chronic renal failure [60]. Thus synthesis o f the ketoacid is probably impaired, possibly because transketolase activity is reduced in uraemia [33]. It would not be surprising, however, if transamination were deficient in uraemia. For example, we found that one uraemic patient was apparently unable to transaminate the keto acids of either or both valine and phenyl­ alanine sufficiently to maintain nitrogen balance [42], Transamination of branched-chain essential amino acids might be particularly affected in chronic

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renal failure if the kidney were the richest source of branched-chain amino acid transaminases (BATase) in man as in the rat [26,36]. In our experiments in rats, BATase activity was not reduced to a greater extent per gram of muscle by protein restriction and uraemia than by protein restriction alone; the mass of renal tissue was, however, reduced in the uraemic animals [6]. Alanine aminotransferase (AIT) activity decreased during protein restriction but was less reduced in protein-restricted uraemic rats than in similarly proteinrestricted rats with normal renal function [6]. In acute renal failure, the pattern of protein synthesis in the rat was altered so that protein synthesis increased in liver and heart and decreased in skeletal muscle [51]; there is no data to show whether or not the same is true of man. Although few discrete abnormalities in protein metabolism have been identified in advanced chronic renal failure, there can be little doubt that the overall disturbance may be very profound. Many have referred to the persist­ ently negative nitrogen balance of individuals with advanced chronic renal failure, but it is still uncertain whether insufficient intake of nitrogen and energy, poor absorption, or chemical interference with protein metabolism is primarily responsible. Nitrogen intake itself is probably rarely inadequate. Estimates of minimal nitrogen requirement in uraemia have varied from 3-5.6 g (table I), but when account is taken of the long period often required to equilibrate on a particular diet and the necessity for an adequate energy intake, it is doubtful whether these figures differ significantly from the 3.14.2 g minimal nitrogen requirement for healthy adults (table II). If, however, the diet o f uraemic individuals supplies adequate essential amino acids but is deficient in non-essential nitrogen, endogenous non-amino nitrogen may be utilized to the extent that a positive nitrogen balance has been maintained for a period with a dietary intake of only 2 g nitrogen [17], If, as suggested by R ic h a r d s et al. [43], retained non-amino nitrogen may also be utilized for synthesis of essential amino acids, then the dietary nitrogen might be further reduced (see p.435). On a diet in which several amino acids were replaced by their a-keto acid analogues, positive balance has been maintained on a net nitrogen intake of 1.8 g/day [60]. Albumin metabolism was modified in response to protein restriction irres­ pective of renal function in 12 patients with chronic renal failure. Both albumin catabolism measured with 125I-labelled human serum albumin and albumin synthesis measured by incorporation of 14C into plasma proteins were dim­ inished and a shift o f albumin from the extravascular to the intravascular pool was identified [7]. Uraemia did not obviously alter the general relationship between intravascular albumin and albumin catabolism (fig. 1). C oles et al.

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136

Protein Metabolism in Uraemia

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Table /. Estimates of the minimum nitrogen requirement of uraemic men for maintenance of nitrogen balance when at least 35 cal/kg were supplied daily Source of nitrogen

Nitrogen requirement g/day

Rice [29] Essential amino acids (blood urea > 8 0 mg/100 ml) [17] Essential amino acids with urea, ammonium citrate or glycine (blood urea < 8 0 m g /I0 0 m l)[1 7 ] Mixed protein or egg protein [34] Essential amino acids or egg protein [21] Mixed protein [50] Mixed protein [12] Mixed protein or egg protein [66]

3.2 2 4 3.2 3 31 5.6 > 3.5

1 Nitrogen balance not measured.

Source of nitrogen

nitrogen requirement g/day

Beef [31] Milk [3] Egg [23] Beef [37] Cereal [4] Essential amino acids and glycine [45]

4.2 3.9 3.2 3.1 3.8 3.5

[7] concluded that the increase in plasma albumin and albumin synthesis rate after correction o f uraemia by regular haemodialysis or renal transplantation was due to increased protein intake; they also concluded that it was unnecess­ ary to postulate that uraemia per se reduced albumin synthesis. It has been suggested that the susceptibility of uraemic patients to infection is partly accounted for by ‘increased urine protein loss and toxic inhibition of synthesis’ of immunoglobulins [63], Altered immunoglobulin synthesis was probably

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Table II. Estimates o f the minimum nitrogen requirement o f healthy men for maintenance of nitrogen balance

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138 20 i 18 16 14 12 10

2. 4 -

i

• ••

o •

2

< o

— i---- 1------ 1----- 1------ 1------- 1---- 1------ 1------ 1------- r 0 20 40 60 80 Intravascular albumin, g

100

120

140

160

180

200

not an effect of protein restriction, because serum immunoglobulin concen­ trations were normal in children with protein-energy malnutrition [61]. How­ ever, protein restriction may contribute to susceptibility to infection by im­ pairing leucocyte response, lymphocyte function, and synthesis of complement proteins. Whether uraemia by itself interferes with cell-mediated immunity or with the complement system is uncertain [48,49,52,53]. The nitrogen intake of an uraemic individual who is not vomiting is prob­ ably rarely below his minimal requirement for total nitrogen, although methio­ nine may be inadequate in some low-protein diets [50], Yet the ability to use the nitrogen effectively may be critically dependent on a sufficient energy intake, and in this respect diets may often be inadequate. A low energy supply (30 kcal/kg body weight) probably explains the failure o f H erndon et al. [24] to achieve nitrogen balance in uraemic patients on a low-nitrogen diet. F ord et al. [12] concluded that energy intake did not affect nitrogen metabolism in chronic renal failure, but they did not compare the effect o f different energy intakes when nitrogen intake was fixed. H yne et al. [25] have clearly shown

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Fig. I. The relationship between albumin catabolism and intravascular albumin (a) in patients with chronic renal failure (O), and (b) in patients with hypoalbuminaemia due to malabsorption, cirrhosis or malnutrition ( • ) . From C oles et al. [7] by courtesy of Clinical Science.

Protein Metabolism in Uraemia

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that in the range o f energy intake of 35-55 kcal/kg on a protein nitrogen intake of 2.1-3.7 g/day, nitrogen balance correlated with energy intake; the greater the energy intake, the more nearly positive the nitrogen balance. Once nitrogen balance is disturbed in an individual with chronic renal failure, it may be difficult to reverse the change quickly. On the other hand, once an intercurrent illness is over, a period o f prolonged anabolism may be seen. For example, a 57-year-old woman developed pyelonephritis and renal failure after a gynaecological operation in November, 1968. In December, 1968, her blood urea was 260 mg/100 ml; bilateral retrograde pyelograms showed no obstruction but revealed polycystic kidneys. She had repeated urinary tract infections which were treated with ampicillin, cloxacillin and nitrofurantoin; she did not receive tetracycline. In February her blood urea was 340 m g/100 ml. Her general condition then improved, and on a 20-gram protein diet her blood urea fell to 37 mg/100 ml over the next month, although the creatinine clearance was only 7 ml/min. The remarkable fall in blood urea concentration in the face of a urinary nitrogen excretion less than her intake prompted the balance study shown in figure 2. Although her protein intake

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Fig. 2. Strongly positive nitrogen balance o f a 57-year-old woman with polycystic kidneys during recovery from an episode of acute-on-chronic renal failure. Nitrogen excretion in urine and stool is plotted upwards from the intake level.

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was steadily increased, neither the urinary nitrogen nor the blood urea in­ creased greatly, and her nitrogen balance was strongly positive. Her renal failure did not improve; over the next year her plasma creatinine remained between 5 and 6 ml/min. By May, 1969 her blood urea was 140 mg/100 ml when she took approximately 40 g protein daily, and in August, 1969, it was 210 mg/100 ml. Some uraemic patients who are generally unwell may remain in persistently negative nitrogen balance on a diet containing sufficient nitrogen and calories to maintain balance in other individuals. Although the blood urea concen­ tration may fall, this does not necessarily indicate either reutilization of ureanitrogen for protein synthesis or positive nitrogen balance. Figure 3 shows the nitrogen balance of a 25-year-old drug addict who had had chronic renal failure since a septicaemic illness 2 years before. His plasma albumin was 3.3 g/100 ml and creatinine 13.5 mg/100 ml with a creatinine clearance of 6 ml/min. Although his blood urea fell when he took a diet supplying 40 g protein and approximately 45 kcal/kg in hospital, his nitrogen balance re­ mained negative and did not improve in response to injections o f nandrolone 25 mg daily for 7 days. The explanation of the persistently negative nitrogen balance is not clear. His proteinuria was not sufficiently heavy to explain it, there was no evidence o f infection, and although for the first few days he vomited at least once a day, vomiting ceased and the diet was fully consumed thereafter. It is tempting to invoke a ‘catabolic effect’ of uraemia per se, but more carefully controlled studies are needed to prove or disprove it, particu­ larly in view of the fact that a persistently negative balance has been described in individuals with malignant disease [69]. Whereas intravenous feeding re­ versed negative nitrogen balance in uraemia, it failed to do so in patients suffering from malignant disease [69], F ü r st et al. [14] have shown that intravenous infusion of essential amino acids in uraemia increased the incorporation of 15N from labelled urea into both plasma and muscle protein. They also reported that 15N-ammonia was handled more efficiently when given intravenously than orally; incorporation into muscle protein and globulin was relatively greater than into albumin, and the overall incorporation was greater [15], The extent to which intestinal absorption of amino acids may be impaired in chronic renal failure is uncertain. Preliminary experiments by G ulyassy et al. [22] suggested that absorption of both trytophan and the leucine analogue cycloleucine was impaired in uraemic individuals. Evidence of pyridoxine deficiency has been reported [10], but no data are available to show whether poor diet, poor absorption, or increased demand for pyridoxine was respon-

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140

Protein Metabolism in Uraemia

141

Days

Fig. 3. Persistently negative nitrogen balance in spite o f a steady fall in blood urea in a 25-year-old man with chronic renal failure. Nitrogen balance has been corrected for changes in the body urea pool. Treatment with an anabolic steroid, nandrolone, did not improve nitrogen balance.

sible. The GOT activity of erythrocytes was reduced in uraemia and was restored to normal by pyridoxine 300 mg daily [10]. Of possibly greater im­ portance was the observation that the diminished reactivity of mixed lympho­ cyte cultures was restored to normal by pyridoxine [10], a finding which raised the possibility that suppression of delayed hypersensitivity in uraemia might be partly due to pyridoxine deficiency.

The steady blood urea concentration of stable chronic uraemia conceals a highly dynamic urea metabolism. Bacterial ureases in the colon continually hydrolyse urea to ammonia and carbon dioxide. Urea production, measured from the decay in plasma 14C urea activity, exceeded urea excretion. The difference was attributed by W alser and B odenlos [59] to resynthesis of urea from ammonia liberated from urea in the colon and recycled to the liver in

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Recycled Urea Nitrogen

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142

B O IE T 3.5g N ( 22 g P R O T E IN )

a

D IE T 16g N ( 100g P R O T E IN )

RECYCLED

N

*

RECYCLED N

r e d u c e d to

?i g

R E C Y C L E D N i n c r e a s e d to

■>5 x g

Fig.4. Diagrammatic representation of nitrogen recycling in health on a normal (A) and low-protein diet (B) and in chronic renal failure on a low-protein diet (C). If the amount of urea hydrolyzed were directly proportional to the blood urea nitrogen (BUN), the proportional amounts of urea nitrogen would be as shown. The value o f x is 3-4 g [59],

portal blood. They confirmed their hypothesis by showing that when an anti­ biotic was given the difference was reduced so that synthesis almost equalled excretion; a small difference remained as would be expected because their treatment would not completely have eliminated urease-producing organisms. A wide variety o f evidence, which has recently been reviewed [32,39], proves that man and other monogastric animals can utilize ammonia nitrogen for protein synthesis. Whether ammonia nitrogen released from urea retained in renal failure is of nutritional significance depends on the amount released and on the efficiency with which it is used. The amount of ammonia generated in the colon in chronic renal failure is disputed, because the evidence is con­ flicting. How much is used is even less certain, because it depends on the total nitrogen and amino acid composition of the diet. If release of ammonia from urea in the colon is directly proportional to the blood urea concentration, substantial quantities would be released in uraemic individuals on a lowprotein diet and insignificant amounts released in protein-deprived healthy individuals [40a] (fig. 4).

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*

C D I E T 3. 5g N (2 2 g PRO TEIN )

Protein Metabolism in Uraemia

143

Figure 5 summarizes the findings o f four groups who have studied urea metabolism in chronic renal failure using a similar technique. Three of them found that ammonia was released from urea in direct proportion to the size of the urea pool (p [ 2 uaX; 0.06 * 1 u ; Ul ^ 0.05 /l 004 o ° 003

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urea, was apparently used to convert the keto acids to essential amino acids, but how much nitrogen was utilized is uncertain, because the diet always con­ tained a little protein. Furthermore, the increase in the ‘urea appearance’ (urinary urea excretion plus change in the urea nitrogen pool) and decrease in the positivity o f the corrected nitrogen balance were small when the keto acidsubstituted diet was replaced by an isonitrogenousdiet containing the essential amino acids: urea nitrogen appearance increased by a mean of 0.64 g, and

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Fig. 8. 15N-excess in valine from hydrolysate of plasma albumin and the nitrogen balance of two young women who received 2 g sodium salt of a-ketoisovalcric acid for 5 days when taking a valine-free diet. Nitrogen balance improved, and incorporation of I5N increased when the keto acid was given. Reproduced by courtesy of Lancet [20],

148

R ichards

nitrogen balance fell from +0.95 g to -0 .4 7 g. If all the keto acids supplied had been animated, 1.23 g nitrogen would have been required. The possibility thus remains that the keto acid-substituted diet in some way (possibly by enzyme-induction) induced a more efficient nitrogen turnover. The blood urea nitrogen of one practically anuric patient with end-stage renal failure in­ creased by only 21 m g/100 ml in 26 days on a nitrogen intake of 1.4 g/day with the keto acid-substituted diet. However, the slow rise of urea did not prevent a steady increase in serum creatinine concentration nor the onset of confusion and uraemic pleurisy. If treatment with a keto acid-substituted diet has a place in treatment of end-stage chronic renal failure, it would at present seem to be for those for whom regular dialysis and/or transplantation are not available, and whose deterioration of renal function is very slow. It remains to be proved that such a diet would maintain better health and procure a longer life than a conventional 20-gram protein diet.

Conclusion Whether because o f uraemic ‘toxins’ or - more likely - because o f poor energy intake, uraemic patients readily become malnourished and develop negative nitrogen balance. To avoid malnutrition, the dietary protein intake in uraemia should be as liberal as symptoms will allow. Harm and no benefit accrues from protein restriction simply to achieve an arbitrary reduction of blood urea. As soon as good health can no longer be maintained on a 20-gram protein diet, further measures are essential. Regular dialysis and renal trans­ plantation are the only two long-term treatments of proved value at this ad­ vanced stage of renal disease, but they are neither available nor suitable for all patients. The possibility remains that dietary manipulation to induce the fullest reutilization of endogenous non-amino and amino nitrogen would usefully prolong life in such patients.

References

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3 B ricker, M .; M itchell, H .H ., and K insman, G. M.: The protein requirements of adult human subjects in terms of the protein contained in individual foods and food combinations. J. N utr. 30: 269-283 (1945). 4 B ricker, M .L .; S hively, R .F.; Smith, J.M .; M itchell, H .H ., and H amilton, T .S.: The protein requirements of college women on high cereal diet with observations on the adequacy o f short diet periods. J. Nutr. 37: 163-183 (1949). 5 Brown , C.L.; H ill , M. J., and R ichards, P .: Bacterial ureases in uraemic men. Lancet ii: 406-408 (1971). 6 B rown , C. L.; H oughton , B.J.; Souhami, R.L., and R ichards, P.: The effects of low-protein diet and uraemia upon urea-cycle enzymes and transaminases in rats. Clin. Sei. 43: 371-376 (1972). 7 C oles, G .A .; P eters, D. K., and J ones, J.H.: Albumin in chronic renal failure. Clin. Sei. 39: 423-435 (1970). 8 D e Santo, N .G .; D e Pascale, C.; Esposito, R.; Balestrieri, C.; G iordano, C., and P luvio, N .: Biochem. Appl. 15: 556 (1968); quoted by B ergström et al.[2], 9 D f.ane, N .; D esir, W., and U meda, T.: The production and extra-renal metabolism of urea in patients with chronic renal failure treated with diet and dialysis. Proc.europ. Dialysis and Transpl. Ass. 4: 245-249 (1968). 10 D obbelstein, H.; K örner, W .; M empel, W ., and Edel, H.: Pyridoxine deficiency in chronic uraemia and its possible implications for depression of immune responses. Abstracts 5th Int. Congr. Nephrol., p. 166 (1972). 11 F ischer, H.; Brush, M .K., and G riminger, P.: Reassessment o f aminoacid require­ ments of young women on low-nitrogen diets. I. Lysine and tryptophan. Amcr. J.clin. Nutr. 22: 1190-1196(1969). 12 F ord , J.; P hillips , M .E .;T oye, F.E.; L uck , V. A., and W ardener, H.E. d e : Nitrogen balance in patients with chronic renal failure on diets containing varying quantities of protein. Brit. med.J.i: 735-740(1969). 13 F ürst, P .: 15N-studies in severe renal failure. II. Evidence for the essentiality of histidine. Scand. J.clin. Lab. Invest.30: 307-312 (1972). 14 F ürst, P .; Bergström, J., and J osephson, B .: 15N studies in severe renal failure. I. In­ fluence of aminoacid administration on the nitrogen metabolism. Scand. J.clin.Lab. Invest. 30: 299-305 (1972). 15 F ürst, P.; J onsson, A.; J osephson, B„ and Vinnars, E.: Distribution in muscle and liver vein protein of 15N administered as ammonium acetate to man. J. appl. Physiol. 29: 307-312(1970). 16 G allina, D. L.; D ominguez, J. M.; H oschoian, J.C., and Barrio, J .R .: Maintenance of nitrogen balance in a young woman by substitution of a-ketoisovaleric acid for valine. J. Nutr. 101: 1165-1168(1971). 17 G iordano, C .: Use o f exogenous and endogenous urea for protein synthesis in normal and uremic subjects. J. Lab.clin. Med.62: 231-245 (1963). 18 G iordano, C .; de P ascale, C .; Balestrieri, C ; C ittadini, D., and C rescenzi, A.: Incorporation of urea 15N in amino acids of patients with chronic renal failure on low nitrogen diet. Amer. J.clin.N utr.27: 394-402 (1968). 19 G iordano, C.; D e P ascale, C ; C ristofaro, D .; Capodicasa, G.; Balestrieri, C., and Baczyk , K .: Protein malnutrition in the treatment of chronic uremia; in Berlyne Nutrition in renal disease, pp. 23-34 (Livingston, Edinburgh 1968).

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Protein Metabolism in Uraemia

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Protein metabolism in uraemia.

Nephron 14: 134-152(1975) Protein Metabolism in Uraemia P eter R ich ar ds St. George’s Hospital and Medical School, Hyde Park Corner, London Abstra...
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