Branched-chain amino acids and branched-chain ketoacids in uremia.

Guarnieri G, Panetta G, Toigo G (eds): Metabolic and Nutritional Abnormalities in Kidney Disease. Contrib Nephrol. Basel, Karger, 1992, vol 98, pp 44-58

Branched-Chain Amino Acids and Branched-Chain Ketoacids in Uremia Peter Fürsta, Anders Alvestrandb, Jonas Bergström b

`Plasma concentrations of amino acids deviate little in acute and chronic uremia from the patterns seen in normal individuals and the normal plasma values imply that serious depletion of the labile amino acid pool is absent.' This early statement by Rubini and Gordon [1] also was consistent with the conclusions reached by many other investigators in the 1960s. Technical difficulties inherent with the sampling and sample processing, as well as inferior analytical techniques, might have concealed grossly pathological amino acid concentrations now known to exist in plasma of chronic and acute uremic patients. Actually, the plasma aminogram in chronic renal failure is, in many respects, similar to that found in protein malnutrition. Among the consistent findings are high concentrations of several nonessential amino acids, decreased concentrations of essential amino acids, and a decreased ratio of tyrosine/phenylalanine and of valine/glycine. Importantly, this amino acid pattern is present in both clinically stable nondialyzed chronically uremic patients and in those undergoing maintenance hemodialysis [2-5]. Indeed, major abnormalities in uremia relate to the branched-chain amino acid (BCAA) metabolism [6]. In the present compilation the distorted extra- and intracellular BCAA pattern will be described and the pathogenesis of the abnormalities will be discussed. Finally, therapeutical efficacy of BCAA and branched-chain ketoacid (BCKA) supplementation will be evaluated.

Downloaded by: Université de Paris 193.51.85.197 - 1/13/2020 5:22:33 AM

alnstitute for Biological Chemistry and Nutrition, Hohenheim University, Stuttgart, FRG, and bDepartment of Renal Medicine, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden

BCAA and BCKA in Uremia

45

Of the three BCAA in plasma, valine consistently exhibits low concentrations. Valine is also the plasma amino acid most closely interrelated with other nutritional variables used to assess protein-energy malnutrition [7]. Changes in BCAA concentrations in erythrocytes of chronically uremic patients are similar to those in plasma [8]. Cerebrospinal fluid concentrations of valine and leucine are also lower in uremic patients than in controls [9]. The BCKA are the transamination products of BCAA. The plasma levels of all three BCKA are reported to be significantly lower in dialyzed and nondialyzed patients than in healthy adult volunteers [ 10] while in uremic children only the level of 2-ketoísocaproíc acid (KICA) is low [1 1 ]. The low BCKA concentrations possibly also reflect protein malnutrition in uremia. In a recent study mean plasma concentrations of the three BCKA were not different from those observed in normal subjects [ 12]. However, multiple-regression analysis showed that plasma ketoisocaproate was strongly correlated with glomerular filtration rate, negatively correlated with serum triglyceride concentration, and positively correlated with protein intake [ 12]. The concentrations of muscle free BCAA are of special interest. Most studies of muscle free amino acids in adult patients with chronic uremia have revealed a typical intracellular BCAA pattern with markedly reduced valine concentration and normal [13-16] or in patients with intermittent peritoneal dialysis [ 17], even high concentrations of isoleucine and leucine, in face of reduced plasma concentrations of these amino acids. In children normal BCAA concentrations are reported in severe renal failure [18], but decreased concentrations of all three muscle BCAA are claimed in moderate renal failure, with valine being most markedly reduced [ 19]. Free amino acid concentrations in plasma and muscle are critically dependent on age and sex, factors which should be considered when evaluating changes in free BCAA concentrations in uremic patients. Most studies give no information on the controls in these respects and, therefore, the result should be evaluated with caution. Exceptions are the pediatric patients, who were compared with age-matched controls, and more recent studies by our group using age- and sex-matched controls [14, 15]. The importance of sex and age became evident to us when we re-evaluated free amino acid data in chronic hemodialysis patients, comparing them with age- and sex-matched controls, and found plasma and muscle free valine concentrations to be low [15]. We had previously reported valine to be


BCAA Concentrations

Fürst/Alvestrand/Bergström

03 —

46

NS

ι

ιι

***

ο

ι

Healthy controls

ι

***

ιι

NS

~ Uremic patients . Age-and sexmatched controls

normal in these patients when compared with controls not matched for age and sex [20]. Thus, an adequately controlled data base is of the utmost importance in evaluating the results. As exemplified in figure 1, patient data may reveal a completely normal level of an amino acid when compared with healthy controls but the value is, as a matter of fact, significantly and markedly reduced when the comparison is made with adequate age- and sex-matched controls. In contrast, an apparently increased value is in reality completely normal when age- and sex-matched controls are used for comparison [21].


Fig. 1. The amino acid concentrations in plasma and muscle as a function of sex and age in chronic uremic patients compared with data derived either from mixed healthy controls or from age- and sex-matched controls. *** p < 0.001; NS = non significant. [Results adapted from 15, 20.]


47

BCAA Metabolism

Pathogenesis of BCAA Abnormalities The pathogenesis of BCAA abnormalities in chronic renal failure is unclear. Low plasma levels of all three BCAA have been found, along with selective intracellular depletion of valine [28] in the presence of normal or high [13] muscle levels of isoleucine and leucine (fig. 2). These abnormalities in the BCAA pattern partly resemble those observed in rats fed a low protein diet containing an excess of leucine. This suggests a nutritional antagonism among the BCAA possibly associated with deterioration of growth and amino acid utilization [29]. Selective depletion of free valine in uremia would require that this amino acid be preferentially catabolized. It is generally believed that the same transaminase is involved in the degradation of all BCAA [30] and that a single dehydrogenase complex controls the rate-limiting decarboxy-


Interorgan Exchange Splanchnic uptake of valine in chronically uremic patients is claimed to be normal [22]. Importantly, a controversial observation, relative to splanchnic handling of valine, was made by Alvestrand et al. [23], who reported an increased uptake of this amino acid in chronic uremic patients and suggested that this might contribute to lowering extra- and intracellular free valine pools. Low cerebral uptake of BCAA correlated with low plasma levels in chronic renal failure [22, 23], but renal metabolism of BCAA did not differ from that of controls [22, 24]. One concludes that changes in splanchnic metabolism observed in chronic renal insufficiency have only minor effects on the abnormality of circulating BCAA in the postabsorptive state. Current investigations from Tizianello's group [25, 26] suggest that postprandial variations in splanchnic amino acid metabolism are of great importance in uremia. They concluded that in patients with chronic renal failure splanchnic organs metabolize ingested amino acids in such an abnormal way that they export an increased and unbalanced bulk of amino acids into the systemic circulation, thereby severely affecting postprandial arterial amino acid levels. The authors also emphasize that the interorgan flow of nitrogen nutrients is altered throughout the day. The consequences of abnormal postprandial splanchnic amino acid metabolism in uremia may indeed affect amino acid pools and protein synthesis because of an unsuitable amino acid profile at the ribosomal site [27].


48

Normal . Chronically uremic patients 0.3*** 0.1o

Valine

Leucine

-1 Isoleucine

— Antagonism

***

0

Ι

Valine

ΙΙ nil

Leucine

Isoleucine

BCAA antagonism in uremia. [Adapted from 13-15].

lation of the BCKA [31 ]. However, the demonstration in man of metabolic defects involving only one or two of the BCAA [32], suggests that decarboxylation of the BCKA may occur by more than one enzymatic mechanism [33]. There is also the possibility that the affinity of the individual BCKA for one or more enzymes of the dehydrogenase complex is changed owing to a change in pH [34] or to the presence of high concentrations of one or several metabolites that accumulate in the uremic state. The fractional splanchnic uptake for valine, but not for leucine or isoleucine, was markedly enhanced in the basal preabsorptive state in uremic patients. The same was true in euglycemic clamp studies of hyperinsulinemia [23]. These data suggest that degradation in the liver may contribute to depletion of valine pools. Carbohydrate intolerance is universally present in uremic subjects [35] and is primarily due to peripheral


Fig. 2.

•

***


49

Acidosis: A Critical Factor for the BCAA Antagonism in Hemodialysis Patients BCAA are mainly metabolized in muscle by deamination to their ketoanalogues, followed by oxidation, mediated through a common BCKA dehydrogenase complex, which is rate-limiting for BCAA degradation [37]. It has recently been reported that in normal and uremic rats acidosis appears to enhance protein degradation in muscle [38, 39], and that this effect could be attributed to stimulation of BCAA decarboxylation, thereby bringing about depletion of the BCAA [40]. The amino acid most affected is valine [15]. Since BCKA decarboxylation was not stimulated when muscles were incubated in acidified media, it appears that the acidosis must be chronic to cause a change in BCKA decarboxylation [41]. When acidosis was prevented by giving sodium bicarbonate the decarboxylation of BCAA and the increase in protein catabolism were abolished, indicating that acidosis and not uremia was the catabolic stimulus. We observed a significant correlation between the predialysis standard bicarbonate concentration and the valine concentration in muscle (fig. 3), but not with the concentration of valine in plasma. Similarly, there was no correlation with the concentrations of leucine or isoleucine in plasma or muscle [42]. These findings suggest that acidosis is an important factor for the imbalance of the BCAA in uremia with selective valine depletion. Acidosis may presumably influence the BCAA metabolism not only by stimulating BCAA decarboxylation [40], but also by modulating the metabolic activity towards preferential degradation of valine. Whether uremia independently of acidosis additionally influences BCAA metabolism cannot be evaluated from our data. It is conceivable that under conditions of low protein intake or increased catabolic stress, valine depletion might be a limiting factor for protein synthesis in maintenance hemodialysis patients. Full correction of acidosis to normal plasma bicarbonate levels before dialysis is therefore an obvious goal of therapy to prevent selective degradation of valine. It has been reported that correction of


tissue insensitivity to insulin [36]. Hyperinsulinemia elicits a similar decrease of plasma BCAA in both uremic patients and normal subjects. Consequently, the hyperinsulinemia of chronic renal failure may contribute to the abnormal BCAA concentrations and influence the distorted distribution pattern, though insulin resistance in uremia, thus, may not directly influence BCAA transport.

Fiirst/Alvestrand/Bergstrbm

400 -

50

y =-162.0 +19.1x r = 0.82, p < 0.01

Muscle valine, µmοΙ/I ICW

■ 300 -

■

200 -

100 16

ι Ι I 18 20 22 24 Predíalysis standard bicarbonate concentration, mmol/I

26

Fig. 3. Relationship between predialysis standard bicarbonate and muscle valine concentration in 10 hemodialysis patients. [Adapted from 42.]

metabolic acidosis improves nitrogen balance in nondialyzed chronic uremic patients [43]. One may speculate whether this effect is mediated by a correction of the BCAA imbalance.

The efficacy of treatment with a very low protein diet of 20-30 g or less per day with addition of amino acids in proportions according to Rose [44] (considered to be optimal for normal subjects) has been evaluated in numerous studies by means of nitrogen balance and extra- and intracellular free amino acid concentrations [for reference, cf. 45]. Valine concentrations remained low, a consistent observation, even though the patients had


Effects of Therapy with Low Protein Diets and Essential Amino Acid Supplementation on BCAA Metabolism

51

been given extra essential amino acids, providing two or three times the minimum requirement [cf. 45]. Thus, the defect in valine concentration could not be normalized and the abnormal distribution of leucine was still present with low concentrations in plasma and normal concentrations in the cells (fig. 2). Additional persisting abnormalities were low intracellular tyrosine and threonine concentrations [13-15, 45]. The fact that uremic patients seem to have higher requirements for essential amino acids does not necessarily imply that all the essential amino acids need to be given in increased amounts. Hence, there is the possibility that protein synthesis in uremia may be limited by low intracellular pools of valine, threonine and tyrosine. The studies in patients with near end-stage renal failure have shown that some but not all intracellular amino acid abnormalities can be corrected by nutritional means, which prompted us to modify the composition of our oral amino acid preparation. Based on intracellular amino acid results, a new amino acid formula was devised with changed proportions of the BCAA, adding more valine than leucine and complemented with tyrosine [ 13, 14]. The content of threonine was also increased, whereas the relative amounts of histidine, leucine, isoleucine, lysine, methionine, and phenylalanine were reduced [45]. By providing a low protein diet supplemented with this new amino acid mixture, intracellular valine concentration was normalized and the earlier observed antagonism between the three BCAA was abolished (fig. 4). Similarly, intracellular tyrosine and threonine concentrations became normal. Simultaneously with the partly normalized intracellular amino acid pattern, we also observed a slightly positive nitrogen balance in chronically uremic patients (fig. 5), suggesting that these patients were in nitrogen equilibrium [46]. These results demonstrate that it is possible to correct certain abnormalities in plasma and muscle free amino acid concentrations in uremia by manipulating the amino acid composition of the diet. Effective protein synthesis does not occur in the presence of low amino acid concentrations at sites of protein synthesis. Although tRNA charging should be adequate even at low concentrations, compartmentation in the cell resulting in lower amino acid concentrations at the site of protein synthesis than in the tissues as a whole may reduce charging and inhibit protein synthesis [47]. Therefore, it is conceivable that the positive nitrogen balance seen with the old preparations (fig. 5) was due to the repletion of the intracellular free amino acid pools, which are low and possibly limiting for protein synthesis in uremia.



Fürst/ΑΙν estrand/Bergström

Normal

52

l Chronically uremic patients . Long-term treatment with a new amino acid formula t

030 2-

***

01 -

Plasma,mmol/I

0

0201 -

0

Valine

i

Ζ

i

sΖ

Leucine

Isoleucine

Antagonism ***

Valine

Leucine

n fl Isoleucine

Fig. 4. The effect of nutrition on BCAA antagonism in uremia. [Adapted from 1315, 46.]

The possible use of ketoacid analogues as a substitute for the corresponding essential amino acid is based on observations that all essential amino acids, except threonine, lysine, and, in uremia, histidine [48], can be generated from the corresponding ketoacid analogues by transamination [49]. For these amino acids only the carbon skeleton, not the entire amino acid is essential. The first trial to apply this principle in clinical routine with a complete ketoacid/essential amino acid mixture was reported by Walser et al. [50] who used the analogues of BCAA, phenylalanine and methionine together with the amino acids threonine, lysine, tryptophan, and histidine. The composition of this ketoacid/essential amino acid prep-


Utilization of BCKA in Uremia


53

aration, which was given orally, followed the minimal requirements of Rose [44], except that in later experiments BCKA were given in threefold higher amounts than the corresponding BCAA in Rose's formula, since earlier experiments with isolated, perfused rat liver had shown that BCKA undergo a high degree of degradation relative to transamination [51]. The ketoanalogues of valine, isoleucine, leucine, and phenylalanine and the hydroxyanalogue of methionine are generally provided as calcium salts, together with the essential amino acids lysine, threonine, histidine, tryptophan, and tyrosine [52]. Ketoanalogues have also been given as salts of the basic amino acids ornithine or lysine rather than as calcium salts [53]. Such amino acid mixtures provide more amino groups on a molar basis than the corresponding essential amino acids since ornithine is a dibasic amino acid. Treatment with such a preparation sacrifices the original principle of `nitrogen-free' nutrition. To compensate for less than 100% utilization of ketoanalogues as amino acids, commercially available products contain ketoanalogues as calcium salts, either in molar proportions of essential amino acids according to Rose's [44] proportions without tyrosine [54] or in two or three times higher proportions of essential amino acids with added tyrosine (modified Walser formula) [55]. There are scarce data with respect to what extent ketoanalogues are utilized in healthy and uremic man. Halliday et al. [56] gave 13C-labelled a-ketoanalogues of valine and phenylalanine orally or intravenously to


Fig. 5. Corrected nitrogen balance in patients treated with protein-poor diets without () and with essential amino acid supplementation (• = old formula; /y, = new formula). The nitrogen balances were corrected for changes in total body urea (total body water X serum urea nitrogen). [Adapted from 13, 46.]


54

healthy subjects and uremic patients. The degree of conversion of these two a-ketoacids into essential amino acids was on the order of 25-50%, regardless of route of administration or subjects' health. The same degree of utilization of the ketoanalogues ketovaline and ketoleucine was observed in normal and uremic rats [57]. However, with a very low protein diet, ketoleucine conversion occurred with about 68-78% efficacy [58]. These studies strongly indicate that not only the proportions but also the amounts of the individual ketoacids must be critically scrutinized prior to suggesting an optimum ketoacid preparation. Theoretically, substituting ketoanalogues for the corresponding amino acids could provide essential carbon skeletons without nitrogen, thereby decreasing the nitrogen burden in severe renal failure. Ketoacid supplementation might be advantageous in patients with near end-stage renal failure in whom nitrogen supply has to be more restricted than is possible with low protein diets and supplementary essential amino acids in order to obviate excessive accumulation of nonprotein nitrogen and thus prevent or alleviate uremic symptoms. Another potential advantage of supplementation with ketoacid analogues is that it might be used together with a less protein-restricted diet to obtain the same total nitrogen supply and the same nitrogen-sparing effect as with more marked protein restriction with essential amino acids. Thus, less protein-restricted diets may mean improved palatability and better compliance. However, the data of Burns et al. [59] suggest that this cannot be achieved with ketoacid supplementation, since with strictly isonitrogenous nitrogen intake (30 g protein with or without glycine), ketoacid supplementation failed to give a positive nitrogen balance. In our own studies, supplementing a low protein diet with a ketoacid analogue mixture (modified Walser formula) failed to normalize the intracellular amino acid pattern after more than 3 months of treatment and resulted in a slightly negative nitrogen balance [15, 60]. It is still not known whether modifying the relative proportions of these ketoanalogues might provide any advantages over existing preparations.

l Rubini M, Gordon S: Individual plasma free amino acids in uremics: Effect of hemodialysis. Nephron 1968;5:339-351. 2 Bergström J: Amino acid abnormalities in renal failure; in Halsted C, Rucker R (eds): Nutrition and the Origins of Disease. San Diego Academic Press, 1989, pp 185-202.


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58

Prof. Dr. Peter Fürst, Institute of Biological Chemistry and Nutrition, University of Hohenheim, Garbenstrasse 30, D-W-7000 Stuttgart 70 (FRG)


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