muscle amino acid metabolism and the control of muscle protein turnover in patients with chronic...

REVIEW ARTICLE Nutrition Vol. 15, No. 2, 1999

Muscle Amino Acid Metabolism and theControl of Muscle Protein Turnover inPatients With Chronic Renal Failure

GIACOMO GARIBOTTO, MD

From the Dipartimento di Medicina Interna, Divisione di Nefrologia, Genova, Italy

Date accepted: 22 February 1998

ABSTRACT

Malnutrition is frequently observed in patients with end-stage renal disease. Studies indicate that poor nutritional status playsa major role among factors adversely affecting patient outcome. Therefore prevention and treatment of malnutrition in renalpatients is a major issue. In this article the potential mechanisms for alterations in muscle protein metabolism in uremia areexplored. Malnutrition has been mainly attributed to inadequate intake of nutrients, superimposed illnesses, or both. However,both clinical and experimental evidence show that uremia per se may adversely affect the control of muscle protein and aminoacid metabolism. Available evidence suggests that catabolic factors appear to be distinct for patients at different stages of chronicrenal failure and require different modalities of treatments. Both nutritional requirements and the prevalence of malnutritionincrease as end-stage renal disease progresses. Muscle protein degradation is increased by metabolic acidosis, which is oftenfound in uremic patients. Another relevant, but less proven cause for increased protein degradation is insulin resistance.Furthermore, specific defects in muscle amino acid metabolism, resistance to growth hormone, insulin-like growth factor 1, ora very low protein intake can reduce muscle protein synthesis. Finally, the hemodialytic procedure per se can stimulate proteinbreakdown or reduce protein synthesis. All these factors may potentiate the effects of concurrent catabolic illnesses, anorexia,and physical inactivity often found in uremic patients.Nutrition 1999;15:145–155. ©Elsevier Science Inc. 1999

Key words: protein synthesis, amino acids, muscle, uremia, acidosis, growth hormone, insulin-like growth factor 1

Malnutrition and muscle catabolism, resulting in muscle wast-ing and fatigue, are frequently observed in patients with end-stagerenal disease (ESRD). Although malnutrition is encountered moreoften in an advanced stage of ESRD,1,2 there is also evidence thatit may be prevalent even before the start of renal replacementtherapy.2 Studies indicate that a poor nutritional status plays amajor role among factors adversely affecting patient outcome1,2;therefore prevention and treatment of malnutrition in renal pa-tients is a major issue. Malnutrition has been mainly attributed toinadequate intake of nutrients or superimposed illnesses or both.However, the effects that uremia may have per se on muscleprotein metabolism remain an unanswered question. The occur-rence of alterations in levels of circulating amino acids (AA) andAA interorgan exchange, even in patients with moderately ad-vanced renal failure and without evidence of malnutrition, sug-gests that chronic renal failure (CRF) can adversely affect AAmetabolism and protein turnover.3,4 However, information onprotein metabolism in patients with CRF is still limited and the

changes in whole body and muscle protein turnover occurring inrenal patients before and after the onset of malnutrition are notfully understood. In this review the major mechanisms responsiblefor alterations in muscle protein metabolism in uremia are dis-cussed. Recent evidence suggests that an abnormal AA metabo-lism, metabolic acidosis, and a resistance to anabolic hormonesare some of the major factors impairing the control of muscleprotein metabolism in patients with CRF.

ABNORMALITIES OF MUSCLE AA METABOLISM

Patients with CRF exhibit many blood abnormalities and, to alesser degree, muscle AA profiles.3,5 Essential AA, notablybranched-chain AA (BCAA), are lower in the blood of CRFpatients than in control subjects with the same protein intake.6

Typical alterations in blood AA levels in patients with moderatelyadvanced CRF and non-reduced protein intakes are: increasedlevels of citrulline, 1- and 3-methylhistidine, proline, glycine, andcyst(e)ine; and decreased levels of valine, serine, tyrosine, and

Correspondence to: Giacomo Garibotto, MD, Dipartimento di Medicina Interna, Divisione di Nefrologia, Viale Benedetto XV, 6, 16132 Genova, Italy.

Nutrition 15:145–155, 1999©Elsevier Science Inc. 1999 0899-9007/99/$20.00Printed in the USA. All rights reserved. PII S0899-9007(98)00166-X

total tryptophan.3 Some of these alterations in the blood AAprofile can be accounted for by derangements AA exchange acrossthe organs, indicating an abnormal AA metabolism deriving fromendogenous protein turnover.3 In advanced uremia a low protein/calorie intake can cause even more prominent abnormalities.3,4

Alterations in AA muscle metabolism are likely responsible forsome changes in AA blood levels observed in CRF. In patientswith CRF, a reduced release of valine from muscle is likelyresponsible for its reduced blood levels.7 The release of valinefrom peripheral tissues is diminished even when compared to therelease of phenylalanine, lysine, or tyrosine, which are markers ofnet protein breakdown.8 It has been hypothesized that an increasedmuscle degradation of valine, probably due to metabolic acidosis9

or impaired glucose utilization,3 account for the low release of AAfrom peripheral tissues. Studies in animals indicate that the cor-rection of metabolic acidosis raises both plasma and muscleBCAA levels by decreasing the transamination and decarboxyl-ation of BCAA in muscle.9,10 Studies in humans are in agreementwith these findings. The intracellular concentration of valine inmuscle biopsies is correlated with blood bicarbonate concentrationin hemodialysis (HD) patients.5 Moreover, the whole body proteindegradation and oxidation of leucine are reduced by the correctionof metabolic acidosis in patients with CRF.11 During the course ofCRF, abnormalities due to low protein/energy intake may overlapwith those caused by acidosis, and the declining plasma valinelevels become an index of poor nutrition and reduced lean bodymass.12

An increased release of alanine from muscle has been found inuremic rats13 and in patients with CRF under unrestricted diets.14

In the context of muscle protein dynamics, it that been found thatalanine was directly correlated with both muscle protein degrada-tion and net protein balance.14 These data suggest that an impor-tant portion of alanine released from the peripheral tissues derivesfrom proteolysis. However, due to a release of alanine in amountssomewhat greater than net protein balance, an increased de novosynthesis of alanine in patients can also be hypothesized.14 Anincreased transamination from BCAA can provide N for synthesisof alanine. The splanchnic uptake of alanine has been found to beincreased in CRF patients suggesting an increased gluconeogen-esis from this AA.15

An abnormal pattern of sulphur plasma AA has been describedin CRF patients. Both free and protein-bound cysteine and homo-cysteine, and cysteinsulphinic acid (CSA) are high in plasma ofuremic patients, whereas methionine is normal and taurine levelhas been reported to decrease.4,16–18In muscle, major alterationsresult in reduced pools of taurine and increased pools of methio-nine.17 The causes for the low muscle taurine levels are stillunknown: an interesting possibility is an inhibition of CSA decar-boxylase by uremia.18 In renal patients there is also a decreasedfractional uptake of cyst(e)ine by peripheral tissues and this alter-ation may be at least in part responsible for the increase in bloodof the same AA.8,14The consequences of the reduced intracellulartaurine pools in renal patients are not known. Taurine may have arole in heart muscle contractility, and is involved in a wide rangeof metabolic effects in other organs, such as the brain and theretina.19

The normal kidney is actively involved in the metabolism ofAA, and therefore the loss of functioning renal mass may be animportant factor regarding AA abnormalities found in CRF. Thenormal kidney metabolizes citrulline to arginine, and its inabilityto synthesize arginine accounts for the high levels of citrulline inCRF.20 Although the nutritional consequences of the low synthesisof arginine are not understood, it has been speculated that it wouldincrease the risk of low availability of arginine to cells during highdemand of this AA, such as after infection or trauma.21,22 More-over, the human kidney is an important site for the synthesis of

serine and tyrosine and, in CRF patients, the renal output of theseAA is reduced.20 It is interesting that muscle serine concentrationis reduced in muscle of HD patients, whereas tyrosine has beenfound normal or decreased.5,17 In patients with moderate CRF,contrary to the normal condition, the forearm muscle does not takeup serine from the arterial blood.14 Whether this defect is due todecreased levels of serine owing to a defective renal synthesis orto a specific defect in the transport of serine by muscle is un-known. It is possible that in advanced uremia, when renal releaseof these AA is negligible, serine and tyrosine become essentialAA.23,24

Tryptophan, unlike other amino acids, is largely protein bound.In postabsorptive patients with CRF total serum or plasma tryp-tophan is reduced due to displacement of protein-bound trypto-phan by ligands or toxins that accumulate. However, free trypto-phan has been reported to be high, normal, or low.25 In untreatedpredialysis patients, serum-free tryptophan is in the normal range,whereas protein-bound tryptophan varies with protein intake anddecreases in the presence of hypoalbuminemia.25 So far, it isuncertain if bound or free tryptophans are involved in tryptophanexchange across the organs. Brain uptake of tryptophan fromblood seems to be dependent on bound tryptophan.26 After a loadof tryptophan is given alone or after a meat meal, total tryptophanrises less in blood than in the normal condition.27 The mechanismsfor abnormalities in tryptophan metabolism in renal failure are stillobscure: both a decreased intestinal absorption or an increasedliver catabolism have been claimed.27 Changes in tryptophanmetabolism occurring in uremia may be important for severalreasons: 1) tryptophan is an essential amino acid that is requiredfor protein synthesis and has a role in the regulation of proteinturnover; 2) tryptophan metabolism by the brain may induce theformation of neurotoxins (i.e., quinolinic acid); and 3) it has beensuggested that, besides nutritional consequences, tryptophan me-tabolism may play a role in the progression of chronic renalfailure.25

Abnormal cellular AA metabolism contributes to muscle wast-ing in renal patients. In addition to serine and tyrosine, it ispossible that uremic patients have increased requirements forother AA, such as valine, histidine, and probably arginine andtaurine.18,23,24 Some of the blood and muscle intracellular AAabnormalities may be corrected by specially designed supple-ments.28,29Partial correction of muscle AA abnormalities has beenfound to be associated with a more positive N balance.28

EFFECTS OF CRF ON THE INTERRELATIONSHIPS BETWEENSPLANCHNIC AND MUSCLE AA METABOLISM IN THE

PROTEIN-FED STATE

That the liver and muscle cooperate in the homeostasis ofblood AA levels after a protein meal has been known for a longtime.30 Several observations suggest that CRF markedly alters thiscooperative role between liver and muscle. Under normal condi-tions, the splanchnic organs play a selective role in the metabolismof ingested proteins. Most non-essential AA (NEAA) are capturedand metabolized by the splanchnic organs, particularly the liver,whereas the essential AA (EAA), mainly BCAA, escape largelyfrom the splanchnic organs and enter the hepatic veins.30 Accord-ingly, under normal conditions, the postprandial AA profile ischaracterized by large increases of EAA, but only slight elevationsof NEAA. Thus, splanchnic manipulation of ingested proteinmodifies the pattern of circulating AAs that are supplied to extra-splanchnic organs. This phase is crucial for N repletion in periph-eral tissues, where a stimulation of protein synthesis and inhibitionof protein degradation occur.30,31

It has been shown that the ingestion of a beefsteak27 or of AA32

are followed by exaggerated increases of NEAA in arterial bloodof patients with chronic renal failure. Thus a protein meal high-

MUSCLE AMINO ACID METABOLISM IN RENAL FAILURE146

lights the altered blood pattern of AA already observed in thepostabsorptive state.32–34 This alteration arises from a defect inAA metabolism by splanchnic organs. Figure 1 shows the frac-tional splanchnic escape of individual AA (calculated by relatingthe splanchnic escape of individual AA to the amount ingested ofthe same AA) following the ingestion of an AA mixture incontrols and in CRF patients.34 A very high escape was observedfor proline and threonine, which showed a fractional escape sim-ilar to that of leucine, which is the AA that under normal condi-tions undergoes the greatest escape. Many other AA, especiallyNEAA, show a fractional splanchnic escape greater than in con-trols. When total essential AA and NEAA are taken into account,splanchnic exchange area for EAA in patients was 67% higher,whereas that for NEAA increased by 135% in comparison tocontrols. The reason(s) why splanchnic organs in CRF fail toregulate the amount and composition of the AAsupply to thesystemic circulation are not clear. Abnormalities are not theconsequences of variations in splanchnic blood flow, becausethe increases in blood flow are similar in patients and con-trols.15 An intrinsic defect of the liver cell in the transport ormetabolism of AA, or both, must be assumed. Alanine, glycine,serine, proline, and threonine, which account for 60% of excessAA escaping splanchnic organs in CRF, are transported bysystem A, which is hormone sensitive. Alterations in splanch-nic AA handling do not depend on insulin availability, becausearterial insulin levels increase normally following AA or pro-tein ingestion.15 It is interesting that results obtained in isolatedCRF rat hepatocytes are in keeping with an alteration of gly-colysis and ureagenesis.35 It has also been shown that thehepatocytes of CRF rats are resistant to the action of insulinand glucagon with regard to the uptake of 2-aminoisobutyricacid36 suggesting that CRF causes an inhibition of hormone-sensitive AA transport system(s).

A more likely explanation for the altered splanchnic AA me-tabolism could come from the effects that metabolic acidosis hason AA transport. AA transport by liver cells is a pH-controlledstep of ureagenesis.37 Studies in vitro have shown that AA trans-

port through system A and N is inhibited by low pH.37 In fed rats,acid loading causes an increase in arterial levels in many NEAA,which are transported in the liver by systems A and N.38 More-over, it has been shown that the hepatic uptake of alanine andglycine, as well as total AA uptake, are reduced in rats withhydrochloric acid acute acidosis as compared with alkalosis.39

Recently, we have looked into possible relationships betweenmetabolic acidosis and the altered splanchnic AA metabolism.40 Itis interesting that after AA ingestion the splanchnic escape and thearterial increments of AA that are transported by systems A and Nare inversely related to arterial bicarbonate levels, both in patientswith CRF and in controls: the lower the bicarbonate levels, thehigher the splanchnic escape of AA and their arterial increments.40

This observation suggests that in chronic renal failure metabolicacidosis modifies both liver AA uptake and the delivery of AA toperipheral tissues in the protein-fed state.

Complementing the altered splanchnic and arterial AA profile,we observed an altered pattern of AA repletion in peripheraltissues after the ingestion of an AA meal in CRF patients.41 Theabnormalities in muscle AA uptake paralleled those observed inarterial concentrations. The peripheral uptake of total EAA wassimilar to controls, however peripheral tissues met the increasedarterial supply of AA, mainly NEAA, with an increased uptake. Alarge percentage of the AA taken up by the leg during the absorp-tive period was no longer accounted for by BCAA but by NEAA(Fig. 2). Therefore, these data indicate that in patients with CRF

FIG. 1. Fractional splanchnic escape of individual amino acid (AA)following the ingestion of an AA mixture in controls (h) and in chronicrenal failure patients (o). (Reproduced with permission from Tizianello etal.34 Kidney Int 1987;S32:S181.)

FIG. 2. Leg uptake of total amino acid (A), of non-essential amino acid(NEAA), and branched-chain AA (BCAA) (B) after AA ingestion inpatients with chronic renal failure and in controls. Leg AA - exchangearea, area under curves of variations in leg exchange of AA relative tobasal values during the 75-min absorptive period. (Reproduced with per-mission from Garibotto et al.41 Am J Clin Nutr 1995;62:136. © AmericanSociety for Clinical Nutrition.)

MUSCLE AMINO ACID METABOLISM IN RENAL FAILURE 147

the primacy of BCAA in supplying N to peripheral tissues isovercome by the increase in arterial blood of NEAA. Both theincrease in NEAA in arterial blood and the amount of NEAAtaken up by leg muscle are dependent on the blood bicarbonateconcentration (Fig. 3), suggesting that metabolic acidosis pro-motes the altered AA metabolism both in the splanchnic bed andperipheral tissues. It is unknown if the altered AA exchange in theprotein-fed state has effects on muscle protein metabolism. Inmuscle, NEAA are taken up in excess with respect to their contentin muscle protein and are likely oxidized, or increase transitorilythe muscle-free AA pool. The imbalanced profile of AA taken upby peripheral tissues may affect protein synthesis, because anappropriate pattern of AA is necessary to replenish N in muscle.42

In this regard, when considering the percent ratios of individualAA in the leg exchange area, that is, the amount of individual AA

taken up relative to total AA, it was found that the uptake ofleucine, isoleucine, and tyrosine relative to total AA uptake waslower in patients (Fig. 4). It is interesting that when the molarpercent of each AA in muscle43 is compared with the molarpercent of AA taken up by the leg, isoleucine and tyrosine aretaken up in CRF in amounts similar or below their proportion inmuscle proteins. Therefore, even if total N uptake by peripheraltissues is higher in patients than in controls, their use for proteinsynthesis may be less, and some AA, such as BCAA and tyrosine,could be rate-limiting protein synthesis. The possibility that animbalance in AA levels induced by metabolic acidosis affectsprotein nutrition in the protein-fed state may be also supposed byobservations in animals. In acidotic rats with normal renal func-tion the arterial and intracellular muscle AA profiles show alter-ations mirroring those observed in protein-fed patients with CRF,

FIG. 3. Relations of (A) arterial concentrations of non-essential amino acids (NEAA) and (B) leg uptake of NEAA to arterial [HCO3] in patients withchronic renal failure (■) and control subjects (h) after AA ingestion. Arterial NEAA area, areas under the curves of variations in arterial NEAAconcentrations; Leg NEAA - exchange area, areas under the curves of variations in leg exchange of AA relative to basal values. (Reproduced withpermission from Garibotto et al.41 Am J Clin Nutr 1995;62:136. © American Society for Clinical Nutrition.)


and these abnormalities occur together with a decrease in bodyweight gain, suggesting the responsibility of the unbalanced mus-cle AA uptake for the reduced anabolism.38

METABOLIC ACIDOSIS AND MUSCLE PROTEIN TURNOVER

Considerable evidence has been accumulated on the cataboliceffects of metabolic acidosis in CRF (for review see refs. 10 and44). Chronic metabolic acidosis is associated with increased pro-tein degradation and growth retardation both in animals and hu-mans.10,44Metabolic acidosis is common in CRF patients and maybe an important cause of lean body mass wasting.10,44 In patientswith CRF, correction of metabolic acidosis improves both nitro-gen and potassium balance.45 Recently, it has been observed thatcorrection of metabolic acidosis by administering NaHCO3 for 4wk to CRF patients was followed by a 28–29% decrease of wholebody protein degradation and leucine oxidation.11 The mainte-

nance of normal blood and muscle BCAA (mainly leucine) levelsis important not only because these AA are substrates for newprotein synthesis, but also because both leucine and ketoisocap-roate inhibit protein degradation.44,46

Skeletal muscle protein degradation likely plays an importantrole in the increase in whole body catabolism induced by acidosis.This effect has been ascertained in studies both in cultured myo-cytes47 and on muscle protein metabolism in vivo in animals.44

Recent investigations by Mitch and coworkers44,48have identifiedthe pathways involved in the increased muscle protein degradationof acidotic uremic rats. It has been found that the adenosinetriphosphate (ATP)-dependent, ubiquitin-requiring is the most im-portant pathway activated by acidosis. Both acidosis and glucocor-ticoids are needed to stimulate muscle protein degradation; on theother hand, neither glucocorticoid administration nor acidosisalone are sufficient to increase this proteolytic pathway.44 Thefindings thus indicate an interaction between the two factors topromote a catabolic response in muscle. It is interesting that theubiquitin-proteasome proteolytic pathway has been found to beincreased in muscle during sepsis, denervation, cancer, burns, andstarvation.49 Thus the mechanisms being elucidated for acidosisappear relevant to the loss of body proteins in a variety of othercatabolic states.

Early studies in patients with CRF examined net AA exchangeacross peripheral tissues by using the classic organ balance tech-nique.3,8,50 It was observed that the release of AA from the leg isnot increased in postabsorptive CRF patients,3,8,50at variance withdata obtained in uremic rats. Recently, the forearm balance tech-nique associated with the measurement of the3H phenylalaninekinetics has been applied to the estimate of synthesis and degra-dation of muscle proteins in moderately advanced CRF patientsunder unrestricted protein diets.14 In these patients, muscle proteinturnover was found to be increased. Although the net balance ofphenylalanine, an expression of net protein balance, was the sameas in controls, there was a significantly inverse correlation be-tween the net balance of phenylalanine and blood bicarbonateconcentration and a direct correlation between the net balance ofphenylalanine and plasma cortisol (Fig. 5). However, as shown bymultiple regression analysis, cortisol was the only determinant ofchanges in muscle phenylalanine net balance. Although the cata-bolic effect of cortisol on protein metabolism is well established,

FIG. 4. Percent ratios of the leg exchange areas for leucine, isoleucine, andtyrosine to the leg exchange areas for total amino acid (AA) after an AAmeal in controls (h) and chronic renal failure patients (o) and the percentAA composition in mixed muscle proteins (■). *, statistically differentfrom controls (see refs. 41 and 43).

FIG. 5. Relationships of forearm phenylalanine net balance (A) and the ratio of the disposal to the appearance of phenylalanine (B) to plasma cortisolinpatients with chronic renal failure in the postabsorptive state. The rate of disposal of phenylalanine across the forearm is an expression of proteinsynthesis,whereas the rate of appearance of phenylalanine expresses protein degradation. Phenylalanine net balance is an expression of net protein balance.(Reproduced with permission from Garibotto et al.14 Kidney Int 1994;45:1432.)


the quantitative importance of this response both in uremia and inother catabolic conditions is unclear. It is interesting that cortisollevels in patients with CRF are in the normal range; however, thelevels are inversely related to arterial bicarbonate concentration,14

suggesting that during acidosis an increased secretion or dimin-ished catabolism, or both, may occur. These findings also supportthe hypothesis that cortisol primes the metabolic pathways forprotein degradation that are stimulated by acidosis, somewhat inaccordance with data obtained in uremic rats.44 Preliminary datasuggest that the level of protein intake, which per se stimulatescortisol secretion, and metabolic acidosis are both important de-terminants of the increase in muscle protein turnover observed inpatients under unrestricted diets, because protein degradation de-clines when protein intake is diminished and is further reducedwhen metabolic acidosis is corrected.51

Recent studies indicate that metabolic acidosis, in addition toits effects on increasing protein degradation, also causes a resis-tance to the action of anabolic hormones, such as growth hormone(GH) and insulin-like growth factor-1 (IGF-1).52,53 IGF-1 is pro-duced locally in most tissues, but the liver is the major source forcirculating IGF-1.53 Plasma levels of IGF-1 are low in ammoniumchloride metabolic acidosis.53 Chan and coworkers53 found thatmetabolic acidosis significantly reduces the liver GH receptormessenger RNA (mRNA) in rats, thereby inducing a state of GHresistance. In Sprague-Dawley rats made acidemic with ammo-nium chloride the expression of liver IGF-1 is also reduced, andthis is associated with impaired weight gain.53 However, theeffects of acidosis in the expression of liver IGF-1 may be partlymediated by malnutrition.53 The changes on the GH/IGF-1 axisinduced by acidosis, in combination with the inhibition of GHsecretion, may be an important cause for growth failure in childrenwith renal tubular acidosis and may have additive catabolic effectsin adults with CRF.

Over the past several years considerable evidence has beengathered on the role of cell volume in the regulation of a varietyof cellular functions, including protein degradation. The effects ofvolume regulation on protein turnover have been recently re-viewed.54 Protein synthesis is stimulated, whereas protein degra-dation is inhibited by cell swelling in hepatocytes.55 In a variety ofcatabolic states a decrease in muscle cell volume correlates withhypercatabolism.54 In uremia extracellular osmolarity increasesdue to accumulation of urea. It is possible that the high extracel-lular urea gradient may cause cell shrinkage and protein degrada-tion by influencing the set point for volume regulatorymechanisms.54

RESISTANCE TO ANABOLIC HORMONES

Several hormonal derangements, including insulin resistance,hyperparathyroidism, hyperglucagonemia, and altered thyroidhormone metabolism, are also implicated as factors contributing toloss of lean body mass in CRF patients.1,2 A postreceptor defect ininsulin responsiveness of muscle is the cause of insulin resistanceoccurring in patients with CRF.56 However, it is not well under-stood whether insulin resistance regarding glucose metabolismalso extends to the antiproteolytic action of this hormone. If so, itwould contribute to the muscle wasting that is often found inuremic patients. Alvestrand et al.50 found that physiological hy-perinsulinemia obtained by the insulin clamp technique in dialysispatients was followed by a positive AA leg balance and a declinein intracellular AA that were similar to controls. More recently, ithas been shown that after euglycemic hyperinsulinemia, wholebody14C-leucine flux, leucine oxidation, and nonoxidative leucinedisposal of CRF patients are similar to the normal condition.57

Reaich et al.58 recently examined the effects of metabolic acidosison insulin sensitivity regarding both glucose and protein metabo-lism in moderately advanced CRF patients. Whole body13C-

leucine kinetics were measured in the basal state and after ahyperinsulinemic euglycemic clamp before and after alkali ther-apy. The correction of acidosis significantly increased whole bodyglucose disposal and decreased the basal leucine rate of appear-ance. However, the decline in leucine appearance during insulininfusion was similar, whether acidosis was present or not.58 Theseresults suggest that acidosis may contribute to the insulin resis-tance of CRF regarding glucose metabolism but does not seem toalter the insulin-mediated changes in whole body protein degra-dation during physiologic hyperinsulinemia.

Although the results of these studies suggest that the effect ofphysiologic hyperinsulinemia on whole body protein metabolismis not altered in uremic patients, there is still the possibility thatsubtle defects of insulin sensitivity occur at low insulin levels.Both in normal subjects14,59and in type II diabetes60 basal rates ofmuscle protein degradation as well as net proteolysis are inverselyrelated to insulin levels, suggesting that an inhibitory action ofbasal insulin levels on protein degradation takes place. However,such a relationship has not been found in renal patients,14 sug-gesting the occurrence of insulin resistance to basal insulin levelsin CRF. In this same setting, the degree of acidemia and serumcortisol levels are the major determinants of variations in muscleprotein balance.14

Clinical and experimental observations indicate that chronicrenal failure per se is characterized by a resistance to GH andIGF-1.52,53 Resistance to GH may be responsible for both thestunted growth of uremic children and an altered control of proteinmetabolism in the adult population. Circulating levels of GH arenormal or increased in CRF patients.52,53 Increased levels ofcirculating GH binding protein and a decrease in liver GH receptormRNA53,61may be involved in the pathogenesis of GH resistanceas observed in rats. Available evidence suggests that a resistanceto growth factors in CRF may be also due to circulating inhibitors.Both children and adults with CRF present an increased IGFbinding capacity, owing to an increase in the levels of insulin-likegrowth factor binding protein (IGFBP)-1, IGFBP-2, andIGFBP-3.52,53Moreover, the occurrence of circulating low molec-ular weight inhibitors of IGF-1 action is suggested by the obser-vation that hemodialysis increases the somatomedin bioactivity.62

A reduced protein or calorie intake, or both, may also enhance thealtered effects of GH or IGF-1, or both, in uremia.53

Recently, it has been found that in CRF rats there is also adirect end-organ resistance to IGF-1. The response of isolatedepithroclearis muscle to the anabolic effects of IGF-1 is blunted inrats with CRF,63 thus indicating that the skeletal muscle may be aprimary site of resistance to GH and IGF-1. More recently, it hasbeen shown that this alteration is due to a post-receptor defect.64

HEMODIALYSIS AND PROTEIN METABOLISM

It has been estimated that the protein requirements of predi-alysis CRF patients are similar to those of the normal population.Therefore, a daily protein intake of approximately 0.6 g/kg, witha “safe level” of 0.75 g/kg is needed to maintain N balance ofpatients with moderate-advanced CRF.1,2 However, both hemo-and peritoneal dialysis are associated with an increase in proteinrequirements. The safe protein requirements for dialysis patientsappears to be higher than in the normal condition and 1.2 gzprotein21 z kg21 z d21 may be required to obtain a positive Nbalance. However, surveys indicate that dialysis patients ofteningest an amount of calories or proteins, or both, lower than thatprescribed.1,2 Hemodialysis has long been considered a catabolicprocess. The nutrient losses during hemodialysis or peritonealdialysis are important components of dialysis-related catabo-lism.1,2 During hemodialysis there is an average loss of 6–10 g ofAA with minimal protein losses.1 Lim and coworkers65 studiedwhole body13C-leucine turnover before and after hemodialysis.


Hemodialysis was not associated with changes in whole bodyleucine appearance but with reduced non-oxidative leucine dis-posal, an index of whole body protein synthesis. The decrease inprotein synthesis is likely due to a decrease of the leucine bloodlevels during treatment, resulting from AA losses during thedialytic session. More recently, it has been shown that hemodial-ysis acutely decreases protein synthesis in muscle.66

Besides effects on circulating AA levels, extensive reports inthe literature indicate that activation of the alternate pathway ofcomplement is a major mechanism leading to adverse clinicaleffects during hemodialysis,1,2 with cellulosic membranes hav-ing the greatest effects. The exposure of whole blood to cellu-losic membranes result in leucocyte synthesis and release ofinterleukin-1 and tumor necrosis factor-a, which may inducemuscle protein degradation and excess AA release. However, ithas also shown that cytokine-specific inhibitory proteins such asinterleukin-1 receptor antagonist and soluble tumor necrosis factorreceptors are higher in uremia, raising questions concerning therole of cytokines in dialysis-related morbidity. A number of ex-cellent reviews deal with the effects of hemodialysis on cytokineproduction and the possible effects on nutrition.1,2

IMPAIRED ADAPTATION TO LOW NUTRIENT INTAKES

The body responds to a reduced intake of proteins with inte-grated and adaptive metabolic changes involving a reduction inAA oxidation with more efficient use of AA deriving from proteindegradation,67 a decrease in protein degradation and, ultimately, adecrease in whole body protein synthesis. Impaired ability toactivate these mechanisms would impair N conservation whennutrient intake is reduced because of anorexia or dietary interven-tion. It is interesting that an abnormal energy metabolism may alsoincrease N requirements in CRF.1,2 Muscle protein degradationincreases with the decreases in lipid stores in rats with CRF andthe release of lactate from muscle in rats with acute renal fail-ure.10,44 In patients with CRF, metabolic acidosis induces insulinresistance and impairs fat utilization.56 It has been suggested thatmetabolic acidosis can hinder in CRF patients the metabolicadaptations to a low protein/calorie intake or fasting.10,44 Thebody responds to metabolic acidosis with a variety of metabolicadaptations that contribute to the return of pH to normal values.40

There is general consensus on the concept that, although many ofthese adaptations are beneficial, the body’s response to excess acidingestion or production may also have detrimental consequencesto patients,10,68and imitates in some way the “trade off” responseleading to hyperparathyroidism.10,44The “trade off” for the adap-tation to chronic metabolic acidosis may include a loss of leanbody mass caused by stimulation of protein degradation whennutrient intake is reduced,10,44 bone mineral loss,68 and progres-sion of CRF.69 A few studies have been performed in renalpatients to evaluate the whole body metabolic response to a lowprotein intake. Goodship et al.70 observed that in non-acidoticpatients with moderate chronic renal failure the adaptive responseto a standard low protein diet (0.6 gz kg21 z day21), includedboth a normal decline in the rates of whole body leucine oxidationand protein degradation. Moreover, it has been shown that theadministration of a very low protein diet (0.28 gz protein21 zkg21) supplemented with ketoacids or AA in non-acidotic CRFpatients is followed by a neutral body nitrogen balance that isachieved by a marked reduction in whole body AA oxidation andpostprandial inhibition of protein degradation.71 Although theresults of these studies suggest that in patients with CRF theadaptation to a low protein intake is preserved, it is unknown ifpatients with severe uremia or metabolic acidosis, or both, alsoadapt normally.

The metabolic adaptations of protein metabolism occurring inmuscle of uremic patients in response to a low protein/energy

intake are even less known. Preliminary observations of our lab-oratory indicate that the adaptation to a low protein intake isfollowed by a marked reduction in muscle protein turnover inpatients with moderate-advanced CRF.51

CHANGES IN MUSCLE STRUCTURE AND REDUCTION OFNUTRITIVE BLOOD FLOW

Blood flow is a major determinant of protein turnover, as itmodulates the supply of AA, oxygen, and other nutrients toorgans. An emerging issue in studies on muscle perfusion is therole of the vasculature, which in conjunction with hormonal ef-fects plays an important role in the control of muscle metabolismand function.72 Although some hormones may act directly onmuscle by direct endocrine effects, a vascular component of theiraction is now showing. Actually, some effects of anabolic hor-mones, such as insulin and GH/IGF-1 on protein turnover, may bepartly mediated by an increase in peripheral blood flow and localnitric oxide production.73

Several reports indicate that both muscle structure and bloodflow are altered in renal patients and these changes could in turnimpair muscle nutrition and performance. In HD patients, even iftreated with erythropoietin, an impaired skeletal muscle functionis the most important factor limiting the capacity of exercise.63,74

Changes in muscle include atrophy with increased fibrous tissue,low skeletal muscle alkali soluble proteins, and increased intra-cellular water.74 Magnetic resonance imaging (MRI) studies sug-gest limitation of exchange of metabolites between muscle andblood because of dissociation between capillary supply and mus-cle cell requirements, presumably secondary to decreased capil-lary density.75 It has also been shown that nutritive blood flowmuscle of HD patients is impaired and that the response of bloodflow to exercise is reduced.75 Studies by MRI have documented asubnormal muscle oxidative energy metabolism and low activityof energy production enzymes in muscle of ESRD patients.74,76

The question has been raised as to whether the correction ofanemia could lead to an improved AA metabolism in uremia andmuscle function. It has been claimed that treatment with erythro-poietin can reverse many of the abnormalities in circulating AA.77

However, other studies have not confirmed theses findings.78

WHOLE BODY PROTEIN METABOLISM IN PATIENTS WITH CRF

Somewhat conflicting results have been obtained when rates ofwhole body protein synthesis and degradation have been com-pared in renal patients to healthy controls. Whole body proteinsynthesis and degradation and AA oxidation have been reported tobe normal65,70 or decreased57 in patients with moderately severeCRF and unrestricted diets. Berkelhammer and coworkers79 ob-served that HD patients with metabolic acidosis have decreasedprotein synthesis in the presence of normal protein breakdown. Onthe other hand, Lim and coworkers80 described normal rates ofwhole body protein turnover, yet enhanced proteolytic response tothyroid hormones in HD patients. Several factors may account forthese discrepancies: 1) the nutritional state and protein intake ofthe patients; 2) different stages of CRF and treatment modalities(i.e., HD patients versus patients with moderate CRF or patientstreated with peritoneal dialysis); and 3) acid-base status (i.e.,whether metabolic acidosis was present or not). However, it isdifficult to extrapolate data from whole body to muscle consider-ing that muscle accounts for no more than 25–50% of whole bodyprotein turnover.81 Moreover, it has to be underlined that thenormal kidney is characterized by a high protein turnover andaccounts for significant proportions of whole body protein turn-over and leucine oxidation.81 Therefore, the loss of metabolizingrenal tissue is expected to influence, at least in part, the overallwhole body rates of protein turnover and AA oxidation in CRFpatients.


TREATMENT OF MALNUTRITION WITH GROWTH HORMONE

Because malnutrition increases the risk of morbidity and mor-tality in HD patients, its prevention and treatment are of primaryimportance. In spite of the variety of nutritional strategies devel-oped to overcome this problem, none has proved to be effective.52

Recombinant human GH (rhGH) treatment causes protein anabo-lism and reduces N losses in a variety of catabolic conditions.52

Several studies indicate that rhGH causes an anabolic action inanimals with CRF.2,52A few studies in humans with CRF indicatethat rhGH may improve N balance, diminish ureagenesis, andameliorate some biochemical nutritional parameters.2,52 Howeverit is a topic for discussion, given the impairment of metabolicactions of GH in uremia, whether rhGH administration in mal-nourished CRF patients is followed by any favorable action onmuscle protein metabolism.

Recently, we evaluated the effects of a short course of rhGH onmuscle protein metabolism in a group of HD patients with protein-calorie malnutrition.82 Protein turnover was estimated by using theforearm perfusion technique associated with3H-phenylalanineinfusion.14,59Patients had lost weight during intercurrent illnessesmore than 6 mo before the study and had a stabilized, chronicmalnutrition. Although their protein intake was 0.9–1.4 g/kg, avalue that is considered safe for this patient population, theircalorie intake was lower (28–30 kcal/d) than prescribed (30–35kcal). At the baseline patients presented circulating IGF-1 andIGFBP-3 levels in the normal range, whereas IGFBP-1 was in-creased several times over normal values.82 This pattern of alteredIGFBP profile has previously been described in children withCRF, and is supposed to reduce the amount of free IGF-1, thuscurtailing its bioavailability to tissues.53

Baseline rates of appearance and disposal of phenylalaninemeasured in this group of malnourished patients were about 30%lower than those measured in well-nourished CRF patients underunrestricted diets.14 During all the protein turnover studies the rateof appearance of phenylalanine from the forearm (an expression ofmuscle protein degradation) was higher than the rate of disposal(an expression of muscle protein synthesis), in keeping with thenegative protein balance occurring in muscle in the postabsorptivestate. However, after a 6-wk rhGH course, the forearm phenylal-anine net balance decreased by 46% and the phenylalanine rate ofdisposal increased by 25%, with no change in the phenylalaninerate of appearance.82

The effects of GH on protein anabolism are considered mainlyto be mediated by IGF-1. However, the potential interactions ofGH and IGF-1 are complex: on one hand the action of GH maydepend exclusively on IGF-1; on the other hand GH may actdirectly via its own tissue receptors. The actions of IGF-1 appeareven more complex when looking at the IGFBPs and their possi-ble control of the biological action of IGF-1. It has been suggestedthat, in physiologic states as well as in pathologic conditions, theextent of IGF-1 binding, rather than total serum IGF-1 levels perse, is predictive of the IGF-1 metabolic effects.53 Our studystrongly suggests that the improvement in muscle protein balanceobserved in malnourished renal patients occurs as a consequenceof an increase in free, but not total, IGF-1 levels and that theincreased binding capacity present in patients with CRF is likelya cause for resistance to GH action. After rhGH, serum IGF-1increased by 36% and this rise was associated with a less prom-inent increase in IGFBP-3 levels and, particularly, with a decreasein IGFBP-1. Moreover, we observed no relationship between therates of protein synthesis or degradation and serum levels of IGF-1and IGFBPs. There was also no relationship between changes inthe net forearm phenylalanine balance and serum IGF-1. More-over both in the rhGH and wash-out periods the percent decreasein forearm phenylalanine net balance was directly related to serum

IGFBP-1 levels (Fig. 5) and, inversely, to the percent increase inthe IGF-1/IGFBP-3 ratio (Figs. 6 and 7). As shown by multipleregression analysis, these two factors accounted for a substantialproportion (more than 60%) of variations in net protein balance,thus suggesting that the amount of IGF-1 free from ligand bindingwith IGFBPs is responsible for the decreased muscle net proteincatabolism.

Complementing the results on protein turnover, total AA re-lease from the forearm decreased significantly after GH.82 Alsothe forearm release of BCAA declined markedly. This is in linewith the GH-related effects of reducing leucine oxidation andincreasing the use of leucine for protein synthesis. The diminishedmuscle output of BCAA was probably accompanied by a reducedutilization by splanchnic organs, in order to keep their circulatinglevels unchanged. There was also a marked decline in the forearmrelease of glutamine, whereas the glutamate uptake was aug-mented. It is tempting to speculate that intracellular glutaminelevels were increased by treatment, and this may have favorableeffects on protein synthesis in muscle.21

These data indicate that a short-term rhGH treatment in chronic

FIG. 6. Relationship between percent decrease in the net forearm phenyl-alanine balance during and after recombinant human growth hormoneadministration and serum IGFBP-1 in malnourished hemodialysis patients.(Reproduced from Garibotto et al.82 J Clin Invest 1997;99:97, by copyrightpermission of The American Society for Clinical Investigation.)

FIG. 7. Relationships between percent decrease in the net forearm phe-nylalanine balance and percent increase in the serum IGF-1/IGFBP-3 ratioduring and after growth hormone administration. (Reproduced from Gari-botto et al.82 J Clin Invest 1997;99:97, by copyright permission of TheAmerican Society for Clinical Investigation.)


malnourished HD patients is followed by an increase in muscleprotein synthesis and by a decrease in the negative muscle proteinobserved in the postabsorptive state. Several short-term studiesalso document favorable effects on nutritional parameters.2 Theseeffects, if sustained during chronic therapy, could substantiallyimprove nutrition in malnourished renal patients.

SUMMARY

In conclusion (see Fig. 8), recent studies performed in animalsand humans have consistently increased our knowledge of effectsof uremia on muscle protein and AA metabolism. However, theprimary mechanisms for net muscle protein loss in patients withchronic renal failure are not completely understood. Availableevidence suggests that catabolic factors appear to be different forpatients at different stages of CRF and different modalities oftreatments. Both nutritional requirements and prevalence of mal-nutrition increase with progression towards ESRD and the dura-tion of uremia. Muscle protein degradation is increased by meta-bolic acidosis, which is often encountered in uremic patients.Another relevant but less proven cause for an increase in proteindegradation is insulin resistance. On the other hand, specificdefects in muscle AA metabolism, resistance to GH or IGF-1, orboth, or a very low protein or calorie intake can reduce muscleprotein synthesis. Moreover, the hemodialytic procedure per se

can stimulate protein breakdown or reduce protein synthesis.Oxidation of essential amino acids, mainly leucine, may be in-creased by metabolic acidosis. Reduced muscle pools of leucineand ketoleucine might, in turn, increase protein degradation. Allthese factors may potentiate the effects of concurrent catabolicillnesses, anorexia and physical inactivity that are often encoun-tered in uremic patients.

These observations outline how the sensitive sequences ofchecks and balances by which protein metabolism is controlledcan be influenced by the uremic state. These observations alsostress the need for in vivo human studies to fully shed light on thealterations of protein and AA metabolism associated with uremia.

ACKNOWLEDGMENTS

The authors are grateful to Francesca Tincani and Gilda Palmafor their assistance in the preparation of the manuscript andfigures. The studies were supported by grants from Baxter (Ex-tramural Grant Program), the Ministero dell’Universita` e dellaRicerca Scientifica e Tecnologica (Assegnazione per la ricercascientifica 40%), and by grants from the National Research Coun-cil (CNR)-Target project “Prevention and Control Disease Fac-tors; Subproject Sp 1 Alimentazione” and Progetti di Ricerca diAteneo Universita` di Genova.

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