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Purpose of Review: Despite technological innovations in renal replacement therapy, mortality is still high in patients with end-stage renal disease. This increase in mortality is not only limited to dialysis patients, but also includes all stages of chronic kidney disease (CKD) and is mainly because of cardiovascular disease. Protein-energy wasting becomes clinically manifest at an advanced CKD stage, early before or during the dialytic stage, and increases the morbidity and mortality in this patients' population. The purpose of this article is to review the recent observations on alterations of amino acid and protein metabolism which cause wasting and increase cardiovascular risk., Recent Findings: Recent studies have consistently increased our understanding of mechanisms causing wasting and vascular disease in CKD patients. These include changes in amino acid and lipoprotein metabolism potentially leading to alterations of biology and function of the vascular wall, anorexia and endocrine dysfunction, altered muscle intracellular signaling through the insulin receptor substrate/phosphatidylinositol 3-kinase/Akt pathway, and defective myocyte regeneration. These mechanisms may trigger wasting through an increase in protein degradation and/or acceleration of apoptotic processes in skeletal muscle and may be accelerated by hemodialysis, leading to progression of vascular disease and wasting., Summary: The new understanding holds promise for new treatments which can prevent/treat vascular diseases and wasting in CKD patients.

The progressive loss of kidney function in patients with chronic kidney disease (CKD) is associated with a number of complications, including cardiovascular diseases, anemia, hyperparathyroidism, inflammation, metabolic acidosis, malnutrition and protein-energy wasting. The excess cardiovascular risk related to CKD is due in part to a higher prevalence of traditional atherosclerotic risk factors, in part to non-traditional, emerging risk factors peculiar to CKD. While even minor renal dysfunction is an independent predictor of adverse cardiovascular prognosis, nutritional changes are more often observed in an advanced setting. In addition, factors related to renal-replacement treatment may be implicated in the pathogenesis of heart disease and protein-energy wasting in dialysis-treated patients. Progressive alterations in kidney metabolism may cause progressive effects on cardiovascular status and nutrition. Altered kidney amino acid/protein metabolism and or excretion may be a key factor in the homeostasis of several vasoactive compounds and hormones in patients with more advanced disease. In this discussion recent research regarding the kidney handling of amino acids and protein turnover and their potential link with cardiovascular disease, progressive kidney dysfunction and nutritional status are reviewed., (Copyright 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

This review is concerned with the status of our current research related to the exchange of amino acids across organs. Accumulation of knowledge regarding how amino acid pools are maintained within the body remains a work in progress. In recent years, the use of organ balance measurement techniques in combination with isotopic tracers has much increased our understanding of the role of the kidney and splanchnic organs in amino acid metabolism, and in kidney and liver gluconeogenesis from amino acids. An interorgan cooperation between the kidney and splanchnic organs for leucine-ketoisocaproate metabolism has also been demonstrated.

The mechanisms controlling protein metabolism in the human kidney are not well understood. During adult life, kidney protein content and the size of the kidney remain fairly constant, indicating that protein synthesis and degradation within the kidney are tightly regulated. However, kidney protein turnover may change in response to stimuli such as alterations in substrate availability, hormones or growth factors, acid-base balance, renal work or renal injury with a progressive decrease in the number of nephrons. These factors have been evaluated mainly in animals, in vitro or in vivo. Amino acids, the kidneys substrates for protein synthesis, are provided by several routes. Like in other organs, amino acids can reach the kidney cells through the arterial blood flow. However, they may also come from the degradation of reabsorbed low-molecular weight proteins filtered by the glomerulus. The human kidney has high rates of protein turnover and leucine oxidation. The magnitude of the protein turnover across the human kidney suggests that the protein dynamics is partly determined by intrarenal protein catabolism. As evaluated by a steady-state leucine multiple compartment analysis, kidney protein synthesis is dependent to a similar extent on intrarenal generation of amino acids from protein breakdown and from amino acids taken up from the arterial blood. Kidney mass may therefore depend not only on the availability of free amino acids, but also on filtered proteins which are degraded within the kidney. Future studies could define the mechanisms, metabolic pathways and mediators influencing kidney protein turnover in humans, with a view to better comprehension of the mechanisms of disease.

Malnutrition is frequently observed in patients with end-stage renal disease. Studies indicate that poor nutritional status plays a major role among factors adversely affecting patients outcome. Therefore prevention and treatment of malnutrition in renal patients is a major issue. In this article the potential mechanisms for alterations in muscle protein metabolism in uremia are explored. 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 amino acid metabolism. Available evidence suggests that catabolic factors appear to be distinct for patients at different stages of chronic renal failure and require different modalities of treatments. Both nutritional requirements and the prevalence of malnutrition increase as end-stage renal disease progresses. Muscle protein degradation is increased by metabolic acidosis, which is often found 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, or a very low protein intake can reduce muscle protein synthesis. Finally, the hemodialytic procedure per se can stimulate protein breakdown or reduce protein synthesis. All these factors may potentiate the effects of concurrent catabolic illnesses, anorexia, and physical inactivity often found in uremic patients.

Metabolic acidosis causes a cooperative participation of different organs such as the liver, kidney, and muscle in restoring acid-base balance. In splanchnic organs, metabolic acidosis has repercussions on several nitrogen metabolism pathways. The decrease in urea synthesis due to reduced activity of urea cycle enzymes, ammonia uptake and amino acid transport, and changes in glutamine metabolism support renal ammoniagenesis thus offering a response to rid the body of excess protons. While some of the mechanisms are adaptive others may be harmful for the body. Metabolic acidosis may have effects on splanchnic protein turnover. In severe acidosis, synthesis of secreted liver proteins may be reduced. Acidosis may also modulate the response of the liver to growth hormone (GH) for insulin-like growth factor-I synthesis, thus inducing a state of GH resistance. Splanchnic abnormalities in acidosis might contribute to the malnutrition observed in uremia.

Muscle exchange of amino acids (AAs) was evaluated by using the arteriovenous-difference technique across the leg in seven patients with chronic renal failure (CRF) and eight control subjects before and for 75 min after the ingestion of an AA mixture simulating an animal-protein meal. Total AAs increased in arterial blood much more in patients with CRF after AA ingestion than in control subjects, as a consequence of an exaggerated increase in nonessential AAs (NEAAs) (+127%). Moreover, total AAs were taken up by the leg in larger amounts than in control subjects (+71%, P < 0.0025) because of increased uptake of NEAAs (+156%, P < 0.005). Branched-chain AA uptake by the leg was, in absolute values, similar to that of control subjects; however, because of the increased uptake of total AAs, branched-chain AA uptake was only 30% of total AA extraction, compared with 46% in control subjects. Abnormalities in AA uptake by muscle paralleled those in arterial AAs. In fact the same AAs that increased abnormally in blood were taken up by the leg at higher rates than in control subjects. Variations in arterial concentrations and muscle uptake of AAs were inversely related to arterial bicarbonate concentration, suggesting a role for acid-base status in modifying both the arterial supply and muscle metabolism of AAs. Results indicate that in CRF patients the normal pattern of postprandial AA repletion is disrupted. Muscle tissue faces the increased and unbalanced postprandial supply of AAs with an augmented and unbalanced uptake. Data are consistent with an abnormal use of exogenous AAs in CRF patients, possibly induced by metabolic acidosis.

Arterial whole blood levels of amino acids were determined in patients with chronic renal failure and in healthy subjects before and after 270 min after the ingestion of a grilled beefsteak (4 g/kg). In patients, total nonessential amino acids increased significantly more (+46%) than in controls owing to an exaggerated rise of serine, glutamine, proline, glycine, cyst(e)ine and alanine. Total essential amino acids increased as much as in controls; however, threonine, histidine and phenylalanine showed greater increases, while tryptophan had a smaller increment. Abnormalities in amino acid levels were even more evident in the postprandial period than in the postabsorptive state owing to reduced levels of valine, leucine, tryptophan, tyrosine, aspartate and glutamate and higher levels of glutamine, proline, glycine, cyst(e)ine, threonine, histidine and phenylalanine. Moreover, after the meal, the ratios total essential amino acids/total nonessential amino acids, valine/glycine, and branched-chain amino acids/total amino acids rose but persisted to be reduced whereas tryptophan/total amino acids and tyrosine/phenylalanine ratios increased in controls, but did not change in patients. In conclusion, in chronic renal failure, protein ingestion enhances the imbalance in amino acid levels already present in the postabsorptive state. The all data indicate that in patients with chronic renal failure, the metabolism of exogenous protein is impaired and the flow of amino acids to the organs is altered during the phase of body nitrogen replenishment.

Muscle protein turnover and amino acid (AA) exchange were studied in 4 patients with chronic renal failure (CRF) and in 5 controls in the postabsorptive state by using the forearm perfusion method together with the systemic infusion of 3H-Phe. In CRF patients muscle protein breakdown is increased and is associated with a parallel increase in protein synthesis. Protein breakdown is inversely related to arterial bicarbonate. Net proteolysis is unchanged. The release of total AA, glutamine and alanine is not different from controls, whereas the release of valine and leucine is reduced and serine uptake tends to be decreased. In conclusion, in postabsorptive patients with CRF, well before the uremic stage, an increased protein breakdown associated with metabolic acidosis takes place; net proteolysis is unaffected. Alterations in BCAA metabolism suggest the occurrence of increased BCAA degradation proceeding beyond the transamination step.

Renal metabolism of amino acids (AAs) was evaluated in 5 patients with early IDDM, and in 7 controls (C) in the basal state for 80 minutes after the ingestion of an AA mixture simulating an animal protein meal. Insulin was withdrawn 20 hours before the study. Renal metabolism of AAs was evaluated by the arterial-venous difference technique. In the basal state in IDDM, as in C, the kidney takes up large amounts of a few nonessential AAs (NEAAs): it releases many NEAAs and a few essential AAs (EAAs). After AA ingestion in C, renal extraction of most EAAs, mainly BCAAs, Lys, and Thr, occurs; Pro extraction also increases and a significant uptake of Gly, Glu, Asp, Orn, and Tyr takes place. EAA extraction accounts for 30-40% of total AA uptake. In IDDM, after AA ingestion, a) renal uptake of total AAs is significantly lower, owing mainly to a markedly lower uptake of BCAAs, Lys, and also of Pro, Orn, and Ala; b) renal EAA uptake accounts for less than 20% of total AA extraction. These results indicate that in IDDM postprandial renal N repletion is impaired and unbalanced.

Splanchnic exchange (net uptake or release) of amino acids (AAs) was evaluated by measuring arterial-hepatic venous differences for AAs and hepatic blood flow in patients with chronic renal insufficiency (CRI) and control subjects before and for 70 min after the ingestion of an AA mixture simulating an animal protein meal. In CRI after AA ingestion, splanchnic exchange area for total nonessential AAs (NEAAs) is increased 135% over control subjects because of an augmented escape of proline, glutamate, serine, glycine, alanine, and cyst(e)ine; contrarily, glutamine shows an increased splanchnic uptake. Splanchnic exchange area for total essential AAs (EAAs) is increased only by 67% over controls because of a higher escape of threonine, isoleucine, phenylalanine, and histidine. Abnormalities in arterial areas for AAs parallel those in splanchnic areas except for glutamine and isoleucine. Data indicate that in CRI, at least for 70 min after an AA meal, splanchnic organs metabolize abnormally ingested AAs and export an increased and unbalanced bulk of AAs, severely affecting postprandial arterial profile of AAs.

The study of amino acid metabolism across the splanchnic organs can be useful for investigating derangements in nitrogen metabolism in chronic renal insufficiency. For this purpose, arterial-hepatic venous differences for 19 free amino acids, ammonia and urea, determined in whole blood, were measured in six patients with chronic renal insufficiency and in six subjects with normal renal function. In normal conditions, the hepatosplanchnic bed significantly extracts glutamine, alanine, glycine, serine, threonine, lysine, arginine, phenylalanine, valine, tyrosine, histidine, leucine, and ammonia, and releases glutamate, citrulline, and urea. In chronic renal insufficiency, glutamine uptake decreases, serine, valine and ammonia uptake disappears, proline extraction becomes present, citrulline output is no longer detectable and glutamate release falls slightly. Furthermore, the splanchnic uptake of ammonia and the output of urea into the hepatic veins are markedly reduced. Since glutamine and ammonia are major substrates for urea synthesis, their lower uptakes, as observed in renal insufficiency, may be consistent with the reduced urea output. The changes in splanchnic metabolism observed in chronic renal insufficiency have a minor effect on the abnormalities in circulating amino acids. Finally, the splanchnic metabolism shows an important role in the homeostasis of circulating tyrosine and proline.

Arterial portal-venous differences (A-PV) of ammonia (NH3) and amino acids (AA) were measured in patients with chronic renal insufficiency (CRI) and in controls. In CRI, NH3 release by the portal-vein-drained viscera (PDV) is not different from controls, Gln uptake decreases, Glu extraction occurs, Pro and Thr output increases and Ser release becomes evident; one third of N released as NH3 and AA can be accounted for by Gln and Glu uptake. The N exchange across the PDV is similar in CRI and in controls.

The net renal metabolism of amino acids and ammonia in the post absorptive state was evaluated in subjects with normal renal function and in patients with chronic renal insufficiency by measuring renal uptake and release, and urinary excretion of free amino acids and ammonia. In normal subjects the kidney extracts glutamine, proline, citrulline, and phenylalanine and releases serine, arginine, taurine, threonine, tyrosine, ornithine, lysine, and perhaps alanine. The renal uptake of amino acids from arterial blood occurs by way of plasma only, whereas approximately a half of amino acid release takes place by way of blood cells. Glycine is taken up from arterial plasma, while similar amounts of this amino acid are released by way of blood cells. In the same subjects total renal ammonia production can be largely accounted for by glutamine extracted. In patients with chronic renal insufficiency (a) the renal uptake of phenylalanine and the release of taurine and ornithine disappear; (b) the uptake of glutamine and proline, and the release of serine and threonine are reduced by 80--90%; (c) the uptake of citrulline and the release of alanine, arginine, tyrosine, and lysine are reduced by 60--70%; (d) no exchange of glycine is detectable either by way of plasma or by way of blood cells; (e) exchange of any other amino acid via blood cells disappears, and (f) total renal ammonia production is reduced and not more than 35% of such production can be accounted for by glutamine extracted, so that alternative precursors must be used. A 140% excess of nitrogen release found in the same patients suggests an intrarenal protein and peptide breakdown, which eventually provides free amino acids for ammonia production.

Arterial whole blood levels of amino acids (AA) were determined in patients with chronic renal failure (CRF) and in healthy volunteers before and for 75 min after the ingestion of an AA mixture simulating the AA content of an animal-protein meal. In CRF patients, total AA increased more than in control subjects as a consequence of an exaggerated rise in nonessential AA (+86%), mainly glutamine, proline, glutamate, serine, glycine, and alanine. Total essential AA in patients increased as much as in control subjects; however, threonine and phenylalanine showed greater increases while leucine had a smaller increase. As a consequence of the observed alterations, a striking unbalance in the postprandial pattern of arterial AA ensued in CRF patients. The flow of AA to all the organs is altered during the absorptive phase, which is crucial for body nitrogen-pool replenishment.

Leg metabolism of amino acids and ammonia in the postabsorptive state was evaluated in 10 patients with chronic renal failure (CRF) and in 10 patients with normal renal function (controls) by measuring the arterial-femoral venous (A-FV) differences for free amino acids and ammonia. Total amino acid release from the leg and alanine and glutamine release, which accounts for the greatest amount of the total amino acid release, are similar in patients and controls. Total amino acid uptake from the arterial blood and glutamate uptake, which is the amino acid extracted at the highest rate, are comparable in both groups. Taken together these data, in addition to the similarity of A-FV differences for proteolytic markers, namely tyrosine, phenylalanine and histidine, suggest that protein breakdown in peripheral tissues is not increased in patients with CRF. In CRF selective metabolic abnormalities for some amino acids are evident. Whilst only the A-FV differences for valine, leucine and isoleucine are decreased, additional alterations are observed by relating the A-FV difference for each amino acid to that of proteolytic markers. Such a procedure demonstrates that in CRF histidine release relative to that of proteolytic markers is reduced, whereas proline and arginine release is increased. In CRF the reduced release of some amino acids, mainly branched-chain amino acids, by the leg probably affects the pattern of circulating amino acids. Finally, both in patients and in controls a significant uptake of ammonia is observed; the ammonia uptake is related to arterial levels of this metabolite, confirming the role of peripheral tissues in removing ammonia from circulation.