Current Opinion in Clinical Nutrition & Metabolic Care:
PROTEIN, AMINO ACID METABOLISM AND THERAPY: Edited by Olav Rooyackers and John Brosnan
Effect of kidney failure and hemodialysis on protein and amino acid metabolism
Garibotto, Giacomo; Bonanni, Alice; Verzola, Daniela
Department of Internal Medicine, University of Genoa, Azienda Ospedaliera Universitaria San Martino, Genoa, Italy
Correspondence to Giacomo Garibotto, MD, Division of Nephrology, Department of Internal Medicine, Viale Benedetto XV 6, 16132 Genoa, Italy. Tel: +39 0103538989; fax: +39 01035389589; e-mail: email@example.com
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.
Despite technological innovations in dialytic treatment have led to extraordinary advances in the care of patients with chronic kidney disease (CKD), mortality and morbidity persist to be high in this patients’ population. Although even minor renal dysfunction is an independent predictor of adverse cardiovascular prognosis, malnutrition and cachexia become clinically manifest at an advanced stage, early before or during the dialytic stage. In patients with end-stage renal disease (ESRD), malnutrition is strongly associated with cardiovascular mortality . Uremia-induced alterations in protein metabolism and gastrointestinal tract function can result in poor nutritional status, which in turn increases the risks of cardiovascular disease (CVD) and infection. The classical risk factors for CVD are over-represented in the CKD population, which almost consists of patients affected by hypertension and diabetes. However, the excess of risk related to CKD may be due in part to a higher prevalence of nontraditional risk factors peculiar to CKD which per se may promote endothelial dysfunction and/or atherogenesis. 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 in CKD.
THE HANDLING OF S-ADENOSYLHOMOCYSTEINE BY THE HUMAN KIDNEY
Methylation processes play a major role in the epigenetic regulation of protein expression, and changes in human DNA methylation patterns are an important feature of many diseases, including atherosclerosis and cancer . S-Adenosylhomocysteine (SAH) accumulates in blood in uremia. As SAH is a potent feedback inhibitor of most methyltransferases, this compound plays an essential role in the control of transmethylation rates. To explore the sites and mechanisms underlying the regulation of circulating SAH levels, the arterio-venous differences of SAH were measured across the kidney, splanchnic bed and lung in patients undergoing venous catheterizations . The lungs did not remove or add any circulating SAH, whereas the liver released it into the hepatic veins. The kidney extracted 40% of arterial SAH and the SAH arterio-venous difference across the kidney was directly related to its arterial levels. Thus, the kidney plays a major role in maintaining SAH levels and may, indirectly, control tissue transmethylation reactions (see  for review).
ALTERED METABOLISM OF ASYMMETRIC DIMETHYLARGININE
The generation of nitric oxide from L-arginine plays a central regulatory reaction in the endothelium. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase which causes endothelial dysfunction and aggravates experimental atherosclerosis. ADMA is elevated in the plasma of patients with CKD and is an independent marker of progression of renal dysfunction, vascular complications and death. Lu et al.[5▪▪] recruited 298 consecutive CKD patients scheduled to undergo coronary angiography and measured plasma ADMA and estimated glomerular filtration rate (eGFR). The plasma ADMA levels correlated significantly with eGFR. During the median follow-up period of 2.7 years, multivariate Cox analysis revealed that an increase of 0.1 μmol/l in plasma ADMA level was associated with a 37% increased risk of all-cause deaths, nonfatal myocardial infarctions, and strokes. In another study, Luksha et al. showed that arterial flow-mediated dilatation is attenuated and nitric oxide contribution to flow is lacking in ESRD patients. The mechanisms underlying the increase in plasma ADMA in CKD patients are not clearly understood, and include loss of renal clearance and decreased metabolism by liver dimethylarginine dimethylaminohydrolase 1 and 2 (DDAH). A better understanding of the biochemical pathways that regulate ADMA homeostasis in patients with CKD can provide a rationale for the development of targeted therapies. Pharmacological modulation of DDAH is now proposed to lower ADMA concentrations, regulating the production of nitric oxide .
Patients with proteinuria exhibit reduced very low density lipoprotein (VLDL) apoB-100 removal as well as increased albumin and fibrinogen secretion rates. In addition, CKD per se is associated with reduced HDL and low-density lipoprotein (LDL) and an increase in plasma triglycerides (see  for review). These changes inhibit vascular relaxation and are associated with CVD. In addition to reducing HDL levels, CKD may impair HDL structure and function. Holzer et al.[9▪▪] used mass spectrometry and biochemical analysis to investigate proteome and lipid composition of HDL in hemodialysis patients. They found an increased amount of acute-phase protein, serum amyloid A1, albumin, lipoprotein-associated phospholipase A2 and apoC-II in HDL from uremic patients, whereas the HDL content of phospholipid was reduced. These changes may inhibit HDL cardioprotective properties in uremia. To identify the mechanisms underlying the increase of apolipoprotein C III (apoC-III), a competitive inhibitor of lipoprotein lipase, Ooi et al.[10▪] investigated the kinetics of plasma apoC-III in patients with moderate CKD. The elevated plasma apoC-III concentration in patients with CKD was chiefly a consequence of impaired catabolism of apoC-III. In addition, they observed that elevated apoC-III concentration was associated with elevated VLDL cholesterol and VLDL triglyceride concentrations. These data indicate that altered plasma apoC-III metabolism is a feature of dyslipidemia in CKD which might affect CVD risk already in patients with moderate disease.
MECHANISM OF WASTING IN EXPERIMENTAL UREMIA AND IN CHRONIC KIDNEY DISEASE PATIENTS: ANOREXIA
Anorexia and endocrine dysfunction independently play an important role in wasting (see  for review) and could be responsible for alterations of the vascular wall. Suneja et al.[12▪] described a combination of hormonal abnormalities involved in the regulation of energy homeostasis (high leptin, peptideYY, and neuropeptideY with suppressed ghrelin), which might predispose dialysis patients to adverse vascular events.
SPLANCHNIC PROTEIN TURNOVER IN METABOLIC ACIDOSIS
Metabolic acidosis is common in CKD patients and causes wasting  by increasing protein catabolism. Its effects on splanchnic protein turnover and energy expenditure have never been studied in humans. Tessari et al.[14▪▪] investigated the effects of experimentally induced, chronic metabolic acidosis (mean HCO3 = 17 mmol/l) on splanchnic protein dynamics and oxygen consumption in humans by using a leucine tracer and mass-balance technique. On the basis of plasma measurements, patients with metabolic acidosis showed reduced protein synthesis rates and a negative splanchnic leucine balance. However, based on measurements in whole blood, splanchnic protein degradation and synthesis did not differ significantly between acidotic and control individuals. These data show that moderate acidosis reduces splanchnic protein turnover and results in a negative leucine balance, an effect that apparently is offset by the contribution of blood cells to protein dynamics. As an additional finding, the authors observed that protein synthesis itself accounts for a major proportion (∼67%) of splanchnic energy expenditure. The same study provides an estimate of the energy cost for each gram of protein synthesis (∼24.1 kJ) in splanchnic organs. This figure is remarkably similar to 21.5 kJ/g protein reported by early studies in animals .
INSULIN RESISTANCE AND DEFECTIVE IRS/PI3K/AKT SIGNALING IN SKELETAL MUSCLE
An acceleration of muscle protein breakdown, which depends on the upregulation of the ubiquitin–proteasome system, is a feature of animal models of atrophy [16▪]. Bailey et al. recently identified a series of abnormal postreceptor signaling changes in the insulin/IGF-1 pathway in the muscle of rats with CKD which lead to decreased phosphorylation of the downstream effector Akt (pAkt). The low pAkt activity has been shown to stimulate the expression of specific E3 ubiquitin-conjugating enzymes, atrogin-1/MAFbx and MuRF1. Further, a decrease in muscle PI3K activity could activate Bax leading to stimulation of caspase-3 activity and increase protein degradation. It is interesting that these catabolic responses are partially abolished by the activity of the X chromosome-linked inhibitor of apoptosis protein XIAP [18▪], suggesting that apoptosis and enhanced protein degradation share common mechanisms in the regulation of muscle physiology.
Resistance to growth hormone (GH)/IGF-1 causes growth retardation in uremic children. Recently, Chen et al.[19▪▪] observed decreased GH-stimulated JAK2 transducers and activators of transcription 5 (STAT5) phosphorylation and nuclear translocation in uremic rodents. In addition, they observed that the binding of available phospho-STAT5b to DNA is decreased, thus contributing to impaired IGF-1 gene expression in the liver. It is interesting that endotoxin-induced inflammation markedly increases the resistance to GH-mediated STAT5b signaling, and further decreases STAT5b binding to DNA and IGF-1 gene expression. These perturbations appear to be related to increased cytokine expression . Overall, these observations indicate that resistance to GH-induced IGF-1 expression in uremia arises because of defects in STAT5b phosphorylation and its impaired binding to DNA, and that these processes are further aggravated by inflammation. These observations are important, as sepsis-induced inflammation is relatively common in uremia and causes wasting.
Impaired function of satellite cells is another possible link between impaired insulin/IGF-I signaling and wasting [21▪▪]. Isolated satellite cells from mice with CKD had less MyoD and suppressed myotube formation. In vivo, CKD delayed the regeneration of injured muscle and decreased MyoD and myogenin expression. These observations suggest that CKD impairs the proliferation and differentiation of satellite cells. Taken together, impaired IGF-1 signaling in CKD might lead not only to abnormal protein metabolism, but also to impaired satellite cells’ function in muscle. These signaling pathways may hold potential therapeutic targets to reduce CKD-related muscle wasting and need further studies in humans.
INFLAMMATION AND MYOKINES
Although myokines are considered to exert a beneficial anti-inflammatory effect in diabetes and atherosclerosis , circulating interleukin (IL)-6 is a strong positive predictor of mortality and morbidity in CKD patients . Studies from two different laboratories have documented an upregulation of IL-6 expression and release from skeletal muscle of CKD patients in the basal state  or during hemodialysis , suggesting that peripheral tissues are a major site for IL-6 export. The release of IL-6 from peripheral tissues is associated with increased muscle net protein catabolism, indicating that muscle IL-6 per se is either cause or consequence of a catabolic condition. Recently, Zhang et al.[26▪▪] in a rodent model of CKD demonstrated that myostatin is upregulated in skeletal muscle and that myostatin suppression decreased the levels of circulating inflammatory cytokines, including TNF-α and IL-6. Moreover, they observed that TNF-α stimulates myostatin expression, whereas myostatin stimulates IL-6 production. This study sheds light on the involvement of multiple catabolic signal transduction pathways which may promote wasting and impair muscle regeneration in uremia. Recently, Verzola et al.[27▪] observed an upregulation of myostatin gene expression in skeletal muscle of predialysis CKD patients. Myostatin was associated with IL-6 gene expression and upregulated phosphorylated JNK, suggesting that microinflammatory changes taking place in muscle cells and myostatin are also metabolically linked in humans.
ALTERED BRANCHED-CHAIN AMINO ACID METABOLISM
Reduced intake and increased muscle oxidation account for low branched-chain amino acid (BCAA) circulating pools in patients with CKD . It is of note that leucine cooperates with IGF-1 in stimulating the activation of myogenic satellite cells, which are responsible for muscle regeneration. The leucine-induced activation of satellite cells depends on the mammalian target of rapamycin (mTOR) signaling. Chen et al.[29▪] established that CKD impairs basal leucine-induced signaling through the mTOR pathway. However, despite this abnormality, leucine was able to partially stimulate this signaling pathway. Thus, even though there is some resistance to leucine in CKD, the data suggests a potential role for leucine-rich supplements in the management of uremic muscle wasting.
ACCELERATED APOPTOSIS IN SKELETAL MUSCLE
In the pathogenesis of muscle atrophy, the loss of skeletal myonuclei by apoptosis also needs to be considered . Failure in the satellite cells and/or the decrease in the availability or sensitivity to growth factors which are necessary to maintain muscle mass and satellite cell survival could cause sarcopenia and atrophy. In-vivo time-lapse microscopy [31,32] supports the concept that apoptosis in atrophy regards mainly nonmyocyte cells (satellite cells and stromal cells). In animal models, uremia impairs the proliferation and differentiation of satellite cells and delays the regeneration of injured muscle [21▪▪]. These events appear to follow CKD-induced impaired Akt phosphorylation. Recently, Verzola et al.[27▪] analyzed muscle apoptosis and myostatin mRNA and their related intracellular signals in rectus abdominis samples obtained from stage V CKD patients before the beginning of peritoneal dialysis. Apoptosis, determined both by antisingle-stranded DNA antibody and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay (TUNEL), was three-fold to five-fold increased and was related to low pAkt. Even if only a few of apoptotic satellite cells were observed, it is possible that an imbalance between regeneration and loss processes takes place in the muscle of patients with CKD, as demonstrated recently in rodents with CKD [21▪▪]. Therefore, this issue needs to be specifically addressed in humans.
EFFECTS OF HEMODIALYSIS ON PROTEIN METABOLISM
Hemodialysis has a two-edge sword effect on the nutritional state of patients with CKD. On the one hand, the recommended hemodialysis dose (corresponding to a GFR of about 12 ml/min) is sufficient enough to increase appetite and nutrient intake in anorectic patients with stage V CKD. On the other hand, hemodialysis-related factors can boost the risk of wasting and CVD. It appears more and more important to administer an ‘ideal’ treatment that can get as close as possible to the glomerular basement membrane, using biocompatible (which do not cause complement activation) dialysis membrane to effectively remove a wide range of substances. A further need is to eliminate the risk of endotoxin-contaminated dialysate. A hemodialysis session may impair protein metabolism in different ways: because of the associated losses of amino acids and because of the promotion of net protein catabolism by the process itself. About 6–12 g of amino acids are lost in the dialysate per hemodialysis session . However, amino acid loss could not account for changes in protein turnover observed in some studies , suggesting that other factors might be at play. Studies on the effects of hemodialysis on protein turnover have shown a dissociation between whole-body and muscle protein turnover (see [34,35] for review). Although whole-body protein turnover shows decreased protein synthesis after dialysis (an effect which may be explained by amino acid loss in the dialysate), protein breakdown is not increased. Muscle protein kinetics studies, however, identify enhanced muscle protein breakdown with inadequate compensatory increases in synthesis as the cause of the catabolism. A current hypothesis is that the microinflammatory state observed in a significant percentage of patients with CKD is boosted by hemodialysis, thus increasing the risk of cachexia and cardiovascular complications. Proinflammatory cytokines released from peripheral blood mononuclear cells and skeletal muscle during hemodialysis are likely to be the major factors in the sequence of catabolic events and may provide a link between wasting and cardiovascular events. An increase in C-reactive protein has been observed during a single dialysis session in 25% of patients and this increase was independently associated with a higher mortality risk . However, these findings could not be replicated in the study published by Meuwese et al.. During hemodialysis, direct correlations between IL-6 and synthesis rates of albumin and fibrinogen and muscle protein catabolism have been observed, suggesting that the cytokine activation by dialysis directly or indirectly promotes proteolysis  and blunts the suppressive effects of amino acid supplements on protein breakdown. Boivin et al. measured caspase-3 activity in the skeletal muscle of hemodialysis patients before and after hemodialysis. Both caspase-3 activity and actin fragments (14 kDa) generated by caspase-3-mediated cleavage of actomyosin were higher in patients than in controls in the basal state, and increased further during hemodialysis. In addition, apoptosis, as well as IL-6 content in the soluble fraction of the skeletal muscle increased at the end of hemodialysis. Protein degradation was higher in ESRD patients during hemodialysis compared with prehemodialysis and control individuals. This study supports the hypothesis that the increase in IL-6 expression in skeletal muscle and amino acid depletion during hemodialysis result in overt activation of proteolytic and apoptotic pathways resulting in net protein loss and muscle atrophy.
The activation of the alternate pathway of complement may be an additional mechanism leading to malnutrition in dialysis patients . However, the mechanisms and signals responsible for the complement-dependent activation of the inflammatory response by hemodialysis are not fully elucidated. There is also a lack of controlled studies exploring the muscle proteolytic response to different filter materials. By a proteomic approach, Mares et al. studied the processes that take place on dialysis membranes by eluting proteins adsorbed to the polysulfone dialyzer membranes. These proteins included ficolin-2 (an essential component of innate immunity that contributes to the immune recognition of pathogens), clusterin, complement C3c fragment, and apolipoprotein A1. In addition , the hemodialysis-induced decrease in plasma ficolin-2 was associated with leukopenia and C5a production, suggesting that ficolin-2 adsorption to polysulfone dialyzer initiates the lectin pathway of complement activation.
Several mechanisms which may predispose CKD patients to wasting have been recently identified in rodent models of uremia and, at least in part, in patients (Fig. 1). These include resistance to insulin/IGF-1 and altered PI3K regulation, as well as upregulation of myostatin and inflammation in skeletal muscle. These mechanisms may cause muscle atrophy by an enhancement of apoptotic processes and changes in protein degradation in skeletal muscle. A current hypothesis is that hemodialysis boosts the catabolic and atherogenic pathways which are already upregulated in the muscle of nondialyzed CKD patients. Mechanisms causing wasting in CKD overlap those already operating in aging and in comorbid conditions, such as diabetes and sepsis, to orchestrate the wasting syndrome and boost cardiovascular risk.
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This study was supported by the grants from Fondazione Carige and the Baxter Clinical Evidence Council (CEC) Extramural Program.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 96).
1. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 2003; 108:2154–2169.
2. Handy DE, Castro R, Loscalzo J. Epigenetic modifications: basic mechanisms and role in cardiovascular disease. Circulation 2011; 123:2145–2156.
3. Garibotto G, Valli A, Anderstam B, et al. The kidney is the major site of S-adenosylhomocysteine disposal in humans. Kidney Int 2009; 76:293–296.
4. Dwivedi RS, Herman JG, McCaffrey TA, Raj DS. Beyond genetics: epigenetic code in chronic kidney disease. Kidney Int 2011; 79:23–32.
Lu TM, Chung MY, Lin CC, et al. Asymmetric dimethylarginine and clinical outcomes in chronic kidney disease. Clin J Am Soc Nephrol 2011; 6:1566–1572.
In this prospective study including 298 consecutive CKD patients followed for 2.7 years, an increase of 0.1 μmol/l in plasma ADMA level was associated with a 37% increased risk of all-cause deaths, nonfatal myocardial infarctions, and strokes.
6. Luksha N, Luksha L, Carrero JJ, et al. Impaired resistance artery function in patients with end-stage renal disease. Clin Sci 2011; 120:525–536.
7. Leiper J, Nandi M. The therapeutic potential of targeting endogenous inhibitors of nitric oxide synthesis. Nat Rev Drug Discov 2011; 10:277–291.
8. Kaysen GA. New insights into lipid metabolism in chronic kidney disease. J Ren Nutr 2011; 21:120–123.
Holzer M, Birner-Gruenberger R, Stojakovic T, et al.
Uremia alters HDL composition and function. J Am Soc Nephrol 2011; 22:1631–1641.
Proteome and lipid composition of HDL was investigated in hemodialysis patients. The HDL content of phospholipid was reduced, while that of serum amyloid A1, albumin, lipoprotein-associated phospholipase A2, and apoC-II were decreased. These changes may inhibit HDL cardioprotective properties in uremia.
Ooi EM, Chan DT, Watts GF, et al. Plasma apolipoprotein C-III metabolism in patients with chronic kidney disease. J Lipid Res 2011; 52:794–800.
An interesting investigation on the role of altered plasma apoC-III kinetics in the determination of dyslipidemia and subsequent increased cardiovascular risk in CKD patients.
11. Mak RH, Cheung WW, Zhan JY, et al.
Cachexia and protein-energy wasting in children with chronic kidney disease. Pediatr Nephrol 2011. doi: 10.1007/s00467-011-1765-5.
Suneja M, Murry DJ, Stokes JB, Lim VS. Hormonal regulation of energy–protein homeostasis in hemodialysis patients: an anorexigenic profile that may predispose to adverse cardiovascular outcomes. Am J Physiol Endocrinol Metab 2011; 300:55–64.
Despite the increase in blood of several factors (high leptin, peptideYY, and neuropeptideY with suppressed ghrelin) involved in the regulation of appetite and energy homeostasis, dialysis patients maintained a good nutritional balance, suggesting an adaptation to anorexigenic factors.
13. Mitch WE. Metabolic and clinical consequences of metabolic acidosis. J Nephrol 2006; 19:70–75.
Tessari P, Sofia A, Saffioti S, et al. Effects of chronic metabolic acidosis on splanchnic protein turnover and oxygen consumption in human beings. Gastroenterology 2010; 138:1557–1565.
The effects of experimentally induced chronic metabolic acidosis (mean HCO3 = 17 mmol/l) on splanchnic protein dynamics and oxygen consumption were investigated in human beings by using a leucine tracer and mass-balance technique. These data show that moderate degree acidosis reduces splanchnic protein turnover and results in a negative leucine balance – an effect that is offset by the contribution of blood cells to protein dynamics. A contribution of blood cell to interorgan amino acid transport has been shown in early studies, but the underlying mechanisms are still unknown. The same study provides for the first time an estimate of the energy cost for 1 g of protein synthesis (∼24.1 kJ) in splanchnic organs in humans. This figure is remarkably similar to studies performed in vitro and in vivo in animals.
15. Reeds PJ, Cadenhead A, Fuller MF, et al. Protein turnover in growing pigs: effects of age and food intake. Br J Nutr 1980; 43:445–455.
Lecker SH, Mitch WE. Proteolysis by the ubiquitin–proteasome system and kidney disease. J Am Soc Nephrol 2011; 22:821–824.
An updated review on the ubiquitin–proteasome system in uremic muscle which gives also insight into the pathogenesis of kidney disease.
17. Bailey JL, Zheng B, Hu Z, et al. Chronic kidney disease causes defects in signaling through the insulin receptor substrate/phosphatidylinositol 3-kinase/Akt pathway: implications for muscle atrophy. J Am Soc Nephrol 2006; 17:1388–1394.
Hu J, Du J, Zhang L, et al. XIAP reduces muscle proteolysis induced by CKD. J Am Soc Nephrol 2010; 21:1174–1183.
In an experimental model of CKD, stimulated caspase-3 activity and protein degradation are partially abolished by the X chromosome-linked inhibitor of apoptosis protein XIAP, suggesting that apoptosis and enhanced protein degradation share common mechanisms.
Chen Y, Biada J, Sood S, Rabkin R. Uremia attenuates growth hormone-stimulated insulinlike growth factor-1 expression, a process worsened by inflammation. Kidney Int 2010; 78:89–95.
An elegant study clarifying the mechanisms of GH and insulin resistance in uremia.
20. Chen Y, Sood S, Krishnamurthy VM, et al. Endotoxin-induced growth hormone resistance in skeletal muscle. Endocrinology 2009; 150:3620–3626.
Zhang L, Wang XH, Wang H, et al. Satellite cell dysfunction and impaired IGF-1 signaling cause CKD-induced muscle atrophy. J Am Soc Nephrol 2010; 21:419–427.
This study underlies the role of satellite cells dysfunction and impaired insulin/IGF-1 signaling in CKD-related muscle wasting.
22. Pedersen BK. The anti-inflammatory effect of exercise: its role in diabetes and cardiovascular disease control. Essays Biochem 2006; 42:105–117.
23. Carrero JJ, Ortiz A, Qureshi AR, et al. Additive effects of soluble TWEAK and inflammation on mortality in hemodialysis patients. Clin J Am Soc Nephrol 2009; 4:110–118.
24. Garibotto G, Sofia A, Procopio V, et al. Peripheral tissue release of interleukin-6 in patients with chronic kidney diseases: effects of end-stage renal disease and microinflammatory state. Kidney Int 2006; 70:384–390.
25. Raj DS, Moseley P, Dominic EA, et al. Interleukin-6 modulates hepatic and muscle protein synthesis during hemodialysis. Kidney Int 2008; 73:1054–1061.
Zhang L, Rajan V, Lin E, et al. Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease. FASEB J 2011; 25:1653–1663.
Myostatin suppression decreased the levels of muscle and circulating inflammatory cytokines, including TNF-α and IL-6 in an experimental model of uremia in rodents. This study sheds light on the involvement of multiple catabolic signal transduction pathways which may promote wasting and impair muscle regeneration in uremia.
Verzola D, Procopio V, Sofia A, et al. Apoptosis and myostatin mRNA are upregulated in the skeletal muscle of patients with chronic kidney disease. Kidney Int 2011; 79:773–782.
Myostatin gene expression was upregulated in skeletal muscle of a cohort of predialysis CKD patients. Myostatin was associated with IL-6 gene expression and upregulated phosphorylated JNK, suggesting that microinflammatory changes taking place in muscle cells and myostatin are metabolically linked.
28. Reaich D, Channon SM, Scrimgeour CM, et al. Correction of acidosis in humans with CRF decreases protein degradation and amino acid oxidation. Am J Physiol 1993; 265:230–235.
Chen Y, Sood S, McIntire K, et al.
Leucine stimulated mTOR signaling is partly attenuated in skeletal muscle of chronically uremic rats especially when work overloaded. Am J Physiol Endocrinol Metab 2011. doi: 10.1152/ajpendo.00068.2011.
This study, conducted on a murine model, suggests a potential role for leucine-rich supplements in the management of uremic muscle wasting.
30. Lenk K, Schuler G, Adams V. Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training. J Cachexia Sarcopenia Muscle 2010; 1:9–21.
31. Bruusgaard JC, Gundersen K. In vivo time-lapse microscopy reveals no loss of murine myonuclei during weeks of muscle atrophy. J Clin Invest 2008; 118:1450–1457.
32. Bruusgaard JC, Johansen IB, Egner IM, et al.
Myonuclei acquired by overload exercise precede hypertrophy and are not lost on detraining. Proc Natl Acad Sci U S A 2010; 107:15111–15116.
33. Dukkipati R, Kopple JD. Causes and prevention of protein-energy wasting in chronic kidney failure. Semin Nephrol 2009; 29:39–49.
34. Lim VS, Ikizler TA, Raj DS, Flanigan MJ. Does hemodialysis increase protein breakdown? Dissociation between whole-body amino acid turnover and regional muscle kinetics. J Am Soc Nephrol 2005; 16:862–868.
35. Raj DS, Oladipo A, Lim VS. Amino Acid and protein kinetics in renal failure: an integrated approach. Semin Nephrol 2006; 26:158–166.
36. Korevaar JC, van Manen JG, Dekker FW, et al. NECOSAD study groupEffect of an increase in C-reactive protein level during a hemodialysis session on mortality. J Am Soc Nephrol 2004; 15:2916–2922.
37. Meuwese CL, Halbesma N, Stenvinkel P, et al. Variations in C-reactive protein during a single haemodialysis session do not associate with mortality. Nephrol Dial Transplant 2010; 25:3717–3723.
38. Boivin MA, Battah SI, Dominic EA, et al. Activation of caspase-3 in the skeletal muscle during haemodialysis. Eur J Clin Invest 2010; 40:903–910.
39. Gutierrez A, Alvestrand A, Wahren J, Bergström J. Effect of in vivo contact between blood and dialysis membranes on protein catabolism in humans. Kidney Int 1990; 38:487–494.
40. Mares J, Thongboonkerd V, Tuma Z, et al. Specific adsorption of some complement activation proteins to polysulfone dialysis membranes during hemodialysis. Kidney Int 2009; 76:404–413.
41. Mares J, Richtova P, Hricinova A. Proteomic profiling of blood-dialyzer interactome reveals involvement of lectin complement pathway in hemodialysis-induced inflammatory response. Proteomics Clin Appl 2010; 4:829–838.
chronic kidney disease; hemodialysis; protein-energy wasting; skeletal muscle
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