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Koike M, Sato T, Shiozaki Y, Komiya A, Miura M, Higashi A, Ishikawa A, Takayanagi K, Uga M, Miyamoto KI, Segawa H. Involvement of α-klotho in growth hormone (GH) signaling. J Clin Biochem Nutr 2024; 74:221-229. [PMID: 38799134 PMCID: PMC11111466 DOI: 10.3164/jcbn.23-127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Accepted: 01/10/2024] [Indexed: 05/29/2024] Open
Abstract
Growth hormone (GH) exerts multiple effects on different organs directly or via its main mediator, insulin-like growth factor1 (IGF1). In this study, we focused on the novel relationship between GH action and the antiaging hormone α-klotho. Immunofluorescent staining of α-klotho was observed in the renal distal tubules and pituitary glands of somatostatin- and GH-positive cells in wild-type (WT) mice. Treatment of 4-week-old WT mice with GH increased IGF1 mRNA expression in the pituitary gland, liver, heart, kidney, and bone but increased α-klotho mRNA expression only in the pituitary gland, kidney, and bone. Increased α-klotho protein levels were observed in the kidney but not in the pituitary gland. No induction of α-klotho RNA expression by GH was observed in juvenile mice with kidney disease, indicating GH resistance. Furthermore, GH and α-klotho supplementation in HEK293 cells transfected with GHR increased Janus kinase 2 mRNA (a GH downstream signal) expression compared to supplementation with GH alone. In conclusion, we suggest that 1) the kidney is the main source of secreted α-klotho, which is detected in blood by the downstream action of GH, 2) α-klotho induction by GH is resistant in kidney disease, and 3) α-klotho might be an enhanced regulator of GH signaling.
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Affiliation(s)
- Megumi Koike
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Tetsuhiko Sato
- General Medicine, Nagoya Daini Red Cross Hospital, 2-9 Myoken-cho, Showa-ku, Nagoya 466-8650, Japan
| | - Yuji Shiozaki
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Aoi Komiya
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Mizuki Miura
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Ayami Higashi
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Akane Ishikawa
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Kaori Takayanagi
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Minori Uga
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Ken-ichi Miyamoto
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
- Graduate School of Agriculture, Ryukoku University, 1-5 Yokotani, Seta Oe-cho, Otsu, Shiga 520-2194, Japan
| | - Hiroko Segawa
- Department of Applied Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
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Li J, Li H, Deng W, Meng L, Gong W, Yao H. The Effect of Combination Use of Hemodialysis and Hemoperfusion on Microinflammation in Elderly Patients with Maintenance Hemodialysis. Blood Purif 2022; 51:739-746. [DOI: 10.1159/000518857] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 07/24/2021] [Indexed: 11/19/2022]
Abstract
<b><i>Background:</i></b> Patients with maintenance hemodialysis (MHD) generally have a microinflammatory state. The aim of this study was to investigate the effects of hemodialysis (HD) combined with hemoperfusion (HP) on microinflammatory state in elderly patients with MHD. <b><i>Methods:</i></b> One hundred and fifty elderly patients with MHD were randomly divided into the control group and the observation group. The control group received simple HD treatment, and the observation group received combined HD + HP treatment on the basis of the control group. After 6 months of continuous treatment, the patients were evaluated to compare the quality of life, inflammation, adverse reactions, and nutritional indicators in the 2 groups before and after treatment. <b><i>Results:</i></b> There was no significant difference in the quality of life between the 2 groups before treatment. After treatment, the scores of psychological aspects, physiological aspects, social aspects, environmental aspects, and independent ability in the observation group were higher than those in the control group, with statistical significance (<i>p</i> < 0.05). There was no statistical significance in the level of inflammation between 2 groups before treatment. After treatment, the levels of hs-CRP, Hcy, IL-6, and TNF-α in the observation group were significantly lower than those in the control group, with statistical significance (<i>p</i> < 0.05). The incidence of dry mouth, skin reaction, neuritis, and subcutaneous tissue fibrosis in the observation group was lower than that in the control group, with statistical significance (<i>p</i> < 0.05). There was no statistical significance in nutritional level indexes between 2 groups before treatment (<i>p</i><sub>1</sub> > 0.05). After treatment, the levels of hemoglobin, total protein, albumin, and transferrin in the observation group were significantly higher than those in the control group, with statistical significance (<i>p</i> < 0.05). <b><i>Conclusion:</i></b> The clinical effect of HD combined with HP in elderly MHD patients is significant, which can effectively reduce the incidence of adverse reactions and inflammation in the patients and improve the quality of life and nutritional indicators of the patients.
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Garibotto G, Saio M, Aimasso F, Russo E, Picciotto D, Viazzi F, Verzola D, Laudon A, Esposito P, Brunori G. How to Overcome Anabolic Resistance in Dialysis-Treated Patients? Front Nutr 2021; 8:701386. [PMID: 34458305 PMCID: PMC8387577 DOI: 10.3389/fnut.2021.701386] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 07/12/2021] [Indexed: 02/05/2023] Open
Abstract
A current hypothesis is that dialysis-treated patients are "anabolic resistant" i. e., their muscle protein synthesis (MPS) response to anabolic stimuli is blunted, an effect which leads to muscle wasting and poor physical performance in aging and in several chronic diseases. The importance of maintaining muscle mass and MPS is often neglected in dialysis-treated patients; better than to describe mechanisms leading to energy-protein wasting, the aim of this narrative review is to suggest possible strategies to overcome anabolic resistance in this patient's category. Food intake, in particular dietary protein, and physical activity, are the two major anabolic stimuli. Unfortunately, dialysis patients are often aged and have a sedentary behavior, all conditions which per se may induce a state of "anabolic resistance." In addition, patients on dialysis are exposed to amino acid or protein deprivation during the dialysis sessions. Unfortunately, the optimal amount and formula of protein/amino acid composition in supplements to maximixe MPS is still unknown in dialysis patients. In young healthy subjects, 20 g whey protein maximally stimulate MPS. However, recent observations suggest that dialysis patients need greater amounts of proteins than healthy subjects to maximally stimulate MPS. Since unneccesary amounts of amino acids could stimulate ureagenesis, toxins and acid production, it is urgent to obtain information on the optimal dose of proteins or amino acids/ketoacids to maximize MPS in this patients' population. In the meantime, the issue of maintaining muscle mass and function in dialysis-treated CKD patients needs not to be overlooked by the kidney community.
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Affiliation(s)
| | - Michela Saio
- Department of Internal Medicine, University of Genoa, Genova, Italy
| | - Francesca Aimasso
- Clinical Nutrition Unit, Istituto di Ricerca a Carattere Scientifico Ospedale Policlinico San Martino, Genova, Italy
| | - Elisa Russo
- Department of Internal Medicine, University of Genoa, Genova, Italy
- Clinica Nefrologica, Dialisi e Trapianto, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Daniela Picciotto
- Department of Internal Medicine, University of Genoa, Genova, Italy
- Clinica Nefrologica, Dialisi e Trapianto, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Francesca Viazzi
- Department of Internal Medicine, University of Genoa, Genova, Italy
- Clinica Nefrologica, Dialisi e Trapianto, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Daniela Verzola
- Department of Internal Medicine, University of Genoa, Genova, Italy
| | - Alessandro Laudon
- Division of Nephrology and Dialysis, Ospedale Santa Chiara, Trento, Italy
| | - Pasquale Esposito
- Department of Internal Medicine, University of Genoa, Genova, Italy
- Clinica Nefrologica, Dialisi e Trapianto, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Giuliano Brunori
- Division of Nephrology and Dialysis, Ospedale Santa Chiara, Trento, Italy
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Garibotto G, Picciotto D, Saio M, Esposito P, Verzola D. Muscle protein turnover and low-protein diets in patients with chronic kidney disease. Nephrol Dial Transplant 2020; 35:741-751. [PMID: 32378720 DOI: 10.1093/ndt/gfaa072] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 02/28/2020] [Indexed: 02/07/2023] Open
Abstract
Adaptation to a low-protein diet (LPD) involves a reduction in the rate of amino acid (AA) flux and oxidation, leading to more efficient use of dietary AA and reduced ureagenesis. Of note, the concept of 'adaptation' to low-protein intakes has been separated from the concept of 'accommodation', the latter term implying a decrease in protein synthesis, with development of wasting, when dietary protein intake becomes inadequate, i.e. beyond the limits of the adaptive mechanisms. Acidosis, insulin resistance and inflammation are recognized mechanisms that can increase protein degradation and can impair the ability to activate an adaptive response when an LPD is prescribed in a chronic kidney disease (CKD) patient. Current evidence shows that, in the short term, clinically stable patients with CKD Stages 3-5 can efficiently adapt their muscle protein turnover to an LPD containing 0.55-0.6 g protein/kg or a supplemented very-low-protein diet (VLPD) by decreasing muscle protein degradation and increasing the efficiency of muscle protein turnover. Recent long-term randomized clinical trials on supplemented VLPDs in patients with CKD have shown a very good safety profile, suggesting that observations shown by short-term studies on muscle protein turnover can be extrapolated to the long-term period.
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Affiliation(s)
- Giacomo Garibotto
- Division of Nephrology, Dialysis and Transplantation, Department of Internal Medicine and IRCCS Ospedale Policlinico San Martino, University of Genova, Genova, Italy
| | - Daniela Picciotto
- Division of Nephrology, Dialysis and Transplantation, Department of Internal Medicine and IRCCS Ospedale Policlinico San Martino, University of Genova, Genova, Italy
| | - Michela Saio
- Division of Nephrology, Dialysis and Transplantation, Department of Internal Medicine and IRCCS Ospedale Policlinico San Martino, University of Genova, Genova, Italy
| | - Pasquale Esposito
- Division of Nephrology, Dialysis and Transplantation, Department of Internal Medicine and IRCCS Ospedale Policlinico San Martino, University of Genova, Genova, Italy
| | - Daniela Verzola
- Division of Nephrology, Dialysis and Transplantation, Department of Internal Medicine and IRCCS Ospedale Policlinico San Martino, University of Genova, Genova, Italy
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Verzola D, Bonanni A, Sofia A, Montecucco F, D'Amato E, Cademartori V, Parodi EL, Viazzi F, Venturelli C, Brunori G, Garibotto G. Toll-like receptor 4 signalling mediates inflammation in skeletal muscle of patients with chronic kidney disease. J Cachexia Sarcopenia Muscle 2017; 8:131-144. [PMID: 27897392 PMCID: PMC5326826 DOI: 10.1002/jcsm.12129] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 05/16/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Inflammation in skeletal muscle is implicated in the pathogenesis of insulin resistance and cachexia but why uremia up-regulates pro-inflammatory cytokines is unknown. Toll-like receptors (TLRs) regulate locally the innate immune responses, but it is unknown whether in chronic kidney disease (CKD) TLR4 muscle signalling is altered. The aim of the study is to investigate whether in CKD muscle, TLRs had abnormal function and may be involved in transcription of pro-inflammatory cytokine. METHODS TLR4, phospho-p65, phospho-ikBα, tumour necrosis factor (TNF)-α, phospho p38, Murf 1, and atrogin were studied in skeletal muscle from nondiabetic CKD stage 5 patients (n = 29) and controls (n = 14) by immunohistochemistry, western blot, and RT-PCR. Muscle cell cultures (C2C12) exposed to uremic serum were employed to study TLR4 expression (western blot and RT-PCR) and TLR-driven signalling. TLR4 signalling was abrogated by a small molecule chemical inhibitor or TLR4 siRNA. Phospho AKT and phospho p38 were evaluated by western blot. RESULTS CKD subjects had elevated TLR4 gene and protein expression. Also expression of NFkB, p38 MAPK and the NFkB-regulated gene TNF-α was increased. At multivariate analysis, TLR4 protein content was predicted by eGFR and Subjective Global Assessment, suggesting that the progressive decline in renal function and wasting mediate TLR4 activation. In C2C12, uremic serum increased TLR4 as well as TNF-α and down-regulated pAkt. These effects were prevented by blockade of TLR4. CONCLUSIONS CKD promotes muscle inflammation through an up-regulation of TLR4, which may activate downward inflammatory signals such as TNF-α and NFkB-regulated genes.
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Affiliation(s)
- Daniela Verzola
- Department of Internal Medicine, Nephrology Division and First Clinic of Internal MedicineUniversity of Genova and IRCCS AOU San Martino‐IST, and Ospedale Santa ChiaraTrentoItaly
| | - Alice Bonanni
- Department of Internal Medicine, Nephrology Division and First Clinic of Internal MedicineUniversity of Genova and IRCCS AOU San Martino‐IST, and Ospedale Santa ChiaraTrentoItaly
| | - Antonella Sofia
- Department of Internal Medicine, Nephrology Division and First Clinic of Internal MedicineUniversity of Genova and IRCCS AOU San Martino‐IST, and Ospedale Santa ChiaraTrentoItaly
| | - Fabrizio Montecucco
- Department of Internal Medicine, Nephrology Division and First Clinic of Internal MedicineUniversity of Genova and IRCCS AOU San Martino‐IST, and Ospedale Santa ChiaraTrentoItaly
| | - Elena D'Amato
- Department of Internal Medicine, Nephrology Division and First Clinic of Internal MedicineUniversity of Genova and IRCCS AOU San Martino‐IST, and Ospedale Santa ChiaraTrentoItaly
| | - Valeria Cademartori
- Department of Internal Medicine, Nephrology Division and First Clinic of Internal MedicineUniversity of Genova and IRCCS AOU San Martino‐IST, and Ospedale Santa ChiaraTrentoItaly
| | - Emanuele Luigi Parodi
- Department of Internal Medicine, Nephrology Division and First Clinic of Internal MedicineUniversity of Genova and IRCCS AOU San Martino‐IST, and Ospedale Santa ChiaraTrentoItaly
| | - Francesca Viazzi
- Department of Internal Medicine, Nephrology Division and First Clinic of Internal MedicineUniversity of Genova and IRCCS AOU San Martino‐IST, and Ospedale Santa ChiaraTrentoItaly
| | - Chiara Venturelli
- Department of Internal Medicine, Nephrology Division and First Clinic of Internal MedicineUniversity of Genova and IRCCS AOU San Martino‐IST, and Ospedale Santa ChiaraTrentoItaly
| | - Giuliano Brunori
- Department of Internal Medicine, Nephrology Division and First Clinic of Internal MedicineUniversity of Genova and IRCCS AOU San Martino‐IST, and Ospedale Santa ChiaraTrentoItaly
| | - Giacomo Garibotto
- Department of Internal Medicine, Nephrology Division and First Clinic of Internal MedicineUniversity of Genova and IRCCS AOU San Martino‐IST, and Ospedale Santa ChiaraTrentoItaly
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Tu J, Cheung WW, Mak RH. Inflammation and nutrition in children with chronic kidney disease. World J Nephrol 2016; 5:274-282. [PMID: 27152263 PMCID: PMC4848150 DOI: 10.5527/wjn.v5.i3.274] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 09/02/2015] [Accepted: 03/09/2016] [Indexed: 02/06/2023] Open
Abstract
Chronic inflammation and nutritional imbalance are important comorbid conditions that correlate with poor clinical outcomes in children with chronic kidney disease (CKD). Nutritional disorders such as cachexia/protein energy wasting, obesity and growth retardation negatively impact the quality of life and disease progression in children with CKD. Inadequate nutrition has been associated with growth disturbances in children with CKD. On the other hand, over-nutrition and obesity are associated with poor outcomes in children with CKD. The exact mechanisms leading to these unfavorable conditions are not fully elucidated and are most likely multifactorial. In this review, we focus on the pathophysiology of nutrition disorders and inflammation and their impact on clinical outcomes in children with CKD.
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Frailty phenotype and chronic kidney disease: a review of the literature. Int Urol Nephrol 2015; 47:1801-7. [DOI: 10.1007/s11255-015-1112-z] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2015] [Accepted: 09/14/2015] [Indexed: 02/07/2023]
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McIntire KL, Chen Y, Sood S, Rabkin R. Acute uremia suppresses leucine-induced signal transduction in skeletal muscle. Kidney Int 2013; 85:374-82. [PMID: 23783244 DOI: 10.1038/ki.2013.216] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2012] [Revised: 04/02/2013] [Accepted: 04/11/2013] [Indexed: 12/30/2022]
Abstract
Adequate nutrient intake in acute uremia is a key part of patient management especially as food utilization is usually impaired. Leucine is important as it comprises about one-fifth of essential amino acid needs and, apart from serving as a substrate, it directly activates the mTOR signaling pathway stimulating protein synthesis and inhibiting autophagy. Here we tested whether leucine activation of the mTOR signaling pathway in muscle is severely disrupted in acute uremia. Several abnormalities were identified in bilateral ureteral ligated (model of acute uremia) compared to sham-operated pair-fed control rats. Levels of several signaling proteins increased significantly while leucine-induced phosphorylation of mTOR and downstream proteins, 4e-BP1 and S6K1, was completely suppressed. Levels of LC3B-II, a specific autophagosomal membrane-associated protein used as a marker of autophagy, increased threefold in uremia. Furthermore, while leucine suppressed LC3B-II levels in controls, it failed to do so in uremic rats. Muscle IL-6 mRNA levels increased, while IGF-1 mRNA levels decreased in uremia. These findings establish that, in acute uremia, severe resistance to leucine-induced activation of the mTOR anabolic signaling pathway develops. Thus, leucine resistance, together with the reduction in IGF-1 and increase in IL-6 expression, may explain why the anabolic effect of nutritional therapy is diminished in acute uremic patients.
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Affiliation(s)
- Kevin L McIntire
- 1] Research Service, Veterans Affairs Palo Alto Health Care System (VAPAHCS), Palo Alto, California, USA [2] Renal Division, Department of Medicine, Stanford University, Stanford, California, USA
| | - Yu Chen
- 1] Research Service, Veterans Affairs Palo Alto Health Care System (VAPAHCS), Palo Alto, California, USA [2] Renal Division, Department of Medicine, Stanford University, Stanford, California, USA
| | - Sumita Sood
- 1] Research Service, Veterans Affairs Palo Alto Health Care System (VAPAHCS), Palo Alto, California, USA [2] Renal Division, Department of Medicine, Stanford University, Stanford, California, USA
| | - Ralph Rabkin
- 1] Research Service, Veterans Affairs Palo Alto Health Care System (VAPAHCS), Palo Alto, California, USA [2] Renal Division, Department of Medicine, Stanford University, Stanford, California, USA
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Reinhard M, Frystyk J, Jespersen B, Bjerre M, Christiansen JS, Flyvbjerg A, Ivarsen P. Effect of hyperinsulinemia during hemodialysis on the insulin-like growth factor system and inflammatory biomarkers: a randomized open-label crossover study. BMC Nephrol 2013; 14:80. [PMID: 23557110 PMCID: PMC3637492 DOI: 10.1186/1471-2369-14-80] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2012] [Accepted: 03/27/2013] [Indexed: 12/16/2022] Open
Abstract
Background A marked reduction in serum levels of bioactive insulin-like growth factor-I (IGF-I) has been observed in fasting hemodialysis (HD) patients during a 4-h HD session. The aim of the present study was to investigate the beneficial effect of hyperinsulinemia during HD on bioactive IGF-I and inflammatory biomarkers. Methods In a randomized cross-over study, 11 non-diabetic HD patients received a standardised HD session with either: 1) no treatment, 2) glucose infusion (10% glucose, 2.5 mL/kg/h), or 3) glucose-insulin infusion (10% glucose added 30 IU NovoRapid® per litre, 2.5 mL/kg/h). Each experiment consisted of three periods: pre-HD (−120 to 0 min), HD (0 to 240 min), and post-HD (240 to 360 min). A meal was served at baseline (−120 min); infusions were administered from baseline to 240 min. The primary outcome was change in bioactive IGF-I during the experiment. Secondary outcomes were changes in high-sensitivity C-reactive protein, interleukin-1β, interleukin-6, and tumor necrosis factor α. Comparisons were performed using mixed-model analysis of variance for repeated measures. Results From baseline to the end of study, no significant differences were observed in the changes in either serum bioactive IGF-I or total IGF-I between study days. Overall, serum bioactive IGF-I levels rose above baseline at 120 to 300 min with a maximum increase of 20% at 120 min (95% confidence interval (CI), 9 to 31%; p < 0.001), whereas total IGF-I levels rose above baseline at 180 to 300 min with a maximum increase of 5% at 240 min (95% CI, 2 to 9%; p = 0.004). A significant difference was observed in the changes in serum IGF-binding protein-1 (IGFBP-1) between study days (p = 0.008), but differences were only significant in the post-HD period. From baseline to the end of HD, no significant difference was observed in the changes in serum IGFBP-1 levels between study days, and in this time period overall serum IGFBP-1 levels were below baseline at all time points with a maximum decrease of 51% at 180 min (95% CI, 45 to 57%; p < 0.001). None of the investigated inflammatory biomarkers showed any differences in the changes over time between study days. Conclusions Postprandial insulin secretion stimulated the IGF-system during HD with no further effect of adding glucose or glucose-insulin infusion. Hyperinsulinemia during HD had no effect on biomarkers of inflammation. Trial registration ClinicalTrials.gov registry: NCT01209403
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Leal VO, Lobo JC, Stockler-Pinto MB, Farage NE, Velarde GC, Fouque D, Leite M, Mafra D. Zinc-α2-glycoprotein: is there association between this new adipokine and body composition in hemodialysis patients? Ren Fail 2012; 34:1062-7. [PMID: 22906217 DOI: 10.3109/0886022x.2012.712859] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Peptides involved in the regulation of body composition are of interest in hemodialysis (HD) patients because protein wasting associated with high fat mass (FM) is present in these patients. Zinc-α2-glycoprotein (ZAG), a new adipokine, is involved in the regulation of lipid metabolism, adiposity, and energy balance. The purpose of this study was to evaluate ZAG levels and its relationship with body composition and dietary intake in HD patients. Forty-nine HD patients (28 men, 53.1 ± 12.5 years, and BMI 24.0 ± 4.3 kg/m2) were studied and compared with 20 healthy subjects (9 men, 49.5 ± 15.2 years, and BMI 25.6 ± 4.1 kg/m(2)). Plasma ZAG levels were measured using the ELISA methods and body composition was evaluated through anthropometric data. Dietary intake was assessed 3 days by 24-hour food recall. Although most of the HD patients (59.2%) were eutrophic according to BMI, 92.3% presented high percentage of body fat (BF), and 43.5%, reduced fat-free mass according to midarm muscle circumference values. ZAG levels were ∼2.5-fold higher in HD patients (135.9 ± 40.9 mg/L) compared with healthy individuals (54.6 ± 23.0 mg/L) (p < 0.0001). Circulating ZAG was not associated with dietary intake; however, this peptide was negatively correlated with %BF and, for each 1% reduction in BF, ZAG levels increased by 2.4 mg/L (p = 0.02). In summary, circulating ZAG is increased and inversely correlated with adiposity in HD patients; however, in spite of its higher plasma levels, the majority of HD patients did not show low BF.
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Affiliation(s)
- Viviane O Leal
- Programa de Pós Graduação em Ciências Médicas, Universidade Federal Fluminense, Niterói, Brasil.
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Garibotto G, Bonanni A, Verzola D. Effect of kidney failure and hemodialysis on protein and amino acid metabolism. Curr Opin Clin Nutr Metab Care 2012; 15:78-84. [PMID: 22108097 DOI: 10.1097/mco.0b013e32834d9df6] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
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.
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Affiliation(s)
- Giacomo Garibotto
- Department of Internal Medicine, University of Genoa, Azienda Ospedaliera Universitaria San Martino, Genoa, Italy.
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Chen Y, Sood S, McIntire K, Roth R, Rabkin R. Leucine-stimulated mTOR signaling is partly attenuated in skeletal muscle of chronically uremic rats. Am J Physiol Endocrinol Metab 2011; 301:E873-81. [PMID: 21791619 DOI: 10.1152/ajpendo.00068.2011] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The branched-chain amino acid leucine stimulates muscle protein synthesis in part by directly activating the mTOR signaling pathway. Furthermore, leucine, if given in conjunction with resistance exercise, enhances the exercise-induced mTOR signaling and protein synthesis. Here we tested whether leucine can activate the mTOR anabolic signaling pathway in uremia and whether it can enhance work overload (WO)-induced signaling through this pathway. Chronic kidney disease (CKD) and control rats were studied after 7 days of surgically induced unilateral plantaris muscle WO and a single leucine or saline load. In the basal state, 4E-BP1 phosphorylation was modestly depressed in non-WO muscle of CKD rats, whereas rpS6 phosphorylation was nearly completely suppressed. After oral leucine mTOR, S6K1 and rpS6 phosphorylation increased similarly in both groups, whereas the phospho-4E-BP1 response was modestly attenuated in CKD. WO alone activated the mTOR signaling pathway in control and CKD rats. In WO CKD, muscle leucine augmented mTOR and 4E-BP1 phosphorylation, but its effect on S6K1 phosphorylation was attenuated. Taken together, this study has established that the chronic uremic state impairs basal signaling through the mTOR anabolic pathway, an abnormality that may contribute to muscle wasting. However, despite this abnormality, leucine can stimulate this signaling pathway in CKD, although its effectiveness is partially attenuated, including in skeletal muscle undergoing sustained WO. Thus, although there is some resistance to leucine in CKD, the data suggest a potential role for leucine-rich supplements in the management of uremic muscle wasting.
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Affiliation(s)
- Yu Chen
- Research Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, USA
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Janjua HS, Mahan JD. Growth in chronic kidney disease. Adv Chronic Kidney Dis 2011; 18:324-31. [PMID: 21896373 DOI: 10.1053/j.ackd.2011.02.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2010] [Revised: 01/18/2011] [Accepted: 02/14/2011] [Indexed: 11/11/2022]
Abstract
Poor growth is a common sequela of CKD in childhood. It not only affects the psychosocial development of a child but also has significant effects even in the adult life. The multifactorial etiology and severe consequences of growth failure in CKD warrant evaluation of all the modifiable and nonmodifiable causes. Treatment strategies must be directed toward the specific factors for each child with CKD. Among the various metabolic, nutritional, and hormonal disturbances complicating CKD, disordered growth hormone (GH) and insulin-like growth factor-1 axis are important contributors toward poor growth in children with CKD. CKD is recognized as a state of GH resistance rather than GH deficiency, with multiple mechanisms contributing to this GH resistance. Recombinant GH (rGH) therapy can be used in this population to accelerate growth velocity. Although its use has been shown to be effective and safe in children with CKD, there continues to be some uncertainty and reluctance among practitioners and families regarding its usage, thereby resulting in a surprisingly low use in children with CKD. This review focuses on the pathogenesis of growth failure, its effect, and management strategies in children with CKD.
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Bonanni A, Mannucci I, Verzola D, Sofia A, Saffioti S, Gianetta E, Garibotto G. Protein-energy wasting and mortality in chronic kidney disease. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2011; 8:1631-54. [PMID: 21655142 PMCID: PMC3108132 DOI: 10.3390/ijerph8051631] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2011] [Revised: 04/29/2011] [Accepted: 05/03/2011] [Indexed: 02/06/2023]
Abstract
Protein-energy wasting (PEW) is common in patients with chronic kidney disease (CKD) and is associated with an increased death risk from cardiovascular diseases. However, while even minor renal dysfunction is an independent predictor of adverse cardiovascular prognosis, PEW becomes clinically manifest at an advanced stage, early before or during the dialytic stage. Mechanisms causing loss of muscle protein and fat are complex and not always associated with anorexia, but are linked to several abnormalities that stimulate protein degradation and/or decrease protein synthesis. In addition, data from experimental CKD indicate that uremia specifically blunts the regenerative potential in skeletal muscle, by acting on muscle stem cells. In this discussion recent findings regarding the mechanisms responsible for malnutrition and the increase in cardiovascular risk in CKD patients are discussed. During the course of CKD, the loss of kidney excretory and metabolic functions proceed together with the activation of pathways of endothelial damage, inflammation, acidosis, alterations in insulin signaling and anorexia which are likely to orchestrate net protein catabolism and the PEW syndrome.
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Affiliation(s)
- Alice Bonanni
- Division of Nephrology, Dialysis and Transplantation, Department of Internal Medicine, Azienda Ospedale Università San Martino, Genoa University, Viale Benedetto XV 6, Genoa, Italy; E-Mails: (A.B.); (I.M.); (D.V.); (A.S.); (S.S.)
| | - Irene Mannucci
- Division of Nephrology, Dialysis and Transplantation, Department of Internal Medicine, Azienda Ospedale Università San Martino, Genoa University, Viale Benedetto XV 6, Genoa, Italy; E-Mails: (A.B.); (I.M.); (D.V.); (A.S.); (S.S.)
| | - Daniela Verzola
- Division of Nephrology, Dialysis and Transplantation, Department of Internal Medicine, Azienda Ospedale Università San Martino, Genoa University, Viale Benedetto XV 6, Genoa, Italy; E-Mails: (A.B.); (I.M.); (D.V.); (A.S.); (S.S.)
| | - Antonella Sofia
- Division of Nephrology, Dialysis and Transplantation, Department of Internal Medicine, Azienda Ospedale Università San Martino, Genoa University, Viale Benedetto XV 6, Genoa, Italy; E-Mails: (A.B.); (I.M.); (D.V.); (A.S.); (S.S.)
| | - Stefano Saffioti
- Division of Nephrology, Dialysis and Transplantation, Department of Internal Medicine, Azienda Ospedale Università San Martino, Genoa University, Viale Benedetto XV 6, Genoa, Italy; E-Mails: (A.B.); (I.M.); (D.V.); (A.S.); (S.S.)
| | - Ezio Gianetta
- Department of Surgery, Azienda Ospedale Università San Martino, Genoa University, Largo R. Benzi, Genoa, Italy; E-Mail:
| | - Giacomo Garibotto
- Division of Nephrology, Dialysis and Transplantation, Department of Internal Medicine, Azienda Ospedale Università San Martino, Genoa University, Viale Benedetto XV 6, Genoa, Italy; E-Mails: (A.B.); (I.M.); (D.V.); (A.S.); (S.S.)
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