|
1
|
Rahbar Saadat Y, Abbasi A, Hejazian SS, Hekmatshoar Y, Ardalan M, Farnood F, Zununi Vahed S. Combating chronic kidney disease-associated cachexia: A literature review of recent therapeutic approaches. BMC Nephrol 2025; 26:133. [PMID: 40069669 PMCID: PMC11895341 DOI: 10.1186/s12882-025-04057-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Accepted: 03/05/2025] [Indexed: 03/15/2025] Open
Abstract
In 2008, the Society on Sarcopenia, Cachexia, and Wasting Disorders introduced a generic definition for all types of cachexia: "a complex metabolic syndrome associated with the underlying illness characterized by a loss of muscle, with or without fat loss". It is well-known that the presence of inflammatory burden in end-stage renal disease (ESRD) patients may lead to the evolution of cachexia. Since the etiology of cachexia in chronic kidney disease (CKD) is multifactorial, thus the successful treatment must involve several concomitant measures (nutritional interventions, appetite stimulants, and anti-inflammatory pharmacologic agents) to provide integrated effective therapeutic modalities to combat causative factors and alleviate the outcomes of patients. Given the high mortality rate associated with cachexia, developing new therapeutic modalities are prerequisite for ameliorating patients with CKD worldwide. The present review aims to discuss some therapeutic strategies and provide an update on advances in nutritional approaches to counteract cachexia.
Collapse
Affiliation(s)
| | - Amin Abbasi
- Student Research Committee, Department of Food Science and Technology, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Science and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyyed Sina Hejazian
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Neuroscience Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yalda Hekmatshoar
- Medical Biology Department, School of Medicine, Altinbas University, Istanbul, Türkiye
| | | | - Farahnoosh Farnood
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | | |
Collapse
|
|
2
|
Ju SH, Yi HS. Clinical features and molecular mechanism of muscle wasting in end stage renal disease. BMB Rep 2023; 56:426-438. [PMID: 37482754 PMCID: PMC10471459 DOI: 10.5483/bmbrep.2023-0097] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/10/2023] [Accepted: 07/17/2023] [Indexed: 11/22/2024] Open
Abstract
Muscle wasting in end-stage renal disease (ESRD) is an escalating issue due to the increasing global prevalence of ESRD and its significant clinical impact, including a close association with elevated mortality risk. The phenomenon of muscle wasting in ESRD, which exceeds the rate of muscle loss observed in the normal aging process, arises from multifactorial processes. This review paper aims to provide a comprehensive understanding of muscle wasting in ESRD, covering its epidemiology, underlying molecular mechanisms, and current and emerging therapeutic interventions. It delves into the assessment techniques for muscle mass and function, before exploring the intricate metabolic and molecular pathways that lead to muscle atrophy in ESRD patients. We further discuss various strategies to mitigate muscle wasting, including nutritional, pharmacological, exercise, and physical modalities intervention. This review seeks to provide a solid foundation for future research in this area, fostering a deeper understanding of muscle wasting in ESRD, and paving the way for the development of novel strategies to improve patient outcomes. [BMB Reports 2023; 56(8): 426-438].
Collapse
Affiliation(s)
- Sang Hyeon Ju
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 35015, Korea
| | - Hyon-Seung Yi
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 35015; Laboratory of Endocrinology and Immune System, Chungnam National University School of Medicine, Daejeon 35015, Korea
| |
Collapse
|
|
3
|
Ju SH, Yi HS. Clinical features and molecular mechanism of muscle wasting in end stage renal disease. BMB Rep 2023; 56:426-438. [PMID: 37482754 PMCID: PMC10471459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/10/2023] [Accepted: 07/17/2023] [Indexed: 07/25/2023] Open
Abstract
Muscle wasting in end-stage renal disease (ESRD) is an escalating issue due to the increasing global prevalence of ESRD and its significant clinical impact, including a close association with elevated mortality risk. The phenomenon of muscle wasting in ESRD, which exceeds the rate of muscle loss observed in the normal aging process, arises from multifactorial processes. This review paper aims to provide a comprehensive understanding of muscle wasting in ESRD, covering its epidemiology, underlying molecular mechanisms, and current and emerging therapeutic interventions. It delves into the assessment techniques for muscle mass and function, before exploring the intricate metabolic and molecular pathways that lead to muscle atrophy in ESRD patients. We further discuss various strategies to mitigate muscle wasting, including nutritional, pharmacological, exercise, and physical modalities intervention. This review seeks to provide a solid foundation for future research in this area, fostering a deeper understanding of muscle wasting in ESRD, and paving the way for the development of novel strategies to improve patient outcomes. [BMB Reports 2023; 56(8): 426-438].
Collapse
Affiliation(s)
- Sang Hyeon Ju
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 35015, Korea
| | - Hyon-Seung Yi
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 35015, Korea
- Laboratory of Endocrinology and Immune System, Chungnam National University School of Medicine, Daejeon 35015, Korea
| |
Collapse
|
|
4
|
Brusach K, Lorbach S, Quimby J, Nijveldt E, Paschall R, Kinsella H, Parker V, Toribio R. Measurement of Ghrelin as a Marker of Appetite Dysregulation in Cats with and without Chronic Kidney Disease. Vet Sci 2023; 10:464. [PMID: 37505868 PMCID: PMC10385538 DOI: 10.3390/vetsci10070464] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 07/11/2023] [Accepted: 07/11/2023] [Indexed: 07/29/2023] Open
Abstract
Appetite abnormalities and weight loss are important comorbidities in the treatment of chronic kidney disease (CKD) in cats. Ghrelin, a key hormone involved in the regulation of appetite and metabolism, is a potential marker of appetite dysregulation in cats with CKD. The aim of this study was to compare the plasma concentrations of acylated, desacyl, and total ghrelin in normal cats and cats with CKD. Storage methodology was investigated prior to evaluating ghrelin concentrations in normal and CKD cats to facilitate clinical sample collection. Twelve normal cats and twelve cats with CKD were enrolled. Plasma acylated and total ghrelin concentrations were measured using radioimmunoassay. Desacyl ghrelin was calculated (total ghrelin minus acylated ghrelin). Cats with CKD had significantly increased total ghrelin and calculated desacyl ghrelin concentrations in comparison to normal cats (p < 0.0001 and p = 0.0001). There was no significant difference in active ghrelin concentrations between groups. Both total ghrelin and calculated desacyl ghrelin were significantly correlated with serum creatinine concentrations (p < 0.0001, r = 0.70 and p < 0.0001, r = 0.73). Elevated plasma desacyl ghrelin concentrations in cats with CKD provides evidence for dysregulation of appetite in feline CKD.
Collapse
Affiliation(s)
- Katelyn Brusach
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Sarah Lorbach
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Jessica Quimby
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Eline Nijveldt
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Rene Paschall
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Hannah Kinsella
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Valerie Parker
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Ramiro Toribio
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA
| |
Collapse
|
|
5
|
Wang XH, Mitch WE, Price SR. Pathophysiological mechanisms leading to muscle loss in chronic kidney disease. Nat Rev Nephrol 2022; 18:138-152. [PMID: 34750550 DOI: 10.1038/s41581-021-00498-0] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/01/2021] [Indexed: 12/16/2022]
Abstract
Loss of muscle proteins is a deleterious consequence of chronic kidney disease (CKD) that causes a decrease in muscle strength and function, and can lead to a reduction in quality of life and increased risk of morbidity and mortality. The effectiveness of current treatment strategies in preventing or reversing muscle protein losses is limited. The limitations largely stem from the systemic nature of diseases such as CKD, which stimulate skeletal muscle protein degradation pathways while simultaneously activating mechanisms that impair muscle protein synthesis and repair. Stimuli that initiate muscle protein loss include metabolic acidosis, insulin and IGF1 resistance, changes in hormones, cytokines, inflammatory processes and decreased appetite. A growing body of evidence suggests that signalling molecules secreted from muscle can enter the circulation and subsequently interact with recipient organs, including the kidneys, while conversely, pathological events in the kidney can adversely influence protein metabolism in skeletal muscle, demonstrating the existence of crosstalk between kidney and muscle. Together, these signals, whether direct or indirect, induce changes in the levels of regulatory and effector proteins via alterations in mRNAs, microRNAs and chromatin epigenetic responses. Advances in our understanding of the signals and processes that mediate muscle loss in CKD and other muscle wasting conditions will support the future development of therapeutic strategies to reduce muscle loss.
Collapse
Affiliation(s)
- Xiaonan H Wang
- Renal Division, Department of Medicine, Emory University, Atlanta, GA, USA
| | - William E Mitch
- Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - S Russ Price
- Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC, USA. .,Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
| |
Collapse
|
|
6
|
Kiang JG, Zhai M, Lin B, Smith JT, Anderson MN, Jiang S. Co-Therapy of Pegylated G-CSF and Ghrelin for Enhancing Survival After Exposure to Lethal Radiation. Front Pharmacol 2021; 12:628018. [PMID: 33603673 PMCID: PMC7884820 DOI: 10.3389/fphar.2021.628018] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 01/07/2021] [Indexed: 12/17/2022] Open
Abstract
Exposure to ionizing radiation (radiation injury, RI) in nuclear-related episode is evident to be life-threatening. RI occurs at levels of organs, tissues, cytosols, or nucleus. Their mechanisms are still not fully understood. FDA approves pegylated granulocyte colony-stimulating factor (Neulasta™, Peg-G-CSF) for acute hematopoietic syndrome and has been shown to save lives after lethal RI. We aimed to test whether Ghrelin enhanced Peg-G-CSF's efficacy to save more lives after lethal RI. B6D2F1/J female mice were used for the study. They received 9.5 Gy (LD50/30 at 0.4 Gy/min) emitted from the 60Co-γ-photon radiation facility. Peg-G-CSF was injected subcutaneously at 1 mg/kg once on days 1, 8, and 15 after irradiation. Ghrelin contains 28 amino acid and is a hunger peptide that has been shown to stimulate food intake, promote intestinal epithelial cell proliferation, elevates immunity, inhibits brain hemorrhage, and increases stress-coping. Ghrelin was injected subcutaneously at 113 μg/kg once on days 1, 2, and 3 after irradiation. Survival, body weight, water consumption, hematology, spleen weight, splenocytes, bone marrow cells, and histology of bone marrow and ileum were performed. We observed that radiation resulted in 30-days survival by 30%. RI decreased their body weights and water consumption volumes. On the 30th day post-RI, platelets and WBCs such as basophils, eosinophils, monocytes, lymphocytes, neutrophils and leukocytes were still significantly decreased in surviving mice. Likewise, their RBC, hemoglobin, hematocrit, and splenocytes remained low; splenomegaly was found in these mice. Bone marrow in surviving RI animals maintained low cellularity with high counts of fat cells and low counts of megakaryocytes. Meanwhile, ileum histology displayed injury. However, mice co-treated with both drugs 24 h after RI resulted in 30-days survival by 45% above the vehicle group. Additionally, the body-weight loss was mitigated, the acute radiation syndrome was reduced. This co-therapy significantly increased neutrophils, eosinophils, leukocytes, and platelets in circulation, inhibited splenomegaly, and increased bone marrow cells. Histopathological analysis showed significant improvement on bone marrow cellularity and ileum morphology. In conclusion, the results provide a proof of concept and suggest that the co-therapy of Peg-G-CSF and Ghrelin is efficacious to ameliorate RI.
Collapse
Affiliation(s)
- Juliann G. Kiang
- Radiation Combined Injury Program, Armed Forces Radiobiology Research Institute, Bethesda, MD, United States
- Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
- Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Min Zhai
- Radiation Combined Injury Program, Armed Forces Radiobiology Research Institute, Bethesda, MD, United States
| | - Bin Lin
- Radiation Combined Injury Program, Armed Forces Radiobiology Research Institute, Bethesda, MD, United States
| | - Joan T. Smith
- Radiation Combined Injury Program, Armed Forces Radiobiology Research Institute, Bethesda, MD, United States
| | - Marsha N. Anderson
- Radiation Combined Injury Program, Armed Forces Radiobiology Research Institute, Bethesda, MD, United States
| | - Suping Jiang
- Radiation Combined Injury Program, Armed Forces Radiobiology Research Institute, Bethesda, MD, United States
| |
Collapse
|
|
7
|
Abstract
Cachexia is common in end-stage renal disease (ESRD) patients, and it is an important risk factor for poor quality of life and increased mortality and morbidity. Chronic inflammation is an important cause of cachexia in ESRD patients. In the present review, we examine recent evidence suggesting that adipokines or adipocytokines such as leptin, adiponectin, resistin, tumor necrosis factor α, interleukin-6, and interleukin-1β may play important roles in uremic cachexia. We also review the physiology and the potential roles of gut hormones, including ghrelin, peptide YY, and cholecystokinin in ESRD. Understanding the molecular pathophysiology of these novel hormones in ESRD may lead to novel therapeutic strategies.
Collapse
Affiliation(s)
- Robert H. Mak
- Division of Pediatric Nephrology, Oregon Health and Science University, Portland, Oregon
- Division of Pediatric Nephrology, University of California at San Diego, La Jolla, California, U.S.A
| | - Wai Cheung
- Division of Pediatric Nephrology, Oregon Health and Science University, Portland, Oregon
- Division of Pediatric Nephrology, University of California at San Diego, La Jolla, California, U.S.A
| |
Collapse
|
|
8
|
de la Nuez Veulens A, Rodríguez Fernández RE, Álvarez Ginarte YM, Montero Cabrera LA. In silico strategy for detailing the binding modes of a novel family of peptides proven as ghrelin receptor agonists. J Mol Model 2020; 26:294. [PMID: 33015729 DOI: 10.1007/s00894-020-04553-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 09/17/2020] [Indexed: 11/26/2022]
Abstract
Ghrelin is a peptide hormone involved in multiple functions, including growth hormone release stimulation, food intake regulation, and metabolic and cytoprotective effect. A novel family of peptides with internal cycles was designed as ghrelin analogs and the biological activity of two of them (A228 and A233) was experimentally studied in-depth. In this work, an in silico strategy was developed for describing and assessing the binding modes of A228 and A233 to GHS-R1a (ghrelin receptor) comparing it with ghrelin and GHRP-6 peptides. Several reported structures of different G protein coupled receptors were used as templates, to obtain a good quality model of GHS-R1a. The best model was selected by preliminary molecular docking with ghrelin and GHRP-6. Docking was used to estimate peptide orientations in the binding site of the best model, observing a superposition of its N-terminal and its first aromatic residue. To test the complex stability in time, the C-terminal fragments of each peptide were added and the complexes were inserted a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membrane, performing a molecular dynamic simulation for 100 ns using the CHARMM36 force field. Despite of the structural differences, the studied peptides share a common binding mode; the N-terminal interacts with E124 and the aromatic residue close to it, with the aromatic cluster (F279, F309, and F312). A preliminary pharmacophore model, consisting in a positive charged amine and an aromatic ring at an approximate distance of 0.79 nm, can be proposed. The results here described could represent a step forward in the efficient search of new ghrelin analogs.
Collapse
Affiliation(s)
| | | | - Yoanna M Álvarez Ginarte
- Laboratory of Theoretical and Computational Chemistry, Faculty of Chemistry, University of Havana, Havana, Cuba
| | - Luis A Montero Cabrera
- Laboratory of Theoretical and Computational Chemistry, Faculty of Chemistry, University of Havana, Havana, Cuba.
- Department of Chemistry, Johns Hopkins University, Baltimore, MD, USA.
| |
Collapse
|
|
9
|
Sabatino A, Cuppari L, Stenvinkel P, Lindholm B, Avesani CM. Sarcopenia in chronic kidney disease: what have we learned so far? J Nephrol 2020; 34:1347-1372. [PMID: 32876940 PMCID: PMC8357704 DOI: 10.1007/s40620-020-00840-y] [Citation(s) in RCA: 231] [Impact Index Per Article: 46.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 08/12/2020] [Indexed: 02/07/2023]
Abstract
The term sarcopenia was first introduced in 1988 by Irwin Rosenberg to define a condition of muscle loss that occurs in the elderly. Since then, a broader definition comprising not only loss of muscle mass, but also loss of muscle strength and low physical performance due to ageing or other conditions, was developed and published in consensus papers from geriatric societies. Sarcopenia was proposed to be diagnosed based on operational criteria using two components of muscle abnormalities, low muscle mass and low muscle function. This brought awareness of an important nutritional derangement with adverse outcomes for the overall health. In parallel, many studies in patients with chronic kidney disease (CKD) have shown that sarcopenia is a prevalent condition, mainly among patients with end stage kidney disease (ESKD) on hemodialysis (HD). In CKD, sarcopenia is not necessarily age-related as it occurs as a result of the accelerated protein catabolism from the disease and from the dialysis procedure per se combined with low energy and protein intakes. Observational studies showed that sarcopenia and especially low muscle strength is associated with worse clinical outcomes, including worse quality of life (QoL) and higher hospitalization and mortality rates. This review aims to discuss the differences in conceptual definition of sarcopenia in the elderly and in CKD, as well as to describe etiology of sarcopenia, prevalence, outcome, and interventions that attempted to reverse the loss of muscle mass, strength and mobility in CKD and ESKD patients.
Collapse
Affiliation(s)
- Alice Sabatino
- Division of Nephrology, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Lilian Cuppari
- Division of Nephrology, Federal University of São Paulo and Oswaldo Ramos Foundation, São Paulo, Brazil
| | - Peter Stenvinkel
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Technology and Intervention, Karolinska Institute, Stockholm, Sweden
| | - Bengt Lindholm
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Technology and Intervention, Karolinska Institute, Stockholm, Sweden
| | - Carla Maria Avesani
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Technology and Intervention, Karolinska Institute, Stockholm, Sweden.
- Nutrition Institute, Rio de Janeiro State University, Rio de Janeiro, Brazil.
| |
Collapse
|
|
10
|
Mak RH, Cheung W, Purnell J. Ghrelin in Chronic Kidney Disease: Too Much or Too Little? Perit Dial Int 2020. [DOI: 10.1177/089686080702700112] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Affiliation(s)
- Robert H. Mak
- Department of Pediatrics Oregon Health & Science University Portland, Oregon, USA
| | - Wai Cheung
- Department of Pediatrics Oregon Health & Science University Portland, Oregon, USA
| | - Jonathan Purnell
- Department of Medicine Oregon Health & Science University Portland, Oregon, USA
- Center for the Study of Weight Regulation Oregon Health & Science University Portland, Oregon, USA
| |
Collapse
|
|
11
|
Behavioural characterization of ghrelin ligands, anamorelin and HM01: Appetite and reward-motivated effects in rodents. Neuropharmacology 2020; 168:108011. [PMID: 32067989 DOI: 10.1016/j.neuropharm.2020.108011] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 02/12/2020] [Accepted: 02/13/2020] [Indexed: 12/14/2022]
Abstract
The ghrelinergic system has been steadily investigated as a therapeutic target in the treatment of metabolic disorders and modulation of appetite. While endogenous ghrelin activates the full complement of the growth hormone secretagogue receptor (GHSR-1a) pathways, synthetic GHSR-1a ligands display biased signalling and functional selectivity, which have a significant impact on the intended and indeed, unintended, therapeutic effects. The widespread expression of the GHSR-1a receptor in vivo also necessitates an imperative consideration of the biodistribution of GHSR-1a ligands. Here, we investigate anamorelin and HM01, two recently described synthetic GHSR-1a ligands which have shown promising effects on food intake in preclinical and clinical studies. We compare the downstream signalling pathways in cellular in vitro assays, including calcium mobilization, IP-one, internalization and β-arrestin recruitment assays. We describe a novel divergent activation of central reward circuitry by anamorelin and HM01 using c-Fos immunostaining as well as behavioural effects in food intake and reward paradigms. Interestingly, we found a paradoxical reduction in reward-related behaviour for anamorelin and HM01 treated animals in our chosen paradigms. The work highlights the critical importance to consider signalling bias in relation to future ghrelin-based therapies. In addition, central access of GHSR-1a ligands, particularly to reward areas of the brain, remains a crucial factor in eliciting potent appetite-stimulating effects. The precise characterization of downstream ghrelinergic signalling and biodistribution of novel GHSR-1a ligands will be decisive in their successful development and will allow predictive modelling and design of future synthetic ligands to combat metabolic and appetite disorders involving the ghrelinergic system. This article is part of the special issue on 'Neuropeptides'.
Collapse
|
|
12
|
Oliveira EA, Zheng R, Carter CE, Mak RH. Cachexia/Protein energy wasting syndrome in CKD: Causation and treatment. Semin Dial 2019; 32:493-499. [PMID: 31286575 DOI: 10.1111/sdi.12832] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Cachexia is a multifactorial syndrome defined by significant body weight loss, fat and muscle mass reduction, and increased protein catabolism. Protein energy wasting (PEW) is characterized as a syndrome of adverse changes in nutrition and body composition being highly prevalent in patients with CKD, especially in those undergoing dialysis, and it is associated with high morbidity and mortality in this population. Multiple mechanisms are involved in the genesis of these adverse nutritional changes in CKD patients. There is no obvious distinction between PEW and cachexia from a pathophysiologic standpoint and should be considered as part of the spectrum of the same nutritional disorder in CKD with similar management approaches for prevention and treatment based on current understanding. A plethora of factors can affect the nutritional status of CKD patients requiring a combination of therapeutic approaches to prevent or reverse protein and energy depletion. At present, there is no effective pharmacologic intervention that prevents or attenuates muscle atrophy in catabolic conditions like CKD. Prevention and treatment of uremic muscle wasting involve optimal nutritional support, correction of acidosis, and physical exercise. There has been emerging consistent evidence that active treatment, perhaps by combining nutritional interventions and resistance exercise, may be able to improve but not totally reverse or prevent the supervening muscle wasting and weakness. Active research into more direct pharmacological treatment based on basic mechanistic research is much needed for this unmet medical need in patients with CKD.
Collapse
Affiliation(s)
- Eduardo A Oliveira
- Division of Pediatric Nephrology, Rady Children's Hospital San Diego, University of California San Diego, California
- Pediatric Nephrourology Division, Department of Pediatrics, School of Medicine, Federal University of Minas Gerais (UFMG), Minas Gerais, Brazil
| | - Ronghao Zheng
- Department of Pediatric Nephrology, Rheumatology and Immunology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Caitlin E Carter
- Division of Pediatric Nephrology, Rady Children's Hospital San Diego, University of California San Diego, California
| | - Robert H Mak
- Division of Pediatric Nephrology, Rady Children's Hospital San Diego, University of California San Diego, California
| |
Collapse
|
|
13
|
Ookawara S, Kaku Y, Ito K, Kizukuri K, Namikawa A, Nakahara S, Horiuchi Y, Inose N, Miyahara M, Shiina M, Minato S, Shindo M, Miyazawa H, Hirai K, Hoshino T, Murakoshi M, Tabei K, Morishita Y. Effects of dietary intake and nutritional status on cerebral oxygenation in patients with chronic kidney disease not undergoing dialysis: A cross-sectional study. PLoS One 2019; 14:e0223605. [PMID: 31600287 PMCID: PMC6786594 DOI: 10.1371/journal.pone.0223605] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 09/24/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Dietary management is highly important for the maintenance of renal function in patients with chronic kidney disease (CKD). Cerebral oxygen saturation (rSO2) was reportedly associated with the estimated glomerular filtration rate (eGFR) and cognitive function. However, data concerning the association between cerebral rSO2 and dietary intake of CKD patients is limited. METHODS This was a single-center observational study. We recruited 67 CKD patients not undergoing dialysis. Cerebral rSO2 was monitored using the INVOS 5100c oxygen saturation monitor. Energy intake was evaluated by dietitians based on 3-day meal records. Daily protein and salt intakes were calculated from 24-h urine collection. RESULTS Multivariable regression analysis showed that cerebral rSO2 was independently associated with energy intake (standardized coefficient: 0.370) and serum albumin concentration (standardized coefficient: 0.236) in Model 1 using parameters with p < 0.10 in simple linear regression analysis (body mass index, Hb level, serum albumin concentration, salt and energy intake) and confounding factors (eGFR, serum sodium concentration, protein intake), and the energy/salt index (standardized coefficient: 0.343) and Hb level (standardized coefficient: 0.284) in Model 2 using energy/protein index as indicated by energy intake/protein intake and energy/salt index by energy intake/salt intake in place of salt, protein and energy intake. CONCLUSIONS Cerebral rSO2 is affected by energy intake, energy/salt index, serum albumin concentration and Hb level. Sufficient energy intake and adequate salt restriction is important to prevent deterioration of cerebral oxygenation, which might contribute to the maintenance of cognitive function in addition to the prevention of renal dysfunction in CKD patients.
Collapse
Affiliation(s)
- Susumu Ookawara
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
- Department of Nutrition, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Yoshio Kaku
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Kiyonori Ito
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Kanako Kizukuri
- Department of Nutrition, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Aiko Namikawa
- Department of Nutrition, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Shinobu Nakahara
- Department of Nutrition, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Yuko Horiuchi
- Department of Nutrition, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Nagisa Inose
- Department of Nutrition, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Mayako Miyahara
- Department of Nutrition, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Michiko Shiina
- Department of Nutrition, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Saori Minato
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Mitsutoshi Shindo
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Haruhisa Miyazawa
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Keiji Hirai
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Taro Hoshino
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Miho Murakoshi
- Department of Nutrition, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Kaoru Tabei
- Department of Internal Medicine, Minami-uonuma City Hospital, Niigata, Japan
| | - Yoshiyuki Morishita
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| |
Collapse
|
|
14
|
Campbell GA, Patrie JT, Gaylinn BD, Thorner MO, Bolton WK. Oral ghrelin receptor agonist MK-0677 increases serum insulin-like growth factor 1 in hemodialysis patients: a randomized blinded study. Nephrol Dial Transplant 2019; 33:523-530. [PMID: 28340044 DOI: 10.1093/ndt/gfw474] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 12/27/2016] [Indexed: 01/09/2023] Open
Abstract
Background Protein-energy wasting (PEW) in end-stage renal disease (ESRD) patients is associated with increased morbidity and mortality, but options for treatment are limited. Growth hormone (GH) increases insulin-like growth factor 1 (IGF-1), with improved nutritional parameters, but must be given subcutaneously and does not provide normal GH secretion patterns. MK-0677, an oral ghrelin receptor agonist (GRA), maintains normal GH secretion and increases lean body mass in normal subjects; it has not been studied in dialysis patients, an essential step in assessing efficacy and safety prior to clinical trials. Methods We performed a randomized crossover double-blind study in assessing the effect of MK-0677 versus placebo on IGF-1 levels, the primary outcome, in hemodialysis patients. In total, 26 subjects enrolled and 22 completed the 3-month crossover study. Results The geometric mean IGF-1 was 1.07-fold greater [95% confidence interval (CI) 0.89-1.27; P = 0.718] after placebo. In patients receiving MK-0677, the geometric mean IGF-1 were 1.76-fold greater (95% CI 1.48-2.10; P < 0.001) following MK-0677. When the data were adjusted for preintervention IGF-1 concentration, the ratio of geometric means (MK-0677 relative to placebo) for the pre- versus postintervention change in the IGF-1 was 1.65 (95% CI 1.33-2.04; P < 0.001). These data demonstrate a 65% greater increase (95% CI 33-104%) in IGF-1 in MK-0677-dosed subjects compared with placebo. There were no serious adverse effects attributable to MK-0677. Conclusions MK-0677 increased serum IGF-1 levels with minimal adverse effects in hemodialysis subjects. Studies are needed to evaluate whether long-term therapy with MK-0677 improves PEW, lean body mass, physical strength, quality of life and survival in CKD/ESRD patients.
Collapse
Affiliation(s)
- Garland A Campbell
- Division of Nephrology, University of Virginia Health Sciences Center, Charlottesville, VA, USA
| | - James T Patrie
- PBHS Public Health Sciences Administration, Public Health Sciences, University of Virginia Health Sciences Center, Charlottesville, VA, USA
| | - Bruce D Gaylinn
- Division of Endocrinology, University of Virginia Health Sciences Center, Charlottesville, VA, USA
| | - Michael O Thorner
- Division of Endocrinology, University of Virginia Health Sciences Center, Charlottesville, VA, USA
| | - Warren K Bolton
- Division of Nephrology, University of Virginia Health Sciences Center, Charlottesville, VA, USA
| |
Collapse
|
|
15
|
Zoccali C, Mallamaci F. Obestatin, a Ghrelin-Cognate Protein, and Clinical Outcomes in Hemodialysis Patients. Am J Nephrol 2019; 47:251-253. [PMID: 29694953 DOI: 10.1159/000488287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 03/07/2018] [Indexed: 11/19/2022]
Affiliation(s)
- Carmine Zoccali
- CNR-IFC, Clinical Epidemiology and Pathophysiology of Hypertension and Renal Diseases, Reggio Calabria, Italy
| | - Francesca Mallamaci
- CNR-IFC, Clinical Epidemiology and Pathophysiology of Hypertension and Renal Diseases, Reggio Calabria, Italy.,Nephrology, Hypertension and Renal Transplantation Unit, Ospedali Riuniti Reggio Calabria, Reggio Calabria, Italy
| |
Collapse
|
|
16
|
Sakao Y, Ohashi N, Sugimoto M, Ichikawa H, Sahara S, Tsuji T, Kato A, Fujigaki Y, Sugimoto K, Furuta T, Yasuda H. Gender Differences in Plasma Ghrelin Levels in Hemodialysis Patients. Ther Apher Dial 2018; 23:65-72. [PMID: 30259652 DOI: 10.1111/1744-9987.12764] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 08/16/2018] [Accepted: 09/25/2018] [Indexed: 01/29/2023]
Abstract
Ghrelin is an orexigenic hormone mainly secreted by the stomach, and it decreases according to the severity of gastric atrophy. Ghrelin has multiple favorable functions, including protein anabolism enhancement, anti-inflammatory activity, and cardiovascular protection, and is associated with survival in hemodialysis (HD) patients. Although the plasma level and role of ghrelin may be different depending on gender, they have not been completely assessed in HD patients. We enrolled 80 (male/female: 51/29) maintenance HD patients. An upper gastrointestinal endoscopic examination was performed for all patients to determine the severity of gastric mucosal atrophy and Helicobacter pylori infection. We measured plasma acyl and desacyl ghrelin levels and assessed the association between ghrelin levels and relevant clinical parameters, including nutrition, inflammation, atherosclerosis, and bone metabolism, by gender. Both acyl and desacyl ghrelin levels in female HD patients were significantly higher than those in male HD patients. When stratified by gastric mucosal atrophy, these gender differences were observed only in patients without gastric atrophy. In female patients, acyl ghrelin level was negatively correlated with age. In male patients, both acyl and desacyl ghrelin levels were positively correlated with bone mineral density. Multiple regression analysis showed significant positive correlations between both ghrelin levels and female gender after adjusting for confounding factors. Plasma ghrelin levels were higher in female HD patients than in male HD patients. The gender difference was more evident in patients without gastric atrophy.
Collapse
Affiliation(s)
- Yukitoshi Sakao
- Hamana Clinic, Shizuoka, Japan.,Internal Medicine I, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Naro Ohashi
- Internal Medicine I, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Mitsushige Sugimoto
- Internal Medicine I, Hamamatsu University School of Medicine, Shizuoka, Japan.,Division of Digestive Endoscopy, Shiga University of Medical Science Hospital, Otsu, Japan
| | - Hitomi Ichikawa
- Internal Medicine I, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Shu Sahara
- Internal Medicine I, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Takayuki Tsuji
- Internal Medicine I, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Akihiko Kato
- Blood Purification Unit, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Yoshihide Fujigaki
- Internal Medicine I, Hamamatsu University School of Medicine, Shizuoka, Japan.,Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Ken Sugimoto
- Internal Medicine I, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Hideo Yasuda
- Internal Medicine I, Hamamatsu University School of Medicine, Shizuoka, Japan
| |
Collapse
|
|
17
|
Ichikawa H, Sugimoto M, Sakao Y, Sahara S, Ohashi N, Sano K, Tadokoro S, Azekura H, Shimomura A, Yamashita F, Sugiyama D, Fukuta K, Furuta T, Kato A, Sugimoto K, Yasuda H. Eradication therapy for Helicobacter pylori infection improves nutrition status in Japanese hemodialysis patients: a pilot study. J Clin Biochem Nutr 2018; 64:91-95. [PMID: 30705518 PMCID: PMC6348417 DOI: 10.3164/jcbn.18-61] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 06/25/2018] [Indexed: 12/28/2022] Open
Abstract
Plasma ghrelin level is influenced by Helicobacter pylori (H. pylori) status and the severity of gastric mucosal atrophy, and the ghrelin level is associated with nutrition status in hemodialysis patients. Here, we investigated the efficacy of H. pylori eradication therapy in improving nutrition status in relation to the ghrelin level in H. pylori-positive hemodialysis patients. Of H. pylori-positive patients receiving hemodialysis at 8 dialysis center, 21 patients underwent gastroduodenoscopy for evaluation of the severity of gastric atrophy, and nutrition markers and plasma ghrelin levels before and 1 year after H. pylori eradication therapy were evaluated. Serum cholinesterase level was significantly increased after H. pylori eradication compared with the level before eradication (303.2 ± 76.0 vs 287.3 ± 68.1 IU/L, p = 0.029). In particular, cholesterol (before, 196.6 ± 23.2 mg/dl; after, 206.1 ± 25.9 mg/dl, p = 0.042) and cholinesterase levels (before, 296.9 ± 70.8 IU/L; after, 316.4 ± 73.8 IU/L, p = 0.049) increased more strongly in patients with mild–moderate atrophy than those with severe atrophy, irrespective of improvement of plasma acyl-ghrelin and desacyl-ghrelin levels after eradication therapy. In conclusion, H. pylori eradication may improve nutrition status by increasing serum cholinesterase and cholesterol levels in hemodialysis patients, especially those with mild and moderate gastric mucosal atrophy.
Collapse
Affiliation(s)
- Hitomi Ichikawa
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Mitsushige Sugimoto
- Division of Digestive Endoscopy, Shiga University of Medical Science Hospital, Seta, Tsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Yukitoshi Sakao
- Hamana Clinic, 235-1 Numa, Hamakita-ku, Hamamatsu, Shizuoka 434-0037, Japan
| | - Shu Sahara
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Naro Ohashi
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Koji Sano
- Sano Clinic, 1818 Tennou-cho, Higashi-ku, Hamamatsu, Shizuoka 435-0052, Japan
| | - Shigeru Tadokoro
- Tadokoro Clinic, 1239 Uchino, Hamakita-ku, Hamamatsu, Shizuoka 434-0044, Japan
| | - Hisanori Azekura
- Sanaru Sun Clinic, 2-14-39 Higashiiba, Naka-ku, Hamamatsu, Shizuoka 432-8036, Japan
| | - Akira Shimomura
- Sanarudai Asahi Clinic, 5-20-10 Sanarudai, Naka-ku, Hamamatsu, Shizuoka 432-8021, Japan
| | - Fuyuki Yamashita
- Yamashita Clinic, 2-1-5 Nakaizumi, Iwata, Shizuoka 438-0078, Japan
| | - Daiki Sugiyama
- Satsuki no Mori Clinic, 1665-2 Nakase, Hamakita-ku, Hamamatsu, Shizuoka 434-0012, Japan
| | - Ken Fukuta
- Hiryu Clinic, 304-9 Akura, Futamata-cho, Tenryu-ku, Hamamatsu, Shizuoka 431-3311, Japan
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Akihiko Kato
- Blood Purification Unit, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Ken Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Hideo Yasuda
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| |
Collapse
|
|
18
|
Sarav M, Friedman AN. Use of Intradialytic Parenteral Nutrition in Patients Undergoing Hemodialysis. Nutr Clin Pract 2018; 33:767-771. [PMID: 30207411 DOI: 10.1002/ncp.10190] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Intradialytic parenteral nutrition (IDPN) is a form of supplemental nutrition used to treat patients with malnutrition who receive hemodialysis. Once the diagnosis of malnutrition is made in such patients, encouragement of oral intake is the first-line treatment. If this fails, then enteral or parenteral nutrition may be needed. This review examines the literature on the use of IDPN and summarizes the current recommendations. There is considerable controversy over indications and benefits of IDPN, and well-controlled, long-term studies are needed to help tease out these issues. In the interim, clinical judgment should be used when considering IDPN for individual patients.
Collapse
Affiliation(s)
- Menaka Sarav
- Division of Nephrology and Hypertension, Department of Medicine, NorthShore University HealthSystem, Evanston, Illinois, USA
| | - Allon N Friedman
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| |
Collapse
|
|
19
|
Gortan Cappellari G, Zanetti M, Vinci P, Guarnieri G, Barazzoni R. Unacylated Ghrelin: A Novel Regulator of Muscle Intermediate Metabolism With Potential Beneficial Effects in Chronic Kidney Disease. J Ren Nutr 2018; 27:474-477. [PMID: 29056169 DOI: 10.1053/j.jrn.2017.05.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 05/02/2017] [Indexed: 11/11/2022] Open
Abstract
In patients with chronic kidney disease (CKD), malnutrition with loss of skeletal muscle mass has a negative impact on morbidity and mortality. Emerging evidence indicates that a cluster of oxidative stress, inflammation, and insulin resistance directly contributes to skeletal muscle catabolism by favoring protein breakdown over synthesis. Ghrelin is a gastric hormone discovered and initially studied in its acylated orexigenic form. More recently, a role of unacylated ghrelin (UnAG) has been described to reduce skeletal muscle mitochondrial reactive oxygen species generation, inflammation, and insulin resistance both in experimental models and in clinical studies. UnAG administration could therefore represent a potential comprehensive therapeutic approach for CKD-related metabolic and nutritional complications. Studies of UnAG administration in experimental and clinical CKD are needed to test the hypothesis that UnAG may chronically improve nutritional status and outcome in CKD patients.
Collapse
Affiliation(s)
| | - Michela Zanetti
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Pierandrea Vinci
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Gianfranco Guarnieri
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Rocco Barazzoni
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
| |
Collapse
|
|
20
|
Wang Z, Oliveira EA, Mak RH. Unacylated ghrelin and obestatin in pediatric CKD: are they important in protein energy wasting? Pediatr Nephrol 2018; 33:741-743. [PMID: 29453692 DOI: 10.1007/s00467-018-3891-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Revised: 01/10/2018] [Accepted: 01/10/2018] [Indexed: 10/18/2022]
Affiliation(s)
- Zhen Wang
- Division of Pediatric Nephrology, Rady Children's Hospital San Diego, University of California San Diego, 9500 Gilman Drive, MC 0630, La Jolla, CA, 92093-0630, USA.,Department of Pediatrics, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Eduardo A Oliveira
- Division of Pediatric Nephrology, Rady Children's Hospital San Diego, University of California San Diego, 9500 Gilman Drive, MC 0630, La Jolla, CA, 92093-0630, USA.,Pediatric Nephro-Urology Division, Department of Pediatrics, School of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Robert H Mak
- Division of Pediatric Nephrology, Rady Children's Hospital San Diego, University of California San Diego, 9500 Gilman Drive, MC 0630, La Jolla, CA, 92093-0630, USA.
| |
Collapse
|
|
21
|
Monzani A, Perrone M, Prodam F, Moia S, Genoni G, Testa S, Paglialonga F, Rapa A, Bona G, Montini G, Edefonti A. Unacylated ghrelin and obestatin: promising biomarkers of protein energy wasting in children with chronic kidney disease. Pediatr Nephrol 2018; 33:661-672. [PMID: 29150712 DOI: 10.1007/s00467-017-3840-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 08/17/2017] [Accepted: 10/23/2017] [Indexed: 12/01/2022]
Abstract
BACKGROUND Impairment in orexigenic/anorexigenic hormone balance may be key in the pathogenesis of protein energy wasting in children with chronic kidney disease (CKD). Measurement of ghrelin and obestatin concentrations in children with CKD would help assess the potential contribution of these hormones to uremic protein energy wasting. METHODS This was a cross-sectional case-control study. Acylated and unacylated ghrelin and obestatin were measured in 42 children on conservative treatment (CT), 20 children on hemodialysis, 48 pediatric renal transplant (RTx) recipients and 43 controls (CTR) (mean age 11.9, range 5-20 years). Weight, height and bicipital, tricipital, subscapular and suprailiac folds were measured, and the body mass index-standard deviation score (BMI-SDS), percentage of fat mass and fat-free mass were calculated. Urea and creatinine were measured and the glomerular filtration rate (GFR) calculated. RESULTS Unacylated ghrelin level was higher in patients than controls (p = 0.0001), with the highest levels found in hemodialysis patients (p = 0.001 vs. CKD-CT, p = 0.0001 vs. RTx, p < 0.0001 vs. CTR). Obestatin level was significantly higher in patients on hemodialysis than those on conservative treatment, RTx recipients and controls (p < 0.0001 in each case). Unacylated ghrelin negatively correlated with weight-SDS (p < 0.0001), BMI-SDS (p = 0.0005) and percentage fat mass (p = 0.004) and positively correlated with percentage fat-free mass (p = 0.004). Obestatin concentration negatively correlated with weight-SDS (p = 0.007). Unacylated ghrelin and obestatin concentrations positively correlated with creatinine and urea and inversely with eGFR, even after adjustments for gender, age, puberty and BMI-SDS (p < 0.0001 for each model). CONCLUSIONS Unacylated ghrelin and obestatin, negatively related to renal function, seem to be promising inverse indicators of nutritional status in children with CKD. Potential therapeutic implications in terms of optimization of their removal in patients on hemodialysis could be hypothesized.
Collapse
Affiliation(s)
- Alice Monzani
- Division of Pediatrics, Department of Health Sciences, Università del Piemonte Orientale, V. Solaroli 17, 28100, Novara, Italy
| | - Michela Perrone
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione Cà Granda IRCCS, Ospedale Maggiore Policlinico, Milan, Italy
| | - Flavia Prodam
- Division of Pediatrics, Department of Health Sciences, Università del Piemonte Orientale, V. Solaroli 17, 28100, Novara, Italy
| | - Stefania Moia
- Division of Pediatrics, Department of Health Sciences, Università del Piemonte Orientale, V. Solaroli 17, 28100, Novara, Italy
| | - Giulia Genoni
- Division of Pediatrics, Department of Health Sciences, Università del Piemonte Orientale, V. Solaroli 17, 28100, Novara, Italy.
| | - Sara Testa
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione Cà Granda IRCCS, Ospedale Maggiore Policlinico, Milan, Italy
| | - Fabio Paglialonga
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione Cà Granda IRCCS, Ospedale Maggiore Policlinico, Milan, Italy
| | - Anna Rapa
- Division of Pediatrics, Department of Health Sciences, Università del Piemonte Orientale, V. Solaroli 17, 28100, Novara, Italy
| | - Gianni Bona
- Division of Pediatrics, Department of Health Sciences, Università del Piemonte Orientale, V. Solaroli 17, 28100, Novara, Italy
| | - Giovanni Montini
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione Cà Granda IRCCS, Ospedale Maggiore Policlinico, Milan, Italy.,Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Alberto Edefonti
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione Cà Granda IRCCS, Ospedale Maggiore Policlinico, Milan, Italy
| |
Collapse
|
|
22
|
Cachexia in children with chronic kidney disease: challenges in diagnosis and treatment. Curr Opin Support Palliat Care 2018; 10:293-297. [PMID: 27258684 DOI: 10.1097/spc.0000000000000217] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
PURPOSE OF REVIEW Although cachexia is highly prevalent in adult patients with chronic kidney disease (CKD), it is understudied and less well characterized in children. Recent evidence suggests that cachexia is also prevalent in children with CKD but presents challenges in diagnosis and treatment. RECENT FINDINGS A study from the CKD in children cohort showed that CKD cachexia or protein-energy wasting, using modified pediatric diagnostic criteria, such as lack of expected weight gain instead of weight loss and BMI for height age, had a prevalence of 7-20%. When growth indices such as height SD score (SDS)/height velocity SDS was included in the criteria, cachexia or PEW correlated with the morbidity outcome of increased hospitalization risk in children with CKD. Conversely, aggressive nutritional supplementation in children with advanced CKD, with nasogastric or gastric tube feeding, led to prevalence of obesity over that of cachexia. Body habitus of underweight and obesity have been shown to be associated with the worst clinical outcomes in both adults and children with CKD. SUMMARY Optimal nutritional therapy remains the mainstay of treatment of cachexia in CKD children with therapeutic goals of maintaining BMI as well as linear growth within the normal range.
Collapse
|
|
23
|
Impact of ghrelin on body composition and muscle function in a long-term rodent model of critical illness. PLoS One 2017; 12:e0182659. [PMID: 28796827 PMCID: PMC5552127 DOI: 10.1371/journal.pone.0182659] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 07/22/2017] [Indexed: 01/14/2023] Open
Abstract
Background Patients with multiple injuries or sepsis requiring intensive care treatment invariably develop a catabolic state with resultant loss of lean body mass, for which there are currently no effective treatments. Recovery can take months and mortality is high. We hypothesise that treatment with the orexigenic and anti-inflammatory gastric hormone, ghrelin may attenuate the loss of body mass following critical illness and improve recovery. Methods Male Wistar rats received an intraperitoneal injection of the fungal cell wall derivative zymosan to induce a prolonged peritonitis and consequent critical illness. Commencing at 48h after zymosan, animals were randomised to receive a continuous infusion of ghrelin or vehicle control using a pre-implanted subcutaneous osmotic mini-pump, and continued for 10 days. Results Zymosan peritonitis induced significant weight loss and reduced food intake with a nadir at Day 2 and gradual recovery thereafter. Supra-physiologic plasma ghrelin levels were achieved in the treated animals. Ghrelin-treated rats ate more food and gained more body mass than controls. Ghrelin increased adiposity and promoted carbohydrate over fat metabolism, but did not alter total body protein, muscle strength nor muscle morphology. Muscle mass and strength remained significantly reduced in all zymosan-treated animals, even at ten days post-insult. Conclusions Continuous infusion of ghrelin increased body mass and food intake, but did not increase muscle mass nor improve muscle function, in a long-term critical illness recovery model. Further studies with pulsatile ghrelin delivery or additional anabolic stimuli may further clarify the utility of ghrelin in survivors of critical illness.
Collapse
|
|
24
|
Colldén G, Tschöp MH, Müller TD. Therapeutic Potential of Targeting the Ghrelin Pathway. Int J Mol Sci 2017; 18:ijms18040798. [PMID: 28398233 PMCID: PMC5412382 DOI: 10.3390/ijms18040798] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 04/03/2017] [Accepted: 04/06/2017] [Indexed: 02/07/2023] Open
Abstract
Ghrelin was discovered in 1999 as the endogenous ligand of the growth-hormone secretagogue receptor 1a (GHSR1a). Since then, ghrelin has been found to exert a plethora of physiological effects that go far beyond its initial characterization as a growth hormone (GH) secretagogue. Among the numerous well-established effects of ghrelin are the stimulation of appetite and lipid accumulation, the modulation of immunity and inflammation, the stimulation of gastric motility, the improvement of cardiac performance, the modulation of stress, anxiety, taste sensation and reward-seeking behavior, as well as the regulation of glucose metabolism and thermogenesis. Due to a variety of beneficial effects on systems’ metabolism, pharmacological targeting of the endogenous ghrelin system is widely considered a valuable approach to treat metabolic complications, such as chronic inflammation, gastroparesis or cancer-associated anorexia and cachexia. The aim of this review is to discuss and highlight the broad pharmacological potential of ghrelin pathway modulation for the treatment of anorexia, cachexia, sarcopenia, cardiopathy, neurodegenerative disorders, renal and pulmonary disease, gastrointestinal (GI) disorders, inflammatory disorders and metabolic syndrome.
Collapse
Affiliation(s)
- Gustav Colldén
- Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
| | - Matthias H Tschöp
- Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
- Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany.
| | - Timo D Müller
- Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
- Institute for Diabetes and Obesity (IDO), Business Campus Garching-Hochbrück, Parkring 13, 85748 Garching, Germany.
| |
Collapse
|
|
25
|
From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation. Int J Mol Sci 2017; 18:ijms18020273. [PMID: 28134808 PMCID: PMC5343809 DOI: 10.3390/ijms18020273] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 01/19/2017] [Indexed: 12/20/2022] Open
Abstract
Ghrelin is the only known peripherally-derived orexigenic hormone, increasing appetite and subsequent food intake. The ghrelinergic system has therefore received considerable attention as a therapeutic target to reduce appetite in obesity as well as to stimulate food intake in conditions of anorexia, malnutrition and cachexia. As the therapeutic potential of targeting this hormone becomes clearer, it is apparent that its pleiotropic actions span both the central nervous system and peripheral organs. Despite a wealth of research, a therapeutic compound specifically targeting the ghrelin system for appetite modulation remains elusive although some promising effects on metabolic function are emerging. This is due to many factors, ranging from the complexity of the ghrelin receptor (Growth Hormone Secretagogue Receptor, GHSR-1a) internalisation and heterodimerization, to biased ligand interactions and compensatory neuroendocrine outputs. Not least is the ubiquitous expression of the GHSR-1a, which makes it impossible to modulate centrally-mediated appetite regulation without encroaching on the various peripheral functions attributable to ghrelin. It is becoming clear that ghrelin’s central signalling is critical for its effects on appetite, body weight regulation and incentive salience of food. Improving the ability of ghrelin ligands to penetrate the blood brain barrier would enhance central delivery to GHSR-1a expressing brain regions, particularly within the mesolimbic reward circuitry.
Collapse
|
|
26
|
Beberashvili I, Sinuani I, Azar A, Shapiro G, Feldman L, Doenyas-Barak K, Stav K, Efrati S. Interaction between acyl-ghrelin and BMI predicts clinical outcomes in hemodialysis patients. BMC Nephrol 2017; 18:29. [PMID: 28100170 PMCID: PMC5242040 DOI: 10.1186/s12882-017-0442-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 01/06/2017] [Indexed: 12/14/2022] Open
Abstract
Background Ghrelin, a gastric orexigenic peptide, and body mass index (BMI) are known as inversely associated to each other and are both linked to cardiovascular (CV) risk and mortality in maintenance hemodialysis (MHD) patients. However, it is unclear whether the interaction between ghrelin and BMI is associated with a risk of all-cause and CV death in this population. Methods A prospective observational study was performed on 261 MHD outpatients (39% women, mean age 68.6 ± 13.6 years) recruited from October 2010 through April 2012, and were followed until November 2014 (median follow-up-28 months, interquartile range-19–34 months). We measured acyl-ghrelin (AG) levels, appetite, nutritional and inflammatory markers, prospective all-cause and cardiovascular (CV) mortality. Results During follow-up, 109 patients died, 51 due to CV causes. A significant interaction effect of high BMI and high AG (defined as levels higher than median) on all-cause mortality was found. Crude Cox HR for the product termed BMI x AG was 0.52, with a 95% confidence interval (CI): 0.29 to 0.95 (P = 0.03). Evaluating the interaction on an additive scale revealed that the combined predictive value of BMI and AG is larger than the sum of their individual predictive values (synergy index was 1.1). Across the four BMI-AG categories, the group with high BMI and high AG exhibited better all-cause and cardiovascular mortality irrespective of appetite and nutritional status (multivariable adjusted hazard ratios were 0.31, 95% CI 0.16 to 0.62, P = 0.001, and 0.35, 95% CI 0.13 to 0.91, P = 0.03, respectively). Data analyses made by dividing patients according to fat mass-AG, but not to lean body mass-AG categories, provided similar results. Conclusions Higher AG levels enhance the favourable association between high BMI and survival in MHD patients irrespective of appetite, nutritional status and inflammation.
Collapse
Affiliation(s)
- Ilia Beberashvili
- Nephrology Division, Assaf Harofeh Medical Center, Zerifin. Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Inna Sinuani
- Department of pathology, Assaf Harofeh Medical Center, Zerifin. Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ada Azar
- Nutrition Department, Assaf Harofeh Medical Center, Zerifin. Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Gregory Shapiro
- Nephrology Division, Assaf Harofeh Medical Center, Zerifin. Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Leonid Feldman
- Nephrology Division, Assaf Harofeh Medical Center, Zerifin. Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Keren Doenyas-Barak
- Nephrology Division, Assaf Harofeh Medical Center, Zerifin. Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Kobi Stav
- Urology Department, Assaf Harofeh Medical Center, Zerifin. Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shai Efrati
- Nephrology Division, Assaf Harofeh Medical Center, Zerifin. Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| |
Collapse
|
|
27
|
Ichikawa H, Sugimoto M, Sakao Y, Sahara S, Ohashi N, Kato A, Sugimoto K, Furuta T, Andoh A, Sakao T, Yasuda H. Relationship between ghrelin, Helicobacter pylori and gastric mucosal atrophy in hemodialysis patients. World J Gastroenterol 2016; 22:10440-10449. [PMID: 28058025 PMCID: PMC5175257 DOI: 10.3748/wjg.v22.i47.10440] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 10/18/2016] [Accepted: 11/13/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the relationship between plasma ghrelin level, Helicobacter pylori (H. pylori) infection status and the severity of atrophy in hemodialysis patients.
METHODS One hundred eights patients who received hemodialysis and 13 non-hemodialysis H. pylori-negative controls underwent gastroduodenoscopy to evaluate the severity of gastric atrophy. Serum levels of pepsinogen (PG) were measured as serum markers of gastric atrophy. H. pylori infection was evaluated by anti-H. pylori IgG antibody, rapid urease test and culture test. We classified H. pylori infection status as non-infection, present infection and past infection. In addition, plasma acyl-ghrelin and desacyl-ghrelin levels were measured by enzyme-linked immunosorbent assay.
RESULTS Infection rate of H. pylori was 45.4% (49/108). Acyl-ghrelin level in the non-infection group (39.4 ± 23.0 fmol/mL) was significantly higher than in the past (23.4 ± 19.9 fmol/mL, P = 0.005) and present infection groups (19.5 ± 14.0 fmol/mL, P < 0.001). Furthermore, desacyl-ghrelin level in the non-infection group (353.2 ± 190.2 fmol/mL) was significantly higher than those in the past (234.9 ± 137.5 fmol/mL, P = 0.008) and present infection groups (211.8 ± 124.2 fmol/mL, P < 0.001). Acyl-ghrelin was positively correlated with the PG I level and PG I/II ratio (|R| = 0.484, P < 0.001 and |R| = 0.403, P < 0.001, respectively). Both ghrelins were significantly decreased in accordance with the progress of endoscopic atrophy (both P < 0.001) and acyl-ghrelin was significantly lower in patients with mild, moderate and severe atrophy (24.5 ± 23.1 fmol/mL, 20.2 ± 14.9 fmol/mL and 18.3 ± 11.8 fmol/mL) than in those with non-atrophy (39.4 ± 22.2 fmol/mL, P = 0.039, P = 0.002 and P < 0.001, respectively).
CONCLUSION In hemodialysis patients, plasma ghrelin level was associated with the endoscopic and serological severity of atrophy related to H. pylori infection.
Collapse
|
|
28
|
Two ghrelin receptor agonists for adults with malnutrition: a systematic review and meta-analysis. Nutr J 2016; 15:97. [PMID: 27852245 PMCID: PMC5112740 DOI: 10.1186/s12937-016-0214-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2016] [Accepted: 10/31/2016] [Indexed: 12/26/2022] Open
Abstract
Background Ghrelin receptor agonists have been established to be important in ameliorating the nutritional conditions in patients with malnutrition. However, some studies have reported inconsistent results. We aimed to coalesce the available evidence on the efficacy of ghrelin receptor agonists for the treatment of malnutrition. Methods We searched PubMed, the Cochrane Central Register of Controlled Trials, and EMBASE for relevant articles published through March 2016. Studies comparing the efficacy of ghrelin receptor agonists versus placebo in malnourished patients were eligible for inclusion. Results A total of 12 studies involving 1377 patients were included. Compared with placebo, ghrelin receptor agonists could increase the energy intake (standard mean difference [SMD] 2.67, 95% confidence interval [CI] 1.48 to 3.85, P < 0.001), lean body mass (weighted mean difference [WMD] 0.25 kg, 95% CI 0.07 to 0.42, P = 0.006), fat mass (WMD 0.92 kg, 95% CI 0.05 to 1.8, P = 0.038), and grip strength (WMD 0.31 kg, 95% CI 0.207 to 0.414, P < 0.001) of patients with malnutrition. Conclusion Our analysis indicated that ghrelin receptor agonists could improve the poor nutritional state of malnourished patients by increasing their energy intake, ameliorating their irregular body composition and improving their grip strength. However, these results might be less conclusive due to the limited sample sizes and one potential publication that has not been released.
Collapse
|
|
29
|
Abstract
Age-related changes in gastrointestinal symptoms need to be considered in peritoneal dialysis (PD) patients. A diminishing appetite is associated with aging and may be exacerbated by renal failure and PD treatment, meaning that attention to dietary adequacy is important in the older patient. Constipation and its treatment may increase the risk of peritonitis, but is important for comfort as well as trouble-free dialysis. Diverticulosis increases with age, and whilst there may be ethnic differences in the patterns of this condition, there is conflicting evidence regarding the risks of peritonitis associated with asymptomatic disease. Hernias, urinary incontinence, and prolapse are also common and made worse by PD, so it is important to know about these issues prior to starting. Whilst data around these topics are scant and some studies conflicting, further understanding these issues and considering mitigation strategies may improve technique survival and quality of life.
Collapse
Affiliation(s)
| | - Stephen G Holt
- Royal Melbourne Hospital, Melbourne, Australia The University of Melbourne, Melbourne, Australia
| |
Collapse
|
|
30
|
Bianchi E, Boekelheide K, Sigman M, Lamb DJ, Hall SJ, Hwang K. Ghrelin ameliorates adhesions in a postsurgical mouse model. J Surg Res 2015; 201:226-34. [PMID: 26850207 DOI: 10.1016/j.jss.2015.10.044] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Revised: 10/03/2015] [Accepted: 10/29/2015] [Indexed: 10/22/2022]
Abstract
BACKGROUND Peritoneal adhesion formation is a well-recognized consequence of abdominal and pelvic surgery, causing infertility, chronic pelvic pain, and intestinal obstruction. We hypothesized that ghrelin, a 28-amino acid peptide predominantly found in the stomach, plays an important role in preventing postoperative surgical adhesions. The purpose of this study was to develop a new surgical peritoneal adhesion model to define the role that ghrelin plays in wound healing and adhesion formation. MATERIALS AND METHODS C57BL/6 wild-type mice (n = 40) and growth hormone secretagogue receptor-knockout (GHSR KO) mice (n = 20) underwent a midline laparotomy to establish a peritoneal adhesion model characterized by the combination of two different techniques: ischemic peritoneal buttons and cecal multiple abrasion. All mice received intraperitoneal injections with ghrelin (0.16 mg/kg) or saline twice daily for 20 d after surgery. Peritoneal ischemic buttons were harvested to determine protein expression of collagen (Masson trichrome, picrosirius red stain, and Western blot). RESULTS The novel mouse model demonstrated consistent and easily reproducible formation of intra-abdominal adhesions. Ghrelin administration significantly reduced postoperative adhesion formation (P < 0.001) in wild-type mice. The antifibrotic effect of ghrelin in wild-type mice was confirmed by measuring collagen I protein levels via Western blot analysis. The anti-adhesion effect of ghrelin seen in wild-type mice was not detected in GHSR KO mice demonstrating that this effect is mediated by the GHSR-1a receptor. CONCLUSIONS Ghrelin administration may improve surgical outcome by reducing peritoneal adhesion formation and fibrotic response in a mouse model.
Collapse
Affiliation(s)
- Enrica Bianchi
- Department of Surgery, Division of Urology, Brown University, Providence, Rhode Island; Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island
| | - Kim Boekelheide
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island
| | - Mark Sigman
- Department of Surgery, Division of Urology, Brown University, Providence, Rhode Island; Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island
| | - Dolores J Lamb
- Department of Urology, Baylor College of Medicine, Houston, Texas
| | - Susan J Hall
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island
| | - Kathleen Hwang
- Department of Surgery, Division of Urology, Brown University, Providence, Rhode Island; Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island.
| |
Collapse
|
|
31
|
Shouman MG, Ismail NA, Badr A, Abdelrahman SM, Ragab S, Farouk H. Fetuin-A and Ghrelin Levels in Children with End Stage Renal Disease and the Effect of a Single Hemodialysis Session on Them. Open Access Maced J Med Sci 2015; 3:391-6. [PMID: 27275256 PMCID: PMC4877825 DOI: 10.3889/oamjms.2015.081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 06/25/2015] [Accepted: 06/26/2015] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND Fetuin-A and ghrelin have been implicated in cardiovascular diseases and mortality among end stage renal disease patients. The exact mechanisms have not been fully elucidated. There is robust data supporting an association between ghrelin and various cardiovascular conditions, and some common processes such as inflammation, oxidative stress, and endoplasmic reticulum stress have been implicated. AIM This study was conducted to assay serum fetuin-A and ghrelin in chronic renal failure pediatric patients and to study changes in their level that may occur after a single hemodialysis. MATERIAL AND METHODS Forty nine pediatric patients suffering from ESRD on maintenance hemodialysis (HD), 20 patients with chronic renal failure (CRF) not on dialysis and 35 healthy subjects as control group were included. The mean age of the study population was 10.58 ± 3.94, 10.62 ± 3.24 and 10.61 ± 3.97 years respectively. Serum fetuin-A and plasma acyl ghrelin levels were measured by using ELISA method. RESULTS The present study revealed that predialysis serum fetuin-A level was significantly increased in pediatric HD patients compared with the normal population, while ghrelin levels were significantly reduced. Furthermore, serum levels of fetuin-A decreased significantly after a single HD session. CONCLUSION Our study concluded that fetuin-A and acyl ghrelin may play a role in inflammatory process among HD pediatric patients which may account for cardiovascular insults and mortality but their use as biochemical markers among ESRD pediatric patients have limitations due to wide fluctuations.
Collapse
Affiliation(s)
| | | | - Ahmed Badr
- Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Shadia Ragab
- Department of Clinical Pathology, National Research Centre, Cairo, Egypt
| | - Hebatallah Farouk
- Department of Clinical Pathology, National Research Centre, Cairo, Egypt
| |
Collapse
|
|
32
|
|
|
33
|
Müller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, Batterham RL, Benoit SC, Bowers CY, Broglio F, Casanueva FF, D'Alessio D, Depoortere I, Geliebter A, Ghigo E, Cole PA, Cowley M, Cummings DE, Dagher A, Diano S, Dickson SL, Diéguez C, Granata R, Grill HJ, Grove K, Habegger KM, Heppner K, Heiman ML, Holsen L, Holst B, Inui A, Jansson JO, Kirchner H, Korbonits M, Laferrère B, LeRoux CW, Lopez M, Morin S, Nakazato M, Nass R, Perez-Tilve D, Pfluger PT, Schwartz TW, Seeley RJ, Sleeman M, Sun Y, Sussel L, Tong J, Thorner MO, van der Lely AJ, van der Ploeg LHT, Zigman JM, Kojima M, Kangawa K, Smith RG, Horvath T, Tschöp MH. Ghrelin. Mol Metab 2015; 4:437-60. [PMID: 26042199 PMCID: PMC4443295 DOI: 10.1016/j.molmet.2015.03.005] [Citation(s) in RCA: 760] [Impact Index Per Article: 76.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 03/11/2015] [Accepted: 03/11/2015] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. SCOPE OF REVIEW In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery. MAJOR CONCLUSIONS In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.
Collapse
Affiliation(s)
- T D Müller
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, München, Germany
| | - R Nogueiras
- Department of Physiology, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas, University of Santiago de Compostela (CIMUS)-Instituto de Investigación Sanitaria (IDIS)-CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
| | - M L Andermann
- Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Z B Andrews
- Department of Physiology, Faculty of Medicine, Monash University, Melbourne, Victoria, Australia
| | - S D Anker
- Applied Cachexia Research, Department of Cardiology, Charité Universitätsmedizin Berlin, Germany
| | - J Argente
- Department of Pediatrics and Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain ; Department of Pediatrics, Universidad Autónoma de Madrid and CIBER Fisiopatología de la obesidad y nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - R L Batterham
- Centre for Obesity Research, University College London, London, United Kingdom
| | - S C Benoit
- Metabolic Disease Institute, Division of Endocrinology, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - C Y Bowers
- Tulane University Health Sciences Center, Endocrinology and Metabolism Section, Peptide Research Section, New Orleans, LA, USA
| | - F Broglio
- Division of Endocrinology, Diabetes and Metabolism, Dept. of Medical Sciences, University of Torino, Torino, Italy
| | - F F Casanueva
- Department of Medicine, Santiago de Compostela University, Complejo Hospitalario Universitario de Santiago (CHUS), CIBER de Fisiopatologia Obesidad y Nutricion (CB06/03), Instituto Salud Carlos III, Santiago de Compostela, Spain
| | - D D'Alessio
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
| | - I Depoortere
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - A Geliebter
- New York Obesity Nutrition Research Center, Department of Medicine, St Luke's-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - E Ghigo
- Department of Pharmacology & Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - P A Cole
- Monash Obesity & Diabetes Institute, Monash University, Clayton, Victoria, Australia
| | - M Cowley
- Department of Physiology, Faculty of Medicine, Monash University, Melbourne, Victoria, Australia ; Monash Obesity & Diabetes Institute, Monash University, Clayton, Victoria, Australia
| | - D E Cummings
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - A Dagher
- McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| | - S Diano
- Dept of Neurobiology, Yale University School of Medicine, New Haven, CT, USA
| | - S L Dickson
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - C Diéguez
- Department of Physiology, School of Medicine, Instituto de Investigacion Sanitaria (IDIS), University of Santiago de Compostela, Spain
| | - R Granata
- Division of Endocrinology, Diabetes and Metabolism, Dept. of Medical Sciences, University of Torino, Torino, Italy
| | - H J Grill
- Department of Psychology, Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA
| | - K Grove
- Department of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA
| | - K M Habegger
- Comprehensive Diabetes Center, University of Alabama School of Medicine, Birmingham, AL, USA
| | - K Heppner
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - M L Heiman
- NuMe Health, 1441 Canal Street, New Orleans, LA 70112, USA
| | - L Holsen
- Departments of Psychiatry and Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - B Holst
- Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen N, Denmark
| | - A Inui
- Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - J O Jansson
- Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - H Kirchner
- Medizinische Klinik I, Universitätsklinikum Schleswig-Holstein Campus Lübeck, Lübeck, Germany
| | - M Korbonits
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London, Queen Mary University of London, London, UK
| | - B Laferrère
- New York Obesity Research Center, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - C W LeRoux
- Diabetes Complications Research Centre, Conway Institute, University College Dublin, Ireland
| | - M Lopez
- Department of Physiology, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas, University of Santiago de Compostela (CIMUS)-Instituto de Investigación Sanitaria (IDIS)-CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
| | - S Morin
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, München, Germany
| | - M Nakazato
- Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki, Japan
| | - R Nass
- Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA, USA
| | - D Perez-Tilve
- Department of Internal Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - P T Pfluger
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, München, Germany
| | - T W Schwartz
- Department of Neuroscience and Pharmacology, Laboratory for Molecular Pharmacology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
| | - R J Seeley
- Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - M Sleeman
- Department of Physiology, Faculty of Medicine, Monash University, Melbourne, Victoria, Australia
| | - Y Sun
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - L Sussel
- Department of Genetics and Development, Columbia University, New York, NY, USA
| | - J Tong
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
| | - M O Thorner
- Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA, USA
| | - A J van der Lely
- Department of Medicine, Erasmus University MC, Rotterdam, The Netherlands
| | | | - J M Zigman
- Departments of Internal Medicine and Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - M Kojima
- Molecular Genetics, Institute of Life Science, Kurume University, Kurume, Japan
| | - K Kangawa
- National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
| | - R G Smith
- The Scripps Research Institute, Florida Department of Metabolism & Aging, Jupiter, FL, USA
| | - T Horvath
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - M H Tschöp
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, München, Germany ; Division of Metabolic Diseases, Department of Medicine, Technical University Munich, Munich, Germany
| |
Collapse
|
|
34
|
Massanet PL, Petit L, Louart B, Corne P, Richard C, Preiser JC. Nutrition rehabilitation in the intensive care unit. JPEN J Parenter Enteral Nutr 2015; 39:391-400. [PMID: 25587007 DOI: 10.1177/0148607114567901] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 11/24/2014] [Indexed: 11/17/2022]
Abstract
The maintenance of homeostasis after severe injury requires the restoration of the physiological regulation of food intake. A wide array of functional alterations can hinder the intake of adequate amounts of nutrients to support the recovery from critical illness. These alterations encompass changes in the preprandial phase, reflected by a loss of appetite; changes in the prandial phase, yielding swallowing disorders; and changes in the postprandial phase, including impairments of gastric emptying, gut motility, and satiety. This tutorial aims to review these often overlooked features and to suggest recommendations for the nutrition rehabilitation of the critically ill.
Collapse
Affiliation(s)
| | - Laurent Petit
- Surgical and Trauma Intensive Care Unit, Pellegrin University Hospital, Bordeaux, France
| | - Benjamin Louart
- Medical Intensive Care Unit, Nimes University Hospital, Nimes, France
| | | | - Celine Richard
- Clinical Dietitian Department, Gui De Chauliac Hospital, Montpellier, France
| | | |
Collapse
|
|
35
|
Fischer K, Finan B, Clemmensen C, van der Ploeg LHT, Tschöp MH, Müller TD. The Pentapeptide RM-131 Promotes Food Intake and Adiposity in Wildtype Mice but Not in Mice Lacking the Ghrelin Receptor. Front Nutr 2015; 1:31. [PMID: 25988130 PMCID: PMC4428373 DOI: 10.3389/fnut.2014.00031] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Accepted: 12/18/2014] [Indexed: 12/13/2022] Open
Abstract
The gastrointestinal peptide hormone ghrelin is the endogenous ligand of the growth hormone secretagogue receptor (a.k.a. ghrelin receptor, GHR). Currently, ghrelin is the only circulating peripheral hormone with the ability to promote a positive energy balance by stimulating food intake while decreasing energy expenditure and body fat utilization, as defined in rodents. Based on these and additional, beneficial effects on metabolism, the endogenous ghrelin system is considered an attractive target to treat diverse pathological conditions including those associated with eating/wasting disorders and cachexia. As the pharmacological potential of ghrelin is hampered by its relatively short half-life, ghrelin analogs with enhanced pharmacokinetics offer the potential to sustainably improve metabolism. One of these ghrelin analogs is the pentapeptide RM-131, which promotes food intake and adiposity with higher potency as compared to native ghrelin in rodents. Whereas, the effect of RM-131 on energy metabolism is solidly confirmed in rodents, it remains elusive whether RM-131 exerts its effect solely via the ghrelin receptor. Accordingly, we assessed the receptor specificity of RM-131 to promote food intake and adiposity in mice lacking the GHR. Our data show that in wildtype mice RM-131 potently promotes weight gain and adiposity through stimulation of food intake. However, RM-131 fails to affect food intake and body weight in mice lacking the GHR, underlining that the anabolic effects of RM-131 are mediated via the ghrelin receptor in mice.
Collapse
Affiliation(s)
- Katrin Fischer
- Institute for Diabetes and Obesity (IDO) and Helmholtz Diabetes Center, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH) , Neuherberg , Germany ; Division of Metabolic Diseases, Department of Medicine, Technische Universität München , Munich , Germany
| | - Brian Finan
- Institute for Diabetes and Obesity (IDO) and Helmholtz Diabetes Center, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH) , Neuherberg , Germany ; Division of Metabolic Diseases, Department of Medicine, Technische Universität München , Munich , Germany
| | - Christoffer Clemmensen
- Institute for Diabetes and Obesity (IDO) and Helmholtz Diabetes Center, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH) , Neuherberg , Germany ; Division of Metabolic Diseases, Department of Medicine, Technische Universität München , Munich , Germany
| | | | - Matthias H Tschöp
- Institute for Diabetes and Obesity (IDO) and Helmholtz Diabetes Center, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH) , Neuherberg , Germany ; Division of Metabolic Diseases, Department of Medicine, Technische Universität München , Munich , Germany
| | - Timo D Müller
- Institute for Diabetes and Obesity (IDO) and Helmholtz Diabetes Center, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH) , Neuherberg , Germany ; Division of Metabolic Diseases, Department of Medicine, Technische Universität München , Munich , Germany
| |
Collapse
|
|
36
|
Sun GX, Ding R, Li M, Guo Y, Fan LP, Yue LS, Li LY, Zhao M. Ghrelin attenuates renal fibrosis and inflammation of obstructive nephropathy. J Urol 2014; 193:2107-15. [PMID: 25481038 DOI: 10.1016/j.juro.2014.11.098] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/26/2014] [Indexed: 10/24/2022]
Abstract
PURPOSE Ghrelin is a gastric peptide that modulates multiple biological functions, of which the stimulation of food intake is the most well-known function. Ghrelin also exerts potential anti-inflammatory and antifibrotic properties in different organs but to our knowledge whether ghrelin inhibits the progression of renal fibrosis is unknown. Thus, we investigated the effect and underlying mechanisms of ghrelin in a rat model of renal fibrosis. MATERIALS AND METHODS Male Sprague Dawley® rats were divided into 4 groups, including vehicle or ghrelin treated sham operated groups and vehicle or ghrelin treated unilateral ureteral obstruction groups. Kidneys harvested on postoperative day 7 or 14 were evaluated for renal inflammation, fibrosis and apoptosis, and the expression of profibrotic and proinflammatory factors. RESULTS Ghrelin inhibited renal fibrosis by attenuating collagen production, extracellular matrix deposition, and α-smooth muscle actin and fibronectin expression. Ghrelin administration decreased macrophage infiltration and several proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1β and monocyte chemotactic protein-1, as well as phosphorylated nuclear factor-κB p65. Ghrelin also inhibited myofibroblast accumulation by blocking the transforming growth factor-β1/Smad3 signaling pathway. Furthermore, ghrelin attenuated renal tubular cell apoptosis and epithelial-mesenchymal transition processes induced by unilateral ureteral obstruction injury. CONCLUSIONS These findings indicate that ghrelin is a potent antifibrotic agent that may have therapeutic potential in patients with obstructive nephropathy.
Collapse
Affiliation(s)
- Guang-Xi Sun
- Department of Organ Transplantation and National Key Clinic Specialty, Neurosurgery Institute of Guangdong Province, Department of Neurosurgery (RD), Zhujiang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Rui Ding
- Department of Organ Transplantation and National Key Clinic Specialty, Neurosurgery Institute of Guangdong Province, Department of Neurosurgery (RD), Zhujiang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Ming Li
- Department of Organ Transplantation and National Key Clinic Specialty, Neurosurgery Institute of Guangdong Province, Department of Neurosurgery (RD), Zhujiang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Ying Guo
- Department of Organ Transplantation and National Key Clinic Specialty, Neurosurgery Institute of Guangdong Province, Department of Neurosurgery (RD), Zhujiang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Li-Pei Fan
- Department of Organ Transplantation and National Key Clinic Specialty, Neurosurgery Institute of Guangdong Province, Department of Neurosurgery (RD), Zhujiang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Liang-Sheng Yue
- Department of Organ Transplantation and National Key Clinic Specialty, Neurosurgery Institute of Guangdong Province, Department of Neurosurgery (RD), Zhujiang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Liu-Yang Li
- Department of Organ Transplantation and National Key Clinic Specialty, Neurosurgery Institute of Guangdong Province, Department of Neurosurgery (RD), Zhujiang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Ming Zhao
- Department of Organ Transplantation and National Key Clinic Specialty, Neurosurgery Institute of Guangdong Province, Department of Neurosurgery (RD), Zhujiang Hospital, Southern Medical University, Guangzhou, People's Republic of China.
| |
Collapse
|
|
37
|
von Haehling S, Anker SD. Treatment of cachexia: an overview of recent developments. J Am Med Dir Assoc 2014; 15:866-72. [PMID: 25455531 DOI: 10.1016/j.jamda.2014.09.007] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Accepted: 09/09/2014] [Indexed: 12/12/2022]
Abstract
Body wasting in the context of chronic illness is associated with reduced quality of life and impaired survival. Recent clinical trials have investigated different approaches to improve patients' skeletal muscle mass and strength, exercise capacity, and survival in the context of cachexia and body wasting, many of them in patients with cancer. The aim of this article was to summarize clinical trials published over the past 2 years. Therapeutic approaches discussed include appetite stimulants, such as megestrol acetate, L-carnitine, or melatonin, anti-inflammatory drugs, such as thalidomide, pentoxyphylline, or a monoclonal antibody against interleukin-1α as well as ghrelin and the ghrelin agonist anamorelin; nutritional support, and anabolics, such as enobosarm and testosterone.
Collapse
Affiliation(s)
- Stephan von Haehling
- Division of Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Centre Göttingen, Göttingen, Germany; Applied Cachexia Research, Department of Cardiology, Charité Medical School, Campus Virchow-Klinikum, Berlin, Germany.
| | - Stefan D Anker
- Division of Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Centre Göttingen, Göttingen, Germany
| |
Collapse
|
|
38
|
Clinical application of ghrelin in the field of surgery. Surg Today 2014; 45:801-7. [PMID: 25366350 DOI: 10.1007/s00595-014-1040-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 08/06/2014] [Indexed: 12/24/2022]
Abstract
Ghrelin was discovered as an intrinsic ligand for the growth hormone (GH)-secretagogue receptor (GHS-R) in 1999. The endogenous production of ghrelin occurs mainly in the stomach. Ghrelin has multiple functions; it has orexigenic action, stimulates GH secretion, has anti-inflammatory activities, stimulates gastrointestinal activity, stabilizes heart function and has other metabolic roles. Moreover, ghrelin is the only gastrointestinal hormone known to stimulate appetite. In the past decade, clinical applications of ghrelin have been attempted for various pathologies, based on its anabolic function, including applications for patients with anorexia nervosa and cachexia due to chronic heart, renal or pulmonary diseases. In the field of surgery, we have conducted several clinical trials using exogenous ghrelin in patients undergoing total gastrectomy, esophagectomy and neoadjuvant chemotherapy, including cisplatin treatment, and consistently obtained unique and striking benefits in these patients. Ghrelin comprehensively improves the patients' general conditions and quality of life via its pleiotropic physiological functions. This characteristic is unique and different from the existing drugs; therefore, ghrelin may be an indispensable supplement to prevent surgical stress and postoperative sequelae. This review summarizes the recent advances toward the clinical application of ghrelin.
Collapse
|
|
39
|
Abstract
In patients with chronic kidney disease (CKD), loss of cellular proteins increases the risks of morbidity and mortality. Persistence of muscle protein catabolism in CKD results in striking losses of muscle proteins as whole-body protein turnover is great; even small but persistent imbalances between protein synthesis and degradation cause substantial protein loss. No reliable methods to prevent CKD-induced muscle wasting currently exist, but mechanisms that control cellular protein turnover have been identified, suggesting that therapeutic strategies will be developed to suppress or block protein loss. Catabolic pathways that cause protein wasting include activation of the ubiquitin-proteasome system (UPS), caspase-3, lysosomes and myostatin (a negative regulator of skeletal muscle growth). These pathways can be initiated by complications associated with CKD, such as metabolic acidosis, defective insulin signalling, inflammation, increased angiotensin II levels, abnormal appetite regulation and impaired microRNA responses. Inflammation stimulates cellular signalling pathways that activate myostatin, which accelerates UPS-mediated catabolism. Blocking this pathway can prevent loss of muscle proteins. Myostatin inhibition could yield new therapeutic directions for blocking muscle protein wasting in CKD or disorders associated with its complications.
Collapse
Affiliation(s)
- Xiaonan H Wang
- Renal Division, Department of Medicine, Emory University, 1639 Pierce Drive, WMB 338, Atlanta, GA 30322, USA
| | - William E Mitch
- Nephrology Division, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, ABBR R705, Houston, TX 77030, USA
| |
Collapse
|
|
40
|
|
|
41
|
Reid J, Noble HR, Porter S, Shields JS, Maxwell AP. A literature review of end-stage renal disease and cachexia: understanding experience to inform evidence-based healthcare. J Ren Care 2014; 39:47-51. [PMID: 23432742 DOI: 10.1111/j.1755-6686.2013.00341.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Cachexia is a major cause of morbidity and mortality in people who have end-stage renal disease (ESRD). The majority of research into cachexia in ESRD has focused on the biological aspects of the syndrome and potential treatment modalities. While this research is necessary, it predominately focuses on the physical impact of cachexia in ESRD. The multi-dimensional psychosocial ramifications of this syndrome have been highlighted in other end-stage illness trajectories, but have not been systematically explored in persons who have ESRD. AIM This paper discusses why this research is necessary, alongside further studies to help define the pathophysiology of this syndrome. CONCLUSION The rich insightful data gained from understanding the patients' illness experience will positively contribute to the limited knowledge base available and inform future holistic patient-centred care delivery which recognises and responds to not only the biological but also the psychosocial impact of cachexia.
Collapse
Affiliation(s)
- Joanne Reid
- School of Nursing and Midwifery, Queen's University, Belfast, UK.
| | | | | | | | | |
Collapse
|
|
42
|
Malnutrition Markers and Serum Ghrelin Levels in Hemodialysis Patients. INTERNATIONAL SCHOLARLY RESEARCH NOTICES 2014; 2014:765895. [PMID: 27433541 PMCID: PMC4897115 DOI: 10.1155/2014/765895] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/19/2014] [Revised: 09/28/2014] [Accepted: 10/02/2014] [Indexed: 11/18/2022]
Abstract
Objective. The aim of study was to investigate the changes levels of serum ghrelin in HD patients and its relationship to some malnutrition markers compared with healthy controls. Methods. Forty-five patients on hemodialysis and forty healthy controls were studied. Biochemical parameters and serum ghrelin levels were measured. Both daily dietary intakes and body mass index (BMI) assessments were performed for evaluation of nutritional status. Results. Ghrelin concentrations were significantly reduced in patients undergoing hemodialysis when compared to healthy controls (5 ± 0.68 (1.1–18.5) pg/mL versus 7.8 ± 0.84 (2.4–18.3) pg/mL; P = 0.004). BMI and serum albumin in HD patients were markedly reduced compared to controls. The patients with an insufficient intake of energy and protein demonstrated slightly lower levels of serum ghrelin. A negative correlation between serum ghrelin concentration with age (r = −0.34, P = 0.02), BUN (r = −0.26, P < 0.01), and serum creatinine (r = −0.27, P < 0.01) was observed in HD patients. Conclusions. The findings suggest that decreased ghrelin levels in HD patients might be associated with anorexia. Further studies are needed to determine changes in serum ghrelin levels during dialysis and to clarify whether the decrease in ghrelin levels contributes to the malnutrition that is common in these patients.
Collapse
|
|
43
|
Abstract
Protein energy wasting is common in patients with CKD and ESRD and is associated with adverse clinical outcomes, such as increased rates of hospitalization and death, in these patients. A multitude of factors can affect the nutritional and metabolic status of patients with CKD, including decreased dietary nutrient intake, catabolic effects of renal replacement therapy, systemic inflammation, metabolic and hormonal derangements, and comorbid conditions (such as diabetes and depression). Unique aspects of CKD also confound reliable assessment of nutritional status, further complicating management of this comorbid condition. In patients in whom preventive measures and oral dietary intake from regular meals cannot help them maintain adequate nutritional status, nutritional supplementation, administered orally, enterally, or parenterally, is effective in replenishing protein and energy stores. The advantages of oral nutritional supplements include proven efficacy, safety, and compliance. Anabolic steroids and exercise, with nutritional supplementation or alone, improve protein stores and represent potential additional approaches for the treatment of PEW. There are several emerging novel therapies, such as appetite stimulants, anti-inflammatory interventions, and anabolic agents.
Collapse
Affiliation(s)
- T Alp Ikizler
- Department of Medicine, Division of Nephrology, Vanderbilt University School of Medicine, Nashville, Tennessee
| |
Collapse
|
|
44
|
Sharma R, Agrawal S, Saxena A, Pandey M, Sharma RK. Association of genetic variants of ghrelin, leptin and UCP2 with malnutrition inflammation syndrome and survival in end-stage renal disease patients. GENES AND NUTRITION 2013; 8:611-21. [PMID: 23925522 DOI: 10.1007/s12263-013-0353-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2013] [Accepted: 07/03/2013] [Indexed: 11/24/2022]
Abstract
Malnutrition inflammation syndrome (MIS) is common among ESRD patients. In the present study, we have investigated the association of genetic markers associated with appetite and energy regulation with malnutrition inflammation syndrome among end-stage renal disease (ESRD) patients. Two hundred and fifty-seven patients on maintenance hemodialysis and 200 normal healthy controls were included in the study. Nutritional assessment was done by subjective global assessment scores (SGA). Genotyping of leptin-2548 G/A (rs7799039), ghrelin Leu72Met (rs696217-408 C/A), Arg51Gln (rs34911341-346 G/A) and uncoupling protein 2 (UCP2) 45 bp insertion deletion was done using PCR-RFLP. Levels of leptin and acyl ghrelin were assessed using ELISA. Leptin-2548 AA genotype was associated with twofold higher risk of disease susceptibility while UCP2 insertion-deletion heterozygotes showed protective effect. Ghrelin Gln51Gln and Met72Met genotype were associated with 3.4- and 2.5-fold higher disease susceptibility. The Met72 and Gln51 allele showed 3.3- and 2.1-fold higher susceptibility to malnutrition in severe SGA group. Further, the levels of acyl ghrelin were significantly less in severe category of malnutrition and in poor appetite group. On combined analysis, the group 2 (presence of 3-4 risk alleles) showed 1.5- and twofold higher susceptibility to disease and malnutrition, respectively. On docking analysis, it was observed that higher receptor binding energy was associated with the mutant form of ghrelin (Gln51). Moderate and severe SGA were associated with 2.2- and 4.1-fold higher death hazard. Our study suggests that ghrelin may be major marker contributing to susceptibility to MIS among ESRD patients.
Collapse
Affiliation(s)
- Richa Sharma
- Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Raebareli Road, Lucknow, 226014, UP, India,
| | | | | | | | | |
Collapse
|
|
45
|
Massanet P, Richard C, Jonquet O, Corne P. La reprise de la nutrition orale en réanimation. MEDECINE INTENSIVE REANIMATION 2013. [DOI: 10.1007/s13546-013-0708-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
|
46
|
Gupta RK, Kuppusamy T, Patrie JT, Gaylinn B, Liu J, Thorner MO, Bolton WK. Association of plasma des-acyl ghrelin levels with CKD. Clin J Am Soc Nephrol 2013; 8:1098-105. [PMID: 23744005 DOI: 10.2215/cjn.09170912] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND OBJECTIVES There are no effective therapies for malnutrition in CKD/ESRD patients. This study hypothesized that ghrelin, an endogenous orexigenic hormone, would correlate with renal function and might suggest therapeutic interventions for CKD/ESRD malnutrition. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Fifty-one CKD and 15 hemodialysis patients were enrolled. Acyl ghrelin (AG) and des-acyl ghrelin (DG) were determined using separate two-site-specific assays. Leptin, insulin, growth hormone, insulin-link growth factor-1, C-reactive protein, TNF-α, and IL-6 were also measured. RESULTS Univariate correlation analyses showed that CKD stage was highly, positively correlated with the levels of preprandial and postprandial DG and positively correlated with TNF-α, IL-6, leptin, and age. Multivariate partial-correlation analyses showed that CKD was independently associated with the proportion of preprandial and postprandial DG, whereas TNF-α, IL-6, leptin, insulin, and age were not independently associated with either. Geometric mean (GM) preprandial and postprandial AG were comparable between CKD stages ≤2 and >2, whereas GM preprandial DG and postprandial DG were 1.95-fold and 2.17-fold greater, respectively, for CKD stage >2 versus stage ≤2. DG was the dominant form of ghrelin preprandially and postprandially for both CKD stages ≤2 and >2. Dialysis had no effect on AG, but reduced DG by 73% to levels even lower (GM 48.7 pg/ml) than those seen postprandially in CKD stage ≤2 patients (GM 77.0 pg/ml). CONCLUSIONS This study shows a strong and independent correlation of DG with CKD stage. Postprandial suppression of ghrelin is impaired with reduced renal function. Hemodialysis selectively removes DG but not AG.
Collapse
Affiliation(s)
- Rohit K Gupta
- Division of Nephrology, Department of Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, USA
| | | | | | | | | | | | | |
Collapse
|
|
47
|
Garin MC, Burns CM, Kaul S, Cappola AR. Clinical review: The human experience with ghrelin administration. J Clin Endocrinol Metab 2013; 98:1826-37. [PMID: 23533240 PMCID: PMC3644599 DOI: 10.1210/jc.2012-4247] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
CONTEXT Ghrelin is an endogenous stimulator of GH and is implicated in a number of physiological processes. Clinical trials have been performed in a variety of patient populations, but there is no comprehensive review of the beneficial and adverse consequences of ghrelin administration to humans. EVIDENCE ACQUISITION PubMed was utilized, and the reference list of each article was screened. We included 121 published articles in which ghrelin was administered to humans. EVIDENCE SYNTHESIS Ghrelin has been administered as an infusion or a bolus in a variety of doses to 1850 study participants, including healthy participants and patients with obesity, prior gastrectomy, cancer, pituitary disease, diabetes mellitus, eating disorders, and other conditions. There is strong evidence that ghrelin stimulates appetite and increases circulating GH, ACTH, cortisol, prolactin, and glucose across varied patient populations. There is a paucity of evidence regarding the effects of ghrelin on LH, FSH, TSH, insulin, lipolysis, body composition, cardiac function, pulmonary function, the vasculature, and sleep. Adverse effects occurred in 20% of participants, with a predominance of flushing and gastric rumbles and a mild degree of severity. The few serious adverse events occurred in patients with advanced illness and were not clearly attributable to ghrelin. Route of administration may affect the pattern of adverse effects. CONCLUSIONS Existing literature supports the short-term safety of ghrelin administration and its efficacy as an appetite stimulant in diverse patient populations. There is some evidence to suggest that ghrelin has wider ranging therapeutic effects, although these areas require further investigation.
Collapse
Affiliation(s)
- Margaret C Garin
- Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-5160, USA
| | | | | | | |
Collapse
|
|
48
|
Gunta SS, Mak RH. Ghrelin and leptin pathophysiology in chronic kidney disease. Pediatr Nephrol 2013; 28:611-6. [PMID: 23229444 DOI: 10.1007/s00467-012-2380-9] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Revised: 11/16/2012] [Accepted: 11/16/2012] [Indexed: 12/19/2022]
Abstract
Ghrelin is an orexigenic hormone with additional effects on the regulation of inflammation and the cardiovascular system. It may play an important role in the pathogenesis of cachexia/protein-energy wasting (PEW), inflammation and cardiovascular complications in chronic kidney disease (CKD). There are three circulating gene products of ghrelin, namely, acyl ghrelin, des-acyl ghrelin and obestatin, each with individual distinct functions. Perturbations of these circulating ghrelin proteins impact the overall milieu of CKD. Leptin is an anorexigenic hormone which is secreted from the adipocytes and interacts with ghrelin and other appetite-regulating hormones. Leptin also plays a role in regulating inflammation and the cardiovascular system. Indeed, ghrelin and leptin may play yin-and-yang roles in CKD pathophysiology. Clinical trials involving the use of the mimetics or antagonists of these hormones are limited to short-term phase I/II studies. Further understanding of their interactions in CKD pathophysiology is needed for potential large-scale clinical trials, which may impact the quality of life and survival of patients with CKD.
Collapse
Affiliation(s)
- Sujana S Gunta
- Division of Pediatric Nephrology, University of California San Diego-Rady Children's Hospital, San Diego, CA, USA
| | | |
Collapse
|
|
49
|
Tennankore KK, Bargman JM. Nutrition and the kidney: recommendations for peritoneal dialysis. Adv Chronic Kidney Dis 2013; 20:190-201. [PMID: 23439379 DOI: 10.1053/j.ackd.2012.10.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2012] [Revised: 10/19/2012] [Accepted: 10/25/2012] [Indexed: 12/22/2022]
Abstract
Protein energy wasting (PEW) is highly prevalent in peritoneal dialysis (PD) and is associated with poor outcomes, including hospitalization and mortality. Recognizing and diagnosing PEW in PD is important; although studies are limited, there are interventions that may be associated with improved outcomes. In this review of nutritional aspects of PD, we highlight some of the important causes of PEW and explore the current diagnostic tools that are used to assess PEW. Finally, we discuss the established and experimental therapies for PEW in PD.
Collapse
|
|
50
|
|