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Jung CY, Chang JW. Hepatorenal syndrome: Current concepts and future perspectives. Clin Mol Hepatol 2023; 29:891-908. [PMID: 37050843 PMCID: PMC10577351 DOI: 10.3350/cmh.2023.0024] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 04/10/2023] [Accepted: 04/10/2023] [Indexed: 04/14/2023] Open
Abstract
Hepatorenal syndrome (HRS), a progressive but potentially reversible deterioration of kidney function, remains a major complication in patients with advanced cirrhosis, often leading to death before liver transplantation (LT). Recent updates in the pathophysiology, definition, and classification of HRS have led to a complete revision of the nomenclature and diagnostic criteria for HRS type 1, which was renamed HRS-acute kidney injury (AKI). HRS is characterized by severe impairment of kidney function due to increased splanchnic blood flow, activation of several vasoconstriction factors, severe vasoconstriction of the renal arteries in the absence of kidney histologic abnormalities, nitric oxide dysfunction, and systemic inflammation. Diagnosis of HRS remains a challenge because of the lack of specific diagnostic biomarkers that accurately distinguishes structural from functional AKI, and mainly involves the differential diagnosis from other forms of AKI, particularly acute tubular necrosis. The optimal treatment of HRS is LT. While awaiting LT, treatment options include vasoconstrictor drugs to counteract splanchnic arterial vasodilation and plasma volume expansion by intravenous albumin infusion. In patients with HRS unresponsive to pharmacological treatment and with conventional indications for kidney replacement therapy (KRT), such as volume overload, uremia, or electrolyte imbalances, KRT may be applied as a bridging therapy to transplantation. Other interventions, such as transjugular intrahepatic portosystemic shunt, and artificial liver support systems have a very limited role in improving outcomes in HRS. Although recently developed novel therapies have potential to improve outcomes of patients with HRS, further studies are warranted to validate the efficacy of these novel agents.
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Affiliation(s)
- Chan-Young Jung
- Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jai Won Chang
- Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Dragičević M, Košuta I, Kruezi E, Lovrenčić MV, Mrzljak A. Association of Asymmetric Dimethylarginine and Nitric Oxide with Cardiovascular Risk in Patients with End-Stage Liver Disease. MEDICINA (KAUNAS, LITHUANIA) 2020; 56:622. [PMID: 33218157 PMCID: PMC7698953 DOI: 10.3390/medicina56110622] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 11/11/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND OBJECTIVES Endothelial dysfunction has been proposed to be an underlying mechanism of the pronounced cardiovascular morbidity in end-stage liver disease (ESLD), but clinical evidence is still limited. In this study, we investigated the association of circulating levels of asymmetric dimethylarginine (ADMA) and nitric oxide (NO) with estimated cardiovascular risk in patients with ESLD awaiting liver transplantation. MATERIALS AND METHODS ADMA and NO levels were measured in the sera of 160 adult ESLD patients. The severity of hepatic dysfunction was assessed by the model for end-stage liver disease (MELD) score. The cardiovascular risk was estimated with the European Society of Cardiology Systematic Coronary Risk Estimation (SCORE) index, which was used to dichotomize patients in the subgroups depicting higher and lower cardiovascular risk. RESULTS Severe hepatic dysfunction (MELD ≥ 18) was present in 38% of the patients, and a higher cardiovascular risk was present in almost half of the patients (N = 74). ADMA and NO both significantly increased with the progression of liver disease and were independently associated with higher cardiovascular risk. Fasting glucose also independently predicted a higher cardiovascular risk, while HDL cholesterol and the absence of concomitant hepatocellular carcinoma were protective factors. CONCLUSIONS These results suggest a remarkable contribution of the deranged arginine/NO pathway to cardiovascular risk in patients with end-stage liver disease.
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Affiliation(s)
- Maro Dragičević
- Department of Cardiology, Merkur University Hospital, 10000 Zagreb, Croatia;
| | - Iva Košuta
- Department of Internal Medicine, University Hospital Centre, 10000 Zagreb, Croatia;
| | - Egon Kruezi
- Department of Gynaecology and Obstetrics, Sisters of Charity University Hospital Centre, 10000 Zagreb, Croatia;
| | - Marijana Vučić Lovrenčić
- Department of Clinical Chemistry and Laboratory Medicie, Merkur University Hospital, 10000 Zagreb, Croatia
| | - Anna Mrzljak
- Department of Gastroenterology, Merkur University Hospital, 10000 Zagreb, Croatia;
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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Esse R, Barroso M, Tavares de Almeida I, Castro R. The Contribution of Homocysteine Metabolism Disruption to Endothelial Dysfunction: State-of-the-Art. Int J Mol Sci 2019; 20:E867. [PMID: 30781581 PMCID: PMC6412520 DOI: 10.3390/ijms20040867] [Citation(s) in RCA: 201] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 02/05/2019] [Accepted: 02/12/2019] [Indexed: 02/07/2023] Open
Abstract
Homocysteine (Hcy) is a sulfur-containing non-proteinogenic amino acid formed during the metabolism of the essential amino acid methionine. Hcy is considered a risk factor for atherosclerosis and cardiovascular disease (CVD), but the molecular basis of these associations remains elusive. The impairment of endothelial function, a key initial event in the setting of atherosclerosis and CVD, is recurrently observed in hyperhomocysteinemia (HHcy). Various observations may explain the vascular toxicity associated with HHcy. For instance, Hcy interferes with the production of nitric oxide (NO), a gaseous master regulator of endothelial homeostasis. Moreover, Hcy deregulates the signaling pathways associated with another essential endothelial gasotransmitter: hydrogen sulfide. Hcy also mediates the loss of critical endothelial antioxidant systems and increases the intracellular concentration of reactive oxygen species (ROS) yielding oxidative stress. ROS disturb lipoprotein metabolism, contributing to the growth of atherosclerotic vascular lesions. Moreover, excess Hcy maybe be indirectly incorporated into proteins, a process referred to as protein N-homocysteinylation, inducing vascular damage. Lastly, cellular hypomethylation caused by build-up of S-adenosylhomocysteine (AdoHcy) also contributes to the molecular basis of Hcy-induced vascular toxicity, a mechanism that has merited our attention in particular. AdoHcy is the metabolic precursor of Hcy, which accumulates in the setting of HHcy and is a negative regulator of most cell methyltransferases. In this review, we examine the biosynthesis and catabolism of Hcy and critically revise recent findings linking disruption of this metabolism and endothelial dysfunction, emphasizing the impact of HHcy on endothelial cell methylation status.
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Affiliation(s)
- Ruben Esse
- Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
| | - Madalena Barroso
- University Children's Research@Kinder-UKE, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
| | - Isabel Tavares de Almeida
- Laboratory of Metabolism and Genetics, Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon, Portugal.
| | - Rita Castro
- Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon, Portugal.
- Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon, Portugal.
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
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Alipoor E, Mohammad Hosseinzadeh F, Hosseinzadeh-Attar MJ. Adipokines in critical illness: A review of the evidence and knowledge gaps. Biomed Pharmacother 2018; 108:1739-1750. [PMID: 30372877 DOI: 10.1016/j.biopha.2018.09.165] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 09/27/2018] [Accepted: 09/28/2018] [Indexed: 12/28/2022] Open
Abstract
Adipose tissue products or adipokines play a major role in chronic endocrine and metabolic disorders; however, little is known about critical conditions. In this article, the experimental and clinical evidence of alterations of adipokines, adiponectin, leptin, resistin, visfatin, asymmetric dimethylarginine (ADMA), and ghrelin in critical illness, their potential metabolic, diagnostic, and prognostic value, and the gaps in the field have been reviewed. The results showed considerable changes in the concentration of the adipokines; while the impact of adipokines on metabolic disorders such as insulin resistance and inflammation has not been well documented in critically ill patients. There is no consensus about the circulatory and functional changes of leptin and adiponectin. However, it seems that lower concentrations of adiponectin at admission with gradual consequent increase might be a useful pattern in determining better outcomes of critical illness. Some evidence has suggested the adverse effects of elevated resistin concentration, potential prognostic importance of visfatin, and therapeutic value of ghrelin. High ADMA levels and low arginine:ADMA ratio were also proposed as predictors of ICU mortality and morbidities. However, there is no consensus on these findings. Although primary data indicated the role of adipokines in critical illness, further studies are required to clarify whether the reason of these changes is pathophysiological or compensatory. The relationship of pathophysiological background, disease severity, baseline nutritional status and nutrition support during hospitalization, and variations in body fat percentage and distribution with adipokines, as well as the potential prognostic or therapeutic role of these peptides should be further investigated in critically ill patients.
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Affiliation(s)
- Elham Alipoor
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran; Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Mohammad Hosseinzadeh
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Javad Hosseinzadeh-Attar
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran; Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, Australia.
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Mindikoglu AL, Pappas SC. New Developments in Hepatorenal Syndrome. Clin Gastroenterol Hepatol 2018; 16:162-177.e1. [PMID: 28602971 PMCID: PMC5831376 DOI: 10.1016/j.cgh.2017.05.041] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 05/26/2017] [Accepted: 05/28/2017] [Indexed: 02/07/2023]
Abstract
Hepatorenal syndrome (HRS) continues to be one of the major complications of decompensated cirrhosis, leading to death in the absence of liver transplantation. Challenges in precisely evaluating renal function in the patient with cirrhosis remain because of the limitations of serum creatinine (Cr) alone in estimating glomerular filtration rate (GFR); current GFR estimating models appear to underestimate renal dysfunction. Newer models incorporating renal biomarkers, such as the Cr-Cystatin C GFR Equation for Cirrhosis appear to estimate measured GFR more accurately. A major change in the diagnostic criteria for HRS based on dynamic serial changes in serum Cr that regard HRS type 1 as a special form of acute kidney injury promises the possibility of earlier identification of renal dysfunction in patients with cirrhosis. The diagnostic criteria of HRS still include the exclusion of other causes of kidney injury. Renal biomarkers have been disappointing in assisting with the differentiation of HRS from prerenal azotemia and other kidney disorders. Serum metabolomic profiling may be a more powerful tool to assess renal dysfunction, although the practical clinical significance of this remains unclear. As a result of the difficulties of assessing renal function in cirrhosis and the varying HRS diagnostic criteria and the rigor with which they are applied, the precise incidence and prevalence of HRS is unknown, but it is likely that HRS occurs more commonly than expected. The pathophysiology of HRS is rooted firmly in the setting of progressive reduction in renal blood flow as a result of portal hypertension and splanchnic vasodilation. Progressive marked renal cortical ischemia in patients with cirrhosis parallels the evolution of diuretic-sensitive ascites to diuretic-refractory ascites and HRS, a recognized continuum of renal dysfunction in cirrhosis. Alterations in nitrous oxide production, both increased and decreased, may play a major role in the pathophysiology of this evolution. The inflammatory cascade, triggered by bacterial translocation and endotoxemia, increasingly recognized as important in the manifestation of acute-on-chronic liver failure, also may play a significant role in the pathophysiology of HRS. The mainstay of treatment remains vasopressor therapy with albumin in an attempt to reverse splanchnic vasodilation and improve renal blood flow. Several meta-analyses have confirmed the value of vasopressors, chiefly terlipressin and noradrenaline, in improving renal function and reversing HRS type 1. Other interventions such as renal replacement therapy, transjugular intrahepatic portosystemic shunt, and artificial liver support systems have a very limited role in improving outcomes in HRS. Liver transplantation remains the definitive treatment for HRS. The frequency of simultaneous liver-kidney transplantation has increased dramatically in the Model for End-stage Liver Disease era, with changes in organ allocation policies. This has resulted in a more urgent need to predict native kidney recovery from HRS after liver transplantation alone, to avoid unnecessary simultaneous liver-kidney transplantation.
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Affiliation(s)
- Ayse L. Mindikoglu
- Baylor College of Medicine, Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation,Baylor College of Medicine, Margaret M. and Albert B. Alkek Department of Medicine, Section of Gastroenterology and Hepatology
| | - Stephen C. Pappas
- Baylor College of Medicine, Margaret M. and Albert B. Alkek Department of Medicine, Section of Gastroenterology and Hepatology
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Ghashut RA, Blackwell S, Ryan S, Willox L, McMillan DC, Kinsella J, Talwar D. Assessment of asymmetrical dimethylarginine metabolism in patients with critical illness. Eur J Clin Invest 2017; 47:279-288. [PMID: 27930821 DOI: 10.1111/eci.12710] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 12/01/2016] [Indexed: 11/28/2022]
Abstract
BACKGROUND Critically ill patients experience metabolic disorders including hypercatabolic state and hyperglycaemia, and these are associated with poor outcome. Hyperglycaemia and asymmetrical dimethylarginine (ADMA) are reported to have significant influences on endothelial dysfunction. The aim of this study was to examine the relationship between plasma ADMA and related arginine metabolism in patients with critical illness. MATERIALS AND METHOSDS Two venous blood samples (EDTA) (104 patients), on admission and follow-up sample in the last day in intensive care unit (ICU) (died or discharge sample median 7, interquartile range (IQR) 6-8, range 5-15). Plasma ADMA, arginine, homoarginine and SDMA were measured by high-performance liquid chromatography (HPLC). RESULT ADMA (P < 0·01) and SDMA (P < 0·05) were elevated, and homoarginine was decreased (P < 0·05) in nonsurvivors and was directly associated with predicted mortality rate (P < 0·05 and P < 0·001), Sequential Organ Failure Assessment (SOFA) (P < 0·05, P < 0·001), ICU stay (P < 0·05, P < 0·001) and mortality (P < 0·01, P < 0·05). ADMA was directly associated with SDMA (P < 0·001), albumin (P < 0·05), ICU stay and mortality (P < 0·01). SDMA was directly associated with creatinine (P < 0·001) and Acute physiology and Chronic Health Evaluation II score (P < 0·001). In the follow-up measurements, there was a significant decrease in SOFA score (P < 0·01), homoarginine (P < 0·01), aminotransferase (P < 0·01), Laboratory Glucose (P < 0·01) and albumin (P < 0·01). In contrast, there was an increase in arginine (P < 0·01), ADMA (P < 0·01), ADMA:SDMA ratio (P < 0·01) and the norepinephrine administration (P < 0·01). CONCLUSION In the present longitudinal study, ADMA metabolism was altered in patients with critical illness and was associated with disease severity and mortality.
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Affiliation(s)
- Rawia A Ghashut
- Academic Unit of Anaesthesia, College of Medical, Veterinary and Life of Sciences - University of Glasgow, Royal Infirmary, Glasgow, UK.,Academic Unit of Surgery, College of Medical, Veterinary and Life of Sciences - University of Glasgow, Royal Infirmary, Glasgow, UK
| | - Scott Blackwell
- Department of Biochemistry, The Scottish Trace Element and Micronutrient Reference Laboratory, Royal Infirmary, Glasgow, UK
| | - Sylvia Ryan
- Department of Biochemistry, The Scottish Trace Element and Micronutrient Reference Laboratory, Royal Infirmary, Glasgow, UK
| | - Laura Willox
- Department of Biochemistry, The Scottish Trace Element and Micronutrient Reference Laboratory, Royal Infirmary, Glasgow, UK
| | - Donald C McMillan
- Academic Unit of Surgery, College of Medical, Veterinary and Life of Sciences - University of Glasgow, Royal Infirmary, Glasgow, UK
| | - John Kinsella
- Academic Unit of Anaesthesia, College of Medical, Veterinary and Life of Sciences - University of Glasgow, Royal Infirmary, Glasgow, UK
| | - Dinesh Talwar
- Department of Biochemistry, The Scottish Trace Element and Micronutrient Reference Laboratory, Royal Infirmary, Glasgow, UK
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Lappalainen M, Hämäläinen S, Juutilainen A, Koivula I, Pulkki K, Jantunen E. Asymmetric dimethylarginine in the assessment of febrile neutropenia in hematological patients. Scandinavian Journal of Clinical and Laboratory Investigation 2017; 77:130-134. [PMID: 28218011 DOI: 10.1080/00365513.2017.1286518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Asymmetric dimethylarginine (ADMA) has been recognized as an independent prognostic factor for sepsis mortality in intensive care units. No data are available on kinetics or prognostic value of ADMA in hematological patients. We evaluated the ability of ADMA to act as a predictor for complicated course of febrile neutropenia, defined as bacteremia and/or septic shock in adult hematological patients receiving intensive chemotherapy. This prospective study included 87 adult hematological patients with febrile neutropenia after an intensive chemotherapy for acute myeloid leukemia (AML) or after an autologous stem cell transplantation (ASCT). Plasma ADMA and serum C-reactive protein (CRP) levels were measured from the onset of fever (d0) and for 2 days (d1-d2) thereafter. The levels of ADMA were stable or had only minimal changes during the study period. There was no difference between the levels at any time-point in patients having complicated course compared to those without it. On the other hand, CRP levels were significantly higher on d1 (p = 0.016) in patients with bacteremia and/or septic shock than in those without. ADMA was not able to differentiate hematological patients with a complicated course from those without complications. Elevated ADMA levels are probably associated with organ dysfunction, which is rare in this group of patients, of whom about 95% can be successfully managed at the hematology ward.
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Affiliation(s)
- Marika Lappalainen
- a Department of Internal Medicine , Central Hospital of Central Finland , Jyväskylä , Finland
| | - Sari Hämäläinen
- b Department of Medicine , Kuopio University Hospital , Kuopio , Finland
| | - Auni Juutilainen
- b Department of Medicine , Kuopio University Hospital , Kuopio , Finland.,c Institute of Clinical Medicine/Internal Medicine , University of Eastern Finland , Kuopio , Finland
| | - Irma Koivula
- b Department of Medicine , Kuopio University Hospital , Kuopio , Finland
| | - Kari Pulkki
- d Department of Clinical Chemistry , University of Eastern Finland and Eastern Finland Laboratory Centre , Kuopio , Finland
| | - Esa Jantunen
- b Department of Medicine , Kuopio University Hospital , Kuopio , Finland
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Segarra G, Cortina B, Mauricio MD, Novella S, Lluch P, Navarrete-Navarro J, Noguera I, Medina P. Effects of asymmetric dimethylarginine on renal arteries in portal hypertension and cirrhosis. World J Gastroenterol 2016; 22:10545-10556. [PMID: 28082806 PMCID: PMC5192265 DOI: 10.3748/wjg.v22.i48.10545] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [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: 09/17/2016] [Accepted: 10/10/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the effects of asymmetric dimethylarginine (ADMA) in renal arteries from portal hypertensive and cirrhotic rats.
METHODS Rat renal arteries from Sham (n = 15), pre-hepatic portal hypertension (PPVL; n = 15) and bile duct ligation and excision-induced cirrhosis (BDL; n = 15) were precontracted with norepinephrine, and additional contractions were induced with ADMA (10-6-10-3 mol/L), an endogenous inhibitor of nitric oxide (NO) synthase. Concentration-response curves to acetylcholine (1 × 10-9-3 × 10-6 mol/L) were determined in precontracted renal artery segments with norepinephrine in the absence and in the presence of ADMA. Kidneys were collected to determine the protein expression and activity of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that catabolizes ADMA.
RESULTS In renal arteries precontracted with norepinephrine, ADMA caused endothelium-dependent contractions. The pD2 values to ADMA were similar in the Sham and PPVL groups (4.20 ± 0.08 and 4.11 ± 0.09, P > 0.05, respectively), but were lower than those of the BDL group (4.79 ± 0.16, P < 0.05). Acetylcholine-induced endothelium-dependent relaxation that did not differ, in terms of pD2 and maximal relaxation, among the 3 groups studied. Treatment with ADMA (3 × 10-4 mol/L) inhibited acetylcholine-induced relaxation in the 3 groups, but the inhibition was higher (P < 0.05) in the BDL group compared with that for the Sham and PPVL groups. The mRNA and protein expression of DDAH-1 were similar in kidneys from the three groups. Conversely, DDAH-2 expression was increased (P < 0.05) in PPVL and further enhanced (P < 0.05) in the BDL group. However, renal DDAH activity was significantly decreased in the BDL group.
CONCLUSION Cirrhosis increased the inhibitory effect of ADMA on basal- and induced-release of NO in renal arteries, and decreased DDAH activity in the kidney.
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Lluch P, Mauricio MD, Vila JM, Segarra G, Medina P, Del Olmo JA, Rodrigo JM, Serra MA. Accumulation of Symmetric Dimethylarginine in Hepatorenal Syndrome. Exp Biol Med (Maywood) 2016; 231:70-5. [PMID: 16380646 DOI: 10.1177/153537020623100108] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
In patients with cirrhosis, nitric oxide (NO), asymmetric dimethylarginine (ADMA), and possibly symmetric dimethylarginine (SDMA) have been linked to the severity of the disease. We investigated whether plasma levels of dimethylarginines and NO are elevated in patients with hepatorenal syndrome (HRS), compared with patients with cirrhosis without renal failure (no-HRS). Plasma levels of NO, ADMA, SDMA, and l-arginine were measured in 11 patients with HRS, seven patients with no-HRS, and six healthy volunteers. SDMA concentration in HRS was higher than in no-HRS and healthy subjects (1.47 ± 0.25 vs. 0.38 ± 0.06 and 0.29 ± 0.04 μM, respectively; P < 0.05). ADMA and NOx concentrations were higher in HRS and no-HRS patients than in healthy subjects (ADMA, 1.20 ± 0.26, 1.11 ± 0.1, and 0.53 ± 0.06 μM, respectively; P < 0.05; NOx, 94 ± 9.1, 95.5 ± 9.54, and 37.67 ± 4.62 μM, respectively; P < 0.05). In patients with HRS there was a positive correlation between serum creatinine and plasma SDMA (r2 = 0.765, P < 0.001) but not between serum creatinine and ADMA or NOx. The results suggest that renal dysfunction is a main determinant of elevated SDMA concentration in HRS. Accumulation of ADMA as a result of impaired hepatic removal may be the causative factor initiating renal vasoconstriction and SDMA retention in the kidney.
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Affiliation(s)
- Paloma Lluch
- Servicio de Hepatología, Hospital Clínico Universitario, Departamento de Medicina, Universidad de Valencia, Valencia, Spain
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Abstract
The plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is the resultant of many processes at cellular and organ levels. Post-translational methylation of arginine residues of pro teins plays a crucial role in the regulation of their functions, which include processes such as transcription, translation and RNA splicing. Because protein methylation is irreversible, the methylation signal can be turned off only by proteolysis of the entire protein. Consequently, most methylated proteins have high turnover rates. Free ADMA, which is formed during proteolysis, is actively degraded by the intracellular enzyme dimethylarginine dimethylaminohydrolase (DDAH). Some ADMA escapes degradation and leaves the cell via cationic amino acid transporters. These trans porters also mediate uptake of ADMA by neighboring cells or distant organs, thereby facilitating active interorgan transport. Clearance of ADMA from the plasma occurs in small part by urinary excretion, but the bulk of ADMA is degraded by intracellular DDAH, after uptake from the circulation. This review discusses the various processes involved in ADMA metabolism: protein methylation, proteolysis of methylated proteins, metabolism by DDAH, and interorgan transport. In addition, the role of the kidney and the liver in the clearance of ADMA is highlighted.
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Affiliation(s)
- Tom Teerlink
- 1Department of Clinical Chemistry, VU University Medical
Center, Amsterdam, The Netherland
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Pesek JJ, Matyksa MT, Modereger B, Hasbun A, Phan VT, Mehr Z, Guzman M, Watanable S. The separation and analysis of symmetric and asymmetric dimethylarginine and other hydrophilic isobaric compounds using aqueous normal phase chromatography. J Chromatogr A 2016; 1441:52-9. [DOI: 10.1016/j.chroma.2016.02.071] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Revised: 02/19/2016] [Accepted: 02/22/2016] [Indexed: 10/22/2022]
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Lluch P, Segarra G, Medina P. Asymmetric dimethylarginine as a mediator of vascular dysfunction in cirrhosis. World J Gastroenterol 2015; 21:9466-9475. [PMID: 26327755 PMCID: PMC4548108 DOI: 10.3748/wjg.v21.i32.9466] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 06/05/2015] [Accepted: 07/18/2015] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis is associated with marked abnormalities in the circulatory function that involve a reduction in systemic vascular resistance. An important cause of this vasodilatation is the increased production or activity of nitric oxide (NO) in the splanchnic circulation. During portal hypertension and cirrhosis an increased endothelial NO synthase (eNOS) activity is demonstrated in splanchnic vessels. In contrast, the activity of eNOS in the cirrhotic liver is decreased, which suggests a different regulation of eNOS in the liver and in the splanchnic vessels. Asymmetric dimethylarginine (ADMA) is an endogenous NO inhibitor and higher plasma levels of ADMA are related to increased cardiovascular risk in both the general population and among patients with cirrhosis. It has been demonstrated that the liver is a key player in the metabolism of ADMA. This observation was further supported by investigations in human patients, showing a close correlation between ADMA plasma levels and the degree of hepatic dysfunction. ADMA is degraded to citrulline and dimethylamine by dimethylarginine dimethylaminohydrolases (DDAHs). DDAHs are expressed as type 1 and 2 isoforms and are widely distributed in various organs and tissues, including the liver. In this review, we discuss experimental and clinical data that document the effects of dimethylarginines on vascular function in cirrhosis. Our increasing understanding of the routes of synthesis and metabolism of methylarginines is beginning to provide insights into novel mechanisms of liver disease and allowing us to identify potential therapeutic opportunities.
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Ferrigno A, Di Pasqua LG, Berardo C, Richelmi P, Vairetti M. Liver plays a central role in asymmetric dimethylarginine-mediated organ injury. World J Gastroenterol 2015; 21:5131-5137. [PMID: 25954086 PMCID: PMC4419053 DOI: 10.3748/wjg.v21.i17.5131] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 02/24/2015] [Accepted: 03/31/2015] [Indexed: 02/06/2023] Open
Abstract
Asymmetric-dimethylarginine (ADMA) competes with L-arginine for each of the three isoforms of nitric oxide synthase: endothelial; neuronal; inducible. ADMA is synthesized by protein methyltransferases followed by proteolytic degradation. ADMA is metabolized to citrulline and dimethylamine, by dimethylarginine dimethylaminohydrolase (DDAH) and enters cells through cationic amino-acid transporters extensively expressed in the liver. The liver plays a crucial role in ADMA metabolism by DDAH-1 and, as has been recently demonstrated, it is also responsible for ADMA biliary excretion. A correlation has been demonstrated between plasma ADMA levels and the degree of hepatic dysfunction in patients suffering from liver diseases with varying aetiologies: plasma ADMA levels are increased in patients with liver cirrhosis, alcoholic hepatitis and acute liver failure. The mechanism by which liver dysfunction results in raised ADMA concentrations is probably due to impaired activity of DDAH due to severe inflammation, oxidative stress, and direct damage to DDAH. High plasma ADMA levels are also relevant as they are associated with the onset of multi-organ failure (MOF). Increased plasma concentration of ADMA was identified as an independent risk factor for MOF in critically-ill patients causing enhanced Intensive Care Unit mortality: a significant reduction in nitric oxide synthesis, leading to malperfusion in various organs, eventually culminating in multi organs dysfunction.
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Wijnands KAP, Castermans TMR, Hommen MPJ, Meesters DM, Poeze M. Arginine and citrulline and the immune response in sepsis. Nutrients 2015; 7:1426-63. [PMID: 25699985 PMCID: PMC4377861 DOI: 10.3390/nu7031426] [Citation(s) in RCA: 116] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Revised: 01/15/2015] [Accepted: 01/26/2015] [Indexed: 01/01/2023] Open
Abstract
Arginine, a semi-essential amino acid is an important initiator of the immune response. Arginine serves as a precursor in several metabolic pathways in different organs. In the immune response, arginine metabolism and availability is determined by the nitric oxide synthases and the arginase enzymes, which convert arginine into nitric oxide (NO) and ornithine, respectively. Limitations in arginine availability during inflammatory conditions regulate macrophages and T-lymfocyte activation. Furthermore, over the past years more evidence has been gathered which showed that arginine and citrulline deficiencies may underlie the detrimental outcome of inflammatory conditions, such as sepsis and endotoxemia. Not only does the immune response contribute to the arginine deficiency, also the impaired arginine de novo synthesis in the kidney has a key role in the eventual observed arginine deficiency. The complex interplay between the immune response and the arginine-NO metabolism is further underscored by recent data of our group. In this review we give an overview of physiological arginine and citrulline metabolism and we address the experimental and clinical studies in which the arginine-citrulline NO pathway plays an essential role in the immune response, as initiator and therapeutic target.
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Affiliation(s)
- Karolina A P Wijnands
- Department of Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht 6200 MD, The Netherlands.
| | - Tessy M R Castermans
- Department of Surgery, Maastricht University Medical Center, Maastricht 6200MD, The Netherlands.
| | - Merel P J Hommen
- Department of Surgery, Maastricht University Medical Center, Maastricht 6200MD, The Netherlands.
| | - Dennis M Meesters
- Department of Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht 6200 MD, The Netherlands.
| | - Martijn Poeze
- Department of Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht 6200 MD, The Netherlands.
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Aydemir O, Ozcan B, Yucel H, Yagmur Bas A, Demirel N. Asymmetric dimethylarginine andl-arginine levels in neonatal sepsis and septic shock. J Matern Fetal Neonatal Med 2014; 28:977-82. [DOI: 10.3109/14767058.2014.939950] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Sheen JM, Chen YC, Tain YL, Huang LT. Increased circulatory asymmetric dimethylarginine and multiple organ failure: bile duct ligation in rat as a model. Int J Mol Sci 2014; 15:3989-4006. [PMID: 24603538 PMCID: PMC3975379 DOI: 10.3390/ijms15033989] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Revised: 02/04/2014] [Accepted: 02/26/2014] [Indexed: 02/06/2023] Open
Abstract
Bile duct ligation (BDL)-treated rats exhibit cholestasis, increased systemic oxidative stress, and liver fibrosis, which ultimately lead to liver cirrhosis. Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of nitric oxide synthase that can decrease the synthesis of nitric oxide. BDL rats have higher plasma and hepatic ADMA levels, which may be due to increased hepatic protein arginine methyltransferase-1 and decreased dimethylarginine dimethylaminohydrolase expression. BDL rats also exhibit renal and brain damage characterized by increased tissue ADMA concentrations. The increased plasma ADMA levels and multiple organ damages seen here are also observed following multiple organ failures associated with critical illness. This review discusses the dysregulation of ADMA in major organs in BDL rats and the role of increased ADMA in multiple organ damages.
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Affiliation(s)
- Jiunn-Ming Sheen
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
| | - Yu-Chieh Chen
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
| | - You-Lin Tain
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
| | - Li-Tung Huang
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
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Brinkmann SJH, de Boer MC, Buijs N, van Leeuwen PAM. Asymmetric dimethylarginine and critical illness. Curr Opin Clin Nutr Metab Care 2014; 17:90-7. [PMID: 24281375 DOI: 10.1097/mco.0000000000000020] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Asymmetric dimethylarginine (ADMA) is an analog of arginine and functions as an endogenous inhibitor of the nitric oxide synthase, which forms nitric oxide. Nitric oxide is crucial for perfusion of vital organs and is an important signaling agent in the development of critical illness. The role of ADMA in the pathophysiological mechanisms underlying critical illness is widely studied in the last decades, and recently it has become clear that ADMA should not be overlooked by clinicians working at the ICU. The aim of this review is to describe new insights into the role of ADMA in critical illness and its clinical relevance. RECENT FINDINGS High levels of ADMA are found in critically ill patients, because of higher levels of protein methylation, increased rate of protein turnover, decreased activity of dimethylamine dimethylaminohydrolase, and impaired renal and hepatic clearance capacity. These high levels are an independent risk factor for cardiac dysfunction, organ failure, and ICU mortality. The arginine : ADMA ratio in particular is of clinical importance and the restoration of this ratio is expedient to restore several functions that are disturbed during critical illness. SUMMARY Elevated ADMA levels occur in critically ill patients, which is detrimental for morbidity and mortality. The arginine : ADMA ratio should be restored to maintain nitric oxide production and therewith improve the clinical outcome of the patient.
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Affiliation(s)
- Saskia J H Brinkmann
- aDepartment of Plastic and Reconstructive Surgery bDepartment of Surgery, VU University Medical Center, Amsterdam, the Netherlands
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Mindikoglu AL, Weir MR. Current concepts in the diagnosis and classification of renal dysfunction in cirrhosis. Am J Nephrol 2013; 38:345-54. [PMID: 24107793 DOI: 10.1159/000355540] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 09/11/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND Renal dysfunction is one of the most common complications of cirrhosis with high morbidity and mortality. SUMMARY In subjects with cirrhosis, renal dysfunction can present either as a direct consequence of cirrhosis (e.g. hepatorenal syndrome type I and type II) or secondary to etiologies other than cirrhosis (chronic kidney disease due to diabetic nephropathy, prerenal azotemia), or patients with cirrhosis may have renal dysfunction resulting directly from cirrhosis and an underlying chronic kidney disease. KEY MESSAGES Given the challenges in the differential diagnosis of renal dysfunction and insufficient accuracy of serum creatinine and creatinine-based glomerular filtration rate estimating equations in cirrhosis, there is an urgent need for more accurate biomarkers of renal dysfunction in this population. This review will discuss novel concepts for the diagnosis and classification of renal dysfunction in cirrhosis to overcome at least some of the diagnostic and therapeutic challenges. Additionally, a new classification will be proposed for renal dysfunction in cirrhosis.
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Affiliation(s)
- Ayse L Mindikoglu
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Md., USA
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Luiking YC, Ten Have GAM, Wolfe RR, Deutz NEP. Arginine de novo and nitric oxide production in disease states. Am J Physiol Endocrinol Metab 2012; 303:E1177-89. [PMID: 23011059 PMCID: PMC3517635 DOI: 10.1152/ajpendo.00284.2012] [Citation(s) in RCA: 163] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Arginine is derived from dietary protein intake, body protein breakdown, or endogenous de novo arginine production. The latter may be linked to the availability of citrulline, which is the immediate precursor of arginine and limiting factor for de novo arginine production. Arginine metabolism is highly compartmentalized due to the expression of the enzymes involved in arginine metabolism in various organs. A small fraction of arginine enters the NO synthase (NOS) pathway. Tetrahydrobiopterin (BH4) is an essential and rate-limiting cofactor for the production of NO. Depletion of BH4 in oxidative-stressed endothelial cells can result in so-called NOS3 "uncoupling," resulting in production of superoxide instead of NO. Moreover, distribution of arginine between intracellular transporters and arginine-converting enzymes, as well as between the arginine-converting and arginine-synthesizing enzymes, determines the metabolic fate of arginine. Alternatively, NO can be derived from conversion of nitrite. Reduced arginine availability stemming from reduced de novo production and elevated arginase activity have been reported in various conditions of acute and chronic stress, which are often characterized by increased NOS2 and reduced NOS3 activity. Cardiovascular and pulmonary disorders such as atherosclerosis, diabetes, hypercholesterolemia, ischemic heart disease, and hypertension are characterized by NOS3 uncoupling. Therapeutic applications to influence (de novo) arginine and NO metabolism aim at increasing substrate availability or at influencing the metabolic fate of specific pathways related to NO bioavailability and prevention of NOS3 uncoupling. These include supplementation of arginine or citrulline, provision of NO donors including inhaled NO and nitrite (sources), NOS3 modulating agents, or the targeting of endogenous NOS inhibitors like asymmetric dimethylarginine.
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Affiliation(s)
- Yvette C Luiking
- Center for Translational Research in Aging & Longevity, Dept. of Health & Kinesiology, Texas A&M Univ., College Station, TX 77843, USA
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Endotoxemia exacerbates kidney injury and increases asymmetric dimethylarginine in young bile duct-ligated rats. Shock 2012; 37:441-8. [PMID: 22193869 DOI: 10.1097/shk.0b013e318244b787] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cirrhosis increases the risk of kidney injury and sepsis, leading to increased mortality. Elevated levels of plasma asymmetric dimethylarginine (ADMA) occur in patients critically ill with cirrhosis, renal failure, and sepsis. We used a rat model of cirrhosis with superimposed sepsis to assess the relationship of plasma and tissue ADMA profiles with acute kidney injury and survival. Seventeen-day-old male Sprague-Dawley rats (n = 37) were randomly assigned to four groups: (1) sham operation plus diet control (n = 6); (2) bile duct ligation (BDL, n = 8); (3) sham operation plus lipopolysaccharide (LPS, n = 9); and (4) BDL plus LPS (n = 14). Lipopolysaccharide was given by intraperitoneal injection (1 mg/kg in saline) 3 h before sacrifice. All rats were sacrificed 14 days after surgery. Lipopolysaccharide increased the rate of BDL-associated death and dysfunction of the liver and kidneys. These results were supported by increased levels of plasma ADMA and a decreased L-arginine/ADMA ratio (AAR). Plasma and tissue levels of ADMA and AAR were not correlated. Lipopolysaccharide restored BDL-induced ADMA level elevation in the liver but increased ADMA level in the kidneys. Lipopolysaccharide increased hepatic AAR, decreased renal AAR, and paradoxically mediated the expression of neuronal nitric oxide synthase-β in the liver and kidneys. A novel mechanism underlies the LPS-mediated L-arginine-ADMA-nitric oxide pathway activation and exacerbation of kidney injury and mortality in our BDL model. In the presence of cirrhosis with superimposed sepsis, simultaneous lowering of ADMA levels and enhancement of L-arginine levels to restore plasma and renal AARs may be an optimal strategy for the treatment of kidney injury.
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Abstract
OBJECTIVE Increased plasma concentrations of the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, decreased arginine bioavailability, and mitochondrial dysfunction have been reported in adult sepsis. We studied whether asymmetric dimethylarginine, arginine, and carnitine metabolism (a measure of mitochondrial dysfunction) are altered in pediatric sepsis and whether these are clinically useful biomarkers. DESIGN : Prospective, observational study. SETTING Pediatric intensive care unit at an academic medical center. PATIENTS : Ninety patients ≤ 18 yrs old, 30 with severe sepsis or septic shock, compared with 30 age-matched febrile and 30 age-matched healthy control subjects. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Plasma asymmetric dimethylarginine and whole blood arginine, citrulline, ornithine, and acylcarnitine:free carnitine ratio were measured daily for septic patients and once for control subjects using tandem mass spectrometry. Plasma asymmetric dimethylarginine concentration (median; interquartile range µmol/L) on day 1 was lower in severe sepsis and septic shock (0.38; 0.30-0.56) compared with febrile (0.45; 0.40-0.59) and healthy (0.60; 0.54-0.67) control subjects (p < .001), although decreased asymmetric dimethylarginine was predominantly found in neutropenic patients. Day 1 arginine was lower in septic (10; interquartile range, 7-20 µmol/L) compared with healthy patients (32; interquartile range, 23-40; p < .001), and the arginine:ornithine ratio was decreased in sepsis, indicating increased arginase activity (an alternative pathway for arginine metabolism). The arginine:asymmetric dimethylarginine and acylcarnitine:free carnitine ratios did not differ between septic and control patients. Asymmetric dimethylarginine was inversely correlated with organ dysfunction by Pediatric Logistic Organ Dysfunction score (r = -0.50, p = .009), interleukin-6 (r = -0.55, p = .01), and interleukin-8 (r = -0.52, p = .03) on admission. Arginine, arginine:asymmetric dimethylarginine, and acylcarnitine:free carnitine were not associated with organ dysfunction or outcomes. CONCLUSIONS Asymmetric dimethylarginine was decreased in pediatric sepsis and was inversely associated with inflammation and organ dysfunction. This suggests that inhibition of nitric oxide synthase by asymmetric dimethylarginine accumulation is unlikely to impact sepsis pathophysiology in septic children despite decreased arginine bioavailability. We did not find an association of asymmetric dimethylarginine with altered carnitine metabolism nor were asymmetric dimethylarginine, arginine, and acylcarnitine:free carnitine useful as clinical biomarkers.
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Davids M, van Hell AJ, Visser M, Nijveldt RJ, van Leeuwen PAM, Teerlink T. Role of the human erythrocyte in generation and storage of asymmetric dimethylarginine. Am J Physiol Heart Circ Physiol 2012; 302:H1762-70. [PMID: 22367507 DOI: 10.1152/ajpheart.01205.2011] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Proteolytic activity in whole blood may lead to release of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). We investigated the role of the human erythrocyte in storage and generation of ADMA in healthy controls (n = 36) and critically ill patients (n = 38). Both free and total (sum of free and protein-incorporated) ADMA were measured. Upon incubation of intact erythrocytes with extracellular ADMA (0 to 40 μmol/l), equilibrium between intra- and extracellular ADMA was reached within 3 h. Compared with controls, patients had significantly higher basal concentrations of ADMA in plasma (0.88 ± 0.75 vs. 0.41 ± 0.07 μmol/l) and erythrocytes (1.28 ± 0.55 vs. 0.57 ± 0.14 μmol/l). Intracellular and plasma ADMA were significantly correlated in the patient group only (r = 0.834). Upon lysis, followed by incubation at 37°C for 2 h, free ADMA increased sevenfold (to 8.60 ± 3.61 μmol/l in patients and 3.90 ± 0.78 μmol/l in controls). In lysates of controls, free ADMA increased further to 9.85 ± 1.35 μmol/l after 18 h. Total ADMA was 15.43 ± 2.44 μmol/l and did not change during incubation. The increase of free ADMA during incubation corresponded to substantial release of ADMA from the erythrocytic protein-incorporated pool (21.9 ± 4.6% at 2 h and 60.8 ± 7.6% at 18 h). ADMA was released from proteins other than hemoglobin, which only occurred after complete lysis and was blocked by combined inhibition of proteasomal and protease activity. Neither intact nor lysed erythrocytes mediated degradation of free ADMA. We conclude that intact erythrocytes play an important role in storage of ADMA, whereas upon erythrocyte lysis large amounts of free ADMA are generated by proteolysis of methylated proteins, which may affect plasma levels in hemolysis-associated diseases.
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Affiliation(s)
- Mariska Davids
- Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
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Imbalance of arginine and asymmetric dimethylarginine is associated with markers of circulatory failure, organ failure and mortality in shock patients. Br J Nutr 2011; 107:1458-65. [PMID: 22129964 DOI: 10.1017/s0007114511004648] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
In shock, organ perfusion is of vital importance because organ oxygenation is at risk. NO, the main endothelial-derived vasodilator, is crucial for organ perfusion and coronary patency. The availability of NO might depend on the balance between a substrate (arginine) and an inhibitor (asymmetric dimethylarginine; ADMA) of NO synthase. Therefore, we investigated the relationship of arginine, ADMA and their ratio with circulatory markers, disease severity, organ failure and mortality in shock patients. In forty-four patients with shock (cardiogenic n 17, septic n 27), we prospectively measured plasma arginine and ADMA at intensive care unit admission, Acute Physiology and Chronic Health Evaluation (APACHE) II-(predicted mortality) and Sequential Organ Failure Assessment (SOFA) score, and circulatory markers to investigate their relationship. Arginine concentration was decreased (34·6 (SD 17·9) μmol/l) while ADMA concentration was within the normal range (0·46 (SD 0·18) μmol/l), resulting in a decrease in the arginine:ADMA ratio. The ratio correlated with several circulatory markers (cardiac index, disseminated intravascular coagulation, bicarbonate, lactate and pH), APACHE II and SOFA score, creatine kinase and glucose. The arginine:ADMA ratio showed an association (OR 0·976, 95 % CI 0·963, 0·997, P = 0·025) and a diagnostic accuracy (area under the curve 0·721, 95 % CI 0·560, 0·882, P = 0·016) for hospital mortality, whereas the arginine or ADMA concentration alone or APACHE II-predicted mortality failed to do so. In conclusion, in shock patients, the imbalance of arginine and ADMA is related to circulatory failure, organ failure and disease severity, and predicts mortality. We propose a pathophysiological mechanism in shock: the imbalance of arginine and ADMA contributes to endothelial and cardiac dysfunction resulting in poor organ perfusion and organ failure, thereby increasing the risk of death.
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Golbidi S, Badran M, Laher I. Diabetes and alpha lipoic Acid. Front Pharmacol 2011; 2:69. [PMID: 22125537 PMCID: PMC3221300 DOI: 10.3389/fphar.2011.00069] [Citation(s) in RCA: 157] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2011] [Accepted: 10/18/2011] [Indexed: 12/25/2022] Open
Abstract
Diabetes mellitus is a multi-faceted metabolic disorder where there is increased oxidative stress that contributes to the pathogenesis of this debilitating disease. This has prompted several investigations into the use of antioxidants as a complementary therapeutic approach. Alpha lipoic acid, a naturally occurring dithiol compound which plays an essential role in mitochondrial bioenergetic reactions, has gained considerable attention as an antioxidant for use in managing diabetic complications. Lipoic acid quenches reactive oxygen species, chelates metal ions, and reduces the oxidized forms of other antioxidants such as vitamin C, vitamin E, and glutathione. It also boosts antioxidant defense system through Nrf-2-mediated antioxidant gene expression and by modulation of peroxisome proliferator activated receptors-regulated genes. ALA inhibits nuclear factor kappa B and activates AMPK in skeletal muscles, which in turn have a plethora of metabolic consequences. These diverse actions suggest that lipoic acid acts by multiple mechanisms, many of which have only been uncovered recently. In this review we briefly summarize the known biochemical properties of lipoic acid and then discussed the oxidative mechanisms implicated in diabetic complications and the mechanisms by which lipoic acid may ameliorate these reactions. The findings of some of the clinical trials in which lipoic acid administration has been tested in diabetic patients during the last 10 years are summarized. It appears that the clearest benefit of lipoic acid supplementation is in patients with diabetic neuropathy.
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Affiliation(s)
- Saeid Golbidi
- Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia Vancouver, BC, Canada
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Blackwell S, O'Reilly DSJ, Reid D, Talwar D. Plasma dimethylarginines during the acute inflammatory response. Eur J Clin Invest 2011; 41:635-41. [PMID: 21175611 DOI: 10.1111/j.1365-2362.2010.02451.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Asymmetric dimethylarginine (ADMA) concentrations are increased in critically ill patients and may play a role in multiple organ failure. However, plasma ADMA concentrations during the development of the inflammatory response have not been documented. We measured plasma ADMA, as well as urinary excretion of its major metabolite dimethylamine, and nitrate as a marker of nitric oxide synthase (NOS) activity, in a cohort of patients undergoing elective knee arthroplasty that is known to provoke a significant inflammatory response. METHODS Thirty-eight patients were recruited. Fasting venous blood samples were obtained pre-operatively and at 12h and daily until the fifth post-operative day. ADMA and symmetric dimethylarginine (SDMA) were measured by high-performance liquid chromatography (HPLC). Urinary dimethylamine and nitrate were measured pre-operatively and on each of the post-operative mornings using HPLC and expressed as a ratio to creatinine. RESULTS Plasma ADMA fell by a median of 31% during the post-operative period, reaching a nadir on day 2, and recovering to baseline by the end of the study. SDMA showed no significant changes. No increase in urinary dimethylamine excretion was noted until day 5 post-op, whereupon it doubled. Urinary nitrate showed a small, but nonsignificant decrease on day 2, suggesting no major activation of NOS activity. CONCLUSIONS Plasma ADMA concentration decreases rapidly and transiently during the first 48h of acute inflammation. This appears not be caused by increased catabolism and may reflect increased cellular partitioning. This may serve to regulate NOS activity and prevent harmful increases in inducible NOS in situations where it is not appropriate.
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Affiliation(s)
- Scott Blackwell
- Department of Clinical Biochemistry, Royal Infirmary, Glasgow, UK
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Deshpande P, Rausa K, Turner J, Johnson M, Golestaneh L. Acute kidney injury as a causal factor in mortality associated with hepatorenal syndrome. Hepatol Int 2011; 5:751-8. [DOI: 10.1007/s12072-011-9269-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2010] [Accepted: 03/04/2011] [Indexed: 12/14/2022]
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Hermansen SE, Kalstad T, How OJ, Myrmel T. Inflammation and reduced endothelial function in the course of severe acute heart failure. Transl Res 2011; 157:117-27. [PMID: 21316028 DOI: 10.1016/j.trsl.2010.12.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2010] [Revised: 12/05/2010] [Accepted: 12/10/2010] [Indexed: 11/27/2022]
Abstract
Systemic inflammation and elevated circulating levels of the endogenous nitric oxide inhibitor asymmetrical dimethylarginine (ADMA) have been associated with increased risk in cardiogenic shock (CS). In this prospective study, we assessed, over 4 consecutive days, the changes and possible associations between vascular function, markers of inflammation, and circulating ADMA levels in patients with CS (n = 12) and postcardiotomy heart failure (n = 12, PC-HF). Vasodilator function was measured as a reactive hyperemia index (RH-index) using a finger plethysmograph. Blood samples were analyzed for plasma ADMA, interleukine-6, interleukine-8, intracellular adhesion molecule-1, and vascular adhesion molecule-1. Baseline RH-index was significantly attenuated compared with healthy controls (2.28) for both CS and PC-HF (1.35 and 1.45, respectively, P = 0.001). Although vasodilator function improved in PC-HF patients, it remained attenuated in CS. Inflammatory markers were markedly elevated followed by a significant fall during the observation period in both groups. ADMA levels increased significantly during the observation period for PC-HF, whereas no pattern of change was observed for CS. No association was found between the longitudinal changes in RH-index, markers of inflammation, or ADMA in CS. However, an improved RH-index was associated with decreasing inflammatory markers in PC-HF. ADMA correlated to arterial lactate levels and the degree of organ dysfunction in CS. In conclusion, CS and PC-HF were characterized by a marked inflammatory activation accompanied by an attenuated vasodilator function. ADMA was related to organ dysfunction and degree of hypoperfusion during CS but showed no correlations to inflammation or hampered vasodilator function. The pathogenic significance of these responses needs clarification.
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Affiliation(s)
- Stig E Hermansen
- Department of Cardiothoracic and Vascular Surgery, University Hospital of North Norway, Tromsø, Norway.
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Laskowska M, Laskowska K, Leszczyńska-Gorzelak B, Oleszczuk J. Asymmetric dimethylarginine in normotensive pregnant women with isolated fetal intrauterine growth restriction: a comparison with preeclamptic women with and without intrauterine growth restriction. J Matern Fetal Neonatal Med 2010; 24:936-42. [PMID: 21142768 DOI: 10.3109/14767058.2010.535873] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
OBJECTIVE The aim of this study was to evaluate maternal asymmetric dimethylarginine (ADMA) levels in pregnancies complicated by isolated fetal intrauterine growth restriction (IUGR), in preeclamptic pregnancies with and without IUGR, and in healthy normotensive pregnant women with proper weight fetuses. PATIENTS AND METHODS The study was carried out on 54 normotensive pregnant patients with pregnancy complicated by IUGR, 35 patients with IUGR in the course of preeclampsia, 29 preeclamptic patients with appropriate-for-gestational-age weight infants and 54 healthy normotensive pregnant patients. The ADMA concentrations were evaluated using an ELISA assay. RESULTS The preeclamptic women and normotensive patients with pregnancy complicated by isolated IUGR revealed higher levels of maternal serum ADMA. The mean values of maternal serum ADMA were 0.5730 ± 0.1769 μmol/l in the P group, 0.5727 ± 0.1756 μmol/l in the PI group, 0.6129 ± 0.1517 μmol/l in the IUGR group, and 0.5017 ± 0.1116 μmol/l in the control group. The levels of ADMA were additionally higher in the patients with HELLP syndrome and in patients with pregnancy complicated by eclampsia. CONCLUSIONS It seems that ADMA is an active agent not only in preeclamptic patients, but also in normotensive pregnant women with isolated fetal IUGR and could be a marker of severity of preeclampsia.
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Affiliation(s)
- Marzena Laskowska
- Department of Obstetrics and Perinatology, Medical University of Lublin, Poland.
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An Z, Chen Y, Zhang R, Song Y, Sun J, He J, Bai J, Dong L, Zhan Q, Abliz Z. Integrated ionization approach for RRLC-MS/MS-based metabonomics: finding potential biomarkers for lung cancer. J Proteome Res 2010; 9:4071-81. [PMID: 20560663 DOI: 10.1021/pr100265g] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
An integrated ionization approach of electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), and atmospheric pressure photoionization (APPI) combining with rapid resolution liquid chromatography mass spectrometry (RRLC-MS) has been developed for performing global metabonomic analysis on complex biological samples. This approach was designed to overcome the low ionization efficiencies of endogenous metabolites due to diverse physicochemical properties as well as ion suppression, and obtain comprehensive metabolite profiles in LC-MS analysis. Ionization capability and applicability were manifested by improved ionization efficiency and enlarged metabolite coverage in analysis on typical urinary metabolite standards and urine samples from healthy volunteers. The method was validated by the limit of detection and precision. When applied to the global metabonomic studies of lung cancer, more comprehensive biomarker candidates were obtained to reflect metabolic traits between healthy volunteers and lung cancer patients, including 74 potential biomarkers in positive ion mode and 59 in negative ion mode. Taking identical potential biomarkers of any two or three ionization methods into account, analysis using ESI-MS in positive (+) and negative (-) ion mode contributed to 70 and 64% of the total potential biomarkers, respectively. The biomarker discovery capability of (+/-) APCI-MS accounted for 45 and 42% of the overall; meanwhile (+/-) APPI-MS amounted for 39 and 54%. These results indicated that potential biomarkers with vital biological information could be missed if only a single ionization method was used. Furthermore, 11 potential biomarkers were identified including amino acids, nucleosides, and a metabolite of indole. They revealed elevated amino acid and nucleoside metabolism as well as protein degradation in lung cancer patients. This proposed approach provided a more comprehensive picture of the metabolic changes and further verified identical biomarkers that were obtained simultaneously using different ionization methods.
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Affiliation(s)
- Zhuoling An
- Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, P. R. China
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Yeo TW, Lampah DA, Tjitra E, Gitawati R, Darcy CJ, Jones C, Kenangalem E, McNeil YR, Granger DL, Lopansri BK, Weinberg JB, Price RN, Duffull SB, Celermajer DS, Anstey NM. Increased asymmetric dimethylarginine in severe falciparum malaria: association with impaired nitric oxide bioavailability and fatal outcome. PLoS Pathog 2010; 6:e1000868. [PMID: 20421938 PMCID: PMC2858698 DOI: 10.1371/journal.ppat.1000868] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2009] [Accepted: 03/22/2010] [Indexed: 11/18/2022] Open
Abstract
Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is a predictor of mortality in critical illness. Severe malaria (SM) is associated with decreased NO bioavailability, but the contribution of ADMA to the pathogenesis of impaired NO bioavailability and adverse outcomes in malaria is unknown. In adults with and without falciparum malaria, we tested the hypotheses that plasma ADMA would be: 1) increased in proportion to disease severity, 2) associated with impaired vascular and pulmonary NO bioavailability and 3) independently associated with increased mortality. We assessed plasma dimethylarginines, exhaled NO concentrations and endothelial function in 49 patients with SM, 78 with moderately severe malaria (MSM) and 19 healthy controls (HC). Repeat ADMA and endothelial function measurements were performed in patients with SM. Multivariable regression was used to assess the effect of ADMA on mortality and NO bioavailability. Plasma ADMA was increased in SM patients (0.85 microM; 95% CI 0.74-0.96) compared to those with MSM (0.54 microM; 95%CI 0.5-0.56) and HCs (0.64 microM; 95%CI 0.58-0.70; p<0.001). ADMA was an independent predictor of mortality in SM patients with each micromolar elevation increasing the odds of death 18 fold (95% CI 2.0-181; p = 0.01). ADMA was independently associated with decreased exhaled NO (r(s) = -0.31) and endothelial function (r(s) = -0.32) in all malaria patients, and with reduced exhaled NO (r(s) = -0.72) in those with SM. ADMA is increased in SM and associated with decreased vascular and pulmonary NO bioavailability. Inhibition of NOS by ADMA may contribute to increased mortality in severe malaria.
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Affiliation(s)
- Tsin W Yeo
- International Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia.
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Jones CE, Darcy CJ, Woodberry T, Anstey NM, McNeil YR. HPLC analysis of asymmetric dimethylarginine, symmetric dimethylarginine, homoarginine and arginine in small plasma volumes using a Gemini-NX column at high pH. J Chromatogr B Analyt Technol Biomed Life Sci 2010; 878:8-12. [PMID: 19945921 DOI: 10.1016/j.jchromb.2009.10.035] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2009] [Revised: 10/24/2009] [Accepted: 10/30/2009] [Indexed: 11/28/2022]
Abstract
There is increasing recognition of the clinical importance of endogenous nitric oxide synthase inhibitors in critical illness. This has highlighted the need for an accurate high performance liquid chromatography (HPLC) method for detection of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) in small volumes of blood. Here, the validation of an accurate, precise HPLC method for the determination of ADMA, SDMA, homoarginine and arginine concentrations in plasma is described. Solid phase extraction is followed by derivatisation with AccQ-Fluor and reversed phase separation on a Gemini-NX column at pH 9. Simultaneous detection by both UV-vis and fluorescence detectors affords extra validation. This solid phase extraction method gives absolute recoveries of more than 85% for ADMA and SDMA and relative recoveries of 102% for ADMA and 101% for SDMA. The intra-assay relative standard deviations are 2.1% and 2.3% for ADMA and SDMA, respectively, with inter-assay relative standard deviations of 2.7% and 3.1%, respectively. Advantages of this method include improved recovery of all analytes using isopropanol in the solid phase extraction; sharp, well-resolved chromatographic peaks using a high pH mobile phase; a non-endogenous internal standard, n-propyl L-arginine; and accurate and precise determination of methylated arginine concentrations from only 100microL of plasma.
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Affiliation(s)
- Catherine E Jones
- Menzies School of Health Research, Rocklands Drive, Tiwi, Darwin, NT, Australia
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Teerlink T, Luo Z, Palm F, Wilcox CS. Cellular ADMA: regulation and action. Pharmacol Res 2009; 60:448-60. [PMID: 19682580 PMCID: PMC2767414 DOI: 10.1016/j.phrs.2009.08.002] [Citation(s) in RCA: 187] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2009] [Revised: 08/03/2009] [Accepted: 08/04/2009] [Indexed: 02/07/2023]
Abstract
Asymmetric (N(G),N(G)) dimethylarginine (ADMA) is present in plasma and cells. It can inhibit nitric oxide synthase (NOS) that generates nitric oxide (NO) and cationic amino acid transporters (CATs) that supply intracellular NOS with its substrate, l-arginine, from the plasma. Therefore, ADMA and its transport mechanisms are strategically placed to regulate endothelial function. This could have considerable clinical impact since endothelial dysfunction has been detected at the origin of hypertension and chronic kidney disease (CKD) in human subjects and may be a harbinger of large vessel disease and cardiovascular disease (CVD). Indeed, plasma levels of ADMA are increased in many studies of patients at risk for, or with overt CKD or CVD. However, the levels of ADMA measured in plasma of about 0.5micromol.l(-1) may be below those required to inhibit NOS whose substrate, l-arginine, is present in concentrations many fold above the Km for NOS. However, NOS activity may be partially inhibited by cellular ADMA. Therefore, the cellular production of ADMA by protein arginine methyltransferase (PRMT) and protein hydrolysis, its degradation by N(G),N(G)-dimethylarginine dimethylaminohydrolase (DDAH) and its transmembrane transport by CAT that determines intracellular levels of ADMA may also determine the state of activation of NOS. This is the focus of the review. It is concluded that cellular levels of ADMA can be 5- to 20-fold above those in plasma and in a range that could tonically inhibit NOS. The relative importance of PRMT, DDAH and CAT for determining the intracellular NOS substrate:inhibitor ratio (l-arginine:ADMA) may vary according to the pathophysiologic circumstance. An understanding of this important balance requires knowledge of these three processes that regulate the intracellular levels of ADMA and arginine.
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Affiliation(s)
- Tom Teerlink
- Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
| | - Zaiming Luo
- Division of Nephrology and Hypertension, and Hypertension, Kidney and Vascular Center, Georgetown University, Washington, D.C
| | - Fredrik Palm
- Division of Nephrology and Hypertension, and Hypertension, Kidney and Vascular Center, Georgetown University, Washington, D.C
| | - Christopher S. Wilcox
- Division of Nephrology and Hypertension, and Hypertension, Kidney and Vascular Center, Georgetown University, Washington, D.C
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Blackwell S. The biochemistry, measurement and current clinical significance of asymmetric dimethylarginine. Ann Clin Biochem 2009; 47:17-28. [PMID: 19940201 DOI: 10.1258/acb.2009.009196] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase and an important cause of endothelial dysfunction. Its increased plasma concentration is associated with a variety of traditional cardiovascular risk factors, and may mediate their effects on the vascular endothelium. ADMA is also an independent predictor of cardiovascular events and mortality, and predicts outcomes in critically ill patients in the intensive care unit. This work has provided insights into the role of ADMA as an endogenous regulator of nitric oxide synthesis. At present there is no specific therapy to modify ADMA concentration, but increasing interest and work on protein arginine methyltransferases and dimethylarginine dimethylaminohydrolase, which synthesize and metabolize ADMA, respectively, might provide novel therapeutic targets.
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Affiliation(s)
- Scott Blackwell
- Department of Clinical Biochemistry, Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK.
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Lluch P, Cortina B, Vila JM, Segarra G, Mauricio MD, del Olmo JA, Serra MA, Lluch S, Rodrigo JM. Unchanged plasma levels of dimethylarginines and nitric oxide in chronic hepatitis C. Scand J Gastroenterol 2009; 44:224-8. [PMID: 18951278 DOI: 10.1080/00365520802400917] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Previous studies have shown that asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and nitric oxide (NO) play a prominent role in liver dysfunction. The objective of this study was to determine whether plasma levels of ADMA, SDMA and NO are altered in patients with chronic hepatitis C. MATERIAL AND METHODS Plasma levels of ADMA, SDMA and NO (nitrite plus nitrate) were measured in 22 patients with chronic hepatitis C and 24 patients with sustained virologic response after treatment with peginterferon plus ribavirin. Seven healthy volunteers served as controls. RESULTS Plasma levels of ADMA, SDMA and NO were not significantly different between groups: chronic hepatitis C, ADMA 0.55+/-0.06, SDMA 0.22+/-0.03, NO 36.3+/-5.9 micromol/l; treated patients, ADMA 0.60+/-0.15, SDMA 0.31+/-0.05, NO 36.1+/-5.5 micromol/l; controls, ADMA 0.65+/-0.08, SDMA 0.28+/-0.05, NO 40.7+/-8.9 micromol/l). CONCLUSIONS Our results show that plasma NO, ADMA and SDMA concentrations are not changed in patients with chronic hepatitis C without superimposed signs of acute inflammatory activity. Furthermore, no significant differences in plasma values of NO and dimethylarginines were observed between the group of untreated patients and the group of patients treated with interferon plus ribavirin.
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Affiliation(s)
- Paloma Lluch
- Servicio de Hepatologia, Hospital Clinico Universitario, Valencia, Spain
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37
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Low arginine/asymmetric dimethylarginine ratio deteriorates systemic hemodynamics and organ blood flow in a rat model. Crit Care Med 2009; 37:2010-7. [DOI: 10.1097/ccm.0b013e31819ffdaf] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Szuba A, Chachaj A, Wróbel T, Dzietczenia J, Mazur G, Antonowicz-Juchniewicz J, Kuliczkowski K, Andrzejak R. Asymmetric dimethylarginine in hematological malignancies: a preliminary study. Leuk Lymphoma 2009; 49:2316-20. [PMID: 19052979 DOI: 10.1080/10428190802510323] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Asymmetric dimethylarginine (ADMA) is a product of protein hydrolysis and an endogenous competitive inhibitor of nitric oxide synthase. It is considered a new independent risk factor for endothelial dysfunction and cardiovascular diseases. Increased protein turnover, oxidative stress and impaired dimethylarginine dimethylaminohydrolase activity occurring in hematological malignancies may lead to increased dimethylarginines production. We have measured ADMA, symmetric dimethylarginine (SDMA) and L-arginine plasma levels in 43 patients with different types of hematological malignancies and in control group of 43 healthy volunteers. Mean ADMA and L-arginine plasma levels were higher in hematological group than in control group (1.59 vs 0.64; p<0.001 and 34.84 vs 28.35; p=0.044 respectively). Mean plasma levels of SDMA were not significantly different between the groups. Elevated ADMA plasma levels in patients with hematological malignancies interfere with nitric oxide metabolism and may influence their prognosis. Further prognostic studies are postulated to assess this phenomenon.
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Affiliation(s)
- Andrzej Szuba
- Department of Internal Medicine, Wroclaw Medical University, Poland.
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Richir MC, Bouwman RH, Teerlink T, Siroen MPC, de Vries TPGM, van Leeuwen PAM. The prominent role of the liver in the elimination of asymmetric dimethylarginine (ADMA) and the consequences of impaired hepatic function. JPEN J Parenter Enteral Nutr 2009; 32:613-21. [PMID: 18974239 DOI: 10.1177/0148607108321702] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), the enzyme which converts the amino acid arginine into nitric oxide (NO). ADMA has been identified as an important risk factor for cardiovascular diseases. Besides the role of ADMA in cardiovascular diseases, it also seems to be an important determinant in the development of critical illness, (multiple) organ failure, and the hepatorenal syndrome. ADMA is eliminated from the body by urinary excretion, but it is mainly metabolized by the dimethylarginine dimethylaminohydrolase (DDAH) enzymes that convert ADMA into citrulline and dimethylamine. DDAH is highly expressed in the liver, which makes the liver a key organ in the regulation of the plasma ADMA concentration. The prominent role of the liver in the elimination of ADMA and the consequences of impaired hepatic function on ADMA levels will be discussed in this article.
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Affiliation(s)
- Milan C Richir
- Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands
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40
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Siroen MPC, Wiest R, Richir MC, Teerlink T, Rauwerda JA, Drescher FT, Zorger N, Leeuwen PAMV. Transjugular intrahepatic portosystemic shunt-placement increases arginine/asymmetric dimethylarginine ratio in cirrhotic patients. World J Gastroenterol 2008; 14:7214-9. [PMID: 19084936 PMCID: PMC2776879 DOI: 10.3748/wjg.14.7214] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the change of dimethylarginine plasma levels in cirrhotic patients receiving transjugular intrahepatic portosystemic shunt (TIPS).
METHODS: To determine arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and nitric oxide (NO) plasma levels, blood samples were collected from the superior cava, hepatic, and portal vein just before, directly after, and 3 mo after TIPS-placement.
RESULTS: A significant increase in the arginine/ADMA ratio after TIPS placement was shown. Moreover, TIPS placement enhanced renal function and thereby decreased systemic SDMA levels. In patients with renal dysfunction before TIPS placement, both the arginine/ADMA ratio and creatinine clearance rate increased significantly, while this was not the case in patients with normal renal function before TIPS placement. Hepatic function did not change significantly after TIPS placement and no significant decline in ADMA plasma levels was measured.
CONCLUSION: The increase of the arginine/ADMA ratio after TIPS placement suggests an increase in intracellular NO bioavailability. In addition, this study suggests that TIPS placement does not alter dimethylarginine dimethylaminohydrolase (DDAH) activity and confirms the major role of the liver as an ADMA clearing organ.
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Becker T, Mevius I, de Vries DK, Schaapherder AFM, zu Vilsendorf AM, Klempnauer J, Frölich JC, Tsikas D. The L-arginine/NO pathway in end-stage liver disease and during orthotopic liver and kidney transplantation: biological and analytical ramifications. Nitric Oxide 2008; 20:61-7. [PMID: 18948222 DOI: 10.1016/j.niox.2008.10.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2008] [Revised: 08/08/2008] [Accepted: 10/03/2008] [Indexed: 12/21/2022]
Abstract
The L-arginine/nitric oxide (L-Arg/NO) pathway is altered in liver and kidney diseases. However, the status of the L-Arg/NO pathway during and after orthotopic transplantation is insufficiently investigated and findings are uncertain because of analytical shortcomings. Also, most human studies have focused on individual members of the L-Arg/NO pathway such as nitrate or asymmetric dimethylarginine (ADMA). In the present article we report on a pilot study investigating extensively the status of the L-Arg/NO pathway before and during orthotopic liver transplantation (OLT). By using fully validated, highly sensitive and specific GC-MS and GC-MS/MS methods nitrite, nitrate, ADMA and its hydrolysis product dimethylamine (DMA), L-arginine and L-ornithine were measured in blood and urine. Our study gives strong evidence of the exceptional importance of hepatic dimethylarginine dimethylaminohydrolase (DDAH) activity for the elimination of systemic ADMA. In end-stage liver disease the synthesis of NO and ADMA as well as the DDAH activity are elevated. However, increase in DDAH activity is insufficient to efficiently eliminate overproduced ADMA. The transplanted liver graft is capable of clearing ADMA in a rapid and sufficient manner. In contrast to studies from other groups, our study shows that in OLT as well as in living donor kidney transplantation, the second study reported here, reperfusion of the graft does not cause drastic alterations to the L-Arg/NO pathway with regard to NO synthesis. In the OLT study the concentration of circulating L-arginine fell temporally dramatically, while L-ornithine levels increased diametrically, most likely due to elevation of arginase activity. However, the relatively long-lasting decrease in plasmatic L-arginine in OLT seems not to have affected NO synthesis after reperfusion. Our OLT study suggests that liver reperfusion is associated with greatly elevated activity of proteolytic and hydrolytic enzymes including DDAH and arginase. Suppression of proteolytic and hydrolytic activity in transplantation could be a useful measure to improve outcome and remains to be investigated in further studies on larger patient collectives. The importance of analytical chemistry in this area of research is also discussed in this article.
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Affiliation(s)
- Thomas Becker
- Department of Visceral and Transplant Surgery, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
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Berkers J, Gunst J, Vanhorebeek I, Van den Berghe G. Glycaemic control and perioperative organ protection. Best Pract Res Clin Anaesthesiol 2008; 22:135-49. [PMID: 18494393 DOI: 10.1016/j.bpa.2007.08.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The concept of stress hyperglycaemia as an adaptive, beneficial response in critical illness has recently been challenged. Two large prospective randomized controlled trials in the Leuven University Hospital surgical and medical ICUs demonstrated that maintenance of normoglycaemia with intensive insulin therapy substantially prevents morbidity and reduces mortality. Strict normoglycaemia is required to gain most clinical benefit. With this therapy the risk of hypoglycaemia increased, but without inducing obvious clinical sequellae. Other studies have been used to advocate against implementation of intensive insulin therapy by showing lack of benefit or questioning safety. However, these studies are inconclusive on this subject, due to problems of not reaching normal glucose levels clearly separated from the standard glycaemic group or lack of statistical power. Clearly, future studies should be adequately powered and comply with the study protocol in order to confirm the survival and other clinical benefits of intensive insulin therapy.
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Affiliation(s)
- Joost Berkers
- Department of Intensive Care Medicine, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
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Landburg PP, Teerlink T, Muskiet FAJ, Duits AJ, Schnog JJB. Plasma concentrations of asymmetric dimethylarginine, an endogenous nitric oxide synthase inhibitor, are elevated in sickle cell patients but do not increase further during painful crisis. Am J Hematol 2008; 83:577-9. [PMID: 18383318 DOI: 10.1002/ajh.21184] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, are elevated in the clinically asymptomatic state of sickle cell disease (SCD). However, the role of ADMA during vaso-occlusive complications has not been defined. ADMA concentrations were determined in HbSS (n = 43) and HbSC (n = 25) patients with healthy blood donors (HbAA) as controls. In the clinically asymptomatic state ADMA concentrations were elevated in sickle cell patients as compared to healthy controls (HbSS 0.70 micromol/L, HbSC 0.54 micromol/L, HbAA 0.39 micromol/L) (P < 0.001). Yet plasma ADMA concentrations did not increase further at presentation with a painful crisis implicating no role of primary importance during vaso-occlusive crises.
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Affiliation(s)
- Precious P Landburg
- Immunology Laboratory Department, Red Cross Blood Bank Foundation Curaçao, Curaçao, Netherlands Antilles
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44
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Antioxidants for the Treatment of Endothelial Dysfunction in Critical Illness. Intensive Care Med 2007. [DOI: 10.1007/978-0-387-49518-7_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Insulin therapy in the pediatric intensive care unit. Clin Nutr 2007; 26:677-90. [PMID: 17950500 DOI: 10.1016/j.clnu.2007.08.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2007] [Revised: 08/22/2007] [Accepted: 08/29/2007] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS Hyperglycemia is a major risk factor for increased morbidity and mortality in the intensive care unit. Insulin therapy has emerged in adult intensive care units and several pediatric studies are currently being conducted. This review discusses hyperglycemia and the effects of insulin on metabolic and non-metabolic pathways, with a focus on pediatric critical illness. METHODS A PubMed search was performed by using the following keywords and limits (("hyperglycemia"[MeSH terms] or ("insulin resistance"[MeSH major topic]) and ("critical care"[MeSH terms] or "critical illness"[MeSH terms])) in different combinations with ("metabolism"[MeSH terms] or "metabolic networks and pathways"[MeSH terms]) and ("outcome"[all fields]) and ("infant"[MeSH terms] or "child"[MeSH terms] or "adolescent"[MeSH terms]). Quality assessment of selected studies included clinical pertinence, publication in peer-reviewed journals, objectivity of measurements and techniques used to minimize bias. Reference lists of such studies were included. RESULTS The magnitude and duration of hyperglycemia are associated with increased morbidity and mortality in the pediatric intensive care unit (PICU), but prospective, randomized controlled studies with insulin therapy have not been published yet. Evidence concerning the mechanism and the effect of insulin on glucose and lipid metabolism in pediatric critical illness is scarce. More is known about the positive effect on protein homeostasis, especially in severely burned children. The effect in septic children is less clear and seems age dependent. Some non-metabolic properties of insulin such as the modulation of inflammation, endothelial dysfunction and coagulopathy have not been fully investigated in children. CONCLUSION Future studies on the effect of insulin on morbidity and mortality as well as on the mechanisms through which insulin exerts these effects are necessary in critically ill children. We propose these studies to be conducted under standardized conditions including precise definitions of hyperglycemia and rates of glucose intake.
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Böger RH. Live and let die: asymmetric dimethylarginine and septic shock. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2007; 10:169. [PMID: 17094795 PMCID: PMC1794448 DOI: 10.1186/cc5076] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
Nitric oxide (NO) is an important mediator of host defence and of vascular tone. In septic shock, upregulation of inducible NO synthase leads to the production of vast amounts of NO, which contribute to pathogen elimination but also to inappropriate vasodilation and to loss of vascular resistance. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthases shown to contribute to the regulation of vascular tone. ADMA was recently identified as a marker of organ dysfunction and mortality in intensive care patients and as a novel cardiovascular risk factor. In the present issue of Critical Care, a study by O'Dwyer and colleagues identifies ADMA as a potential regulator of NO production in septic shock. Being an inhibitor of NO production, ADMA may at least partly counteract pathological hypotension, but at the same time may impair the NO-dependent host defence. A mechanism is proposed by which the interplay between ADMA and inducible NO synthase activity is mediated. ADMA levels should be determined in future studies evaluating the regulation of NO in the intensive care setting.
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Affiliation(s)
- Rainer H Böger
- Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology, University Hospital Hamburg-Eppendorf, Germany.
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47
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Mookerjee RP, Dalton RN, Davies NA, Hodges SJ, Turner C, Williams R, Jalan R. Inflammation is an important determinant of levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) in acute liver failure. Liver Transpl 2007; 13:400-5. [PMID: 17318866 DOI: 10.1002/lt.21053] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Acute liver failure (ALF) is characterized by rapid progressive organ failure and poor outcome. The pathophysiology of multiorgan dysfunction in ALF remains unclear but increased systemic inflammatory response is believed to be an important determining factor. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, results from proteolysis and the liver is a major site for its metabolism. ADMA has been shown to independently predict outcome in multiorgan failure associated with severe liver dysfunction. In this study, we tested the hypothesis that proinflammatory cytokine driven responses are important in modulating ADMA levels in patients with acetaminophen-induced ALF. Blood samples were collected from 10 ALF patients (grade IV encephalopathy) from admission until the time of transplantation or death, and assayed for cytokines and ADMA. A total of 8 patients required treatment for raised intracranial pressure and all patients were managed with standard of care, including full mechanical ventilation and veno-venous hemofiltration. ADMA levels were markedly higher in ALF patients compared to age-matched controls (P < 0.001) and correlated with the levels of proinflammatory cytokines. In pretransplantation patients undergoing hepatic venous catheterization, we demonstrated no significant uptake of ADMA across the failing liver. However, following liver transplantation, ADMA levels reduced acutely. A timed study of ADMA levels during transplantation demonstrated a slight increase during the anhepatic phase but a marked and sustained reduction in ADMA following liver reperfusion. In conclusion, our data show a significant correlation between ADMA levels and proinflammatory cytokines, supporting a hypothesis that proinflammatory cytokines may regulate ADMA metabolism in ALF.
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Affiliation(s)
- Rajeshwar P Mookerjee
- Liver Failure Group, Institute of Hepatology, Division of Medicine, University College London, London, UK
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Abstract
PURPOSE OF REVIEW Recent results are reviewed on the effects of L-arginine supplements in excess of standard nutritional practices during severe sepsis and septic shock. RECENT FINDINGS Septic shock has been alternatively viewed as an L-arginine-deficient state or as a syndrome caused by excess nitric oxide, a vasoactive product of L-arginine metabolism. L-Arginine has many physiologic and pharmacologic effects that indicate its potential to affect survival in septic patients. Animal studies have documented immunologic effects of L-arginine and of commercial 'immune-enhancing' diets. However, survival studies in small animals have not consistently favored L-arginine. L-Arginine monotherapy in a canine model of septic shock found significant harm at infusion rates of less than twice that administered in standard formulations of total parenteral nutrition. Meanwhile, clinical studies have suffered from lack of statistical power, patient heterogeneity, randomization failures, and use of complex nutritional formulas. Meta-analyses have noted heterogeneity between the effects of immune-enhancing diets in surgical versus medical patients and mixed critically ill populations that include subjects with sepsis, indicating that these results may not be reliably pooled. SUMMARY To date, published evidence has not established the safety and efficacy of L-arginine at doses above standard dietary practices in severe sepsis or septic shock.
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Affiliation(s)
- Andre C Kalil
- Infectious Diseases Division, Department of Internal Medicine, University of Nebraska, Omaha, Nebraska, USA.
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49
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Abstract
Critically ill patients usually develop hyperglycemia, a condition referred to as "diabetes of injury." More and more evidence argues against the concept that this is an adaptive beneficial response. Indeed, the development of hyperglycemia seems to be detrimental for the outcome of critically ill patients, because maintenance of normoglycemia with intensive insulin therapy prevents morbidity and reduces mortality of critically ill patients to a large extent. The mechanisms underlying these clinical benefits are being studied further.
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Affiliation(s)
- Ilse Vanhorebeek
- Department of Intensive Care Medicine, Katholieke Universiteit Leuven, Herestraat 49, B-300 Leuven, Belgium
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50
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Kalil AC, Sevransky JE, Myers DE, Esposito C, Vandivier RW, Eichacker P, Susla GM, Solomon SB, Csako G, Costello R, Sittler KJ, Banks S, Natanson C, Danner RL. Preclinical trial of L-arginine monotherapy alone or with N-acetylcysteine in septic shock. Crit Care Med 2006; 34:2719-28. [PMID: 16971848 DOI: 10.1097/01.ccm.0000242757.26245.03] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
OBJECTIVE L-arginine supplementation in sepsis is controversial. Septic shock has been alternatively viewed as an L-arginine-deficient state or as a syndrome caused by excess nitric oxide, an end-product of L-arginine metabolism. DESIGN Randomized, placebo-controlled, and double-blinded (investigators, veterinarians, and pharmacists). SETTING Laboratory. SUBJECTS Purpose-bred, 1- to 2-yr-old, 10- to 12-kg beagles. INTERVENTIONS The effects of parenteral L-arginine alone or in combination with N-acetylcysteine were compared with vehicle alone in a well-characterized canine model of Escherichia coli peritonitis. Two doses were studied that delivered approximately 1.5-fold (10 mg x kg(-1) x hr(-1)) and 15-fold (100 mg x kg(-1) x hr(-1)) the L-arginine dose typically administered with standard total parenteral nutrition. Animals in the low- and high-dose L-arginine arms were further randomized to receive vehicle alone or N-acetylcysteine (20 mg x kg(-1) x hr(-1)) as an antioxidant to prevent peroxynitrite formation. MEASUREMENTS AND MAIN RESULTS The main measurements were hemodynamics, plasma arginine and ornithine, serum nitrate/nitrite, laboratory studies for organ injury, and survival. Both doses of L-arginine similarly increased mortality (p = .02), and worsened shock (p = .001 for reduced mean arterial pressure). These effects were associated with significant increases in plasma arginine (p = .0013) and ornithine (p = .0021). In addition, serum nitrate/nitrite (p = .02), liver enzymes (p = .08), and blood urea nitrogen/creatinine ratios (p = .001) rose, whereas arterial pH (p = .001) and bicarbonate levels (p = .001) fell. N-acetylcysteine did not significantly decrease any of the harmful effects of L-arginine. Thus, parenteral L-arginine monotherapy was markedly harmful in animals with septic shock. CONCLUSIONS These findings suggest that supplemental parenteral L-arginine, at doses above standard dietary practices, should be avoided in critically ill patients with septic shock.
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Affiliation(s)
- Andre C Kalil
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
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