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Zhou Z, Yao X. Dietary niacin intake and mortality among chronic kidney disease patients. Front Nutr 2024; 11:1435297. [PMID: 39639940 PMCID: PMC11617148 DOI: 10.3389/fnut.2024.1435297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 11/04/2024] [Indexed: 12/07/2024] Open
Abstract
Background The relationship between niacin and the risk of mortality in chronic kidney disease (CKD) patients remains unclear. This study aims to investigate the potential correlation. Methods This cohort study utilized data from the 2003-2018 National Health and Nutrition Examination Survey (NHANES). The study included 6,110 patients with CKD aged 18 years or older. Weighted Cox proportional hazards models and restricted cubic splines (RCS) were employed to estimate hazard ratios for all-cause mortality and cardiovascular disease (CVD) mortality. Niacin intake was estimated using the 24 h dietary recall method, based on the type and amount of food consumed. All-cause mortality and cardiac mortality rates were determined using National Death Index (NDI) mortality data (as of 31 December 2018). Results The median niacin intake was 20.89 mg/day, with an interquartile range of 15.67-27.99 mg/day. During the follow-up period (median of 87 months), there were 1,984 all-cause deaths, including 714 CVD deaths. Compared with low niacin intake, the multivariate-adjusted hazard ratio for dietary intake of 22 mg or higher was 0.71 (95% CI, 0.57-0.88) for all-cause mortality and 0.75 (95% CI, 0.57, 0.98) for CVD mortality. Conclusion Dietary niacin intake is associated with a reduction in all-cause and cardiac mortality among CKD patients.
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Affiliation(s)
- Zhengxi Zhou
- Department of Urology, Ningbo Mingzhou Hospital, Zhejiang, China
| | - Xiaotian Yao
- Department of Urology, Ningbo Mingzhou Hospital, Zhejiang, China
- The Division of Nephrology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
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2
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Moritz L, Schumann A, Pohl M, Köttgen A, Hannibal L, Spiekerkoetter U. A systematic review of metabolomic findings in adult and pediatric renal disease. Clin Biochem 2024; 123:110703. [PMID: 38097032 DOI: 10.1016/j.clinbiochem.2023.110703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 12/03/2023] [Accepted: 12/07/2023] [Indexed: 12/29/2023]
Abstract
Chronic kidney disease (CKD) affects over 0.5 billion people worldwide across their lifetimes. Despite a growingly ageing world population, an increase in all-age prevalence of kidney disease persists. Adult-onset forms of kidney disease often result from lifestyle-modifiable metabolic illnesses such as type 2 diabetes. Pediatric and adolescent forms of renal disease are primarily caused by morphological abnormalities of the kidney, as well as immunological, infectious and inherited metabolic disorders. Alterations in energy metabolism are observed in CKD of varying causes, albeit the molecular mechanisms underlying pathology are unclear. A systematic indexing of metabolites identified in plasma and urine of patients with kidney disease alongside disease enrichment analysis uncovered inborn errors of metabolism as a framework that links features of adult and pediatric kidney disease. The relationship of genetics and metabolism in kidney disease could be classified into three distinct landscapes: (i) Normal genotypes that develop renal damage because of lifestyle and / or comorbidities; (ii) Heterozygous genetic variants and polymorphisms that result in unique metabotypes that may predispose to the development of kidney disease via synergistic heterozygosity, and (iii) Homozygous genetic variants that cause renal impairment by perturbing metabolism, as found in children with monogenic inborn errors of metabolism. Interest in the identification of early biomarkers of onset and progression of CKD has grown steadily in the last years, though it has not translated into clinical routine yet. This systematic review indexes findings of differential concentration of metabolites and energy pathway dysregulation in kidney disease and appraises their potential use as biomarkers.
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Affiliation(s)
- Lennart Moritz
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Anke Schumann
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Martin Pohl
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Anna Köttgen
- Institute of Genetic Epidemiology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Luciana Hannibal
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany.
| | - Ute Spiekerkoetter
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany.
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3
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DiNicolantonio JJ, McCarty MF, Barroso-Aranda J, Assanga S, Lujan LML, O'Keefe JH. A nutraceutical strategy for downregulating TGFβ signalling: prospects for prevention of fibrotic disorders, including post-COVID-19 pulmonary fibrosis. Open Heart 2021; 8:openhrt-2021-001663. [PMID: 33879509 PMCID: PMC8061562 DOI: 10.1136/openhrt-2021-001663] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/30/2021] [Indexed: 12/14/2022] Open
Affiliation(s)
- James J DiNicolantonio
- Preventive Cardiology, Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA
| | | | | | - Simon Assanga
- Department of Research and Postgraduate Studies in Food, University of Sonora, Sonora, Mexico
| | | | - James H O'Keefe
- University of Missouri-Kansas City, Saint Lukes Mid America Heart Institute, Kansas City, Missouri, USA
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4
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Theodorakopoulou M, Raptis V, Loutradis C, Sarafidis P. Hypoxia and Endothelial Dysfunction in Autosomal-Dominant Polycystic Kidney Disease. Semin Nephrol 2020; 39:599-612. [PMID: 31836042 DOI: 10.1016/j.semnephrol.2019.10.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Autosomal-dominant polycystic kidney disease (ADPKD) is the most prevalent inherited kidney disease, characterized by growth of bilateral renal cysts, hypertension, and multiple extrarenal complications that eventually can lead to renal failure. It is caused by mutations in PKD1 or PKD2 genes encoding the proteins polycystin-1 and polycystin-2, respectively. Over the past few years, studies investigating the role of primary cilia and polycystins, present not only on the surface of renal tubular cells but also on vascular endothelial cells, have advanced our understanding of the pathogenesis of ADPKD and have shown that mechanisms other than cyst formation also contribute to renal functional decline in this disease. Among them, increased oxidative stress, endothelial dysfunction, and hypoxia may play central roles because they occur early in the disease process and precede the onset of hypertension and renal functional decline. Endothelial dysfunction is linked to higher asymmetric dimethylarginine levels and reduced nitric oxide bioavailability, which would cause regional vasoconstriction and impaired renal blood flow. The resulting hypoxia would increase the levels of hypoxia-inducible-transcription factor 1α and other angiogenetic factors, which, in turn, may drive cyst growth. In this review, we summarize the existing evidence for roles of endothelial dysfunction, oxidative stress, and hypoxia in the pathogenesis of ADPKD.
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Affiliation(s)
- Marieta Theodorakopoulou
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Vasileios Raptis
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Charalampos Loutradis
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Pantelis Sarafidis
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece..
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5
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Kalantari S, Nafar M. An update of urine and blood metabolomics in chronic kidney disease. Biomark Med 2019; 13:577-597. [DOI: 10.2217/bmm-2019-0008] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Chronic kidney disease is considered as a serious obstacle in global health, with increasing incidence and prevalence. In spite of numerous attempts by using recent omics technologies, specially metabolomics, for understanding pathophysiology, molecular mechanism and identification reliable consensus biomarkers for diagnosis and prognosis of this complex disease, the current biomarkers are still insensitive and many questions about its pathomechanism are still to be unanswered. This review is focused on recent findings about urine and serum/plasma metabolite biomarkers and changes in the pathways that occurs in the disease conditions. The urine and blood metabolome content in the normal and disease state is investigated based on the current metabolomics studies and well known metabolite candidate biomarkers for chronic kidney disease are discussed.
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Affiliation(s)
- Shiva Kalantari
- Chronic Kidney Disease Research Center, Shahid Beheshti University of Medical Sciences, Number 103, Boostan 9th Street, Pasdaran Avenue, 1666663111 Tehran, Iran
| | - Mohsen Nafar
- Chronic Kidney Disease Research Center, Shahid Beheshti University of Medical Sciences, Number 103, Boostan 9th Street, Pasdaran Avenue, 1666663111 Tehran, Iran
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Zhao WC, Li G, Huang CY, Jiang JL. Asymmetric dimethylarginine: An crucial regulator in tissue fibrosis. Eur J Pharmacol 2019; 854:54-61. [PMID: 30951718 DOI: 10.1016/j.ejphar.2019.03.055] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 03/21/2019] [Accepted: 03/28/2019] [Indexed: 02/06/2023]
Abstract
Fibrosis is a reparative process with very few therapeutic options to prevent its progression to organ dysfunction. Chronic fibrotic diseases contribute to an estimated 45% of all death in the industrialized world. Asymmetric dimethylarginine (ADMA), an endothelial nitric oxide synthase inhibitor, plays a crucial role in the pathogenesis of various cardiovascular diseases associated with endothelial dysfunction. Recent reports have focused on ADMA in the pathogenesis of tissue fibrosis. This review discusses the current knowledge about ADMA biology, its association with risk factors of established fibrotic diseases and the potential pathophysiological mechanisms implicating ADMA in the process of tissue fibrosis.
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Affiliation(s)
- Wei-Chen Zhao
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410078, China
| | - Ge Li
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410078, China; Faculty of Medical Public Courses, Xinhua College of Sun Yat-sen University, Guangzhou, Guangdong, 510520, China
| | - Chu-Yi Huang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410078, China
| | - Jun-Lin Jiang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410078, China; Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, 410078, China.
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Abstract
Cardiovascular disease (CVD) is highly prevalent in the peritoneal dialysis (PD) population, affecting up to 60% of cohorts. CVD is the primary cause of death in up to 40% of PD patients in Australia, New Zealand, and the United States. Cardiovascular mortality rates are reported to be approximately 14 per 100 patient-years, which are 10- to 20-fold greater than those of age- and sex-matched controls. The excess risk of CVD is related to a combination of traditional risk factors (such as hypertension, dyslipidemia, obesity, smoking, sedentary lifestyle, and insulin resistance), nontraditional (kidney disease-related) risk factors (such as anemia, chronic volume overload, inflammation, malnutrition, hyperuricemia, and mineral and bone disorder), and PD-specific risk factors (such as dialysis solutions, glycation end products, hypokalemia, residual kidney function, and ultrafiltration failure). Interventions targeting these factors may mitigate cardiovascular risk, although high-level clinical evidence is lacking. This review summarizes the evidence relating to cardiovascular interventions targeting modifiable CVD risk factors in PD patients, as well as highlighting the key recommendations of the International Society for Peritoneal Dialysis Cardiovascular and Metabolic Guidelines.
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8
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Abstract
Chronic kidney disease is currently assessed by estimated glomerular filtration rate, a mathematical construct based on creatinine or creatinine and cystatin concentration. Creatinine-based equations have improved with standardization efforts and the Modification of Diet in Renal Disease Study (MDRD) and CKD-Epidemiology Collaboration Study (CKD-EPI). Because the measurement of creatinine is subject to interference from non-GFR determinants, alternative markers have long been sought. These have included cystatin C and low molecular weight proteins like β2-microglobulin and beta trace protein. Tubular disease often occurs before glomerular filtration is impaired and investigators have investigated the excretion of other low molecular weight proteins such as Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Injury Molecule-1 and N-acetyl-β-d-glucosaminidase. While preliminary, there is some evidence linking these analytes with GFR, disease stage and mortality. Although asymmetrical dimethyl arginine, an inhibitor of nitric oxide, has been shown to be associated with progression of renal disease, symmetric dimethyl arginine may be a better marker. Recent work has also explored the potential of microRNA (miRNA) analysis and metabolomics studies to further elucidate this complex pathophysiologic disease process. Investigators hope to improve our ability to detect CKD by the use of test panels, i.e., various marker combinations thereof. Unfortunately, most of these markers lack standardization unlike traditional measures that rely on creatinine and cystatin C measurement.
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9
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Fulton MD, Brown T, Zheng YG. Mechanisms and Inhibitors of Histone Arginine Methylation. CHEM REC 2018; 18:1792-1807. [PMID: 30230223 PMCID: PMC6348102 DOI: 10.1002/tcr.201800082] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 08/27/2018] [Indexed: 12/16/2022]
Abstract
Histone methylation plays an important regulatory role in chromatin restructuring and RNA transcription. Arginine methylation that is enzymatically catalyzed by the family of protein arginine methyltransferases (PRMTs) can either activate or repress gene expression depending on cellular contexts. Given the strong correlation of PRMTs with pathophysiology, great interest is seen in understanding molecular mechanisms of PRMTs in diseases and in developing potent PRMT inhibitors. Herein, we reviewed key research advances in the study of biochemical mechanisms of PRMT catalysis and their relevance to cell biology. We highlighted how a random binary, ordered ternary kinetic model for PRMT1 catalysis reconciles the literature reports and endorses a distributive mechanism that the enzyme active site utilizes for multiple turnovers of arginine methylation. We discussed the impacts of histone arginine methylation and its biochemical interplays with other key epigenetic marks. Challenges in developing small-molecule PRMT inhibitors were also discussed.
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Affiliation(s)
- Melody D Fulton
- Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, University of Georgia, Athens, GA 30602
| | - Tyler Brown
- Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, University of Georgia, Athens, GA 30602
| | - Y George Zheng
- Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, University of Georgia, Athens, GA 30602
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10
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Raptis V, Loutradis C, Sarafidis PA. Renal injury progression in autosomal dominant polycystic kidney disease: a look beyond the cysts. Nephrol Dial Transplant 2018; 33:1887-1895. [DOI: 10.1093/ndt/gfy023] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
Affiliation(s)
- Vasileios Raptis
- Section of Nephrology and Hypertension, 1st Department of Medicine, AHEPA Hospital, Thessaloniki, Greece
| | - Charalampos Loutradis
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Pantelis A Sarafidis
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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11
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Ramachandran S, Loganathan S, Cheeran V, Charles S, Munuswamy-Ramanujan G, Ramasamy M, Raj V, Mala K. Forskolin attenuates doxorubicin-induced accumulation of asymmetric dimethylarginine and s-adenosylhomocysteine via methyltransferase activity in leukemic monocytes. Leuk Res Rep 2018; 9:28-35. [PMID: 29892545 PMCID: PMC5993357 DOI: 10.1016/j.lrr.2018.02.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 12/15/2017] [Accepted: 02/09/2018] [Indexed: 10/25/2022] Open
Abstract
Doxorubicin (DOX) is an antitumor drug, associated with cardiomyopathy. Strategies to address DOX-cardiomyopathy are scarce. Here, we identify the effect of forskolin (FSK) on DOX-induced-asymmetric-dimethylarginine (ADMA) accumulation in monocytoid cells. DOX-challenge led to i) augmented cytotoxicity, reactive-oxygen-species (ROS) production and methyltransferase-enzyme-activity identified as ADMA and s-adenosylhomocysteine (SAH) accumulation (SAH-A). However, except cytotoxicity, other DOX effects were decreased by metformin and FSK. FSK, did not alter the DOX-induced cytotoxic effect, but, decreased SAH-A by >50% and a combination of three drugs restored physiological methyltransferase-enzyme-activity. Together, protective effect of FSK against DOX-induced SAH-A is associated with mitigated methyltransferase-activity, a one-of-a-kind report.
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Key Words
- ADMA, asymmetric dimethylarginine
- CT, chemotherapy
- CVD, cardiovascular disease
- Cancer
- Cardiovascular disease
- DDAH, dimethylarginine diaminohydrolase
- DOX, doxorubicin
- Endothelial dysfunction
- FSK, forskolin
- Forskolin
- HCY, homocysteine
- HTRF, homogenous time-resolved fluorescence
- L-arg, L-arginine
- L-cit, L-citrulline
- MET, metformin
- Metformin
- Methyltransferase
- NAD+, nicotinamide adenine dinucleotide
- OS, oxidative stress
- PRMT1, protein arginine methyltransferase1
- ROS, reactive oxygen species
- SAH, s-adenosylhomocysteine;
- SAH-A, SAH accumulation
- SAHH, s-adenosylhomocysteine hydrolase
- SAM, s-adenosylmethionine
- SIRT1, sirtuin1
- cAMP, cyclic AMP
- eNOS, endothelial nitric oxide synthase
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Affiliation(s)
- Sandhiya Ramachandran
- Department of Biotechnology, School of Bioengineering, SRM University, Kattankulathur 603203, India
| | - Swetha Loganathan
- Department of Biotechnology, School of Bioengineering, SRM University, Kattankulathur 603203, India
| | - Vinnie Cheeran
- Interdisciplinary Institute of Indian System of Medicine, SRM University, Kattankulathur 603203, India
| | - Soniya Charles
- Department of Biotechnology, School of Bioengineering, SRM University, Kattankulathur 603203, India.,Medical College Hospital and Research Center, SRM University, Kattankulathur 603203, India
| | | | - Mohankumar Ramasamy
- Interdisciplinary Institute of Indian System of Medicine, SRM University, Kattankulathur 603203, India
| | - Vijay Raj
- Medical College Hospital and Research Center, SRM University, Kattankulathur 603203, India
| | - Kanchana Mala
- Medical College Hospital and Research Center, SRM University, Kattankulathur 603203, India
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12
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Hypertension in dialysis patients: a consensus document by the European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension (ESH). J Hypertens 2017; 35:657-676. [PMID: 28157814 DOI: 10.1097/hjh.0000000000001283] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
In patients with end-stage renal disease treated with hemodialysis or peritoneal dialysis, hypertension is very common and often poorly controlled. Blood pressure (BP) recordings obtained before or after hemodialysis display a J-shaped or U-shaped association with cardiovascular events and survival, but this most likely reflects the low accuracy of these measurements and the peculiar hemodynamic setting related with dialysis treatment. Elevated BP by home or ambulatory BP monitoring is clearly associated with shorter survival. Sodium and volume excess is the prominent mechanism of hypertension in dialysis patients, but other pathways, such as arterial stiffness, activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, endothelial dysfunction, sleep apnea and the use of erythropoietin-stimulating agents may also be involved. Nonpharmacologic interventions targeting sodium and volume excess are fundamental for hypertension control in this population. If BP remains elevated after appropriate treatment of sodium-volume excess, the use of antihypertensive agents is necessary. Drug treatment in the dialysis population should take into consideration the patient's comorbidities and specific characteristics of each agent, such as dialysability. This document is an overview of the diagnosis, epidemiology, pathogenesis and treatment of hypertension in patients on dialysis, aiming to offer the renal physician practical recommendations based on current knowledge and expert opinion and to highlight areas for future research.
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13
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Sarafidis PA, Persu A, Agarwal R, Burnier M, de Leeuw P, Ferro CJ, Halimi JM, Heine GH, Jadoul M, Jarraya F, Kanbay M, Mallamaci F, Mark PB, Ortiz A, Parati G, Pontremoli R, Rossignol P, Ruilope L, Van der Niepen P, Vanholder R, Verhaar MC, Wiecek A, Wuerzner G, London GM, Zoccali C. Hypertension in dialysis patients: a consensus document by the European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension (ESH). Nephrol Dial Transplant 2017; 32:620-640. [PMID: 28340239 DOI: 10.1093/ndt/gfw433] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Accepted: 11/14/2016] [Indexed: 01/07/2023] Open
Abstract
In patients with end-stage renal disease (ESRD) treated with haemodialysis or peritoneal dialysis, hypertension is common and often poorly controlled. Blood pressure (BP) recordings obtained before or after haemodialysis display a J- or U-shaped association with cardiovascular events and survival, but this most likely reflects the low accuracy of these measurements and the peculiar haemodynamic setting related to dialysis treatment. Elevated BP detected by home or ambulatory BP monitoring is clearly associated with shorter survival. Sodium and volume excess is the prominent mechanism of hypertension in dialysis patients, but other pathways, such as arterial stiffness, activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, endothelial dysfunction, sleep apnoea and the use of erythropoietin-stimulating agents may also be involved. Non-pharmacologic interventions targeting sodium and volume excess are fundamental for hypertension control in this population. If BP remains elevated after appropriate treatment of sodium and volume excess, the use of antihypertensive agents is necessary. Drug treatment in the dialysis population should take into consideration the patient's comorbidities and specific characteristics of each agent, such as dialysability. This document is an overview of the diagnosis, epidemiology, pathogenesis and treatment of hypertension in patients on dialysis, aiming to offer the renal physician practical recommendations based on current knowledge and expert opinion and to highlight areas for future research.
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Affiliation(s)
- Pantelis A Sarafidis
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Alexandre Persu
- Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, and Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Rajiv Agarwal
- Department of Medicine, Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
| | - Michel Burnier
- Service of Nephrology and Hypertension, Lausanne University Hospital, Lausanne, Switzerland
| | - Peter de Leeuw
- Department of Medicine, Maastricht University Medical Center, Maastricht and Zuyderland Medical Center, Geleen/Heerlen, The Netherlands
| | - Charles J Ferro
- Department of Renal Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Jean-Michel Halimi
- Service de Néphrologie-Immunologie Clinique, Hôpital Bretonneau, François-Rabelais University, Tours, France
| | - Gunnar H Heine
- Saarland University Medical Center, Internal Medicine IV-Nephrology and Hypertension, Homburg, Germany
| | - Michel Jadoul
- Division of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Faical Jarraya
- Department of Nephrology, Sfax University Hospital and Research Unit, Faculty of Medicine, Sfax University, Sfax, Tunisia
| | - Mehmet Kanbay
- Department of Medicine, Division of Nephrology, Koc University School of Medicine, Istanbul, Turkey
| | - Francesca Mallamaci
- CNR-IFC, Clinical Epidemiology and Pathophysiology of Hypertension and Renal Diseases Unit, Ospedali Riuniti, Reggio Calabria, Italy
| | - Patrick B Mark
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Alberto Ortiz
- IIS-Fundacion Jimenez Diaz, School of Medicine, University Autonoma of Madrid, FRIAT and REDINREN, Madrid, Spain
| | - Gianfranco Parati
- Department of Cardiovascular, Neural, and Metabolic Sciences, San Luca Hospital, Istituto Auxologico Italiano and Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Roberto Pontremoli
- Università degli Studi and IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genova, Italy
| | - Patrick Rossignol
- INSERM, Centre d'Investigations Cliniques Plurithématique 1433, UMR 1116, Université de Lorraine, CHRU de Nancy, F-CRIN INI-CRCT Cardiovascular and Renal Clinical Trialists, and Association Lorraine de Traitement de l'Insuffisance Rénale, Nancy, France
| | - Luis Ruilope
- Hypertension Unit & Institute of Research i?+?12, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Patricia Van der Niepen
- Department of Nephrology and Hypertension, Universitair Ziekenhuis Brussel - VUB, Brussels, Belgium
| | - Raymond Vanholder
- Nephrology Section, Department of Internal Medicine, Ghent University Hospital, Gent, Belgium
| | - Marianne C Verhaar
- Department of Nephrology and Hypertension, University Medical Center Utrecht, The Netherlands
| | - Andrzej Wiecek
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia in Katowice, Katowice, Poland
| | - Gregoire Wuerzner
- Service of Nephrology and Hypertension, Lausanne University Hospital, Lausanne, Switzerland
| | | | - Carmine Zoccali
- CNR-IFC, Clinical Epidemiology and Pathophysiology of Hypertension and Renal Diseases Unit, Ospedali Riuniti, Reggio Calabria, Italy
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14
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Hocher B, Adamski J. Metabolomics for clinical use and research in chronic kidney disease. Nat Rev Nephrol 2017; 13:269-284. [PMID: 28262773 DOI: 10.1038/nrneph.2017.30] [Citation(s) in RCA: 232] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Chronic kidney disease (CKD) has a high prevalence in the general population and is associated with high mortality; a need therefore exists for better biomarkers for diagnosis, monitoring of disease progression and therapy stratification. Moreover, very sensitive biomarkers are needed in drug development and clinical research to increase understanding of the efficacy and safety of potential and existing therapies. Metabolomics analyses can identify and quantify all metabolites present in a given sample, covering hundreds to thousands of metabolites. Sample preparation for metabolomics requires a very fast arrest of biochemical processes. Present key technologies for metabolomics are mass spectrometry and proton nuclear magnetic resonance spectroscopy, which require sophisticated biostatistic and bioinformatic data analyses. The use of metabolomics has been instrumental in identifying new biomarkers of CKD such as acylcarnitines, glycerolipids, dimethylarginines and metabolites of tryptophan, the citric acid cycle and the urea cycle. Biomarkers such as c-mannosyl tryptophan and pseudouridine have better performance in CKD stratification than does creatinine. Future challenges in metabolomics analyses are prospective studies and deconvolution of CKD biomarkers from those of other diseases such as metabolic syndrome, diabetes mellitus, inflammatory conditions, stress and cancer.
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Affiliation(s)
- Berthold Hocher
- Department of Basic Medicine, Medical College of Hunan University, 410006 Changsha, China
| | - Jerzy Adamski
- Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany
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15
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Sitar ME. Asymmetric Dimethylarginine and Its Relation As a Biomarker in Nephrologic Diseases. Biomark Insights 2016; 11:131-137. [PMID: 27980388 PMCID: PMC5144928 DOI: 10.4137/bmi.s38434] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 10/18/2016] [Accepted: 10/27/2016] [Indexed: 02/06/2023] Open
Abstract
It is encouraging to observe that a search for publications on "asymmetric dimethylarginine (ADMA)" in PubMed, as updated on June 2016, yielded >2500 items, 24 years after a splendid paper published by Vallance et al in which the authors proposed that ADMA accumulation could be a cardiovascular risk factor in chronic kidney diseases. ADMA is the endogenous inhibitor of nitric oxide synthase and is related to endothelial dysfunction, which plays an important role in vascular damage elicited by various cardiometabolic risk factors. Although current knowledge suggests that ADMA has critical central roles in renal diseases, there are still unexplained details. The present article aims to provide a review on ADMA and its relation as a biomarker in nephrologic diseases. We aimed to systematize articles in which ADMA levels were assessed in order to clarify its role in many diseases and establish its reference values in different populations.
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Affiliation(s)
- Mustafa E Sitar
- Faculty of Medicine, Department of Clinical Biochemistry, Maltepe University, Maltepe, Istanbul, Republic of Turkey
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16
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Morris SM. Arginine Metabolism Revisited. J Nutr 2016; 146:2579S-2586S. [PMID: 27934648 DOI: 10.3945/jn.115.226621] [Citation(s) in RCA: 245] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 01/22/2016] [Accepted: 02/05/2016] [Indexed: 01/20/2023] Open
Abstract
Mammalian arginine metabolism is complex due to the expression of multiple enzymes that utilize arginine as substrate and to interactions or competition between specific enzymes involved in arginine metabolism. Moreover, cells may contain multiple intracellular arginine pools that are not equally accessible to all arginine metabolic enzymes, thus presenting additional challenges to more fully understanding arginine metabolism. At the whole-body level, arginine metabolism ultimately results in the production of a biochemically diverse range of products, including nitric oxide, urea, creatine, polyamines, proline, glutamate, agmatine, and homoarginine. Included in this group of compounds are the methylated arginines (e.g., asymmetric dimethylarginine), which are released upon degradation of proteins containing methylated arginine residues. Changes in arginine concentration also can regulate cellular metabolism and function via a variety of arginine sensors. Although much is known about arginine metabolism, elucidation of the physiologic or pathophysiologic roles for all of the pathways and their metabolites remains an active area of investigation, as exemplified by current findings highlighted in this review.
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Affiliation(s)
- Sidney M Morris
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA
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17
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Hu H, Luo C, Zheng YG. Transient Kinetics Define a Complete Kinetic Model for Protein Arginine Methyltransferase 1. J Biol Chem 2016; 291:26722-26738. [PMID: 27834681 DOI: 10.1074/jbc.m116.757625] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 11/10/2016] [Indexed: 12/31/2022] Open
Abstract
Protein arginine methyltransferases (PRMTs) are the enzymes responsible for posttranslational methylation of protein arginine residues in eukaryotic cells, particularly within the histone tails. A detailed mechanistic model of PRMT-catalyzed methylation is currently lacking, but it is essential for understanding the functions of PRMTs in various cellular pathways and for efficient design of PRMT inhibitors as potential treatments for a range of human diseases. In this work, we used stopped-flow fluorescence in combination with global kinetic simulation to dissect the transient kinetics of PRMT1, the predominant type I arginine methyltransferase. Several important mechanistic insights were revealed. The cofactor and the peptide substrate bound to PRMT1 in a random manner and then followed a kinetically preferred pathway to generate the catalytic enzyme-cofactor-substrate ternary complex. Product release proceeded in an ordered fashion, with peptide dissociation followed by release of the byproduct S-adenosylhomocysteine. Importantly, the dissociation rate of the monomethylated intermediate from the ternary complex was much faster than the methyl transfer. Such a result provided direct evidence for distributive arginine dimethylation, which means the monomethylated substrate has to be released to solution and rebind with PRMT1 before it undergoes further methylation. In addition, cofactor binding involved a conformational transition, likely an open-to-closed conversion of the active site pocket. Further, the histone H4 peptide bound to the two active sites of the PRMT1 homodimer with differential affinities, suggesting a negative cooperativity mechanism of substrate binding. These findings provide a new mechanistic understanding of how PRMTs interact with their substrates and transfer methyl groups.
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Affiliation(s)
- Hao Hu
- From the Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia 30602 and
| | - Cheng Luo
- the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Y George Zheng
- From the Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia 30602 and
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18
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Hu H, Qian K, Ho MC, Zheng YG. Small Molecule Inhibitors of Protein Arginine Methyltransferases. Expert Opin Investig Drugs 2016; 25:335-58. [PMID: 26789238 DOI: 10.1517/13543784.2016.1144747] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
INTRODUCTION Arginine methylation is an abundant posttranslational modification occurring in mammalian cells and catalyzed by protein arginine methyltransferases (PRMTs). Misregulation and aberrant expression of PRMTs are associated with various disease states, notably cancer. PRMTs are prominent therapeutic targets in drug discovery. AREAS COVERED The authors provide an updated review of the research on the development of chemical modulators for PRMTs. Great efforts are seen in screening and designing potent and selective PRMT inhibitors, and a number of micromolar and submicromolar inhibitors have been obtained for key PRMT enzymes such as PRMT1, CARM1, and PRMT5. The authors provide a focus on their chemical structures, mechanism of action, and pharmacological activities. Pros and cons of each type of inhibitors are also discussed. EXPERT OPINION Several key challenging issues exist in PRMT inhibitor discovery. Structural mechanisms of many PRMT inhibitors remain unclear. There lacks consistency in potency data due to divergence of assay methods and conditions. Physiologically relevant cellular assays are warranted. Substantial engagements are needed to investigate pharmacodynamics and pharmacokinetics of the new PRMT inhibitors in pertinent disease models. Discovery and evaluation of potent, isoform-selective, cell-permeable and in vivo-active PRMT modulators will continue to be an active arena of research in years ahead.
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Affiliation(s)
- Hao Hu
- a Department of Pharmaceutical and Biomedical Sciences , The University of Georgia , Athens , GA , USA
| | - Kun Qian
- a Department of Pharmaceutical and Biomedical Sciences , The University of Georgia , Athens , GA , USA
| | - Meng-Chiao Ho
- b Institute of Biological Chemistry , Academia Sinica , Nankang , Taipei , Taiwan
| | - Y George Zheng
- a Department of Pharmaceutical and Biomedical Sciences , The University of Georgia , Athens , GA , USA
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19
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Lee KH, Tsai WJ, Chen YW, Yang WC, Lee CY, Ou SM, Chen YT, Chien CC, Lee PC, Chung MY, Lin CC. Genotype polymorphisms of genes regulating nitric oxide synthesis determine long-term arteriovenous fistula patency in male hemodialysis patients. Ren Fail 2015; 38:228-37. [PMID: 26643995 DOI: 10.3109/0886022x.2015.1120096] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVES Nitric oxide (NO) is a pivotal vasoactive substance modulating arteriovenous fistula (AVF) patency for hemodialysis (HD). Since genetic background could be the predicting factor of AVF malfunction, we aimed to investigate whether the NO-related genotype polymorphisms determine AVF survival rates. METHODS This is a retrospective, observational, multi-center study involving eight HD units in Taiwan, enrolled 580 patients initiating maintenance HD via AVFs. Genotype polymorphisms of NO-biosynthesis regulating enzymes (DDAH-1, DDAH-2, eNOS and PRMT1) were compared between HD patients with (n = 161) and without (n = 419) history of AVF malfunction. Subgroup analyses by gender were performed to evaluate the genetic effect in difference sexes. RESULTS In overall population, statistically significant associations were not found between AVF malfunction and the genetic polymorphisms. In the male subgroup (n = 313), a single nucleotide polymorphism (SNP) of PRMT1, rs10415880 (IVS9-193 A/G), showed a significant association with AVF malfunction. Male patients with AA/AG genotype had inferior AVF outcomes compared to GG genotype, regarding primary patency (70.6% vs. 40.9%, p = 0.001), assisted primary patency (81.0% vs. 58.4%, p < 0.001) and secondary patency (83.7% vs. 63.3%, p < 0.001) at a 5-year observation period. From multivariate Cox regression model, the AA/AG genotypes of PRMT1 were an independent risk factor for AVF malfunction in men (HR: 4.539, 95% CI 2.015-10.223; p < 0.001). However, such associations were not found in women. CONCLUSIONS rs10415880, the SNP of PRMT1 could be a novel genetic marker associated with AVF malfunction risk in male HD patients. Those with AA and AG genotypes of rs10415880 may predict a poorer long-term patency of AVF.
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Affiliation(s)
- Kuo-Hua Lee
- a School of Medicine, National Yang-Ming University , Taipei , Taiwan ;,b Department of Medicine , Taipei Veterans General Hospital , Taipei , Taiwan ;,c Division of Nephrology , Taipei Veterans General Hospital , Taipei , Taiwan
| | - Wen-Jung Tsai
- d Institute of Genome Sciences, National Yang-Ming University , Taipei , Taiwan ;,e Department of Medical Research , Taipei Veterans General Hospital , Taipei , Taiwan
| | - Yu-Wei Chen
- a School of Medicine, National Yang-Ming University , Taipei , Taiwan ;,b Department of Medicine , Taipei Veterans General Hospital , Taipei , Taiwan ;,c Division of Nephrology , Taipei Veterans General Hospital , Taipei , Taiwan
| | - Wu-Chang Yang
- a School of Medicine, National Yang-Ming University , Taipei , Taiwan ;,b Department of Medicine , Taipei Veterans General Hospital , Taipei , Taiwan ;,c Division of Nephrology , Taipei Veterans General Hospital , Taipei , Taiwan
| | - Chiu-Yang Lee
- a School of Medicine, National Yang-Ming University , Taipei , Taiwan ;,f Division of Cardiovascular Surgery, Department of Surgery , Taipei Veterans General Hospital , Taipei , Taiwan
| | - Shuo-Ming Ou
- a School of Medicine, National Yang-Ming University , Taipei , Taiwan ;,b Department of Medicine , Taipei Veterans General Hospital , Taipei , Taiwan ;,c Division of Nephrology , Taipei Veterans General Hospital , Taipei , Taiwan
| | - Yung-Tai Chen
- a School of Medicine, National Yang-Ming University , Taipei , Taiwan ;,g Division of Nephrology, Department of Medicine , Taipei City Hospital-Heping Branch , Taipei , Taiwan
| | - Chih-Chiang Chien
- h Department of Nephrology , Chi-Mei Medical Center , Tainan , Taiwan ;,i Department of Medical Research , Chi-Mei Medical Center , Tainan , Taiwan ;,j Department of Food Nutrition , Chung Hwa University of Medical Technology , Tainan , Taiwan
| | - Pui-Ching Lee
- b Department of Medicine , Taipei Veterans General Hospital , Taipei , Taiwan
| | - Ming-Yi Chung
- d Institute of Genome Sciences, National Yang-Ming University , Taipei , Taiwan ;,e Department of Medical Research , Taipei Veterans General Hospital , Taipei , Taiwan
| | - Chih-Ching Lin
- a School of Medicine, National Yang-Ming University , Taipei , Taiwan ;,b Department of Medicine , Taipei Veterans General Hospital , Taipei , Taiwan ;,c Division of Nephrology , Taipei Veterans General Hospital , Taipei , Taiwan
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Pertynska-Marczewska M, Diamanti-Kandarakis E, Zhang J, Merhi Z. Advanced glycation end products: A link between metabolic and endothelial dysfunction in polycystic ovary syndrome? Metabolism 2015; 64:1564-73. [PMID: 26386695 DOI: 10.1016/j.metabol.2015.08.010] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Revised: 08/16/2015] [Accepted: 08/17/2015] [Indexed: 01/07/2023]
Abstract
Polycystic ovary syndrome (PCOS), a heterogeneous syndrome of reproductive and metabolic alterations, is associated with increased long-term risk of cardiovascular complications. This phenomenon has been linked to an increase in oxidative stress and inflammatory markers. Advanced glycation end products (AGEs) are pro-inflammatory molecules that trigger a state of intracellular oxidative stress and inflammation after binding to their cell membrane receptors RAGE. The activation of the AGE-RAGE axis has been well known to play a role in atherosclerosis in both men and women. Women with PCOS have systemic chronic inflammatory condition even at the ovarian level as represented by elevated levels of serum/ovarian AGEs and increased expression of the pro-inflammatory RAGE in ovarian tissue. Data also showed the presence of sRAGE in the follicular fluid and its potential protective role against the harmful effect of AGEs on ovarian function. Thus, whether AGE-RAGE axis constitutes a link between metabolic and endothelial dysfunction in women with PCOS is addressed in this review. Additionally, we discuss the role of hormonal changes observed in PCOS and how they are linked with the AGE-RAGE axis in order to better understand the nature of this complex syndrome whose consequences extend well beyond reproduction.
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Affiliation(s)
| | - Evanthia Diamanti-Kandarakis
- Department of Medicine, Endocrine Unit, Medical School University of Athens, Mikras Asias 75, Goudi 115002D27, Athens, Greece.
| | - John Zhang
- Reproductive Medicine, New Hope Fertility Center, 4 Columbus Circle, New York, NY, USA.
| | - Zaher Merhi
- Department of Obstetrics and Gynecology, Division of Reproductive Biology, NYU School of Medicine, 180 Varick Street, sixth floor, New York, NY, USA.
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21
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Streja E, Kovesdy CP, Streja DA, Moradi H, Kalantar-Zadeh K, Kashyap ML. Niacin and Progression of CKD. Am J Kidney Dis 2015; 65:785-98. [DOI: 10.1053/j.ajkd.2014.11.033] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 11/19/2014] [Indexed: 12/17/2022]
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Lopez-Giacoman S, Madero M. Biomarkers in chronic kidney disease, from kidney function to kidney damage. World J Nephrol 2015; 4:57-73. [PMID: 25664247 PMCID: PMC4317628 DOI: 10.5527/wjn.v4.i1.57] [Citation(s) in RCA: 218] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 10/21/2014] [Accepted: 11/10/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic kidney disease (CKD) typically evolves over many years, with a long latent period when the disease is clinically silent and therefore diagnosis, evaluation and treatment is based mainly on biomarkers that assess kidney function. Glomerular filtration rate (GFR) remains the ideal marker of kidney function. Unfortunately measuring GFR is time consuming and therefore GFR is usually estimated from equations that take into account endogenous filtration markers like serum creatinine (SCr) and cystatin C (CysC). Other biomarkers such as albuminuria may precede kidney function decline and have demonstrated to have strong associations with disease progression and outcomes. New potential biomarkers have arisen with the promise of detecting kidney damage prior to the currently used markers. The aim of this review is to discuss the utility of the GFR estimating equations and biomarkers in CKD and the different clinical settings where these should be applied. The CKD-Epidemiology Collaboration equation performs better than the modification of diet in renal disease equation, especially at GFR above 60 mL/min per 1.73 m2. Equations combining CysC and SCr perform better than the equations using either CysC or SCr alone and are recommended in situations where CKD needs to be confirmed. Combining creatinine, CysC and urine albumin to creatinine ratio improves risk stratification for kidney disease progression and mortality. Kidney injury molecule and neutrophil gelatinase-associated lipocalin are considered reasonable biomarkers in urine and plasma to determine severity and prognosis of CKD.
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Asymmetric Dimethylarginine (ADMA) in cardiovascular and renal disease. Clin Chim Acta 2015; 440:36-9. [DOI: 10.1016/j.cca.2014.11.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 10/22/2014] [Accepted: 11/02/2014] [Indexed: 11/16/2022]
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Hu H, Owens EA, Su H, Yan L, Levitz A, Zhao X, Henary M, Zheng YG. Exploration of cyanine compounds as selective inhibitors of protein arginine methyltransferases: synthesis and biological evaluation. J Med Chem 2015; 58:1228-43. [PMID: 25559100 PMCID: PMC4610307 DOI: 10.1021/jm501452j] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
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Protein arginine methyltransferase
1 (PRMT1) is involved in many biological activities, such as gene
transcription, signal transduction, and RNA processing. Overexpression
of PRMT1 is related to cardiovascular diseases, kidney diseases, and
cancers; therefore, selective PRMT1 inhibitors serve as chemical probes
to investigate the biological function of PRMT1 and drug candidates
for disease treatment. Our previous work found trimethine cyanine
compounds that effectively inhibit PRMT1 activity. In our present
study, we systematically investigated the structure–activity
relationship of cyanine structures. A pentamethine compound, E-84
(compound 50), showed inhibition on PRMT1 at the micromolar
level and 6- to 25-fold selectivity over CARM1, PRMT5, and PRMT8.
The cellular activity suggests that compound 50 permeated
the cellular membrane, inhibited cellular PRMT1 activity, and blocked
leukemia cell proliferation. Additionally, our molecular docking study
suggested compound 50 might act by occupying the cofactor
binding site, which provided a roadmap to guide further optimization
of this lead compound.
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Affiliation(s)
- Hao Hu
- Department of Pharmaceutical and Biomedical Sciences, The University of Georgia , Athens, Georgia 30602, United States
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Raptis V, Georgianos PI, Sarafidis PA, Sioulis A, Makedou K, Makedou A, Grekas DM, Kapoulas S. Elevated asymmetric dimethylarginine is associated with oxidant stress aggravation in patients with early stage autosomal dominant polycystic kidney disease. Kidney Blood Press Res 2014; 38:72-82. [PMID: 24577239 DOI: 10.1159/000355756] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/10/2014] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS In experimental models of polycystic kidney disease impaired bioavailability of nitric oxide (NO) and elevated mRNA expression of oxidative stress markers at the kidney level was noted. However, clinical studies investigating the potential role of endothelial dysfunction and oxidative stress in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) are limited. We evaluated asymmetric dimethylarginine (ADMA) as marker of NO synthase inhibitor as well as 15-F2t-Isoprostane and oxidized-low density lipoprotein (oxidized-LDL) as measures of oxidative stress in patients with early stages ADPKD. METHODS We recruited 26 ADPKD patients (Group A) with modestly impaired renal function (eGFR 45-70 ml/min/1.73 m(2)), 26 age- and sex-matched ADPKD patients (Group B) with relatively preserved renal function (eGFR)>70 ml/min/1.73 m(2)), and 26 age- and sex-matched controls (Group C). Determination of circulating levels of ADMA, 15-F2t-Isoprostane, oxidized-LDL and routine biochemistry was performed. RESULTS Group A and B had significantly higher ADMA levels as compared to controls (1.68 ± 0.7 vs 0.51 ± 0.2 μmol/l, P<0.001 and 1.26 ± 0.7 vs 0.51 ± 0.2 μmol/l, P<0.001, respectively). 15-F2t-IsoP and oxidized-LDL levels were also significantly higher in Group B relative to controls (788.8 ± 185.0 vs 383.1 ± 86.0 pgr/ml, P<0.001 and 11.4 ± 6.6 vs 6.4 ± 2.6 EU/ml, P<0.05 respectively) and were further elevated in Group A. In correlation analysis, ADMA levels exhibited strong associations with levels of 15-F2t-Isoprostane (r=0.811, P<0.001) and oxidized-LDL (r=0.788, P<0.001), whereas an inverse correlation was evident between ADMA and eGFR (r=-0.460, P<0.001). CONCLUSION This study shows elevation in circulating levels of ADMA along with aggravation of oxidative stress from the early stages of ADPKD. © 2014 S. Karger AG, Basel.
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Affiliation(s)
- Vassilios Raptis
- Section of Nephrology and Hypertension, 1st Department of Medicine, AHEPA University Hospital, Thessaloniki, Greece
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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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