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Myette RL, Lamarche C, Odutayo A, Verdin N, Canney M. Cardiovascular Risk in Patients With Glomerular Disease: A Narrative Review of the Epidemiology, Mechanisms, Management, and Patient Priorities. Can J Kidney Health Dis 2024; 11:20543581241232472. [PMID: 38404647 PMCID: PMC10894549 DOI: 10.1177/20543581241232472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 01/09/2024] [Indexed: 02/27/2024] Open
Abstract
Purpose of review Cardiovascular (CV) disease is a major cause of morbidity and mortality for patients with glomerular disease. Despite the fact that mechanisms underpinning CV disease risk in this population are likely distinct from other forms of kidney disease, treatment and preventive strategies tend to be extrapolated from studies of patients with undifferentiated chronic kidney disease (CKD). There is an unmet need to delineate the pathophysiology of CV disease in patients with glomerular disease, establish unique risk factors, and identify novel therapeutic targets for disease prevention. The aims of this narrative review are to summarize the existing knowledge regarding the epidemiology, molecular mechanisms, and management of CV disease in patients with common glomerular disease, highlight the patient perspective, and propose specific areas for future study. Sources of information The literature for this narrative review was accessed using common research search engines, including PubMed, PubMed Central, Medline, and Google Scholar. Information for the patient perspective section was collected through iterative discussions with a patient partner. Methods We reviewed the epidemiology, molecular mechanisms of disease, management approaches, and the patient perspective in relation to CV disease in patients with glomerulopathies. Throughout, we have highlighted the current knowledge and have discussed future research approaches, both clinical and translational, while integrating the patient perspective. Key findings Patients with glomerular disease have significant CV disease risk driven by multifactorial, molecular mechanisms originating from their glomerular disease but complicated by existing comorbidities, kidney disease, and medication side effects. The current approach to risk stratification and treatment relies heavily on existing data from CKD patients, but this may not always be appropriate given the unique pathophysiology and mechanisms associated with CV disease risk in patients with glomerular disease. We highlight the need for ongoing glomerular disease-focused studies aimed to better delineate CV disease risk, while integrating the patient perspective. Limitations This is a narrative review and does not represent a comprehensive and systematic review of the literature.
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Affiliation(s)
- Robert L. Myette
- Division of Nephrology, Children’s Hospital of Eastern Ontario, Ottawa, Canada
- The Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Caroline Lamarche
- Hôpital Maisonneuve-Rosemont Research Center, Department of Medicine, Division of Nephrology, Université de Montréal, ON, Canada
| | - Ayodele Odutayo
- Division of Nephrology, University Health Network, Toronto, ON, Canada
| | | | - Mark Canney
- The Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa, ON, Canada
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Ameer OZ. Hypertension in chronic kidney disease: What lies behind the scene. Front Pharmacol 2022; 13:949260. [PMID: 36304157 PMCID: PMC9592701 DOI: 10.3389/fphar.2022.949260] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 09/26/2022] [Indexed: 12/04/2022] Open
Abstract
Hypertension is a frequent condition encountered during kidney disease development and a leading cause in its progression. Hallmark factors contributing to hypertension constitute a complexity of events that progress chronic kidney disease (CKD) into end-stage renal disease (ESRD). Multiple crosstalk mechanisms are involved in sustaining the inevitable high blood pressure (BP) state in CKD, and these play an important role in the pathogenesis of increased cardiovascular (CV) events associated with CKD. The present review discusses relevant contributory mechanisms underpinning the promotion of hypertension and their consequent eventuation to renal damage and CV disease. In particular, salt and volume expansion, sympathetic nervous system (SNS) hyperactivity, upregulated renin–angiotensin–aldosterone system (RAAS), oxidative stress, vascular remodeling, endothelial dysfunction, and a range of mediators and signaling molecules which are thought to play a role in this concert of events are emphasized. As the control of high BP via therapeutic interventions can represent the key strategy to not only reduce BP but also the CV burden in kidney disease, evidence for major strategic pathways that can alleviate the progression of hypertensive kidney disease are highlighted. This review provides a particular focus on the impact of RAAS antagonists, renal nerve denervation, baroreflex stimulation, and other modalities affecting BP in the context of CKD, to provide interesting perspectives on the management of hypertensive nephropathy and associated CV comorbidities.
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Affiliation(s)
- Omar Z. Ameer
- Department of Pharmaceutical Sciences, College of Pharmacy, Alfaisal University, Riyadh, Saudi Arabia
- Department of Biomedical Sciences, Faculty of Medicine, Macquarie University, Sydney, NSW, Australia
- *Correspondence: Omar Z. Ameer,
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Zanoli L, Mikhailidis DP. Narrative Review of Carotid disease and the kidney. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1210. [PMID: 34430651 PMCID: PMC8350722 DOI: 10.21037/atm-20-5001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 09/09/2020] [Indexed: 11/28/2022]
Abstract
Patients with chronic kidney disease (CKD) have an increased cardiovascular (CV) risk that is only in part explained by established risk factors. Carotid arteriosclerosis and atherosclerosis are increased in CKD, play a role in the causation of CV disease in these patients and can affect the progression of renal disease. The arterial stiffening process is evident even in CKD patients with a very mild reduction of glomerular filtration rate (GFR) whereas arterial thickening is evident in more advanced stages. Possible mechanisms include functional and structural alterations of the arterial wall. Arterial stiffness can mediate the effect of CKD on target organs (i.e., brain, kidney and heart). In this review we discuss the arterial phenotype of patients with CKD. This is characterized by increased common carotid artery stiffness and outward remodeling (enlargement and thickening of the arterial wall) and a normal/reduced stiffness paired with an inward remodeling (narrowing of the arterial wall) of muscular arteries. We also discuss the consequences of carotid dysfunction, including the involvement of large elastic arteries stiffness on ventricular-vascular coupling, the mechanisms linking carotid stiffening and increased cardio- and cerebrovascular risk in CKD patients, and the therapeutic options to improve carotid function.
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Affiliation(s)
- Luca Zanoli
- Nephrology, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital campus, University College London, London, UK
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Abstract
BACKGROUND In chronic kidney disease, the enhanced aortic stiffness increases risk of cardiovascular events. Kidney transplantation (KTx) may improve aortic stiffness; however, it is unclear whether the improvement of aortic stiffness is merely the outcome of the reduction of blood pressure (BP) post-KTx. Furthermore, the long-term trajectory of aortic stiffness remains uncertain, as activation of the immune system may have a negative long-term impact on arterial wall property. METHOD Using aortic stiffness β0 as a BP-independent stiffness parameter, and a statistical adjustment for BP, we aimed to examine the early vs. late changes in aortic stiffness, and to define the characteristics of patients with favourable and unfavourable long-term trajectories of aortic stiffness. In this longitudinal study, aortic stiffness was assessed before, 3, 6 and 24 months after KTx in 79 individuals. Aortic stiffness was determined by carotid-femoral pulse wave velocity (cf-PWV), and aortic stiffness index β0 was obtained by applying the stiffness parameter β0 theory to cf-PWV based on Bramwell-Hill's equation using a reference pressure. RESULTS There was an early reduction of β0 3 months after KTx (29.0 ± 2.0 to 25.8 ± 1.2, P = 0.033) followed by a gradual increase at 6 (28.0 ± 1.4, P = 0.005 vs. 3 months) and 24 months (28.3 ± 1.3, P = 0.003 vs. 3 months). A late increase in β0 was associated with higher levels of the interleukin-6 (P = 0.029) even after adjustment for potential cofounders. Using statistical adjustments for BP showed similar results. CONCLUSION Reduction of aortic stiffness index β0 3 months after KTx suggests that KTx leads to an early de-stiffening of the intrinsic mechanical properties of aorta. However, this improvement is followed by a later stiffening, which is associated with increased interleukin-6, suggesting that activation of the immune system may be involved in arterial wall remodelling in kidney recipients.
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Figueiredo AE, da Costa BEP, Conti A, Poitevin AA, Filho BJA, Torres E, d'Avila DO, Poli de Figueiredo CE. Peritoneal Transport Function and Endothelium-Dependent Vasodilation. ARCH ESP UROL 2020. [DOI: 10.1177/089686080702700219] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
| | - Bartira E. Pinheiro da Costa
- Programa de Pós-Graduação em Medicina e Ciências da Saúde (Nefrologia) Pontifícia Universidade Católica do Rio Grande do Sul/IPB/HSL/FAMED/FAENFI Porto Alegre, Brazil
| | - Adriana Conti
- Programa de Pós-Graduação em Medicina e Ciências da Saúde (Nefrologia) Pontifícia Universidade Católica do Rio Grande do Sul/IPB/HSL/FAMED/FAENFI Porto Alegre, Brazil
| | - André A. Poitevin
- Programa de Pós-Graduação em Medicina e Ciências da Saúde (Nefrologia) Pontifícia Universidade Católica do Rio Grande do Sul/IPB/HSL/FAMED/FAENFI Porto Alegre, Brazil
| | - Breno José Acauan Filho
- Programa de Pós-Graduação em Medicina e Ciências da Saúde (Nefrologia) Pontifícia Universidade Católica do Rio Grande do Sul/IPB/HSL/FAMED/FAENFI Porto Alegre, Brazil
| | - Elton Torres
- Programa de Pós-Graduação em Medicina e Ciências da Saúde (Nefrologia) Pontifícia Universidade Católica do Rio Grande do Sul/IPB/HSL/FAMED/FAENFI Porto Alegre, Brazil
| | - Domingos O. d'Avila
- Programa de Pós-Graduação em Medicina e Ciências da Saúde (Nefrologia) Pontifícia Universidade Católica do Rio Grande do Sul/IPB/HSL/FAMED/FAENFI Porto Alegre, Brazil
| | - Carlos E. Poli de Figueiredo
- Programa de Pós-Graduação em Medicina e Ciências da Saúde (Nefrologia) Pontifícia Universidade Católica do Rio Grande do Sul/IPB/HSL/FAMED/FAENFI Porto Alegre, Brazil
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Iqbal A, Baig A. Management of Dialysis Access. OFFICE-BASED ENDOVASCULAR CENTERS 2020:253-263. [DOI: 10.1016/b978-0-323-67969-5.00032-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2025]
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Chang HM, Chou YC, Jou IM, Yang JM, Ma CH, Wu PT. Clinical outcomes in distal radial fractures with ipsilateral arteriovenous fistulas. J Orthop Surg Res 2019; 14:143. [PMID: 31118080 PMCID: PMC6532144 DOI: 10.1186/s13018-019-1171-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Accepted: 04/26/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND We evaluated the effects on arteriovenous fistula (AVF) function and clinical outcomes in patients given cast fixation, external skeletal fixation [ESF], or volar locking plate fixation [VLPF] for an ipsilateral distal radial fracture (DRF). METHODS Thirteen patients were assigned to the surgery group or the cast group; follow-up was ≥12 months. One-year clinical outcomes and serial AVF function and radiographic outcomes were recorded and analyzed. RESULTS All fractures were union and all AVFs were preserved with continuous hemodialysis. The surgery group had better immediately (radial inclination and articular step-off) and 1-year post-index procedure radiographic findings (radial height, radial inclination, volar tilting, ulnar variance, and articular step-off) and better 1-year functional outcomes (Mayo and QuickDASH score) than did the cast group. The VLPF subgroup had better QuickDASH scores and radiographic outcomes (radial inclination and ulnar variance) than did the ESF subgroup. CONCLUSIONS One year after the index procedure, none of the treatment affected shunt function in DRFs ipsilateral to AVFs. ESF and VLPF yielded better functional and radiographic outcomes than did cast fixation in patients with ipsilateral DRFs and AVFs. LEVEL OF EVIDENCE III.
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Affiliation(s)
- Hao-Ming Chang
- Department of Orthopedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 701 Taiwan
- Medical Device R & D Core Laboratory, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Yi-Chuan Chou
- Department of Orthopedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 701 Taiwan
- Medical Device R & D Core Laboratory, National Cheng Kung University Hospital, Tainan, Taiwan
- Department of Orthopedics, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan
| | - I-Ming Jou
- Department of Orthopedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 701 Taiwan
- Department of Orthopedics, E-Da Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Jui-Ming Yang
- Department of Orthopedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 701 Taiwan
- Department of Orthopedic, Tainan Sin Lau Hospital, Tainan, Taiwan
| | - Ching-Hou Ma
- Department of Orthopedics, E-Da Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Po-Ting Wu
- Department of Orthopedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 701 Taiwan
- Medical Device R & D Core Laboratory, National Cheng Kung University Hospital, Tainan, Taiwan
- Department of Orthopedics, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan
- Department of Orthopedics, National Cheng Kung University Hospital Dou-Liou Branch, College of Medicine, National Cheng Kung University, Dou-Liou, Taiwan
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Vanholder R, Argilés A, Baurmeister U, Brunet P, Clark W, Cohen G, Dedeyn P, Deppisch R, Descamps-Latscha B, Henle T, Jörres A, Massy Z, Rodriguez M, Stegmayr B, Stenvinkel P, Wratten M. Uremic Toxicity: Present State of the Art. Int J Artif Organs 2018. [DOI: 10.1177/039139880102401004] [Citation(s) in RCA: 192] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The uremic syndrome is a complex mixture of organ dysfunctions, which is attributed to the retention of a myriad of compounds that under normal condition are excreted by the healthy kidneys (uremic toxins). In the area of identification and characterization of uremic toxins and in the knowledge of their pathophysiologic importance, major steps forward have been made during recent years. The present article is a review of several of these steps, especially in the area of information about the compounds that could play a role in the development of cardiovascular complications. It is written by those members of the Uremic Toxins Group, which has been created by the European Society for Artificial Organs (ESAO). Each of the 16 authors has written a state of the art in his/her major area of interest.
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Affiliation(s)
- R. Vanholder
- The Nephrology Section, Department of Internal Medicine, University Hospital, Gent - Belgium
| | - A. Argilés
- Institute of Human Genetics, IGH-CNRS UPR 1142, Montpellier - France
| | | | - P. Brunet
- Nephrology, Internal Medicine, Ste Marguerite Hospital, Marseille - France
| | - W. Clark
- Baxter Healthcare Corporation, Lessines - Belgium
| | - G. Cohen
- Division of Nephrology, Department of Medicine, University of Vienna, Vienna - Austria
| | - P.P. Dedeyn
- Department of Neurology, Middelheim Hospital, Laboratory of Neurochemistry and Behaviour, University of Antwerp - Belgium
| | - R. Deppisch
- Gambro Corporate Research, Hechingen - Germany
| | | | - T. Henle
- Institute of Food Chemistry, Technical University, Dresden - Germany
| | - A. Jörres
- Nephrology and Medical Intensive Care, UK Charité, Campus Virchow-Klinikum, Medical Faculty of Humboldt-University, Berlin - Germany
| | - Z.A. Massy
- Division of Nephrology, CH-Beauvais, and INSERM Unit 507, Necker Hospital, Paris - France
| | - M. Rodriguez
- University Hospital Reina Sofia, Research Institute, Cordoba - Spain
| | - B. Stegmayr
- Norrlands University Hospital, Medical Clinic, Umea - Sweden
| | - P. Stenvinkel
- Nephrology Department, University Hospital, Huddinge - Sweden
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9
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Saum K, Campos B, Celdran-Bonafonte D, Nayak L, Sangwung P, Thakar C, Roy-Chaudhury P, Owens AP. Uremic Advanced Glycation End Products and Protein-Bound Solutes Induce Endothelial Dysfunction Through Suppression of Krüppel-Like Factor 2. J Am Heart Assoc 2018; 7:e007566. [PMID: 29301761 PMCID: PMC5778969 DOI: 10.1161/jaha.117.007566] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 11/22/2017] [Indexed: 01/01/2023]
Abstract
BACKGROUND Cardiovascular disease is the leading cause of morbidity and mortality in patients with end-stage renal disease. The accumulation of uremic solutes in this patient population is associated with endothelial dysfunction and accelerated cardiovascular disease. In this study, we examined the impact of the uremic milieu on the endothelial transcription factor, Krüppel-like factor 2 (KLF2), a key regulator of endothelial function and activation. METHODS AND RESULTS Using serum from uremic pigs with chronic renal insufficiency, our results show that KLF2 expression is suppressed by the uremic milieu and individual uremic solutes in vitro. Specifically, KLF2 expression is significantly decreased in human umbilical vein endothelial cells after treatment with uremic porcine serum or carboxymethyllysine-modified albumin, an advanced glycation end product (AGE) known to induce endothelial dysfunction. AGE-mediated suppression of KLF2 is dependent on activation of the receptor for AGE, as measured by small interfering RNA knockdown of the receptor for AGE. Furthermore, KLF2 suppression promotes endothelial dysfunction, because adenoviral overexpression of KLF2 inhibits reactive oxygen species production and leukocyte adhesion in human umbilical vein endothelial cells. In addition, the application of hemodynamic shear stress, prolonged serum dialysis, or treatment with the receptor for AGE antagonist azeliragon (TTP488) is sufficient to prevent KLF2 suppression in vitro. To decipher the mechanism by which uremic AGEs suppress KLF2 expression, we assessed the role of the receptor for AGE in activation of nuclear factor-κB signaling, a hallmark of endothelial cell activation. Using a constitutively active form of IκBα, we show that translocation of p65 to the nucleus is necessary for KLF2 suppression after treatment with uremic AGEs. CONCLUSIONS These data identify KLF2 suppression as a consequence of the uremic milieu, which may exacerbate endothelial dysfunction and resultant cardiovascular disease.
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Affiliation(s)
- Keith Saum
- University of Cincinnati Medical Scientist Training Program, The University of Cincinnati College of Medicine, Cincinnati, OH
- Division of Nephrology and Hypertension, The University of Cincinnati College of Medicine, Cincinnati, OH
| | - Begoña Campos
- Division of Nephrology and Hypertension, The University of Cincinnati College of Medicine, Cincinnati, OH
| | - Diego Celdran-Bonafonte
- Division of Nephrology, University of Arizona College of Medicine and Banner University Medical Centers-Tucson and South and Southern Arizona Veterans Affairs Healthcare System, Tucson, AZ
| | - Lalitha Nayak
- Division of Hematology and Oncology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH
| | - Panjamaporn Sangwung
- Department of Physiology and Biophysics, Department of Medicine, Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH
| | - Charuhas Thakar
- Division of Nephrology and Hypertension, The University of Cincinnati College of Medicine, Cincinnati, OH
| | - Prabir Roy-Chaudhury
- Division of Nephrology and Hypertension, The University of Cincinnati College of Medicine, Cincinnati, OH
- Division of Nephrology, University of Arizona College of Medicine and Banner University Medical Centers-Tucson and South and Southern Arizona Veterans Affairs Healthcare System, Tucson, AZ
| | - A Phillip Owens
- Division of Cardiovascular Health and Disease, The University of Cincinnati College of Medicine, Cincinnati, OH
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Sidibé A, Fortier C, Desjardins MP, Zomahoun HTV, Boutin A, Mac-Way F, De Serres S, Agharazii M. Reduction of Arterial Stiffness After Kidney Transplantation: A Systematic Review and Meta-Analysis. J Am Heart Assoc 2017; 6:JAHA.117.007235. [PMID: 29269351 PMCID: PMC5779037 DOI: 10.1161/jaha.117.007235] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Background End‐stage kidney disease is associated with increased arterial stiffness. Although correction of uremia by kidney transplantation (KTx) could improve arterial stiffness, results from clinical studies are unclear partly due to small sample sizes. Method and Results We conducted a systematic review and meta‐analysis of before‐after design studies performed in adult KTx patients with available measures of arterial stiffness parameters (pulse wave velocity [PWV], central pulse pressure [PP], and augmentation index) before and at any time post‐KTx. Mean difference of post‐ and pre‐KTx values of different outcomes were estimated using a random effect model with 95% confidence interval. To deal with repetition of measurement within a study, only 1 period of measurement was considered per study by analysis. Twelve studies were included in meta‐analysis, where a significant decrease of overall PWV by 1.20 m/s (95% CI 0.67‐1.73, I2=72%), central PWV by 1.20 m/s (95% CI 0.16‐2.25, I2=83%), peripheral PWV by 1.17 m/s (95% CI 0.17‐2.17, I2=79%), and brachial‐ankle PWV by 1.21 m/s (95% CI 0.66‐1.75, I2=0%) was observed. Central PP (reported in 4 studies) decreased by 4.75 mm Hg (95% CI 0.78–10.28, I2=50%). Augmentation index (reported in 7 studies) decreased by 10.5% (95% CI 6.9‐14.1, I2=64%). A meta‐regression analysis showed that the timing of assessment post‐KTx was the major source of the residual variance. Conclusions This meta‐analysis suggests a reduction of the overall arterial stiffness in patients with end‐stage kidney disease after KTx.
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Affiliation(s)
- Aboubacar Sidibé
- CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, Canada.,Division of Nephrology, Faculty and Department of Medicine, Université Laval, Québec, Canada.,Department of Social and Preventive Medicine, Faculty of Medicine, Université Laval, Québec, Canada
| | - Catherine Fortier
- CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, Canada.,Division of Nephrology, Faculty and Department of Medicine, Université Laval, Québec, Canada
| | - Marie-Pier Desjardins
- CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, Canada.,Division of Nephrology, Faculty and Department of Medicine, Université Laval, Québec, Canada
| | - Hervé Tchala Vignon Zomahoun
- CHU de Québec Research Center, Université Laval Saint François d'Assise Hospital, Québec, Canada.,Quebec SPOR-SUPPORT Unit, Montreal, Québec, Canada
| | - Amélie Boutin
- Department of Social and Preventive Medicine, Faculty of Medicine, Université Laval, Québec, Canada
| | - Fabrice Mac-Way
- CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, Canada.,Division of Nephrology, Faculty and Department of Medicine, Université Laval, Québec, Canada
| | - Sacha De Serres
- CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, Canada.,Division of Nephrology, Faculty and Department of Medicine, Université Laval, Québec, Canada
| | - Mohsen Agharazii
- CHU de Québec Research Center, L'Hôtel-Dieu de Québec Hospital, Québec, Canada .,Division of Nephrology, Faculty and Department of Medicine, Université Laval, Québec, Canada
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Shang F, Wang SC, Hsu CY, Miao Y, Martin M, Yin Y, Wu CC, Wang YT, Wu G, Chien S, Huang HD, Tarng DC, Shiu YT, Cheung AK, Huang PH, Chen Z, Shyy JYJ. MicroRNA-92a Mediates Endothelial Dysfunction in CKD. J Am Soc Nephrol 2017; 28:3251-3261. [PMID: 28696247 PMCID: PMC5661278 DOI: 10.1681/asn.2016111215] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 05/29/2017] [Indexed: 01/03/2023] Open
Abstract
CKD is an independent risk factor for cardiovascular disease (CVD). The accumulation of uremic toxins in CKD induces oxidative stress and endothelial dysfunction. MicroRNA-92a (miR-92a) is induced by oxidative stress in endothelial cells (ECs) and involved in angiogenesis and atherosclerosis. We investigated a role for oxidative stress-responsive miR-92a in CKD. Our study of patients at three clinical sites showed increased serum miR-92a level with decreased kidney function. In cultured ECs, human CKD serum or uremic toxins (such as indoxyl sulfate), compared with non-CKD serum, induced the levels of miR-92a and suppressed the expression of miR-92a targets, including key endothelial-protective molecules. The antioxidant N-acetylcysteine inhibited these vasculopathic properties. In rats, adenine-induced CKD associated with increased levels of miR-92a in aortas, serum, and CD144+ endothelial microparticles. Furthermore, CD144+ microparticles from human uremic serum contained more miR-92a than those from control serum. Additional analysis showed a positive correlation between serum levels of miR-92a and indoxyl sulfate in a cohort of patients with ESRD undergoing hemodialysis. Collectively, our findings suggest that the uremic toxins accumulated in CKD can upregulate miR-92a in ECs, which impairs EC function and predisposes patients to CVD.
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Affiliation(s)
- Fenqing Shang
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, China
- Division of Cardiology, The First Hospital of Xi'an, Xi'an, China
| | - Shen-Chih Wang
- Department of Medicine, School of Medicine and
- Department of Biological Science and Technology, Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsin-Chu, Taiwan
- Department of Anesthesiology, Taipei Veterans General Hospital
| | - Chien-Yi Hsu
- Cardiovascular Research Center, and
- Division of Cardiology, Department of Medicine and
- Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Yifei Miao
- Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, California
| | | | - Yanjun Yin
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, China
| | - Chih-Cheng Wu
- Cardiovascular Center, National Taiwan University Hospital, Hsinchu Branch, Taipei, Taiwan
- Institute of Biomedical Engineering, National Tsing-Hua University, Hsinchu, Taiwan
| | - Yun-Ting Wang
- Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, California
| | - Gaihong Wu
- Department of Nephrology, Xi'an GaoXin Hospital, Xi'an, China
| | - Shu Chien
- Department of Medicine, School of Medicine and
- Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, California
| | - Hsien-Da Huang
- Department of Biological Science and Technology, Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsin-Chu, Taiwan
| | - Der-Cherng Tarng
- Institutes of Physiology and Clinical Medicine, Genome Research and Infection and Immunity Centers, National Yang-Ming University, Taipei, Taiwan
- Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yan-Ting Shiu
- Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah, Salt Lake City, Utah
| | - Alfred K Cheung
- Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah, Salt Lake City, Utah
- Medical Service, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah; and
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Po-Hsun Huang
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China;
- Division of Cardiology, Department of Medicine and
| | - Zhen Chen
- Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan;
| | - John Y-J Shyy
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China;
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, China
- Department of Medicine, School of Medicine and
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12
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Lowering dialysate sodium improves systemic oxidative stress in maintenance hemodialysis patients. Int Urol Nephrol 2016; 48:1699-704. [PMID: 27473155 DOI: 10.1007/s11255-016-1367-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2015] [Accepted: 07/04/2016] [Indexed: 12/29/2022]
Abstract
PURPOSE The purpose of the current prospective study was to evaluate the effects of low sodium dialysate on oxidative stress parameters, blood pressure (BP) and endothelial dysfunction in maintenance hemodialysis (HD) patients. METHODS After baseline measurements were taken, the dialysate sodium concentration was reduced from 140 to 137 mEq/L. Oxidative stress parameters and flow-mediated dilatation (FMD %) were measured before and after 6 months of HD with low sodium dialysate. Interdialytic weight gain (IDWG) and pre- and post-dialysis BP were monitored during the study. RESULTS A total of 52 patients were enrolled and 41 patients completed the study. There was a significant reduction in systolic blood pressure at the end of the study [130.00 (90.00-190.00) vs. 120.00 (90.00-150.00), p < 0.001]. Similarly, there were significant improvements in IDWG [2670.00 (1670.00-4300.00) vs. 1986.00 (1099.00-3998.00), p < 0.001] and FMD % [7.26 (4.55-8.56) vs. 9.56 (6.55-12.05), p < 0.001]. Serum MDA levels (p < 0.001) were significantly decreased; serum SOD (p < 0.001) and GPx (p < 0.001) activities were significantly increased after low sodium HD compared to standard sodium HD. CONCLUSION Our data seem to suggest a potential role of 137 mEq/L sodium dialysate for improving hemodynamic status, endothelial function and reducing oxidative stress than 140 mEq/L sodium dialysate in maintenance HD patients.
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13
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Dursun I, Yel S, Unsur E. Dynamics of circulating microparticles in chronic kidney disease and transplantation: Is it really reliable marker? World J Transplant 2015; 5:267-275. [PMID: 26722654 PMCID: PMC4689937 DOI: 10.5500/wjt.v5.i4.267] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2015] [Revised: 09/21/2015] [Accepted: 11/04/2015] [Indexed: 02/05/2023] Open
Abstract
The deterioration of endothelial structure plays a very important role in the development of vascular diseases. It is believed that endothelial dysfunction starts in the early stage of kidney disease and is a risk factor of an unfavorable cardiovascular prognosis. Because a direct assessment of biological states in endothelial cells is not applicable, the measurement of endothelial microparticles (EMPs) detached from endothelium during activation or apoptosis is thought to be a marker of early vascular disease and endothelial dysfunction in children with chronic kidney disease (CKD). Few studies have shown increased circulating EMPs and its relationship with cardiovascular risk factors in patients with CKD. MPs contain membrane proteins and cytosolic material derived from the cell from which they originate. EMPs having CD144, CD 146, CD31+/CD41-, CD51 and CD105 may be used to evaluate the vascular endothelial cell damage and determine asymptomatic patients who might be at higher risk of developing cardiovascular disease in CKD and renal transplant.
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14
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Olowu WA. Pre-treatment considerations in childhood hypertension due to chronic kidney disease. World J Nephrol 2015; 4:500-510. [PMID: 26558187 PMCID: PMC4635370 DOI: 10.5527/wjn.v4.i5.500] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 08/25/2015] [Accepted: 10/08/2015] [Indexed: 02/06/2023] Open
Abstract
Hypertension (HTN) develops very early in childhood chronic kidney disease (CKD). It is linked with rapid progression of kidney disease, increased morbidity and mortality hence the imperative to start anti-hypertensive medication when blood pressure (BP) is persistently > 90th percentile for age, gender, and height in non-dialyzing hypertensive children with CKD. HTN pathomechanism in CKD is multifactorial and complexly interwoven. The patient with CKD-associated HTN needs to be carefully evaluated for co-morbidities that frequently alter the course of the disease as successful treatment of HTN in CKD goes beyond life style modification and anti-hypertensive therapy alone. Chronic anaemia, volume overload, endothelial dysfunction, arterial media calcification, and metabolic derangements like secondary hyperparathyroidism, hyperphosphataemia, and calcitriol deficiency are a few co-morbidities that may cause or worsen HTN in CKD. It is important to know if the HTN is caused or made worse by the toxic effects of medications like erythropoietin, cyclosporine, tacrolimus, corticosteroids and non-steroidal anti-inflammatory drugs. Poor treatment response may be due to any of these co-morbidities and medications. A satisfactory hypertensive CKD outcome, therefore, depends very much on identifying and managing these co-morbid conditions and HTN promoting medications promptly and appropriately. This review attempts to point attention to factors that may affect successful treatment of the hypertensive CKD child and how to attain the desired therapeutic BP target.
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15
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Alkhouli M, Sandhu P, Boobes K, Hatahet K, Raza F, Boobes Y. Cardiac complications of arteriovenous fistulas in patients with end-stage renal disease. Nefrologia 2015; 35:234-45. [PMID: 26299166 DOI: 10.1016/j.nefro.2015.03.001] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Accepted: 03/23/2015] [Indexed: 10/23/2022] Open
Abstract
Cardiovascular disease is the leading cause of the death in dialysis patients. Arteriovenous fistulas (AVFs) are associated with lower mortality and are viewed as the desired access option in most patients with advanced kidney disease needing dialysis. However, AVFs have significant and potentially deleterious effects on cardiac functions particularly in the setting of preexisting heart disease. This article provides a comprehensive and contemporary review to what is known about the impact of AVFs on: congestive heart failure, left ventricular hypertrophy, pulmonary hypertension, right ventricular dysfunction, coronary artery disease and valvular heart disease.
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Affiliation(s)
- Mohamad Alkhouli
- Cardiology Department, University of Rochester, Rochester, NY, USA.
| | - Paul Sandhu
- Department of Internal Medicine, Boston University, Boston, MA, USA
| | - Khlaed Boobes
- Department of Nephrology, Northwestern University, Chicago, IL, USA
| | - Kamel Hatahet
- Department of Nephrology, Temple University Hospital, Philadelphia, PA, USA
| | - Farhan Raza
- Cardiology Department, Temple University Hospital, Philadelphia, PA, USA
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16
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Ameer OZ, Boyd R, Butlin M, Avolio AP, Phillips JK. Abnormalities associated with progressive aortic vascular dysfunction in chronic kidney disease. Front Physiol 2015; 6:150. [PMID: 26042042 PMCID: PMC4436592 DOI: 10.3389/fphys.2015.00150] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Accepted: 04/27/2015] [Indexed: 11/13/2022] Open
Abstract
Increased stiffness of large arteries in chronic kidney disease (CKD) has significant clinical implications. This study investigates the temporal development of thoracic aortic dysfunction in a rodent model of CKD, the Lewis polycystic kidney (LPK) rat. Animals aged 12 and 18 weeks were studied alongside age-matched Lewis controls (total n = 94). LPK rodents had elevated systolic blood pressure, left ventricular hypertrophy and progressively higher plasma creatinine and urea. Relative to Lewis controls, LPK exhibited reduced maximum aortic vasoconstriction (Rmax) to noradrenaline at 12 and 18 weeks, and to K+ (12 weeks). Sensitivity to noradrenaline was greater in 18-week-old LPK vs. age matched Lewis (effective concentration 50%: 24 × 10−9 ± 78 × 10−10 vs. 19 × 10−8 ± 49 × 10−9, P < 0.05). Endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) relaxation was diminished in LPK, declining with age (12 vs. 18 weeks Rmax: 80 ± 8% vs. 57 ± 9% and 92 ± 6% vs. 70 ± 9%, P < 0.05, respectively) in parallel with the decline in renal function. L-Arginine restored endothelial function in LPK, and L-NAME blunted acetylcholine relaxation in all groups. Impaired nitric oxide synthase (NOS) activity was recovered with L-Arginine plus L-NAME in 12, but not 18-week-old LPK. Aortic calcification was increased in LPK rats, as was collagen I/III, fibronectin and NADPH-oxidase subunit p47 (phox) mRNAs. Overall, our observations indicate that the vascular abnormalities associated with CKD are progressive in nature, being characterized by impaired vascular contraction and relaxation responses, concurrent with the development of endothelial dysfunction, which is likely driven by evolving deficits in NO signaling.
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Affiliation(s)
- Omar Z Ameer
- Faculty of Medicine and Health Sciences, The Australian School of Advanced Medicine, Macquarie University Sydney, NSW, Australia
| | - Rochelle Boyd
- Faculty of Medicine and Health Sciences, The Australian School of Advanced Medicine, Macquarie University Sydney, NSW, Australia
| | - Mark Butlin
- Faculty of Medicine and Health Sciences, The Australian School of Advanced Medicine, Macquarie University Sydney, NSW, Australia
| | - Alberto P Avolio
- Faculty of Medicine and Health Sciences, The Australian School of Advanced Medicine, Macquarie University Sydney, NSW, Australia
| | - Jacqueline K Phillips
- Faculty of Medicine and Health Sciences, The Australian School of Advanced Medicine, Macquarie University Sydney, NSW, Australia
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17
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MacRae JM, Ahmed S, Hemmelgarn B, Sun Y, Martin BJ, Roifman I, Anderson T. Role of vascular function in predicting arteriovenous fistula outcomes: an observational pilot study. Can J Kidney Health Dis 2015; 2:19. [PMID: 25949818 PMCID: PMC4422532 DOI: 10.1186/s40697-015-0055-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2014] [Accepted: 03/24/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Many arteriovenous fistula (AVF) fail prior to use due to lack of maturation or thrombosis. Determining vascular function prior to surgery may be helpful to predict subsequent AVF success. This is a feasibility study to describe the vascular function in a cohort of chronic kidney disease (CKD) patients who are awaiting AVF creation. METHODS A prospective cohort of 28 CKD patients expected to progress to HD underwent arterial stiffness (pulse wave velocity, PWV) and endothelial function testing (flow mediated dilation FMD, and peripheral arterial tonometry, PAT) one week prior to AVF creation. AVF success was defined as maintaining patency and achieving maturation. Post operative fistula assessment at 8 weeks evaluated maturation (clinical assessment of adequate fistula flowand ultrasound diameter ≥ 0.5 cm). RESULTS The median age 72 years (62 - 78), 75% males, eGFR 15 ml/min/1.73 m(2) (12 - 18). 20 (71%) patients had successful AVF surgery with a mature AVF at 8 weeks. Patients with AVF success had higher mean PAT values 1.87 ± 0.52 than those with failed AVF 1.41 ± 0.24 p = 0.03. CONCLUSIONS Microvascular endothelial function as measured using PAT may be useful as a predictor of AVF maturation and function. This simple non invasive marker of vascular function may be a useful tool to predict AVF outcomes.
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Affiliation(s)
- Jennifer M MacRae
- />Division of Nephrology, Faculty of Medicine, University of Calgary, Calgary, Canada
- />Department of Cardiac Sciences, Faculty of Medicine, University of Calgary, Calgary, Canada
| | - Sofia Ahmed
- />Division of Nephrology, Faculty of Medicine, University of Calgary, Calgary, Canada
| | - Brenda Hemmelgarn
- />Division of Nephrology, Faculty of Medicine, University of Calgary, Calgary, Canada
| | - Yichun Sun
- />Department of Cardiac Sciences, Faculty of Medicine, University of Calgary, Calgary, Canada
| | - Billie-Jean Martin
- />Department of Cardiac Sciences, Faculty of Medicine, University of Calgary, Calgary, Canada
| | - Idan Roifman
- />Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada
| | - Todd Anderson
- />Department of Cardiac Sciences, Faculty of Medicine, University of Calgary, Calgary, Canada
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18
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Abushufa AM, Eldehni MT, Odudu A, Evans PD, O'Sullivan SE, McIntyre CW. Defining uremic arterial functional abnormalities in patients recently started on haemodialysis: combined in vivo and ex vivo assessment. PLoS One 2014; 9:e113462. [PMID: 25546407 PMCID: PMC4278673 DOI: 10.1371/journal.pone.0113462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Accepted: 10/26/2014] [Indexed: 11/18/2022] Open
Abstract
Endothelial dysfunction is a key initiating event in vascular disease in chronic kidney disease (CKD) patients and haemodialysis (HD) patients exhibit significant vascular abnormalities. To understand this further, we examined how ex vivo intrinsic function in isolated arteries correlates with in vivo assessments of cardiovascular status in HD patients. Abdominal fat biopsies were obtained from 11 HD patients and 26 non-uremic controls. Subcutaneous arteries were dissected and mounted on a wire myograph, and cumulative concentration-response curves to noradrenalin, endothelin-1, a thromboxane A2 agonist (U46619), angiotensin II, vasopressin, bradykinin (BK), acetylcholine (ACh) and sodium nitroprusside (SNP) were constructed. Pulse wave velocity and blood pressure were measured in HD patients. Enhanced (P<0.05−0.0001) maximal contractile responses (Rmax) to all spasmogens (particularly vasopressin) were observed in arteries from HD patients compared to controls, and this effect was more pronounced in arteries with an internal diameter>600 µm. The potency (pEC50) of U46619 (P<0.01) and vasopressin (P<0.001) was also increased in arteries>600 µm of HD patients. The maximal relaxant response to the endothelium-dependent dilators ACh and BK were lower in HD patients (P<0.01-P<0.0001) (worse for ACh than BK); however the endothelium-independent dilator SNP was similar in both groups. PWV was significantly correlated with the vasoconstrictor response to vasopressin (P = 0.042) in HD patients. HD patients are primed for hypertension and end organ demand ischaemia by a highly sensitised pressor response. The failure of arterial relaxation is mediated by endothelial dysfunction. Intrinsic vascular abnormalities may be important in sensitising HD patients to recurrent cumulative ischaemic end organ injury.
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Affiliation(s)
- Adil M Abushufa
- Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Mohamed T Eldehni
- Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Nottingham, United Kingdom; Department of Renal Medicine, Royal Derby Hospital, Derby, United Kingdom
| | - Aghogho Odudu
- Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Nottingham, United Kingdom; Department of Renal Medicine, Royal Derby Hospital, Derby, United Kingdom
| | - Philip D Evans
- Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Nottingham, United Kingdom; Department of Renal Medicine, Royal Derby Hospital, Derby, United Kingdom
| | - Saoirse E O'Sullivan
- Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Chris W McIntyre
- Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Nottingham, United Kingdom; Department of Renal Medicine, Royal Derby Hospital, Derby, United Kingdom
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19
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Lankadeva YR, Singh RR, Moritz KM, Parkington HC, Denton KM, Tare M. Renal dysfunction is associated with a reduced contribution of nitric oxide and enhanced vasoconstriction after a congenital renal mass reduction in sheep. Circulation 2014; 131:280-8. [PMID: 25369804 DOI: 10.1161/circulationaha.114.013930] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND Children born with reduced congenital renal mass have an increased risk of hypertension and chronic kidney disease in adulthood, although the mechanisms are poorly understood. Similar sequelae occur after fetal uninephrectomy (uni-x) in sheep, leading to a 30% nephron deficit. We hypothesized that renal dysfunction is underpinned by a reduced contribution of nitric oxide (NO) and vascular dysfunction in uni-x sheep. METHODS AND RESULTS In 5-year-old female uni-x and sham sheep, mean arterial pressure, glomerular filtration rate, and renal blood flow were measured before and during NO inhibition (N(ω)-nitro-l-arginine methyl ester [L-NAME]). Reactivity was assessed in resistance arteries, including renal lobar and arcuate arteries. Basal mean arterial pressure was 15 mm Hg higher and glomerular filtration rate and renal blood flow were ≈30% lower (P<0.001) in uni-x animals. L-NAME increased mean arterial pressure by ≈17 mm Hg in both groups, whereas glomerular filtration rate and renal blood flow were decreased less in uni-x sheep (PInteraction<0.01). Endothelial NO synthase and Ser-1177-phosphorylated endothelial NO synthase protein levels were upregulated in renal cortex of uni-x sheep (P<0.05). Lobar arteries of uni-x sheep had enhanced responsiveness to phenylephrine and nitrotyrosine staining and reduced sensitivity to endothelial stimulation. Vasodilator prostanoid contribution to endothelium-dependent relaxation was reduced in lobar arteries of uni-x sheep, accompanied by reduced cyclooxygenase-1 and -2 gene expression (P<0.05). Neurovascular constriction was enhanced ≈1.5-fold in renal arteries of uni-x sheep (P<0.05). CONCLUSIONS Renal dysfunction after congenital renal mass reduction is associated with impaired regulation of renal hemodynamics by NO. Reductions in renal blood flow and glomerular filtration rate are underpinned by impaired basal NO contribution, endothelial dysfunction, and enhanced vascular responsiveness to sympathetic nerve stimulation.
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Affiliation(s)
- Yugeesh R Lankadeva
- From the Department of Physiology (Y.R.L., R.R.S., H.C.P., K.M.D., M.T.) and Department of Anatomy and Developmental Biology (R.R.S.), Monash University, Victoria, Australia; and School of Biomedical Sciences, University of Queensland, St. Lucia, Australia (R.R.S., K.M.M.)
| | - Reetu R Singh
- From the Department of Physiology (Y.R.L., R.R.S., H.C.P., K.M.D., M.T.) and Department of Anatomy and Developmental Biology (R.R.S.), Monash University, Victoria, Australia; and School of Biomedical Sciences, University of Queensland, St. Lucia, Australia (R.R.S., K.M.M.)
| | - Karen M Moritz
- From the Department of Physiology (Y.R.L., R.R.S., H.C.P., K.M.D., M.T.) and Department of Anatomy and Developmental Biology (R.R.S.), Monash University, Victoria, Australia; and School of Biomedical Sciences, University of Queensland, St. Lucia, Australia (R.R.S., K.M.M.)
| | - Helena C Parkington
- From the Department of Physiology (Y.R.L., R.R.S., H.C.P., K.M.D., M.T.) and Department of Anatomy and Developmental Biology (R.R.S.), Monash University, Victoria, Australia; and School of Biomedical Sciences, University of Queensland, St. Lucia, Australia (R.R.S., K.M.M.)
| | - Kate M Denton
- From the Department of Physiology (Y.R.L., R.R.S., H.C.P., K.M.D., M.T.) and Department of Anatomy and Developmental Biology (R.R.S.), Monash University, Victoria, Australia; and School of Biomedical Sciences, University of Queensland, St. Lucia, Australia (R.R.S., K.M.M.)
| | - Marianne Tare
- From the Department of Physiology (Y.R.L., R.R.S., H.C.P., K.M.D., M.T.) and Department of Anatomy and Developmental Biology (R.R.S.), Monash University, Victoria, Australia; and School of Biomedical Sciences, University of Queensland, St. Lucia, Australia (R.R.S., K.M.M.).
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20
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DuPont JJ, Ramick MG, Farquhar WB, Townsend RR, Edwards DG. NADPH oxidase-derived reactive oxygen species contribute to impaired cutaneous microvascular function in chronic kidney disease. Am J Physiol Renal Physiol 2014; 306:F1499-506. [PMID: 24761000 PMCID: PMC4059972 DOI: 10.1152/ajprenal.00058.2014] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 04/21/2014] [Indexed: 01/11/2023] Open
Abstract
Oxidative stress promotes vascular dysfunction in chronic kidney disease (CKD). We utilized the cutaneous circulation to test the hypothesis that reactive oxygen species derived from NADPH oxidase and xanthine oxidase impair nitric oxide (NO)-dependent cutaneous vasodilation in CKD. Twenty subjects, 10 stage 3 and 4 patients with CKD (61 ± 4 yr; 5 men/5 women; eGFR: 39 ± 4 ml·min(-1)·1.73 m(-2)) and 10 healthy controls (55 ± 2 yr; 4 men/6 women; eGFR: >60 ml·min(-1)·1.73 m(-2)) were instrumented with 4 intradermal microdialysis fibers for the delivery of 1) Ringer solution (Control), 2) 10 μM tempol (scavenge superoxide), 3) 100 μM apocynin (NAD(P)H oxidase inhibition), and 4) 10 μM allopurinol (xanthine oxidase inhibition). Skin blood flow was measured via laser-Doppler flowmetry during standardized local heating (42°C). N(g)-nitro-l-arginine methyl ester (L-NAME; 10 mM) was infused to quantify the NO-dependent portion of the response. Cutaneous vascular conductance (CVC) was calculated as a percentage of the maximum CVC achieved during sodium nitroprusside infusion at 43°C. Cutaneous vasodilation was attenuated in patients with CKD (77 ± 3 vs. 88 ± 3%, P = 0.01), but augmented with tempol and apocynin (tempol: 88 ± 2 (P = 0.03), apocynin: 91 ± 2% (P = 0.001). The NO-dependent portion of the response was reduced in patients with CKD (41 ± 4 vs. 58 ± 2%, P = 0.04), but improved with tempol and apocynin (tempol: 58 ± 3 (P = 0.03), apocynin: 58 ± 4% (P = 0.03). Inhibition of xanthine oxidase did not alter cutaneous vasodilation in either group (P > 0.05). These data suggest that NAD(P)H oxidase is a source of reactive oxygen species and contributes to microvascular dysfunction in patients with CKD.
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Affiliation(s)
- Jennifer J DuPont
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware
| | - Meghan G Ramick
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware
| | - William B Farquhar
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware; Department of Biological Sciences, University of Delaware, Newark, Delaware; and
| | - Raymond R Townsend
- Clinical and Translational Research Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - David G Edwards
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware; Department of Biological Sciences, University of Delaware, Newark, Delaware; and
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21
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Ari E, Kaya Y, Demir H, Asicioglu E, Eren Z, Celik E, Arikan H. Cinacalcet may improve oxidative DNA damage in maintenance hemodialysis patients: an observational study. Int Urol Nephrol 2014; 46:1843-9. [PMID: 24811568 DOI: 10.1007/s11255-014-0723-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2014] [Accepted: 04/21/2014] [Indexed: 01/24/2023]
Abstract
BACKGROUND Oxidative stress is accepted as a non-classical cardiovascular risk factor in patients on maintenance hemodialysis (HD). The aim of this study was to evaluate the impact of cinacalcet on oxidative stress biomarkers, oxidative DNA damage (8-hydroxy-2'-deoxyguanosine/deoxyguanosine), endothelial function (FMD %) and carotid artery intima-media thickness (CIMT) in HD patients. METHODS Forty-two chronic HD patients with secondary hyperparathyroidism undergoing 60 mg/day cinacalcet treatment with a follow-up of 6 months and 38 age- and sex-matched healthy individuals were included in this prospective study. Plasma malondialdehyde (MDA) levels and 8-hydroxy-2'-deoxyguanosine/deoxyguanosine ratio (8-OHdG/dG) were determined as oxidative stress markers. Superoxide dismutase (SOD), paraoxonase (PON), catalase (CAT), carbonic anhydrase (CAN) and glutathione peroxidase (GPx) activities were measured as antioxidants. FMD % and CIMT were assessed by ultrasonography. RESULTS MDA levels were decreased; SOD, PON, CAT, CAN and GPx activities were increased after 6 months of cinacalcet treatment in HD patients. Although CIMT remained stabile, there was a significant improvement in FMD % as well as a notable reduction trend in 8-OHdG/dG ratio after 6 months of treatment. CONCLUSION Our data have demonstrated that cinacalcet improves oxidative stress, genomic damage, endothelial function and increases antioxidant protection in HD patients after 6 months of treatment.
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Affiliation(s)
- Elif Ari
- Department of Nephrology, Kartal Research and Training Hospital, 34890, Istanbul, Turkey,
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22
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Zeng W, Guo YH, Qi W, Chen JG, Yang LL, Luo ZF, Mu J, Feng B. 4-Phenylbutyric acid suppresses inflammation through regulation of endoplasmic reticulum stress of endothelial cells stimulated by uremic serum. Life Sci 2014; 103:15-24. [PMID: 24650493 DOI: 10.1016/j.lfs.2014.03.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Revised: 02/25/2014] [Accepted: 03/03/2014] [Indexed: 02/08/2023]
Abstract
AIMS Endoplasmic reticulum (ER) stress is involved in the pathogenesis of atherosclerosis (AS). Endothelial cell (EC) dysfunction and monocyte migration to the subendothelium are considered to be essential manifestations of AS. We conducted this study to determine whether ER stress was involved in uremic serum-induced EC dysfunction and whether the regulation of ER stress using a chemical chaperone 4-phenylbutyric acid (4-PBA) had a preventative effect. MAIN METHODS Human umbilical vein endothelial cells (HUVECs) were divided into 4 groups: a control serum group (C.S), a uremic serum group (U.S), a uremic serum plus 4-PBA (5mM) treatment group (4-PBA), and a uremic serum plus pyrrolidine dithiocarbamate (PDTC:50 μM) treatment group (PDTC). KEY FINDINGS Lower concentrations of uremic serum (<10%) facilitated the proliferation of HUVECs. In contrast, the proliferative capability of HUVECs was gradually decreased when we continuously increased the concentration of uremic serum. Compared with C.S, HUVEC incubation with uremic serum had high expression levels of GRP78, p-PERK, NF-κB, MCP-1, and VEGF. THP-1 migration was markedly higher than C.S over the indicated time. These alterations were inhibited by the administration of 4-PBA. SIGNIFICANCE These findings suggest that regulation of ER stress coupled with inflammatory activation by 4-PBA would be a promising therapy to reverse the process and development of uremic serum-induced EC dysfunction.
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Affiliation(s)
- Wei Zeng
- Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, PR China
| | - Yan-Hong Guo
- Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, PR China
| | - Wei Qi
- Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, PR China
| | - Ji-Gang Chen
- Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, PR China
| | - Li-Ling Yang
- Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, PR China
| | - Zhi-Feng Luo
- Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, PR China
| | - Jiao Mu
- Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, PR China
| | - Bing Feng
- Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, PR China.
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Kovačević P, Dragić S, Rajkovača Z, Veljković S, Kovačević T. Serum levels of nitric oxide and endothelin-1 in patients treated with continuous ambulatory peritoneal dialysis. Ren Fail 2013; 36:437-40. [DOI: 10.3109/0886022x.2013.867812] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Waldum B, Os I. The cardiorenal syndrome: what the cardiologist needs to know. Cardiology 2013; 126:175-86. [PMID: 24022166 DOI: 10.1159/000353261] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2013] [Accepted: 05/14/2013] [Indexed: 11/19/2022]
Abstract
Interactions between the heart and the kidneys are increasingly acknowledged among both cardiologists and nephrologists. The term cardiorenal syndrome now applies to the bidirectional nature of how disease in one organ system affects the function of the other organ system. Cardiovascular disease is a major threat to patients with chronic kidney disease, while renal dysfunction is prevalent in patients with cardiac disease and is a significant predictor of prognosis in cardiac patients. Still, renal patients with cardiac disease have largely been excluded from the clinical trials that have been the basis of modern cardiologic treatment. In this review, the current understanding of the pathophysiological mechanisms involved in the cardiorenal syndrome and potential therapeutic implications will be summarized from a nephrologist's point of view. Probably, fragile cardiorenal patients will benefit from an enhanced collaboration between cardiologists and nephrologists to secure the best treatment given under safe conditions.
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Affiliation(s)
- Bård Waldum
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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Toba H, Wang J, Ohigashi M, Kobara M, Nakata T. Telmisartan Protects against Vascular Dysfunction with Peroxisome Proliferator-Activated Receptor-γ Activation in Hypertensive 5/6 Nephrectomized Rats. Pharmacology 2013; 92:265-75. [DOI: 10.1159/000355482] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 09/06/2013] [Indexed: 11/19/2022]
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Stolic R. Most important chronic complications of arteriovenous fistulas for hemodialysis. Med Princ Pract 2013; 22:220-8. [PMID: 23128647 PMCID: PMC5586732 DOI: 10.1159/000343669] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2012] [Accepted: 09/17/2012] [Indexed: 12/19/2022] Open
Abstract
The aim of this review was to highlight the most important complications of arteriovenous fistulas (AVFs) for hemodialysis (HD). The quality of vascular access for HD should be suitable for repeated puncture and allow a high blood flow rate for high-efficiency dialysis with minimal complications. The dialysis staff must be well versed in manipulation of the AVF, and there should be a minimal need for corrective interventions. Construction of an AVF creates conditions for increasing the flow of blood through the venous system. Fulfillment of these conditions reduces the risk of turbulence and endothelium injury, which, in turn, minimizes the potential for stenosis. An AVF is closest to the ideal model of vascular access. The most important complications of fistulae for HD are lymphedema, infection, aneurysm, stenosis, congestive heart failure, steal syndrome, ischemic neuropathy and thrombosis. In HD patients, the most common cause of vascular access failure is neointimal hyperplasia. It is important to gain information about early clinical symptoms of AVF dysfunction in order to prevent and adequately treat potential complications.
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Affiliation(s)
- Radojica Stolic
- Faculty of Medicine, University of Pristina, Kosovska Mitrovica, Serbia.
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27
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Telmisartan inhibits vascular dysfunction and inflammation via activation of peroxisome proliferator-activated receptor-γ in subtotal nephrectomized rat. Eur J Pharmacol 2012; 685:91-8. [DOI: 10.1016/j.ejphar.2012.01.026] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2011] [Revised: 01/13/2012] [Accepted: 01/18/2012] [Indexed: 11/23/2022]
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Serum cadmium levels are independently associated with endothelial function in hemodialysis patients. Int Urol Nephrol 2011; 44:1487-92. [PMID: 21904850 DOI: 10.1007/s11255-011-0055-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2011] [Accepted: 08/23/2011] [Indexed: 10/17/2022]
Abstract
OBJECTIVE Hemodialysis (HD) patients are at risk of deficiency of essential trace elements and excess of toxic trace elements. The aim of the study was to evaluate the relation between the serum levels of some trace elements and heavy metals (iron, zinc, manganese, copper, magnesium, cobalt, cadmium, and lead) and endothelial function in HD patients. METHODS Forty-eight chronic HD patients without known atherosclerotic disease and 42 age- and sex-matched healthy individuals were included in the study. The serum levels of trace elements (iron, zinc, manganese, copper, and magnesium) and heavy metals (cobalt, cadmium, and lead) were measured by Atomic Adsorption Spectrophotometer (UNICAM-929). RESULTS The serum levels of iron, zinc, and manganese were lower, and levels of copper, magnesium, cobalt, cadmium, and lead were higher in HD patients compared to controls. Flow-mediated dilatation (FMD %) in HD patients was lower than that in the control group (7.27 ± 0.76 vs. 11.29 ± 0.82, P < 0.001). There was a significant negative correlation between FMD % and serum levels of cobalt (r = -0.313, P = 0.03) and cadmium (r = -0.524, P < 0.01). A linear regression analysis showed that serum cadmium levels were still significantly and negatively correlated with FMD % (regression coefficient = -0.526, P < 0.001). CONCLUSION We first demonstrated that serum cadmium levels independently predict endothelial function in HD patients without known atherosclerotic disease.
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Dupont JJ, Farquhar WB, Townsend RR, Edwards DG. Ascorbic acid or L-arginine improves cutaneous microvascular function in chronic kidney disease. J Appl Physiol (1985) 2011; 111:1561-7. [PMID: 21885796 DOI: 10.1152/japplphysiol.00419.2011] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
We sought to determine whether oxidative stress or a relative deficit of l-arginine plays a role in reducing cutaneous vasodilation in response to local heating in chronic kidney disease (CKD). Eight patients with stage 3-4 CKD and eight age- and sex-matched healthy control (HC) subjects were instrumented with four microdialysis (MD) fibers for the local delivery of 1) Ringers solution (R), 2) 20 mM ascorbic acid (AA), 3) 10 mM l-arginine (l-Arg), and 4) 10 mM N(G)-nitro-l-arginine methyl ester (l-NAME). Red blood cell (RBC) flux was measured via laser Doppler flowmetry. A standardized nonpainful local heating protocol (42°C) was used. Cutaneous vascular conductance (CVC) was calculated as RBC flux/MAP and all data were expressed as a percentage of the maximum CVC at each site (28 mM sodium nitroprusside, T(loc) = 43°C). The plateau %CVC(max) was attenuated in CKD (CKD: 76 ± 4 vs. HC: 91 ± 2%CVC(max); P < 0.05) and the NO contribution to the plateau was lower in CKD (CKD: 39 ± 7, HC: 54 ± 5; P < 0.05). The plateau %CVC(max) in the CKD group was significantly greater at the AA and l-Arg sites compared with R (AA: 89 ± 2; l-Arg: 90 ± 1; R: 76 ± 4; P < 0.05) and did not differ from HC. Initial peak %CVC(max) was also significantly attenuated at the R and l-Arg sites in CKD (P < 0.05) but did not differ at the AA site. These results suggest that cutaneous microvascular function is impaired in stage 3-4 CKD and that oxidative stress and a deficit of l-arginine play a role in this impairment.
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Affiliation(s)
- Jennifer J Dupont
- Dept. of Kinesiology and Applied Physiology, University of Delaware, Newark, DE, USA
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Kaya Y, Ari E, Demir H, Soylemez N, Cebi A, Alp H, Bakan E, Gecit I, Asicioglu E, Beytur A. Accelerated atherosclerosis in haemodialysis patients; correlation of endothelial function with oxidative DNA damage. Nephrol Dial Transplant 2011; 27:1164-9. [PMID: 21821836 DOI: 10.1093/ndt/gfr443] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Accelerated atherosclerosis is the major cause of mortality in patients on chronic haemodialysis (HD). The aim of this study was to evaluate the relationship between oxidative DNA damage [8-hydroxy-2'-deoxyguanosine/deoxyguanosine ratio (8-OHdG/dG ratio)], oxidative stress biomarkers and endothelial function in HD patients as an indicator of atherosclerosis. METHODS Forty-four chronic HD patients without known atherosclerotic disease and 55 age- and sex-matched healthy individuals were included in the study. Plasma malondialdehyde (MDA) levels and 8-OHdG/dG ratio were determined as oxidative stress markers. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured as antioxidants. Endothelial function was assessed by ultrasonography. RESULTS 8-OHdG/dG ratio and MDA levels were higher in HD patients than controls while SOD and GPx activities were lower in HD patients compared to controls. Flow-mediated dilatation FMD% in HD patients were lower than the control group (7.28 ± 0.79 versus 11.18 ± 0.82, P < 0.001). There was a significant negative correlation between FMD% and 8-OHdG/dG ratio (r = -0.678, P < 0.01) and MDA levels (r = -0.517, P < 0.01), while there was a significant positive correlation between FMD% and SOD (r = 0.538, P < 0.01) and GPx levels (r = 0.720, P < 0.01). CONCLUSIONS Our data have demonstrated that HD patients exhibit increased oxidative DNA damage and decreased antioxidant activity. We propose that endothelial function is negatively correlated with 8-OHdG/dG ratio and positively correlated with antioxidant enzymes. To our knowledge, this is the first study to demonstrate the inverse relationship between endothelial function and plasma oxidative DNA damage in HD patients.
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Affiliation(s)
- Yuksel Kaya
- Department of Cardiology, Van Yuksek Ihtisas Hospital, Van, Turkey
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Feng B, Zhang YQ, Mu J, Yuan FH, Ye ZL, Qi W, Guo YH, Zeng W, Luo ZF. Uraemic serum induces dysfunction of vascular endothelial cells: role of ubiquitin-proteasome pathway. Exp Physiol 2011; 96:801-15. [PMID: 21602294 DOI: 10.1113/expphysiol.2011.058149] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The ubiquitin-proteasome pathway (UPP) has been indicated to contribute to dysfunction of endothelial cells (ECs). Nevertheless, the relationship between UPP and vascular complications of uraemia remains unknown. We aimed to determine whether the UPP is activated in vascular ECs when cultured with uraemic serum, and to examine the role of the UPP on dysfunction of ECs in uraemia. Rabbit aortic endothelial cells (RAECs) were cultured with normal serum or different concentrations of uraemic serum. The expression of the ubiquitin-activating enzyme (E1), an indicator of the UPP, was detected by real-time RT-PCR and Western blot; proteasome activity was determined by fluorescence spectrophotometry; and nuclear factor-κB (NF-κB) activity and expression, as well as tumour necrosis factor-α (TNF-α) expression, were also detected. We found that the expression of E1 and the activities of three kinds of proteasomes were increased significantly in RAECs after incubation with uraemic serum. Proliferation of RAECs was increased significantly by incubation with 3-15% uraemic serum but decreased markedly when incubated with uraemic serum above 15% (increased apoptosis). Incubation of RAECs with uraemic serum induced increased NF-B DNA-binding activity and nuclear translocation of NF-κB, decreased nitric oxide production and increased expression of TNF-α, which is the final effector of inflammatory activation of cells. All of these responses in RAECs were suppressed by the specific proteasome inhibitor, MG132. The inhibition of inflammatory responses by MG132 was further supported by a parallel experiment with pyrrolidine dithiocarbamate, a specific inhibitor of κNF-B. These findings suggest that the UPP was activated in RAECs by administration of uraemic serum, and played a pivotal role in the dysfunction of vascular ECs, such as inflammatory activation.
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Affiliation(s)
- Bing Feng
- Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
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Sutliff RL, Walp ER, El-Ali AM, Elkhatib S, Lomashvili KA, O'Neill WC. Effect of medial calcification on vascular function in uremia. Am J Physiol Renal Physiol 2011; 301:F78-83. [PMID: 21478480 DOI: 10.1152/ajprenal.00533.2010] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The contribution of medial calcification to vascular dysfunction in renal failure is unknown. Vascular function was measured ex vivo in control, noncalcified uremic, and calcified uremic aortas from rats with adenine-induced renal failure. Plasma urea was 16 ± 4, 93 ± 14, and 110 ± 25 mg/dl, and aortic calcium content was 27 ± 4, 29 ± 2, and 4,946 ± 1,616 nmol/mg dry wt, respectively, in the three groups. Maximal contraction by phenylephrine (PE) or KCl was reduced 53 and 63% in uremic aortas, and sensitivity to KCl but not PE was increased. Maximal relaxation to acetylcholine was impaired in uremic aortas (30 vs. 65%), and sensitivity to nitroprusside was also reduced, indicating some impairment of endothelium-independent relaxation as well. None of these parameters differed between calcified and noncalcified uremic aortas. However, aortic compliance was reduced in calcified aortas, ranging from 17 to 61% depending on the severity of calcification. We conclude that uremic vascular calcification, even when not severe, significantly reduces arterial compliance. Vascular smooth muscle and endothelial function are altered in renal failure but are not affected by medial calcification, even when severe.
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Affiliation(s)
- Roy L Sutliff
- Department of Medicine, Emory University, Renal Div., WMB 338, 1639 Pierce Dr., Atlanta, GA 30322, USA
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Toba H, Morishita M, Tojo C, Nakano A, Oshima Y, Kojima Y, Yoshida M, Nakashima K, Wang J, Kobara M, Nakata T. Recombinant human erythropoietin ameliorated endothelial dysfunction and macrophage infiltration by increasing nitric oxide in hypertensive 5/6 nephrectomized rat aorta. Eur J Pharmacol 2011; 656:81-7. [DOI: 10.1016/j.ejphar.2011.01.043] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2010] [Revised: 11/24/2010] [Accepted: 01/21/2011] [Indexed: 11/25/2022]
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Aybal Kutlugun A, Erdem Y, Okutucu S, Yorgun H, Atalar E, Arici M. Effects of lowering dialysate sodium on flow-mediated dilatation in patients with chronic kidney disease. Nephrol Dial Transplant 2011; 26:3678-82. [DOI: 10.1093/ndt/gfr092] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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Toba H, Nakashima K, Oshima Y, Kojima Y, Tojo C, Nakano A, Wang J, Kobara M, Nakata T. Erythropoietin prevents vascular inflammation and oxidative stress in subtotal nephrectomized rat aorta beyond haematopoiesis. Clin Exp Pharmacol Physiol 2011; 37:1139-46. [PMID: 20819095 DOI: 10.1111/j.1440-1681.2010.05445.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
1. Recombinant human erythropoietin (rHuEPO) has been used for the management of renal anaemia. Recent studies suggest pleiotropic properties of rHuEPO in various tissues. The aim of the present study was to investigate the vasoprotective effects of rHuEPO in renal failure rats. 2. Rats subjected to 5/6 and 17/18 nephrectomy (5/6Nx and 17/18Nx rats, respectively) were treated with rHuEPO (75 U/kg, s.c.) three times a week for 2 weeks. 3. Administration of rHuEPO to 5/6Nx or 17/18Nx rats had no effect on systolic blood pressure or decreased haematocrit. However, rHuEPO treatment normalized proteinuria and creatinine clearance in 5/6Nx, but not in 17/18Nx, rats. 4. Vasodilation in response to acetylcholine in aortic rings was impaired in 5/6Nx and 17/18Nx rats and improved by rHuEPO in both groups. Immunohistochemical analysis revealed that macrophage infiltration into adventitial areas and the expression of osteopontin were enhanced in aortas from 5/6Nx and 17/18Nx rats, but that rHuEPO suppressed these effects. In addition, rHuEPO attenuated medial hyperplasia and NADPH oxidase-derived superoxide production in 5/6Nx and 17/18Nx rats. 5. Activation of the Akt signalling pathway was evident in rHuEPO-treated rats as the increased expression of phosphorylated Akt and glycogen synthase kinase-3β. Treatment with rHuEPO restored the expression of phosphorylated endothelial nitric oxide synthase in the aorta and urinary excretion of NO(x) in nephrectomized rats. 6. These results suggest that a low dose of rHuEPO results in the normalization of endothelial function, vascular inflammation and oxidative stress in rats with renal ablation beyond haematopoiesis. In addition, these vasoprotective effects are observed even in a state of deteriorating renal dysfunction.
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Affiliation(s)
- Hiroe Toba
- Department of Clinical Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
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36
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Zhang DL, Liu J, Liu S, Zhang Y, Liu WH. The differences of asymmetric dimethylarginine removal by different dialysis treatments. Ren Fail 2011; 32:935-40. [PMID: 20722560 DOI: 10.3109/0886022x.2010.502281] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Asymmetric dimethylarginine (ADMA) as a uremia toxin is accumulated in end-stage renal disease (ESRD) patients. Elevated ADMA level has been shown to be predictive of cardiovascular diseases (CVDs) and all-cause mortality in ESRD. Therefore, we investigated the removal of ADMA by different dialysis treatments. METHODS There were 30 each of hemodialysis (HD), hemodiafiltration (HDF), peritoneal dialysis (PD) patients, and healthy volunteers enrolled. The ADMA concentrations in serum, urine, and spent dialysate samples were determined. The urine and spent dialysate volumes were recorded. The ADMA removals by urine and spent dialysate in 1 week were calculated and compared among four groups. It was also analyzed for the correlations between the total removal of ADMA in 1 week and the parameters of age, durance of dialysis, glomerular filtration rate, urine volume, urinal ADMA level, spent dialysate volume, and spent dialysate ADMA level. RESULTS The serum levels of ADMA in dialysis patients were much higher than in healthy subjects (0.32 +/- 0.09 micromol/L), and their 1-week total removals of ADMA were much lower than healthy controls (249.21 +/- 57.04 micromol/week) (p-values all were less than 0.01). Among dialysis groups, serum ADMA levels decreased significantly in PD patients compared with HD or HDF patients (1.38 +/- 0.30 micromol/L vs. 1.82 +/- 0.38 micromol/L and 1.63 +/- 0.32 micromol/L, p < 0.01), and the total removal of ADMA diminished remarkably by turns of PD, HDF, and HD groups (47.79 +/- 8.20 micromol/week, 31.79 +/- 8.92 micromol/week, 14.63 +/- 6.53 micromol/week, respectively, p < 0.01). The total removal of ADMA in 1 week was related directly with the spent dialysate concentrations of ADMA, the spent dialysate volume, and the urine volume. CONCLUSIONS ADMA was mainly removed by dialysate in dialysis patients. Different dialysis models have different clearance capability on plasma ADMA. PD might be more effective on ADMA removal than HD and HDF, with HDF being more effective than HD.
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Affiliation(s)
- Dong-Liang Zhang
- Department of Nephrology, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China
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Owens CD, Wake N, Kim JM, Hentschel D, Conte MS, Schanzer A. Endothelial function predicts positive arterial-venous fistula remodeling in subjects with stage IV and V chronic kidney disease. J Vasc Access 2010; 11:329-34. [PMID: 21038305 PMCID: PMC3164886 DOI: 10.5301/jva.2010.5833] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/01/2010] [Indexed: 11/20/2022] Open
Abstract
PURPOSE The maturation of an arteriovenous fistula (AVF) requires remodeling of the arterial inflow and the venous outflow limbs to sustain flows sufficient to support hemodialysis. However, factors influencing remodeling of AVF are poorly understood. We hypothesized that AVF remodeling was an endothelium-dependent process. METHODS This is a prospective cohort study of patients (n=25) undergoing autologous AVF formation. Brachial artery vasoreactivity studies were performed pre-operatively to assess endothelium-dependent, flow-mediated vasodilation (FMD). High-resolution ultrasound was used to assess venous and arterial diameters intraoperatively, and at 3 months. RESULTS The mean age was 64.5 ± 13.6 yrs. Twelve patients (48%) had diabetes. The mean FMD for the entire cohort was (mean ± SEM) 5.82 ± 0.9%, (range) 0-17.3%. The vein increased in size 3.19 ± .28 to 6.11 ± .41 mm, 108.4 ± 17.9%, p=.0001, while the artery increased from 3.29 ± .14 to 4.48 ± .30 mm, 20.47 ± 10.8%, p=.013. There was a significant positive correlation between the degree of arterial and venous remodeling, r=.52, p=.023. Brachial artery FMD most strongly correlated with the magnitude of arterial remodeling, r=.47, p=.038. Patients with diabetes failed to undergo venous remodeling to the same extent as did those without diabetes, 59.2 ± 24.4% vs. 141.5 ± 25.4%, p=.04. CONCLUSION Impairment of endothelial function is associated with decreased arterial remodeling and final venous lumen diameter attained at 3 months. Further investigation is needed to determine whether modulation of endothelial function in this cohort can improve AVF maturation.
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Affiliation(s)
- Christopher D Owens
- Division of Vascular and Endovascular Surgery, University of California, San Francisco, CA 94143-0222, USA.
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Dursun I, Poyrazoglu HM, Gunduz Z, Ulger H, Yykylmaz A, Dusunsel R, Patyroglu T, Gurgoze M. The relationship between circulating endothelial microparticles and arterial stiffness and atherosclerosis in children with chronic kidney disease. Nephrol Dial Transplant 2009; 24:2511-8. [PMID: 19244228 DOI: 10.1093/ndt/gfp066] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Endothelial dysfunction is an important factor in the pathogenesis of atherosclerosis, and endothelial microparticles (EMPs) are considered as markers of endothelial dysfunction. In this study, we aimed to examine the relationship between EMPs and arterial stiffness and atherosclerosis in children with chronic kidney disease (CKD). METHODS This cross-sectional study included 37 dialysis patients (12 haemodialysis, 25 peritoneal dialysis), 33 pre-dialysis patients and 18 healthy controls. Both in vivo and in vitro (HUVECs) evaluations were used for the study. Circulating EMPs were measured by flow cytometry. The carotid artery intima-media thickness (cIMT) and pulse wave velocity (PWV) were measured by using high-resolution ultrasound. Study groups were compared for circulating EMP, cIMT and PWV. The relationship between EMPs and arterial stiffness and atherosclerosis was evaluated. RESULTS The levels of PWV, cIMT, CD144 + EMP and CD146 + EMP in the dialysis group were significantly higher than those in the pre-dialysis and control groups (P < 0.05). Additionally, the levels of cIMT, CD144 + EMP and CD146 + EMP in the pre-dialysis group were significantly higher than those in the control group (P < 0.05). In all CKD patients, the CD144 + EMP was significantly positively associated with blood pressures, age, known duration of disease, CRP and PTH, and was significantly negatively associated with haemoglobin, GFR and albumin. The CD146 + EMP was significantly positively associated with blood pressures, age and CRP. In a multiple linear regression analysis, in the CKD group, cIMT was independently related to mean blood pressure and dialysis duration. PWV was independently related to the CD144 + EMP and mean blood pressure. CONCLUSION Our results suggest that endothelial damage starts in the early stage of CKD, that the endothelial dysfunction becomes overt with the increase of cardiovascular risk factors and that EMPs may be a reliable marker of the subclinical atherosclerosis and arterial stiffness.
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Affiliation(s)
- Ismail Dursun
- Department of Pediatric Nephrology, Erciyes University Faculty of Medicine, Kayseri, Turkey.
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Tomić M, Galesić K, Markota I. Endothelin-1 and nitric oxide in patients on chronic hemodialysis. Ren Fail 2009; 30:836-42. [PMID: 18925520 DOI: 10.1080/08860220802356218] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
AIM To establish the role of endothelin-1 and nitric oxide in the pathogenesis of hypertension in patients on chronic hemodialysis by correlating endothelin-1 and NO plasma concentrations to the level of arterial hypertension with respect to angiotensin-converting enzyme (ACE) inhibitor therapy. METHODS We determined plasma concentrations of endothelin-1 and NO in patients on chronic hemodialysis (CHD) before and after hemodialysis treatment. The study included 30 CHD patients and 20 healthy participants as controls. Correlation to blood pressure was determined, as well as the effect of ACE inhibitors on the relationship between both endothelin-1 and NO in correlation with arterial hypertension. MAIN FINDINGS Endothelin-1 plasma concentration was significantly higher in CHD patients before hemodialysis treatment than in healthy controls. Endothelin-1 plasma concentration was also significantly higher in CHD patients after hemodialysis than in healthy controls. There was a significant decrease in endothelin-1 plasma concentration after hemodialysis in comparison with its values before hemodialysis. In CHD patients, a positive correlation was found between endothelin-1 plasma concentration and systolic blood pressure after hemodialysis, irrespective of ACE inhibitors therapy. In CHD patients taking ACE inhibitors, systolic blood pressure increased with increasing endothelin-1 plasma concentration before as well as after hemodialysis. In patients taking ACE inhibitors, there was a tendency for diastolic blood pressure to increase with an increase in endothelin-1 plasma concentration after hemodialysis and to decrease with an increase in NO plasma concentration. CONCLUSION NO and endothelin-1 play a significant role in etiology of the hemodynamic changes of blood pressure during the dialysis.
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Affiliation(s)
- Monika Tomić
- Department of Internal Medicine, Mostar University Hospital Center, Mostar, Bosnia and Herzegovina
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Kocak H, Gumuslu S, Sahin E, Ceken K, Ermis C, Gocmen AY, Yakupoglu G, Ersoy FF, Suleymanlar G, Tuncer M. Relationship between carotid artery intima-media thickness and brachial artery flow-mediated dilation in peritoneal dialysis patients. Int Urol Nephrol 2008; 41:409-16. [PMID: 19115078 DOI: 10.1007/s11255-008-9504-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2008] [Accepted: 11/01/2008] [Indexed: 11/30/2022]
Abstract
BACKGROUND AND AIM Carotid artery intima-media thickness (CIMT) and brachial artery flow-mediated dilation percentage (FMD%) are two commonly used parameters for detecting subclinical atherosclerosis. However, studies investigating the relationship between CIMT and brachial artery FMD% in different populations have produced conflicting results. The aim of this study was to determine the relationship between CIMT and brachial artery FMD% in patients on peritoneal dialysis (PD) METHODS: Fifty-two PD patients without known cardiovascular disease and 30 age-gender matched controls were included in the study. Endothelial function was determined using ultrasonography (US) to measure the FMD of the brachial artery, and this parameter was expressed as the percentage change from the baseline diameter of the brachial artery (FMD%). We also measured CIMT by US and analysed the relationship between CIMT and brachial FMD%. RESULTS The CIMT was significantly higher in patients than in the control group (0.84 +/- 0.08 vs. 0.75 +/- 0.06 mm, P < 0.01), whereas brachial artery FMD% was lower in patients than in the controls (8.2 +/- 5.0 vs. 11.7 +/- 5.5%, P < 0.01). There was no significant correlation between CIMT and FMD% (r = -0.004, P = 0.94). CONCLUSION Although PD patients are known to be characterized by an impaired flow-mediated vasodilatation of brachial artery and increased in CIMT, we did not find a significant correlation between FMD% and CIMT in our PD patient cohort. One possible explanation for our results is that each method measures a different aspect and stage of atherosclerosis.
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Affiliation(s)
- H Kocak
- Department of Nephrology, Faculty of Medicine, Akdeniz University, Kampus, 07070 Antalya, Turkey.
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Kocak H, Gumuslu S, Sahin E, Ceken K, Gocmen YA, Yakupoglu G, Ersoy FF, Tuncer M. Advanced oxidative protein products are independently associated with endothelial function in peritoneal dialysis patients. Nephrology (Carlton) 2008; 14:273-80. [PMID: 19076287 DOI: 10.1111/j.1440-1797.2008.01062.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
AIM Oxidative stress (OS) and asymmetric dimethylarginine (ADMA) are accepted as non-classical cardiovascular risk factors in end-stage renal disease patients. To clarify the role of these factors in the atherosclerotic process, we investigated if OS and ADMA are associated with endothelial function (EF) in peritoneal dialysis (PD) patients. METHODS Fifty-two non-diabetic PD patients without known atherosclerotic disease as well as 30 age- and sex-matched healthy individuals were included. We measured serum thiobarbituric acid-reactive substances (TBARS), malondialdehyde (MDA), advanced glycation end-product (AGE), pentosidine, advanced oxidation protein products (AOPP), ADMA and EF as described by Celermejer et al. in all subjects. RESULTS TBARS, MDA, AOPP, AGE, pentosidine and ADMA levels were significantly higher in PD patients than in controls (P < 0.001). Flow-mediated dilatation (FMD)% and nitrate mediated dilatation (NMD)% in PD patients were lower than in the control group (7.7 +/- 4.0% vs 11.70 +/- 5.50%, P < 0.01 and 17.6 +/- 8.3% vs 26.4 +/- 4.6%, P < 0.01). Additionally, it was found that AOPP are independently correlated with FMD% and NMD% in PD patients (beta = -463, P < 0.01 and beta = -420, P < 0.05). CONCLUSION This study shows that PD patients without known atherosclerotic disease can also be characterized by endothelial dysfunction and AOPP levels independently predict endothelial function level in PD patients.
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Affiliation(s)
- Huseyin Kocak
- Division of Nephrology, Faculty of Medicine, Akdeniz University, Antalya, Turkey.
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Hussein G, Bughdady Y, Kandil ME, Bazaraa HM, Taher H. Doppler assessment of brachial artery flow as a measure of endothelial dysfunction in pediatric chronic renal failure. Pediatr Nephrol 2008; 23:2025-30. [PMID: 18543003 DOI: 10.1007/s00467-008-0874-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2007] [Revised: 03/03/2008] [Accepted: 03/29/2008] [Indexed: 10/22/2022]
Abstract
Cardiovascular morbidity and mortality are highly prevalent among patients with chronic renal failure (CRF). Endothelial dysfunction is regarded as the initial reversible step in the development of atherosclerosis and has been demonstrated in all stages of renal failure. Non-invasive techniques to assess endothelial function have been recently developed and have been proven to predict future mortality in adults. We aimed to assess endothelial function in children with stage 4 chronic kidney disease (CKD 4) on conservative treatment, using a-non invasive, high-resolution, ultrasound Doppler study of the brachial artery flow, correlating it with other clinical and laboratory parameters. This study included 34 children with CKD 4 on conservative treatment who were compared with 30 healthy controls. Flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NTG-MD) and FMD/NTG-MD ratio were estimated. FMD was abnormal (< 5%) in 24 patients (71%). FMD and FMD/NTG-MD ratio were significantly lower in patients than in controls (P = 0.001 and P = 0.01, respectively). FMD correlated positively with serum calcium and negatively with alkaline phosphatase. We concluded that endothelial dysfunction is present in children with CKD 4 on conservative treatment and may reflect increased atherogenic and thrombogenic properties of the endothelium, contributing to subsequent adverse cardiovascular outcome.
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Affiliation(s)
- Gehan Hussein
- Pediatrics Department, Cairo University, Cairo, Egypt
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Turiel M, Sitia S, Tomasoni L, Cicala S, Viganò SM, Menegotto A, Martina V, Bodini BD, Bacchiani G, Ghio L, Cusi D. Subclinical impairment of coronary flow velocity reserve assessed by transthoracic echocardiography in young renal transplant recipients. Atherosclerosis 2008; 204:435-9. [PMID: 19059594 DOI: 10.1016/j.atherosclerosis.2008.09.036] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2008] [Revised: 09/29/2008] [Accepted: 09/30/2008] [Indexed: 11/16/2022]
Abstract
BACKGROUND In renal transplant recipients (RTR) an increased risk to develop cardiovascular injury is present. Transthoracic Doppler echocardiographic assessment of coronary flow velocity reserve (CFVR), a sensitive and minimally invasive technique, was recently employed to detect both macrovascular and microvascular coronary artery disease (CAD) in different clinical settings. The prevalence of coronary involvement in young adult RTR is still unknown. The aim of the study was to investigate the presence of early cardiovascular damage in asymptomatic young adult RTR. METHODS Transthoracic Doppler echocardiographic-derived CFVR and common carotid intima-media thickness (IMT) were assessed in 25 asymptomatic young adult RTR (mean age 25.7+/-7.0 years; range 17.3-43.9) without CAD and 25 healthy controls. RESULTS CFVR was lower in young adult RTR compared to controls (2.8+/-0.6 vs. 3.5+/-0.8; P<0.001), meanwhile left ventricular wall motion and common carotid IMT were comparable in both groups. We found a negative correlation between CFVR and age (r=-0.50; P=0.018) and months on dialysis (r=-0.54; P<0.01). CONCLUSIONS Young adult RTR showed a reduced CFVR reflecting an impaired coronary microcirculation, which is significantly related to the age and duration of dialysis; coronary microvascular damage is detectable in the absence of changes in common carotid IMT. Non-invasive evaluation of CFVR by transthoracic stress echocardiography could be a reliable method for identification of early coronary microvascular involvement in young adult RTR.
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Affiliation(s)
- Maurizio Turiel
- Cardiology Unit, Department of Health Technologies, IRCCS Galeazzi Orthopedic Institute, University of Milan, Milan, Italy.
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Yigla M, Banderski R, Azzam ZS, Reisner SA, Nakhoul F. Arterio-venous access in end-stage renal disease patients and pulmonary hypertension. Ther Adv Respir Dis 2008; 2:49-53. [PMID: 19124358 DOI: 10.1177/1753465808089456] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND The syndrome of pulmonary hypertension (PHT) in end-stage renal disease (ESRD) has been described in patients on chronic hemodialysis (HD) therapy via arterial-venous (A-V) access. However, the exact timing for the development of the PHT is unknown. This study was designed to evaluate changes in pulmonary artery pressure (PAP) following creation of the vascular access. PATIENTS AND METHODS PAP and cardiac-output (CO) values were recorded in 12 pre-dialysis patients without PHT a few months after the access formation, before treatment with HD was started, and the prevalence of PHT was calculated. Clinical data was compared between patients with and without PHT. RESULTS The systolic PAP values were increased in "ve of the 12 pre-dialysis patients (42%) by 21+/-9 mm Hg to more than 35 mm Hg. Patients with and without PHT differed only in that CO was signi"cantly higher among the former. CONCLUSIONS The development of PHT following access formation represents a failure of the pulmonary circulation to accommodate the access-mediated elevated CO. Pre-dialysis patients scheduled for access formation should be screened for the presence of sub-clinical PHT. "Positive" patients should proceed to peritoneal dialysis or advance to kidney transplantation; rather than getting access and HD therapy.
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Affiliation(s)
- Mordechai Yigla
- Division of Pulmonary Medicine, Rambam Medical Center, POB 9602, Haifa 31096, Israel.
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Accelerated arterial stiffening and gene expression profile of the aorta in patients with coronary artery disease. J Hypertens 2008; 26:747-57. [DOI: 10.1097/hjh.0b013e3282f4b3d0] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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Blunted post-ischemic increase of the endothelial skin blood flowmotion component as early sign of endothelial dysfunction in chronic kidney disease patients. Microvasc Res 2007; 75:315-22. [PMID: 17931669 DOI: 10.1016/j.mvr.2007.08.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2007] [Revised: 07/16/2007] [Accepted: 08/13/2007] [Indexed: 01/14/2023]
Abstract
With the aim to investigate microvascular endothelial function in chronic kidney disease (CKD) patients on conservative treatment, skin blood flowmotion (SBF) was explored by spectral Fourier analysis of skin forearm laser Doppler tracing, registered before and following forearm ischemia in 32 III to V stage CKD patients (23 males, mean age: 52+/-12 years), without diabetes or cardiovascular disease, and in 32 age and sex matched healthy subjects. The power spectral density (PSD) of the 0.009-1.6 Hz total spectrum SBF, as well as of five sub-intervals, each of them related to endothelial (0.009-0.02 Hz), sympathetic (0.02-0.06 Hz), myogenic (0.06-0.2 Hz), respiratory (0.2-0.6 Hz) or cardiac (0.6-1.6 Hz) activity, was measured in PU(2)/Hz (PU=perfusion unit; 1 PU=10 mV). Under basal conditions CKD patients and controls did not differ in skin perfusion or in PSD of total spectrum SBF, as well as of each of the five subintervals considered. No substantial difference was also observed in skin post-ischemic hyperemia between patients and controls. A significant post-ischemic increase in the normalized value of endothelial sub-interval was observed in controls (p<0.05, GLM ANOVA analysis of variance), but not in CKD patients. A lower per cent increase in absolute PSD value of endothelial sub-interval was also observed in CKD patients compared to controls (185+/-98 % vs 279+/-243 %, p<0.05). The post-ischemic per cent increase in absolute PSD of endothelial sub-interval was negatively related to the systolic blood pressure (r=-0.45, p<0.01), to the mean arterial blood pressure (r=-0.40, p<0.05) and to the PTH serum levels (r=-0.38, p<0.05) in CKD patients. The blunted post-ischemic increase of the endothelial SBF sub-interval can be considered an early sign of microvascular endothelial dysfunction in the CKD studied patients. Arterial hypertension seems to be the main factor related to this SBF abnormality, together with the hormonal CKD related abnormalities.
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Vaccaro F, Mulè G, Cottone S, Soresi M, Giannitrapani L, Vadalà A, Sparacino V, Calabrese S, Picone FP, Montalto G, Cerasola G. Circulating levels of adhesion molecules in chronic kidney disease correlate with the stage of renal disease and with C-reactive protein. Arch Med Res 2007; 38:534-538. [PMID: 17560459 DOI: 10.1016/j.arcmed.2007.01.013] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2006] [Accepted: 01/04/2007] [Indexed: 11/26/2022]
Abstract
BACKGROUND Patients with chronic renal failure (CRF) suffer from a series of complications linked to the atherosclerotic process in which the endothelial dysfunction mediated by the activation of some adhesion molecules plays an important role. This study aims to evaluate circulating levels of intercellular adhesion molecules-1 (ICAM-1) and vascular cell adhesion molecules-1 (VCAM-1) in patients with predialysis CRF, on maintenance hemodialysis (HD) and after kidney transplantation (KTx) and to correlate them with some inflammation and nutritional indexes. METHODS Thirty two patients with predialysis CRF, 30 on maintenance HD, 36 after KTx and 28 subjects as a control group (C) were included in this study. Circulating levels of ICAM-1 and VCAM-1 were assayed using a specific sandwich ELISA kit. As inflammation indexes, TNFalpha and C-reactive protein (CRP) and, as nutritional indexes, body mass index (BMI), serum albumin, cholesterol, triglycerides, and fibrinogen (F) were evaluated. RESULTS Serum levels of ICAM-1 and VCAM-1 were progressively higher from C to KTx patients, to those with CRF and those on HD (ANOVA for both; p <0.001). TNFalpha values were lower in HD subjects than in CRF patients, even if in both groups TNFalpha levels were greater than in Tx and control subjects. F and CRP were higher in CRF and HD vs. Tx and control subjects (ANOVA for both p <0.001). No significant correlations were observed between soluble adhesion molecules, albumin and cholesterol, whereas significant correlations were found between CRP and ICAM-1 (r = 0.41; p <0.01), CRP and VCAM-1 (r = 0.39; p <0.01) and between CRP and TNFalpha (r = 0.42; p <0.01). These correlations remained statistically significant even after adjustment for age and blood pressure (all p <0.01). BMI did not differ in the three patient groups. CONCLUSIONS Circulating levels of adhesion molecules in our study correlated positively with the stage of disease and with one of the inflammatory indexes (CRP), but not with nutritional indexes such as BMI, cholesterol and albumin. The clinical significance of our findings warrants further investigation.
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Affiliation(s)
- Francesco Vaccaro
- Department of Internal Medicine, Cardiovascular and Renal Disease, Chair of Internal Medicine, University of Palermo, Palermo, Italy
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Stasch JP, Schmidt P, Nedvetsky P, Nedvetskaya TA, Kumar H, Meurer S, Deile M, Taye A, Knorr A, Lapp H, Müller H, Turgay Y, Rothkegel C, Tersteegen A, Kemp-Harper B, Müller-Esterl W, Schmidt H. Endothelial Cell Dysfunction—Can One Outsmart Oxidative Stress by Direct Interaction with the Pathological Oxidized or Heme-Free Soluble Guanyl-Cyclase? J Am Soc Nephrol 2007. [DOI: 10.1681/asn.2007010103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
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Karakitsos D, Patrianakos AP, De Groot E, Boletis J, Karabinis A, Kyriazis J, Samonis G, Parthenakis FI, Vardas PE, Daphnis E. Androgen deficiency and endothelial dysfunction in men with end-stage kidney disease receiving maintenance hemodialysis. Am J Nephrol 2006; 26:536-43. [PMID: 17159341 DOI: 10.1159/000097816] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2006] [Accepted: 11/01/2006] [Indexed: 11/19/2022]
Abstract
OBJECTIVES AND METHODS Two thirds of men with end-stage kidney disease (ESKD) have serum testosterone levels in the hypogonadal range. We examined if low serum testosterone levels were correlated with measures of endothelial dysfunction in ESKD. Bilateral common carotid artery (CCA) intima-media thickness (IMT) and atherosclerotic plaque occurrence, left ventricular mass index, flow- (FMD) and nitrate-mediated vasodilatation (NMD) of the brachial artery were determined by ultrasound imaging in 100 nondiabetic men with ESKD (50 men exhibited androgen deficiency; serum testosterone concentrations <300 ng/dl). RESULTS Left-ventricular mass index, CCA diameter, CCA-IMT and atherosclerotic plaque occurrence were all significantly increased in ESKD patients with androgen deficiency compared with patients without androgen deficiency (p < 0.05). Also, FMD and NMD measurements were significantly reduced in the former compared with the latter (p < 0.05). Testosterone levels were inversely correlated with age and duration of hemodialysis therapy (r = -0.44 and r = -0.55; p < 0.001). Testosterone levels were negatively correlated to CCA-IMT and atherosclerotic plaque occurrence in patients with androgen deficiency (r = -0.32, p < 0.003, and r = -0.23, p < 0.04, respectively). FMD and NMD measurements were positively correlated to total (r = 0.65 and r = 0.61; both p < 0.0001) and free (r = 0.52 and r = 0.48; both p < 0.001) testosterone levels in patients with low androgenicity. CONCLUSION The present results indicated that ESKD patients with androgen deficiency had increased CCA-IMT, atherosclerotic plaque occurrence and reduced FMD and NMD compared with patients without androgen deficiency. Testosterone serum levels were negatively correlated to CCA-IMT and positively correlated to endothelium-dependent vasodilatation in ESKD patients with androgen deficiency.
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Dogra G, Irish A, Chan D, Watts G. Insulin Resistance, Inflammation, and Blood Pressure Determine Vascular Dysfunction in CKD. Am J Kidney Dis 2006; 48:926-34. [PMID: 17162147 DOI: 10.1053/j.ajkd.2006.08.008] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2006] [Accepted: 08/15/2006] [Indexed: 11/11/2022]
Abstract
BACKGROUND Conventional cardiovascular risk equations underestimate the risk for cardiovascular disease (CVD) in patients with chronic kidney disease (CKD), implying a role for novel risk factors. Our aim was to compare vascular function and arterial compliance, known markers of CVD, between patients with CKD and healthy controls and examine their association with traditional and novel CVD risk factors. METHODS Vascular function was determined by using high-resolution ultrasonography to measure brachial artery endothelial-dependent flow-mediated dilatation (FMD) and endothelial-independent glyceryl trinitrate (GTN)-mediated dilatation. Arterial compliance was measured by using pulse contour analysis to generate large-artery (C1) and small-artery (C2) compliance. We also examined the relationship between vascular function, arterial compliance and blood pressure, lipid and lipoprotein levels, insulin resistance, inflammation, oxidative stress, and calcium and phosphate levels in 105 patients with CKD and 40 healthy controls. RESULTS Vascular function and arterial compliance were significantly impaired in patients with CKD compared with healthy controls: mean FMD, 3.8% +/- 0.3% (SE) versus 5.7% +/- 0.6%; GTN-mediated dilatation, 15.7% +/- 0.9% versus 19.6% +/- 1.0%; C1, geometric mean, 12.1 mL/mm Hg; 95% confidence interval (CI), 11.2 to 13.1 versus 15.1 mL/mm Hg; 95% CI, 13.7 to 16.5; and C2, 3.8 mL/mm Hg; 95% CI, 3.4 to 4.3 versus 5.0 mL/mm Hg; 95% CI, 4.2 to 6.0; all P < 0.05. Patients with CKD had greater waist-hip ratios, systolic blood pressures (SBPs), pulse pressures, triglyceride levels, oxidized low-density lipoprotein levels, high-sensitivity interleukin 6 levels, and Homeostasis Model Assessment (HOMA) scores (all P < 0.05) and lower high-density lipoprotein levels (P < 0.001). In patients with CKD, HOMA score and SBP were associated negatively with FMD (model R(2) = 0.28; P < 0.001), and SBP and waist-hip ratio were associated negatively with GTN-mediated dilatation (model R(2) = 0.25; P < 0.001). Pulse pressure was associated negatively with C1 (R(2) = 0.37; P < 0.001), and pulse pressure and high-sensitivity interleukin 6 level were associated negatively with C2 (model R(2) = 0.36; P < 0.001). CONCLUSION Insulin resistance, inflammation, systolic hypertension, and increased pulse pressure, but not dyslipidemia, were associated with vascular dysfunction and may be targets for future interventional strategies to reduce CVD risk in patients with CKD.
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Affiliation(s)
- Gursharan Dogra
- School of Medicine and Pharmacology, University of Western Australia, Australia.
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