| Assessment of arterial stiffness, oxidative stress and inflammation in acute kidney injury. | |
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MedLine Citation:
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PMID: 19538714 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: It is well know that arterial stiffness, oxidative stress and inflammation are features of chronic kidney disease. The arterial changes have a multitude of potential interconnected causes including endothelial dysfunction, oxidative stress, inflammation, atherosclerosis and vascular calcification. There is evidence that arterial stiffness becomes progressively worse as CKD progresses. The contribution of the biochemical changes of uremic toxicity to arterial stiffness is less clear. The aim of this study is to elucidate the vascular changes in acute kidney injury. We hypothesise that arterial stiffness will be increased during acute kidney injury and this will return to normal after kidney function recovers. METHODS/DESIGN: One hundred and forty four patients with acute kidney injury defined as an acute increase in serum creatinine to > 133 micromol/l or urea > 14.3 mmol/l or urine output < 410 ml/day will be recruited. Baseline measures of aortic pulse wave velocity, augmentation index, and brachial and central blood pressure will be recorded along with blood measures for oxidative stress and inflammation. Repeat measures will be taken at six and 12 months after the onset of the acute kidney injury. DISCUSSION: The role and contribution of the biochemical changes to arterial stiffness in the acute phase of kidney disease is not known. This study will primarily assess the time course changes in pulse wave velocity from the onset of acute kidney injury and after recovery. In addition it will assess augmentation index, central blood pressure and oxidative stress and inflammation. This may shed light on the contribution of biochemical kidney toxins on arterial stiffness in both acute kidney injury and chronic kidney disease. TRIAL REGISTRATION: ACTRN 12609000285257. |
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Authors:
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Robert G Fassett; Vincent D'Intini; Helen Healy; John Gowardman; Jay-Sen Gan; James E Sharman; Jeff S Coombes |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-06-18 |
Journal Detail:
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Title: BMC nephrology Volume: 10 ISSN: 1471-2369 ISO Abbreviation: BMC Nephrol Publication Date: 2009 |
Date Detail:
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Created Date: 2009-06-29 Completed Date: 2009-09-28 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 100967793 Medline TA: BMC Nephrol Country: England |
Other Details:
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Languages: eng Pagination: 15 Citation Subset: IM |
Affiliation:
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Renal Medicine, Royal Brisbane and Women's Hospital, Queensland, Australia. rfassett@mac.com |
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| MeSH Terms | |
Descriptor/Qualifier:
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Adult Aged Aged, 80 and over Arteries / physiopathology* Blood Flow Velocity / physiology Blood Pressure / physiology Case-Control Studies Creatinine / blood Disease Progression Elasticity / physiology* Female Humans Inflammation / etiology, physiopathology* Kidney / blood supply, physiopathology Kidney Failure, Acute / blood, complications, physiopathology* Longitudinal Studies Male Middle Aged Outcome Assessment (Health Care) Oxidative Stress / physiology* |
| Chemical | |
Reg. No./Substance:
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60-27-5/Creatinine |
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| Full Text | |
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Journal Information Journal ID (nlm-ta): BMC Nephrol ISSN: 1471-2369 Publisher: BioMed Central |
Article Information Download PDF  Copyright ? 2009 Fassett et al; licensee BioMed Central Ltd. open-access: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Received Day: 18 Month: 5 Year: 2009 Accepted Day: 18 Month: 6 Year: 2009 collection publication date: Year: 2009 Electronic publication date: Day: 18 Month: 6 Year: 2009 Volume: 10First Page: 15 Last Page: 15 ID: 2702366 Publisher Id: 1471-2369-10-15 PubMed Id: 19538714 DOI: 10.1186/1471-2369-10-15 |
| Assessment of arterial stiffness, oxidative stress and inflammation in acute kidney injury | |
| Robert G Fassett156 | Email: rfassett@mac.com |
| Vincent D'Intini1 | Email: Vincent_Dintini@health.qld.gov.au |
| Helen Healy1 | Email: Helen_Healy@health.qld.gov.au |
| John Gowardman2 | Email: John_Gowardman@health.qld.gov.au |
| Jay-Sen Gan3 | Email: Jay.Gan@dhhs.tas.gov.au |
| James E Sharman4 | Email: jsharman@utas.edu.au |
| Jeff S Coombes5 | Email: jcoombes@uq.edu.au |
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1Renal Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia |
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2Intensive Care Unit, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia |
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3Department of Nephrology, Royal Hobart Hospital, Hobart, Tasmania, Australia |
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4Menzies Research Institute, University of Tasmania, Hobart, Tasmania, Australia |
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5School of Human Movement Studies, The University of Queensland, Brisbane, Queensland, Australia |
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6School of Medicine, The University of Queensland, Brisbane, Queensland, Australia |
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Vascular disease, characterised by premature atherosclerosis and large artery stiffness, is a feature of advanced chronic kidney disease (CKD) [1,2]. Central pulse pressure, augmentation index (AIx) and aortic pulse wave velocity (PWV) are all predictors of morbidity and mortality in patients with CKD [1,3,4]. Large artery stiffness may also be related to the progression of CKD. The mechanisms and time frames for the development of arterial stiffness are unclear but may include traditional cardiovascular risk factors such as dyslipidemia and hypertension as well as non-traditional risk factors such as oxidative stress and inflammation. Moreover, to our knowledge no studies have assessed the relationship between arterial stiffness in the uraemic environment of acute kidney injury. Measuring arterial stiffness in this setting would enable us to determine whether changes in arterial stiffness occur due to the biochemical changes associated with acute kidney injury without the interference of factors such as chronic vascular calcification that exist in chronic kidney disease. This may in turn help to understand the potential for reversibility of uremic biochemical effects on arterial stiffness.
This is a longitudinal observational clinical study. Patients from the Royal Brisbane and Women's Hospital and the Launceston General Hospital will be recruited into this study. These hospitals service populations of approximately 1.2 million and 250,000 respectively.
The Tasmanian Statewide Scientific and Ethics Committees and the Human Research and Ethics Committee of the Royal Brisbane and Women's Hospital have approved this study.
One hundred and forty four patients with acute kidney injury and 45 matched controls.
Acute kidney injury participants will be recruited from two settings at each hospital.
1. The Intensive care unit: The distinguishing features of intensive care research are the requirements to recruit and obtain informed consent rapidly when it may be difficult to communicate with the patient. As the patient requirements for this study are minimal and non-invasive it is not expected that these requirements will be problematic. All attempts will be made to gain informed written consent directly from the patient. The patients will be approached by one of the investigators who will explain the study, provide them with the information sheet and request they consider entering the study and therefore sign the consent form. If patients are unable to provide written informed consent themselves (e.g. they are unconscious or too unwell) the next of kin will be approached by one of the investigators who will explain the study, provide them with the information sheet and request that they consider the patient enters the study and sign the consent form on their behalf.
2. The Renal medicine service: This will include the renal inpatients and referrals from General Internal Medicine, Surgery and other departments in the Royal Brisbane and Women's Hospital. For these patients the recruitment will be based on the standard informed consent process as described above for the conscious intensive care unit patient.
Two years
Inclusion criteria: Male and female patients > 18 years of age presenting to the Royal Brisbane and Women's Hospital and the Launceston General Hospital with acute kidney injury but not having started dialysis or continuous venovenous hemofiltration will be eligible for recruitment (Figure 1). Acute kidney injury will be defined as the presence of a serum creatinine > 133 ?mol/l or urea > 14.3 mmol/l or urine output < 410 ml/day [5,6].
Exclusion criteria: Patients receiving vasoactive drugs such as inotropic agents or on dialysis or continuous venovenous hemofiltration will be excluded. In addition, any patients with a condition the treating doctor deems to preclude the patient participating based on safety concerns will be excluded. Patients planned for palliative care, unwilling to comply with trial requirements, or whose life expectancy is severely limited (< six months) due to pre-existing malignancy or other disease will be excluded. Finally, patients that are pregnant or have a planned pregnancy will also be excluded.
To determine the effects of acute kidney injury on arterial stiffness
Patients with acute kidney injury will have increased arterial stiffness compared to matched controls.
Patients who recover kidney function following acute kidney injury will have a concomitant reduction in arterial stiffness.
Carotid to femoral PWV will be derived by electrocardiography-gated sequential applanation tonometry (SPT-301 Mikro-Tip, Millar Instruments, Houston, Texas) using the foot-to-foot method (SphymoCor? 7.01 AtCor, Sydney, Australia) [7]. Testing will be performed in a temperature-controlled room and after 5?10 minutes rest with the subject in the supine position prior to the first measure. Two measures will be averaged for the estimation of aortic PWV. Aortic stiffness (carotid to femoral PWV) will be derived by electrocardiography-gated sequential applanation tonometry using the foot-to-foot method (SphygmoCor 7.01 AtCor, Sydney, Australia) as previously described [7]. Briefly, three ECG electrodes are placed on the patient's chest and they are required to lie quietly for 15 minutes. Brachial blood pressure is measured and then the tonometer is applied sequentially over the radial, carotid and femoral arteries. The procedure takes around 15 minutes, but this may vary depending on patient morphology.
To determine the associations between oxidative stress and inflammation with changes in arterial stiffness and central blood pressure in patients with acute kidney injury.
There will be significant relationships between oxidative stress and inflammation and changes in arterial stiffness and central blood pressure in patients with acute kidney injury.
The outcome measure for oxidative stress will be plasma isoprostanes measured using gas chromatography mass spectrometry [8]. In addition, plasma protein carbonyls, total antioxidant capacity and antioxidant enzyme activities will also be measured to further assess oxidative stress and antioxidant status.
The outcome measure for inflammation will be pentraxin 3 measured using an ELISA assay [9]. In addition, interleukin (IL)-6, IL-8, IL-10, high sensitivity C reactive protein and tumour necrosis factor-alpha will be measured as further markers of inflammation.
The SphygmoCor device will be used to determine central blood pressure and AIx as additional markers of arterial stiffness. A central (ascending aortic) pressure waveform will be derived by radial tonometry as previously described [7]. This method involves placing a tonometer over the radial artery and using a generalised transfer function to transform the radial pressure waveform. Central pulse pressure will be recorded as an estimate of afterload and AIx as a composite measure of systemic arterial stiffness and arterial wave reflection. The central waveform will be calibrated by the average of two measures of brachial blood pressure using a semi-automated device (UA-767, A&D, Saitama, Japan) after five minutes of supine rest.
Routine measures including full blood count, electrolytes, coagulation profile, liver function test and lipid profile will be carried out at the Hospitals' Pathology Laboratories. Other data collected at the time will include demographic details, medical history and medication profile.
Upon collection, blood samples will be placed on ice and then centrifuged (500 g) at 4?C for five minutes. One ml aliquots of plasma will be stored in eppendorf tubes immediately at -80?C for future biochemical analyses of oxidative stress and inflammation.
After patients provide informed consent they will undergo baseline testing to measure resting peripheral and central blood pressure, arterial stiffness and have blood taken for standard biochemistry and measures of oxidative stress and inflammation. Control data will be obtained from a database of one of the authors that contains arterial stiffness measures on healthy individuals with normal kidney function. Subjects from this database will be selected to match with patients included in the analyses.
All measures taken at baseline will be repeated at six and twelve months after the onset of the acute kidney injury.
This will be defined as return of kidney function to normal (eGFR > 60 ml/min/1.73 m2) or, where data is available, a return to the level of kidney function within 5% assessed by eGFR present within three months prior to the acute kidney injury.
If requested, subjects will be withdrawn from the study without prejudice, as documented and explained at the time of consenting.
Sample sizes of 144 acute kidney injury patients and 45 matched controls have been determined as follows. The primary outcome measure is aortic PWV. To our knowledge, there is no published aortic PWV data available for acute kidney injury patients. We therefore used haemodialysis patient aortic PWV data from one of our other investigations, the PEDAL study[10]. We found that the aortic PWV of dialysis patients was 9.4 +/- 1.9 m/sec. Previous work from Blacher et al reported that for each 1 m/sec increase in aortic PWV there is a 34% increase in both cardiovascular and total mortality [11]. We assume that this increase is clinically relevant. Therefore in order to detect a 1 m/sec difference in PWV compared to controls (hypothesis 1) or 1 m/sec change in aortic PWV in the patients (hypothesis 2) 45 patients will be required (beta 1-0.8 = 0.20, alpha = 0.05 using a two tailed paired t test). This assumes the initial aortic PWV will be 9.4 +/- 1.9 m/sec and if the hypotheses are supported the aortic PWV in controls and on restoration of kidney function will be 8.4 +/- 1.9 m/sec. However allowing for 1) a high loss to follow-up rate (50%) because of the mortality associated with acute kidney injury, particularly in ICU, and 2) the expected number of patients who will recover kidney function after 12 months (60%) then at least 144 patients will need to be recruited to achieve the 45 patients required.
General linear modelling will be used to test the hypotheses. Bi-variate and multivariate techniques will be used to assess the secondary aims of the relative independent effects of variables on the outcomes measures. Significance will be assumed if P < 0.05.
The objective of this study is to assess whether the biochemical changes seen in acute kidney injury can affect arterial stiffness. Although arterial stiffness is a feature of vascular dysfunction in chronic kidney disease it is not clear how much, if at all the biochemical abnormalities seen in the circulation account for such changes. In addition, the study will assess augmentation index, central blood pressure and oxidative stress and inflammation. Data from this study may lead to a better understanding of the vascular dysfunction seen in kidney disease.
The authors declare that they have no competing interests.
RGF and JSC designed the study and wrote the protocol. JG provided advice and input and will be involved with the intensive care component of the study. VD and HH provided advice and input and will be involved with the renal medicine department component of the study. J-S G will perform arterial stiffness measures and contributed to manuscript review. JS provide advice and input into the arterial stiffness measures and reviewed the manuscript. All authors read and approved the final manuscript.
The pre-publication history for this paper can be accessed here:
We would like to thank Lisa Anderson, Ritza Driver, Marianne Smith, David Holland, Kirsten Koh, Colleen Morgan and Cheryl Fourie for their assistance in setting up the study. Funding for the study is being kindly provided from a Strategic Research Grant from the Royal Brisbane and Women's Hospital Research Foundation and from a Mayne Bequest Fund Grant from The University of Queensland.
References
| Blacher J,Guerin AP,Pannier B,Marchais SJ,Safar ME,London GM. Impact of aortic stiffness on survival in end-stage renal diseaseCirculation 1999;99:2434–2439. [pmid: 10318666] | |
| DeLoach SS,Townsend RR. Vascular stiffness: its measurement and significance for epidemiologic and outcome studiesClin J Am Soc Nephrol 2008;3:184–192. [pmid: 18178784] [doi: 10.2215/CJN.03340807] | |
| London GM,Blacher J,Pannier B,Guerin AP,Marchais SJ,Safar ME. Arterial wave reflections and survival in end-stage renal failureHypertension 2001;38:434–438. [pmid: 11566918] | |
| Safar ME,Blacher J,Pannier B,Guerin AP,Marchais SJ,Guyonvarc'h PM,London GM. Central pulse pressure and mortality in end-stage renal diseaseHypertension 2002;39:735–738. [pmid: 11897754] [doi: 10.1161/hy0202.098325] | |
| Knaus WA,Zimmerman JE,Wagner DP,Draper EA,Lawrence DE. APACHE-acute physiology and chronic health evaluation: a physiologically based classification systemCrit Care Med 1981;9:591–597. [pmid: 7261642] | |
| Mehta RL,Pascual MT,Soroko S,Chertow GM. Diuretics, mortality, and nonrecovery of renal function in acute renal failureJAMA 2002;288:2547–2553. [pmid: 12444861] [doi: 10.1001/jama.288.20.2547] | |
| Wilkinson IB,Fuchs SA,Jansen IM,Spratt JC,Murray GD,Cockcroft JR,Webb DJ. Reproducibility of pulse wave velocity and augmentation index measured by pulse wave analysisJ Hypertens 1998;16:2079–2084. [pmid: 9886900] [doi: 10.1097/00004872-199816121-00033] | |
| Mori TA,Croft KD,Puddey IB,Beilin LJ. An improved method for the measurement of urinary and plasma F2-isoprostanes using gas chromatography-mass spectrometryAnal Biochem 1999;268:117–125. [pmid: 10036170] [doi: 10.1006/abio.1998.3037] | |
| Rolph MS,Zimmer S,Bottazzi B,Garlanda C,Mantovani A,Hansson GK. Production of the long pentraxin PTX3 in advanced atherosclerotic plaquesArterioscler Thromb Vasc Biol 2002;22:e10–14. [pmid: 12006411] [doi: 10.1161/01.ATV.0000015595.95497.2F] | |
| Koh KP,Fassett RG,Sharman JE,Coombes JS,Williams AD. Intradialytic versus home based exercise training in hemodialysis patients: a randomised controlled trialBMC Nephrol 2009;10:2. [pmid: 19178747] [doi: 10.1186/1471-2369-10-2] | |
| Blacher J,Safar ME,Guerin AP,Pannier B,Marchais SJ,London GM. Aortic pulse wave velocity index and mortality in end-stage renal diseaseKidney Int 2003;63:1852–1860. [pmid: 12675863] [doi: 10.1046/j.1523-1755.2003.00932.x] |
Figures
[Figure ID: F1] |
Figure 1
Study patient flow. |
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