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Jiwani S, Chan WC, Majmundar M, Patel KN, Mehta H, Sharma A, Parmar G, Wiley M, Tadros P, Hockstad E, Yarlagadda SG, Gupta A, Gupta K. Impact of preexisting coronary artery and peripheral artery disease on outcomes in diabetic patients after kidney transplant. Vasc Med 2024; 29:135-142. [PMID: 37936422 DOI: 10.1177/1358863x231205574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2023]
Abstract
BACKGROUND Atherosclerotic cardiovascular disease is highly prevalent in patients with end-stage kidney disease (ESKD). Kidney transplant (KT) improves patient survival and cardiovascular outcomes. The impact of preexisting coronary artery disease (CAD) and peripheral artery disease (PAD) on posttransplant outcomes remains unclear. METHODS This is a retrospective study utilizing the United States Renal Data System. Adult diabetic dialysis patients who underwent first KT between 2006 and 2017 were included. The study population was divided into four cohorts based on presence of CAD/PAD: (1) polyvascular disease (CAD + PAD); (2) CAD without PAD; (3) PAD without CAD; (4) no CAD or PAD (reference cohort). The primary outcome was 3-year all-cause mortality. Secondary outcomes were incidence of posttransplant myocardial infarction (MI), cerebrovascular accidents (CVA), and graft failure. RESULTS The study population included 19,329 patients with 64.4% men, mean age 55.4 years, and median dialysis duration of 2.8 years. Atherosclerotic cardiovascular disease was present in 28% of patients. The median follow up was 3 years. All-cause mortality and incidence of posttransplant MI were higher with CAD and highest in patients with polyvascular disease. The cohort with polyvascular disease had twofold higher all-cause mortality (16.7%, adjusted hazard ratio (aHR) 1.5, p < 0.0001) and a fourfold higher incidence of MI (12.7%, aHR 3.3, p < 0.0001) compared to the reference cohort (8.0% and 3.1%, respectively). There was a higher incidence of posttransplant CVA in the cohort with PAD (3.4%, aHR 1.5, p = 0.01) compared to the reference cohort (2.0%). The cohorts had no difference in graft failure rates. CONCLUSIONS Preexisting CAD and/or PAD result in worse posttransplant survival and cardiovascular outcomes in patients with diabetes mellitus and ESKD without a reduction in graft survival.
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Affiliation(s)
- Sania Jiwani
- Department of Cardiovascular Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Wan-Chi Chan
- Department of Cardiovascular Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Monil Majmundar
- Department of Cardiovascular Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Kunal N Patel
- Department of Cardiovascular Medicine, West Virginia University Hospital, Morgantown, WV, USA
| | - Harsh Mehta
- Department of Cardiovascular Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Aditya Sharma
- Division of Cardiovascular Medicine, University of Virginia, Charlottesville, VA, USA
| | - Gaurav Parmar
- Section of Vascular Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Mark Wiley
- Department of Cardiovascular Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Peter Tadros
- Department of Cardiovascular Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Eric Hockstad
- Department of Cardiovascular Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Sri G Yarlagadda
- Department of Internal Medicine, Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, KS, USA
| | - Aditi Gupta
- Department of Internal Medicine, Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, KS, USA
| | - Kamal Gupta
- Department of Cardiovascular Medicine, University of Kansas Medical Center, Kansas City, KS, USA
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Jethwani P. Overview of Renal Transplantation for Primary Care Physicians: Workup, Complications, and Management. Med Clin North Am 2023; 107:707-716. [PMID: 37258008 DOI: 10.1016/j.mcna.2023.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Kidney transplantation remains the treatment of choice for eligible patients with end-stage kidney disease. The last few decades have seen an expansion in the transplant recipient pool with over 250,000 patients living with a kidney transplant today. Because of limited bandwidth for ongoing follow-up and management of chronic medical conditions, transplant centers are directing more and more patients back to their general nephrologists and primary care doctors for longitudinal care. As a result, it is becoming increasingly important for primary care physicians to have a nuanced understanding of medications, complications, and chronic medical problems unique to transplant recipients. This article reviews the role of the primary care office in helping streamline the pretransplant evaluation process and long-term posttransplant care.
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Affiliation(s)
- Priyanka Jethwani
- James D Eason Transplant Institute, Methodist University Hospital, 1265 Union Avenue, Memphis, TN 38104, USA; Department of Surgery, University of Tennessee Health Sciences Center, 1211 Union Avenue, Memphis, TN 38104, USA.
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Wilson GJ, Van K, O'Lone E, Tong A, Craig JC, Sautenet B, Budde K, Forfang D, Gill J, Herrington WG, Jafar TH, Johnson DW, Krane V, Levin A, Malyszko J, Rossignol P, Sawinski D, Scholes-Robertons N, Strippoli G, Wang A, Winkelmayer WC, Hawley CM, Viecelli AK. Range and Consistency of Cardiovascular Outcomes Reported by Clinical Trials in Kidney Transplant Recipients: A Systematic Review. Transplant Direct 2023; 9:e1398. [PMID: 36518792 PMCID: PMC9742089 DOI: 10.1097/txd.0000000000001398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 08/28/2022] [Accepted: 09/13/2022] [Indexed: 12/13/2022] Open
Abstract
Cardiovascular disease is a major cause of morbidity and mortality in kidney transplant recipients. Trial evidence to improve cardiovascular outcomes is limited by inconsistent reporting of outcomes, which may also lack patient-relevance. This study aimed to assess the range and consistency of cardiovascular outcomes reported by contemporary trials in kidney transplant recipients. Methods A systematic review of all randomized controlled trials involving adult kidney transplant recipients that reported at least 1 cardiovascular outcome from January 2012 to December 2019 was performed, including Embase, MEDLINE, Cochrane, and ClinicalTrials.gov electronic databases. Trial characteristics were extracted and all levels of specification of the cardiovascular outcome measures reported were analyzed (the measure definition, metric' and method of aggregation). Measures assessing a similar aspect of cardiovascular disease were categorized into outcomes. Results From 93 eligible trials involving 27 609 participants, 490 outcome measures were identified. The outcome measures were grouped into 38 outcomes. A cardiovascular composite was the most common outcome reported (40 trials, 43%) followed by cardiovascular mortality (42%) and acute coronary syndrome (31%). Cardiovascular composite was also the most heterogeneous outcome with 77 measures reported followed by cardiovascular mortality (n = 58) and inflammatory biomarkers (n = 51). The most common cardiovascular composite outcome components reported were major cardiovascular events (18 trials), stroke unspecified (11 trials), and myocardial infarction unspecified (10 trials). Conclusions There is substantial heterogeneity in cardiovascular outcome reporting in kidney transplant trials.
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Affiliation(s)
- Gregory J Wilson
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Department of Nephrology, Mater Health Services, Brisbane, QLD, Australia
- Department of Nephrology, Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Kim Van
- Sydney School of Public Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Emma O'Lone
- Sydney School of Public Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Allison Tong
- Sydney School of Public Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Jonathan C Craig
- College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
| | - Benedicte Sautenet
- Service de Nephrologie-Hypertension, Dialyses, Transplantation Rénale, Hopital Bretonneau, Université de Tours, Université de Nantes, INSERM SPHERE U 1246, Tours, France
| | | | | | - John Gill
- University of British Columbia, Vancouver, BC, Canada
| | - William G Herrington
- Nuffield Department of Population Health, Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, United Kingdom
| | | | - David W Johnson
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Department of Nephrology, Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Vera Krane
- University of Würzburg, Würzburg, Germany
| | - Adeera Levin
- University of British Columbia, Vancouver, BC, Canada
| | - Jolanta Malyszko
- Department of Medicine, Division of Nephrology, University of Wurzburg, Wurzburg, Germany
| | - Patrick Rossignol
- Université de Lorraine & FCRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists) Network, Nancy, France
| | | | | | | | - Angela Wang
- The University of Hong Kong, Pok Fu Lam, Hong Kong
| | | | - Carmel M Hawley
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Department of Nephrology, Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Andrea K Viecelli
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Department of Nephrology, Princess Alexandra Hospital, Brisbane, QLD, Australia
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Kant S, Soman S, Choi MJ, Jaar BG, Adey DB. Management of Hospitalized Kidney Transplant Recipients for Hospitalists and Internists. Am J Med 2022; 135:950-957. [PMID: 35472384 DOI: 10.1016/j.amjmed.2022.04.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 04/04/2022] [Accepted: 04/04/2022] [Indexed: 11/01/2022]
Abstract
The number of kidney transplant recipients has grown incrementally over the years. These patients have a high comorbidity index and require special attention to immunosuppression management. In addition, this population has an increased risk for cardiovascular events, electrolyte abnormalities, allograft dysfunction, and infectious complications. It is vital for hospitalists and internists to understand the risks and nuances in the care of this increasingly prevalent, but also high-risk, population.
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Affiliation(s)
- Sam Kant
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Sandeep Soman
- Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, Mich
| | - Michael J Choi
- Division of Nephrology and Hypertension, MedStar Georgetown University Hospital, Washington, DC
| | - Bernard G Jaar
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md; Welch Center for Prevention, Epidemiology, and Clinical Research, Baltimore, Md; Nephrology Center of Maryland, Baltimore.
| | - Deborah B Adey
- Division of Nephrology, Department of Medicine, University of California, San Francisco
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Natale P, Palmer SC, Saglimbene VM, Ruospo M, Razavian M, Craig JC, Jardine MJ, Webster AC, Strippoli GF. Antiplatelet agents for chronic kidney disease. Cochrane Database Syst Rev 2022; 2:CD008834. [PMID: 35224730 PMCID: PMC8883339 DOI: 10.1002/14651858.cd008834.pub4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
BACKGROUND Antiplatelet agents are widely used to prevent cardiovascular events. The risks and benefits of antiplatelet agents may be different in people with chronic kidney disease (CKD) for whom occlusive atherosclerotic events are less prevalent, and bleeding hazards might be increased. This is an update of a review first published in 2013. OBJECTIVES To evaluate the benefits and harms of antiplatelet agents in people with any form of CKD, including those with CKD not receiving renal replacement therapy, patients receiving any form of dialysis, and kidney transplant recipients. SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies up to 13 July 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA We selected randomised controlled trials of any antiplatelet agents versus placebo or no treatment, or direct head-to-head antiplatelet agent studies in people with CKD. Studies were included if they enrolled participants with CKD, or included people in broader at-risk populations in which data for subgroups with CKD could be disaggregated. DATA COLLECTION AND ANALYSIS Four authors independently extracted data from primary study reports and any available supplementary information for study population, interventions, outcomes, and risks of bias. Risk ratios (RR) and 95% confidence intervals (CI) were calculated from numbers of events and numbers of participants at risk which were extracted from each included study. The reported RRs were extracted where crude event rates were not provided. Data were pooled using the random-effects model. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS We included 113 studies, enrolling 51,959 participants; 90 studies (40,597 CKD participants) compared an antiplatelet agent with placebo or no treatment, and 29 studies (11,805 CKD participants) directly compared one antiplatelet agent with another. Fifty-six new studies were added to this 2021 update. Seven studies originally excluded from the 2013 review were included, although they had a follow-up lower than two months. Random sequence generation and allocation concealment were at low risk of bias in 16 and 22 studies, respectively. Sixty-four studies reported low-risk methods for blinding of participants and investigators; outcome assessment was blinded in 41 studies. Forty-one studies were at low risk of attrition bias, 50 studies were at low risk of selective reporting bias, and 57 studies were at low risk of other potential sources of bias. Compared to placebo or no treatment, antiplatelet agents probably reduces myocardial infarction (18 studies, 15,289 participants: RR 0.88, 95% CI 0.79 to 0.99, I² = 0%; moderate certainty). Antiplatelet agents has uncertain effects on fatal or nonfatal stroke (12 studies, 10.382 participants: RR 1.01, 95% CI 0.64 to 1.59, I² = 37%; very low certainty) and may have little or no effect on death from any cause (35 studies, 18,241 participants: RR 0.94, 95 % CI 0.84 to 1.06, I² = 14%; low certainty). Antiplatelet therapy probably increases major bleeding in people with CKD and those treated with haemodialysis (HD) (29 studies, 16,194 participants: RR 1.35, 95% CI 1.10 to 1.65, I² = 12%; moderate certainty). In addition, antiplatelet therapy may increase minor bleeding in people with CKD and those treated with HD (21 studies, 13,218 participants: RR 1.55, 95% CI 1.27 to 1.90, I² = 58%; low certainty). Antiplatelet treatment may reduce early dialysis vascular access thrombosis (8 studies, 1525 participants) RR 0.52, 95% CI 0.38 to 0.70; low certainty). Antiplatelet agents may reduce doubling of serum creatinine in CKD (3 studies, 217 participants: RR 0.39, 95% CI 0.17 to 0.86, I² = 8%; low certainty). The treatment effects of antiplatelet agents on stroke, cardiovascular death, kidney failure, kidney transplant graft loss, transplant rejection, creatinine clearance, proteinuria, dialysis access failure, loss of primary unassisted patency, failure to attain suitability for dialysis, need of intervention and cardiovascular hospitalisation were uncertain. Limited data were available for direct head-to-head comparisons of antiplatelet drugs, including prasugrel, ticagrelor, different doses of clopidogrel, abciximab, defibrotide, sarpogrelate and beraprost. AUTHORS' CONCLUSIONS Antiplatelet agents probably reduced myocardial infarction and increased major bleeding, but do not appear to reduce all-cause and cardiovascular death among people with CKD and those treated with dialysis. The treatment effects of antiplatelet agents compared with each other are uncertain.
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Affiliation(s)
- Patrizia Natale
- Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Suetonia C Palmer
- Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand
| | - Valeria M Saglimbene
- Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
| | - Marinella Ruospo
- Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
| | - Mona Razavian
- Renal and Metabolic Division, The George Institute for Global Health, Newtown, Australia
| | - Jonathan C Craig
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
| | | | - Angela C Webster
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Centre for Transplant and Renal Research, Westmead Millennium Institute, The University of Sydney at Westmead, Westmead, Australia
| | - Giovanni Fm Strippoli
- Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
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Increased Frequency of Nutritional Counseling Improves Weight Status and Lipids in Renal Transplant Recipients. TOP CLIN NUTR 2021. [DOI: 10.1097/tin.0000000000000231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Variations in Circulating Active MMP-9 Levels During Renal Replacement Therapy. Biomolecules 2020; 10:biom10040505. [PMID: 32225016 PMCID: PMC7226477 DOI: 10.3390/biom10040505] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 03/16/2020] [Accepted: 03/23/2020] [Indexed: 12/15/2022] Open
Abstract
Renal replacement therapy (RRT) is complicated by a chronic state of inflammation and a high mortality risk. However, different RRT modalities can have a selective impact on markers of inflammation and oxidative stress. We evaluated the levels of active matrix metalloproteinase (MMP)-9 in patients undergoing two types of dialysis (high-flux dialysis (HFD) and on-line hemodiafiltration (OL-HDF)) and in kidney transplantation (KT) recipients. Active MMP-9 was measured by zymography and ELISA before (pre-) and after (post-) one dialysis session, and at baseline and follow-up (7 and 14 days, and 1, 3, 6, and 12 months) after KT. Active MMP-9 decreased post-dialysis only in HFD patients, while the levels in OL-HDF patients were already lower before dialysis. Active MMP-9 increased at 7 and 14 days post-KT and was restored to baseline levels three months post-KT, coinciding with an improvement in renal function and plasma creatinine. Active MMP-9 correlated with pulse pressure as an indicator of arterial stiffness both in dialysis patients and KT recipients. In conclusion, active MMP-9 is better controlled in OL-HDF than in HFD and is restored to baseline levels along with stabilization of renal parameters after KT. Active MMP-9 might act as a biomarker of arterial stiffness in RRT.
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The Challenges With the Cardiac Evaluation of Liver and Kidney Transplant Candidates. Transplantation 2020; 104:251-258. [DOI: 10.1097/tp.0000000000002951] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Molcho M, Rozen-Zvi B, Shteinmats T, Ben Dor N, Vahav I, Nesher E, Rahamimov R. Temporal changes of proteinuria after kidney transplantation: association with cardiovascular morbidity and mortality. J Nephrol 2020; 33:1059-1066. [PMID: 31953621 DOI: 10.1007/s40620-020-00703-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 01/06/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND Proteinuria is common in kidney transplant recipients and has been established as a risk factor for graft-loss and mortality. In the general population, proteinuria has also been tied to a higher risk of cardiovascular disease. There is limited data exploring the association between changes in proteinuria over time and cardiovascular disease in kidney transplant recipients. METHODS In this retrospective cohort study we evaluated proteinuria as a time-varying covariate using urine dipstick protein values at 6 month intervals post-transplant. The primary outcome was the occurrence a major cardiovascular event (MACE). Univariate and multivariate time varying Cox model was used. RESULTS 579 patients were included in the final cohort. 120 episodes of MACE were documented in 98 patients. Time varying proteinuria was associated with MACE by univariate and multivariate analysis (HR 2.63, 95% CI 1.76-3.93, p < 0.001) and (HR 2.33, 95% CI 1.53-3.54, p < 0.001). Reduction of proteinuria to normal was associated with reduced risk of MACE compared with active proteinuria (HR 0.44, 95% CI 0.28-0.69, p < 0.001) and (HR 0.47, 95% CI 0.3-0.76, p = 0.002) for univariate and multivariate analyses. Exposure to proteinuria for more than 1 year was significantly associated with an increased risk of MACE for univariate and multivariate analysis (HR 2.33, 95% CI 1.48-3.68, p < 0.001) and (HR 2.18, 95% CI 1.37-3.45, p = 0.002) respectively, in comparison to exposure of less than 1 year. CONCLUSION These findings may suggest that we should consider applying clinical interventions that are known to reduce cardiovascular morbidity in these patients.
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Affiliation(s)
- Maya Molcho
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Benaya Rozen-Zvi
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.,Department of Nephrology and Hypertension, Rabin Medical Center, Beilinson campus. 39, Jabutinsky St., Petah-Tikva, Israel
| | - Tali Shteinmats
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.,Department of Nephrology and Hypertension, Rabin Medical Center, Beilinson campus. 39, Jabutinsky St., Petah-Tikva, Israel
| | - Naomi Ben Dor
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.,Department of Nephrology and Hypertension, Rabin Medical Center, Beilinson campus. 39, Jabutinsky St., Petah-Tikva, Israel
| | - Itay Vahav
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Eviatar Nesher
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.,Department of Transplantation, Rabin Medical Center, Beilinson campus, Petah-Tikva, Israel
| | - Ruth Rahamimov
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. .,Department of Nephrology and Hypertension, Rabin Medical Center, Beilinson campus. 39, Jabutinsky St., Petah-Tikva, Israel. .,Department of Transplantation, Rabin Medical Center, Beilinson campus, Petah-Tikva, Israel.
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Asuri K, Bansal V, Chatterjee S, Prajapati O, Misra M. A prospective study of correlation of blood levels of tacrolimus to graft function and adverse effect of tacrolimus in postrenal transplant patients. INDIAN JOURNAL OF TRANSPLANTATION 2020. [DOI: 10.4103/ijot.ijot_65_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Farasyn T, Crowe A, Hatley O, Neuhoff S, Alam K, Kanyo J, Lam TT, Ding K, Yue W. Preincubation With Everolimus and Sirolimus Reduces Organic Anion-Transporting Polypeptide (OATP)1B1- and 1B3-Mediated Transport Independently of mTOR Kinase Inhibition: Implication in Assessing OATP1B1- and OATP1B3-Mediated Drug-Drug Interactions. J Pharm Sci 2019; 108:3443-3456. [PMID: 31047942 PMCID: PMC6759397 DOI: 10.1016/j.xphs.2019.04.019] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 04/11/2019] [Accepted: 04/18/2019] [Indexed: 02/07/2023]
Abstract
Organic anion transporting polypeptides (OATP)1B1 and OATP1B3 mediate hepatic uptake of many drugs including lipid-lowering statins. Current studies determined the OATP1B1/1B3-mediated drug-drug interaction (DDI) potential of mammalian target of rapamycin (mTOR) inhibitors, everolimus and sirolimus, using R-value and physiologically based pharmacokinetic models. Preincubation with everolimus and sirolimus significantly decreased OATP1B1/1B3-mediated transport even after washing and decreased inhibition constant values up to 8.3- and 2.9-fold for OATP1B1 and both 2.7-fold for OATP1B3, respectively. R-values of everolimus, but not sirolimus, were greater than the FDA-recommended cutoff value of 1.1. Physiologically based pharmacokinetic models predict that everolimus and sirolimus have low OATP1B1/1B3-mediated DDI potential against pravastatin. OATP1B1/1B3-mediated transport was not affected by preincubation with INK-128 (10 μM, 1 h), which does however abolish mTOR kinase activity. The preincubation effects of everolimus and sirolimus on OATP1B1/1B3-mediated transport were similar in cells before preincubation with vehicle control or INK-128, suggesting that inhibition of mTOR activity is not a prerequisite for the preincubation effects observed for everolimus and sirolimus. Nine potential phosphorylation sites of OATP1B1 were identified by phosphoproteomics; none of these are the predicted mTOR phosphorylation sites. We report the everolimus/sirolimus-preincubation-induced inhibitory effects on OATP1B1/1B3 and relatively low OATP1B1/1B3-mediated DDI potential of everolimus and sirolimus.
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Affiliation(s)
- Taleah Farasyn
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104
| | - Alexandra Crowe
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104
| | - Oliver Hatley
- Certara UK Ltd., Simcyp Division, Level 2-Acero, 1 Concourse Way, Sheffield S1 2BJ, UK
| | - Sibylle Neuhoff
- Certara UK Ltd., Simcyp Division, Level 2-Acero, 1 Concourse Way, Sheffield S1 2BJ, UK
| | - Khondoker Alam
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104
| | - Jean Kanyo
- Yale MS & Proteomics Resource, Yale University, New Haven, Connecticut 06520
| | - TuKiet T Lam
- Yale MS & Proteomics Resource, Yale University, New Haven, Connecticut 06520; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520
| | - Kai Ding
- Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104
| | - Wei Yue
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.
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12
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Devine PA, Courtney AE, Maxwell AP. Cardiovascular risk in renal transplant recipients. J Nephrol 2019; 32:389-399. [PMID: 30406606 PMCID: PMC6482292 DOI: 10.1007/s40620-018-0549-4] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 10/30/2018] [Indexed: 02/07/2023]
Abstract
Successful kidney transplantation offers patients with end-stage renal disease the greatest likelihood of survival. However, cardiovascular disease poses a major threat to both graft and patient survival in this cohort. Transplant recipients are unique in their accumulation of a wide range of traditional and non-traditional cardiovascular risk factors. Hypertension, diabetes, dyslipidaemia and obesity are highly prevalent in patients with end-stage renal disease. These risk factors persist following transplantation and are often exacerbated by the drugs used for immunosuppression in organ transplantation. Additional transplant-specific factors such as poor graft function and proteinuria are also associated with increased cardiovascular risk. However, these transplant-related factors remain unaccounted for in current cardiovascular risk prediction models, making it challenging to identify transplant recipients with highest risk. With few interventional trials in this area specific to transplant recipients, strategies to reduce cardiovascular risk are largely extrapolated from other populations. Aggressive management of traditional cardiovascular risk factors remains the cornerstone of prevention, though there is also a potential role for selecting immunosuppression regimens to minimise additional cardiovascular injury.
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Affiliation(s)
- Paul A Devine
- Regional Nephrology and Transplant Unit, Belfast City Hospital Northern Ireland, Belfast, BT9 7AB, UK.
- Centre for Public Health, Queen's University Belfast, Belfast, UK.
| | - Aisling E Courtney
- Regional Nephrology and Transplant Unit, Belfast City Hospital Northern Ireland, Belfast, BT9 7AB, UK
| | - Alexander P Maxwell
- Regional Nephrology and Transplant Unit, Belfast City Hospital Northern Ireland, Belfast, BT9 7AB, UK
- Centre for Public Health, Queen's University Belfast, Belfast, UK
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13
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Sandal S, Bae S, McAdams-DeMarco M, Massie AB, Lentine KL, Cantarovich M, Segev DL. Induction immunosuppression agents as risk factors for incident cardiovascular events and mortality after kidney transplantation. Am J Transplant 2019; 19:1150-1159. [PMID: 30372596 PMCID: PMC6433494 DOI: 10.1111/ajt.15148] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 09/30/2018] [Accepted: 10/19/2018] [Indexed: 01/25/2023]
Abstract
Low T cell counts and acute rejection are associated with increased cardiovascular events (CVEs); T cell-depleting agents decrease both. Thus, we aimed to characterize the risk of CVEs by using an induction agent used in kidney transplant recipients. We conducted a secondary data analysis of patients who received a kidney transplant and used Medicare as their primary insurance from 1999 to 2010. Outcomes of interest were incident CVE, all-cause mortality, CVE-related mortality, and a composite outcome of mortality and CVE. Of 47 258 recipients, 29.3% received IL-2 receptor antagonist (IL-2RA), 33.3% received anti-thymocyte globulin (ATG), 7.3% received alemtuzumab, and 30.0% received no induction. Compared with IL-2RA, there was no difference in the risk of CVE in the ATG (adjusted hazard ratio [aHR] 0.98, 95% confidence interval [CI] 0.92-1.05) and alemtuzumab group (aHR 1.01, 95% CI 0.89-1.16), but slightly higher in the no induction group (aHR 1.06, 95% CI 1.00-1.14). Acute rejection did not modify this association in the latter group but did increase CVE by 46% in the alemtuzumab group. There was no difference in the hazard of all-cause or CVE-related mortality. Only in the ATG group, a 7% lower hazard of the composite outcome of mortality and CVE was noted. Induction agents are not associated with incident CVE, although prospective trials are needed to determine a personalized approach to prevention.
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Affiliation(s)
- Shaifali Sandal
- Department of Medicine, Divisions of Nephrology and Multi-Organ Transplant Program, McGill University Health Centre, Montreal, QC
| | - Sunjae Bae
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Mara McAdams-DeMarco
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Allan B. Massie
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Krista L. Lentine
- Center for Abdominal Transplantation, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Marcelo Cantarovich
- Department of Medicine, Divisions of Nephrology and Multi-Organ Transplant Program, McGill University Health Centre, Montreal, QC
| | - Dorry L. Segev
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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14
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Hap K, Madziarska K, Hap W, Zmonarski S, Zielińska D, Kamińska D, Banasik M, Kościelska-Kasprzak K, Klinger M, Mazanowska O. Are Females More Prone Than Males to Become Obese After Kidney Transplantation? Ann Transplant 2019; 24:57-61. [PMID: 30737367 PMCID: PMC6367887 DOI: 10.12659/aot.912096] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Background Being overweight for kidney transplant recipients can cause serious side effects. Weight gain affects two-thirds of kidney transplant recipients and has been attributed to a more liberal diet after transplantation, recovery of appetite due to lack of uremic toxicity, corticosteroid use, and inadequate lifestyle changes. The aim of this study was to assess gender-dependent profile of body mass index (BMI) changes after kidney transplantation (KTx). Material/Methods Sixty-two kidney transplant recipients (38 males and 24 females), aged 46.0±12.8 years at KTx, were observed according to weight gain after KTx. BMI was calculated before transplantation (pre-KTx) and at 6, 12, and 24 months post-KTx. Results During the 24-month observation period, we found an increase in the incidence of kidney transplant recipients being overweight or obese (pre-KTx 43.5% increase and 24-month post-Ktx 61.3% increase, P=0.036). We analyzed a number of factors that could potentially influence a 24-month BMI gain including age at KTx, gender, pre-KTx BMI, time on dialysis, pre-KTx glucose metabolism disorder, and post-KTx diabetes mellitus. For female recipients, there was a significant step-wise post-KTx increase in BMI during the 24-month observation period. The overall pre-KTx to 24-month net increase for female BMI was 2 times greater than that observed for male recipients (1.90±2.20 kg/m2 versus 0.89±1.85 kg/m2, P<0.001). Conclusions Weight gain after KTx was observed in both sexes, but the net BMI increase was more than 2 times greater in females than in males at 24-months post-KTx. This indicated the need for diet education and strict weight control in kidney transplant recipients, especially in female patients.
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Affiliation(s)
- Katarzyna Hap
- Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland
| | - Katarzyna Madziarska
- Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland
| | - Wojciech Hap
- Second Department of General and Oncological Surgery, Wrocław Medical University, Wrocław, Poland
| | - Sławomir Zmonarski
- Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland
| | - Dorota Zielińska
- Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland
| | - Dorota Kamińska
- Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland
| | - Mirosław Banasik
- Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland
| | | | - Marian Klinger
- Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland
| | - Oktawia Mazanowska
- Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland.,Faculty of Medicine and Dentistry, Wrocław Medical University, Wrocław, Poland
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15
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Han N, Han SH, Song YK, Kim MG, Kim YS, Kim IW, Oh JM. Statin therapy for preventing cardiovascular diseases in patients treated with tacrolimus after kidney transplantation. Ther Clin Risk Manag 2017; 13:1513-1520. [PMID: 29200861 PMCID: PMC5701562 DOI: 10.2147/tcrm.s147327] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Background Lipid abnormalities are prevalent in tacrolimus-treated patients. The aim of the study was to evaluate the preventive effects of statin therapy on major adverse cardiovascular events (MACE) in patients treated with tacrolimus-based immunosuppression after kidney transplantation (KT), and to identify the risk factors. Methods This observational cohort study included adult patients who underwent KT and were treated with tacrolimus. Patients who received any lipid-lowering agents except statins, or had a history of immunosuppressant use before transplantation were excluded. The primary outcome was the adjusted risk of the first occurrence of MACE. The secondary outcomes included the risk of individual cardiovascular disease (CVD) and changes in cholesterol level. Subgroup analyses were performed in the statin-user group according to the dosage and/or type of statin. Results Compared with the control group (n=73), the statin-users (n=92) had a significantly reduced risk of MACE (adjusted HR, 0.31; 95% CI, 0.13–0.74). In the Cox regression analysis, old age, history of CVD, and comorbid hypertension were identified as independent factors associated with increased MACE. The total cholesterol levels were not significantly different between the two groups. Subjects with higher cumulative defined daily dose of statins had significantly lower risks of MACE. Conclusion Statin therapy in patients treated with tacrolimus after KT significantly lowered the risk of MACE. Long-term statin therapy is clearly indicated in older kidney transplant recipients for secondary prevention.
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Affiliation(s)
- Nayoung Han
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul
| | - Seung Hee Han
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul.,Department of Pharmacy, Asan Medical Center, Seoul
| | - Yun-Kyoung Song
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul
| | - Myeong Gyu Kim
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul
| | - Yon Su Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul.,College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - In-Wha Kim
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul
| | - Jung Mi Oh
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul
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16
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Halawa A. Evaluation of the Cardiovascular Prior to Transplantation; An Endless Debate. ACTA ACUST UNITED AC 2017. [DOI: 10.15406/unoaj.2017.04.00126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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17
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Abuzeid W, Iwanochko RM, Wang X, Kim SJ, Husain M, Lee DS. Prognostic impact of SPECT-MPI after renal transplantation. J Nucl Cardiol 2017; 24:295-303. [PMID: 27663251 DOI: 10.1007/s12350-016-0547-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Accepted: 05/05/2016] [Indexed: 10/21/2022]
Abstract
BACKGROUND While renal transplantation is increasingly performed for end-stage renal disease, there is a paucity of data on cardiac screening and prognostication post-transplant. We determined the prognostic value of SPECT-MPI in a cohort who underwent renal transplantation. METHODS Among 4933 renal transplant recipients identified from the Canadian Organ Replacement Register, we examined outcomes of patients who underwent SPECT-MPI in Ontario, Canada. We determined morbidity and mortality using hospitalization and vital statistics registries, according to SPECT-MPI findings. RESULTS We studied 282 renal transplant recipients (median age 46 years [25th, 75th percentile 37, 58]) with detailed SPECT-MPI results available, followed for a median of 5.7 (3.3, 7.7) years. Among those undergoing SPECT-MPI (66% pharmacologic stress), 41% had an abnormal summed stress score (SSS > 0) and 31% demonstrated abnormal summed difference score (SDS > 0). Rates of cardiovascular death were 0.4 per 100 person-years among those with normal stress perfusion (SSS = 0) and 0.4 per 100 person-years with SDS = 0. After adjusting for age, sex, prior myocardial infarction (MI), and cardiac risk factors, an SSS ≥ 4 conferred increased risk of cardiovascular death or cardiovascular hospitalization with adjusted hazard ratios of 2.52 (95% CI 1.41, 4.52, P = .002) for SSS 4-6 and 2.61 (95% CI 1.52, 4.49, P < .001) for SSS ≥ 7. SDS was a significant predictor of cardiovascular death or hospitalization, with adjusted hazard ratios of 2.96 (95% CI 1.72, 5.09, P < .001) for SDS 4-6 and 3.26 (95% CI 1.64, 6.50, P < .001) for SDS ≥ 7. CONCLUSION Among renal transplant recipients, SPECT-MPI predicted risk of cardiovascular death and cardiovascular hospitalization events.
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Affiliation(s)
- Wael Abuzeid
- Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada
- University of Toronto, Toronto, ON, Canada
| | - Robert M Iwanochko
- Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada
- University of Toronto, Toronto, ON, Canada
- Robert J. Burns Nuclear Cardiology Laboratory and Joint Department of Medical Imaging, University Health Network, Toronto, ON, Canada
| | - Xuesong Wang
- Institute for Clinical Evaluative Sciences, Toronto, ON, Canada
| | - S Joseph Kim
- University of Toronto, Toronto, ON, Canada
- Division of Nephrology, University Health Network, Toronto, ON, Canada
| | - Mansoor Husain
- Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada
- University of Toronto, Toronto, ON, Canada
- Robert J. Burns Nuclear Cardiology Laboratory and Joint Department of Medical Imaging, University Health Network, Toronto, ON, Canada
- Ted Rogers Centre for Heart Research, Toronto, ON, Canada
| | - Douglas S Lee
- Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada.
- University of Toronto, Toronto, ON, Canada.
- Robert J. Burns Nuclear Cardiology Laboratory and Joint Department of Medical Imaging, University Health Network, Toronto, ON, Canada.
- Institute for Clinical Evaluative Sciences, Toronto, ON, Canada.
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18
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La transplantation rénale et ses défis. Prog Urol 2016; 26:1001-1044. [PMID: 27720627 DOI: 10.1016/j.purol.2016.09.056] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 09/12/2016] [Indexed: 01/09/2023]
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19
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El-Ghar SMGA, Qureshi M, Shoker A, Prasad K. Oxidative Stress in Renal Transplant Patients Who Develop Cardiovascular Disease. J Cardiovasc Pharmacol Ther 2016; 11:203-10. [PMID: 17056834 DOI: 10.1177/1074248406293254] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Cardiovascular disease limits life expectancy of successful renal transplant patients. Reactive oxygen species have been implicated in the development of atherosclerosis, and high levels could be due to increased production or a decrease in antioxidant reserve. Cardiovascular disease in renal transplant recipients could be due to elevated levels of malondialdehyde (an index of levels of reactive oxygen species) and homocysteine and reduced levels of glutathione. Renal transplant recipients with and without cardiovascular disease were studied along with healthy controls. Serum malondialdehyde, plasma homocysteine, and red blood cell glutathione were measured. The results suggest that levels of serum malondialdehyde and plasma homocysteine were higher in patients with or without cardiovascular disease compared with controls; however, the values were similar in both groups of transplant patients. Glutathione levels in red blood cells were similar in all 3 groups. Renal transplant recipients without cardiovascular disease have high levels of oxidative stress and may develop cardiovascular disease with time.
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Affiliation(s)
- Suzan M G A El-Ghar
- Department of Pathology, College of Medicine, University of Saskatchewan, Royal University Hospital, Saskatoon, Saskatchewan, Canada
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20
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Impaired P2Y12 inhibition by clopidogrel in kidney transplant recipients: results from a cohort study. BMC Nephrol 2016; 17:58. [PMID: 27278793 PMCID: PMC4899921 DOI: 10.1186/s12882-016-0270-2] [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: 09/16/2015] [Accepted: 06/01/2016] [Indexed: 12/04/2022] Open
Abstract
Background Cardiovascular complications represent a major cause of morbidity and mortality for patients who received kidney transplantation (KT). However, the impact of KT and chronic immunosuppression on platelet response to clopidogrel in patients undergoing coronary or peripheral revascularization procedures remains unclear. This cohort study compares platelet responsiveness to clopidogrel as assessed byvasodilator-stimulated phosphoprotein (VASP) phosphorylation. Methods The study population was divided between chronic kidney disease (CKD) patients who underwent KT (n = 36) and non-transplanted CKD patients (control group, n = 126). Patients were on maintenance antiplatelet therapy with clopidogrel 75 mg daily for at least 8 days. The mean platelet reactivity index (PRI) VASP values and the prevalence of high on-treatment platelet reactivity (HPR, defined as PRI VASP ≥61 %) were compared. Results The mean PRI VASP value was significantly higher in the transplant group (60.1 ± 3 vs 51.2 ± 1.6 %; p=0.014). HPR was significantly more common in the transplant group on clopidogrel maintenance therapy (58 vs. 31 %; p = 0.011). KT was the only independent predictor of HPR (odds ratio: 2.6; 95 % confidence interval: 1.03–6.27, p = 0.03). The effect of treatment with calcineurin inhibitors on clopidogrel response could not be analyzed separately from the kidney transplant status. Conclusions KT is associated with an increased prevalence of HPR. Our results suggest that plateletfunction tests may be clinically useful for the management of this specific population.
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21
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Agarwal A, Prasad GVR. Post-transplant dyslipidemia: Mechanisms, diagnosis and management. World J Transplant 2016; 6:125-134. [PMID: 27011910 PMCID: PMC4801788 DOI: 10.5500/wjt.v6.i1.125] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 11/26/2015] [Accepted: 02/17/2016] [Indexed: 02/05/2023] Open
Abstract
Post-transplant dyslipidemia is highly prevalent and presents unique management challenges to the clinician. The two major outcomes to consider with post-transplant therapies for dyslipidemia are preserving or improving allograft function, and reducing cardiovascular risk. Although there are other cardiovascular risk factors such as graft dysfunction, hypertension, and diabetes, attention to dyslipidemia is warranted because interventions for dyslipidemia have an impact on reducing cardiac events in clinical trials specific to the transplant population. Dyslipidemia is not synonymous with hyperlipidemia. Numerous mechanisms exist for the occurrence of post-transplant dyslipidemia, including those mediated by immunosuppressive drug therapy. Statin therapy has received the most attention in all solid organ transplant recipient populations, although the effect of proper dietary advice and adjuvant pharmacological and non-pharmacological agents should not be dismissed. At all stages of treatment appropriate monitoring strategies for side effects should be implemented so that the benefits from these therapies can be achieved. Clinicians have a choice when there is a conflict between various transplant society and lipid society guidelines for therapy and targets.
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22
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23
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Rao NN, Dundon BK, Worthley MI, Faull RJ. The Impact of Arteriovenous Fistulae for Hemodialysis on the Cardiovascular System. Semin Dial 2016; 29:214-21. [DOI: 10.1111/sdi.12459] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- Nitesh N. Rao
- Department of Renal Medicine; Royal Adelaide Hospital; Adelaide South Australia Australia
- University of Adelaide; Adelaide South Australia Australia
| | - Benjamin K. Dundon
- Monash Cardiovascular Research Centre; Monash HEART; Monash Health; Melbourne Victoria Australia
| | - Matthew I. Worthley
- Cardiovascular Research Centre at the Royal Adelaide Hospital; Adelaide South Australia Australia
| | - Randall J. Faull
- Department of Renal Medicine; Royal Adelaide Hospital; Adelaide South Australia Australia
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24
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Coombes JS, Sharman JE, Fassett RG. Astaxanthin has no effect on arterial stiffness, oxidative stress, or inflammation in renal transplant recipients: a randomized controlled trial (the XANTHIN trial). Am J Clin Nutr 2016; 103:283-9. [PMID: 26675778 DOI: 10.3945/ajcn.115.115477] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 11/03/2015] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND There is evidence that renal transplant recipients have accelerated atherosclerosis that is manifest by increased cardiovascular morbidity and mortality. The high incidence of atherosclerosis is, in part, related to increased arterial stiffness, vascular dysfunction, elevated oxidative stress, and inflammation associated with immunosuppressive therapy. The carotenoid astaxanthin has shown potent antioxidant and anti-inflammatory properties. OBJECTIVE The aim was to investigate the effects of oral astaxanthin on arterial stiffness, oxidative stress, and inflammation in renal transplant recipients. DESIGN This trial used a randomized, placebo-controlled, double-blind design in which 61 patients received either 12 mg astaxanthin/d or an identical placebo orally for 1 y. Primary outcomes were 1) arterial stiffness measured by aortic pulse wave velocity (PWV), 2) oxidative stress assessed by total plasma F2-isoprostanes, and 3) inflammation assessed by plasma pentraxin-3. Secondary outcomes included vascular function, carotid artery intima-media thickness, augmentation index, central blood pressure, subendocardial viability ratio, and additional measures of oxidative stress and inflammation. Patients underwent assessments at baseline and at 6 and 12 mo. RESULTS Fifty-eight participants completed the study. There were no significant between-group differences in the changes in any of the primary outcome measures (PWV changed by +9.5% and +6.0%, F2-isoprostanes changed by -3.0% and -9.7%, and pentraxin-3 changed by +50.6% and -11.0% in the placebo and astaxanthin groups, respectively). There were no significant between-group differences in secondary outcome measures. Larger-than-expected variability decreased the power of the study and increased the possibility of a type 2 statistical error. CONCLUSION Astaxanthin (12 mg/d for 12 mo) had no effect on arterial stiffness, oxidative stress, or inflammation in renal transplant recipients. This trial was registered at the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) as ACTRN12608000159358.
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Affiliation(s)
- Jeff S Coombes
- School of Human Movement and Nutrition Sciences, University of Queensland, St. Lucia, Australia; and
| | - James E Sharman
- Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia
| | - Robert G Fassett
- School of Human Movement and Nutrition Sciences, University of Queensland, St. Lucia, Australia; and
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25
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Abstract
Over the last two decades in particular there has been a remarkable increase in the number of solid organ transplants being performed worldwide alongside improvements in long-term survival rates. However, the infrastructure at transplant centres has been unable to keep pace with the current volume of the transplant patient work load. These pressures on transplant specialist centres has led to calls for an increased role of the general practitioner (GP) managing particular aspects of transplant patients' medical care. Indeed, many aspects of follow-up care such as screening for malignancies, preventing infection through immunisation programmes, and managing cardiovascular risk factors are already important aspects of family practice medicine. This paper aims to review some of the aspects of transplant patient care that is important for healthcare workers in family practice to manage.
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Affiliation(s)
- Lloyd D. Hughes
- Department of Ageing and Health, Academic Foundation Doctor, NHS Tayside and University of Dundee, 1 Albert Crescent, Newport on Tay, Kingdom of Fife, DD6 8DT, Scotland
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26
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Ryan KJ, Casas JMS, Mash LE, McLellan SL, Lloyd LE, Stinear JW, Plank LD, Collins MG. The effect of intensive nutrition interventions on weight gain after kidney transplantation: protocol of a randomised controlled trial. BMC Nephrol 2014; 15:148. [PMID: 25204676 PMCID: PMC4176865 DOI: 10.1186/1471-2369-15-148] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Accepted: 09/02/2014] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Weight gain and obesity are common after kidney transplantation, particularly during the first year. Obesity is a risk factor for the development of new-onset diabetes after transplantation, and is associated with reduced graft survival. There is a lack of evidence for effective interventions to prevent weight gain after kidney transplantation. METHODS/DESIGN The effect of INTEnsive Nutrition interventions on weight gain after kidney Transplantation (INTENT) trial is a single-blind (outcomes assessor), randomised controlled trial to assess the effect of intensive nutrition interventions, including exercise advice, on weight gain and metabolic parameters in the first year after transplantation. Participants will be randomised during the first post-transplant month to either standard care (four visits with a renal dietitian over twelve months) or intensive nutrition intervention (eight visits with a renal dietitian over the first six months, four visits over the second six months, and three visits over the first six months with an exercise physiologist). In the intensive intervention group, nutrition counselling will be provided using motivational interviewing techniques to encourage quality engagement. Collaborative goal setting will be used to develop personalised nutrition care plans. Individualised advice regarding physical activity will be provided by an exercise physiologist. The primary outcome of the study is weight at six months after transplant, adjusted for baseline (one month post-transplant) weight, obesity and gender. Secondary outcomes will include changes in weight and other anthropometric measures over 12 months, body composition (in vivo neutron activation analysis, total body potassium, dual-energy X-ray absorptiometry, and bioelectrical impedance), biochemistry (fasting glucose, lipids, haemoglobin A1c and insulin), dietary intake and nutritional status, quality of life, and physical function. DISCUSSION There are currently few randomised clinical trials of nutrition interventions after kidney transplantation. The INTENT trial will thus provide important data on the effect of intensive nutrition interventions on weight gain after transplant and the associated metabolic consequences. Additionally, by assessing changes in glucose metabolism, the study will also provide data on the feasibility of undertaking larger multi-centre trials of nutrition interventions to reduce the incidence or severity of diabetes after transplantation. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry Number: ACTRN12614000155695.
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Affiliation(s)
| | | | | | | | | | | | | | - Michael G Collins
- Department of Renal Medicine, Auckland City Hospital, Auckland District Health Board, Private Bag 92024, Auckland 1142, New Zealand.
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Palanisamy AP, Schiltz CE, Pilch NA, Hunt KJ, Nadig SN, Dowden JE, McGillicuddy JW, Baliga PK, Chavin KD, Taber DJ. Cardiovascular risk factors contribute to disparities in graft outcomes in African American renal transplant recipients: a retrospective analysis. Blood Press 2014; 24:14-22. [PMID: 25048253 DOI: 10.3109/08037051.2014.934527] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Data examining cardiovascular (CV) risk factors in renal transplant recipients (RTRs) and their contribution to the disparity in graft survival between African American (AA) patients and non-AAs is limited. A single-center, retrospective analysis of 1003 adult RTRs from January 1, 2000 to May 1, 2008 to inspect the impact of race on post-transplant CV events, treatment of CV risk factors and their independent influence on graft outcomes was performed. AAs experienced a higher incidence of late graft loss, with 1- and 5-year graft survival rates of 93% and 76% vs 95% and 84% in the non-AA group, respectively. AA patients had a higher prevalence of hypertension (HTN) and diabetes mellitus (DM) and demonstrated reduced control of DM post-transplant (AA 74% vs non-AA 82%, p = 0.053). Multivariate analysis for graft survival indicated acute rejection, delayed graft function (DGF) and incidence of CV events were significant risk factors for graft failure, while the use of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) and 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors were protective. In conclusion, after controlling for CV risk factors and events, race did not have an independent effect on outcomes, suggesting CV risk factors and events contribute to this disparity. Clinical summary. AAs experienced a higher rate of graft failure and CV events; after adjusting for multiple immunological and CV risk factors, race no longer remained an independent risk factor for post-transplant CV events or graft failure; although disparities in post-transplant outcomes remain, race alone does not account for the disparity; the racial disparity is due to the higher incidence of DGF and acute rejection, as well as traditional CV risk factors, including HTN and DM.
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28
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Dundon BK, Torpey DK, Nelson AJ, Wong DTL, Duncan RF, Meredith IT, Faull RJ, Worthley SG, Worthley MI. Beneficial cardiovascular remodeling following arterio-venous fistula ligation post-renal transplantation: a longitudinal magnetic resonance imaging study. Clin Transplant 2014; 28:916-25. [DOI: 10.1111/ctr.12402] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/09/2014] [Indexed: 11/28/2022]
Affiliation(s)
- Benjamin K. Dundon
- Cardiovascular Research Centre at the Royal Adelaide Hospital; University of Adelaide; Adelaide SA Australia
- Monash Cardiovascular Research Centre; Monash HEART; Monash Health; Melbourne Vic. Australia
| | - David K. Torpey
- Department of Renal Medicine; Royal Adelaide Hospital; Adelaide SA Australia
| | - Adam J. Nelson
- Cardiovascular Research Centre at the Royal Adelaide Hospital; University of Adelaide; Adelaide SA Australia
| | - Dennis T. L. Wong
- Cardiovascular Research Centre at the Royal Adelaide Hospital; University of Adelaide; Adelaide SA Australia
- Monash Cardiovascular Research Centre; Monash HEART; Monash Health; Melbourne Vic. Australia
| | - Rae F. Duncan
- Cardiovascular Research Centre at the Royal Adelaide Hospital; University of Adelaide; Adelaide SA Australia
| | - Ian T. Meredith
- Monash Cardiovascular Research Centre; Monash HEART; Monash Health; Melbourne Vic. Australia
| | - Randall J. Faull
- Cardiovascular Research Centre at the Royal Adelaide Hospital; University of Adelaide; Adelaide SA Australia
- Department of Renal Medicine; Royal Adelaide Hospital; Adelaide SA Australia
| | - Stephen G. Worthley
- Cardiovascular Research Centre at the Royal Adelaide Hospital; University of Adelaide; Adelaide SA Australia
| | - Matthew I. Worthley
- Cardiovascular Research Centre at the Royal Adelaide Hospital; University of Adelaide; Adelaide SA Australia
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van den Berg E, Pasch A, Westendorp WH, Navis G, Brink EJ, Gans ROB, van Goor H, Bakker SJL. Urinary sulfur metabolites associate with a favorable cardiovascular risk profile and survival benefit in renal transplant recipients. J Am Soc Nephrol 2014; 25:1303-12. [PMID: 24511127 DOI: 10.1681/asn.2013050497] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
In post-transplant conditions, sulfur may be protective by intermediate conversion to hydrogen sulfide and thiosulfate. However, sulfate, the end product of sulfur-containing amino acids (SAAs), contributes to metabolic acid load and may adversely influence acid-base homeostasis. We investigated the association of urinary sulfur metabolites with cardiometabolic parameters in renal transplant recipients (RTRs) and analyzed their predictive capacity for mortality. We studied urinary sulfate and thiosulfate excretion in 24-hour urine samples from 707 RTRs at a median 5.4 years (interquartile range, 1.9 to 12.2) after transplantation as well as from 110 controls. Diet was assessed for SAA content and various risk factors were measured. Urinary sulfate was similar, whereas thiosulfate was higher in RTRs versus controls. SAA intake was lower in RTRs compared with controls and correlated with sulfate but not thiosulfate excretion. Sulfate beneficially associated with eGFR, net acid excretion, systolic BP, high-sensitivity C-reactive protein, N-terminal probrain natriuretic peptide, and proteinuria (all P≤0.01). Thiosulfate beneficially associated with eGFR, serum acidity, high-sensitivity C-reactive protein, and N-terminal probrain natriuretic peptide (all P≤0.001). During a median 27 months (interquartile range, 22-36) of follow-up, 47 RTRs died. After adjustment for age, sex, and eGFR, hazard ratios for mortality were 0.87 (95% confidence interval, 0.82 to 0.92; P<0.001) for urinary sulfate and 0.60 (95% confidence interval, 0.41 to 0.59; P=0.01) for thiosulfate. Thus, despite the association of urinary sulfate with metabolic acid load, urinary sulfate and thiosulfate beneficially associated with survival in RTRs, possibly by influencing cardiovascular parameters. Intervention studies with exogenous sulfur are warranted to elucidate mechanisms underlying these promising associations in RTRs.
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Affiliation(s)
- Else van den Berg
- Top Institute Food and Nutrition, Wageningen, The Netherlands; Kidney Center Groningen, University Medical Center Groningen, University of Groningen, The Netherlands;
| | - Andreas Pasch
- Department of Nephrology and Hypertension, University Hospital and University of Bern, Inselspital, Bern, Switzerland; and
| | | | - Gerjan Navis
- Kidney Center Groningen, University Medical Center Groningen, University of Groningen, The Netherlands
| | | | - Reinold O B Gans
- Internal Medicine, University Medical Center Groningen, University of Groningen, The Netherlands
| | | | - Stephan J L Bakker
- Top Institute Food and Nutrition, Wageningen, The Netherlands; Internal Medicine, University Medical Center Groningen, University of Groningen, The Netherlands
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Palmer SC, Navaneethan SD, Craig JC, Perkovic V, Johnson DW, Nigwekar SU, Hegbrant J, Strippoli GFM. HMG CoA reductase inhibitors (statins) for kidney transplant recipients. Cochrane Database Syst Rev 2014; 2014:CD005019. [PMID: 24470059 PMCID: PMC8860132 DOI: 10.1002/14651858.cd005019.pub4] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND People with chronic kidney disease (CKD) have higher risks of cardiovascular disease compared to the general population. Specifically, cardiovascular deaths account most deaths in kidney transplant recipients. Statins are a potentially beneficial intervention for kidney transplant patients given their established benefits in patients at risk of cardiovascular disease in the general population. This is an update of a review first published in 2009. OBJECTIVES We aimed to evaluate the benefits (reductions in all-cause and cardiovascular mortality, major cardiovascular events, myocardial infarction and stroke, and progression of CKD to requiring dialysis) and harms (muscle or liver dysfunction, withdrawal, cancer) of statins compared to placebo, no treatment, standard care, or another statin in adults with CKD who have a functioning kidney transplant. SEARCH METHODS We searched the Cochrane Renal Group's Specialised Register to 29 February 2012 through contact with the Trials Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-RCTs that compared the effects of statins with placebo, no treatment, standard care, or statins on mortality, cardiovascular events, kidney function and toxicity in kidney transplant recipients. DATA COLLECTION AND ANALYSIS Two authors independently extracted data and assessed risk of bias. Treatment effects were expressed as mean difference (MD) for continuous outcomes (lipids, glomerular filtration rate (GFR), proteinuria) and relative risk (RR) for dichotomous outcomes (major cardiovascular events, mortality, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, elevated muscle or liver enzymes, withdrawal due to adverse events, cancer, end-stage kidney disease (ESKD), acute allograft rejection) together with 95% confidence intervals (CI). MAIN RESULTS We identified 22 studies (3465 participants); 17 studies (3282 participants) compared statin with placebo or no treatment, and five studies (183 participants) compared two different statin regimens.From data generally derived from a single high-quality study, it was found that statins may reduce major cardiovascular events (1 study, 2102 participants: RR 0.84, CI 0.66 to 1.06), cardiovascular mortality (4 studies, 2322 participants: RR 0.68, CI 0.45 to 1.01), and fatal or non-fatal myocardial infarction (1 study, 2102 participants: RR 0.70, CI 0.48 to 1.01); although effect estimates lack precision and include the possibility of no effect.Statins had uncertain effects on all-cause mortality (6 studies, 2760 participants: RR 1.08, CI 0.63 to 1.83); fatal or non-fatal stroke (1 study, 2102 participants: RR 1.18, CI 0.85 to 1.63); creatine kinase elevation (3 studies, 2233 participants: RR 0.86, CI 0.39 to 1.89); liver enzyme elevation (4 studies, 608 participants: RR 0.62, CI 0.33 to 1.19); withdrawal due to adverse events (9 studies, 2810 participants: RR 0.89, CI 0.74 to 1.06); and cancer (1 study, 2094 participants: RR 0.94, CI 0.82 to 1.07).Statins significantly reduced serum total cholesterol (12 studies, 3070 participants: MD -42.43 mg/dL, CI -51.22 to -33.65); low-density lipoprotein cholesterol (11 studies, 3004 participants: MD -43.19 mg/dL, CI -52.59 to -33.78); serum triglycerides (11 studies, 3012 participants: MD -27.28 mg/dL, CI -34.29 to -20.27); and lowered high-density lipoprotein cholesterol (11 studies, 3005 participants: MD -5.69 mg/dL, CI -10.35 to -1.03).Statins had uncertain effects on kidney function: ESKD (6 studies, 2740 participants: RR 1.14, CI 0.94 to 1.37); proteinuria (2 studies, 136 participants: MD -0.04 g/24 h, CI -0.17 to 0.25); acute allograft rejection (4 studies, 582 participants: RR 0.88, CI 0.61 to 1.28); and GFR (1 study, 62 participants: MD -1.00 mL/min, CI -9.96 to 7.96).Due to heterogeneity in comparisons, data directly comparing differing statin regimens could not be meta-analysed. Evidence for statins in people who have had a kidney transplant were sparse and lower quality due to imprecise effect estimates and provided limited systematic evaluation of treatment harm. AUTHORS' CONCLUSIONS Statins may reduce cardiovascular events in kidney transplant recipients, although treatment effects are imprecise. Statin treatment has uncertain effects on overall mortality, stroke, kidney function, and toxicity outcomes in kidney transplant recipients. Additional studies would improve our confidence in the treatment benefits and harms of statins on cardiovascular events in this clinical setting.
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Affiliation(s)
- Suetonia C Palmer
- University of Otago ChristchurchDepartment of Medicine2 Riccarton AvePO Box 4345ChristchurchNew Zealand8140
| | - Sankar D Navaneethan
- Glickman Urological and Kidney Institute, Cleveland ClinicDepartment of Nephrology and HypertensionClevelandOHUSA44195
| | - Jonathan C Craig
- The University of SydneySydney School of Public HealthEdward Ford Building A27SydneyNSWAustralia2006
- The Children's Hospital at WestmeadCochrane Renal Group, Centre for Kidney ResearchWestmeadNSWAustralia2145
| | - Vlado Perkovic
- The George Institute for International HealthRenal and Metabolic DivisionCamperdownNSWAustralia
| | - David W Johnson
- Princess Alexandra HospitalDepartment of NephrologyIpswich RdWoolloongabbaQueenslandAustralia4102
| | - Sagar U Nigwekar
- Harvard Medical SchoolBrigham and Women's Hospital, Massachusetts General Hospital, Scholars in Clinical Sciences ProgramBostonMAUSA
| | - Jorgen Hegbrant
- Diaverum Renal Services GroupMedical OfficePO Box 4167LundSwedenSE‐227 22
| | - Giovanni FM Strippoli
- The Children's Hospital at WestmeadCochrane Renal Group, Centre for Kidney ResearchWestmeadNSWAustralia2145
- Mario Negri Sud FoundationClinical Pharmacology and EpidemiologySanta Maria ImbaroItaly
- Amedeo Avogadro University of Eastern PiedmontNovaraItaly
- DiaverumMedical Scientific OfficeLundSweden
- Diaverum AcademyBariItaly
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Wissing KM, Pipeleers L. Obesity, metabolic syndrome and diabetes mellitus after renal transplantation: prevention and treatment. Transplant Rev (Orlando) 2013; 28:37-46. [PMID: 24507957 DOI: 10.1016/j.trre.2013.12.004] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Accepted: 12/18/2013] [Indexed: 02/06/2023]
Abstract
The prevalence of the metabolic syndrome in dialysis patients is high and further increases after transplantation due to weight gain and the detrimental metabolic effects of immunosuppressive drugs. Corticosteroids cause insulin resistance, hyperlipidemia, abnormal glucose metabolism and arterial hypertension. The calcineurin inhibitor tacrolimus is diabetogenic by inhibiting insulin secretion, whereas cyclosporine causes hypertension and increases cholesterol levels. Mtor antagonists are responsible for hyperlipidemia and abnormal glucose metabolism by mechanisms that also implicate insulin resistance. The metabolic syndrome in transplant recipients has numerous detrimental effects such as increasing the risk of new onset diabetes, cardiovascular disease events and patient death. In addition, it has also been linked with accelerated loss of graft function, proteinuria and ultimately graft loss. Prevention and management of the metabolic syndrome are based on increasing physical activity, promotion of weight loss and control of cardiovascular risk factors. Bariatric surgery before or after renal transplantation in patients with body mass index >35 kg/m(2) is an option but its long term effects on graft and patient survival have not been investigated. Steroid withdrawal and replacement of tacrolimus with cyclosporine facilitate control of diabetes, whereas replacement of cyclosporine and mtor antagonists can improve hyperlipidemia. The new costimulation inhibitor belatacept has potent immunosuppressive properties without metabolic adverse effects and will be an important component of immunosuppressive regimens with better metabolic risk profile. Medical treatment of cardiovascular risk factors has to take potential drug interactions with immunosuppressive medication and drug accumulation due to renal insufficiency into account.
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Affiliation(s)
- Karl Martin Wissing
- Nephrology Department, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium; Nephrology and Dialysis Clinic, Centre Hospitalier Universitaire Brugmann, Brussels, Belgium.
| | - Lissa Pipeleers
- Nephrology Department, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
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Palmer SC, Di Micco L, Razavian M, Craig JC, Perkovic V, Pellegrini F, Jardine MJ, Webster AC, Zoungas S, Strippoli GFM. Antiplatelet agents for chronic kidney disease. Cochrane Database Syst Rev 2013:CD008834. [PMID: 23450589 DOI: 10.1002/14651858.cd008834.pub2] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND Antiplatelet agents are widely used to prevent cardiovascular events. The risks and benefits of antiplatelet treatment may be different in people with chronic kidney disease (CKD) for whom occlusive atherosclerotic events are less prevalent, and bleeding hazards might be increased. OBJECTIVES To summarise the effects of antiplatelet treatment (antiplatelet agent versus control or other antiplatelet agent) for the prevention of cardiovascular and adverse kidney outcomes in individuals with CKD. SEARCH METHODS In January 2011 we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Cochrane Renal Group's Specialised Register without language restriction. SELECTION CRITERIA We selected randomised controlled trials of any antiplatelet treatment versus placebo or no treatment, or direct head-to-head antiplatelet agent studies in people with CKD. Studies were included if they enrolled participants with CKD, or included people in broader at-risk populations in which data for subgroups with CKD could be disaggregated. DATA COLLECTION AND ANALYSIS Two authors independently extracted data from primary study reports and any available supplementary information for study population, interventions, outcomes, and risks of bias. Risk ratios (RR) and 95% confidence intervals (CI) were calculated from numbers of events and numbers of participants at risk which were extracted from each included study. The reported RRs were extracted where crude event rates were not provided. Data was pooled using the random-effects model. MAIN RESULTS We included 50 studies, enrolling 27,139 participants; 44 studies (21,460 participants) compared an antiplatelet agent with placebo or no treatment, and six studies (5679 participants) directly compared one antiplatelet agent with another. Compared to placebo or no treatment, antiplatelet agents reduced the risk of myocardial infarction (17 studies; RR 0.87, 95% CI 0.76 to 0.99), but not all-cause mortality (30 studies; RR 0.93, 95% CI 0.81 to 1.06), cardiovascular mortality (19 studies; RR 0.89, 95% CI 0.70 to 1.12) or stroke (11 studies; RR 1.00, 95% CI 0.58 to 1.72). Antiplatelet agents increased the risk of major (27 studies; RR 1.33, 95% CI 1.10 to 1.65) and minor bleeding (18 studies; RR 1.49, 95% CI 1.12 to 1.97). In terms of dialysis access outcomes, antiplatelet agents reduced access thrombosis or patency failure but had no effect on suitability for dialysis. Meta-regression analysis indicated no differences in the relative benefit or harms of treatment (risk of all-cause mortality, myocardial infarction, or major bleeding) by type of antiplatelet agent or stage of CKD. Limited data were available for direct head-to-head comparisons of antiplatelet drugs, treatment in kidney transplant recipients, primary prevention, or risk of ESKD. AUTHORS' CONCLUSIONS Antiplatelet agents reduce myocardial infarction but increase major bleeding. Risks may outweigh harms among people with low annual risks of cardiovascular events, including those with early stages of CKD who do not have clinically-evident occlusive cardiovascular disease.
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Affiliation(s)
- Suetonia C Palmer
- Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand.
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Chapter 5: Blood pressure management in kidney transplant recipients (CKD T). Kidney Int Suppl (2011) 2012; 2:370-371. [PMID: 25018964 PMCID: PMC4089655 DOI: 10.1038/kisup.2012.55] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
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van den Berg E, Engberink MF, Brink EJ, van Baak MA, Joosten MM, Gans ROB, Navis G, Bakker SJL. Dietary acid load and metabolic acidosis in renal transplant recipients. Clin J Am Soc Nephrol 2012; 7:1811-8. [PMID: 22935845 PMCID: PMC3488949 DOI: 10.2215/cjn.04590512] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2012] [Accepted: 08/01/2012] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND OBJECTIVES Acidosis is prevalent among renal transplant recipients (RTRs) and adversely affects cardiometabolic processes. Factors contributing to acidosis are graft dysfunction and immunosuppressive drugs. Little is known about the potential influence of diet on acidosis in RTRs. This study examined the association of metabolic acid load with acidosis and with cardiovascular risk factors in RTRs and aimed to identify dietary factors associated with acidosis. DESIGN, PARTICIPANTS, SETTING, & MEASUREMENTS: 707 RTRs were included. Metabolic acid load was assessed by measuring 24-hour urinary net acid excretion (NAE; i.e., titratable acid + ammonium - bicarbonate). Acidosis was defined as serum [HCO(3)(-)] < 24 mmol/L. BP and insulin resistance, reflected by hemoglobin A1c, were among cardiovascular risk factors. Diet was assessed with food-frequency questionnaires. Linear regression analysis was applied to investigate association between NAE and acidosis and between dietary factors and acidosis. RESULTS Mean age ± SD was 53 ± 13 years; 57% of patients were male. Acidosis was present in 31% of RTRs. NAE was associated with acidosis (serum HCO(3)(-): β=-0.61; serum pH: β=-0.010; both P<0.001). Patients with high intake of animal protein (i.e., from meat, cheese, and fish) and low intake of fruits and vegetables had significantly lower serum HCO(3)(-) and serum pH. No associations were observed between NAE and cardiovascular risk factors, such as hypertension and insulin resistance. CONCLUSIONS In addition to conventional factors contributing to acidosis, diet might influence acid-base homeostasis in RTRs. Higher intake of fruits and vegetables and lower animal protein intake is associated with less acidosis in RTRs.
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Uchida J, Kuwabara N, Machida Y, Iwai T, Naganuma T, Kumada N, Nakatani T. Conversion of Stable Kidney Transplant Recipients From a Twice-Daily Prograf to a Once-Daily Tacrolimus Formulation: A Short-Term Study on its Effects on Glucose Metabolism. Transplant Proc 2012; 44:128-33. [DOI: 10.1016/j.transproceed.2011.11.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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Belatacept-based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidney transplant recipients (BENEFIT and BENEFIT-EXT studies). Transplantation 2011; 91:976-83. [PMID: 21372756 DOI: 10.1097/tp.0b013e31820c10eb] [Citation(s) in RCA: 130] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Cardiovascular disease, the most common cause of death with a functioning graft among kidney transplant recipients, can be exacerbated by immunosuppressive drugs, particularly the calcineurin inhibitors. Belatacept, a selective co-stimulation blocker, may provide a better cardiovascular/metabolic risk profile than current immunosuppressants. METHODS Cardiovascular and metabolic endpoints from two Phase III studies (BENEFIT and BENEFIT-EXT) of belatacept-based regimens in kidney transplant recipients were assessed at month 12. Each study assessed belatacept in more intensive (MI) and less intensive (LI) regimens versus cyclosporine A (CsA). These secondary endpoints included changes in blood pressure, changes in serum lipids, and the incidence of new-onset diabetes after transplant (NODAT). RESULTS A total of 1209 patients were randomized and transplanted across the two studies. Mean systolic blood pressure was 6 to 9 mm Hg lower and mean diastolic blood pressure was 3 to 4 mm Hg lower in the MI and LI groups versus CsA (P ≤ 0.002) across both studies at month 12. Non-HDL cholesterol was lower in the belatacept groups versus CsA (P<0.01 MI or LI vs. CsA in each study). Serum triglycerides were lower in the belatacept groups versus CsA (P<0.02 MI or LI vs. CsA in each study). NODAT occurred less often in the belatacept groups versus CsA in a prespecified pooled analysis (P<0.05 MI or LI vs. CsA). CONCLUSIONS At month 12, belatacept regimens were associated with better cardiovascular and metabolic risk profiles, with lower blood pressure and serum lipids and less NODAT versus CsA. The overall profile of belatacept will continue to be assessed over the 3-year trials.
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Abdulraof Menesi F, Verzola D, Villaggio B, Russo R, Sofia A, Fontana I, Gallina A, Mannucci I, Mussap M, Garibotto G. Evaluation of Metabolic Acidosis in Patients With a Kidney Graft: Comparison of the Bicarbonate-Based and Strong Ion–Based Methods. Transplant Proc 2011; 43:1055-62. [DOI: 10.1016/j.transproceed.2011.01.120] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Orazio LK, Isbel NM, Armstrong KA, Tarnarskyj J, Johnson DW, Hale RE, Kaisar M, Banks MD, Hickman IJ. Evaluation of dietetic advice for modification of cardiovascular disease risk factors in renal transplant recipients. J Ren Nutr 2011; 21:462-71. [PMID: 21454091 DOI: 10.1053/j.jrn.2010.12.002] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2010] [Revised: 12/05/2010] [Accepted: 12/11/2010] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE To investigate the effect of dietitian involvement in a multidisciplinary lifestyle intervention comparing risk factor modification for cardiovascular disease with standard posttransplant care in renal transplant recipients (RTR) with abnormal glucose tolerance (AGT). DESIGN Randomized controlled trial. SETTING Hospital outpatient department. PATIENTS Adult RTR with AGT. INTERVENTION RTR with AGT were randomized to a lifestyle intervention that consisted of either regular consultations with the dietitian and multidisciplinary team or standard care. MAIN OUTCOME MEASURES Dietary intake, physical activity (PA) levels, cardiorespiratory fitness (CF), and anthropometry. RESULTS Total fat and percent saturated fat intake rates were significantly lower in the intervention group as compared with the control group at 2-year follow-up, 54 g (16 to 105 g) versus 65 g (34 to 118 g), P = .01 and 10% (5% to 17%) versus 13% (4% to 20%), P = .05., respectively. There was a trend for an overweight (but not obese) individual to lose more weight in the intervention group (4% loss vs. a gain of 0.25% at the 2-year follow-up). Overall, RTR were significantly less fit than age- and gender-matched controls, mean peak oxygen uptake was 19.42 ± 7.09 mL/kg per minute versus 28.35 ± 8.80 mL/kg per minute, P = .000. Simple exercise advice was not associated with any improvement in total PA or CF in either group at the 2-year follow-up. CONCLUSION Dietary advice can contribute to healthier eating habits and a trend for weight loss in RTR with AGT. These improvements in conjunction with multidisciplinary care and pharmacological treatment can lead to improvements in cardiovascular risk factors such as lipid profile. Simple advice to increase PA was not effective in improving CF and other measures are needed.
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Affiliation(s)
- Linda K Orazio
- Department of Nephrology, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
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Agena F, Prado EDS, Souza PS, da Silva GV, Lemos FBC, Mion D, Nahas WC, David-Neto E. Home blood pressure (BP) monitoring in kidney transplant recipients is more adequate to monitor BP than office BP. Nephrol Dial Transplant 2011; 26:3745-9. [PMID: 21441398 DOI: 10.1093/ndt/gfr143] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Hypertension is highly prevalent among kidney transplantation recipients and considered as an important cardiovascular risk factor influencing patient survival and kidney graft survival. Aim. Compare the blood pressure (BP) control in kidney transplant patients through the use of home blood pressure monitoring (HBPM) is more comparable with the results of ambulatory blood pressure monitoring compared to the measurement of office blood pressure. METHODS From March 2008 to April 2009 prospectively were evaluated 183 kidney transplant recipients with time after transplantation between 1 and 10 years. Patients underwent three methods for measuring BP: office blood pressure measurement (oBP), HBPM and ambulatory blood pressure monitoring (ABPM). RESULTS In total, 183 patients were evaluated, among them 94 were men (54%) and 89 women (46%). The average age was 50 ± 11 years. The average time of transplant was 57 ± 32 months. Ninety-nine patients received grafts from deceased donors (54%) and 84 were recipients of living donors (46%). When assessed using oBP, 56.3% presented with uncontrolled and 43.7% with adequate control of BP with an average of 138.9/82.3 ± 17.8/12.1 mmHg. However, when measured by HBPM, 55.2% of subjects were controlled and 44.8% presented with uncontrolled BP with an average of 131.1/78.5 ± 17.4/8.9 mmHg. Using the ABPM, we observed that 63.9% of subjects were controlled and 36.1% of patients presented uncontrolled BP with an average 128.8/80.5 ± 12.5/8.1 mmHg. We found that the two methods (oBP and HBPM) have a significant agreement, but the HBPM has a higher agreement that oBP, confirmed P = 0.026. We found that there is no symmetry in the data for both methods with McNemar test. The correlation index of Pearson linear methods for the ABPM with the other two methods were 0.494 for office measurement and 0.768 for HBPM, best value of HBPM with ABPM. Comparing the errors of the two methods by paired t-test, we obtained the descriptive level of 0.837. Looking at the receiver operating characteristic curve for BP measurements in each method, we observed that oBP is lower than those obtained by HBPM in relation to ABPM. CONCLUSION We conclude that the results obtained with HBPM were closer to the ABPM results than those obtained with BP obtained at oBP, being more sensitive to detect poor control of hypertension in renal transplant recipients.
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Affiliation(s)
- Fabiana Agena
- Nephrology Division, Renal Transplantation Service, University of Sao Paulo School of Medicine.
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Subesinghe M, Cherukuri A, Ecuyer C, Baker RJ. Who should have pelvic vessel imaging prior to renal transplantation? Clin Transplant 2011; 25:97-103. [DOI: 10.1111/j.1399-0012.2010.01218.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Pita-Fernández S, Pértega-Díaz S, Valdés-Cañedo F, Seijo-Bestilleiro R, Seoane-Pillado T, Fernández-Rivera C, Alonso-Hernández A, Lorenzo-Aguiar D, López-Calvino B, López-Muñiz A. Incidence of cardiovascular events after kidney transplantation and cardiovascular risk scores: study protocol. BMC Cardiovasc Disord 2011; 11:2. [PMID: 21639867 PMCID: PMC3022886 DOI: 10.1186/1471-2261-11-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2010] [Accepted: 01/10/2011] [Indexed: 12/14/2022] Open
Abstract
Background Cardiovascular disease (CVD) is the major cause of death after renal transplantation. Not only conventional CVD risk factors, but also transplant-specific risk factors can influence the development of CVD in kidney transplant recipients. The main objective of this study will be to determine the incidence of post-transplant CVD after renal transplantation and related factors. A secondary objective will be to examine the ability of standard cardiovascular risk scores (Framingham, Regicor, SCORE, and DORICA) to predict post-transplantation cardiovascular events in renal transplant recipients, and to develop a new score for predicting the risk of CVD after kidney transplantation. Methods/Design Observational prospective cohort study of all kidney transplant recipients in the A Coruña Hospital (Spain) in the period 1981-2008 (2059 transplants corresponding to 1794 patients). The variables included will be: donor and recipient characteristics, chronic kidney disease-related risk factors, pre-transplant and post-transplant cardiovascular risk factors, routine biochemistry, and immunosuppressive, antihypertensive and lipid-lowering treatment. The events studied in the follow-up will be: patient and graft survival, acute rejection episodes and cardiovascular events (myocardial infarction, invasive coronary artery therapy, cerebral vascular events, new-onset angina, congestive heart failure, rhythm disturbances and peripheral vascular disease). Four cardiovascular risk scores were calculated at the time of transplantation: the Framingham score, the European Systematic Coronary Risk Evaluation (SCORE) equation, and the REGICOR (Registre Gironí del COR (Gerona Heart Registry)), and DORICA (Dyslipidemia, Obesity, and Cardiovascular Risk) functions. The cumulative incidence of cardiovascular events will be analyzed by competing risk survival methods. The clinical relevance of different variables will be calculated using the ARR (Absolute Risk Reduction), RRR (Relative Risk Reduction) and NNT (Number Needed to Treat). The ability of different cardiovascular risk scores to predict cardiovascular events will be analyzed by using the c index and the area under ROC curves. Based on the competing risks analysis, a nomogram to predict the probability of cardiovascular events after kidney transplantation will be developed. Discussion This study will make it possible to determine the post-transplant incidence of cardiovascular events in a large cohort of renal transplant recipients in Spain, to confirm the relationship between traditional and transplant-specific cardiovascular risk factors and CVD, and to develop a score to predict the risk of CVD in these patients.
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Affiliation(s)
- Salvador Pita-Fernández
- Clinical Epidemiology and Biostatistics Unit, A Coruña Hospital, Hotel de Pacientes Planta, Spain.
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Vivek V, Bhandari S. Prevalence of modifiable cardiovascular risk factors in long-term renal transplant patients. Int J Nephrol Renovasc Dis 2010; 3:175-82. [PMID: 21694943 PMCID: PMC3108770 DOI: 10.2147/ijnrd.s13866] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2010] [Indexed: 12/14/2022] Open
Abstract
Background: Cardiovascular disease accounts for the majority of morbidity and mortality in renal transplant patients. This relates to a number of modifiable and nonmodifiable risk factors, including new onset diabetes after transplantation (NODAT). We examined the prevalence of these risk factors in a cohort of 126 renal transplant patients. Methods: A retrospective cross-sectional study of 94 nondiabetic post-transplant (ND) patients (mean age 45.7 ± 13.5 years) and 32 NODAT patients (55.2 ± 9.6 years) was performed. Univariate linear regression analysis was used to identify potential factors that affected cardiovascular events. Multivariable analysis was performed on those factors found to achieve a P value of less than 0.20 after univariate analysis to test for significance in relation to cardiovascular risk as the primary factor. Results: Mean serum creatinine levels were 131.1 ± 4.3 μmol/L and 135.2 ± 4.9 μmol/L at 96.9 ± 8.7 and 79.4 ± 14.1 months post-transplantation, respectively. Systolic pressure and pulse pressure were significantly higher in NODAT patients (P = 0.016 and P < 0.005). Adequate target blood pressures were obtained in 80% of patients. Low-density lipoprotein and high-density lipoprotein cholesterol were reduced in NODAT (P = 0.04 and P = 0.005). Homocysteine was similarly elevated in both groups (17.5 and 15.6 μmol/L, respectively). Coronary events and/or coronary disease were present in 19.1% of ND and 37.5% of NODAT patients (P < 0.05). Cardiac deaths were three-fold more common (25% versus 7.4%) in patients with NODAT. Univariate analysis revealed diabetes and age, and subsequent multivariable analysis revealed age only, as being significantly associated with cardiovascular outcomes. Conclusions: Cardiac events are more common in patients with NODAT. Age is an important determinant of cardiovascular risk.
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Affiliation(s)
- Vadamalai Vivek
- Department of Renal Medicine, Hull and East Yorkshire Hospitals NHS Trust and Hull York Medical School, East Yorkshire, UK
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Razavian M, Di Micco L, Palmer SC, Craig JC, Perkovic V, Zoungas S, Webster AC, Jardine MJ, Strippoli GFM. Antiplatelet agents for chronic kidney disease. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2010. [DOI: 10.1002/14651858.cd008834] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Miller LM, Sood MM, Sood AR, Reslerova M, Komenda P, Rigatto C, Bueti J. Cardiovascular disease in end-stage renal disease: the challenge of assessing and managing cardiac disease in dialysis patients. Int Urol Nephrol 2010; 42:1007-14. [PMID: 20960231 DOI: 10.1007/s11255-010-9857-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2009] [Accepted: 09/23/2010] [Indexed: 11/25/2022]
Abstract
Cardiovascular disease (CVD) is the leading cause of mortality in end-stage renal disease (ESRD), approximating a 10- to 20-fold higher risk of death in dialysis patients than in the general population. Despite this, dialysis patients often undergo fewer investigations, receive less invasive procedures, and are prescribed fewer medications compared with age-matched non-ESRD patients. A lack of randomized control trials for evidence-based treatment strategies in this population may explain some of these discrepancies, but there is concern that an attitude of "therapeutic nihilism" may be impacting on the medical care of these patients. In this review, we will explore CVD in the ESRD population. Specifically, we will try to address the following issues in patients with ESRD: (1) mechanisms of CVD, (2) cardiac evaluation and the role of coronary revascularization with percutaneous or coronary artery bypass procedures, and (3) cardiac pharmacotherapy use.
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Affiliation(s)
- Lisa M Miller
- Department of Medicine, Health Sciences Centre, GE-441, 820 Sherbrook St, Winnipeg, MB, R3A 1R9, Canada.
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Amundsen R, Christensen H, Zabihyan B, Asberg A. Cyclosporine A, but not tacrolimus, shows relevant inhibition of organic anion-transporting protein 1B1-mediated transport of atorvastatin. Drug Metab Dispos 2010; 38:1499-504. [PMID: 20519340 DOI: 10.1124/dmd.110.032268] [Citation(s) in RCA: 115] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025] Open
Abstract
The aim of this study was to investigate the potential of calcineurin inhibitors [cyclosporine A (CsA) and tacrolimus (Tac)] to inhibit cellular uptake of atorvastatin mediated by the liver-specific organic anion-transporting polypeptide 1B1 (OATP1B1) in vitro. Patients with solid organ transplants are frequently treated with HMG-CoA reductase inhibitors (statins). CsA increases atorvastatin systemic exposure severalfold, an effect not observed with Tac. The effect of CsA and Tac on atorvastatin transport via OATP1B1 was investigated in transfected human embryonic kidney 293 cells. An in vitro-in vivo extrapolation (IVIVE) was performed to estimate the clinical potential for CsA and Tac to inhibit OATP1B1-mediated transport. CsA inhibited OATP1B1-mediated uptake of atorvastatin approximately 90-fold more efficiently than Tac, with half-maximal inhibitory concentration (IC(50)) values of 0.021 +/- 0.004 and 1.99 +/- 0.42 muM, respectively. Coincubation compared with preincubation with CsA showed a 20-fold lower inhibitory capacity, with an IC(50) value of 0.47 +/- 0.34 muM. The IVIVE showed that clinically obtainable concentrations of CsA, but not Tac, inhibit OATP1B1 transport of atorvastatin. CsA inhibition ranged from 28 to 77% within a dosing interval, whereas it was less than 1% for Tac, considering free concentrations and assuming competitive inhibition. This does not fully explain the clinically observed interaction with CsA, suggesting that a more complex inhibitory mechanism may be present. This is also supported by the decreased IC(50) value of CsA after preincubation. This study provides evidence that OATP1B1 inhibition is a relevant mechanism for the interaction observed between CsA and atorvastatin.
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Affiliation(s)
- Rune Amundsen
- Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Blindern, Oslo, Norway.
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Long-Term Impact of Cyclosporin Reduction with MMF Treatment in Chronic Allograft Dysfunction: REFERENECE Study 3-Year Follow Up. J Transplant 2010; 2010. [PMID: 20706667 PMCID: PMC2913628 DOI: 10.1155/2010/402750] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2010] [Accepted: 06/24/2010] [Indexed: 12/14/2022] Open
Abstract
Calcineurin inhibitor (CNI) toxicity contributes to chronic allograft nephropathy (CAN). In the 2-year, randomized, study, we showed that 50% cyclosporin (CsA) reduction in combination with mycophenolate mofetil (MMF) treatment improves kidney function without increasing the risk for graft rejection/loss. To investigate the long-term effect of this regimen, we conducted a follow up study in 70 kidney transplant patients until 5 years after REFERENCE initiation. The improvement of kidney function was confirmed in the MMF group but not in the control group (CsA group). Four graft losses occurred, 2 in each group (graft survival in the MMF group 95.8% and 90.9% in control group). One death occurred in the control group. There was no statistically significant difference in the occurrence of serious adverse events or acute graft rejections. A limitation is the weak proportion of patient still remaining within the control group. On the other hand, REFERENCE focuses on the CsA regimen while opinions about the tacrolimus ones are still debated. In conclusion, CsA reduction in the presence of MMF treatment seems to maintain kidney function and is well tolerated in the long term.
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Gupta G, Unruh ML, Nolin TD, Hasley PB. Primary care of the renal transplant patient. J Gen Intern Med 2010; 25:731-40. [PMID: 20422302 PMCID: PMC2881977 DOI: 10.1007/s11606-010-1354-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2009] [Revised: 11/30/2009] [Accepted: 03/26/2010] [Indexed: 12/25/2022]
Abstract
There has been a remarkable rise in the number of kidney transplant recipients (KTR) in the US over the last decade. Increasing use of potent immunosuppressants, which are also potentially diabetogenic and atherogenic, can result in worsening of pre-existing medical conditions as well as development of post-transplant disease. This, coupled with improving long-term survival, is putting tremendous pressure on transplant centers that were not designed to deliver primary care to KTR. Thus, increasing numbers of KTR will present to their primary care physicians (PCP) post-transplant for routine medical care. Similar to native chronic kidney disease patients, KTRs are vulnerable to cardiovascular disease as well as a host of other problems including bone disease, infections and malignancies. Deaths related to complications of cardiovascular disease and malignancies account for 60-65% of long-term mortality among KTRs. Guidelines from the National Kidney Foundation and the European Best Practice Guidelines Expert Group on the management of hypertension, dyslipidemia, smoking, diabetes and bone disease should be incorporated into the long-term care plan of the KTR to improve outcomes. A number of transplant centers do not supply PCPs with protocols and guidelines, making the task of the PCP more difficult. Despite this, PCPs are expected to continue to provide general preventive medicine, vaccinations and management of chronic medical problems. In this narrative review, we examine the common medical problems seen in KTR from the PCP's perspective. Medical management issues related to immunosuppressive medications are also briefly discussed.
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Affiliation(s)
- Gaurav Gupta
- Nephrology Division, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
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Cardiovascular disease in kidney transplant recipients: the prognostic value of inflammatory cytokine genotypes. Transplantation 2010; 89:1001-8. [PMID: 20061995 DOI: 10.1097/tp.0b013e3181ce243f] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Cardiovascular disease (CVD) represents the main cause of morbidity and mortality after renal transplantation. In view of the modern paradigm of atherosclerosis as an inflammatory disease, this study investigated the impact of inflammatory cytokine polymorphisms on posttransplant CVD. METHODS The association between cytokine polymorphisms and CVD was assessed in a case-control study to identify the differences in genotype distributions between kidney allografts with or without posttransplant CVD. To validate our results in two independent groups, we divided a cohort of 798 renal transplant recipients according to geographic area: an evaluation cohort of 478 patients from Emilia-Romagna and a validation cohort of 320 patients from the rest of Italy. Tumor necrosis factor (TNF)-alpha, transforming growth factor-beta1, interleukin (IL)-10, IL-6, interferon-gamma, and IL-8 polymorphisms were analyzed, and thereafter, the cytokine production genotype was assigned. RESULTS In the evaluation cohort, the patients in the CVD and no-CVD groups differed significantly in TNF-alpha and IL-10 genotype frequencies. Using multivariate analyses to test the association with CVD, the TNF-alpha high-producer genotype was associated with a significantly increased cardiovascular risk (odds ratio [OR]=4.41, 95% confidence interval (CI)=2.53-7.67). Conversely, the IL-10 high-producer genotype resulted protective against CVD (OR=0.07, 95% CI=0.02-0.29). These findings were confirmed in the validation cohort where the carriers of the TNF-alpha high-producer genotype proved to be at 2.45-fold increased cardiovascular risk (OR=2.45, 95% CI=1.29-4.63), whereas the IL-10 high-producer genotype was associated with a 0.08-fold reduced risk (OR=0.08, 95% CI=0.02-0.36). CONCLUSIONS This work suggests a prognostic value of TNF-alpha and IL-10 genotypes, which might represent cardiovascular risk markers in renal transplant.
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Kolonko A, Pinocy-Mańdok J, Kocierz M, Kujawa-Szewieczek A, Chudek J, Malyszko J, Malyszko JS, Myśliwiec M, Wiecek A. Anemia and erythrocytosis after kidney transplantation: a 5-year graft function and survival analysis. Transplant Proc 2010; 41:3046-51. [PMID: 19857673 DOI: 10.1016/j.transproceed.2009.07.090] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Both anemia and erythrocytosis frequently occur after kidney transplantation. The aim of this study was to analyze the influence of both anemia and erythrocytosis on kidney graft function and long-term patient outcomes following kidney transplantation. PATIENTS AND METHODS Three hundred eight-five consecutive patients with at least 12 months of follow-up after successful kidney transplantation were enrolled into this study. Of the total, 88.3% of patients completed a 5-year follow-up. Anemia occurred in 30.4% of patients (with 17.7% showing a hemoglobin concentration (Hb) <11.0 g/dL), whereas erythrocytosis was observed in 19.0% of patients, including 9.6% with hematocrit (HTC) >55%. We also analyzed graft function every 6 months after transplantation for the impact of anemia or erythrocytosis on the 5-year risk of patient death or graft loss. RESULTS In 57.3% of anemia patients the Hb did not reach the normal range during the observation time. The mean eGFR-Modification of Diet in Renal Disease (MDRD) at 12 months after transplantation was significantly lower among patients with anemia: 43.9 mL/min/1.73 m(2) (39.5-48.4) vs 55.3 mL/min/1.73 m(2) (53.0-57.6; P < .001). Better 12-month graft function was observed among patients with erythrocytosis, namely, 57.7 mL/min/1.73 m(2) (53.5-62.0). Anemia but not erythrocytosis was associated with an increased risk of graft loss (hazard ratio [HR] = 4.11 [95% confidence interval (CI) 2.02-8.37]; P < .001). CONCLUSION Anemia after transplantation was associated with worse kidney graft function and was a strong predictor of graft loss. Erythrocytosis occurs among patients with excellent allograft function; when properly treated it did not increase the risk of graft loss or death.
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Affiliation(s)
- A Kolonko
- Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, ul. Fran-cuska 20/24, 40-027 Katowice, Poland.
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