A randomized, controlled trial of everolimus-based dual immunosuppression versus standard of care in de novo kidney transplant recipients

Kidney transplant recipients receiving calcineurin inhibitor-based immunosuppression incur increased long-term risks of cancer and kidney fibrosis. Switch to mammalian target of rapamycin (mTOR) inhibitors may reduce these risks. Steroid or Cyclosporin Removal After Transplant using Everolimus (SOCRATES), a 36-month, prospective, multinational, open-label, randomized controlled trial for de novo kidney transplant recipients, assessed whether everolimus switch could enable elimination of mycophenolate plus either steroids or CNI without compromising efficacy. Patients received cyclosporin, mycophenolate and steroids for the first 14 days then everolimus with mycophenolate and CNIwithdrawal (CNI- WD); everolimus with mycophenolate and steroid withdrawal (steroid-WD); or cyclosporin, mycophenolate and steroids (control). 126 patients were randomized. The steroid WD arm was terminated prematurely because of excess discontinuations. Mean eGFR at month 12 for CNI-WD versus control was 65.1 ml/ min/1.73 m2 vs. 67.1 ml/min/1.73 m2 by ITT, which met predefined noninferiority criteria (P = 0.026). The CNI-WD group experienced a higher rate of BPAR (31% vs. control 13%, P = 0.048) and showed a trend towards higher composite treatment failure (BPAR, graft loss, death, loss to follow-up). The 12 month results from SOCRATES show noninferiority in eGFR, but a significant excess of acute rejection when everolimus was commenced at week 2 to enable a progressive withdrawal of mycophenolate and cyclosporin in kidney transplant recipients.Steven J. Chadban, Josette Marie Eris, John Kanellis, Helen Pilmore, Po Chang Lee, Soo Kun Lim, Chad Woodcock, Nicol Kurstjens, Graeme Rus

Kidney Donor Profile Index and allograft outcomes: interactive effects of estimated post-transplant survival score and ischaemic time

Background. The Kidney Donor Profile Index (KDPI) is routinely reported by the donation agencies in Australia.We determined the association between KDPI and short-term allograft loss and assessed if this association was modified by the estimated post-transplant survival (EPTS) score and total ischaemic time. Methods. Using data from the Australia and New Zealand Dialysis and Transplant Registry, the association between KDPI (in quartiles) and 3-year overall allograft loss was examined using adjusted Cox regression analysis. The interactive effects between KDPI, EPTS score and total ischaemic time on allograft loss were assessed. Results. Of 4006 deceased donor kidney transplant recipients transplanted between 2010 and 2015, 451 (11%) recipients experienced allograft loss within 3 years post-transplant. Compared with recipients of kidneys with a KDPI of 0–25%, recipients who received donor kidneys with a KDPI >75% experienced a 2-fold increased risk of 3-year allograft loss {adjusted hazard ratio [HR] 2.04 [95% confidence interval (CI) 1.53–2.71]}. The adjusted HRs for kidneys with a KDPI of 26–50% and 51–75% were 1.27 (95% CI 0.94–1.71) and 1.31 (95% CI 0.96–1.77), respectively. There were significant interactions between KDPI and EPTS scores (P-value for interaction <.01) and total ischaemic time (P-value for interaction <.01) such that the associations between higher KDPI quartiles and 3-year allograft loss were strongest in recipients with the lowest EPTS scores and longest total ischaemic time. Conclusion. Recipients with higher post-transplant expected survival and transplants with longer total ischaemia who received donor allografts with higher KDPI scores experienced a greater risk of short-term allograft loss compared with those recipients with reduced post-transplant expected survival and with shorter total ischemia.Janelle Prunster, Germaine Wong, Nicholas Larkins, Kate Wyburn, Ross Francis, William R. Mulley, Esther Ooi, Helen Pilmore, Christopher E. Davies and Wai H. Li

Carvedilol and cardiac biomarkers in dialysis patients: Secondary analysis of a randomized controlled trial

Published online: December 04, 2017Background/Aims: Cardiac biomarkers are associated with cardiac abnormalities and adverse outcomes in dialysis patients. Our aim was to report the effect of the beta-blocker carvedilol on cardiac biomarkers in adult dialysis patients. Methods: The Beta-Blocker to Lower Cardiovascular Dialysis Events Feasibility Study was a randomized controlled trial comparing carvedilol to placebo. Serum and plasma were collected before the run-in, then 6 and 12 months post-randomization to measure B-type Natriuretic Peptide (BNP), N-terminal BNP (NT-ProBNP), high-sensitivity cardiac troponins I (hs-TnI) and T (hs-TnT), and galectin-3. Left ventricular global longitudinal strain (GLS) was measured by echocardiography at baseline. Results: Seventy-two participants were recruited of whom 49 completed the run-in and were randomized to carvedilol (n=26) or placebo (n=23). Baseline echocardiography demonstrated median (inter-quartile range) GLS of -14.27% (-16.63 to -11.93). NTproBNP and hs-TnT correlated with GLS (Spearman’s rho=0.34 [p=0.018] and rho=0.28 [p=0.049], respectively). Median change scores from baseline to 12 months did not differ significantly between participants with complete biomarker data randomized to carvedilol (n=15) or placebo (n=16) for any biomarkers. Conclusions: NT-proBNP and hs-TnT were associated with GLS. However, changes in levels of the biomarkers from baseline to 12 months were not different between groups randomized to carvedilol and placebo.Matthew A. Roberts, Darsy Darssan, Sunil V. Badve, Robert P. Carroll, Magid A. Fahim, Brian A. Haluska, Carmel M. Hawley, Nicole M. Isbel, Mark R. Marshall, Elaine M. Pascoe, Eugenie Pedagogos, Helen L. Pilmore, Paul Snelling, Tony Stanton, Ken-Soon Tan, Andrew M. Tonkin, Liza A. Vergara, Francesco L. Ierin

Chronic Kidney Disease and Coronary Artery Disease: JACC State-of-the-Art Review

Chronic kidney disease (CKD) is a major risk factor for coronary artery disease (CAD). As well as their high prevalence of traditional CAD risk factors, such as diabetes and hypertension, persons with CKD are also exposed to other nontraditional, uremia-related cardiovascular disease risk factors, including inflammation, oxidative stress, and abnormal calcium-phosphorus metabolism. CKD and end-stage kidney disease not only increase the risk of CAD, but they also modify its clinical presentation and cardinal symptoms. Management of CAD is complicated in CKD patients, due to their\ua0likelihood of comorbid conditions and potential for side effects during interventions. This summary of the Kidney\ua0Disease: Improving Global Outcomes (KDIGO) Controversies Conference on CAD and CKD (including end-stage\ua0kidney disease and\ua0transplant recipients) seeks to improve understanding of the epidemiology, pathophysiology, diagnosis, and\ua0treatment of CAD in CKD and to identify knowledge gaps, areas of controversy, and\ua0priorities for research

Chronic kidney disease and valvular heart disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Chronic kidney disease (CKD) is a major risk factor for valvular heart disease (VHD). Mitral annular and aortic valve calcifications are highly prevalent in CKD patients and commonly lead to valvular stenosis and regurgitation, as well as complications including conduction system abnormalities and endocarditis. VHD, especially mitral regurgitation and aortic stenosis, is associated with significantly reduced survival among CKD patients. Knowledge related to VHD in the general population is not always applicable to CKD patients because the pathophysiology may be different, and CKD patients have a high prevalence of comorbid conditions and elevated risk for periprocedural complications and mortality. This Kidney Disease: Improving Global Outcomes (KDIGO) review of CKD and VHD seeks to improve understanding of the epidemiology, pathophysiology, diagnosis, and treatment of VHD in CKD by summarizing knowledge gaps, areas of controversy, and priorities for research

Incidence of cardiovascular events after kidney transplantation and cardiovascular risk scores: study protocol

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>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.</p> <p>Methods/Design</p> <p>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).</p> <p>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).</p> <p>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.</p> <p>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).</p> <p>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.</p> <p>Discussion</p> <p>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.</p

Chronic kidney disease and valvular heart disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies conference

Chronic kidney disease (CKD) is a major risk factor for valvular heart disease (VHD). Mitral annular and aortic valve calcifications are highly prevalent in CKD patients and commonly lead to valvular stenosis and regurgitation, as well as complications including conduction system abnormalities and endocarditis. VHD, especially mitral regurgitation and aortic stenosis, is associated with significantly reduced survival among CKD patients. Knowledge related to VHD in the general population is not always applicable to CKD patients because the pathophysiology may be different, and CKD patients have a high prevalence of comorbid conditions and elevated risk for periprocedural complications and mortality. This Kidney Disease: Improving Global Outcomes (KDIGO) review of CKD and VHD seeks to improve understanding of the epidemiology, pathophysiology, diagnosis, and treatment of VHD in CKD by summarizing knowledge gaps, areas of controversy, and priorities for research

Australia and New Zealand Islets and Pancreas Transplant Registry Annual Report 2018-Pancreas Waiting List, Recipients, and Donors.

Background: This is a synopsis of the registry report from the Australia and New Zealand islet and pancreas transplant registry. The full report is available at http://anziptr.org/reports/. Methods: We report data for all solid organ pancreas transplant activity from inception in 1984 to end 2017. Islet-cell transplantation activity is reported elsewhere. Data analysis was performed using Stata software version 14 (StataCorp, College Station, TX). Results: From 1984 to 2017 a total of 809 solid organ pancreas transplants have been performed in Australia and New Zealand, in 790 individuals. In 2017, 52 people received a pancreas transplant. By center, this was; Auckland (4), Monash (17), and Westmead (31). In 2017, 51 transplants were simultaneous pancreas kidney, whereas 1 was pancreas after kidney, and none were pancreas transplant alone. Conclusions: The number of pancreas transplants performed in Australia and New Zealand was slightly lower in 2017 but continues to increase over time

Reduction in cardiovascular death after kidney transplantation

BackgroundCardiovascular (CVS) disease is the commonest cause of death after kidney transplantation. In the general population, CVS mortality has reduced significantly over the last two decades; however, this trend has not been specifically examined in the kidney transplant population.MethodsWe studied all patients in Australia and New Zealand with a functioning kidney transplant between 1980 and 2007 and examined trends in the cause and timing of all 2195 deaths recorded after kidney transplantation in the Australia and New Zealand Dialysis and Transplant registry. Poisson regression was used to compare death rates over the time periods.ResultsCVS events were the commonest cause of death throughout all the time points examined; however, CVS death rates significantly decreased with an adjusted risk ratio of 0.61 (95% confidence interval, 0.38-0.96; P=0.034) for 2005 to 2007 era. In comparison, death rates due to malignancy have increased significantly over this period. Decreased CVS death rates have occurred despite increasing comorbidity at the time of transplantation. Factors associated with CVS death were older recipient age, preexisting CVS disease, and diabetes mellitus. There was a significantly lower CVS death rate in patients with a glomerular filtration rate >48 mL/min compared with those with poor renal function (risk ratio, 0.66; 95% confidence interval, 0.45-0.95; P=0.024).ConclusionsThese trends suggest improvements in CVS risk management and outcomes in the kidney transplant population in Australia and New Zealand.Helen Pilmore, Hannah Dent, Sean Chang, Stephen P. McDonald, Steven J. Chadba