Steve Chadban

The cost effectiveness of increasing kidney transplantation and home based dialysis

Background:  Renal replacement therapy (RRT) consumes sizable proportions of health budgets internationally, but there is considerable variability in choice of RRT modality among and within countries with major implications for health outcomes and costs. We aimed to quantify these implications for increasing kidney transplantation and improving the rate of home‐based dialysis.

Exercise Training in Solid Organ Transplant Recipients: A Systematic Review and Meta-Analysis

Background Exercise training is effective in improving the cardiovascular risk profiles of nontransplanted patients, but the health benefits and potential harms of routine exercise training after solid organ transplantation are unclear. This study aims to assess the health benefits and harms of supervised exercise training programs in solid organ recipients. Methods We systematically reviewed all randomized controlled trials (RCTs) comparing the outcomes of exercise training programs in solid organ recipients against standard care. MEDLINE, EMBASE, the Transplant Library from the Centre for Evidence in Transplantation, and the Cochrane Central Register of Controlled Trials were searched to June 2012. Results In total, 15 eligible RCTs involving 643 patients (9 cardiac transplants [n=250 patients], 2 kidney transplants [n=164 patients], 3 lung transplants [n=110 patients], and 1 liver transplant [n=119 patients]) were included. Cardiac transplant recipients who engaged in an exercise program after transplantation showed significant improvement in maximal oxygen uptake (standardized mean difference, 0.77; 95% confidence interval, 0.10–1.45) but no improvement in the overall serum lipid profile, blood pressure, and glycemic control compared with standard care. Among other solid organ transplant recipients, no significant improvements in exercise capacity or cardiovascular risk factors such as incidence of new-onset diabetes after transplantation were observed, but all effect estimates were very imprecise. Conclusions Exercise training is a promising but unproven intervention for improving the cardiovascular outcomes of solid organ transplant recipients. Existing trials are small, of relatively short duration, and focused on surrogate outcomes. Large-scale RCTs are urgently required if resources are to be directed toward exercise programs.

Outcomes of Kidney Transplantation From Older Living Donors

Background The disparity between donor kidney availability and demand has increased utilization of kidneys from older living donors (OLD). We compared graft and patient outcomes of patients on maintenance dialysis after transplantation with OLD kidneys to those receiving younger live donor (YLD) kidneys and deceased donor (DD) kidneys. Methods Using Australia and New Zealand Dialysis and Transplant Registry, primary live and deceased donor renal transplant recipients aged 18 years or older between 1997 and 2009 were stratified into six groups: standard criteria deceased donor kidneys with total ischemic time of less than 12 hours (SCD, <12), SCD of 12 or greater, expanded criteria donor (ECD) less than 12, ECD of 12 or greater, YLD (LD, <60 years), and OLD kidneys (LD, ≥60 years). Preemptive and multiple-organ transplants were excluded. Results Of the 6,317 renal transplant recipients, 346 (5.5%) received OLD kidneys. Compared with kidneys from SCD of less than 12 hours, OLD kidneys were associated with a greater risk of death-censored graft failure (DCGF; adjusted HR 2.00; 95% confidence interval, 1.32–3.03) and inferior 5-year graft function (estimated glomerular filtration rate of 45 mL/min vs. 56 mL/min), although no increase in 5-year mortality (HR, 1.18; 95% confidence interval, 0.80–1.76). Outcomes for OLD kidneys were also inferior to YLD recipients, although modestly superior to ECD kidneys. Chronic allograft nephropathy was more commonly reported as the cause of DCGF among recipients of OLD kidneys than other donor types. Conclusion Patient survival was equal, but graft outcomes for recipients of OLD kidneys were inferior to those obtained with YLD and SCD kidneys. This study suggests that OLD kidneys should be utilized cautiously, cognizant of the fact that younger recipients may have a life expectancy in excess of the life of the transplanted kidney.

Research Priorities in CKD: Report of a National Workshop Conducted in Australia

Research aims to improve health outcomes for patients. However, the setting of research priorities is usually performed by clinicians, academics, and funders, with little involvement of patients or caregivers and using processes that lack transparency. A national workshop was convened in Australia to generate and prioritize research questions in chronic kidney disease (CKD) among diverse stakeholder groups. Patients with CKD (n=23), nephrologists/surgeons (n=16), nurses (n=8), caregivers (n=7), and allied health professionals and researchers (n=4) generated and voted on intervention questions across 4 treatment categories: CKD stages 1 to 5 (non-dialysis dependent), peritoneal dialysis, hemodialysis, and kidney transplantation. The 5 highest ranking questions (in descending order) were as follows: How effective are lifestyle programs for preventing deteriorating kidney function in early CKD? What strategies will improve family consent for deceased donor kidney donation, taking different cultural groups into account? What interventions can improve long-term post-transplant outcomes? What are effective interventions for post hemodialysis fatigue? How can we improve and individualize drug therapy to control post-transplant side effects? Priority questions were focused on prevention, lifestyle, quality of life, and long-term impact. These prioritized research questions can inform funding agencies, patient/consumer organizations, policy makers, and researchers in developing a CKD research agenda that is relevant to key stakeholders.

Human leukocyte antigen mismatches associated with increased risk of rejection, graft failure, and death independent of initial immunosuppression in renal transplant recipients

Human leukocyte antigen (HLA) mismatches have been shown to adversely affect renal allograft outcomes and remain an important component of the allocation of deceased donor (DD) kidneys. The ongoing importance of HLA mismatches on transplant outcomes in the era of more potent immunosuppression remains debatable. Using Australia and New Zealand Dialysis and Transplant Registry, live and DD renal transplant recipients between 1998 and 2009 were examined. The association between the number of HLA mismatches and HLA‐loci mismatches and outcomes were examined. Of the 8036 renal transplant recipients, 59% had between 2 and 4 HLA mismatches. Compared with 0 HLA mismatch, increasing HLA mismatches were associated with a higher risk of graft failure and patient death in the adjusted models. HLA mismatches were associated with an incremental risk of rejection although the relative risk was higher for live donor kidney transplants. Increasing HLA‐AB and HLA‐DR mismatches were associated with a greater risk of acute rejection, graft failure, death‐censored graft failure, and/or death. There was no consistent association between initial immunosuppressive regimen and outcomes. Our results corroborate and extend the previous registry analyses demonstrating that HLA mismatches are associated with poorer transplant outcomes independent of immunosuppression and transplant era.

Estimating the total incidence of kidney failure in Australia including individuals who are not treated by dialysis or transplantation

BACKGROUND To date, incidence data for kidney failure in Australia have been available for only those who start renal replacement therapy (RRT). Information about the total incidence of kidney failure, including non-RRT-treated cases, is important to help understand the burden of kidney failure in the community and the characteristics of patients who die without receiving treatment. STUDY DESIGN Data linkage study of national observational data sets. SETTING & PARTICIPANTS All incident treated cases recorded in the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) probabilistically linked to incident untreated kidney failure cases derived from national death registration data for 2003-2007. PREDICTOR Age, sex, and year. OUTCOMES Kidney failure, a combination of incident RRT or death attributed to kidney failure (without RRT). MEASUREMENTS Total incidence of kidney failure (treated and untreated) and treatment rates. RESULTS There were 21,370 incident cases of kidney failure in 2003-2007. The incidence rate was 20.9/100,000 population (95% CI, 18.3-24.0) and was significantly higher among older people and males (26.1/100,000 population; 95% CI, 22.5-30.0) compared with females (17.0/100,000 population; 95% CI, 14.9-19.2). There were similars number of treated (10,949) and untreated (10,421) cases, but treatment rates were influenced highly by age. More than 90% of cases in all age groups between 5 and 60 years were treated, but this percentage decreased sharply for older people; only 4% of cases in persons 85 years or older were treated (ORs for no treatment of 115 [95% CI, 118-204] for men ≥80 years and 400 [95% CI, 301-531] for women ≥80 years compared with women who were <50 years). LIMITATIONS Cross-sectional design, reliance on accurate coding of kidney failure in death registration data. CONCLUSIONS Almost all Australians who develop kidney failure at younger than 60 years receive RRT, but treatment rates decrease substantially above that age.

Global Cardiovascular and Renal Outcomes of Reduced GFR

The burden of premature death and health loss from ESRD is well described. Less is known regarding the burden of cardiovascular disease attributable to reduced GFR. We estimated the prevalence of reduced GFR categories 3, 4, and 5 (not on RRT) for 188 countries at six time points from 1990 to 2013. Relative risks of cardiovascular outcomes by three categories of reduced GFR were calculated by pooled random effects meta-analysis. Results are presented as deaths for outcomes of cardiovascular disease and ESRD and as disability-adjusted life years for outcomes of cardiovascular disease, GFR categories 3, 4, and 5, and ESRD. In 2013, reduced GFR was associated with 4% of deaths worldwide, or 2.2 million deaths (95% uncertainty interval [95% UI], 2.0 to 2.4 million). More than half of these attributable deaths were cardiovascular deaths (1.2 million; 95% UI, 1.1 to 1.4 million), whereas 0.96 million (95% UI, 0.81 to 1.0 million) were ESRD-related deaths. Compared with metabolic risk factors, reduced GFR ranked below high systolic BP, high body mass index, and high fasting plasma glucose, and similarly with high total cholesterol as a risk factor for disability-adjusted life years in both developed and developing world regions. In conclusion, by 2013, cardiovascular deaths attributed to reduced GFR outnumbered ESRD deaths throughout the world. Studies are needed to evaluate the benefit of early detection of CKD and treatment to decrease these deaths.

Role of TLRs and DAMPs in allograft inflammation and transplant outcomes

Graft inflammation impairs the induction of solid organ transplant tolerance and enhances acute and chronic rejection. Elucidating the mechanisms by which inflammation is induced after organ transplantation could lead to novel therapeutics to improve transplant outcomes. In this Review we describe endogenous substances — damage-associated molecular patterns (DAMPs) — that are released after allograft reperfusion and induce inflammation. We also describe innate immune signalling pathways that are activated after solid organ transplantation, with a focus on Toll-like receptors (TLRs) and their signal adaptor, MYD88. Experimental and clinical studies have yielded a large body of evidence that TLRs and MYD88 are instrumental in initiating allograft inflammation and promoting the development of acute and chronic rejection. Ongoing clinical studies are testing TLR inhibition strategies in solid organ transplantation, although avoiding compromising host defence to pathogens is a key challenge. Further elucidation of the mechanisms by which sterile inflammation is induced, maintained and amplified within the allograft has the potential to lead to novel anti-inflammatory treatments that could improve outcomes for solid organ transplant recipients.

High rates of albuminuria but not of low eGFR in Urban Indigenous Australians: the DRUID Study

BackgroundIndigenous Australians have an incidence of end stage kidney disease 8-10 times higher than non-Indigenous Australians. The majority of research studies concerning Indigenous Australians have been performed in rural or remote regions, whilst the majority of Indigenous Australians actually live in urban settings. We studied prevalence and factors associated with markers of kidney disease in an urban Indigenous Australian cohort, and compared results with those for the general Australian population.Methods860 Indigenous adult participants of the Darwin Region Urban Indigenous Diabetes (DRUID) Study were assessed for albuminuria (urine albumin-creatinine ratio≥2.5 mg/mmol males, ≥3.5 mg/mmol females) and low eGFR (estimated glomular filtration rate < 60 mls/min/1.73 m2). Associations between risk factors and kidney disease markers were explored. Comparison was made with the AusDiab cohort (n = 8,936 aged 25-64 years), representative of the general Australian adult population.ResultsA high prevalence of albuminuria (14.8%) was found in DRUID, whilst prevalence of low eGFR was 2.4%. Older age, higher HbA1c, hypertension, higher C-reactive protein and current smoking were independently associated with albuminuria on multiple regression. Low eGFR was independently associated with older age, hypertension, albuminuria and higher triglycerides. Compared to AusDiab participants, DRUID participants had a 3-fold higher adjusted risk of albuminuria but not of low eGFR.ConclusionsGiven the significant excess of ESKD observed in Indigenous versus non-Indigenous Australians, these findings could suggest either: albuminuria may be a better prognostic marker of kidney disease than low eGFR; that eGFR equations may be inaccurate in the Indigenous population; a less marked differential between Indigenous and non-Indigenous Australians for ESKD rates in urban compared to remote regions; or that differences in the pathophysiology of chronic kidney disease exist between Indigenous and non-Indigenous populations.

The expectations and attitudes of patients with chronic kidney disease toward living kidney donor transplantation: a thematic synthesis of qualitative studies.

Background Living kidney donation offers superior outcomes over deceased organ donation, but incurs psychosocial and ethical challenges for recipients because of the risks imposed on their donor. We aimed to describe the beliefs, attitudes, and expectations of patients with chronic kidney disease toward receiving a living kidney donor transplant. Methods We conducted a systematic review of qualitative studies of patients’ attitudes toward living kidney donation using a comprehensive literature search of electronic databases to February 2013. The findings were analyzed using thematic synthesis. Results Thirty-nine studies (n≥1791 participants) were included. We identified six themes: prioritizing own health (better graft survival, accepting risk, and desperate aversion to dialysis), guilt and responsibility (jeopardizing donor health, anticipating donor regret, and causing donor inconvenience), ambivalence and uncertainty (doubting transplant urgency, insufficient information, confronted by unfamiliarity, and prognostic uncertainty), seeking decisional validation (a familial obligation, alleviating family burden, reciprocal benefits for donors, respecting donor autonomy, external reassurance, and religious approval), needing social support (avoiding family conflict, unrelenting indebtedness, and emotional isolation), and cautious donor recruitment (self-advocacy, lacking self-confidence, avoiding donor coercion, emotional vulnerability, respecting cultural, and religious taboos). Conclusion Enhanced education and psychosocial support may help clarify, validate, and address patients’ concerns regarding donor outcomes, guilt, relationship tensions, and donor recruitment. This may encourage informed decision-making, increase access to living kidney donation, and improve psychosocial adjustment for transplant recipients.