Acute Rejection, Overall Graft Loss, and Infection-related Deaths After Kidney Transplantation in Indigenous Australians.

Introduction: Aboriginal and Torres Strait Islander peoples (hereafter respectfully termed Indigenous Australians) experience a 3-fold increased risk of acute rejection after transplantation compared to non-Indigenous Australians. We investigated whether acute rejection explains the association between Indigenous status, infection-related deaths, and all-cause deaths after kidney transplantation, and whether acute rejection mediates the relationship between Indigenous status and overall graft loss. Methods: This cohort study included all recipients who received their first kidney transplant between 2005 and 2018 in Australia, using data from the Australia and New Zealand Dialysis and Transplant registry. Multivariable Cox regression models determined the associations between Indigenous status, graft loss, infection-related deaths, and all-cause deaths. Mediation analyses examined if acute rejection mediated these relationships. Primary outcome was infection-related death. Secondary outcomes included all-cause death and overall graft loss. Results: There were 9993 patients (n = 390 (3.9%) Indigenous Australians) who received a kidney transplant between 2005 and 2018, and they were followed-up with for 56,876 patient-years. A total of 1165 died (12%) (211 infection-related deaths) and 1957 (20%) lost their allografts. Compared with non-Indigenous recipients, the adjusted hazard ratio (HR) (95% confidence interval [CI]) for graft loss, infection-related deaths and all-cause deaths among Indigenous Australians were 2.27 (1.90-2.71), 3.01 (1.90-4.77) and 2.36 (1.89-2.94), respectively. The mediation analysis showed the association between Indigenous status and graft loss (but not infection-related death or all-cause death) was partially mediated by acute rejection (1.06 [1.03-1.09]), and the proportion of effects mediated by acute rejection was 0.10. Conclusion: Indigenous Australians experienced a higher risk of graft loss, a relationship mediated partially through acute rejection. The higher risk of infection-related death was independent of acute rejection.

Improve in-depth immunological risk assessment to optimize genetic-compatibility and clinical outcomes in child and adolescent recipients of parental donor kidney transplants: protocol for the INCEPTION study.

BACKGROUND: Parental donor kidney transplantation is the most common treatment option for children and adolescents with kidney failure. Emerging data from observational studies have reported improved short- and medium-term allograft outcomes in recipients of paternal compared to maternal donors. The INCEPTION study aims to identify potential differences in immunological compatibility between maternal and paternal donor kidneys and ascertain how this affects kidney allograft outcomes in children and adolescents with kidney failure. METHODS: This longitudinal observational study will recruit kidney transplant recipients aged ≤18 years who have received a parental donor kidney transplant across 4 countries (Australia, New Zealand, United Kingdom and the Netherlands) between 1990 and 2020. High resolution human leukocyte antigen (HLA) typing of both recipients and corresponding parental donors will be undertaken, to provide an in-depth assessment of immunological compatibility. The primary outcome is a composite of de novo donor-specific anti-HLA antibody (DSA), biopsy-proven acute rejection or allograft loss up to 60-months post-transplantation. Secondary outcomes are de novo DSA, biopsy-proven acute rejection, acute or chronic antibody mediated rejection or Chronic Allograft Damage Index (CADI) score of > 1 on allograft biopsy post-transplant, allograft function, proteinuria and allograft loss. Using principal component analysis and Cox proportional hazards regression modelling, we will determine the associations between defined sets of immunological and clinical parameters that may identify risk stratification for the primary and secondary outcome measures among young people accepting a parental donor kidney for transplantation. This study design will allow us to specifically investigate the relative importance of accepting a maternal compared to paternal donor, for families deciding on the best option for donation. DISCUSSION: The INCEPTION study findings will explore potentially differential immunological risks of maternal and paternal donor kidneys for transplantation among children and adolescents. Our study will provide the evidence base underpinning the selection of parental donor in order to achieve the best projected long-term kidney transplant and overall health outcomes for children and adolescents, a recognized vulnerable population. TRIAL REGISTRATION: The INCEPTION study has been registered with the Australian New Zealand Clinical Trials Registry, with the trial registration number of ACTRN12620000911998 (14th September 2020).

Socio-economic disparity, access to care and patient-relevant outcomes after kidney allograft failure.

Social disparity is a major impediment to optimal health outcomes after kidney transplantation. In this study, we aimed to define the association between socio-economic status (SES) disparities and patient-relevant outcomes after kidney allograft failure. Using data from the Australia and New Zealand Dialysis and Transplant registry, we included patients with failed first-kidney allografts in Australia between 2005 and 2017. The association between residential postcode-derived SES in quintiles (quintile 1-most disadvantaged areas, quintile 5-most advantaged areas) with uptake of home dialysis (peritoneal or home haemodialysis) within the first 12-months post-allograft failure, repeat transplantation and death on dialysis were examined using competing-risk analysis. Of 2175 patients who had experienced first allograft failure, 417(19%) and 505(23%) patients were of SES quintiles 1 and 5, respectively. Compared to patients of quintile 5, quintile 1 patients were less likely to receive repeat transplants (adjusted subdistributional hazard ratio [SHR] 0.70,95%CI 0.55-0.89) and were more likely to die on dialysis (1.37 [1.04-1.81]), but there was no association with the uptake of home dialysis (1.02 [0.77-1.35]). Low SES may have a negative effect on outcomes post-allograft failure and further research is required into how best to mitigate this. However, small-scale variation within SES cannot be accounted for in this study.

Allograft and Patient Outcomes Between Indigenous and Nonindigenous Kidney Transplant Recipients.

BACKGROUND: Kidney transplant outcomes of indigenous Australians are poorer compared with nonindigenous Australians, but it is unknown whether the type of acute rejection differs between these patient groups or whether rejection mediates the effect between ethnicity, death-censored graft failure (DCGF), and death with a functioning graft (DWFG). METHODS: Biopsy-proven acute rejection (BPAR) rates and types were compared between indigenous and nonindigenous recipients. The associations between ethnicity, BPAR, DCGF, and DWFG were examined using adjusted competing risk analyses, and mediation analysis was conducted to determine whether BPAR mediated the adverse effects between ethnicity and outcomes. RESULTS: Fifty-seven (9.3%) of 616 patients who have received kidney-only transplants between 2000 and 2010 in Western Australia were indigenous. Compared with nonindigenous recipients, BPAR rates were higher in indigenous recipients (42 versus 74 episodes/100 recipients, P < 0.01), with an excess of antibody-mediated rejections. During a median follow-up of 8 years, indigenous recipients were more likely to experience BPAR, DCGF, and DWFG compared with nonindigenous recipients, with adjusted subdistribution hazard ratio of 1.94 (1.39-2.70), 1.53 (0.85-2.76; P = 0.159), and 2.14 (1.13-4.06; P = 0.020), respectively. Although 70% of the effect between ethnicity and DCGF was mediated by BPAR, no similar association was found for DWFG. CONCLUSIONS: Indigenous recipients experienced poorer allograft and patient outcomes compared with nonindigenous recipients, with BPAR an important determinant for DCGF. Future research identifying other risk factors and mediators associated with patient survival in indigenous recipients should be considered a priority.

Impending challenges of the burden of end-stage kidney disease in Australia.

Sex and age-specific incidence rates of patients with treated end-stage kidney disease (ESKD) in Australia are comparable to those in European countries, but substantially lower compared with those in the United States, Canada and many Asian countries. The incidence rates of treated ESKD in Australia increase with advancing age; however, the incidence of ESKD is likely to be underestimated because a proportion of patients with ESKD (about 50%) remain untreated. Late referral to nephrologists has reduced over the past decade, temporally associated with improved ESKD recognition. However, late referral still occurs in one in five Australians with ESKD. One in two Australians with ESKD has diabetes, with up to 35% of cases directly attributed to diabetes. Mortality rates for patients with ESKD remain substantially higher compared with the age-matched general population, although there has been a significant improvement in survival over time. Cardiovascular disease and cancer are the two most common causes of death in patients with ESKD.

Assessment of kidney transplant suitability for patients with prior cancers: is it time for a rethink?

Kidney transplant recipients have up to a 100-fold greater risk of incident cancer compared with the age/sex-matched general population, attributed largely to chronic immunosuppression. In patients with a prior history of treated cancers, the type, stage and the potential for cancer recurrence post-transplant of prior cancers are important factors when determining transplant suitability. Consequently, one of the predicaments facing transplant clinicians is to determine whether patients with prior cancers are eligible for transplantation, balancing between the accelerated risk of death on dialysis, the projected survival benefit and quality of life gains with transplantation, and the premature mortality associated with the potential risk of cancer recurrence post-transplant. The guidelines informing transplant eligibility or screening and preventive strategies against cancer recurrence for patients with prior cancers are inconsistent, underpinned by uncertain evidence on the estimates of the incidence of cancer recurrence and the lack of stage-specific outcomes data, particularly among those with multiple myeloma or immune-driven malignancies such as melanomas. With the advent of newer anti-cancer treatment options, it is unclear whether the current guidelines for those with prior cancers remain appropriate. This review will summarize the uncertainties of evidence informing the current recommendations regarding transplant eligibility of patients with prior cancers.

Survival and Quality of Life Impact of a Risk-based Allocation Algorithm for Deceased Donor Kidney Transplantation.

BACKGROUND: To determine the incremental gains in graft and patient survival under a risk-based, deceased donor kidney allocation compared with the current Australian algorithm. METHODS: Risk-based matching algorithms were applied to first graft, kidney only recipients (n = 7513) transplanted in Australia between 1994 and 2013. Probabilistic models were used to compare the waiting time, life, and QALYs and graft years between the 8 risk-based allocation strategies against current practice. RESULTS: Compared with current practice, Kidney Donor Risk Index-Estimated Posttransplant Survival matching of the lowest 20% of scores reduced median waiting time by 0.64 years (95% confidence interval [CI], 0.52-0.73) for recipients aged 30 years or younger, but increased waiting time by 0.94 years (95% CI, 0.79-1.09) for recipients older than 60 years. Among all age groups, the greatest gains occurred if Kidney Donor Risk Index-Estimated Posttransplant Survival matching of the lowest 30% of scores was used, incurring a median overall gain of 0.63 (95% CI, 0.03-1.25) life years and 0.78 (95% CI, 0.30-1.26) graft years compared with the current practice. A median gain in survival of 1.91 years for younger recipients (aged 30-45 years) was offset by a median reduction in survival (by 0.95 life years) among the older recipients. Prioritization of lower-quality donor kidneys for older candidates reduced the waiting time for recipients older than 45 years, but no changes in graft and patient survivals were observed. CONCLUSIONS: Risk-based matching engendered a moderate, overall increase in graft and patient survivals, accrued through benefits for recipients 45 years or younger but disadvantage to recipients older than 60 years.

Maternal compared with paternal donor kidneys are associated with poorer graft outcomes after kidney transplantation.

Noninherited maternal human leukocyte antigens may be less detrimental on allograft outcomes after kidney transplantation compared with noninherited paternal antigens, but this association in the era of modern immunosuppression remains unknown. Here we determine the association between parental donor kidneys, acute rejection, and graft failure in primary live-donor parental kidney transplant recipients using data from the Australia and New Zealand Dialysis and Transplant Registry between 1997 and 2012. Of the 1139 recipients followed for a median of 7.2 years (8588 person-years), 652 received kidneys from maternal donors. Compared with paternal donor kidneys, maternal donor kidneys were associated with a significantly increased risk of acute rejection (adjusted odds ratio 1.54; 95% confidence interval [CI], 1.14-2.07) and significant overall graft loss. The latter was confined to recipients who have experienced acute rejection (adjusted hazard ratio 1.60; 95%CI, 1.05-2.43) but not in those who did not experience acute rejection. Thus, our study suggests that recipients of maternal donor kidneys have a greater risk of rejection and graft loss. Hence, clinicians and patients should be cognizant of this association when determining which of the 2 parental donors is most suitable for transplantation.

Assessment of current practice and barriers to antimicrobial prophylaxis in peritoneal dialysis patients.

BACKGROUND: Existing Australasian and international guidelines outline antibiotic and antifungal measures to prevent the development of treatment-related infection in peritoneal dialysis (PD) patients. Practice patterns and rates of PD-related infection vary widely across renal units in Australia and New Zealand and are known to vary significantly from guideline recommendations, resulting in PD technique survival rates that are lower than those achieved in many other countries. The aim of this study was to determine if there is an association between current practice and PD-related infection outcomes and to identify the barriers and enablers to good clinical practice. METHODS: This is a multicentre network study involving eight PD units in Australia and New Zealand, with a focus on adherence to guideline recommendations on antimicrobial prophylaxis in PD patients. Current practice was established by asking the PD unit heads to respond to a short survey about practice/protocols/policies and a 'process map' was constructed following a face-to-face interview with the primary PD nurse at each unit. The perceived barriers/enablers to adherence to the relevant guideline recommendations were obtained from the completion of 'cause and effect' diagrams by the nephrologist and PD nurse at each unit. Data on PD-related infections were obtained for the period 1 January 2011 to 31 December 2011. RESULTS: Perceived barriers that may result in reduced adherence to guideline recommendations included lack of knowledge, procedural lapses, lack of a centralized patient database, patients with non-English speaking background, professional concern about antibiotic resistance, medication cost and the inability of nephrologists and infectious diseases staff to reach consensus on unit protocols. The definitions of PD-related infections used by some units varied from those recommended by the International Society for Peritoneal Dialysis, particularly with exit-site infection (ESI). Wide variations were observed in the rates of ESI (0.06-0.53 episodes per patient-year) and peritonitis (0.31-0.86 episodes per patient-year). CONCLUSIONS: Despite the existence of strongly evidence-based guideline recommendations, there was wide variation in adherence to these recommendations between PD units which might contribute to PD-related infection rates, which varied widely between units. Although individual patient characteristics may account for some of this variability, inconsistencies in the processes of care to prevent infection in PD patients also play a role.

Diagnostic Accuracies of Glycated Hemoglobin, Fructosamine, and Homeostasis Model Assessment of Insulin Resistance in Predicting Impaired Fasting Glucose, Impaired Glucose Tolerance, or New Onset Diabetes After Transplantation.

BACKGROUND: New onset diabetes after transplantation (NODAT) is associated with a 3-fold greater risk of cardiovascular disease events, with early identification and treatment potentially attenuating this risk. The optimal screening test to identify those with NODAT remains unclear, and the aim of this study was to examine the diagnostic accuracies of 4 screening tests in identifying impaired fasting glucose, impaired glucose tolerance (IGT), and NODAT. METHODS: This is a single-center prospective cohort study of 83 nondiabetic kidney transplant recipients between 2008 and 2011. Oral glucose tolerance test was considered the gold standard in identifying IFG/IGT or NODAT. Diagnostic accuracies of random blood glucose, glycated hemoglobin (HBA1c), fructosamine, and Homeostasis Model Assessment-Insulin Resistance in predicting IFG/IGT or NODAT were assessed using the area under the receiver operating characteristic curve. RESULTS: Forty (48%) recipients had IFG/IGT or NODAT. Compared with HBA1c with adjusted area under the curve (AUC) of 0.88 (95% confidence interval [95% CI], 0.77-0.93), fructosamine was the most accurate test with adjusted AUC of 0.92 (95% CI, 0.83-0.96). The adjusted AUCs of random blood glucose and Homeostasis Model Assessment-Insulin Resistance in identifying IFG/IGT were between 0.81 and 0.85. Restricting to identifying IGT/NODAT using 2-hour oral glucose tolerance test (n = 66), fructosamine was the most accurate diagnostic test with adjusted AUC of 0.93 (95% CI, 0.84-0.99), but not statistically different to HBA1c with adjusted AUC of 0.88 (95% CI, 0.76-0.96). CONCLUSIONS: Although HBA1c is an acceptable and widely used screening test in detecting IFG/IGT or NODAT, fructosamine may be a more accurate diagnostic test but this needs to be further examined in larger cohorts.

The impact of socioeconomic status and geographic remoteness on access to pre-emptive kidney transplantation and transplant outcomes among children.

BACKGROUND: Low socioeconomic status (SES) and geographic disparity have been associated with worse outcomes and poorer access to pre-emptive transplantation in the adult end-stage kidney disease (ESKD) population, but little is known about their impact in children with ESKD. The aim of our study was to determine whether access to pre-emptive transplantation and transplant outcomes differ according to SES and geographic remoteness in Australia. METHODS: Using data from the Australia and New Zealand Dialysis and Transplant Registry (1993-2012), we compared access to pre-emptive transplantation, the risk of acute rejection and graft failure, based on SES and geographic remoteness among Australian children with ESKD (≤ 18 years), using adjusted logistic and Cox proportional hazard modelling. RESULTS: Of the 768 children who commenced renal replacement therapy, 389 (50.5%) received living donor kidney transplants and 28.5% of these (111/389) were pre-emptive. There was no significant association between SES quintiles and access to pre-emptive transplantation, acute rejection or allograft failure. Children residing in regional or remote areas were 35% less likely to receive a pre-emptive transplant compared to those living in major cities [adjusted odds ratio (OR) 0.65, 95% confidence interval (CI) 0.45-1.0]. There was no significant association between geographic disparity and acute rejection (adjusted OR 1.03, 95% CI 0.68-1.57) or graft loss (adjusted hazard ratio 1.05, 95% CI 0.74-1.41). CONCLUSIONS: In Australia, children from regional or remote regions are much less likely to receive pre-emptive kidney transplantation. Strategies such as improved access to nephrology services through expanding the scope of outreach clinics, and support for regional paediatricians to promote early referral may ameliorate this inequity.

The relative benefits and costs of solid phase bead technology to detect preformed donor specific antihuman leukocyte antigen antibodies in determining suitability for kidney transplantation.

BACKGROUND: Screening for donor-specific anti-HLA antibodies (DSA) using bead-based multiplex assays to determine transplant suitability is standard practice in many countries. We compared the health benefits and costs of screening preformed DSA using bead-based assay as an add-on test to complement-dependent cytotoxicity (CDC) crossmatch with CDC crossmatch alone, and determined the optimal threshold to determine transplant suitability. METHODS: Three probabilistic Markov models were developed to compare bead-based assay with CDC and CDC alone. The model assumed a hypothetical cohort of 10,000 patients who received only a single kidney transplant and terminated when all patients were deceased. RESULTS: Assuming transplantation was permitted for recipients with no DSA or with a DSA mean fluorescence intensity (MFI) value of 500 or less, screening by bead-based assay and CDC saved 6.5 grafts and U.S. $1,192,303 per 100 transplants compared with CDC alone. If the thresholds were increased to an MFI of 2000 or less and 5000 or less, an extra 6.4 and 6.1 grafts would be saved, with cost savings of U.S. $867,203 and U.S. $830,664 per 100 transplants compared with CDC alone. The total number of kidney transplants performed would have increased by 8 and 9, respectively, but at the expense of an extra 0.1 and 0.4 graft lost per 100 transplants after 5 years. CONCLUSIONS: Screening using bead-based assay is cost-saving and improves graft outcomes. The greatest benefits and cost-savings are achieved if transplantation occurs at a threshold of MFI of 500 or less or in those without preformed DSA. Increasing the threshold to an MFI of 2000 or less may provide an acceptable balance for improving transplant eligibility without compromising longer-term outcomes.

Modeling the benefits and costs of integrating an acceptable HLA mismatch allocation model for highly sensitized patients.

BACKGROUND: The Eurotransplant acceptable mismatch program has improved transplantation access for highly sensitized recipients. However, the benefits and costs of implementing such a program remain unknown. METHODS: Using decision analytical modeling, we compared the average waiting time for transplantation, overall survival gains (in life-years and quality-adjusted life-years gained), and costs of integrating an acceptable mismatch allocation model compared with the current deceased-donor kidney allocation model in Australia. RESULTS: Acceptable mismatches were identified in 12 of 28 (43%) highly sensitized recipients using HLAMatchmaker. Inclusion of acceptable mismatches in the current allocation model improved the transplantation access for four (14%) highly sensitized recipients, with an average reduction in waiting time of 34 months (from 86 to 52 months). Compared with the current allocation model, incorporating an acceptable mismatch allocation model achieved an overall lifetime gain of 0.034 quality-adjusted life-years and savings of over $4,000 per highly sensitized patient, with a small consequential loss of 0.005 quality-adjusted life-years and extra costs of $800 for every reallocated patient. CONCLUSIONS: Despite modest overall health gains, application of an acceptable mismatch allocation model is an equitable approach to improve transplantation access for highly sensitized transplant candidates without compromising the overall health benefits among the other patients on the deceased-donor waitlist in Australia.

Lack of impact of donor age on patient survival for renal transplant recipients ≥60years.

There has been an increase in the number of older patients on the transplant waiting list and acceptance of older donor kidneys. Although kidneys from older donors have been associated with poorer graft outcomes, whether there is a differential impact of donor age on outcomes in older recipients remains unclear. The aim of this study was to evaluate the effect of donor age on graft and patient survival in renal transplant (RT) recipients ≥60years. Using the Australia and New Zealand Dialysis and Transplant Registry, outcomes of 1,037 RT recipients ≥60years between 1995 and 2009 were analyzed. Donor age groups were categorized into 0-20, >20-40, >40-60, and >60years. Compared with recipients receiving donor kidneys >60years, those receiving donor kidneys >20-40years had lower risk of acute rejection (odds ratio 0.46, 95% CI 0.27, 0.79; P<0.01) and death-censored graft failure (HR 0.37, 95% CI 0.19, 0.72; P<0.01). There was no association between donor age groups and death. With a corresponding growth in the availability of older donor kidneys and the observed lack of association between donor age and patient survival in RT recipients ≥60years, preferential allocation of older donor kidneys to RT recipients ≥60years may not disadvantage the life expectancy of these patients.

A review of utility-based allocation strategies to maximize graft years of deceased donor kidneys.

With the continuing shortage of deceased donor kidneys coupled with a growing number of older potential recipients, there has been a greater acceptance of using older donor kidneys, including increased utility of expanded criteria donor (ECD) kidneys. In this review, we will look at the impact of using ECD kidneys on graft and patient survival, and to identify modifiable factors that may improve transplant outcomes in recipients receiving ECD kidneys. In addition, we will discuss whether the implementation of utility-based allocation strategies to maximize graft outcomes is an appropriate way forward to provide a better balance between utility and equity in the distribution of deceased donor kidneys.