Interactions between donor age and 12-month estimated glomerular filtration rate on allograft and patient outcomes after kidney transplantation

Reduced estimated glomerular filtration rate (eGFR) at 12-months after kidney transplantation is associated with increased risk of allograft loss, but it is uncertain whether donor age and types modify this relationship. Using Australia and New Zealand registry data, multivariable Cox proportional modelling was used to examine the interactive effects between donor age, types and 12-month eGFR on overall allograft loss. We included 11,095 recipients (4,423 received live-donors). Recipients with lowest 12-month eGFR (60 ml/min/1.73 m²) was 0.67 [0.62–0.74]. The association of 12-month eGFR and allograft loss was modified by donor age (but not donor types) where a higher risk of allograft loss in recipients with lower compared with higher 12-month eGFR being most pronounced in the younger donor age groups (p 60 ml/min/1.73 m², and the magnitude of the increased risk is most marked among recipients with younger donors. Careful deliberation of other factors including donor age when considering eGFR as a surrogate for clinical endpoints is warranted.Wai H. Lim, Esther Ooi, Helen L. Pilmore, David W. Johnson, Stephen P. McDonald, Philip Clayton, Carmel Hawley, William R. Mulley, Ross Francis, Michael G. Collins, Bryon Jaques, Nicholas G. Larkins, Christopher E. Davies, Kate Wyburn, Steve J. Chadban and Germaine Won

Study Protocol for Better Evidence for Selecting Transplant Fluids (BEST-Fluids): a pragmatic, registry-based, multi-center, double-blind, randomized controlled trial evaluating the effect of intravenous fluid therapy with Plasma-Lyte 148 versus 0.9% saline on delayed graft function in deceased donor kidney transplantation

BACKGROUND: Delayed graft function, the requirement for dialysis due to poor kidney function post-transplant, is a frequent complication of deceased donor kidney transplantation and is associated with inferior outcomes and higher costs. Intravenous fluids given during and after transplantation may affect the risk of poor kidney function after transplant. The most commonly used fluid, isotonic sodium chloride (0.9% saline), contains a high chloride concentration, which may be associated with acute kidney injury, and could increase the risk of delayed graft function. Whether using a balanced, low-chloride fluid instead of 0.9% saline is safe and improves kidney function after deceased donor kidney transplantation is unknown. METHODS: BEST-Fluids is an investigator-initiated, pragmatic, registry-based, multi-center, double-blind, randomized controlled trial. The primary objective is to compare the effect of intravenous Plasma-Lyte 148 (Plasmalyte), a balanced, low-chloride solution, with the effect of 0.9% saline on the incidence of delayed graft function in deceased donor kidney transplant recipients. From January 2018 onwards, 800 participants admitted for deceased donor kidney transplantation will be recruited over 3 years in Australia and New Zealand. Participants are randomized 1:1 to either intravenous Plasmalyte or 0.9% saline peri-operatively and until 48 h post-transplant, or until fluid is no longer required; whichever comes first. Follow up is for 1 year. The primary outcome is the incidence of delayed graft function, defined as dialysis in the first 7 days post-transplant. Secondary outcomes include early kidney transplant function (composite of dialysis duration and rate of improvement in graft function when dialysis is not required), hyperkalemia, mortality, graft survival, graft function, quality of life, healthcare resource use, and cost-effectiveness. Participants are enrolled, randomized, and followed up using the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. DISCUSSION: If using Plasmalyte instead of 0.9% saline is effective at reducing delayed graft function and improves other clinical outcomes in deceased donor kidney transplantation, this simple, inexpensive change to using a balanced low-chloride intravenous fluid at the time of transplantation could be easily implemented in the vast majority of transplant settings worldwide. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12617000358347. Registered on 8 March 2017. ClinicalTrials.gov: NCT03829488. Registered on 4 February 2019.Michael G. Collins, Magid A. Fahim, Elaine M. Pascoe, Kathryn B. Dansie, Carmel M. Hawley, Philip A. Clayton, Kirsten Howard, David W. Johnson, Colin J. McArthur, Rachael C. McConnochie, Peter F. Mount, Donna Reidlinger, Laura Robison, Julie Varghese, Liza A. Vergara, Laurence Weinberg, Steven J. Chadban, and for the BEST-Fluids Investigators and the Australasian Kidney Trials Networ

Long-term outcomes after acute rejection in kidney transplant recipients: an ANZDATA analysis

BACKGROUND:Declining rates of acute rejection (AR) and the high rate of 1-year graft survival among patients with AR have prompted re-examination of AR as an outcome in the clinic and in trials. Yet AR and its treatment may directly or indirectly affect longer-term outcomes for kidney transplant recipients. METHODS:To understand the long-term effect of AR on outcomes, we analyzed data from the Australia and New Zealand Dialysis and Transplant Registry, including 13,614 recipients of a primary kidney-only transplant between 1997 and 2017 with at least 6 months of graft function. The associations between AR within 6 months post-transplant and subsequent cause-specific graft loss and death were determined using Cox models adjusted for baseline donor, recipient, and transplant characteristics. RESULTS:AR occurred in 2906 recipients (21.4%) and was associated with graft loss attributed to chronic allograft nephropathy (hazard ratio [HR], 1.39; 95% confidence interval [95% CI], 1.23 to 1.56) and recurrent AR beyond month 6 (HR, 1.85; 95% CI, 1.39 to 2.46). Early AR was also associated with death with a functioning graft (HR, 1.22; 95% CI, 1.08 to 1.36), and with death due to cardiovascular disease (HR, 1.30; 95% CI, 1.11 to 1.53) and cancer (HR, 1.35; 95% CI, 1.12 to 1.64). Sensitivity analyses restricted to subgroups with either biopsy-proven, antibody-mediated, or vascular rejection, or stratified by treatment response produced similar results. CONCLUSIONS:AR is associated with increased risks of longer-term graft failure and death, particularly death from cardiovascular disease and cancer. The results suggest AR remains an important short-term outcome to monitor in kidney transplantation and clinical trials.Philip A. Clayton, Stephen P. McDonald, Graeme R. Russ, and Steven J. Chadba

Statistical analysis plan for Better Evidence for Selecting Transplant Fluids (BEST-Fluids): a randomised controlled trial of the effect of intravenous fluid therapy with balanced crystalloid versus saline on the incidence of delayed graft function in deceased donor kidney transplantation

Published online: 18 January 2022. Corrected by: Correction to: Statistical analysis plan for better evidence for selecting transplant fluids (BEST-fluids): a randomised controlled trial of the effect of intravenous fluid therapy with balanced crystalloid versus saline on the incidence of delayed graft function in deceased donor kidney transplantation (Trials, (2022), 23, 1, (52), 10.1186/s13063-021-05989-w), in Vol. 23, Issue 1, 123. Following the publication of the original article [1], we were notified that an incorrect additional file was published alongside the paper. The original article has been corrected.Background: Delayed graft function, or the requirement for dialysis due to poor kidney function, is a frequent complication of deceased donor kidney transplantation that is associated with inferior outcomes. Intravenous fluids with a high chloride content, such as isotonic sodium chloride (0.9% saline), are widely used in transplantation but may increase the risk of poor kidney function. The primary objective of the BEST-Fluids trial is to compare the effect of a balanced low-chloride crystalloid, Plasma-Lyte 148 (Plasmalyte), versus 0.9% saline on the incidence of DGF in deceased donor kidney transplant recipients. This article describes the statistical analysis plan for the trial. Methods and design: BEST-Fluids is an investigator-initiated, pragmatic, registry-based, multi-centre, double-blind, randomised controlled trial. Eight hundred patients (adults and children) in Australia and New Zealand with endstage kidney disease admitted for a deceased donor kidney transplant were randomised to intravenous fluid therapy with Plasmalyte or 0.9% saline in a 1:1 ratio using minimization. The primary outcome is delayed graft function (dialysis within seven days post-transplant), which will be modelled using a log-binomial generalised linear mixed model with fixed effects for treatment group, minimization variables, and ischaemic time and a random intercept for study centre. Secondary outcomes including early kidney transplant function (a ranked composite of dialysis duration and the rate of graft function recovery), treatment for hyperkalaemia, and graft survival and will be analysed using a similar modelling approach appropriate for the type of outcome.Discussion: BEST-Fluids will determine whether Plasmalyte reduces the incidence of DGF and has a beneficial effect on early kidney transplant outcomes relative to 0.9% saline and will inform clinical guidelines on intravenous fluids for deceased donor kidney transplantation. The statistical analysis plan describes the analyses to be undertaken and specified before completion of follow-up and locking the trial databases. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12617000358347. Prospectively registered on 8 March 2017 ClinicalTrials.gov identifier NCT03829488. Registered on 4 February 2019Elaine M. Pascoe, Steven J. Chadban, Magid A. Fahim, Carmel M. Hawley, David W. Johnson, Michael G. Collins and for the BEST-fluids Investigators and the Australasian Kidney Trials Networ

Socioeconomic disadvantage and kidney disease in the United States, Australia, and Thailand

OBJECTIVES: We sought to determine whether an elevated burden of chronic kidney disease is found among disadvantaged groups living in the United States, Australia, and Thailand. METHODS: We used data on participants 35 years or older for whom a valid serum creatinine measurement was available from studies in the United States, Thailand, and Australia. We used logistic regression to analyze the association of income, education, and employment with the prevalence of chronic kidney disease (estimated glomerular filtration rate<60 mL/min/1.73 m(2)). RESULTS: Age- and gender-adjusted odds of having chronic kidney disease were increased 86% for US Whites in the lowest income quartile versus the highest quartile (odds ratio [OR] = 1.86; 95% confidence interval [CI] = 1.27, 2.72). Odds were increased 2 times and 6 times, respectively, among unemployed (not retired) versus employed non-Hispanic Black and Mexican American participants (OR=2.89; 95% CI=1.53, 5.46; OR=6.62; 95% CI=1.94, 22.64. respectively). Similar associations were not evident for the Australian or Thai populations. CONCLUSIONS: Higher kidney disease prevalence among financially disadvantaged groups in the United States should be considered when chronic kidney disease prevention and management strategies are created. This approach is less likely to be of benefit to the Australian and Thai population

Interleukin-33 Exacerbates IgA Glomerulonephritis in Transgenic Mice Overexpressing B Cell Activating Factor

Background: The cytokine IL-33 is an activator of innate lymphoid cells 2 (ILC2s) in innate immunity and allergic inflammation. B cell activating factor (BAFF) plays a central role in B cell proliferation and differentiation, and high levels of this protein cause excess antibody production, including IgA. BAFF-transgenic mice overexpress BAFF and spontaneously develop glomerulonephritis that resembles human IgA nephropathy. Methods: We administered IL-33 or PBS to wild-type and BAFF-transgenic mice. After treating Rag1- deficient mice with IL-33, with or without anti-CD90.2 to preferentially deplete ILC2s, we isolated splenocytes, which were adoptively transferred into BAFF-transgenic mice. Results: BAFF-transgenic mice treated with IL-33 developed more severe kidney dysfunction and proteinuria, glomerular sclerosis, tubulointerstitial damage, and glomerular deposition of IgA and C3. Compared with wild-type mice, BAFF-transgenic mice exhibited increases of CD191 B cells in spleen and kidney and ILC2s in kidney and intestine, which were further increased by administration of IL-33. Administering IL-33 to wild-type mice had no effect on kidney function or histology, nor did it alter the number of ILC2s in spleen, kidney, or intestine. To understand the role of ILC2s, splenocytes were transferred from IL-33–treated Rag1-deficient mice into BAFF-transgenic mice. Glomerulonephritis and IgA deposition were exacerbated by transfer of IL-33–stimulated Rag1-deficient splenocytes, but not by ILC2 (anti- CD90.2)–depleted splenocytes. Wild-type mice infused with IL-33–treated Rag1-deficient splenocytes showed no change in kidney function or ILC2 numbers or distribution. Conclusions: IL-33–expanded ILC2s exacerbated IgA glomerulonephritis in a mouse model. These findings indicate that IL-33 and ILC2s warrant evaluation as possible mediators of human IgA nephropathy.Yuan Min Wang, Karli Shaw, Geoff Yu Zhang, Edmund Y.M. Chung, Min Hu, Qi Cao, Yiping Wang, Guoping Zheng, Huiling Wu, Steven J. Chadban, Hugh J. McCarthy, David C.H. Harris, Fabienne Mackay, Shane T. Grey, and Stephen I. Alexande