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Background: Right-sided living donor kidneys have longer renal arteries and shorter veins that make vascular anastomosis more challenging. We sought to determine whether recipients of right-sided living donor kidneys have worse outcomes than left-sided kidney recipients. Methods: An observational analysis of the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) was undertaken. We used adjusted logistic regression to determine the association between side and delayed graft function (DGF) and time-stratified adjusted cox regression models for graft and patient survivals. Results: Between 2004 and 2018, 4,050 living donor kidney transplants were conducted with 696 (17.2%) using right kidneys. With reference to left kidneys, the adjusted OR (95% CI) for DGF was 2.01 (1.31-3.09) for recipients with right kidneys. Within 30 days, 46 allografts (1.4%) were lost, with major causes of overall graft loss being technical, primary non-function and death. Recipients of right donor kidneys experienced a greater risk of early graft loss (aHR 2.02 [95% CI 1.06-3.86], p = 0.03), but not beyond 30 days (aHR 0.97 [95% CI 0.80-1.19], p = 0.8]). Conclusion: Technical challenge is the most common cause of early graft loss. The risk of early graft loss among recipients who received right kidneys is doubled compared to those who received left living donor kidneys., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dobrijevic, Au, Rogers, Clayton, Wong and Allen.)

Interstitial fibrosis, tubular atrophy, and inflammation are major contributors to kidney allograft failure. Here we sought an objective, quantitative pathological assessment of these lesions to improve predictive utility and constructed a deep-learning-based pipeline recognizing normal vs. abnormal kidney tissue compartments and mononuclear leukocyte infiltrates. Periodic acid- Schiff stained slides of transplant biopsies (60 training and 33 testing) were used to quantify pathological lesions specific for interstitium, tubules and mononuclear leukocyte infiltration. The pipeline was applied to the whole slide images from 789 transplant biopsies (478 baseline [pre-implantation] and 311 post-transplant 12-month protocol biopsies) in two independent cohorts (GoCAR: 404 patients, AUSCAD: 212 patients) of transplant recipients to correlate composite lesion features with graft loss. Our model accurately recognized kidney tissue compartments and mononuclear leukocytes. The digital features significantly correlated with revised Banff 2007 scores but were more sensitive to subtle pathological changes below the thresholds in the Banff scores. The Interstitial and Tubular Abnormality Score (ITAS) in baseline samples was highly predictive of one-year graft loss, while a Composite Damage Score in 12-month post-transplant protocol biopsies predicted later graft loss. ITASs and Composite Damage Scores outperformed Banff scores or clinical predictors with superior graft loss prediction accuracy. High/intermediate risk groups stratified by ITASs or Composite Damage Scores also demonstrated significantly higher incidence of estimated glomerular filtration rate decline and subsequent graft damage. Thus, our deep-learning approach accurately detected and quantified pathological lesions from baseline or post-transplant biopsies and demonstrated superior ability for prediction of post-transplant graft loss with potential application as a prevention, risk stratification or monitoring tool., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Kidney transplantation is the most common solid organ transplant and the best current therapy for end-stage kidney failure. However, with standard immunosuppression, most transplants develop chronic dysfunction or fail, much of which is due to chronic immune injury. Tregs are a subset of T cells involved in limiting immune activation and preventing autoimmune disease. These cells offer the potential to provide tolerance or to allow reduction in immunosuppression in kidney transplants. The importance of Tregs in kidney transplantation has been shown in a number of seminal mouse and animal studies, including those with T cell receptors (TCRs) transgenic Tregs (TCR-Tregs) or Chimeric Antigen Receptor (CAR) Tregs (CAR-Tregs) showing that specificity increases the potency of Treg function. Here we outline the animal and human studies and clinical trials directed at using Tregs in kidney transplantation and other tolerance settings and the various modifications to enhance allo-specific Treg function in vivo and in vitro ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hu, Rogers, Li, Zhang, Wang, Shaw, O’Connell and Alexander.)

Background: Kidney transplantation is the optimum treatment for kidney failure in carefully selected patients. Technical surgical complications and second warm ischemic time (SWIT) increase the risk of delayed graft function (DGF) and subsequent short- and long-term graft outcomes including the need for post-transplant dialysis and graft failure. Intraoperative organ thermal regulation could reduce SWIT, minimizing surgical complications due to time pressure, and limiting graft ischemia-reperfusion injury., Methods: A novel ischemic-injury thermal protection jacket (iiPJ) was designed and fabricated in silicone composite and polyurethane (PU) elastomer prototypes. Both were compared with no thermal insulation as controls. Time to reach ischemic threshold (15°C) and thermal energy transfer were compared. A water bath model was used to examine the thermal protective properties of porcine kidneys, as a feasibility study prior to in vivo translation., Results: In both iterations of the iiPJ, the time taken to reach the warm ischemia threshold was 35.2 ± 1.4 minutes (silicone) and 38.4 ± 3.1 minutes (PU), compared with 17.2 ± 1.5 minutes for controls (n = 5, P < .001 for both comparisons). Thermal energy transfer was also found to be significantly less for both iiPJ variants compared with controls. There was no significant difference between the thermal performance of the 2 iiPJ variants., Conclusion: Protection from SWIT by using a protective insulation jacket is feasible. With clinical translation, this novel strategy could facilitate more optimal surgical performance and reduce transplanted organ ischemia-reperfusion injury, in particular the SWIT, potentially affecting delayed graft function and long-term outcomes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

For patients with type 1 diabetes mellitus who progress to the point of requiring renal replacement therapy, the relative benefits of simultaneous pancreas and kidney transplantation (SPK) and deceased donor kidney transplantation across different age categories compared to dialysis are uncertain. Using Australian and New Zealand registry data from 2006 to 2016, a probabilistic Markov model (n = 10 000) was built comparing patient survival between SPK and deceased donor kidney transplantation with dialysis. Compared to dialysis, the average life years saved (LYS) and quality-adjusted life years (QALY) for SPK and deceased donor kidney transplantation were 5.48 [95% CI 5.47, 5.49] LYS and 6.48 [6.47, 6.49] QALY, and 3.38 [3.36, 3.40] LYS and 2.46 [2.45, 2.47] QALY, respectively. For recipients aged 50 years or younger, receiving a deceased donor kidney, the average incremental gains compared to dialysis were 4.13 [4.10, 4.16] LYS and 2.99 [2.97, 3.01] QALY, and for recipients older than 50 years, 3.05 [3.02, 3.08] LYS and 2.25 [2.23, 2.27] QALY. Compared to dialysis, SPK transplantation incurs the greatest benefits in LYS and QALY for patients with type 1 diabetes requiring renal replacement therapy. Patients older than 50 years still experience survival benefits from deceased donor kidney transplantation compared to dialysis., (© 2020 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Introduction: Plasma cell-rich rejection is a distinct histological phenomenon associated with poor renal allograft outcomes. Aboriginal and Torres Straight Islander (ATSI) transplant recipients have poorer allograft survival and higher rates of acute rejection. We sought to determine whether a higher incidence of plasma cell-rich infiltrates (PCIR) could account for poorer survival., Methods: Renal transplant biopsies performed in recipients from the Northern Territory of Australia between 1985 and 2007 were reviewed and correlated with outcome. Biopsies were designated PCIR positive when plasma cells constituted >10% of the interstitial infiltrate., Results: Four hundred and seventy-seven biopsies from 177 recipients (108 ATSI) were performed. Median graft survival was shorter for recipients with PCIR: 4.0 years (interquartile range 2.18-6.41) versus 5.4 years (2.0-9.99) (P = 0.013). ATSI recipients had higher rates of plasma cell-rich rejection (RR 1.76, 95% CI 1.43-2.17, P < 0.0001), which occurred earlier (251 vs 869 days, P = 0.03) compared with non-indigenous recipients. On multivariate analysis, PCIR did not independently influence allograft survival. There was a correlation between PCIR and panel reactive antibody peak >20% (RR 1.29, 95% CI 1.03-1.56, P = 0.025), ≥5 human leukocyte antigen mismatches (RR 1.91, 1.41-2.58, p < 0.0001), increasing post-transplant infection rate (>10 infections RR 5.11, 1.69-15.5, P = 0.004), and subsequent death from septicaemia (RR 1.6, 1.17-2.18, P = 0.003)., Conclusion: PCIR is associated with infection and markers of chronic immunological stimulation but does not independently contribute to inferior renal allograft outcomes, even in ATSI recipients., (© 2011 The Authors. Nephrology © 2011 Asian Pacific Society of Nephrology.)

Desensitization protocols reduce donor-specific anti-HLA antibodies (DSA) and enable renal transplantation in patients with a positive complement-dependent cytotoxic cross-match (CDC-CXM). The effect of this treatment on protective antibody and immunoglobulin levels is unknown. Thirteen patients with end-stage renal disease, DSA and positive CDC-CXM underwent desensitization. Sera collected pre- and post-transplantation were analysed for anti-tetanus and anti-pneumococcal antibodies, total immunoglobulin (Ig) levels and IgG subclasses and were compared to healthy controls and contemporaneous renal transplant recipients treated with standard immunosuppression alone. Ten patients developed negative CDC-CXM and enzyme-linked immunosorbent assay (ELISA) and underwent successful transplantation. Eight recipients achieved good graft function without antibody-mediated or late rejection, BK virus or cytomegalovirus infection. One patient had primary non-function due to recurrent oxalosis, and one patient with immediate graft function died from septicaemia. Seven recipients required post-operative transfusion and three developed septicaemia. DSA remained negative by ELISA at 12 months, but were detectable by Luminex(®) . Anti-tetanus and anti-pneumococcal antibodies, total Ig and IgG subclasses were below the normal range but comparable to levels in renal transplant recipients who had not undergone desensitization. Desensitization protocols effectively reduce DSA and allow successful transplantation. Post-operative bleeding and short-term infectious risk is increased. Protective antibody and serum immunoglobulin levels are relatively preserved., (© 2010 The Authors. Journal compilation © 2010 European Society for Organ Transplantation.)

There is definitive experimental proof that a lattice of dendritic cells (DC) exist within the renal parenchyma. Kidney-resident DC (KDC) are an important constituent of passenger leucocytes that initiate the direct component of allograft rejection in transplantation and form a central element of the innate immune response following injurious stimuli to the kidney. DC are recruited to the kidney in pathophysiological states such as glomerulonephritis and ischaemia-reperfusion injury. However, the exact mechanism for engaging and attracting DC to infectious and transplant antigens, and whether specific DC subsets are involved remains unresolved. In addition, the extent to which resident and infiltrating DC contribute to the propagation of injury or rejection is also unclear. Despite consistently expanding published work regarding DC location, phenotype and function, there are a number of deficiencies in our knowledge base, particularly in relation to KDC.

Introduction: BK virus nephropathy (BKVN) is a significant cause of late renal allograft loss. It is characterized histologically by an interstitial nephritis that can be difficult to distinguish from acute cellular rejection (ACR). We investigated whether immunophenotyping of the infiltrate would aid this distinction., Methods: Ten cases of biopsy-proven BKVN, following renal transplantation, were identified from a single transplant centre. The infection was confirmed by renal biopsy and staining for SV-40 T-antigen. Biopsies from 20 consecutive patients with ACR were identified and used as controls. There was no evidence of BK infection serologically or histologically in these patients. Immunohistochemical staining with anti-CD20, perforin and granzyme B was performed on remaining tissue samples., Results: Clustered B cells were demonstrated in both BKVN and ACR. Hence, the CD20-stained component within the interstitial infiltrate was not useful in distinguishing these biopsies. Perforin-stained slides demonstrated fewer cytotoxic T cells in the biopsies with BK virus (average 2.4 +/- 1.4 cells per 100 lymphocytes per field) compared with those samples with acute rejection (8.6 +/- 5.7 cells per 100 lymphocytes, P < 0.0001). No significant difference in granzyme B staining was detected between ACR and BKVN., Conclusion: Clustered B cells and granzyme B staining did not differentiate between ACR and BKVN. However, ACR cellular infiltrate was rich in perforin positive cells suggesting that perforin staining may be a useful marker to discriminate between these conditions.

Aims: Kidney transplant units in Australia are confined to large hospitals in major metropolitan areas, yet this may limit access and diminish outcomes in people who do not live in these large centres. The authors examined the viability of a kidney transplant unit located in northern Australia (NA), with particular emphasis on recipient outcomes and the number of donors., Methods: 'Northern Australia' was arbitrarily defined as 'north of the tropic of Capricorn' for Queensland and Western Australia and included the entire Northern Territory. Data on donors and transplant recipients were provided by ANZDATA and ANZOD registries, identified by postcode., Results: Between 1998 and 2004 in NA there were 163 deceased donor kidneys and 97.5% of available organs were transplanted. There were no Aboriginal/Torres Strait Islander (ATSI) donors from NA. Recipients from NA in this time included 55 patients receiving living grafts and 156 receiving deceased donor grafts, of whom 36% were ATSI, making up half of the total ATSI transplanted in Australia during this time period. Compared with the rest of Australia, NA recipients were older, waited longer on dialysis, had longer ischaemic times and a greater number of human leucocyte antigen mismatches, and were more likely to be diabetic and obese. Despite the longer cold ischaemic time in NA recipients, no difference in immediate graft function was seen. ATSI recipients in NA, when compared with their southern Australian counterparts, had poorer patient survival (HR=3.19, 95% CI 1.44-7.08, P<0.001), but equivalent graft survival (HR=1.67, 95% CI 0.95-2.95, P=not significant) on multivariate analysis. Key factors that would influence feasibility of a Northern Australian transplant unit include adequate staffing, and support services in addition to currently available resources., Conclusion: Current donor numbers in NA are adequate for past recipients of kidney transplant, but may not cover future needs without a significant increase in donor rate. A transplant unit situated in northern Australian would require significant resources to ensure long-term viability and its effect on outcomes is uncertain.

Background: Indigenous Australians develop end-stage renal disease (ESRD) at a significantly higher rate than nonindigenous Australians. Renal transplantation is the preferred treatment modality; however, they are underrepresented in the transplanted population. In addition, despite the morbidity and mortality gains demonstrated in other patient groups, it is unclear whether such an advantage is replicated for indigenous Australians. We have sought to identify some of the factors that lead to poorer outcomes within this group of recipients., Methods: We performed a retrospective analysis of a cohort of renal transplant recipients (indigenous and nonindigenous) from the Northern Territory of Australia., Results: Indigenous patients waited longer on dialysis, were more sensitized at the time of transplantation, and the number of human leukocyte antigen mismatches was greater. Overall renal allograft survival is poorer among indigenous Australians (HR 4.13, 2.0-8.5, P<0.0001) with the majority of grafts lost due to recipient death. The most common cause of death was septicemia. Graft loss due to any cause has not been influenced by the absence of full-time specialist staff at major treatment centers. Infection rates are greatly increased in indigenous patients (RR 4.1, 95% CI 3.5-4.7, P<0.0001), in addition to the incidence of rejection (RR 2.5 95% CI 1.8-3.5, P<0.001) and hospitalization (RR 3.9, 95% CI 3.2-4.9, P<0.0001). There is increased steroid exposure among indigenous recipients., Conclusions: Indigenous recipients of cadaveric kidney transplants have worse outcomes than nonindigenous recipients, mostly due to increased mortality and morbidity from infective causes.

Background Kidneys donated after circulatory death suffer a period of functional warm ischaemia before death, which may lead to early ischaemic injury. Effects of haemodynamic trajectories during the agonal phase on delayed graft function (DGF) is unknown. We aimed to predict the risk of DGF using patterns of trajectories of systolic blood pressure (SBP) declines in Maastricht category 3 kidney donors. Methods We conducted a cohort study of all kidney transplant recipients in Australia who received kidneys from donation after circulatory death donors, divided into a derivation cohort (transplants between 9 April 2014 and 2 January 2018 [462 donors]) and a validation cohort (transplants between 6 January 2018 and 24 December 2019 [324 donors]). Patterns of SBP decline using latent class models were evaluated against the odds of DGF using a two-stage linear mixed effects model. Results In the derivation cohort, 462 donors were included in the latent class analyses and 379 donors in the mixed effects model. Of the 696 eligible transplant recipients, 380 (54.6%) experienced DGF. Ten different trajectories, with distinct patterns of SBP decline were identified. Compared with recipients from donors with the slowest decline in SBP after withdrawal of cardiorespiratory support, the adjusted odds ratio (aOR) for DGF was 5.5 [95% confidence interval (CI) 1.38–28.0] for recipients from donors with a steeper decline and lowest SBP [mean 49.5 mmHg (standard deviation 12.5)] at the time of withdrawal. For every 1 mmHg/min reduction in the rate of decline of SBP, the respective aORs for DGF were 0.95 (95% CI 0.91–0.99) and 0.98 (95% CI 0.93–1.0) in the random forest and least absolute shrinkage and selection operator models. In the validation cohort, the respective aORs were 0.95 (95% CI 0.91–1.0) and 0.99 (95% CI 0.94–1.0). Conclusion Trajectories of SBP decline and their determinants are predictive of DGF. These results support a trajectory-based assessment of haemodynamic changes in donors after circulatory death during the agonal phase for donor suitability and post-transplant outcomes. [ABSTRACT FROM AUTHOR]

Normothermic machine perfusion (NMP) is an emerging modality for kidney preservation prior to transplantation. NMP may allow directed pharmacomodulation of renal ischemia-reperfusion injury (IRI) without the need for systemic donor/recipient therapies. Three proven anti-IRI agents not in widespread clinical use, CD47-blocking antibody (αCD47Ab), soluble complement receptor 1 (sCR1), and recombinant thrombomodulin (rTM), were compared in a murine model of kidney IRI. The most effective agent was then utilized in a custom NMP circuit for the treatment of isolated porcine kidneys, ascertaining the impact of the drug on perfusion and IRI-related parameters. αCD47Ab conferred the greatest protection against IRI in mice after 24 hours. αCD47Ab was therefore chosen as the candidate agent for addition to the NMP circuit. CD47 receptor binding was demonstrated by immunofluorescence. Renal perfusion/flow improved with CD47 blockade, with a corresponding reduction in oxidative stress and histologic damage compared to untreated NMP kidneys. Tubular and glomerular functional parameters were not significantly impacted by αCD47Ab treatment during NMP. In a murine renal IRI model, αCD47Ab was confirmed as a superior anti-IRI agent compared to therapies targeting other pathways. NMP enabled effective, direct delivery of this drug to porcine kidneys, although further efficacy needs to be proven in the transplantation setting. [ABSTRACT FROM AUTHOR]

The mTOR pathway has a central role in the regulation of cell metabolism, growth and proliferation. Studies involving selective gene targeting of mTOR complexes (mTORC1 and mTORC2) in renal cell populations and/or pharmacologic mTOR inhibition have revealed important roles of mTOR in podocyte homeostasis and tubular transport. Important advances have also been made in understanding the role of mTOR in renal injury, polycystic kidney disease and glomerular diseases, including diabetic nephropathy. Novel insights into the roles of mTORC1 and mTORC2 in the regulation of immune cell homeostasis and function are helping to improve understanding of the complex effects of mTOR targeting on immune responses, including those that impact both de novo renal disease and renal allograft outcomes. Extensive experience in clinical renal transplantation has resulted in successful conversion of patients from calcineurin inhibitors to mTOR inhibitors at various times post-transplantation, with excellent long-term graft function. Widespread use of this practice has, however, been limited owing to mTOR-inhibitor- related toxicities. Unique attributes of mTOR inhibitors include reduced rates of squamous cell carcinoma and cytomegalovirus infection compared to other regimens. As understanding of the mechanisms by which mTORC1 and mTORC2 drive the pathogenesis of renal disease progresses, clinical studies of mTOR pathway targeting will enable testing of evolving hypotheses. [ABSTRACT FROM AUTHOR]