CAN AN EARLY BILE DUCT FLUSH DURING DONOR PROCUREMENT REDUCE BILIARY STRICTURES AFTER LIVER TRANSPLANTATION A RANDOMISED CLINICAL STUDY
LY Mark1, PULITANO Carlo2,3, CRAWFORD Michael2
1Royal Prince Alfred Hospital, Sydney, 2Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, 3University of Sydney
Introduction: Experimental studies suggest bile salts play a role in bile duct injury and consequent biliary strictures (BS) in liver transplantation. Animal studies suggested that inadequate flush out of bile during cold ischemia is associated to bile duct injury. However, no clinical study has investigated the importance of early bile duct flush during organ procurement in determining BS. We performed a randomized clinical study to investigate whether an additional earlier bile duct flush reduces the incidence of BS after liver transplantation.
Methods: Brain Dead Donors retrieved and transplanted within NSW, Australia from March 2016 to June 2017 were randomised into two groups. The intervention group received bile duct flushes during cold perfusion and after donor hepatectomy. The control group received a bile duct flush after donor hepatectomy. The primary end point was 12 month incidence of BS in liver transplant recipients. Data was also extracted for donor and recipient characteristics and other post-operative complications.
Results: Sixty-four donors met inclusion criteria (Intervention (N=29), Control (N=35)). The overall incidence of BS was 23.4% (N=15) and there was no difference between groups for BS (p>0.05). There was also no difference between groups for Non Anastomotic Strictures (NAS) (6.9% vs 2.9%) or Anastomotic Strictures (20.7% vs 20%)(p>0.05).
Conclusions: An additional earlier bile duct flush during donor cold perfusion did not reduce the incidence of biliary strictures at 1 year compared to a bile duct flush after hepatectomy alone.
UPDATED SAFETY OUTCOMES AND COST-ANALYSIS OF EARLY URETERIC STENT REMOVAL IN PAEDIATRIC KIDNEY TRANSPLANTATION
TONG Marcus Chen Yee1, LARKINS Nick2, MINCHAM Christine2, CROMPTON Charles2, WILLIS Frank2, HE Bulang1
1WA Liver & Kidney Transplant Service, Sir Charles Gairdner Hospital, Perth, 2Department of Nephrology, Perth Children’s Hospital
Introduction: The insertion of a double-J stent in renal transplantation reduces urological complications but is associated with the risk of urinary tract infection (UTI). Suturing stents to indwelling catheters (IDC) allows for early simultaneously removal (5 days) in contrast to late stent removal via cystoscopy 4-6 weeks post-operation. This study aims to audit the safety and cost of early stent removal amongst paediatric recipients.
Methods: A ten year retrospective review of all paediatric kidney transplantations in a single-centre performed between 2009 and 2019 was conducted. A total of 32 kidney transplants were performed in 31 recipients. The age ranges from 2 to 18 years (median 10 years). Data pertaining to patient demographics and urological complications was collected and analysed with independent samples T-test.
Results: In this cohort, 23 cases of early versus 9 cases of late stent removal were identified. There was one ureteric stenosis resolved by percutaneous balloon dilatation within the early stent removal group. There were 3 patients in each group who had UTI requiring antibiotic therapy – 5 hospital presentations and 0 admissions in the early group versus 10 presentations and 5 admissions in the late group. Early stent removal reduced the incidence of UTIs by 20% (P=0.045). The calculated cost saved by early removal of ureteric stent is $1752 AUD per case.
Conclusion: Early removal of ureteric stents with IDCs results in lower risk of UTIs in paediatric recipients. It has obvious cost-saving merits as it prevents a further day admission for cystoscopy under general anaesthesia.
A SURVEY OF THE CONTEMPORARY USE OF JJ STENTS IN RENAL TRANSPLANTATION IN AUSTRALIA AND NEW ZEALAND AND THE FEASIBILITY OF A CLINICAL TRIAL OF OPTIMAL TIMING OF STENT REMOVAL.
JAMBOTI Jagadish1,2,3, IRISH Ashley2,4, BHANDARI Mayank5,6, HAWLEY Carmel7,8,9
1Fiona Stanley Hospital, 2University of Western Australia, Perth, 3Curtin University, Perth, 4Renal & Transplantation Unit, Fiona Stanley Hospital, 5Department of Surgery, Fiona Stanley Hospital, 6Nephrology and Renal Transplant, 7Renal & Transplantation Unit, Princess Alexandra Hospital, Brisbane, 8University of Queensland, Brisbane, 9AKTN,
A survey of the contemporary use of JJ stents in renal transplantation in Australia and New Zealand and the feasibility of a clinical trial of optimal timing of stent removal.
AIMS: Assess the current practice of JJ stent use, timing of removal and potential complications (Urinary Tract Infection, BK Virus infection) in renal transplant recipients (RTRs) and the feasibility of a clinical trial to test the optimal timing of stent removal.
METHODS: An online survey approved by ANZSN and TSANZ councils and facilitated via AKTN directed to the 20 recognised renal transplant centers in Australia and New Zealand in July 2018.
RESULTS: A total of 18/20 (90%) transplant centers responded, with an estimated annual 1232 RTRs.
1) 100% of the participating renal transplant centers used JJ stents intra-operatively and removed them by cystoscopy.
2) 67% (12/18) centers removed JJ stents after 4 weeks following transplant; 33% (6/18) removed at 2-4 weeks.
3) Estimated Prevalence of UTI requiring antibiotic treatment in the first 3 months was <10% in 39% (7/18) centers and between 10-20% in 61% centers (11/18).
4) 78% (14) of transplant centers screened for BK virus Post-transplant by serum and 17% (3) centers by both urine and serum. Reported BKV prevalence varied widely from 1-20%.
5) 83% of participating centers expressed willingness to be part of a study involving early removal of JJ stents.
CONCLUSIONS and FUTURE DIRECTIONS: JJ stents are routine in RTR in Australia and New Zealand and the majority are removed cystoscopically as outpatients after 4 weeks. There is a significant burden of early post-transplant UTIs. A randomised, controlled study comparing early inpatient removal of JJ stents with current practice is feasible and is widely supported.
CONTEMPORARY MANAGEMENT OF PROSTATE CANCER IN RENAL TRANSPLANT PATIENTS
PEREIRA Ryan1,2, ROBERTSON Ian1, BYRNE Sarah1, GRIFFIN Anthony1, LAWSON Malcolm1,2, PRESTON John1,2, WOOD Simon1,2, RHEE Handoo1,2
1Renal Transplant Unit, Princess Alexandra Hospital, Brisbane, 2Urology, Princess Alexandra Hospital, Brisbane
Aim: Due to the anatomical proximity of the prostate to pelvic positioned renal graft, management of Prostate Cancer (PCa) with surgery or radiation presents a challenge. Traditionally, definitive PCa management was considered high risk due to potential injury to the allograft, vasculature or ureter. The aim of this study was to investigate whether recent advancements in PCa management result in acceptable risks to the RTx graft.
Method: A retrospective chart review between 2010-2018 of RTx patients referred to our unit for assessment and management of PCa was performed.
Results: The mean age was 68.43+/-7.98 years. The mean referring PSA was 98.48 ng/ml (1.1-1260) with a median value 11ng/ml. Reviewing the histology, the median International Society of Urological Pathology grading of PCa was 3 (range 1-5). Mean time to diagnosis from RTx was 6.35+/-4.65 years. Six patients had locally advanced or metastatic disease requiring systemic therapy at presentation. Of those with localized disease, external beam radiotherapy (EBRT) was used in 8 (29.62%) and radical surgery in 6 (22.22%). No significant change in creatinine was identified following EBRT or surgery. Androgen deprivation therapy was used in 10 patients (37.04%). To date, 13 of 27 (48.15%) patients are alive. Three patients (11.11%) died from progressive PCa.
Conclusion: This series from a large tertiary transplant unit did not identify any significant adverse effects of contemporary PCa treatment. As patients who receive RTx are advancing in age, it is reasonable to offer age and risk factor specific PCa screening and treatment.
LAPAROSCOPIC TRANSPLANT NEPHRECTOMY FOR A FAILED INTRA-PERITONEAL TRANSPLANT KIDNEY
HEER MK1, BULL Nick2, TREVILLIAN PR1
1Renal Transplant Unit, John Hunter Hospital, Newcastle, 2Department of Surgery, John Hunter Hospital, Newcastle
Transplant nephrectomy (TN) for failed renal transplant is performed as an open surgery because of adhesions and inflammation which makes dissection challenging. There is risk of significant morbidity due to bleeding, injury to viscera and infection. Minimally invasive surgery has improved outcomes in many other surgeries, but few authors have reported limited success with this approach to TN. We hereby present first case report of laparoscopic transplant nephrectomy from Australia. The recipient is 19 years old, who had received an orthotopic intraperitoneal right renal allograft transplant at the age of 12 years. She lost transplant function to chronic rejection after 6 years and was established on dialysis. An attempt to reduce her immunosuppression resulted in acute graft pain and graft intolerance syndrome. She was referred for TN. We used a laparoscopic approach with standard three ports for mobilization and fourth port for retraction. The graft had dense adhesions especially under the liver and renal hilum but also had peri-renal edema around mid and lower pole which facilitated the dissection. We were able to complete TN after obtaining control of renal allograft vessels with Hem-o-lock® clips (fig1). We also encountered her native renal vessels adherent to graft which needed further ligation. Operation took just below 180 minutes and around 50 ml of blood loss. Patient was discharged home on day 3.
Conclusion: Laparoscopic TN is feasible though challenging and can be safely performed in selected patients.
KIDNEY TRANSPLANTATION USING DONORS WITH SINGLE AND MULTIPLE RENAL ARTERIES – IS THERE A DIFFERENCE?
TRAN Quoc, HERLIHY David, MORITZ Peter, PUTTASWAMY Vikram
Department of Vascular Surgery, Royal North Shore Hospital, Sydney
Aims: Donor kidneys with multiple renal arteries (MRA) have previously been reported to be associated with increased complications and poorer outcomes in recipients. The objective of this study was to investigate the incidence of complications and the impact on the functionality of the transplanted kidney.
Methods: From 2017 to 2019, a total of 100 consecutive kidney transplantations that occurred at Royal North Shore Hospital, Sydney were retrospectively analysed. Patients were assigned to two groups: donors with single renal artery (SRA) and donors with multiple renal arteries (MRA, 26% of cohort). The impact of anatomical abnormalities on short-term outcomes of the transplantation were analysed with respect to warm ischaemic time, biochemical markers, resistive index, and complications requiring return to theatres.
Results: Mean warm ischemia time (in minutes) were similar with 54.2±25.3 vs 46.6±11.5 for transplants using MRA and SRA kidneys respectively. Change in urea at post-operative day 1 was -5.1±39.6% vs -9.6±55.9% and day 7 14.6±97.2% vs 18.7±110.4%. Change in estimated glomerular filtration rate (eGFR) at post-operative day 1 was 71.6±95.0% vs 95.7±130.2% and day 7 456.0±550.6% ± 386.9±443.7%. Change in creatinine clearance at post-operative day 1 was 25.6±28.3% vs 27.7±32.6% and 7 57.0±31.3% vs 49.4±41.1%. On table resistive index were 0.609±0.063 vs 0.607±0.074. Operative complications requiring take back to theatre showed 15.3% vs 9.5%.
Conclusion: Although kidney grafts with MRA have been considered a relative contraindication, this study suggests that kidney transplants using allografts with multiple versus single arteries have similar early outcomes.
WAITLISTING FOR KIDNEY TRANSPLANTATION IN AUSTRALIA: ESTIMATING THE DEMAND
CLAYTON Philip1,2,3, GULYANI Aarti1, SYPEK Matthew1, JESUDASON Shilpa1,2,3, MCDONALD Stephen1,2,3
1ANZDATA, 2Central Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, 3School of Medicine, University of Adelaide
Aims. Fewer than 10% of Australian dialysis patients are wait-listed for transplantation. We examined the predicted 5-year post-transplant survival of prevalent Australian dialysis patients, and predictors of wait-listing in those with >=80% predicted survival.
Methods. Using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry and National Organ Matching System, we included Australian patients who had been on dialysis for >=12 months at 31/12/2016. We used a Cox model developed in an earlier ANZDATA cohort to estimate 5-year survival post-transplant from an average deceased donor. In the subset of patients with predicted survival >=80%, we examined predictors of wait-listing using multilevel logistic regression.
Results. Of the 9,968 patients who met inclusion criteria, 323 (3%) were excluded due to missing data. 772 (8%) of the remaining 9,645 patients were wait-listed. 4,229 (44%) of patients had a predicted post-transplant survival of >=80%, of whom 696 (16%) were wait-listed. 76 patients with a predicted survival <80% were wait-listed, representing 11% of those on the waiting list (figure). Amongst patients with a predicted survival of >=80%, predictors of being listed included younger age, male sex, Asian ethnicity and prior transplantation. Predictors of not being listed included Indigenous status, obesity, all recorded comorbidities, previous cancer, and receiving dialysis in Western Australia or Queensland.
Conclusions. The majority of dialysis patients in Australia with predicted >=80% 5-year post-transplant survival are not wait-listed. Most but not all predictors of wait-listing are also predictors of post-transplant survival. Further study is needed to determine reasons for non-listing.
LIVING KIDNEY DONOR PROFILE INDEX: A POOR PREDICTOR OF OUTCOMES
IRISH Georgina L1,2,3, CHADBAN Steve1,4,5, BOUDVILLE Neil6,7, CAMPBELL Scott8,9, KANELLIS John10,11, CLAYTON Philip A1,2,3
1ANZDATA registry, South Australian Health and Medical Research Institute (SAHMRI), 2Central Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, 3Department of Medicine, University of Adelaide, 4Renal Medicine, Royal Prince Alfred Hospital, Sydney, 5Kidney Node, Charles Perkins Centre, University of Sydney, 6Medical School, University of Western Australia, Perth, 7Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, 8Department of Nephrology, Princess Alexandra Hospital, Brisbane, 9School of Medicine, University of Queensland, Brisbane, 10Department of Nephrology, Monash Health, 11Centre for Inflammatory Diseases, Monash University, Melbourne
Aim Risk scores can aid risk quantification and decision-making in kidney transplantation. The Living Kidney Donor Profile Index (LKDPI), developed in the US, has not been validated in Australia/NZ. We examined its performance in Australian/NZ kidney transplant recipients.
Methods Using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry, we included adult recipients of kidney-only transplants over 2004-2017. Outcomes were overall and death-censored graft survival, and patient survival. For each outcome we constructed Cox models including: 1) LKDPI, 2) recipient factors, 3) LKDPI plus recipient factors. To allow comparison with deceased donor (DD) kidneys we rescaled the LKDPI to its DD KDPI equivalent, created prognosis-matched cohorts of living and DD kidney recipients, and examined the discrimination of the integrated KDPI in matched pairs. For each model Harrell’s C-statistic (C) was used to determine discrimination.
Results 3826 live donor (LD) and 7618 DD recipients were included. The LKDPI’s predictive ability was poor for all LD outcomes (C-statistics 0.54, 0.54 and 0.55 for graft survival, death-censored graft survival (figure) and patient survival respectively in LKDPI-only models). Adding the LKDPI to recipient-only models added minimal discrimination (changes in C +0.01, 0.00, 0.00). In the LD/DD matched analyses, C-statistics were similarly low (0.58, 0.58, 0.57).
Conclusion The LKDPI showed poor ability to discriminate the outcomes of different LD kidneys, and discrimination of outcomes between LD and DD based on the integrated KDPI was also poor. Choosing between kidney donors on the basis of the LKDPI should be done with caution.
OVERALL GRAFT AND PATIENT SURVIVAL AMONGST ELDERLY TRANSPLANT RECIPIENTS
SO Sarah1, AU Eric HK2,3, LEE VWS1,4, WONG Germaine1,2,3
1Renal & Transplantation Unit, Westmead Hospital, Sydney, 2School of Public Health, University of Sydney, 3Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, 4University of Sydney
Aims: To determine the association between recipient and donor factors and clinical outcomes including patient and graft survival in older kidney transplant recipients.
Method: We included all patients aged ≥65 years who received their first kidney transplants between June 2006 and December 2016. Multivariable Cox regression modelling was used to determine factors associated with all-cause death, death with functioning graft, and graft survival.
Results: Of 1324 candidates between June 2006 and December 2016, 802 older patients received their first kidney transplant. Of these, 531 (66.2%) were male, 705 (87.9%) received deceased donor grafts, and the median age at transplantation was 68 (Interquartile range: 66–69) years. Over a follow-up time of 2706.9 patient-years, 136 patients died (111 with functioning graft) and 51 lost their allografts. One and five-years (%)(95%) overall patient survivals, survivals with functioning grafts, overall graft and death-censored survivals were: [95.1 (93.5-96.7) and 79 (75.1-82.9)]; [95.7 (94.3-97.1) and 82.4 (78.7-86.1)]; [92.9 (91.1-94.7) and 75.4 (71.3-79.5)]; [96.8 (95.4-98.2) and 92 (89.8-94.2)], respectively. Factors associated with all-cause death included increasing donor age, total ischemic time, prior history of coronary and cerebrovascular disease and peritoneal dialysis as treatment modality prior to transplantation. Proportion of time off waitlisting was not associated with adverse patient and graft outcomes [adjusted HR (95%)] [1.51 (0.89–2.55)] and [1.01 (0.62–1.64)].
Conclusions: In this selected cohort of elderly transplant recipients, patient and graft survivals exceed 75% five years post-transplant. Recipient factors associated with all-cause death include coronary artery disease, cerebrovascular disease or peritoneal dialysis at transplantation.
LIVE KIDNEY DONATION FOR TYPE 2 DIABETIC (T2D) RECIPIENTS. IS THERE A BENEFIT COMPARED TO DECEASED DONATION?
GOODMAN David1, ULLAH Shahid2,3, MCDONALD Stephen P2,3
1Department of Nephrology, St Vincent’s Hospital, Melbourne, 2Central Northern Adelaide Renal and Transplantation Service, University of Adelaide, 3ANZDATA
Aims Evaluate the benefits of live versus deceased donor kidney transplantation in T2D and non-T2D recipients on patient survival
Methods Data for all adult first kidney transplant recipients from 2005-2014 was extracted from ANZDATA registry. Donor source, age, gender and dialysis duration were included. A cox proportional hazard model was used to predict 5-year graft survival.
Results Of 7010 kidney transplants 15% of recipients were T2D. Live donors comprised 41% of non-T2D and 25% T2D with pre-emptive transplantation in non-T2D 32% and T2D 29%. In non T2D recipient 5-year patient survival was greater for live compared to deceased donors (HR 1.46, 95%CI 1.07-2.00, p=0.02). This was not seen in T2D (HR 1.19, 95% CI 0.68-2.09, p= 0.54). There was no significant interaction between DM and donor type. When recipients were grouped according to dialysis duration pre-emptive transplantation was beneficial to T2D recipients, but the Hazard ratios climbs after the commencement of dialysis (Table). In contrast, non-T2D recipients receiving a live donor transplant within the 1st 12 months of dialysis had the same survival as pre-emptive transplantation.
Conclusion Pre-emptive live kidney transplantation for T2D recipients improves patient survival but the benefit is lost after commencement of dialysis. In non-T2D, live donor kidney transplantation is beneficial both before and after commencement of dialysis. This data highlights the importance of evaluating patients prior to commencement of dialysis and aiming for pre-emptive transplantation particularly in T2D recipients. In T2D with extended dialysis time, medical co-morbidities may negate the benefits of live compared to deceased donor kidney transplantation.
EXTERNAL VALIDATION OF AUSTRALIA AND NEW ZEALAND TYPE 2 DIABETES (T2D) KIDNEY TRANSPLANT RISK CALCULATOR (KTRC) WITH FRENCH DATABASE AND COMPARISON TO ESTIMATED POST TRANSPLANT SURVIVAL SCORE (EPTS).
GOODMAN David1, ULLAH Shahid2,3, MCDONALD Stephen P2,3
1Department of Nephrology, St Vincent’s Hospital, Melbourne, 2Central Northern Adelaide Renal and Transplantation Service, University of Adelaide, 3ANZDATA
Aims Externally validate T2D kidney transplant risk calculator (KTRC) using large French database and compare predictive ability of KTRC with EPTS.
Methods Data for all first adult kidney transplants from 2005-2015 was extracted from the French Renal Epidemiology and Information Network (REIN) registry. Age, gender, BMI, smoking, history of coronary artery disease, cerebrovascular disease, peripheral vascular disease, dialysis duration, donor source and HLA matching was included. The 5-year graft and patient survival (G/PS) was calculated using the previous described 13 variable T2D-KTRC. Cox proportional hazard model was used to predict 5-year G/PS. Goodness of fit was evaluated by receiver operator characteristics (ROC) and C-statistic. EPTS score was calculated from patient cohort utilized to derive KTRC.
Results Data from 2480 French renal transplant recipients with T2D was evaluated. using KTRC and C-statistic calculated (Table). We also removed indigenous patients from Australian cohort to allow a more direct comparison with French cohort. A similar C statistic was seen with French data models (0.66-v-0.64). When Australian and French cohort KTRC scores were compared to EPTS the c-statistic was lower for EPTS in each group, consistent with lower predictive ability (Table).
Conclusion We have validated KTRC using data from a large external cohort of T2D transplant recipients and demonstrated similar predictive ability. When compared to EPTS, KTRC had better predictive ability. A calculator with improved predictive ability is particularly important to ensure equitable allocation of kidneys in countries where organ allocation agencies utilize recipient risk calculators to allocate kidneys.
EVALUATION OF KIDNEY FUNCTION IN LIVING DONORS
GUO Henry, MCGINN Stella, LI Yan
Department of Nephrology & Transplantation, Royal North Shore Hospital, Sydney
Background: Assessment of kidney function is important during evaluation of potential living kidney donors (LKD). Compensatory hyper-filtration post donation results in 30% GFR loss and a small increase to future risk of ESRD. Current methods of assessing GFR have their own pitfalls.
Aim: To compare concordance between 24-hour Creatinine Clearance (CrCl) and estimated GFR (eGFRcr) using the CKD-EPI or MDRD equation against measured GFR (mGFR) using 99mTc-DTPA clearance.
Methods: Potential donors who underwent two or more tests and proceeded to donation between 2008-2018 were included. Reference mGFR was determined using 99mTc-DTPA clearance. Performance of 24hr CrCl and eGFRcr were assessed for accuracy, adjusted for age, gender, weight and ethnicity.
Results: 99 LKDs were included with a mean age of 51 yrs. Most were Caucasian (80%) and female (61%) with mean serum creatinine of 74.3±13.3 µmol/L. Across the entire cohort, bias was greatest using CrCl, with overestimation of GFR (20mL/min, p<0.0001), whilst eGFRcr (CKD-EPI) underestimated GFR (7.53mL, p<0.001) compared to 99mTc-DTPA. Multivariable regression showed significant overestimation with 24hr CrCl in men versus women (p=0.05) and with decreasing age (p=0.03). The KDIGO guidelines now recommend an ideal pre-donation GFR>90mL/min. 32% of our donors would not meet these new criteria using mGFR. 80% of our donors meet criteria when using CrCl in isolation versus 58% with eGFRcr (CKD-EPI) and 42% using eGFRcr (MDRD).
Conclusions: Creatinine based eGFR and 24-hour urinary CrCl are both accompanied by bias and should be interpreted in conjunction with measured GFR and clinical context when assessing potential LKDs.
FACTORS INFLUENCING SOUTH WESTERN SYDNEY LOCAL HEALTH DISTRICT (SWSLHD) DECEASED DONOR RENAL TRANSPLANT WAITING LIST ACTIVATION
CHEUNG Jason, ZAHOROWSKA Beata, SHANMUGALINGAM Renuka, MUNRO Colleen E, WONG Jeffrey KW
Renal Unit, Liverpool Hospital
Introduction: SWSLHD is Australia’s largest non-transplanting (dialysis patients) renal unit (ANZDATA 2017). Most transplant candidates are worked up locally per protocol for assessment at a SWSLHD clinic run by an external transplanting hospital team.
Aims: Review patients referred for transplant wait-listing in SWSLHD over a 5-year period to examine time from clinic review to wait-listing and factors influencing delays.
Methods: Patients whose first pre-transplant clinic visit occurred between January 2014 and December 2018 were identified. Their characteristics and wait-listing date were obtained from electronic medical records and the National Organ Matching Systems database. Dual organ transplants and living-donor transplant assessments were excluded.
Results: 146 patients were referred to the SWSLHD clinic, of which 96 were wait-listed, 19 deemed unsuitable and 31 pending wait-listing. Eight patients (4.6%) were activated at first clinic review, with overall mean activation time of 173 days. Patients activated early (<30 days) were younger than those activated after >30 days (age 46 versus 52, p=0.03) and were less likely to be diabetic (19% versus 40%, p=0.03). On multivariate analysis, BMI>30kg/m2 was the significant characteristic of patients not accepted for wait-listing. Patients whose wait-listing was pending were more likely to have BMI>25kg/m2 compared those that had been activated (p<0.01).
Conclusions: Despite protocoled transplant work-up, the mean activation time was almost 6 months. Our findings suggest targeted work-up is required in our diabetic and overweight-obese dialysis population to accelerate and increase waiting list activation.
IMPACT OF DONOR HOSPITAL LOCATION ON LUNG ACCEPTANCE AND TRANSPLANT OUTCOMES
CAREW AM1, YERKOVICH ST2, HOPKINS PMA2, CHAMBERS DC2,3
1Prince Charles Hospital, Brisbane, 2Queensland Centre for Pulmonary Transplantation and Vascular Disease, Prince Charles Hospital, Brisbane, 3School of Clinical Medicine, University of Queensland, Brisbane
Introduction: Donor lungs in Australia and New Zealand are initially offered to the lung transplant unit in their home state, and if declined are offered to non-home state units on a rotating basis. We hypothesized that increasing donor hospital distance would translate into a lower likelihood of organ acceptance. We examined whether increasing distance presents a higher risk of high-grade primary graft dysfunction (PGD), bronchiolitis obliterans syndrome (BOS), or death.
Methods: We retrospectively reviewed lung donor offers made to the Queensland Lung Transplant Service over a 3-year period (2015-2017), measuring the linear distance between the donor and recipient hospitals. We linked donor hospital distances to lung transplant recipients in the same period and examined rates of grade 3 PGD at 72 hours, BOS and death. We employed univariate and multivariate logistic regression and survival analyses to investigate the effect of distance on outcomes, together with basic donor or recipient demographic data.
Results: 593 lung donor offers were considered from distances of up to 3617.7km. Per additional 100km from the donor hospital, the odds ratio of lung acceptance was 0.93 (95% CI, 0.91-0.96). There was no appreciable impact of increasing distance on the outcome measures of grade 3 PGD at 72 hours (OR 1.05, 95% CI 0.99-1.11), development of BOS (HR 1.05, 95% CI 0.99-1.11), or death (HR 1.05, 95% CI 0.99-1.11).
Conclusion: Increasing lung donor hospital distance was associated with a lower likelihood of organ acceptance, but not with a higher risk of developing high grade PGD, BOS, or death.
PATIENT AND GRAFT OUTCOMES FOLLOWING SIMULTANEOUS LIVER-KIDNEY TRANSPLANTATION: AN ANZDATA REGISTRY ANALYSIS
TANGIRALA NISHANTA1, GRACEY David1,2, WONG Germaine3,2, FINK Michael4, WYBURN Kate1,2, CHADBAN Steven1,2, MCCAUGHAN Geoff5,2, ADAMS Leon6, JEFFREY Gary7, FAWCETT Jonathan8, BYRNE Mandy9, CATALAN Aimee10, LIM Wai11,12
1Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney, 2University of Sydney, 3Department of Renal Medicine, Westmead Hospital, Sydney, 4Hepatobiliary and Liver Transplant Surgery, University of Melbourne, 5Department of Liver Transplantation, Royal Prince Alfred Hospital, Sydney, 6Department of Liver Transplantation, University of Western Australia, Perth, 7Hepatology and Liver Transplant Medicine Unit, University of Western Australia, Perth, 8General, Visceral and Transplant Surgery, University of Queensland at the Princess Alexandra Hospital, 9Liver Transplant Unit Victoria, Austin Hospital, Melbourne, 10Mater Institute, Brisbane, 11Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, 12University of Western Australia, Perth
Aims: To compare patient and kidney allograft outcomes of simultaneous liver-kidney (SLK) transplant recipients in Australia and New Zealand who received pre-emptive kidney transplants (SLK-PET) with those who were dialysis dependent (SLK-D) prior to transplantation.
Methods: We used multivariable-adjusted Cox regression shared frailty modeling to examine associations between pre-emptive status, all-cause mortality and kidney allograft failure, accounting for the potential intra-cluster correlation within transplanting centres.
Results: Of the 84 SLK transplants performed between 1989-2017, 20 (24%) received PET. The leading cause of ESKD was polycystic disease (27%), followed by glomerulonephritis (17%), oxalosis (10%) and amyloidosis (6%). The mean (SD) age of SLK-PET and SLK-D recipients were 48.7 (13.8) and 44.2 (16.2) years respectively (p=0.27). The median (IQR) waiting time for SLK-D recipients was 35.3 (13.6-73.1) months. For those who received PET, the median (IQR) eGFR at time of transplant was 21.7 (11.5-29.4) ml/min/1.73m2. The 3-year patient and kidney allograft survivals for SLK-PET recipients were 79% (52%-91%) and 79% (52%-91%), respectively; compared with 91% (81%-96%; p=0.3) and 90% (79%-95%; p=0.4), respectively for SLK-D recipients. Compared to SLK-D recipients, the adjusted HRs for all-cause mortality and kidney allograft failure were 1.32 (0.40-4.35) and 1.06 (0.25-4.45), respectively for SLK-PET recipients. Figure 1 shows the adjusted cumulative failure curves for all-cause mortality and kidney allograft failure according to pre-emptive status.
Conclusion: Kidney allograft and patient survival following SLK transplants are acceptable. No patient or graft survival benefit from receiving SLK-PET compared to SLK-D was observed.
RESPONSE PROCESS OF A PROPOSED CORE OUTCOME MEASURE FOR LIFE PARTICIPATION FOR TRIALS IN KIDNEY TRANSPLANT RECIPIENTS: A COGNITIVE PILOT STUDY
BAUMGART Amanda1,2, TONG Allison1,2, HOWELL Martin1,2, CRAIG Jonathan C1,2, JOSEPHSON Michelle3, JU Angela1,2
1School of Public Health, University of Sydney, 2Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, 3Department of Medicine, University of Chicago
Background: Life participation, the ability to engage in meaningful activities, has been identified by the Standardised Outcomes in Nephrology – Kidney Transplantations initiative as a critically important core outcome for all clinical trials. However, with no specific life-participation measure validated in this population, we examined the suitability of the PROMIS Short Form v2.0 – Ability to Participate in Social Roles and Activities 4a (Figure 1).
Methods: Semi-structured interviews were conducted with 20 kidney transplant recipients from seven countries. The four domains of comprehension, retrieval of relevant cognitive information, processes of judgement and response scale usability were explored using descriptive synthesis.
Results: Participants interpreted items consistently, although some found the first and fourth to be similar. Various information retrieval cognitive strategies were used, including recalling incidents (e.g., avoiding gatherings with ill relatives) and relying on a ‘general idea’. The majority indicated a recall period greater than one month (three months most commonly recommended) was necessary to capture variation in activities which could be affected by fluctuating health or seasons. Most found formulating responses to be ‘straightforward’ and the response scale to be clear; however, some considered the middle response option difficult to differentiate. Six preferred a response scale assessing the severity of restricted life participation instead of frequency.
Conclusions: The PROMIS measure for life participation appears to be comprehensible and meaningful. Nonetheless, modifications are warranted to ensure kidney transplant recipients can clearly distinguish between all items and response options and that the recall period is relevant to recipients yet appropriate for clinical trials.
Figure 1. Patient-Reported Outcomes Measurement Information System (PROMIS) Short Form v2.0 – Ability to Participate in Social Roles and Activities 4a
CLINICAL CHARACTERISTICS OF SIMULTANEOUS LIVER KIDNEY TRANSPLANT RECIPIENTS AND AN ANALYSIS OF THEIR LONG-TERM RENAL ALLOGRAFT AND PATIENT OUTCOMES COMPARED TO KIDNEY TRANSPLANT ALONE RECIPIENTS: AN ANZDATA REGISTRY ANALYSIS
TANGIRALA Nishanta1, LIM Wai2,3, WONG Germaine4,5, FINK Michael6, CHADBAN Steven1,5, WYBURN Kate1,5, MCCAUGHAN Geoffrey7,5, ADAMS Leon8, FAWCETT Jonathan9, JEFFREY Gary10, CATALAN Aimee11, BYRNE Mandy12, GRACEY David1,5
1Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney, 2Department of Renal Medicine, University of Western Australia, Perth, 3Sir Charles Gairdner Hospital, Perth, 4Department of Renal Medicine, Westmead Hospital, Sydney, 5University of Sydney, 6Department of Liver Transplantation, Austin Hospital, Melbourne, 7Department of Gastroenterology, Royal Prince Alfred Hospital, Sydney, 8Hepatology and Liver Transplant Medicine Unit, University of Western Australia, Perth, 9General, Visceral and Transplant Surgery, University of Queensland at the Princess Alexandra Hospital, 10Department of Liver Transplantation, University of Western Australia, Perth, 11Mater Institute, Brisbane, 12Liver Transplant Unit Victoria, Austin Hospital, Melbourne
Aims: To describe the characteristics and long-term outcomes of simultaneous liver-kidney (SLK) transplant recipients compared to kidney transplant alone (KTA) recipients.
Methods: Using the Australia and New Zealand Dialysis and Transplant Registry (1989-2017), characteristics of SLK recipients were examined. Unadjusted 5-year kidney allograft and patient survivals were calculated for SLK (n=84) and first deceased donor KTA recipients (n=12,231).
Results: Of the 84 SLK transplants, 53/84 were performed in the most recent transplant era (2010-2017); a six-fold increase since 1989. The leading causes of ESKD in SLK recipients were polycystic disease (27%), glomerulonephritis (17%), oxalosis (10%) and amyloidosis (6%). In the SLK group, 20 (24%) received pre-emptive kidney transplants. The two groups were similar in age (mean [SD] 45years SLK vs 48years KTA) and BMI (24kg/m2 SLK vs 26kg/m2 KTA) at transplantation. SLK recipients were less sensitised (peak PRA>50%, 4.8% vs 10%; p<0.001), more likely to have received kidneys from younger donors (mean[SD] donor age 35years vs 42years), more likely to have received HLA-mismatched kidneys (mean[SD] HLA-mismatches 4.4 vs 3.3; p>0.001) but have lower burden of vascular disease or diabetes compared to KTA recipients. The 5-year kidney allograft and patient survivals for SLK recipients were 83% (95%CI 72%-90%) and 84% (73%-91%), respectively. These compared with 78% (78-79%; log-rank p=0.02) and 88% (87-88%; log-rank p=0.57), respectively for KTA recipients.
Conclusion: Long-term kidney allograft and patient outcomes were comparable between SLK and KTA recipients, although the donor, recipient and transplant characteristics between the two cohorts were dissimilar.
VACCINATION SERORESPONSE AS A PREDICTOR FOR SUBSEQUENT KIDNEY TRANSPLANT REJECTION AND SERIOUS INFECTION
TA’EED A1, POLKINGHORNE KR1,2, MULLEY WR1,2
1Department of Nephrology, Monash Medical Centre, Melbourne, 2Centre for Inflammatory Disease, Monash University, Melbourne
Aims: We hypothesized that seroconversion to vaccination in renal transplant recipients (RTRs) could provide a functional measure of immunosuppression adequacy with seroconversion predicting future rejection episodes and failure of seroconversion predicting subsequent infection.
Methods: We followed 151 RTRs who received the monovalent pandemic H1N1 vaccine in 2009 until December 2016. The incidence of rejection, serious infection (requiring hospitalisation), patient and graft survival was compared between seroconverters and non-seroconverters by Cox regression. Data were obtained from ANZDATA and chart review. Additionally, we assessed whether rejection episodes prior to vaccination were associated with the likelihood of seroconverting to vaccination by logistic regression.
Results: Twenty-six rejection episodes and fifty-eight serious infections occurred in the follow-up period. Seroconversion was not associated with an increased risk of subsequent rejection (HR 1.20, 95% CI 0.50-2.83, p=0.678) or serious infection (HR 0.94, 95% CI 0.50-1.75, p=0.835) on univariable or multivariable analysis. Seroconversion did not predict patient or graft survival and using a mixed model, there was no difference in eGFR at 5 years post-vaccination between seroconverters and non-seroconverters (p=0.256). Rejection prior to vaccination was associated with half the odds of seroconversion, however this association had reduced significance after adjustment for eGFR and mycophenolate dose (OR 0.51, 95%CI 0.23-1.14, p=0.10).
Conclusion: Vaccine response was not associated with the immunologic events of rejection or infection post-vaccination. It will be of interest to examine whether seroresponses to other vaccine types, such as polysaccharide vaccines, are more valuable in predicting immune events.
HUMAN LEUKOCYTE ANTIGEN MATCHING IN DECEASED DONOR ALLOCATION DOES NOT PREDICT ACUTE REJECTION EPISODES
GRAMLICK Madelyn E1,2, YAUSIS Samuel3, TREVILLIAN Paul R3,2,4,5, HEER Munish K3,6,4
1Department of Surgery, John Hunter Hospital, Newcastle, 2Faculty of Health and Medicine, The University of Newcastle, 3Newcastle Transplant Unit, John Hunter Hospital, Newcastle, 4Hunter Transplant Research Foundation, Newcastle, 5Hunter Medical Research Institute, Hunter Medical Research Institute, Newcastle, 6The University of Newcastle, New South Wales, Australia
AIMS: Human leukocyte antigen (HLA) matching has been a fundamental element of kidney allocation policies. With increasing knowledge of additional immunological risk factors the significance of HLA matching appears to be reducing. We aimed to assess the impact of HLA matching on graft rejection in patients undergoing deceased donor kidney transplant.
METHODS: The study population included all adult deceased donor kidney recipients at our unit from 2006 to 2018. Data was extracted from electronic health records. Patients were divided in two groups based on number of HLA mismatches (HLAMM) on HLA A, B and DR loci. Group 1 = HLAMM <=2 and Group 2 = HLAMM =>3. Data was analysed using SPSS.
RESULTS: 206 patients were included for analysis: 90/206 (43.7%) in Group 1 and 116/206 (56.3%) in Group 2. The demographic profile was comparable in two groups (table 1). Group 1 patients had no previous transplant, whilst 7/116 (6.03%) of Group 2 patients had received prior renal transplant (p=0.018). There was no significant difference in the number of patients suffering rejection: group 1 = 19/90 (21.1%), group 2 = 37/116 (31.9%) (p=0.084). However, patients in group 2 suffered rejection episodes sooner after transplant. There was also no significant difference in mean creatinine at 1 and 3 years.
CONCLUSIONS: A high proportion of patients received HLA-matched kidneys however this did not confer a significant benefit in terms of decreased episodes of rejection or mean creatinine at 1and 3 years compared to patients who received a kidney based on wait-time allocation.
EVALUATION OF THE EQUATIONS TO ESTIMATE THE RENAL FUNCTION OF KIDNEY TRANSPLANT RECIPIENTS FOCUSING ON CREATININE CLEARANCE
MARUI Yuhji, YOZA Naoto, SATO Yoshitsugu, MATSUMURA Kaori, USUBA Wataru, AOKI Naoto, NISHI Tomohiro, KATSUOKA Yuichiv, NAKAZAWA Ryuto, SASAKI Hideo, CHIKARAISHI Tatsuya
Department of Urology, St marianna University School of Medicine
Background: Currently in Japan, the estimated glomerular filtration rate (eGFR) calculated by the 3-variable Japanese equation has been widely incorporated into clinical practice to recognize the renal function of CKD patients including kidney transplant recipients. In the meanwhile, creatinine clearance (CCr) is an important index of renal function as contributors to total renal drug clearance, and Cockcroft-Gault equation (CG) has been used to estimate CCr.
Aim: To examine the correlation of eGFR and CG to CCr of the kidney transplant recipients.
Methods: From 2016-2018, 27 kidney transplant recipients of our hospital were evaluated about age, weight, height, serum Cr (sCr), eGFR, CG and CCr. The regression lines were calculated to evaluate the correlation of eGFR and CG to CCr.
Results: With mean follow-up time of 107 (1-237) months 32 data sets were examined. The mean of eGFR, CG and CCr were 40.7±15.3ml/min/1.73m2, 48.5±20.2ml/min and 52.0±23.3ml/min respectively. The regression lines were shown in figure. The correlation coefficients of eGFR and CG with cCCr were 0.73 and 0.86 respectively. The regression coefficient of CG was closer to 1 than eGFR.
Conclusions: For our kidney transplant recipients CG demonstrated greater concordance with CCr than eGFR, which tended to be underestimated against CCr. As CCr is a composite index of renal function including glomerular filtration and tublar secretion, CG appears to be more beneficial in kidney transplant recipients, especially with regard to the use of narrow-therapeutic-window drug.
SATISFACTORY PERFORMANCE OF THE ABBOTT ARCHITECT I2000 TACROLIMUS IMMUNOASSAY AGAINST THE LC-MS/MS TACROLIMUS ASSAY DEMONSTRATED IN KIDNEY TRANSPLANT PATIENTS FROM THE NORTHERN TERRITORY, AUSTRALIA
KAREPALLI Vijay K1, RATHNAYAKE Geetha2, MOGULLA Manohar1, ASHFORD Jenna2, MAJONI Sandawana William1,3,4, SALLUSTIO Benedetta C5
1Department of Nephrology, Royal Darwin Hospital, 2Department of Pathology, Royal Darwin Hospital, 3Flinders University, Northern Territory Medical program, Royal Darwin Hospital, 4Menzies Research Institute, Royal Darwin Hospital, 5Department of Clinical Pharmacology, The Queen Elizabeth Hospital, Adelaide
Background: Tacrolimus is a post-transplant immunosuppressive drug with a narrow therapeutic window requires close monitoring of levels to avoid under-immunosuppression or toxicity. Top End Renal Services in the Northern Territory (NT) refer to South Australia (SA) for drug levels as there was no local service. We aimed to evaluate the Abbott ARCHITECTi2000 immunoassay against the liquid chemistry tandem mass spectroscopy (LC-MS/MS) used in SA for measuring tacrolimus levels to provide on-site service in NT.
Methods: 465 specimens collected over 5 months and performed over several reagent lots. We used Passing-Bablok regression plots and Bland–Altman plots to assess the agreement between tacrolimus results on both platforms.
Results: The Passing-Bablok regression plot demonstrated a slope of 1.172 (CI 1.136 to 1.207) with an intercept of 0.262 (CI 0.040 to 0.472). In Deming analysis the slope was 1.095 (CI 1.074 to 1.116) with an intercept of 0.773 (CI 0.592 to 0.955), correlation coefficient (r) was 0.9782. Bland-Altman plot demonstrated positive bias for Abbott ARCHITECT results. The mean absolute bias was 1.494 ug/L and the mean percentage bias was 18.78%. Within run imprecision, Co-efficient of Variation (%) was 5.1, 2.7, 4.3, 3.4 and 3.5 at tacrolimus concentration levels of 4.2, 6.5, 9.5, 17.2 and 24.4 µg/L. TAT has improved by 80% from local assay.
Conclusion: The results demonstrate that Abbott ARCHITECT i2000 is an acceptable method to monitor levels of tacrolimus. The positive bias could be justifiable if the drug levels are initially based and then monitored on results from the same platform.
Graph: Bland-Altman bias plot for percentage difference for Abbott ARCHITECT i2000 tacrolimus results vs LC-MS/MS results. Mean= mean bias, 95% LOA=95% of Limit of agreement.
TRAJECTORY OF DECLINE IN KIDNEY FUNCTION AND ASSOCIATION WITH ALL-CAUSE GRAFT LOSS IN AUSTRALIAN KIDNEY TRANSPLANT PATIENTS: JOINT LATENT CLASS MIXED MODELS
VON HUBEN Amy1,2, TEIXEIRA-PINTO Armando1,2, AU Eric2,1, WONG Germaine2,1
1School of Public Health, University of Sydney, 2Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney
Background: End-stage kidney disease (ESKD) is a serious and costly chronic disease in Australia. Kidney transplantation is not a cure for ESKD; with one-year/five-year all-cause graft survival rates remaining approximately 95%/85% over 2007 to 2016.
Aim: To identify classes of patients with estimated glomerular filtration rate (eGFR) trajectory progression associated with poorer survival times after kidney transplant for the purposes of early intensive risk factor management.
Method: We have applied a joint latent class mixed model (jlcmm) to kidney transplant patients from the national registry ANZDATA (1995 to 2014), to identify patterns of decline in renal function and investigate their association with clinical factors and all-cause graft loss.
Results: We have found evidence of at least two latent classes of patients with eGFR trajectories associated with differing all-cause graft survival curves (see Figure 1). Approximately 90% of patients have a stable eGFR trajectory after transplant, whilst the remaining patients have a curved trajectory associated with a more than doubling of the hazard of all-cause graft loss; hazard ratio 2.13 (95% CI: 1.93, 2.37). Of the patients with a curved trajectory, 91% had a deceased kidney donor.
Conclusion: The application of a joint latent class mixed model to Australian kidney transplant patients over 1995 to 2014 identifies two latent classes of patients: Class 1 has approximately 10% of patients, a curved eGFR trajectory, is highly associated with having a deceased kidney donor, and results in a more than doubling of the hazard of all-cause graft loss compared with Class 2.
Figure 1 Results of applying the joint latent class mixed model to Australian kidney transplant patients, 1995 to 2014. Observed log(eGFR) trajectories by class, raw and smoothed. Kaplan-Meier survival curves for all-cause graft loss by latent class.
ANALYSING THE EFFECTS OF CLINICAL PREDICTIVE VARIABLES ON KIDNEY TRANSPLANT OUTCOMES IN RANDOM FOREST MODELS
PAIZIS Kathy1, SLOGGETT Clare2, SYPEK Matthew3,4,5, IERINO Francesco6,7
1Renal & Transplantation Unit, Austin Hospital, Melbourne, 2Melbourne Bioinformatics, University of Melbourne, 3ANZDATA, 4Department of Nephrology, Melbourne Health, 5Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, 6Department of Nephrology, St Vincent’s Hospital, Melbourne, 7University of Melbourne
Aims: Machine learning approaches have become of interest in studying clinical data. Random forests are a popular approach due to their flexibility and wide applicability. Compared to regression models, ML approaches have the capacity to capture more complex associations and detect variable interactions without previous specification of interaction terms. The disadvantage can be that the resulting model is more difficult to interpret. We present a method for investigating the effects of clinical variables on transplant outcomes in a Random Forest model.
Methods: A Random Forest model was applied to ANZDATA/ANZOD renal transplant data 1994-present, incorporating a wide range of potentially predictive pre-transplant variables. By tracing predicted probabilities, we are able to examine the role of these variables in detail, and to compare the effects in different graft cohorts under the same model.
Results: We plot the effects of variable manipulation within the model to explore interactions and assist in hypothesis generation (see Figure for example). We are also able to examine non-trivial behaviour for some predictive variables, such as the non-linear risk associated with patient age.
Conclusions: The method has to date suggested interesting hypotheses including: (a) older kidneys may have a noticeably lower detrimental effect in older patient cohorts; (b) Noradrenaline may have a protective effect on lower-quality or older kidneys in particular; (c) patient age may begin to affect outcomes more severely at a critical “threshold” age. Further investigation of predictive variables as well as validation of effects discovered so far would be valuable.
EFFECT OF LANGUAGE AND COUNTRY OF BIRTH ON MEDICAL SUITABILITY AND CONSENT IN SOLID ORGAN DONOR REFERRALS IN NEW SOUTH WALES 2010-2015 – A LINKED-DATA COHORT STUDY
WALLER Karen1,2, HEDLEY James1,3, DE LA MATA Nicole1,3, ROSALES Brenda1,3, WYBURN Kate2,4, KELLY Patrick1,3, O’LEARY Michael5, CAVAZZONI Elena5, WEBSTER Angela1,3,6
1Centre for Organ Donor Evidence, University of Sydney, 2Sydney School of Medicine, Faculty of Health and Medicine, University of Sydney, 3Sydney School of Public Health, Faculty of Health and Medicine, University of Sydney, 4Renal Unit, Royal Prince Alfred Hospital, Sydney, 5NSW Organ and Tissue Donation Service, 6Centre for Transplant and Renal Research, Westmead Hospital, Sydney
Introduction: Culturally and linguistically diverse populations in Australia are over-represented on transplant waiting lists but under-represented in actual organ donor populations.
Aims: We sought to compare medical suitability and family consent outcomes between donor referrals based on primary language and country of birth.
Methods: We used linked-data from the NSW Biovigilance Register. This Register linked NSW donor referrals from 2010-2015 with the NSW Admitted Patient Data Collection and Emergency Department Data Collection. Effects of primary language (English vs. non-English) and country of birth (Australian vs. overseas born) on referral outcomes were determined using logistic regression (odds ratios with 95%CI).
Results: Of 2,957 referrals from NSW, 2,644 (89%) were likely to proceed (donor did not recover, no donor registered refusal, and no coroner refusal), and of these 2,383 (90%) had complete data for analysis. Family consent was sought for 1,302 (55%) and was granted for 846 (65%) referrals. There were 991 (42%) referrals medically suitable for donation. Language and country of birth were not associated with families being asked for consent (p>0.1) or being deemed medically suitable (p>0.9). Families of Non-English speakers were less likely to consent to donation if asked (adjusted OR 0.48; 95%CI 0.31-0.75; p=0.001). Families of overseas born referrals were also less likely to consent to donation (adjusted OR 0.46; 95%CI 0.34-0.63; p<0.001). There were no interaction effects (p=0.4).
Conclusions: Culturally and linguistically diverse referrals were less likely to obtain family consent to donation, but there were no differences in being asked for consent or medical suitability.
Figure 1: Forest plot of adjusted logistic regression results
A WINDOW TO TOLERANCE - HUMAN LUNG ALLOGRAFTS ARE ENRICHED FOR CD39+FOXP3+ REGULATORY T CELLS
DE SILVA Tharushi1,2, O’SULLIVAN Brendan1,2,3, APTE Simon2,3, VOISEY Joanne1, DIVITHOTAWELA Chandima2, TAN Maxine3,2, HOPKINS Peter4,3, CHAMBERS Daniel2,3
1School of Biomedical Sciences, Queensland University of Technology, Brisbane, 2Lung Transplant Service, Prince Charles Hospital, Brisbane, 3School of Clinical Medicine, University of Queensland, Brisbane, 4Prince Charles Hospital, Brisbane
Aims: Regulatory T cells (Tregs) play a vital role in the induction and maintenance of transplant tolerance. Though suppressive pathways of Tregs are well defined, identifying phenotypes with respect to local tissue environment is of importance to understand their role in graft tolerance. Adenosine triphosphate (ATP) is released from apoptotic, necrotic cells and from inflammatory cells and platelets during inflammation and infection. The ecto-enzyme CD39 hydrolyses ATP to immunosuppressive adenosine which functions to limit effector T cell proliferation and enhance suppressive function of Tregs. Since inflammation is associated with poor outcome in transplant recipients, we compared the proportion of blood and lung CD39+Treg in T cells with the aim of determining if immunosuppressive CD39+Tregs are present in the lung post-transplant.
Methods: Blood and bronchoalveolar lavage (BAL) cells isolated from 23 transplant patients (median 13.07 (1-140) months post-transplant; 11 female; 12 male; 13 CF; 4 IPF; 5 COPD; 1 Histiocytsis). These cells were analysed by a newly developed multicolour flow cytometry panel comprising 14 fluorescent antibody markers to identify Treg subsets.
Results: CD39+ FoxP3+ Treg were more prevalent in BAL than in blood (2.13 ± 0.58 (SEM) vs 0.69 ± 0.17 (SEM) of total CD4+ T cells, p=0.02(Figure 1A)). There was no correlation between BAL and blood CD39+ FoxP3+ Treg (r= -0.059, p= 0.788 (Figure 1B)).
Conclusions: The lung allograft is enriched with a specialized subpopulation of FOXP3+CD39+ Tregs with capability of metabolising pro-inflammatory ATP to enrich the lung microenvironment with immunosuppressive adenosine. Future work will examine the frequency and functional capacity of these cells.
Figure 1 A: Proportion of CD39+FOXP3+ Tregs in BAL and PBMC. B: Correlation between CD4+CD39+FOXP3+ Cells in blood and BAL
HIGH FIBRE DIET PREVENTS KIDNEY ALLOGRAFT REJECTION AND PROTECTS AGAINST TRANSPLANT-ASSOCIATED DYSBIOSIS
SINGER Julian1,2,3, WU Huiling1,3,2, KWAN Tony1,3, LOH Yik Wen4,3, WANG Chuanmin1,3, TAN Jian1,3, LI Yan J1, LAI Sum Wing Christina1, MACIA Laurence4,3, ALEXANDER Stephen I5,3, CHADBAN Stephen J1,2,3
1Kidney Node Laboratory, Charles Perkins Centre, 2Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney, 3School of Medicine, University of Sydney, 4Nutritional Immunometabolism Lab, Charles Perkins Centre, 5Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney
Aim: To investigate the impact of dietary supplementation with high-fiber (HF), or the short-chain fatty acid sodium acetate (SA) on kidney allograft rejection in a murine model.
Methods: Kidney transplants were performed from BALB/c(H2d) to B6(H2b) or B6(H2b):GPR43-/- mice as allografts. Allograft mice received normal chow (WT+NC), a HF diet (WT+HF), or SA supplementation (WT+SA; GPR43-/-+SA). Gut microbiota composition was assessed by 16S rRNA sequencing.
Results: WT+HF allografts had prolonged survival compared to WT+NC allografts (Figure 1, p<0.01), and were protected from acute (day 14: lower creatinine (p<0.01), less tubulitis (p<0.001)) and chronic (day 100: lower creatinine (p<0.05), less proteinuria (p<0.01) and glomerulosclerosis (p<0.001)) rejection. Transplantation led to dysbiosis in WT+NC mice, with gut microbial diversity decreased at day 14, but not in WT+HF mice where diversity was enhanced (p<0.05). Following transplant, bacteria known to produce SA and induce Tregs were enhanced (Clostridiales p<0.0001) or remained dominant in WT+HF mice (Bifidobacterium p<0.05) as compared to WT+NC animals. Similarly, WT+SA allografts exhibited superior survival to WT controls (Figure 1, p<0.05), were protected from rejection and exhibited donor specific tolerance confirmed by acceptance of donor strain but rejection of 3rd party skin grafts (p<0.01). The survival benefit conferred by SA was broken by depletion of CD25+ Tregs and was ineffective in GPR43-/- allograft recipients (p<0.05).
Conclusions: HF diet prevented transplant-associated dysbiosis and afforded protection against allograft rejection. Protection was mediated, at least in part, by SA and was dependent on a CD4+CD25+Foxp3+ regulatory mechanism and signalling via GPR43.
THE IMMUNOSUPPRESSIVE AGENT DILIXIMAB (ANTI-CD2) IS SUPERIOR TO ANTITHYMOCYTE GLOBULIN IN HAVING REDUCED PROTHROMBOTIC AND CELL-ACTIVATING EFFECTS
BONGONI Anjan K1, SALVARIS Evelyn J1, LEW Andrew M2, COWAN Peter J1,3
1Immunology Research Centre, St Vincent’s Hospital, Melbourne, 2Walter and Eliza Hall Institute, Parkville, 3Department of Medicine, University of Melbourne
Background: Antithymocyte globulin (ATG) is used to deplete T cells in transplantation. Although ATG is highly effective, its non-specific polyclonal composition can cause adverse side effects including systemic coagulation. We have previously developed a chimeric anti-CD2 monoclonal antibody (diliximab), which depletes and blocks costimulation of T cells, as a potential alternative to ATG.
Aims: To compare the prothrombotic and cell-activating effects of diliximab and ATG on human monocytes (THP-1 cell line) and peripheral blood mononuclear cells (PBMCs).
Methods: THP-1 cells (2x106) were treated with diliximab or ATG (200µg/ml) and incubated with 100% normal human plasma in the presence or absence of the complement inhibitor compstatin (10µg/ml). Surface procoagulant tissue factor (TF) activity was measured using a chromogenic factor (F)Xa generation assay. Whole blood and PBMCs were treated with diliximab or ATG (500µg/ml, 24 hrs) and cytokine secretion was analysed by ELISA.
Results: Diliximab had a small effect on monocyte TF procoagulant activity, measured by FXa generation (2.0±0.02-fold increase versus untreated). In contrast, ATG markedly increased FXa generation (20.0±0.7-fold increase). ATG’s prothrombotic effect, which has been shown to be complement-dependent, was completely inhibited by compstatin. Diliximab treatment of whole blood or PBMCs showed minimal supernatant cytokine concentrations that were similar to isotype antibody treatment. However, ATG significantly increased cytokine levels (Table 1).
Conclusion: Our data show that diliximab lacks the prothrombotic and cell-activating side effects of ATG, and warrant its further development for the prevention and treatment of T cell-mediated rejection in transplantation.
Developing a Model of Kidney Directed T Cell Therapy Using CAR T Cells
LU B1, ZHANG GY2, HU M3, ROBINSON S2, WILARUS A2, WAN H2, ALEXANDER SI2, WANG YM2
1Centre for Transplant and Renal Research, Westmead Hospital, Sydney, 2Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, 3Centre for Transplant and Renal Research, Westmead Millennium Institute, Westmead Hospital, Sydney
Abstract: Modulation of T cell function has been a major component of solid organ transplantation; initially using immunosuppression, but more recently using regulatory cells including Tregs. This has now reached clinical use with the One Study in Europe. Increasing the specificity of Tregs to the target organ has major advantages in improving efficacy. This can be achieved by directing T cells to a transplant using T cell receptors constructed to target HLA.
Aim: To target CAR T cells to HLA-A2 expressed on donor tissues in a mouse model of transplantation.
Methods: An MIGR-1 retrovirus containing a scFv targeted at HLA-A2 and the signalling component of the TCR were transfected into CD4 lymphocytes purified from splenocytes of B6 mice. Skin and kidney transplants from B6-HLA2 tg mice were transplanted into immunodeficient RAG mice recipients. The kidney transplants were done as orthotopic transplants with one recipient kidney removed and the other left in place.
Results: CD4 T cells were successfully transfected with an HLA-A2 construct. Immunohistochemistry of D8 skin-grafts identified HLA-2 scFv transfected T cells in HLA-A2 transgenic skin-grafts but not in third party BALB/c skin grafts and control CD4 T cells were not found in either graft but both were present in spleen.
Conclusions: CD4 T cells expressing a CAR construct containing a scFV targeted at HLA-A2 preferentially target tissues expressing HLA-A2 suggesting that Class I can be used as a transplant organ and tissue targeting strategy.
HUMAN CD27+HLA-DR+ MEMORY LIKE TREG SHOW XENOANTIGEN SPECIFIC SUPPRESSION OF PORCINE ISLET XENOGRAFT REJECTION IN HUMANIZED MICE
XIAOQIAN Ma1,2, HU Min1, CAO Lu1,2, ZHAO Yuanfei1, HUANG Dandan1, BURNS Heather1, HAWTHORNE Wayne1, YI Shounan1, O’CONNELL Phillip1
1Centre for Transplant and Renal Research, Westmead Millennium Institute, Westmead Hospital, Sydney, 2Institute for cell transplantation and gene therapy, The Third Xiangya Hospital of Central South University
Aims: To achieve effective suppression and avoid opportunistic infection and malignancy for clinical xenotransplantation, xenoantigen-specific Treg will be required. Previously, we have shown that a CD27+HLA-DR+subset of Treg separated from xenoantigen stimulated human Treg (XnTreg) were potent and xenoantigen-specific in vitro. In this study, we aim to determine their xenoantigen specificity and potency in protecting against neonatal porcine islet cell clusters (NICC) xenograft rejection in vivo.
Methods: Human XnTreg were separated by cell sorting, using the Treg cell surface markers CD27 and HLADR, into non-selected, CD27+HLADR+ and non-CD27+HLADR+ Treg subsets prior to cotransfer into NICC recipient NOD-SCID IL2rg-/- mice in association with autologous PBMC at a 1:25 ratio of Treg (4x105): PBMC (1x107). Serum, spleen and NICC xenografts were harvested from recipient mice at day 60 after human cell transfer for analysis of xenograft survival and Treg in vivo function.
Results: Recipient mice transferred with human PBMC alone rejected their xenografts completely within 35 days. Co-transfer with CD27+HLADR+ Treg prolonged NICC xenograft survival beyond 60 days with detectable serum porcine C-peptide and intact xenografts which stained positive for insulin and were surrounded but not infiltrated by a few human CD8+ effector cells. By contrast, non-selected and non-CD27+HLADR+ Treg co-transferred at the same ratio did not protect against rejection.
Conclusions: Human CD27+HLADR+ memory-like Treg were sufficient to suppress porcine islet xenograft rejection at a 5-fold decreased cell number compared to that previously reported for polyclonal Treg in same model, suggesting they are more potent at preventing rejection than polyclonal Treg in vivo.
ASSESSMENT OF 3D-BIOPRINTED HUMAN REGULATORY T-CELLS FOR CO-PRINTING WITH HUMAN PANCREATIC ISLETS
KIM Juewan1, HOPE Christopher M2, PERKINS Griffith B1, YUE Zhilian3, LIU Xiao3, DROGEMULLER Christopher J4,5, CARROLL Robert P4,5, BARRY Simon C2,6, WALLACE Gordon G3, COATES P Toby4,5
1Department of Molecular and Cellular Biology, University of Adelaide, 2Discipline of Paediatrics, University of Adelaide, 3Intelligent Polymer Research Institute, University of Wollongong, 4Central Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, 5Discipline of Medicine, University of Adelaide, 6Molecular Immunology Group, University of Adelaide
Introduction: 3D-bioprinting facilitates the fabrication of complex 3D-architectures. 3D-bioprinting of regulatory T-cells (Tregs) with islets may overcome the immunosuppressive shortcomings inherent in islet transplantation. This project aims to characterize 3D-bioprinted human Tregs using alginate-GelMA bioink supplemented with IL-2 and CCL1.
Method: Natural Tregs were FACS sorted from peripheral blood, whereas induced Tregs were induced from naïve CD4+ T-cells. Tregs were suspended in media (‘non-printed’) or printed in a photo- and chemically-crosslinked alginate-GelMA bioink, with and without IL-2 and CCL1. Tregs were analyzed by flow cytometry for viability (propidium iodide), phenotype (CD25 and FOXP3) and functionality (TGF-β, CD69, CD39 and CTLA-4). CD154 suppression assay evaluated Treg function. Trans-well migration assays were performed to evaluate the bioprinted Treg migration and recruitment capability of CCL1-supplemented bioink.
Results: In the presence of IL-2, 3D-bioprinted Tregs retained viability above 80% with no significant decreases compared to non-printed cells, up to 3 days post-bioprinting. However, in the absence of IL-2, 3D-bioprinted Treg viability significantly decreased below 50%, by day 3 (p<0.0001). 3D-bioprinting maintained expression of Treg phenotypic and functionality markers and suppressive capacity. Furthermore, 3D-bioprinting was shown to halt migration of Tregs. CCL1-supplemented bioink demonstrated recruitment of Tregs and enhancement of Treg function.
Conclusion: 3D-bioprinting had a minimal impact on viability, phenotype and function of Tregs. Secondly, bioink supplementation with IL-2 displayed a positive impact on 3D-bioprinted Tregs. Furthermore, we demonstrated printing prevents Treg migration from the 3D-bioprinted structures. Lastly, bioink supplementation with CCL1 enabled Treg recruitment and enhanced Treg function.
Organ Donation and Preservation
DONOR SOURCE OF KIDNEY TRANSPLANTATION IN NEW ZEALAND BY ETHNICITY: A LONGITUDINAL COHORT STUDY
CROSS Nicholas1, DONNELLAN Sine1, WILLIMAN Jonathon2, PALMER Suetonia1,3
1Department of Nephrology, Christchurch Hospital, New Zealand, 2Biostatistics and Computational Biology Unit, University of Otago, Christchurch, New Zealand, 3Department of Medicine, University of Otago, Christchurch, New Zealand
Aims: To explore whether donor source for kidney transplantation in New Zealand was associated with recipient ethnicity adjusting for socioeconomic and clinical factors.
Methods: We performed a longitudinal cohort study in patients ≥18 years who commenced RRT in New Zealand between 2006-2015, using ANZDATA. Deprivation score was obtained by data linkage with the National Health Index. Poisson regression was performed for pre-emptive transplantation and competing risks regression for living and deceased donor transplantation with 95% CI. Estimates were adjusted for age, sex, smoking, deprivation, BMI, late referral, treating centre, diabetes, and coronary artery disease.
Results: Among the 5106 participants, 822 received a kidney only transplant. Compared to European patients, Māori and Pacific patients were younger, and more frequently had diabetes and referred late to specialist care, and lived in more socioeconomically deprived areas. In European patients, 65% received a live donor kidney transplant, while the proportion was smaller for Asian (44%), Māori (44%), and Pacific (39%) patients. Compared to European patients, patients who identified as Māori, Pacific and Asian were markedly less likely to receive a pre-emptive and living donor kidney transplant after adjustment for socioeconomic factors, comorbidity, and late referral(Table 1). The difference in transplantation rates between patient groups based on ethnicity was less marked for deceased donor kidney transplantation and was not evident for Māori and Asian patients after adjustment.
Conclusion: Transplantation rates for pre-emptive and live donor but not deceased donor kidneys varies with ethnicity, socioeconomic factors and late referral to specialist services within New Zealand.
THE CHANGING PATTERN OF LIVING KIDNEY DONATION IN AUSTRALIA AND NEW ZEALAND
ALLEN Richard1, DOBRIJEVIC Ellen2, CLAYTON Phil3,4, WONG Germaine5, CROSS Nicholas6, ROAKE Justin7, VASILARAS Arthur8, PLEASS Henry9,10
1Sydney Medical School, University of Sydney, 2Clinical Westmead Hospital, University of Sydney, 3Central Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, 4ANZDATA Registry, Royal Adelaide Hospital, 5Centre for Transplant and Renal Research, Westmead Hospital, Sydney, 6Department of Renal Medicine, Christchurch Hospital, NZ, 7Department of Surgery, Christchurch Hospital, NZ, 8Transplantation Services, Royal Prince Alfred Hospital, Sydney, 9Department of Surgery, Westmead Hospital, Sydney, 10Department of Surgery, University of Sydney
Living donor nephrectomy (LDN) surgery is a procedure of necessity when deceased donation (DD) of kidneys is insufficient to meet transplant demand.
Aim: Assess patterns of LDN surgery technique and activity and to correlate with DD activity.
Methods: Analysis of data contributed annually by 25 centres to the ANZDATA Living Kidney Donor Registry, from establishment in 2004, to 2017.
Results: 4,644 LD kidneys were transplanted into 4287 adults and 377 children. Two (0.044%) LDN related deaths occurred. Paired kidney exchange (PKE) countered for 281(6%) of LDK procedures. LDN side data was missing for 74 donors (1.6%). Left kidneys was donated in 3,777(82.6%) LDN procedures and 813 were right sided. Five centres have avoided right-sided LDN surgery. Open LDN has declined from 36% in 2004 to 4% by 2011. By 2017, there were 18 transplant centres and 61% of LDN were performed by pure laparoscopic surgery and 36% by hand-assisted surgery. LDN activity peaked in 2008(n=386). Despite introduction of PKE in 2009, LDN activity fell and plateaued from 2011. LDs provided 24.6% and 36.9% of kidneys transplanted in Australia and New Zealand in 2017 respectively.
Conclusions: Two LDN related donor deaths highlight risks undertaken by living kidney donors. Importantly, the necessity for living kidney donation has diminished. Despite introduction of PKE and minimally invasive LDN surgery, LDN activity continues to fall as a percentage of annual number of kidney transplant recipients. PKE may however have contributed to a reduction of transplant centres because of their need to undertake right-sided LDN surgery.
COLD PERFUSION MACHINE ALLOWS PROLONGED STORAGE OF DONOR MATCHED KIDNEYS WITHOUT ADVERSE OUTCOME
BYRNE Sarah1, PEREIRA Ryan1, ROBERTSON Ian2, TAN Ai Lin1, LOCKWOOD David1, KANAGARAJAH Vijay1, RAY Mark1, PRESTON John1, WOOD Simon1, LAWSON Malcolm1, GRIFFIN Anthony1, RHEE Handoo1
1Department of Surgery, Princess Alexandra Hospital, Brisbane, 2Renal Transplant Unit, Princess Alexandra Hospital, Brisbane
Aims: To compare outcomes of hypothermic perfusion storage and static hypothermic storage of renal allografts at the Princess Alexandra Hospital (PAH) since the procurement of cold perfusion machines (CPM).
Methods: All deceased donor renal transplants occurring at the PAH from 2011 to 2017 were included. Data reports from the CPM parameters were analysed. Outcome data was obtained from medical records and statistical analyses were performed. Primary outcome was delayed graft function (DGF).
Results: During this period, 1136 renal transplants occurred and the CPM was used on 109 occasions. Of the 109 renal allografts, 66 were donated after brain death (DBD) and 43 were donated after cardiac death (DCD). The mean total storage time was 17.19 +/- 4.71 hours with a mean CPM time of 10.91 +/- 4.22 hours. Datasets from the CPM showed that an allograft with reduced flow rates was associated with a dialysis requirement. Cold ischaemic time (CIT) >18hrs was associated with reduced rates of DGF in DCD kidneys placed on the CPM compared with CIT <18 hrs but results did not power statistical significance. There was no difference in the DGF or 1 year serum creatinine for paired kidneys where one was placed on the CPM and one was transplanted immediately.
Figure. Comparison of paired kidneys.
Conclusions: Outcomes of renal transplants placed on the CPM are comparable to static hypothermic storage. There was no difference in DGF or 1 year serum creatinine. CPM datasets may be used to predict outcome such as need for dialysis after transplantation. Increased CIT is not associated with poor clinical outcome.
COLD PERFUSION MACHINE DATASETS USED FOR KIDNEY TRANSPLANTS MAY PREDICT DELAYED GRAFT FUNCTION INCLUDING THE NEED FOR POST-TRANSPLANT DIALYSIS
BYRNE Sarah1, PEREIRA Ryan2, ROBERTSON Ian2, TAN Ai Lin2, LOCKWOOD David3, KANAGARAJAH Vijay2, RAY Mark2, PRESTON John2, WOOD Simon2, LAWSON Malcolm2, GRIFFIN Anthony2, RHEE Handoo2
1Renal Transplant Unit, Princess Alexandra Hospital, Brisbane, 2Department of Surgery, Princess Alexandra Hospital, Brisbane, 3Princess Alexandra Hospital, Brisbane
Aims: To assess outcomes of renal transplant allografts that underwent a period of hypothermic perfusion storage at the Princess Alexandra Hospital (PAH) since the procurement of cold perfusion machines (CPM).
Method: All deceased donor renal transplants that were stored on the CPM at the PAH were analysed from 2011 to 2017. Datasets available from the CPM include systolic and diastolic pressure, flow rate, resistance and temperature. Data reports from the CPM parameters were analysed. Outcome data was obtained from electronic medical records. Primary outcome was delayed graft function (DGF).
Results: During this period 109 renal allografts were placed on the CPM. Of the 109 kidneys, 43 were donated after cardiac death (DCD) and 66 were donated after brain death (DBD). There was no difference in systolic/diastolic pressure, flow rate or resistance between DCD and DBD allografts on the CPM. Kidneys that required postoperative dialysis were associated with lower flow rates on the CPM compared to kidneys that did not require dialysis 123.8 ml/min vs 141.8 ml/min, p=0.0427. Subgroup analysis of the upper and lower 50% of CPM datasets showed statistical significance for flow rates and diastolic pressure. Increased CPM time was not associated with adverse outcome. There was a trend for improved DGF with longer CPM time.
Figure. Upper and lower 50% of CPM datasets have demonstrated that poor flow may predict increased risk for dialysis post-transplant. Higher diastolic pressures were associated with lower rates of DGF.
Conclusion: Reduced flow rates and lower diastolic pressure in renal allografts on the CPM may be a predictor of DGF requiring postoperative dialysis. Prolonged CPM time is not associated with adverse outcome.
IDENTIFICATION OF BARRIERS FOR INDIGNEOUS AUSTRALIANS GAINING ACCESS TO THE KIDNEY TRNASPLANT WAITING LIST: A VICTORIAN PILOT STUDY
ATKINSON Amy1, FORD Sharon2, GOCK Hilton1, IERINO Frank1, GOODMAN David1
1Department of Nephrology, St Vincent’s Hospital, Melbourne, 2Department of Nephrology, St Vincent’s Institute, Melbourne
Aims To identify the barriers to Indigenous Australians gaining access to the kidney transplant waiting list.
Methods All Indigenous Australians with end stage renal failure linked to a single Victorian hospital over a 10-year period were included in the study. All living participants were interviewed, and hospital medical and tissue typing records were examined to plot the patients transplant journey. Reasons why patients were not listed for transplantation and delays in transplant work-up pathway were recorded.
Results: Of the 39 patients in the study, 7 have received a kidney transplant, 11 remain on dialysis and 21 are deceased. Currently there are no patients on waiting list. Most of the patients had diabetes mellites (>70%). Those receiving a transplant were younger, had less ischaemic heart disease and had ceased smoking. Seven of 9 patients listed for transplantation received a transplant with good outcomes. Psychosocial factors such as fear, lack of interest, depression and adherence to medications and dialysis attendance accounted for up to one-third of patients not being listed for transplant. Only 1 of 29 patients achieved the state KPI (list for transplant within 3 months of starting dialysis, target 30%). It took between 2-3 years before 9 of 29 patients (31%) were listed for transplant.
Conclusion: Medical co-morbidities and psychosocial factors are the main barriers to Indigenous Australians gaining access to the transplant list. This early data supports a focused attention to early culturally appropriate education and management of co-morbidities before commencement of dialysis to provide Indigenous Australians greater access to transplantation.
IATROGENIC LIVER INJURY SUSTAINED DURING DECEASED DONOR ORGAN PROCUREMENT: AN ANALYSIS OF THE RISK FACTORS AND CONSEQUENCES IN AN AUSTRALIAN TRANSPLANT CENTRE
WALCOTT James1,2, FINK Michael1, MURALIDHARAN Vijayaragavan1, CHRISTOPHI Christopher1,2
1Department of Surgery, Austin Hospital, Melbourne, 2Department of Surgery, University of Melbourne
Introduction: Liver transplantation is an established treatment for various liver diseases, and its success relies on the quality of the donated organ. Studies on procurement-related liver injury may not apply to modern day practice. This is the first Australasian study examining risk factors and consequences of procurement-related injury.
Method: The Victorian Liver Transplant database was examined for injuries from deceased liver donors for the calendar years 2010 – 2017. Information regarding the donor, the procurement surgery and subsequent transplantation was obtained. Injury information was sought from the “organ retrieval report form” (ORRF). Risk factors for injury were calculated using multivariate regression. Outcomes of complications and survival were calculated.
Results: A total of 639 offers for whole liver donation resulted in 468 transplantations of which there were 420 accompanying ORRF forms. There were 46 injuries in 45 livers. Aberrant anatomy increased the risk of vascular injury (OR 4.80 CI 1.99-611.60, p<0.001). Surgeon inexperience increased the risk of parenchymal injury (OR 16.24, CI 2.15-122.64, p<0.01). There was no difference in overall or graft survival for injured grafts. Complication rates were the same in the presence of injury with the exception of a decreased risk of anastomotic biliary strictures in the presence of a vascular injury (OR 0.13, CI 0.02-0.95, p=0.04).
Conclusion: This study shows that procurement related liver injuries are common, and that aberrant anatomy and surgeon inexperience increase the risk of injury. Similar outcomes for transplantation despite the presence of injury indicate that injuries are being appropriately managed in the Australasian setting.
MISSED OPPORTUNITIES FOR ORGAN DONATION AMONG DONORS WITH PRIMARY BRAIN MALIGNANCIES (PBMS): NEW SOUTH WALES (NSW) COHORT STUDY 2010-2015
THOMSON Imogen1,2, HEDLEY James1, ROSALES Brenda1, WYBURN Kate3,1, WEBSTER Angela1,4
1School of Medicine, Faculty of Health Sciences, University of Sydney, 2JMO Unit, John Hunter Hospital, Newcastle, 3Renal Unit, Royal Prince Alfred Hospital, Sydney, 4Centre for Transplant and Renal Research, Westmead Hospital, Sydney
Aims: Most PBMs are not a contraindication to organ donation as risk of tumour transmission is low. We sought to characterise organ donor referrals with PBMs in NSW, identify any transmission events, and describe missed opportunities for donation for referrals declined due to PBMs.
Methods: We undertook a retrospective review of 2010-2015 donor referrals in SAFEBOD, a register linking NSW Organ and Tissue Donation Service referral logs to donor and recipient health records, identifying referrals with PBMs. Tumours were classified using World Health Organization (WHO) grading and risk-assessed using Transplant Society of Australia and New Zealand (TSANZ) guidelines.
Results: Of 2957 referrals, 76 (3%) with PBMs were identified. Issues other than PBM meant that 47 (62%) were unsuitable for donation. 10 (13%) donors donated organs to 23 recipients in NSW. The remaining 19 (25%) were missed donor opportunities, and were significantly younger (47.7 vs. 58.6 years, p<0.001) and had fewer comorbidities (0.8 vs. 2.1, p<0.001) than referrals overall. WHO-I tumours were most common among PBM referrals (36, 47%) and PBM donors (8, 80%), but WHO-IV tumours predominated among missed opportunities (12, 68%) including glioblastoma multiforme (GBM) (11, 63%). All PBM donors had TSANZ ‘low risk’ or ‘not contraindicated’ malignancies. No referrals with GBM or ventriculo-peritoneal shunt donated organs. No transmission events occurred after 860 months total follow up.
Conclusion: There exist opportunities to increase organ donation rates in NSW through greater consideration of donors with PBM. This must be balanced against risk of transmission, especially when evaluating referrals with GBM.
1 Presence of malignancy excluding PBM. 2 High-risk behaviours included drug use (IVDU non-IVDU), recent incarceration, sex work, high-risk partners and MSM). 3 Two missed opportunities with unclassified PBMs have been excluded from this section as grade and transmission risk could not be determined.
THE IMPORTANCE OF DONOR CANCER HISTORY IN DETERMINING USE OF KIDNEYS FROM CONSENTED DONORS
AU Eric HK1,2, PHILLIPS Jessica3, OPDAM Helen4,5, MCDONALD Mark6, CHAPMAN Jeremy R7, MCDONALD Stephen8,9, JOHNSON David10,11, KANELLIS John12, WONG Germaine1,2,7, LIM Wai H3,13
1School of Public Health, University of Sydney, 2Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, 3Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, 4Organ and Transplant Authority, 5Department of Intensive Care, Austin Hospital, Melbourne, 6Organ and Tissue Authority, 7Centre for Transplant and Renal Research, Westmead Hospital, Sydney, 8ANZDATA, South Australian Health and Medical Research Institute, 9Adelaide Medical School, University of Adelaide, 10Department of Nephrology, Princess Alexandra Hospital, 11Faculty of Medicine, University of Queensland, Brisbane, 12Department of Nephrology, Monash Medical Centre, Melbourne, 13Faculty of Health and Medical Sciences, University of Western Australia, Perth
Aim: To determine whether a history of prior donor cancer influences the decision to use kidneys from consented donors in Australia and New Zealand.
Methods: This study included all consented (intended and actual) donors recorded in the ANZDATA and ANZOD registries between 1989 and 2017. The relationship between donor factors [including prior cancer (excluding non-melanoma skin cancers), age, gender, ethnicity, HCV status, body mass index (BMI), comorbid conditions and terminal eGFR] and non-use of donor kidney (i.e. not retrieved or utilised) were examined using Least Absolute Shrinkage and Selection Operator (LASSO) penalised logistic regression and random forests.
Results: A total of 9485 donors (865 intended and 8620 actual) were identified [57.8% female, median age 42.9 years (IQR 28.0-57.0)]. Kidneys from 1645 (17.3%) donors were not retrieved or utilised. The most common cause of donor death was intracranial haemorrhage (21.0%). Donor factors associated with non-use [Odds Ratio (95% CI)] included increasing age [1.16 per 10 years (1.09-1.23)], cancer history [2.10 (1.43-3.06)], hypertension [1.65 (1.36-2.00)], current smoker [1.24 (1.02-1.49)], insulin-requiring diabetes mellitus [3.28 (1.94-5.54)], cause of death, HCV NAT positivity [54.8 (22.3-134)] and terminal eGFR [0.78 per 30 mL/min/1.732 increase (0.72-0.83)]. Donor ethnicity and BMI were not associated with non-use. The most important donor factors in determining non-use using random forest classifiers were terminal GFR and donor age.
Conclusion: Prior cancer history was associated with a 2-fold increased risk of non-use of consented donor kidneys. However, the most important donor factors in determining non-use were terminal eGFR and donor age.
MISSED OPPORTUNITIES FOR ORGAN DONATION? USE OF LINKED HEALTH DATA TO VERIFY INCREASED BLOODBORNE VIRUS (BBV) RISK AMONG NSW ORGAN DONOR REFERRALS, 2010-2015
DE LA MATA Nicole1, WALLER Karen1, HEDLEY James H1, ROSALES Brenda1, KELLY Patrick J1, WYBURN Kate2,3, O’LEARY Michael4, CAVAZZONI Elena4, WEBSTER Angela C1,5
1School of Public Health, University of Sydney, 2Sydney Medical School, University of Sydney, 3Renal Unit, Royal Prince Alfred Hospital, Sydney, 4NSW Organ and Tissue Donation Service, 5Centre for Transplant and Renal Research, Westmead Hospital, Sydney
Background: Donors with bloodborne viruses (BBV) may transmit infection to transplant recipients. Often medical information is limited at the time of referral, and donors may be declined when social or medical history suggests increased risk of BBV without serology or NAT confirmation.
Aims: To determine potential missed opportunities for organ donation using linked health data when referrals were declined due to increased BBV risk at referral.
Methods: We included all donor referrals 2010-2015 from the NSW Biovigilance Public Health Register, SAFEBOD. This Register linked donor referrals in NSW to administrative health databases, including the hospital admissions data, notifiable conditions information management system and the death register. Increased BBV risk at referral was defined as an active infection, past infection or high-risk behaviour for HIV, HBV or HCV. In the Register, active or past infection were indicated by ICD-10-AM codes in NSW health datasets.
Results: Of 2,850 persons referred for organ donation in NSW, 156 persons did not donate due to increased BBV risk at referral (Figure 1). Among these, no evidence of active infection was found in 150 persons for HIV, 141 persons for HBV and 84 persons for HCV. Overall, 75 of 156 persons referred who did not donate due to increased BBV risk at referral had no evidence of active BBV infection up to their terminal contact with health services.
Conclusions: Utilizing routinely collected administrative health data has identified potential missed donation opportunities and, if available in real-time, may provide a useful additional information source to aid decision-making.
Figure 1. Potential missed opportunities for organ donation due to increased bloodborne virus (BBV) risk in NSW, 2010-2015.
BLOODBORNE VIRUS (BBV) INFECTIONS IN NSW ORGAN DONOR REFERRALS USING LINKED HEALTH DATA: THE SAFEBOD COHORT, 2010-2015
DE LA MATA Nicole1, WALLER Karen1, HEDLEY James H1, ROSALES Brenda1, KELLY Patrick J1, WYBURN Kate2,3, O’LEARY Michael4, CAVAZZONI Elena4, WEBSTER Angela C1,5
1School of Public Health, University of Sydney, 2Sydney Medical School, University of Sydney, 3Renal Unit, Royal Prince Alfred Hospital, Sydney, 4Other, NSW Organ and Tissue Donation Service, 5Centre for Transplant and Renal Research, Westmead Hospital, Sydney
Background: Misclassification of bloodborne viruses (BBV) may lead to potential donors being unnecessarily declined, or to infected donor organs being used.
Aims: To compare perceived BBV risk at referral with verified BBV risk from linked health datasets.
Methods: We included all donor referrals, 2010-2015, from the NSW Biovigilance Public Health Register (SAFEBOD). This Register linked all organ donor referrals in NSW to administrative health databases, including the hospital admissions data and notifiable conditions information management system. Perceived BBV risk was based on information available at referral, including serology, nucleic acid testing, and high-risk behaviour. Verified BBV risk was based on ICD-10-AM codes indicating active infection, past infection and exposure to HIV, HBV or HCV in SAFEBOD. We used cross tabulations and Cohen’s Kappa to compare perceived and verified BBV risk.
Results: Of 2,850 donor referrals, 1,727 were either not medically suitable or their family declined consent. Among the 1,123 remaining referrals, agreement between perceived and verified BBV risk occurred for 1,010 persons (934 baseline BBV risk; 75 active BBV infection; 1 past BBV infection) (Table 1). There was substantial agreement for any active BBV infection (Kappa=0.69, p value<0.001). Eight referrals perceived to have baseline risk were verified with active BBV infection (1 HIV; 3 HBV; 4 HCV). 15 active infections at referral (1 HIV; 4 HBV; 10 HCV) were not verified from linked health data.
Conclusions: Data linkage to existing administrative health data can aid assessment of donor referrals, revealing unrealised biovigilance risk to recipients and potential additional donor opportunities
DONOR REFERRALS WITH PRIMARY BRAIN TUMOUR – PERCEIVED VS. VERIFIED RISK
THOMSON Imogen1,2, HEDLEY James1,3, DE LA MATA Nicole1,3, ROSALES Brenda1,3, O’LEARY Michael4, CAVAZZONI Elena4, KELLY Patrick1,3, WYBURN Kate2,5, WEBSTER Angela1,3,6
1Centre for Organ Donor Evidence, University of Sydney, 2Sydney Medical School, Faculty of Health and Medicine, University of Sydney, 3Sydney School of Public Health, Faculty of Health and Medicine, University of Sydney, 4Other, NSW Organ and Tissue Donation Service, 5Renal Unit, Royal Prince Alfred Hospital, Sydney, 6Centre for Transplant and Renal Research, Westmead Hospital, Sydney
Introduction: In Australia, organ donation is not contraindicated for referred donors with most types of primary brain tumour (PBT). However, the perceived risk of transmission is based only on information available at referral, which may be incomplete or inaccurate.
Aims: We sought to determine the accuracy of perceived risk of PBT transmission at the time of referral compared to verified risk using linked-data.
Methods: We used organ donor referrals 2010-2015 from the NSW Biovigilance Register. This Register linked NSW organ donor referrals and transplant recipients to NSW Admitted Patient Data Collection and the Central Cancer Registry. We classified risk based on tumour type using the Transplant Society of Australia and New Zealand (TSANZ) guidelines. Perceived risk was determined from referral logs, with verified risk based on NSW Biovigilance register.
Results: We analysed 2,957 referrals for donation and identified 76 (3%) with PBT; 11 (14%) from referral logs, 5 (6%) from other health records, and 62 (79%) from both. The perceived risk agreed with verified risk in 45 referrals (59%), was overestimated in 19 (25%), and underestimated in 12 (16%). There was no difference in agreement based on donation outcome (p=0.8). Cohen’s Kappa was 0.39 suggesting fair agreement. All 10 (14%) actual donors were verified minimal risk with disagreement in 1 (9%) perceived low risk.
Conclusions: Assessment of PBT transmission risk cannot always be determined accurately at referral. Perceived risk is more frequently overestimated than verified risk, suggesting risk averse decision-making. Evidence based decision support may have a future role.
Figure 1: Perceived vs. verified risk for referrals with primary brain tumour by donation outcome
HBA1C AS A PREDICTOR OF POSTOPERATIVE KIDNEY COMPENSATORY HYPERTROPHY IN MALE LIVING DONORS
KOSUKE Tanaka1, KOHEI Kinoshita1, YUJI Hidaka1, MARIKO Toyoda2, AKITO Inadome3, ASAMI Takeda4, JUN Shoji5, SHIGEYOSHI Yamanaga1
1Department of Surgery, Japanese Red Cross Kumamoto Hospital, 2Department of Medicine, Japanese Red Cross Kumamoto Hospital, 3Urology, Japanese Red Cross Kumamoto Hospital, 4Department of Nephrology, Japanese Red Cross Nagoya Daini Hospital, 5Department of Nephrology, UCSF Connie Frank Transplant Center
Aims: Renal function of the remaining kidney in living donors recovers up to 60~70% of pre-donation estimated-glomerular filtration rate (eGFR). Degree of compensatory renal function recovery is related with chronic interstitial fibrosis and tubular atrophy (ci+ct) score and arteriolar hyalinosis (ah) score. We examined living donor characteristics to identify potential clinical predictors of chronic renal lesions and postoperative hypertrophy.
Methods: This was a single-center, retrospective analysis of 155 living donors. We reviewed 1-hour post-perfusion renal biopsies and divided the 155 donors into two groups; chronic change (CC) group (n=21) with ci+ct > 1 and ah > 1 as well as the rest of donors as a control group (n=134). We examined age, sex, tobacco use, blood pressure, HbA1c, aortic calcification index, BMI as possible predictive factors. The recovery rate of eGFR was measured at one year after surgery.
Results: Out of the 155 donors, 53 (34.2%) were male. There was a significant difference in HbA1c between the CC group and the control group in male donors (6.02±0.18 vs 5.7±0.54, p=0.032). Multivariate analysis also showed that HbA1c was significantly different for male donors (odds ratio 1.25 per 0.1%, p=0.039). Cut-off value of HbA1c was 6.05% (AUC 0.737, p=0.034). There was a higher recovery rate of eGFR among males whose HbA1c was lower than 6.05% (60.7±6.3% vs 53.6±7.4%, p=0.013)
Conclusions: Although HbA1c value may meet criteria for living donation, this may serve as a possible marker for the insufficient recovery of postoperative renal function.
COMBATING LOSS TO FOLLOW UP OF LIVING KIDNEY DONORS
GUO Henry, MCGINN Stella, LI Yan
Department of Nephrology & Transplantation, Royal North Shore Hospital, Sydney
Background: Whilst great efforts and resources are placed on identifying suitable living donors to minimize their future risk, there remains incomplete post donation follow up with little long-term data of living kidney donors in Australia.
Aim: To assess factors associated with loss to follow up post kidney donation at our transplant centre.
Methods: We conducted a single centre retrospective cohort study of living kidney donors between 2008 and 2018 at Royal North Shore Hospital, Sydney. Date of transplantation, date of last follow up, demographics, renal function and prevalence of cardiovascular risk factors were collected from medical records.
Results: Out of 98 donors, 60% were female, with 26% travelling from interstate or overseas to donate. The mean duration of follow up was 4.1 ± 2.9 years. Follow up rates were 76.3% and 42.7% at 1 and 5 years respectively. Tendency to follow up declined with younger age and increasing distance from our transplant centre. Follow up rates at 5 years did not differ between related, unrelated or altruistic donors. Of the donors still being followed up at 5 years, 28% had eGFR<60mL/min, 20% had hypertension and 67% had treated hypercholesterolemia.
Conclusions: Despite the risks associated with kidney donation, long term follow up remains poor. Future interventions should target improving long term follow up care for all living kidney donors.
IMPLEMENTATION OF INCREASED VIRAL RISK DONOR WAITING LIST IN VICTORIA – A USEFUL ADDITION TO THE DONOR POOL
LEE Darren1,2, SENG Nina3, GRAMNEA Indra3, HUDSON Fiona4, D’COSTA Rohit3, MCEVOY Leanne3, SASADEUSZ Joe5, GOPAL Basu6, KAUSMAN Joshua7, MASTERSON Rosemary8, PAIZIS Kathy2, KANELLIS John9, HUGHES Peter8, GOODMAN David10, WHITLAM John2
1Department of Renal Medicine, Eastern Health, Melbourne, 2Department of Nephrology, Austin Hospital, Melbourne, 3DonateLife Victoria, 4Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, 5Department of Infectious Diseases, Royal Melbourne Hospital, 6Department of Renal Medicine, Alfred Hospital, Melbourne, 7Department of Nephrology, Royal Children’s Hospital, Melbourne, 8Department of Nephrology, Royal Melbourne Hospital, 9Department of Nephrology, Monash Medical Centre, Melbourne, 10Department of Nephrology, St Vincent’s Hospital, Melbourne
Aims: Increased viral risk donors (IVRDs) with at-risk behaviours for blood borne virus infection and negative nucleic acid testing (NAT) have a low absolute risk of window period infection. A program allocating these kidneys to pre-consented recipients was recently implemented in Victoria. We reviewed the performance after seven months in operation.
Methods: We retrospectively compared the characteristics of IVRDs (defined by PHS 2013 criteria and open window periods) and non-IVRDs (31/07/2018-28/02/2019) and examined the serological and NAT results of IVRDs at donation and recipients post-transplant. Continuous data was expressed as median (IQR).
Results: 24.4% of waitlisted patients were pre-consented. Twelve IVRDs (23 kidneys) were utilised, comprising 13.5% of all kidneys transplanted. No suitable recipients were found for two IVRDs. Risk factors included intravenous drug use (58%) and increased risk sexual behaviour (42%). NAT was performed 3 (1-4) days after admission. Three IVRDs had abnormal serology results (2 HCV Ab positive, 1 HBcAb and HCV Ab positive) but negative NAT. Recipients of HCV Ab positive IVRDs seroconverted, but no viraemia was detected in recipients from all IVRDs to date. Compared with non-IVRDs (n=82), IVRDs were significantly younger (36 (29-43) versus 51 (36-60) years; P<0.01). Kidney donor profile index (KDPI) was significantly lower (21 (10-39) versus 60 (26-76); P<0.01), more likely ≤20 (50% versus 18%; P<0.05) and none had a KDPI >85 (0% versus 12%; P=0.35).
Conclusions: IVRDs appear to offer better quality kidneys from a historically under-utilised donor pool. Increasing the pre-consent rate may improve utilisation and benefit more waitlisted recipients.
CORRELATION AND AGREEMENT BETWEEN HLA-DRB AND HLA-DQ EPLET MISMATCHES BY LINKAGE DISEQUILIBRIUM AND HIGH-RESOLUTION HLA TYPING
LARKINS NG1,2, TAVERNITI A3, SHARMA A4,3,5, DE SANTIS D6, IRISH A7, CHAKERA A8,9,10, D’ORSOGNA L11,10, WONG G4,5,3, LIM WH9,10
1Department of Nephrology, Perth Children’s Hospital, 2School of Paediatrics and Child Health, University of Western Australia, Perth, 3Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, 4Department of Nephrology, Westmead Hospital, Sydney, 5School of Public Health, University of Sydney, 6Transplant Immunobiology Laboratory, Fiona Stanley Hospital, 7Department of Nephrology, Fiona Stanley Hospital, 8Translational Renal Research Group, Harry Perkins Institute of Medical Research, 9Department of Nephrology, Sir Charles Gairdner Hospital, Perth, 10School of Medicine & Pharmacology, University of Western Australia, Perth, 11Department of Immunology, Fiona Stanley Hospital
Aims: To determine the concordance and agreement of the HLA-DR and HLA-DQ eplet mismatches load calculated using common allelic haplotype association for HLA-DQA1 and DRB3/4/5 typing compared to high resolution typing for HLA-DRB1, DRB345, DQA1 and DQB1.
Methods: A retrospective cohort of 126 donor/kidney transplant recipient pairs in a single centre in Western Australia were included. Total number of eplet mismatches at HLA-DQ (HLA-DQA1+DQB1) and HLA-DR (HLA-DRB1+DRB3/4/5) were calculated using HLAMatchmaker from high-resolution typing (Next Generation Sequencer [NGS-typing]) across all alleles and from linkage disequilibrium (LD-typing) to assign HLA-DRB3/4/5 and HLA-DQA1 from HLA-DRB1 and HLA-DQB1 (LD-typing). Concordance and agreement between NGS-typing and LD-typing were determined.
Results: Of 126 donor/recipient pairs, 10 (8%) and 50 (40%) recipients were non-Caucasian and females, respectively. There were no Indigenous donors/recipients. The concordance coefficients for calculated HLA-DR+DQ eplet mismatches between the two methods was 0.997 (95%CI 0.996-0.998), with a tighter concordance for HLA-DQ>HLA-DR. The 95% limits of agreement contain 95% of the difference scores. The mean difference (bias) of the measurements between NGS-typing and LD-typing was 0.32 (95%CI 0.10 to 0.53). The SD of the difference was 1.22 and the width of the 95% limits of agreements was -2.08 (95%CI -2.46 to -1.71) to 2.72 (95%CI 2.34 to 3.09). There were 10 (8%) donor/recipient pairs with discordant results, of which 6 (5%) pairs had a difference of at least 5 eplet mismatches (see Table).
Conclusions: Allelic typing of HLA-DRB1 and DQB1 allows the assignment of HLA-DRB3/4/5 and DQA1 typing with a high degree of confidence in over 90% of donor/recipient pairs.
ABO INCOMPATIBLE LIVING DONOR KIDNEY TRANSPLANTATION IN AUSTRALIA AND NEW ZEALAND: A REPORT FROM THE ANZDATA REGISTRY
CLAYTON Philip1, DANSIE Kathryn2, CAMPBELL Scott3, COATES Toby1, COHNEY Solomon4, IERINO Frank5, IRISH Ashley6, ISBEL Nicole3, HUGHES Peter7, KANELLIS John8, LIM Wai9, MULLEY William8, PILMORE Helen10, RUSS Graeme1, TREVILLIAN Paul11, WONG Germaine12, WYBURN Kate13
1Central Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, 2Australia and New Zealand Dialysis and Transplant Registry (ANZDATA), South Australian Health and Medical Research Institute (SAHMRI), 3Department of Nephrology, Princess Alexandra Hospital, Brisbane, 4Department of Medicine, University of Melbourne, 5Department of Nephrology, St Vincent’s Hospital, Melbourne, 6Renal Unit, Fiona Stanley Hospital, 7Renal Unit, Royal Melbourne Hospital, 8Department of Nephrology, Monash Medical Centre, Melbourne, 9Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, 10Department of Renal Medicine, Auckland City Hospital, 11Department of Nephrology, John Hunter Hospital, Newcastle, 12Department of Renal Medicine, Westmead Hospital, Sydney, 13Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney
Aim: To describe outcomes of ABO incompatible (ABOi) living kidney donor (LKD) transplantation in Australia and New Zealand.
Methods: We included all LKD recipients in Australia/NZ over 2006-17 from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. Outcomes were overall and death-censored graft survival, patient survival, delayed graft function (DGF), time to first rejection and first antibody-mediated rejection (AMR), and estimated GFR (eGFR). We used adjusted Cox models to examine time-to-event data, chi-squared tests to compare proportions and a linear mixed model to compare eGFR.
Results: 3989 transplants met inclusion criteria and contained ABO data, of which 449 (11%) were ABOi. ABOi recipients were older (49 vs 45 years), with older donors (52 vs 50 years) who were more commonly receiving antihypertensives (13 vs 10%) and had more HLA mismatches. ABOi recipients received more B cell depletion at induction (24% vs <1%) and were more likely to receive tacrolimus at baseline (94% vs 69%). Death-censored graft survival for ABOi recipients was worse in the first month (hazard ratio (HR) 2.2, 95% CI 1.1-4.3) but not thereafter (HR 1.1, 95% CI 0.8-1.7) (figure). There was more rejection in the ABOi group driven by excess AMR (HR 2.0, 95% CI 1.5-2.7). There were no differences in overall graft survival or eGFR, and patient survival and DGF were similar.
Conclusion: ABOi recipients experienced more AMR and slightly worse death-censored graft survival in the first month post-transplant, but overall results were similar to ABO compatible recipients.
DEVELOPMENT OF DE NOVO HLA DONOR SPECIFIC ANTIBODIES AND ALLOGRAFT REJECTION POST BLOOD TRANSFUSION IN KIDNEY TRANSPLANT RECIPIENTS
JALALONMUHALI Maisarah1,2, CARROLL Robert1, CLAYTON Philip1, COATES Toby1
1Central Northern Adelaide Renal and Transplantation Service, Central Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, 2Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia
Aim: To look at the incidence of de novo HLA donor specific antibody (DSA) formation and the immediate allograft rejection post blood transfusion in highly immunosuppressed kidney transplant recipients (KTR).
Methods: KTR who had blood transfusion within 1 week of surgery at Royal Adelaide Hospital (RAH) between 2010 and 2018 were recruited. They received either basiliximab or ATG as an induction therapy, followed by tacrolimus (trough level 8-12 ng/mL), mycophenolate mofetil 1500 mg bd and prednisolone 30 mg od as maintenance therapy. HLA DSA positivity was determined by MFI of ≥ 500 as measured by Luminex xMAP™ technology. The test was performed between 2 weeks to 3-month post-transplant.
Results: A total of 706 patients underwent kidney transplant at RAH between 2010 and 2018 (8 patients were excluded from analysis – 2 had graft biopsy prior to blood transfusion, 6 with non-functioning graft (0.8%)). 203 (29%) patients received blood transfusion during 1 week perioperative period. Out of this, 134 patients needed transfusion within 48 hours. Mean age was 52.61 ± 13.29 with 110 (54.2%) patients were male. The perioperative hemoglobin was 111.12 ± 11.75 g/L and the lowest hemoglobin was 74.74 ± 9.55 g/L in the transfusion group. Table 1 illustrated the main outcome of blood transfusion.
Conclusions: Blood transfusion with immunosuppression cover was not associated with any significance impact on development of de novo HLA DSA and acute rejection. This has been illustrated in pediatric pre-kidney transplant blood transfusion with cyclosporine cover1.
1.Niaudet P et al. Pretransplant blood transfusions with cyclosporine in pediatric renal transplantation. Padiatr Nephrol. 2000 Jun; 14(6): 451-6.
1.Central Northern Adelaide Renal and Transplantation Services (CNART)
2.International Society of Nephrology (ISN)
RAPID REDUCTION OF DONOR-SPECIFIC ANTIBODIES IN SIMULTANEOUS LIVER-KIDNEY TRANSPLANTATION
NEWMAN Allyson1, LAI Sum Wing Christina1, ABOU-DAHER Frederika2, WALTON Duncan2, WATSON NARELLE2, MAWSON JANE1, WYBURN KATE1, CHADBAN STEVE1, GRACEY DAVID1
1Renal & Transplantation Unit, Royal Prince Alfred Hospital, Sydney, 2Australian Red Cross Blood Service
Background: Kidney transplantation performed in the presence of high-titre donor-specific antibodies (DSA) may result in hyper-acute or accelerated antibody-mediated rejection and graft loss. Previous studies have shown that this risk may be mitigated in cases of simultaneous liver-kidney transplantation (SLKT); however, the mechanisms are not well defined. Here we report the evolution of pre-formed, high level DSAs in two highly sensitised liver-kidney transplant recipients at various timepoints peri-operatively and describe a profound sustained depletion of all DSAs from the time of liver anastomosis.
Methods: HLA antibody samples were collected pre-operatively, and immediately post-liver and post-kidney revascularisation. HLA Matchmaker was used to assess HLA epitope and Complement Dependant Cytotoxicity (CDC) cross-matches were performed. Both patients received standard immunosuppression with Basiliximab and Methylprednisolone as induction therapy and Prednisolone, Mycophenolate and Tacrolimus as maintenance therapy.
Results: Both patients were highly sensitised with PRA up to 97%. One patient had positive B- and T-cell crossmatch pre-transplant. HLA antibodies rapidly reduced post-liver revascularisation and remained low. In particular, HLA antibodies associated with graft specific eplets showed greater reduction (Figure 1) and the observation was apparent with C1q result. Positive CDC crossmatches became negative within 3 hours post-liver revascularisation. Both patients maintained good graft function with no rejection on liver and kidney biopsies at 10 weeks post-transplant.
Conclusion: The reduction in DSAs occurred immediately post-liver revascularisation. These cases supports the hypothesis of the protective immunoregulatory mechanism of the liver in the setting of SLKT with no extra antibody removal treatment required peri-operatively for highly sensitised patients.
INCIDENCE AND OUTCOMES OF ANTIBODY MEDIATED REJECTION IN THE AUSTRALIAN AND NEW ZEALAND RENAL TRANSPLANT POPULATION
DANSIE Kathryn1, CLAYTON Philip2
1Australia and New Zealand Dialysis and Transplant Registry (ANZDATA), South Australian Health and Medical Research Institute (SAHMRI), 2Central Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital
Aim: To describe the incidence and outcomes of antibody mediated rejection (AMR) in the Australian and New Zealand renal transplant population.
Methods: Using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry, we included all antibody mediated rejection episodes for patients transplanted from 2005-2017. Incidence of AMR was calculated separately for less than and greater than 6 months following transplantation. Treatment regimens were examined through descriptive analysis and graft survival was observed from Kaplan-Meier curves.
Results: There were 1426 AMR cases for transplants conducted between 2005 and 2017, with an incidence rate of 12.87 rejections per 100 transplant years for less than 6 months following transplantation and 1.07 rejections per 100 transplant years for greater than 6 months following transplantation. A large variation in treatment regimens was observed (76 different treatment combinations) across 80 treating hospitals in Australia and New Zealand, with “steroids, plasmapheresis and intravenous immunoglobin”; “plasmapheresis and intravenous immunoglobin” and “steroids only” being most frequently employed (18.6%, 11.0% and 8.8% respectively). Median graft survival following primary AMR was 8 years which varied with response to treatment. Patients whose rejection episode resolved, with or without improvement of graft function, fared better than patients whose rejection episode did not resolve median survival for resolved: 8.5 years; not resolved: 0.04 years)(figure).
Conclusions: There is considerable variation in the treatment of AMR episodes in the Australian and New Zealand renal transplant population. Graft survival following AMR is greater for patients whose AMR episodes were completely or partially resolved.
IDENTIFICATION OF DONOR ANTI-HLA ANTIBODIES IN MULTIPLE TRANSPLANT RECIPIENTS
HIHO Steven1,2, KUMMROW Megan2, LEVVEY Bronwyn3, SULLIVAN Lucy4,5, WESTALL Glen1, SNELL Greg1
1Lung Transplant Unit, Alfred Hospital, Melbourne, 2Transplantation Laboratory, Australian Red Cross Blood Service, 3Lung Transplant Service, Alfred Hospital, Melbourne, 4Department of Microbiology, University of Melbourne, 5Department of Microbiology, Doherty Institute
Monitoring for anti-HLA antibodies post-transplant is an important tool in early detection of rejection episodes and may direct clinical treatment therapies. We recently reported a case of the passive transfer of HLA antibodies in all organ recipients from a cadaveric donor. These anti-HLA antibody profiles were not directed towards donor HLA, but matched the donors HLA antibody profile. Here we describe this and another case and the clinical management used.
Method: Patient and donor HLA antibody testing was performed with Luminex single antigen beads (One Lambda) with a MFI cut-off of 1000. HLAMatchmaker (V2.1) was used for eplet analysis, and HLA typing was performed using Luminex LABType (One Lambda) for recipients and donors.
Results: The HLA class I antibody specificities were identified to be directed at the 65GKA & 166ES eplets and were identified in all organ recipients of each donor and were not Donor Specific Antibodies (DSAs). Pregnancy and sensitising history of donors were unable to be confirmed but donor antibody profiles suggest at least one sensitising event. Lung recipients had normal lung function at 8 and 12 months post-transplant, however one patient died of pancreatitis (with normal lung function).
Conclusion: We suggest that donor B cells, were passengers with the transplanted organs, and appear to be a variant of Passenger lymphocyte syndrome (PLS) that may complicate the post-transplant treatment and identification of DSA. Further studies are continuing to identify cases and confirm origin of these antibodies.
IN VITRO EXPANSION OF IL-10-COMPETENT HUMAN B CELLS
PERKINS Griffith1, COATES Toby2,3, HURTADO Plinio2,3
1School of Biological Sciences, University of Adelaide, 2School of Medicine, University of Adelaide, 3Renal Unit, Royal Adelaide Hospital
Aim: To develop a system for expanding IL-10-competent B cells from human peripheral blood.
Methods: Transitional, naïve and memory B cell populations were isolated by fluorescence-activated cell sorting based on differential expression of CD24 and CD38. Cells were expanded for 7 days by co-culture with CD40-ligand-expressing NIH3T3 cells plus IL-4 and/or IL-2. Fold-expansion of CD19+ cells was enumerated at Day 7, and IL-10 concentrations in supernatants were measured at 24-hour intervals by ELISA. Thirty immunomodulatory factors were investigated for their capacity to induce IL-10-competence and secretion in the expanded populations, where ‘competence’ is quantified by the amount of IL-10 secreted per cell after 5-hours of PMA/ionomycin-driven cytokine production.
Results: CD24hiCD38hi (transitional), CD24intCD38int (naïve), and CD24hiCD38neg (memory) populations expanded on average 3-4-fold over 7-days and secreted detectable amounts of IL-10 during expansion, peaking around Day 7. In all expanded populations, the combination of CpG-B (2.7µg/mL) and IFN-α and/or IFN-β (2,000-50,000U/mL) induced the greatest IL-10 secretion into supernatants. Expanded transitional cells demonstrated the greatest IL-10 competence following CpG/IFN-α/β treatment, and secreted more IL-10 when expanded with IL-2 and IL-4, compared with IL-2 or IL-4 alone. Expanded transitional cells produced more IL-10 than non-expanded transitional cells similarly treated with CpG/IFN-α/β.
Conclusion: We compare, for the first time, the capacity of expanded transitional, naïve and memory B cells to produce IL-10, and report a reproducible cell culture system for expanding IL-10-competent B cells from human transitional B cells, which will facilitate the study of their potential therapeutic use in transplantation to promote immune tolerance.
EXPRESSION OF DONOR MHC CLASS I IN RECIPIENT HEPATOCYTES DOES NOT INDUCE LINKED SUPPRESSION TO H-Y
LEONG Mario1, PAUL-HENG Moumita1, WANG Chuanmin1, SON Taeyoung1, BERTOLINO Patrick2, BISHOP Alex1, BOWEN David1,3, SHARLAND Alexandra1
1Transplantation Immunobiology Group, Central Clinical School, Faculty of Medicine and Health, University of Sydney, 2Royal Prince Alfred Hospital and University of Sydney, 3AW Morrow Gastroenterology & Liver Centre, Royal Prince Alfred Hospital and University of Sydney
Background: Expression of allogeneic MHC I by recipient hepatocytes results in tolerance to subsequent skin grafts expressing the same mismatched MHC allele. To determine whether tolerance to allogeneic MHC I could induce linked suppression to minor antigen mismatches, we examined responses to the minor antigens H-Y in association with the allogeneic MHC I allele H-2Kd.
Methods: Female B6.Kd or C57BL/6 mice inoculated with AAV-Kd 5x1011 vgc received skin grafts from female C57BL/6, female B6.Kd or male B6.Kd donors. Graft survival and Kd expression were monitored.
Results: Tolerance to female B6.Kd skin was achieved in all AAV-Kd treated female C57BL/6. Conversely, Kd treated female C57BL/6 mice receiving simultaneous grafts of male and female skin rejected both grafts (MST 16.2 d and 27.3 d). Kd-tolerant female mice rejected secondary female and male B6.Kd grafts with similar tempo (MST 22 d and 24 d) and tolerance to the original female B6.Kd skin grafts was also broken. Kd expression in all recipient livers persisted despite skin graft rejection. Female B6.Kd mice receiving simultaneous male and female B6.Kd skin grafts also rejected 50% of the syngeneic female grafts (MST 32.5 d) suggesting that a bystander effect may be responsible for female graft destruction.
Conclusions: Expression of Kd in C57BL/6 hepatocytes does not induce linked suppression to H-Y. In C57BL/6 mice, two class I H-Y epitopes are known. Co-expression of these as single chain trimers (Db-HY) may synergise with Kd heavy chain to induce tolerance across the sex-mismatch in this stringent skin graft model.
THE SELF-PEPTIDE REPERTOIRE PLAYS A CRITICAL ROLE IN TRANSPLANT TOLERANCE INDUCTION
SON Eric1, PAUL-HENG Moumita1, LEONG Mario1, FARIDI Pouya2, MIFSUD Nicole2, ALEXANDER Ian3,4, BERTOLINO Patrick5, PURCELL Anthony2, BOWEN David1,5, SHARLAND Alexandra1
1Transplantation Immunobiology Group, Central Clinical School, Faculty of Medicine and Health, University of Sydney, 2Department of Biochemistry and Molecular Biology, Monash University, Melbourne, 3Gene Therapy Research Unit, Children’s Medical Research Institute, University of Sydney, Faculty of Medicine and Health and Sydney Children’s Hospitals Network, 4Discipline of Child and Adolescent Health, the University of Sydney, Sydney Medical School, 5AW Morrow Gastroenterology & Liver Centre, Royal Prince Alfred Hospital and University of Sydney
Background: Donor-specific tolerance can be induced by adeno-associated viral vector (AAV) mediated expression of donor MHC-I heavy chains (HC) in the recipient liver. Tolerance induction depends upon direct recognition of intact donor MHC-I. The role of the hepatocyte endogenous peptide repertoire in tolerance induction is unknown.
Methods: To express high levels of donor class I while excluding binding of naturally-processed endogenous peptides, we engineered AAV vectors expressing a single-chain trimer (SCT) of β2-microglobulin, MHC heavy chain and a defined peptide sequence (KIITYRNL or SIINFEKL). B10.BR or B10.BR-RAG mice reconstituted with Des-RAG cells (which recognise the Kb-KIITYRNL epitope), were inoculated with either Kb, SCT-Kb_KIITYRNL or SCT-Kb_SIINFEKL vectors, then challenged with Kb-bearing skin grafts. The Kb immunopeptidomes of liver, skin and spleen were determined using mass spectrometry and self-peptides were screened by tetramer binding (Figure).
Results: B10.BR-RAG mice reconstituted with Des-RAG cells accepted Kb-bearing skin grafts indefinitely when transduced with SCT-Kb_KIITYRNL but rejected grafts with a MST of 20 days after inoculation with SCT-Kb_SIINFEKL (p<0.0005). Conversely, while inoculation of B10.BR mice with AAV-Kb induced tolerance, treatment with either SCT-Kb vector only prolonged graft survival by a few days (p<0.0005). From a pilot pool of self-peptides, we identified one immunodominant peptide recognized by 27% of activated alloreactive CD8+ T cells, and two subdominant peptides. Screening is ongoing.
Conclusions: Self-peptides play a critical role in tolerance induction. Identification of individual pMHC epitopes is feasible using mass spectrometry and multimer staining. These findings have broad implications for allorecognition and transplant tolerance induction.
Transplant Outcomes and Complications
RISK FACTORS FOR ADVANCED COLORECTAL NEOPLASIA IN KIDNEY TRANSPLANT RECIPIENTS
AU Eric HK1,2, HOWARD Kirsten1, CHAPMAN Jeremy R3, CASTELLS Antoni4,5, ROGER Simon6, BOURKE Michael J7, MACASKILL Petra1, TURNER Robin1,8, WILLIAMS Gabrielle1, LIM Wai H9, LOK Charmaine E10, DIEKMAN Fritz11, CROSS Nicholas12, SEN Shaundeep13, ALLEN Richard DM14, CHADBAN Steven J14,15, POLLOCK Carol A16, TONG Allison1,2, TEIXEIRA-PINTO Armando1,2, YANG Jean YH17, WILLIAMS Narelle1,2, KIEU Anh1,2, JAMES Laura1,2, CRAIG Jonathan18, WONG Germaine1,2,3
1School of Public Health, University of Sydney, 2Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, 3Centre for Transplant and Renal Research, Westmead Hospital, Sydney, 4Gastroenterology Department, Hospital Clinic, Hospital Clinic, University of Barcelona, 5University of Barcelona,, 6Department of Renal Medicine, Gosford Hospital, 7Department of Gastroenterology, Westmead Hospital, Sydney, 8Biostatistics Unit, Dunedin School of Medicine, University of Otago, 9Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, 10Faculty of Medicine, University of Toronto, 11Department of Nephrology and Kidney Transplantation, Hospital Clinic, Barcelona, Spain, 12Department of Nephrology and Kidney Transplantation, Christchurch Hospital and University of Otago, 13Department of Renal Medicine, Concord Repatriation General Hospital, 14Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney, 15Charles Perkins Centre, University of Sydney, 16Department of Medicine, Northern Clinical School, Kolling Institute of Medical Research, 17School of Mathematics and Statistics, University of Sydney, 18College of Medicine and Public Health, Flinders University
Background: The incidence of colorectal cancer is over 1.5-times higher in kidney transplant recipients than the general population, but the risk factors are poorly understood.
Aim: To identify risk factors for developing advanced colorectal neoplasia in kidney transplant recipients.
Methods: Kidney transplant recipients across eleven sites in Australia, New Zealand, Canada and Spain were screened for colorectal neoplasm using faecal immunochemical test (FIT) as part of the DETECT study (n=1706) on screening using FIT across all CKD stages. Advanced colorectal neoplasia were confirmed through a 2-step process with colonoscopies performed for positive FIT and 2-years follow-up for all patients. Potential risk factors for advanced colorectal neoplasia were assessed using multivariable logistic regression.
Results: A total of 497 transplant recipients (63% male, median age 54.3 years) received FIT screening. Of these, 96 (19.3%) had colonoscopy for positive FIT and 28 advanced colorectal neoplasia were identified (detection rate 5.6 %). One patient with negative FIT was diagnosed with advanced colorectal neoplasia during 2-year follow-up. Factors associated with advanced colorectal neoplasia included male sex [Odds ratio 4.5 (95% CI 1.5-13.4)], older age [1.2 per 5-year increase (1.0-1.5)] and anticoagulant use [5.0 (1.6-15.6)]. The number of acute rejection episodes [0.38 (0.15-0.96)] and mycophenolate mofetil (MMF) use [0.36 (0.16-0.84)] were associated with lower odds of advanced colorectal neoplasia.
Conclusion: Older age, male sex, and anticoagulant use were independent predictors for advanced colorectal neoplasia in transplant recipients. Prior acute rejection episodes and users of MMF may be associated with lower risk for colorectal neoplasia.
CANCER TRANSMISSION FROM DECEASED ORGAN DONORS WITH PRIOR CANCERS
PHILLIPS Jessica1, WONG Germaine2, AU Eric2, MCDONALD Stephen3, CHAPMAN Jeremy2, OPDAM Helen4, MCDONALD Mark5, PILMORE Helen6, KANELLIS John7, LIM Wai8
1Renal Medicine, Sir Charles Gairdner Hospital, Perth, 2Westmead Hospital, Sydney, 3Royal Adelaide Hospital, 4Austin Hospital, Melbourne, 5Organ Transplant Australia, 6Auckland City Hospital, 7Monash Medical Centre, Melbourne, 8Sir Charles Gairdner Hospital, Perth
Aims: We aimed to describe the characteristics of deceased organ donors with prior cancers and the outcomes of kidney transplant recipients who received kidneys from donors with prior cancers or were reported to have lost their grafts/died from donor cancers.
Methods: The study included all actual donors with prior cancers recorded in the ANZOD registry between 1989-2017. Donor cancer characteristics and rate of donor-transmitted cancer are described. The characteristics of recipients of kidneys from donors without prior cancers but were recorded to have lost their grafts/died from donor cancer are also described.
Results: Of 259 actual donors with a prior cancer history, kidneys from 197(76%) donors were transplanted into 366 recipients. The most common cancer type was non-melanoma skin cancers(30%), followed by gynaecological cancers(16%), brain cancers(9%), melanoma, breast and prostate cancers(all 7%). The median(IQR) time from cancer diagnosis to donation was 6.5(0.8-14.8)years. Of the 366 recipients who have received kidneys from donors with cancers, 5(1.4%) were recorded as experiencing graft loss from donor cancer, with 1 developed cancer in the allograft 255-days post-transplant(Table). There were 12 recipients from 10 donors without prior cancer history recorded as experiencing graft loss from donor cancer, with 2 cases of melanoma (same donor) detected in the allografts at 12-months post-transplant. Data relating to the ascertainment of donor-transmitted cancer were not collected.
Conclusion: There appears to be a low-rate of donor cancer transmission but the establishment of structured reporting to collect more detailed/accurate records of donor cancer history and characteristics of donor-transmitted cancers is required.
VALIDATION OF THE METROTICKET 2.0 MODEL FOR 5-YEAR HCC SPECIFIC SURVIVAL IN AN AUSTRALIAN LIVER TRANSPLANT COHORT
STOKLOSA Ted1, SANTHAKUMAR Cositha1, FERNANDES Brian1, PERERA Nadia1, HU Xinxin1, TATIANA Tsoutsman1, LIU Ken1,2,3, MCCAUGHAN Geoffrey1,2,3, STRASSER Simone1,2, MAJUMDAR Avik1,2
1Department of Gastroenterology, Royal Prince Alfred Hospital, Sydney, 2University of Sydney, 3Centenary Institute of Cancer Medicine and Cell Biology, Sydney
Background: Predicting the prognosis of patients with hepatocellular carcinoma (HCC) who undergo liver transplant (LT) is complex. The Metroticket 2.0 model (1) has recently been described to predict HCC-specific survival. We aimed to evaluate this model in an Australian context.
Methods: All adult patients who underwent LT for HCC between 01/01/1998 and 15/03/2014 at our centre were included (N=182). Milan and Metroticket 2.0 criteria were compared to predict post LT five-year HCC-specific survival (5Y-HSS). Data were collected at waitlisting and at the time of last imaging prior to LT.
Results: Hepatitis C was the most common aetiology (55%) and 128 (70%) had prior locoregional therapy. Median post LT follow-up was 7.2 [IQR 5.0- 11.1] years. 59 (32%) patients died with 14 due to HCC recurrence. At waitlisting, 180/182 (99%) were within Milan, 179/182 (98%) within Metroticket 2.0. 5-year overall survival was 77%. At waitlisting, Metroticket 2.0 predicted median 5YHSS was 95% (IQR 93%-98%), similar to the observed 5Y-HSS of 93% (Figure 1a). Prior to LT (median time last imaging and LT was 1 month [1-2]), there was a difference in 5Y-HSS for patients outside Metroticket 2.0, unlike Milan criteria (Figure 1b&c). The sensitivity and specificity for 5Y-HSS were respectively: Metroticket 2.0; 98% and 17%, Milan; 96% and 17%. The positive and negative predictive values were respectively: Metroticket 2.0; 94% and 33%, Milan; 94% and 22%.
Conclusions: Metroticket 2.0 predicted 5Y-HSS is similar to observed outcomes. The Metroticket 2.0 model has better discriminatory value for 5Y-HSS prior to LT compared with Milan.
Mazzaferro, et al. Gastroenterology. 2018;154(1):128-39.
METASTATIC ROUND CELL SARCOMA IN A RENAL TRANSPLANT RECIPIENT
SHETTIGAR Reshma1, PUTT Tracey2, SCHOLLUM John2, WALKER Robert2
1Department of Renal Medicine, Dunedin Public Hospital, 2Department of Nephrology, Dunedin Public Hospital
57-year-old male, end stage renal failure due to polycystic kidneys, underwent deceased donor renal transplantation. Patient received standard induction immunosuppression with basiliximab and maintainence immunosuppression of mycophenolate, tacrolimus and prednisone. 6 months post transplant patient noticed a lump about 4 cm in diameter on the medial side of the lower end of his thigh. Ultrasound showed that this mass was arising from the Sartorius muscle. He further underwent a biopsy of this mass, which showed un-differentiated round cell sarcoma. Staging CT scan did not show any evidence of metastatic disease. It was decided patient would have radiation therapy followed by surgical removal of sarcoma. A week prior to surgery, he presented with severe back pain and epistaxis. Blood test revealed thrombocytopenia with platelet count of 9* 109/litre. CT scan showed several metastatic lesions in lumbar spine and femur and lungs. Patient was deemed to unwell to tolerate chemotherapy. Patient was managed with platelet transfusion and analgesia with a plan to offer radiation therapy for pain. Patient passed away 2 weeks later.
Discussion: Sarcomas are rare and heterogeneous group of aggressive malignant tumors of mesenchymal origin that make up less than 1% of adult malignancies. Unlike Kaposis sarcoma, which is associated with immunosuppression, round cell sarcoma has never been reported in renal transplant recipient. Role of immunosuppression contributing to the genesis and progression of the tumor is unknown. Despite treatment with aggressive chemotherapy and radiation therapy, prognosis with metastatic round cell sarcoma is extremely poor.
RAPIDLY PROGRESSIVE METASTATIC ADENOCARCINOMA OF UNKNOWN PRIMARY 2 MONTHS FOLLOWING DECEASED DONOR RENAL TRANSPLANTATION, RECIPIENT OR DONOR DERIVED – A CASE REPORT
MCMICHAEL Lachlan1,2, CARROLL Robert1
1Central Northern Adelaide Renal and Transplantation Service, Central Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, 2Discipline of Medicine, University of Adelaide
Background: Malignancy is the most common cause of death with a functioning graft but is rarely encountered within the first-year post-transplantation. Differentiating donor versus recipient derived malignancies remains a clinical challenge with significant clinical implications if incorrectly identified.
Case Report: 72-year-old man with a background history of end-stage renal failure secondary to diabetic kidney disease, ischaemic heart disease, hypertension and type 2 diabetes mellitus. Underwent deceased donor renal transplantation from a 66-year-old female donor with a background history of chronic pancreatitis, hypertension and diabetes mellitus. Day 54 post-transplant admitted for further investigation of deranged liver function tests. Initial investigations included upper abdominal ultrasonography and magnetic resonance cholangiopancreatography identifying diffuse heterogenous change of the liver parenchyma. Liver biopsy was performed identifying invasive adenocarcinoma. Immunohistochemistry consistent with an upper gastrointestinal tract adenocarcinoma with strong staining for CK19 and CK7, weak CK20 staining and negative staining for Hepar-1, TTF-1 and CDX2. Given the rapidity of onset and donor history of chronic pancreatitis further evaluation for a donor derived malignancy was performed including tissue karyotyping, fluorescence in situ hybridization (FISH), CA 19-9 tumour markers on stored donor/recipient sera and formal DNA sequencing of the malignant tissue. Testing was consistent with a recipient-derived malignancy.
Conclusions: Development of malignancy within the acute period following transplantation is a rarely described entity. Appropriate investigation to identify whether the malignancy is recipient or donor derived remains an important process to ensure appropriate management of the recipient affected and recipients of other organs from the same donor.
COLONIC MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA IN A KIDNEY TRANSPLANT RECIPIENT
MARTIN Kylie1, TAYLOR Andrew2, TAM Constantine3, HILL Prue4, MACHET David5, GOODMAN David1
1Department of Nephrology, St Vincent’s Hospital, Melbourne, 2Department of Gastroenterology, St Vincent’s Hospital, Melbourne, 3Department of Haematology, St Vincent’s Hospital, Melbourne, 4Department of Anatomical Pathology, St Vincent’s Hospital, Melbourne, 5Anatpath
Case: We describe a case of a 62-year-old male with colonic extra-nodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) 14 years after kidney transplantation. Colonoscopy following a positive faecal occult blood test identified MALT lymphoma in 1 of 3 sessile sigmoid polyps. A clone on bone marrow biopsy had the same peripheral blood flow cytometric characteristics as seen on peripheral blood flow cytometry and immunoprofile of the colonic MALT lymphoma. Positron Emission Tomography scan was negative for other sites of disease. Gastric biopsy showed mild chronic gastritis with focal intestinal metaplasia with no evidence of Helicobacter pylori (H. pylori). However his H.pylori IgG was positive. He received H.pylori eradication treatment and is being managed expectantly. Immunosuppression was unchanged with prednisolone, mycophenolate mofetil and cyclosporine A with stable renal allograft function.
Discussion: MALT lymphoma is rare in the solid-organ transplant recipient. MALT lymphoma It is most commonly found in the gastrointestinal tract. Colonic involvement is found in only 2.5% of cases. Although complete remission occurs in 70-80% of localised gastric MALT lymphoma cases after H.pylori eradication, there is no standardised therapy for extra-gastric sites. This case highlights the importance of histopathological diagnosis of colonic lesions in immunosuppressed solid-organ transplant recipients and consideration of conservative management in extra-gastric MALT lymphoma as MALT lymphoma in the immunosuppressed solid organ-transplant recipient does not appear to be clinically aggressive and behaves like MALT lymphoma in the immunocompetent patient.
INCIDENCE AND PREDICTORS OF INFECTIOUS-RELATED MORTALITY IN RECIPIENTS OF A KIDNEY TRANSPLANT: A REGISTRY STUDY
CHAN Samuel1,2,3,4, PASCOE Elaine Mary2,3,4, CLAYTON Philip Andrew1,5,6, MCDONALD Stephen Peter1,5,6, LIM Wai Hon1,7, SYPEK Matthew Peter1,5,6, PALMER Suetonia Cressida8, ISBEL Nicole Maree9,3, FRANCIS Ross Simon9,3, CAMPBELL Scott Bryan1,9,3, HAWLEY Carmel Mary1,9,3,4, JOHNSON David Wayne1,9,3,4
1ANZDATA, 2Princess Alexandra Hospital, Brisbane, 3Australasian Kidney Trials Network, University of Queensland at the Princess Alexandra Hospital, 4Translational Research Institute, University of Queensland at the Princess Alexandra Hospital, 5Central Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, 6School of Medicine, University of Adelaide, 7Sir Charles Gairdner Hospital Unit, University of Western Australia, Perth, 8Department of Medicine, University of Otago, Christchurch, New Zealand, 9Department of Nephrology, Princess Alexandra Hospital, Brisbane
Background: The burden of infectious disease is high among kidney transplant recipients due to concomitant immunosuppression. In this study, the incidence of infectious-related mortality and associated factors were evaluated.
Methods: In this registry-based retrospective, longitudinal cohort study, recipients of a first kidney transplant in Australia and New Zealand between 1997-2015 were included. Cumulative incidence of infectious-related mortality was estimated using competing risk regression (using non-infectious mortality as a competing risk event), and compared with age and sex-matched populated-based data using standardised incidence ratios (SIR).
Results: Among 12,519 patients, (median age 46yrs, 63% male, 15% persons with diabetes, 6% Indigenous), 416 (3.3%) died from infection. Infection-related mortality reduced over time from 15.6 per 100,000-person-years in 1997-2000 to 4.7 per 10,000-person-years in 2011-2015 (p<0.001). Compared with the age-matched general population, kidney transplant recipients had a markedly higher risk of infectious-related death (SIR 7.8, 95%CI 7.1-8.6). Infectious mortality was associated with older age (≥60yrs adjusted subdistribution hazard ratio [SHR] 4.16, 95%CI 2.15-8.05; reference 20-30yrs;), female sex (SHR 1.62, 95%CI 1.19-2.29), Indigenous ethnicity (SHR 2.87, 95%CI 1.84-4.46; reference Caucasian), earlier transplant era (2011-2015 SHR 0.39, 95%CI 0.20-0.76; reference 1997-2000), and use of T-cell depleting therapy (SHR 2.43, 95%CI 1.36-4.33). Live donor transplantation was associated with lower risk of infectious-related mortality (SHR 0.53, 95%CI 0.37-0.76).
Conclusions: Infectious-related mortality in kidney transplant recipients is significantly higher than the general population, but has reduced over time. Risk factors include older age, female sex, Indigenous ethnicity, T-cell depleting therapy and deceased donor transplantation.
DOES EARLY REMOVAL OF URETERIC STENT SIMULTANEOUSLY WITH INDWELLING URETHRAL CATHETER POST KIDNEY TRANSPLANTATION REDUCE INFECTION RATES AND HEALTHCARE COSTS?
TRAPNELL FRANK1, HEIN Martin1, MOU Lingjun2, JAQUES Bryon2,1, BOUDVILLE Neil3,1, CHAKERA Aron3,1, HE Bulang2,1
1School of Medicine, Faculty of Health Sciences, University of Western Australia, Perth, 2Renal Transplant Unit, Sir Charles Gairdner Hospital, Perth, 3Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth
Aim: Ureteric stents have proven efficacy in reducing major urological complications (MUCs) when inserted prophylactically during kidney transplantation. However, ureteric stents are associated with an increased risk of UTIs and require an additional procedure for removal. It is theorised that an earlier stent removal time may reduce UTI risk whilst still protecting against MUCs. This research aims to investigate if early ureteric stent removal at 4-5 days post-transplantation results in a significant reduction in UTIs and health care costs, without a significant increase in MUCs.
Methods: This is a single centre prospective study, with a retrospective control group. The control group has received a kidney transplant within the past 2 years, and had their ureteric stents removed 4-6 weeks post transplantation with cystoscopy. The prospective group will have their ureteric stents removed 4-5 days post-transplantation using a non-cystoscopic traction technique (Figure 1) aiming for a 20% UTI reduction. Both cohorts will consist of 80 participants with a 12 month follow up.
Results: Preliminary data from 14 early removal participants and 35 control participants demonstrates significantly lower UTI rates in the prospective early removal group (0% vs 36%, p=0.01). Thus far, one ureteric stenosis and one urine leak has been recorded in the control group and zero in the early removal group. Estimated savings of $713AUD per case have been achieved.
Conclusion: Preliminary data demonstrates that early non-cystoscopic ureteric stent removal may reduce the incidence of UTIs and reduce costs without increasing the risk of urological complications.
Figure 3. Non-cystoscopic traction technique for ureteric stent removal in prospective early removal group.
CRYPTOCOCCUS INFECTION IN RENAL TRANSPLANT RECIPIENTS: A CASE CONTROL STUDY
ZAHOROWSKA Beata1, CHEN Sharon CA2, KABLE Kathryn3, NANKIVELL Brian J3
1Renal Unit, Liverpool Hospital, 2Department of Infectious Diseases, Westmead Hospital, Sydney, 3Renal & Transplantation Unit, Westmead Hospital, Sydney
Background: Renal transplant recipients have among the lowest incidence of invasive fungal infections compared with other solid organ transplants, however where fungal infection does occur Cryptococcus infection predominates and is associated with significant morbidity and mortality. We undertook to investigate the risk factors for Cryptococcus infection in renal and renal and pancreas transplant recipients.
Methods: A retrospective, matched case control analysis of Cryptococcus infection cases occurring between June 2005 and June 2017 post transplantation at our centre was performed.
Results: 24 cases of Cryptococcus infection post renal transplant were analysed with 2:1 control transplant recipients. Tacrolimus level and prednisone dose were identified as risk factors for Cryptococcus infection in this population (p=0.038 and p=0.019, respectively) and Cryptococcus infection was significantly associated with the outcome of death or graft loss at 12 months (odds ratio 4.53 [95% CI 1.15-14.89]). A novel finding of increased case diagnosis in Australian spring months was observed.
Conclusion:Cryptococcus infection risk factors confirmed in this study can be used to inform clinical practice of immunosuppression management and guide further research into Cryptococcus screening and potential prophylaxis design.
A CASE OF MALAKOPLAKIA MIMICKING MALIGNANCY IN A RENAL TRANSPLANT PATIENT
SRINIVASA Vinay, GOVINDARAJULU Sridevi
Department of Nephrology, Darling DOwns Hospital and Health Services
Introduction: Malakoplakia is a rare granulomatous disease, occurring in immunocompromised patients. It is associated with immunosuppression in solid organ transplantation, particularly with kidney transplantation.
The true incidence of this condition is not known. 700 cases have been reported in the literature. Over 40 of these patients are kidney transplant patients. In Australia, 8 cases of malakoplakia have been described in the literature; only 2 cases including ours, reported bladder involvement.
Case Presentation: A 53-year-old male, renal transplant recipient, on standard triple immunosuppressive therapy, presented to clinic with frank macroscopic haematuria and history of two episodes of urinary tract infection in 3 months. Other positive history included sigmoid diverticulitis necessitating antibiotic treatment 3 months ago. His background renal disease was Autosomal Dominant Polycystic Kidney Disease.
Bladder ultrasound and abdominal CT confirmed a suspicious mass in the sigmoid colon and bladder. Primary malignancy of sigmoid colon with urinary bladder invasion and metastases was suspected. PET reported a FDG avid mass involving the sigmoid colon invading into the bladder. An enlarged FDG avid portocaval lymph node was observed. Colonoscopy showed no endoluminal mass within the sigmoid colon. Cystoscopy and biopsy followed. Surprisingly, histology revealed Michaelis-Guttman bodies typical of Malakoplakia. The patient underwent high anterior resection of rectum and resection of the colovesical fistula.
Conclusion: Malakoplakia is a rare granulomatous disorder associated with standard immunosuppressive therapy in transplant patients. Clinical presentation may mimic malignancy and awareness of this condition is important.
SUCCESSFUL KIDNEY TRANSPLANTATION OF A HEPATITIS B SURFACE ANTIGEN MUTANT POSITIVE DONOR TO A HEPATITIS B NEGATIVE RECIPIENT
WILSON Gregory1,2, FRANCIS Ross1,2
1Department of Nephrology, Princess Alexandra Hospital, Brisbane, 2School of Medicine, University of Queensland, Brisbane
Background: The use of kidney donors with active hepatitis B (HBV) infection into uninfected recipients is typically contraindicated except in exceptional circumstances. HBV serology is mandatory in all donors however this may not detect HBV surface antigen mutant infections.
Case Report: We describe the case of a HBV negative, 30-year-old male who received a deceased donor kidney transplant from a 64-year-old donor with occult HBV surface antigen mutant infection (negative HBV sAg, low level HBV viraemia (62 IU/mL)). The recipient was highly sensitised (cPRA 99%), and had been on the deceased donor list for several years with no offers. The transplant had significant immunological benefits with 2 HLA mismatches and no donor specific antibodies. He had previously been immunized against HBV but at time of transplantation did not have detectable HBV sAb.
A 2-into-1 kidney transplant was performed with informed consent including the very high likelihood of HBV transmission. He received standard induction and maintenance immune suppression. He was commenced on entecavir immediately following his transplant and HBV immunoglobulin (400 IU) was administered at time of transplantation, daily for 1 week, then weekly for 4 weeks. HBV DNA PCR was routinely tested and remains negative at 6 months. Allograft function remains stable (serum creatinine 197 µmol/L).
Conclusion: We report the case of a kidney transplant from a donor with an active HBV surface antigen mutant infection into an uninfected recipient. This case highlights the importance of prospective HBV NAT testing for deceased organ donors – even if HBV sAg is negative.
ATYPICAL HAEMOLYTIC URAEMIC SYNDROME POST-TRANSPLANTATION
SO Sarah, SPICER Timothy
Renal Unit, Liverpool Hospital
Case: A 72-year-old lady, seven months post-renal transplant for polycystic kidney disease, was admitted with diarrhoea and acute kidney injury. Her creatinine was 250 umol/L (baseline 150 umol/L) and haemoglobin 106 g/L. Stool cultures and CMV PCR were negative. Immunosuppression included Prednisone 12.5 mg daily, Sirolimus 4 mg daily and Tacrolimus 5 mg twice daily (intolerant of Mycophenolate due to leukopaenia). After one week, she developed recurrent episodes of pulmonary oedema and creatinine rose from 271 to 500 umol/L over 72 hours, requiring CVVHDF. She developed microangiopathic haemolytic anaemia with a haemoglobin drop to 79 g/L, thrombocytopaenia (84x10^9/L), and fragments on blood film. At D12, Sirolimus was ceased, Prednisone increased and Mycophenolate recommenced. Differentials included acute rejection, thrombotic thrombocytopaenic purpura or haemolytic uraemic syndrome. Repeat stool cultures were negative. ADAMTS13 level normal (18%). Tacrolimus was ceased at D23. At D26, she commenced intravenous methylprednisolone to empirically treat rejection and received her first dose of eculizumab for possible aHUS. A renal biopsy subsequently demonstrated acute tubular necrosis. Renal function improved and dialysis was ceased at D37. Tacrolimus was recommenced at D51 without further haemolysis. At discharge, her creatinine was 140 umol/L and she remains on fortnightly eculizumab.
Conclusions: This case demonstrates post-transplant aHUS in a patient being treated with combined mTOR and calcineurin inhibitors. Combination treatment may be higher risk for causing aHUS compared to usage of either agent alone. The successful reintroduction of Tacrolimus suggests that graft outcomes can be reasonable after drug-associated aHUS, if the mTOR inhibitor is ceased.
METABOLIC HEALTH POST LIVING KIDNEY DONATION
GUO Henry, MCGINN Stella, LI Yan
Department of Nephrology & Transplantation, Royal North Shore Hospital, Sydney
Background: Kidney transplantation remains the best treatment for ESRD, with living donation now accounting for 24% of transplants in Australia. With recent evidence pointing towards a small increased lifetime risk of developing ESRD, estimating pre-existing cardiovascular burden and identifying modifiable risk factors is increasingly important.
Aim: To analyse metabolic health of living kidney donors (LKD) pre and post donation.
Methods: LKDs from 2008-2018 who were followed up for at least 12 months were included. Demographics, baseline weight, body mass index (BMI), glycaemic status and cardiovascular risk factors were obtained from medical records.
Results: 78 LKDs were included with mean follow up of 38 months. Median age at donation was 53±10.4 years with majority being Caucasian (80%) and female (61%). Mean baseline weight was 75.4kg, corresponding to BMI of 26, which increased to 82kg (BMI=29) by 1-year post donation. Five LKDs gained ≥10kg in the first year post donation. Mean reduction in eGFR at 1-year was 25±10 mL/min/1.73m2 with no difference between overweight and healthy donors. Twelve donors developed new hypercholesterolemia, all of which were associated with weight gain in the first year post donation. Mean pre-donation BP was 121/76 mmHg with 11% diagnosed as hypertensive. Blood pressure and incidence of hypertension remain unchanged at 1 year. At baseline, 4 LKDs had impaired glucose tolerance, however none developed diabetes during the follow up period.
Conclusions: Despite stringent screening practices pre-donation, continued vigilance with long term monitoring of weight, glycaemic status and other risk factors remains important after living kidney donation.
SURGICAL APPROACHES FOR MANAGING THE DIFFICULT ABDOMINAL WALL IN KIDNEY TRANSPLANT RECIPIENTS: CASE REPORTS
LAM Susanna, LAURENCE Jerome, VERRAN Deborah
Transplantation Services, Royal Prince Alfred Hospital, Sydney
Introduction: The surgical approaches for managing early deep abdominal wall complications in the setting of infection in kidney transplant patients are not well described. Managing wound complications is difficult and the use of mesh can be controversial. We describe successful management of wound dehiscence and renal allograft compartment syndrome (RACS) in the context of contamination or infection, using a combination of mesh and negative pressure wound therapy (NPWT) in a series of kidney transplant recipients.
Aims: To describe the surgical treatment of abdominal wall dehiscence and RACS in the setting of infection in kidney transplant recipients.
Methods: Retrospective analysis of kidney transplant recipients from 2015-2017 was performed.
Results: Out of 341 recipients, 5(1.5%) required reoperation for dehiscence or suspected RACS. Average age was 54-years and BMI: 33kg/m2. Average time to dehiscence was 20-days. Surgical repair involved securing preperitoneal mesh to fascia, with NPWT placed over mesh either primarily or after failed primary wound closure secondary to wound infection. Average time to wound healing was 79-days. Time to reoperation for RACS was 3 days. Once allograft perfusion is confirmed, onlay polyglactin mesh was sutured into fascia, over the allograft and NPWT placed over mesh. Time to wound healing was 72-days.
Conclusion: We describe an approach to managing the difficult abdominal wall in the context of fascial dehiscence and RACS by using a combination of abdominal wall mesh repair and NPWT which has allowed for successful wound healing in complex, immunosuppressed kidney transplant patients.
COMPLICATIONS RESULTING FROM THE USE OF A SURGICAL MESH PATCH IN PAEDIATRIC RENAL TRANSPLANT RECIPIENTS
DURKAN Anne1,2, TAHER Amir1, THOMAS Gordon3,2, SHUN Albert3,2
1Department of Nephrology, The Children’s Hospital at Westmead, Sydney, 2School of Medicine, University of Sydney, 3Department of Surgery, The Children’s Hospital at Westmead, Sydney
Aims: To review the complications encountered in paediatric renal transplant recipients in whom a surgical mesh patch, Surgisis, (Cook Surgical, Bloomington, IN) was used to aid closure of the abdomen and prevent abdominal compartment syndrome.
Methods: A retrospective manual case note review was performed for all paediatric renal transplant recipients at a single centre between Sept 2006 and Sept 2018. Clinical and epidemiological data were collected.
Results: 111 transplant recipients were identified of whom seven had a surgical mesh placed. The median age at transplantation of these seven patients was 2.8 years and the median weight was 9.8kg compared to 10.8 years and 27kg, respectively, in those without mesh. Five children had a living related donor and just one had a pre-emptive transplant. Three children developed large fluid collections between the subcutaneous layers and the mesh, requiring surgical drainage in the early post-operative period. Three children presented 2, 10 and 26 weeks after transplantation with vomiting and abdominal pain, including one child who had required surgical drainage of a fluid collection. At laparotomy, all three were found to have bowel obstruction related to the mesh, necessitating bowel resection in one child. A fourth child presented 11 years post transplantation with bowel obstruction requiring bowel resection, but an association with the mesh could not be established in this patient.
Conclusions: The use of a surgical mesh patch in young renal transplant recipients is associated with a high complication rate. The routine use of these patches should be avoided.
ASSOCIATION BETWEEN THE SIDE OF LIVE DONOR KIDNEYS AND TRANSPLANT RECIPIENT OUTCOMES
DOBRIJEVIC Ellen1,2, WONG Germaine2,3, CLAYTON Phil4,5, ALLEN Richard6,2
1School of Medicine, University of Sydney, 2Centre for Transplant and Renal Research, Westmead Millennium Institute, Westmead Hospital, Sydney, 3School of Public Health, University of Sydney, 4ANZDATA, 5Nephrology and Renal Transplant, Royal Adelaide Hospital, 6Department of Surgery, University of Sydney
For ease of surgery, donor and recipient surgeons prefer left-sided living donor kidneys (LDKs). Aim: Determine the impact of left versus right LDKs on recipient outcomes, including delayed graft function (DGF), death-censored graft loss (DCGL) and overall graft survival.
Methods: Using ANZDATA and ANZOD registry data, a piecewise multivariable Cox regression model was performed using recipient data matched with donor details.
Results: 4,222 LDKs were transplanted into adult recipients in 25 centers from 2004-2017 and followed for a median of 6.5 years, of which 17.6% were right kidneys. Overall graft survival (%) (95%CI) at one and five years after transplantation were 97.3 (96.8-97.8) and 89.2 (88.1-90.2). Incidence of DGF was 2.7% for left versus 5.7% for right (p<0.001). 59 (1.4%) LDKs were lost within 30 days of transplantation. Nine deaths occurred in the first month, 6 from cardiovascular events. Grouped causes of graft loss within 30 days of transplantation were technical (59.3%), non-technical (25.4%) and death with functioning graft (15.3%). Compared with left donor kidneys, adjusted HR (95%CI) for DCGL among recipients of right kidneys was 2.45 (1.31-4.57), within 30 days after transplantation, and 0.89 (0.67-1.18) beyond 30 days. Within 30 days after transplantation, primary non-function (PNF) accounted for 7.9% of left kidneys lost compared to 28.6% of right kidneys (p=0.05).
Conclusion: Adult right LDKs recipients experience an increased risk of PNF, DGF and DCGL within 30 days of transplantation. This information should be included in the recipient patient consent process and factored into immunosuppression trial analyses.
GENETIC TESTING SHOWS HIGH FREQUENCY OF MENDELIAN DISORDERS IN PAEDIATRIC KIDNEY TRANPLANT RECIPIENTS
MCCARTHY Hugh1, HOLMAN K2, HO G2, BENNETTS B2, ALEXANDER SI3
1Centre for Kidney Research,, 2Molecular Genetics, children’s Hospital at Westmead, 3Centre for Kidney Research, Children’s Hospital at Westmead
Abstract: Testing and identification of underlying genetic aetiologies of end stage renal failure in children, has been improved with high throughput genetic testing.
Aim: To identify the genetic aetiology of end stage kidney failure in the paediatric kidney transplant population in an unselected, real-world cohort.
Methods: We reviewed the charts and genetic testing results of 103 children less than 18 years at the time of transplant who had received kidney transplants between 2009-19 at the Children’s Hospital at Westmead.
Results: The clinical presentations included Congenital Abnormalities of Kidney and Urinary Tract (CAKUT) 28 patients; Nephrotic Syndrome (NS) 17 patients; polycystic kidney disease 7 patients; tubular disorders 3 patients; Nephronophthisis 21 patients; glomerulonephritis 11 patients; VACTERL 3 patients; ESRF no obvious cause 2 patients; econdary in 11 patients including a number with Wilm’s tumours.
Genetic causes were identified in 41 of them, including NPHS1, NPHS2, ADCK4, PLCE1 and TRPC6 in children with NS, NPHP1, NPHP3, NPHP4 CEP290, CEP164, INVS, and OFD1 in patients with nephronophthisis, AGXT and CTNS in patients with hyperoxaluria and cystinosis and CAKUT related mutations including PAX2 and a number of copy number variations including Chr 6 duplication and Trisomy 21.
Conclusions: A high rate of genetic disorders is found in paediatric transplant recipients as the underlying cause of their kidney failure. These results may have important prognostic and clinical significance for them and their families.
A CASE OF ABO INCOMPATIBLE RENAL TRANSPLANTATION FOLLOWING BLOOD GROUP SWITCHING IN THE RENAL TRANSPLANT PATIENT
LAM Susanna1, HULTIN Sebastian2, PRESTON John1, CAMPBELL Scott2
1Urology and Renal Transplant, Princess Alexandra Hospital, Brisbane, 2Division of Medicine, Princess Alexandra Hospital, Brisbane
Aim: We describe an unanticipated ABO incompatible renal transplant in a recipient with a previous allogeneic stem cell transplant, who was found to have reverted to his original blood group, after organ allocation.
Case: A 66 year old male with ESKD secondary to membranous nephropathy was listed to undergo deceased donor renal transplantation at our centre. His blood group changed from B to A following allogeneic stem cell transplantation for thrombocythaemia in 2007. It had been confirmed to be A several times. The recipient was unsensitised with a cPRA of 0%. He was offered a donation after circulatory death (DCD) 0/6 HLA mismatch organ with a donor blood group A. Blood tested at admission revealed reversion to his original blood group B. An urgent anti A titre was 1:2. We proceeded to transplantation following ABOi protocol with standard immunosuppression. Following delayed graft function attributed to a prolonged cold ischaemic time of 17 hours, his creatinine fell spontaneously on day 5. His post-operative anti-A titre was persistently 1:1.
Conclusion: Despite confirmed ABO conversion after stem cell transplantation, the recipient’s original blood group B cells had regrafted with only low anti-A titres. We demonstrate a successful DCD ABOi transplant with standard immunosuppression in a recipient with possible bone marrow chimerism. Although a rare circumstance, it is important to consider regrafting of patient’s own stem cells with altered blood group in this clinical situation.
EHEALTH INTERVENTIONS FOR SOLID ORGAN TRANSPLANT RECIPIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMISED CONTROLLED TRIALS
TANG James1,2,3, JAMES Laura1,2, HOWELL Martin1,2, TONG Allison1,2, WONG Germaine1,2,3
1School of Public Health, University of Sydney, 2Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, 3Centre for Transplant and Renal Research, Westmead Hospital, Sydney
Background: Self-management after organ transplantation consists of complex regime of tasks. Lack of support for self-management may contribute to adverse health outcomes. eHealth has the potential to support self-management, but evidence in solid organ transplantation remains unclear. This review aims to summarise the evidence for eHealth interventions after solid organ transplantation.
Methods: CENTRAL, MEDLINE and Embase databases were searched for randomised trials of eHealth interventions in solid organ transplant recipients. Risk ratios or standardised mean difference of outcomes of the intervention compared to standard care were calculated, and summary estimates determined using the random effects model. The quality of evidence was assessed by Cochrane risk of bias and Grading of Recommendations, Assessment, Development and Evaluations.
Results: Fourteen trials from 5 countries involving 1348 participants were included. eHealth interventions were grouped into functionality (Table 1). Outcomes were categorised into domains: clinical, adherence, healthcare utilisation, patient-reported outcomes, and knowledge/attitudes/behavioural change. Compared with standard care, eHealth improved adherence to medicine taking (RR 1.63, CI: 1.32 to 2.01) and self-monitoring responsibilities (RR 2.86, CI: 2.05 to 3.99), up to 12 months post-transplant. There were no differences in other outcomes including acute rejection and graft loss. Five studies reported harms including stress, anxiety and failure of intervention. Overall risk of bias was considered low or unclear, and the quality of evidence was low to very low for all outcomes.
Conclusion: eHealth interventions may improve adherence to medicine taking and self-monitoring in the short-term, but it is uncertain whether eHealth will improve long-term patient relevant outcomes.
CANCER INCIDENCE IN DONOR REFERRALS - A NSW COHORT STUDY 2010-2015 USING DATA LINKAGE
HEDLEY James1,2, DE LA MATA Nicole1,2, ROSALES Brenda1,2, O’LEARY Michael3, CAVAZZONI Elena3, KELLY Patrick1,2, WYBURN Kate4,5, WEBSTER Angela1,2,6
1Centre for Organ Donor Evidence, University of Sydney, 2Sydney School of Public Health, Faculty of Health and Medicine, University of Sydney, 3Other, NSW Organ and Tissue Donation Service, 4Sydney Medical School, Faculty of Health and Medicine, University of Sydney, 5Renal Unit, Royal Prince Alfred Hospital, Sydney, 6Centre for Transplant and Renal Research, Westmead Hospital, Sydney
Introduction: Detailed medical history is not always available at donor referral, impeding suitability assessment. Donor referrals with possible cancer history may be rejected if details are uncertain. Timely cancer verification could reduce potential missed donor opportunities.
Aims: We sought to determine cancer incidence in donor referrals by primary site, and to compare the information available at time of referral with linked administrative health-data.
Methods: We used organ donor referrals 2010-2015 from the NSW Biovigilance Register. This Register linked donor referrals and transplant recipients to the NSW Admitted Patient Data Collection and Central Cancer Registry. Primary cancer site was grouped using ICD-10-AM codes.
Results: Of 2,957 referrals for donation, 433 (15%) had cancers reported at time of referral (458 cancers). Of these, 303 cancers (70%) were also reported in NSW health datasets. The most common cancers reported at time of referral were 76 (3%) brain, 44 (1%) colorectal, 42 (1%) breast, 34 (1%) leukaemia, 33 (1%) prostate, 32 (1%) lung, and 30 (1%) melanoma. Among these 291 most common cancers, 191 (66%) were verified. Agreement was highest in cancers of the prostate (94%), colorectal (77%), melanoma (77%) and breast (74%). Lowest agreement was found in cancers of the brain (43%) and leukaemia (56%) (Figure 1).
Conclusions: Cancers are quite commonly reported for donor referrals, but many cancers cannot be verified in the cancer registry, suggesting misclassification. Real-time health record access at referral could clarify uncertainty and potentially increase donation.
Figure 1: Perceived and verified cancers in NSW donor referrals 2010-2015
ENDOTHELIAL GLYCOCALYX DYSFUNCTION IN ORGAN DONORS IS ASSOCIATED WITH DELAYED GRAFT FUNCTION IN RENAL TRANSPLANT RECIPIENTS BUT NOT EARLY ALLOGRAFT DYSFUNCTION IN LIVER RECIPIENTS
SLADDEN TM1,2, YERKOVICH S1, JAFFREY L3, REILING J4, FAWCETT J4, ISBEL N3, CHAMBERS D1,2
1Queensland Centre for Pulmonary Transplantation and Vascular Disease, Prince Charles Hospital, Brisbane, 2School of Medicine, University of Queensland, Brisbane, 3Department of Nephrology, Princess Alexandra Hospital, Brisbane, 4Lung Transplant Service, Princess Alexandra Hospital, Brisbane
Aims: Early post-transplant organ dysfunction is associated with deleterious long term outcomes, with the incidence increasing with the use of extended criteria organs. The endothelial glycocalyx, a fragile luminal structure, has been demonstrated to be essential in vascular function and shed post-transplant. We hypothesised injury to the glycocalyx in organ donors, as determined by increased peripheral blood levels of glycocalyx breakdown products, would predispose grafts to the developed of delayed graft function (DGF) in renal recipients and early allograft dysfunction (EAD) in liver recipients.
Methods: Kidney and/or liver organ donors, where consent for research was obtained, between 2009 -2015 and who had a blood sample available were included. Recipients all received their transplant at the Princess Alexandria Hospital. Endothelial glycocalyx breakdown products: hyaluronan, syndecan-1, heparan sulphate and CD44 were measured in the peripheral blood of organ donors.
Results: From 192 organ donors, recipient follow-up was available for 111 liver recipients with 15 recipients (13.5%) developing EAD and 321 renal recipients, 86 (26.8%) developing stage 4 DGF. Elevated hyaluronan (OR:1.16 (0.99-1.35); p=0.05), CD44 (OR:1.21 (0.98-1.49); p=0.07) and syndecan-1(OR:1.02 (1.00-1.04); p=0.03) were all associated with the development of Stage 4 DGF in renal recipients by univariate analysis. In multivariate analysis, hyaluronan was independently associated with Stage 4 DGF (per 100ng/ml OR:1.23; p=0.04). No there was no association between glycocalyx breakdown products with liver EAD.
Conclusions: Endothelial glycocalyx shedding in renal organ donors was associated with the development of severe DGF highlighting endothelial glycocalyx dysfunction as a novel injury pathway.
EFFECT OF PROTON PUMP INHIBITOR ON MYCOPHENOLIC ACID EXPOSURE IN KIDNEY AND LIVER TRANSPLANT RECIPIENTS: A DOUBLE-BLIND RANDOMISED CROSS-OVER TRIAL
SUNDERLAND Andrew1, RUSS Graeme2, SALLUSTIO Benedetta3, CERVELLI Matthew3, JOYCE David4, JEFFREY Gary5, BOUDVILLE Neil6, CHAKERA Aron6, DOGRA Sharan6, CHAN Doris6, WONG Germaine7, LIM Wai6
1Sir Charles Gairdner Hospital, Perth, 2Nephrology and Renal Transplant, Royal Adelaide Hospital, 3Department of Clinical Pharmacology, Royal Adelaide Hospital, 4School of Medicine & Pharmacology, University of Western Australia, Perth, 5Hepatology and Liver Transplant Medicine Unit, Sir Charles Gairdner Hospital, Perth, 6Nephrology and Renal Transplant, Sir Charles Gairdner Hospital, Perth, 7School of Medicine, University of Sydney
Aim: To determine the effect of the proton-pump inhibitor (PPI) pantoprazole on mycophenolic acid (MPA) exposure in stable kidney/liver transplant recipients maintained on Mycophenolate Mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS).
Methods: A multicentre randomised, prospective, double-blind placebo-controlled cross-over study was conducted to determine the effect of gastric acid suppression (pantoprazole 40mg daily or matching placebo) on the MPA-AUC over 12 hours (MPA-AUC12h) and maximum concentration (MPA-Cmax) in recipients ≥6 months post-transplant maintained on MMF (≥1g/daily in equally divided doses) or EC-MPS (≥1080mg/daily in equally divided doses), with calcineurin-inhibitor and corticosteroids.
Results: Of 40 participants randomised, 19 (47.5%) and 21 (52.5%) were maintained on MMF and EC-MPS, respectively. The mean (SD) age was 58 (11) years and 67% of participants were males. Almost 50% were maintained on PPI, which was ceased for 2-weeks prior to randomisation. Almost 70% of participants were maintained on tacrolimus-based immunosuppressive regimen. In recipients maintained on MMF, concomitant treatment with pantoprazole significantly reduced mean MPA-AUC12h by 19% (absolute reduction of 10.8 [95%CI 4.1, 17.5] mg.h/L; paired t-test 0.003) and MPA-Cmax by 33% (absolute reduction of 6.0 [2.3,9.7] mg/L; paired t-test 0.003). In contrast, pantoprazole significantly increased the MPA-AUC12h (19% absolute increase p=0.037) but not for MPA-Cmax in recipients maintained on EC-MPS (Figure 1).
Conclusion: The co-administration of pantoprazole substantially reduced the bioavailability of MPA in patients maintained on MMF, and therefore, clinicians should be cognisant of this drug interaction, which may have important clinical implications.
Liver, Islet and Pancreas Transplantation
LONG-TERM OUTCOMES OF UTILISING DONATION AFTER CIRCULATORY DEATH GRAFTS IN LIVER TRANSPLANTATION – AN AUSTRALIAN 12-YEAR COHORT STUDY
SASTRY Vinay, PANDYA Keval, PANLILIO Mara, WEST Claire, VIRTUE Susan, WELLS Mark, CRAWFORD Michael, PULITANO Carlo, STRASSER Simone, MCCAUGHAN Geoff, MAJUMDAR Avik, LIU Ken
Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney
Aims: Use of donation circulatory death donors (DCDs) has been one strategy to expand the donor pool, however data on long-term outcomes in recipients of DCD grafts are mixed. We studied the characteristics, utilisation and recipient outcomes of DCDs.
Methods: We retrospectively studied consecutive adults who underwent deceased-donor LT between 2006-2018. Donor and recipient data at time of LT and recipient outcomes were collected. The primary outcome of interest was graft survival (time to re-transplantation or death).
Results: During the study period, 739 donors were utilised for LT. Of these, 53 (7.2%) were DCDs. Compared to donation after brain death donors (DBDs), DCDs were younger (30vs.50years), more likely to have history of pre-donation cardiac arrest (71.2%vs.34.8%), had longer intubation time (3vs.2days), less inotrope requirements (32.7%vs.7.8% on no agents) and higher AST (59vs.46U/L) (median values presented, P<0.01 for all). DCDs also had shorter cold ischaemia time (5.75vs.6.85hours,P=0.005) and higher donor risk index (1.68vs.1.56, P<0.001). As per our unit policy, recipients of DCD grafts were less likely to be PSC (1.9vs.9.0%, P=0.076) or re-transplant patients (0vs.6%, P=0.067). Similarly, DCD recipients did not receive split grafts (0vs.15.3%, P<0.001). The proportion of DCDs among utilised grafts increased from 4.8%(2006-2009) to 7.8%(2010-2012) and remained stable afterwards. DCD grafts had similar long-term graft survival compared to DBDs, although DCDs recipients with high pre-LT MELD scores>20 appeared to have worse outcomes (Figure1).
Conclusion: Long-term outcomes of DCD grafts are similar to DBD grafts especially when matched with appropriately selected recipients (first transplant, non-PSC patients with low MELD<20).
LONG-TERM OUTCOMES OF UTILISING EXTENDED CRITERIA DECEASED DONORS IN LIVER TRANSPLANTATION – AN AUSTRALIAN 12-YEAR COHORT STUDY
PANDYA Keval, SASTRY Vinay, PANLILIO Mara, WEST Claire, VIRTUE Susan, WELLS Mark, CRAWFORD Michael, PULITANO Carlo, STRASSER Simone, MCCAUGHAN Geoff, MAJUMDAR Avik, LIU Ken
Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney
Aims: Use of extended criteria donors (ECDs) has been one strategy to increase the donor pool. Long-term outcomes in recipients of ECD livers have not been well studied. We studied the characteristics, utilisation and recipient outcomes of ECDs.
Methods: We retrospectively studied consecutive adults who underwent deceased-donor LT between 2006-2018. Donor and recipient data at time of LT and recipient outcomes were collected. ECD was defined using Eurotransplant criteria. The primary outcome of interest was graft survival (time to re-transplantation or death).
Results: During the study period (median follow-up 50.6months), 739 donors were utilised for LT. Of these, 432 (58.4%) were ECDs. Elevated ALT/AST was the most common ECD criterion (31.5%), followed by age>65 (16.5%) and BMI>30 (16.0%). ECDs were older (51vs.47years), with higher BMI (26.4vs.24.5kg/m2), transaminases (ALT 42vs.24U/L) and graft steatosis (11.4%vs.0% ≥S2) compared to non-ECDs (median values presented, P<0.001 for all). ECDs had worse renal function (creatinine 80vs.67umol/L, P<0.001) and higher donor risk index (1.65vs.1.52, P<0.001). There were no differences in recipient characteristics of ECD vs. non-ECD grafts except ECD recipients were less likely receive a split graft (10.9%vs.18.9%, P=0.002). The proportion of ECDs among utilised grafts did not change over time. 157 patients experienced graft loss during follow-up (31 re-transplants, 126 deaths). ECDs had similar long-term graft survival compared to non-ECDs, although outcomes appeared to be worse when ≥3 criteria were met (Figure 1).
Conclusion: ECD livers meeting up to 2 Eurotransplant criteria can be safely used without impacting long-term graft survival. This has implications for organ utilisation.
IGLS CRITERIA APPLIED TO THE AUSTRALIAN ISLET TRANSPLANT PROGRAM.
KAY Thomas1, GOODMAN David2, LOUDOVARIS Thomas3, RADFORD Toni4, ANDERSON Patricia5,6, HOWE Kathy2, COATES Toby7, O’CONNELL Philip5,6
1St Vincent’s Institute, Melbourne, 2Department of Nephrology, St Vincent’s Hospital, Melbourne, 3Islet Transplantation Facility, St Vincent’s Institute, Melbourne, 4Royal Adelaide Hospital, 5Centre for Transplant and Renal Research, Westmead Hospital, Sydney, 6Westmead Millennium Institute, Westmead Hospital, Sydney, 7Department of Medicine, Royal Adelaide Hospital
The Igls criteria have been proposed as a way of documenting outcome of islet transplantation that is simple and clinically useful and can be compared to other treatments including both transplant and technology approaches.
Aims: We aimed to apply the Igls criteria to the database for the Australian Islet Transplant Consortium and to use the criteria as a way to define outcomes of transplants carried between 2007 and 2018. In this period the Consortium carried out transplants in three centres and islet isolations in two centres. A total of 105 islet infusions were done into 50 recipients.
Results: 12 months after the initial islet infusion 71% (30/42) of recipients met the Igls criteria for a successful transplant ie with either an “optimal” or “good” outcome. The percent successful was 64%(25/39) at 2y, 50% (16/32) at 3y, 54% (15/28) at 4y, 42% (8/19) at 5y and 62% (8/13) at 8y. In addition CGM parameters were recorded and compared with optimal and good outcomes. As expected CGM parameters were improved most in the “optimal” group.
Conclusion: In the majority of T1D patients receiving an islet transplant for severe hypoglycaemia with hypoglycaemia unawareness, HbA1c of <7% and resolution of hypoglycaemia can be achieved and in most cases this is stable for several years.
FACTORS INFLUENCING ISLET ISOLATION OUTCOMES: 20-YEAR DATA FROM THE WESTMEAD ISLET TRANSPLANT PROGRAM
CHEW Yi Vee1, WILLIAMS Lindy1, BURNS Heather2, JIMENEZ-VERA Elvira1, HUANG Dandan2, O’CONNELL Philip1, HAWTHORNE Wayne1,3
1Centre for Transplant and Renal Research, Westmead Hospital, Sydney, 2Centre for Transplant and Renal Research, Westmead Millennium Institute, Westmead Hospital, Sydney, 3Department of Surgery, Westmead Hospital, Sydney
Aims: Successful islet cell isolation to treat type 1 diabetes is influenced by multiple factors including donor selection, organ procurement and isolation parameters. This study aimed to identify factors that affected the outcome of an islet preparation in order to proceed to transplantation.
Methods: Islets were isolated from DBD donor pancreata using collagenase and neutral protease (SERVA). Donor characteristics, procurement data, isolation yield and outcomes were analysed to determine variables associated with transplantable yields. Data was further divided into Transplanted (Tx) and Non-transplanted (NTx) to identify factors significantly related to successful outcomes.
Results: Data collected from 250 islet isolations between July 2000 and February 2019 were evaluated. On average, 28% of islet preparations were transplanted, with 54% of isolations in 2016-2019 reaching release criteria. Transplantable yields (defined as 300,000 IEQ; 4,000 IEQ/kg for a 75kg recipient) were obtained from donors aged between 20-60 years, with BMI >20kg/m2, and weight >60kg. Cold ischaemia times exceeding 10hrs were found to negatively affect isolation yields.
Compared to NTx (n=180), Tx (n=70) had significantly higher total IEQ (573,977±29,352 VS 325,563±14,625 IEQ) and IEQ/g pancreas (7,018±388 VS 5,085±274 IEQ/g). The Tx group was significantly associated (p<0.01) with higher donor weight, BMI, pancreas weight, and lower CIT compared to NTx. Tx islets also exhibited significantly higher viability, purity, beta cell viability and stimulation indices compared to Non-tx (p<0.05).
Conclusion: A focus on increased donor BMI/weight and lower CIT would contribute significantly to successful islet isolation outcomes, resulting in transplantable yields of islets for treatment of Type 1 diabetes.
A SYSTEMATIC REVIEW AND META-ANALYSIS TO IDENTIFY THE RISK FACTORS FOR PANCREATIC ALLOGRAFT THROMBOSIS FOLLOWING SIMULTANEOUS PANCREAS-KIDNEY TRANSPLANTATION
BLUNDELL Jian1,2, SHAHRESTANI Sara1,2, LENDZION Rebecca2, HAWTHORNE Wayne1,2,3
1School of Medicine, University of Sydney, 2Department of Surgery, Westmead Hospital, Sydney, 3Centre for Transplant and Renal Research, Westmead Millennium Institute, Westmead Hospital, Sydney
Simultaneous pancreas-kidney (SPK) transplantation remains the most effective treatment option for achieving consistent and long-lasting euglycaemia in Type 1 diabetic patients with associated renal failure. Thrombosis of the pancreatic vasculature continues to contribute significantly to early graft failure and loss.
Aim: To compare the rate of thrombosis to graft loss, and systematically review the risk factors for early thrombosis of the pancreas allograft following SPK transplantation.
Method: We systematically searched the MEDLINE, EMBASE, The Cochrane Library and PREMEDLINE databases for studies reporting thrombosis following pancreas transplantation, and additional studies were compiled through relevant reference lists. Identified publications were screened for inclusion and synthesised accordingly into a data extraction sheet. The Newcastle-Ottawa Scale was used to appraise included studies. 51 studies satisfied the eligibility criteria; 32 cohort studies, 18 conference abstracts and one meta-analysis. Bias assessment revealed well conducted cohort studies of low bias risk.
Results: Meta-analysis of these studies revealed a 9% event rate for thrombosis, and 7% rate of graft loss secondary to thrombosis. This review established significant associations between donor and recipient characteristics, procurement and preservation methodology, transplantation technique, post-operative management and an increased risk of early thrombosis in the pancreas allograft.
Conclusion: Further investigation into HTK preservation fluid, prophylactic heparin protocol and exocrine drainage method is necessary to clarify their thrombotic influence on the pancreas graft. By continuing to investigate these contributory factors, it is hoped that the high thrombosis rates plaguing pancreas transplants can be appropriately addressed, ultimately resulting in improved patient outcomes following SPK transplantation.
YOUNG WOMAN WITH TYPE 1 DIABETES AND SEVERE SUB-CUTANEOUS SKIN REACTION TO INSULIN, BECOMES INSULIN INDEPENDENT AFTER ISLET TRANSPLANT
RADFORD Toni1,2, DROGEMULLER Christopher1,2,3, LOUDOVARIS Thomas4,2, KAY Thomas5,2, O’CONNELL Philip6,2, HAWTHORNE Wayne7,2, TORPY David1,2, COATES TOBY1,2
1Central Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, 2Australian Islet Transplantation Consortium, Australian Islet Transplantation Consortium, 3Centre for Transplant and Renal Research, University of Adelaide, 4Islet Transplantation Facility, St Vincent’s Institute, Melbourne, 5Islet Transplantation Facility, Tom Mandel Islet Program, Melbourne, 6Islet Transplantation Facility, Westmead Hospital, Sydney, 7Islet Transplantation Facility, Westmead Millennium Institute, Westmead Hospital, Sydney
While allergies to insulin are less common since the introduction of human insulins, they can still occur. In this case study I report a patient who presented with a severe insulin allergy which was treated with an islet transplant.
TD is a 37 year old woman diagnosed with type 1 diabetes in 2002. Initially using multiple injections, she changed to an insulin pump in 2008. In 2011, she noticed small lumps around the cannula injection sites. Over the following 5 years, she trialled re-siting the cannula 2 to 3 times a week with various insulins, with no benefit. A trial of subcutaneous injections resulted in immediate formation of lumps that took 2-6 weeks to resolve. The patient felt well with no other systemic effects.
A skin biopsy in 2016 diagnosing mixed lobular panniculitis induced by possible phagocytosis of insulin with clearly defined, deeply indurated nodules with minimal surface erythema. No microorganisms or foreign bodies were detected in the tissue.
Hydrocortisone was administered simultaneously with insulin using an insulin pump. Antiprotease inhibitor Nafamostat was trialled to reduce insulin resistance and for its anti-inflammatory effect. Topical steroid cream was applied and systemic glucocorticoids were commenced. An insulin desensitisation protocol was completed. Oral Azathioprine 50mg daily was also trialled. These all had no effect.
The condition worsened and doses of insulin up to 75u was required to control blood glucose levels. The HbA1c was >10%. It was suspected that insulin was not being absorbed through the inflamed subcutaneous tissue.
A central catheter enabled intravenous insulin via a pump to be administered after 2 admission to hospital with DKA. The risks of using intravenous insulin prompted her endocrinologist to refer her to the islet transplant team.
TD was listed in early 2017. Her first islet infusion yielded 9218 islet equivalents per kg (IEq/Kg) of body weight. Her insulin requirement dropped from 75u to 16u within 3 months. Sub-cutaneous insulin was re-trialled after 4 weeks due to her highly immunosuppressed state with no evidence of nodules recurring. A second infusion 5 months after her first, provided another 6179 IEq/Kg.
TD became insulin independent on day 56 post second infusion. Her HbA1c is stable at 5.5%, with C-peptide levels >300picomols/L. Her immunosuppressive regimen is Tacrolimus 5mg BD and Myfortic 360 mg BD.
This presents an interesting case of a patient allergic to exogenous insulin but not endogenous insulin produced by an allo-islet transplant.
More broadly this study presents an example where the usual criteria of hypoglycaemia unawareness for islet transplantation, has been extended.
USING DONOR BILE DUCT INJURY SCORES TO PREDICT BILIARY STRICTURES AFTER LIVER TRANSPLANTATION: RESULTS FROM THE AUSTRALIAN NATIONAL LIVER TRANSPLANTATION UNIT
LY Mark1, PULITANO Carlo2,3, MCKENZIE Catriona4, KENCH James4,3, CRAWFORD Michael2
1Royal Prince Alfred Hospital, Sydney, 2Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, 3University of Sydney, 4Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney
Introduction: Donor histological bile duct injury scores have been correlated with the incidence of Biliary Strictures (BS) after liver transplantation, particularly peribiliary gland injury, mural necrosis and vascular plexus injury. We performed a clinical study to evaluate the correlation between bile duct injury scores and the development of BS after liver transplantation in Australian donors.
Methods: Bile duct samples were taken from brain dead donors retrieved and transplanted in NSW, Australia from March 2016 and June 2017. Samples were taken at the backtable, prior to transplantation. Samples were scored according to the grading system developed by Op Den Dries et al by two independent pathologists who were blinded from outcomes. Recipients were followed up and the primary outcome was BS at 12 months. Data on donor, recipient characters and post-operative complication data was extracted.
Results: Bile duct samples were taken from 58 grafts and the overall incidence of BS was 25.9% (n=15). There were 13 Anastomotic Strictures (AS) and 3 Non-Anastomotic Strictures. Decreased levels of inflammation in bile duct samples was associated with BS (p=0.005) and AS (p=0.005). All samples had evidence of biliary epithelial injury however this was not associated with BS. No association was observed for mural stromal necrosis, vascular plexus injury or peribiliary gland injury, and developing BS at 12 months (p>0.05).
Conclusions: Decreased inflammation scores were associated with Biliary and Anastomotic Strictures which may reflect poorer microvascular circulation. Our study did not observe the same correlations between bile duct injury scores as previous studies.
IRI, Immunobiology and GvHD
LONG-TERM P2X7 BLOCKADE REDUCES LIVER GRAFT-VERSUS-HOST DISEASE IN HUMANISED MICE
GERAGHTY Nicholas1,2,3, WATSON Debbie1,2,3, SLUYTER Ronald1,2,3
1School of Chemistry and Molecular Bioscience, University of Wollongong, 2Molecular Horizons, University of Wollongong, 3Illawarra Health and Medical Research Institute, University of Wollongong
INTRODUCTION: Graft-versus-host disease (GVHD) is a complication of bone marrow transplantation, where donor leukocytes mount an immune response against the recipient. Extracellular adenosine triphosphate (ATP) activates P2X7 to promote GVHD in allogeneic mouse models. Short-term P2X7 blockade with Brilliant Blue G (BBG) reduces serum human interferon gamma (hIFN-γ) and histological GVHD in a humanised mouse model.
AIM: To investigate long-term P2X7 blockade on GVHD development in a humanised mouse model.
METHODS: NOD-SCID-IL2γnull (NSG) mice injected with 10 x 106 human (h) peripheral blood mononuclear cells (PBMC), were injected with BBG (50 mg/kg) or saline thrice weekly for up to 10 weeks. Weight loss and clinical parameters for GVHD were assessed. Flow cytometry for human cell engraftment, ELISA for serum cytokines, and histological and immunohistochemical analysis of liver damage were performed.
RESULTS: BBG did not impact human cell engraftment (hCD45+, hCD3+, hCD4+, hCD8+ and NK cells). Both groups showed similar weight loss, clinical score and survival (median survival time; BBG, 45.5 days, n = 10, Saline, 50 days, n = 7) (P = 0.3014). However, BBG-mice demonstrated reduced histological damage and leukocyte infiltration (52% reduction) in the liver (P = 0.0020). Further, BBG-mice had reduced apoptosis (57% reduction) in the liver (P = 0.0244). Contrary to a short-term regime, long-term P2X7 blockade with BBG did not impact serum hIFN-γ concentrations.
CONCLUSION: P2X7 plays a role in liver GVHD in this humanised mouse model, but further investigation into P2X7 blockade is warranted before it can be used as a therapeutic strategy for GVHD in humans.
A20 IS PROTECTIVE AGAINST ACUTE KIDNEY INJURY REGARDLESS OF IMMUNOLOGICAL ENVIRONMENT
LI Jennifer1,2, NGUYEN-NGO Danny1,2, ZAMMIT Nathan3, EL-RASHID Maryam1,2, MINHAS Nikita4, GREY Shane3, ROGERS Natasha1,2
1Centre for Transplant and Renal Research, Westmead Millennium Institute, Westmead Hospital, Sydney, 2Westmead Clinical School, University of Sydney, 3Transplant Immunobiology Laboratory, Garvan Institute of Medical Research, Sydney, 4Centre for Transplant and Renal Research, University of Sydney
Inflammation is an important mechanism for acute kidney injury, which contributes to overall mortality of hospitalized patients. The pro-inflammatory cytokine, tumor necrosis factor (TNF-α) upregulates A20 (a zinc finger protein), which has an important role in maintaining homeostasis in inflammation and immunity. Various single nucleotide polymorphisms (SNP) within the A20 gene have been associated with increased susceptibility to inflammatory diseases.
Aim: Examine the effect of I325N single nucleotide polymorphism within the A20 locus on inflammation and acute kidney injury.
Methods: Age- and gender-matched littermate control (wild-type), heterozygous (A20Δ/+) and homozygous (A20Δ/Δ) I325N SNP mutant mice were challenged by renal ischemia reperfusion injury (IRI) and had subsequent analysis of renal function and biomolecular phenotyping.
Results: Mutant A20Δ/+ and A20Δ/Δ mice were protected from renal IRI, with lower serum creatinine compared to littermate controls at 24hr reperfusion, reduced TUNEL-positive staining and histological damage of kidney tissue. Paradoxically, these A20 mutant mice demonstrated upregulation of pro-inflammatory cytokines TNF-α, CCL2 and CXCL2, increased CD11c+ dendritic cells (DC), F4/80+CD11b+ macrophages (expressing maturation markers CD80 and CD40), and both CD103+ DC and CD8+ T cells. A20Δ/Δ mice also demonstrated upregulation of nitrosative stress, downregulation of superoxide dismutase expression, and was associated with increased phospho-NFκB expression in renal parenchymal and tubular epithelial cells. Cell lines transfected with A20 constructions (wild-type or I325N variant) and incubated with TNF-α did not change cell viability.
Conclusions: The I325N SNP variant of A20 leads to NF-κB activation and augmented inflammation but was paradoxically protective in ischemic AKI.
TARGETING INFLAMMATORY MONOCYTES BY IMMUNE-MODIFYING NANOPARTICLES PREVENTS KIDNEY ALLOGRAFT REJECTION
LAI Sum Wing Christina1,2, WU Huiling1, LOH Yik Wen1, SINGER Julian1,3, NIEWOLD Paula1, GETTS Daniel1, KING Nicholas1, CHADBAN Steve1,3
1University of Sydney, 2Renal & Transplantation Unit, Royal Prince Alfred Hospital, Sydney, 3Royal Prince Alfred Hospital, Sydney
Aim: We previously reported the capacity of immune-modifying nanoparticles (IMPs) to bind to circulating inflammatory monocytes/macrophages(MΦ) via the specific scavenger receptor MARCO, thereby causing inflammatory MΦ removal in the spleen with subsequent protection in models of infection, autoimmunity and ischemia injury. Here we investigated the therapeutic potential of IMPs to target MΦ in kidney allograft rejection in a murine model of kidney transplantation.
Methods: Kidney transplants were performed from BALB/c to C57BL/6 mice as WT allografts. A group of WT allograft mice received a daily intravenous injection of 300ul (1.46x1010particles/ml, 500nm in diameter) of negatively-charged IMPs from day 1 post-transplant for 15 days (WT+IMP). Samples were collected at days 14 and 100 post-transplantation.
Results: WT+IMP allografts had prolonged survival compared to WT allografts (Fig.1, p<0.05), and were protected from acute rejection with lower creatinine (23.8±1.4 vs. 48.1±18.7μmol/L, p<0.01) and less tubulitis (95.6±12.6 vs. 140.4±33.9scores, p<0.001). Histologically, accumulation of CD4+ (37.8±13.3 vs. 73.1±31.7cells/HPFs, p<0.01), CD8+ (39.1±17.7 vs. 75.9±39.2cells/HPFs, p<0.05), CD68+ (12.4±4.5 vs. 21.8±6.9%field positive, p<0.01) and CD11c (1.802±0.8573 vs. 12.56±4.658%field positive, p<0.001) cells were reduced in WT+IMP allografts, compared to WT allografts. High dimensional flow cytometry analysis of cells isolated from allografts showed significantly reduced T cells and myeloid cells in WT+IMP. WT+IMP allografts expressed significantly less pro-inflammatory (IL6) and Th1 (IFN) cytokines and cytotoxic molecules (Perforin, GranzymeB & iNOS).
Conclusion: IMP infusion affords significant protection from acute allograft rejection, indicating therapeutic potential. Diverting inflammatory MΦ away from the allograft may be a useful strategy to prevent subsequent adaptive alloimmunity.
Figure 1: WT+IMP prolongs kidney allograft survival.
RECOMBINANT SOLUBLE CR1 TREATMENT IS PROTECTIVE IN A MOUSE MODEL OF RENAL ISCHEMIA REPERFUSION INJURY
BONGONI Anjan K1, MCRAE Jennifer L1, SALVARIS Evelyn J1, VIKSTROM Ingela2, MORELLI Adriana Baz2, WYMANN Sandra2, HARDY Matthew P2, PEARSE Martin J2, COWAN Peter J1,3
1Immunology Research Centre, St Vincent’s Hospital, Melbourne, 2CSL Ltd. Melbourne, 3Department of Medicine, University of Melbourne
Background: Complement, an arm of the innate immune system, is a potent mediator of ischemia-reperfusion (IR) injury (IRI), which significantly affects function and survival of transplanted kidneys. A recombinant truncated and soluble form of complement receptor type 1 (sCR1) with complement inhibitory activity has been generated as a potential therapeutic candidate.
Aims: To test sCR1 as a potential agent for the suppression of complement-mediated IR-induced organ damage in a mouse model of renal IRI.
Methods: Male 10-12 week-old C57BL/6 mice were subjected to right nephrectomy and 22 minutes left renal ischemia at 37°C. Mice (n=8-14/group) were treated with i.p. administration of 60 mg/kg sCR1, or vehicle, 1 hr prior to ischemia. Mice were sacrificed 24 hrs after reperfusion, and blood and kidney samples were collected to assess renal function (serum creatinine, urea), complement activation (plasma C3b, C5a) and deposition (C9), and neutrophil and macrophage infiltration.
Results: Compared to Sham, severe renal injury was induced following IR in the vehicle-treated mice as indicated by significantly increased serum creatinine and urea, plasma C3b and C5a, and tissue C9 deposition, and cellular infiltration. sCR1 treatment significantly protected against IR-induced damage, manifested by significantly lowered renal dysfunction, complement activation and deposition and cellular infiltration.
Conclusion: Complement inhibition using sCR1 protected against IR-mediated renal damage and this was associated with markedly reduced renal dysfunction, as well as lowered complement activation and deposition, and cell infiltration. Blockade of complement activation by sCR1 is thus a promising therapeutic approach to reduce IRI and improve organ transplant function.
NECROPTOSIS IN RENAL ISCHAEMIA REPERFUSION INJURY
PEFANIS A1,2, NACHBUR U3, MCRAE JL2, BONGONI AK4, SALVARIS EJ2, MURPHY JM5,6, IERINO FL1,7, COWAN PJ2,1
1Department of Medicine, University of Melbourne, 2Immunology Research Centre, St Vincent’s Hospital, Melbourne, 3Cell signalling and cell death division, Walter and Eliza Hall Institute of Medical Research, Melbourne, 4Immunology Research Centre, St Vincent’s Institute, Melbourne, 5Cell Signalling, Walter and Eliza Hall Institute of Medical Research, Melbourne, 6Department of Medical Biology, University of Melbourne, 7Department of Nephrology, St Vincent’s Hospital, Melbourne
Background: Ischemia-reperfusion injury (IRI) negatively impacts graft outcomes in kidney transplantation. Necroptosis, a form of regulated necrosis, is triggered by death receptor-mediated recruitment of the kinases RIPK1 and RIPK3 and activation of the pseudokinase MLKL. Active MLKL causes cell death by plasma membrane permeabilisation, driving “necroinflammation”.
Aim: To investigate the role of necroptosis in a mouse model of renal IRI.
Methods: 10-12 week old male mice (MLKL knockout and wild-type littermates) underwent right nephrectomy and 22 min left renal ischemia. A separate cohort of WT mice were treated before ischemia with the novel RIPK1 inhibitor Nec-1s. Samples were collected at 24 hrs to assess MLKL expression (Western blot) and renal injury (serum creatinine, μM).
Results: MLKL was upregulated following IRI in WT mice (Figure 1). Creatinine was not significantly different in MLKL KO and WT mice (116.76±14.24 vs 127.82±14.43, p=0.59; Sham 19.50±0.72). Creatinine in Nec-1s-treated mice was significantly higher than in vehicle-treated mice (179±18.26 vs 107.17±22.27, p=0.034; Sham 18.29±0.29).
Conclusion: The upregulation of MLKL suggests that necroptosis may contribute to renal IRI. However, serum creatinine was not reduced in MLKL KO mice, possibly reflecting the temporal relationship between MLKL upregulation and this readout of kidney injury. We hypothesise that the increase in serum creatinine upon RIPK1 inhibition may be a consequence of RIPK1’s pleotropic nature, as it can stimulate both cell death and cell survival pathways. Histological assessment of injured kidneys and variation of experimental settings will be performed to further investigate the contribution of necroptosis to renal IRI.
Figure 1. Western Blot assessing for MLKL in mice kidneys following IRI and sham procedures.
SELECTIVE RETENTION OF DONOR MYELOID CELLS IN CONGENIC LIVER TRANSPLANTS
DART SJ1, PROSSER A1,2, HUANG WH3, LIU L1, DE BOER B4, JEFFREY G1, DELRIVIERE L3,5, KALLIES A6, LUCAS M1,7
1School of Medicine, University of Western Australia, Perth, 2School of Human Sciences, University of Western Australia, Perth, 3School of Surgery, University of Western Australia, Perth, 4Department of Anatomical Pathology, Fiona Stanley Hospital, PathWest, Perth, 5WA Liver & Kidney Transplant Service, Sir Charles Gairdner Hospital, Perth, 6Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, 7Department of Immunology, Sir Charles Gairdner Hospital, PathWest, Perth
Introduction: Transplantation of solid organs involves the simultaneous transfer of donor immune cells, and myeloid cells play important roles in transplantation outcome. However, the dynamics between donor and recipient myeloid cells and their retention over time has not been investigated in detail using congenic models.
Aims: To characterise and quantify donor and recipient myeloid cell populations in congenic liver transplantation.
Methods: Orthotopic liver transplants were performed between congenically matched mouse strains, expressing either CD45.1 or CD45.2. Leukocytes from donor (CD45.1+) and recipient (CD45.2+) mice were analysed by multi-parameter flow cytometry to quantify M1 and M2 macrophages, CD11b- and CD11b+ dendritic cells, eosinophils, monocytes and neutrophils at 0, 1, 4, 7 and 28 days post-transplantation in the graft and peripheral lymphoid organs.
Results: Following transplantation, the number of donor myeloid cells in the graft rapidly decreases. CD11b+ dendritic cells, eosinophils and M1 macrophages are depleted to less than 98% of their total number at day 0. However, CD11b- dendritic cells, neutrophils, M2 macrophages and monocytes are retained up to day 28 at 10-30% of their total baseline number. Post-transplantation, the liver is infiltrated by all analysed subsets of recipient myeloid cells. Recipient neutrophils and M1 macrophages are the predominant myeloid populations in the liver on day 1 and day 28 post-transplantation.
Conclusions: Following congenic liver transplantation there is selective retention of donor myeloid cell populations within the transplanted organ and periphery. The level of donor cell retention may be important in transplantation outcome, thus further studies with mismatch models are underway.
THE P2X7 ANTAGONIST BRILLIANT BLUE G PRESERVES REGULATORY T CELLS AND REDUCES SERUM HUMAN INTERFERON-GAMMA IN A HUMANISED MOUSE MODEL OF GRAFT-VERSUS-HOST DISEASE
CUTHBERTSON Peter1,2, ADHIKARY Sam1,2, SLUYTER Ronald3,2, WATSON Debbie1,2
1School of Chemistry and Molecular Bioscience, University of Wollongong, 2Illawarra Health and Medical Research Institute, 3School of Chemistry and Molecular Bioscience, Univeristy of Wollongong
Background: Graft-versus-host disease (GVHD) is a severe and often lethal complication arising from donor stem cell transplantation. In allogeneic and humanised mouse models of GVHD, extracellular ATP from damaged tissue activates the P2X7 receptor, leading to increased activation of donor T cells and worsened disease.
Aim: This study aimed to investigate the effects of a modified P2X7 blockade regime in a humanised NOD-scid IL2Rγnull (NSG) mouse model of GVHD.
Methods: NSG mice were injected i.p. with 10x106 human peripheral blood mononuclear cells (day 0), and daily i.p. injections of P2X7 antagonist Brilliant Blue G (BBG) (50mg/kg) or saline (day 0-10). Mice were monitored for clinical GVHD for 3 or 10 weeks. Human cell engraftment and serum human interferon-gamma (hIFNγ) were measured by flow cytometry and ELISA, respectively.
Results: BBG did not affect engraftment of hCD45+ cells. However, the hCD4+CD25+CD127lo regulatory T cells (Treg) frequency was significantly increased in the spleens of BBG (4.9±3.2%, n=8) compared to saline (1.9±1.4%, n=7) mice at week 3 (P=0.03). Serum hIFNγ was significantly decreased in BBG (21.6±52.8pg/uL, n=8) compared to saline (110.0±54.6pg/uL, n=7) mice at week 3 (P=0.01). BBG also reduced clinical score (P=0.05, n=8), but did not significantly affect weight loss or overall survival over 10 weeks.
Conclusion: P2X7 blockade with a modified BBG regime preserved Tregs and reduced serum hIFNγ in humanised mice. Therefore P2X7 blockade using this new regime in combination with other therapies may be of benefit to prevent GVHD.
NORMOTHERMIC MACHINE PERFUSION OF DCD LIVERS – A TOOL THAT COULD HELP EXPAND THE DONOR POOL
REILING Janske1,2,3,4, HODGKINSON Peter1,5, COCO Tina6, BUTLER Nicholas1,5, FACWETT Jonathan1,5
1Faculty of Medicine, University of Queensland, Brisbane, 2Gallipoli Medical Research Institute, Greenslopes private hospital, Brisbane, 3Princess Alexandra Research Foundation, Princess Alexandra Hospital, Brisbane, 4Queensland Liver Transplant Servivce, Princess Alexandra Hospital, Brisbane, 5Queensland Liver Transplant Service, Princess Alexandra Hospital, Brisbane, 6DonateLife Queensland
Introduction: Concerns over unacceptably poor outcomes relating to ischaemic injury currently limit the utilisation of donation after circulatory death (DCD) livers in Australasia. Normothermic machine perfusion (NMP) might enable safer use of DCD livers because it allows for ex-vivo assessment of graft function prior to implantation. We describe our early experience following the first three NMP preserved liver transplants in Australasia using a “back-to-base” approach.
Methods: From July 2018 three DCD livers were procured using standard cold preservation techniques prior to repatriation and NMP using the OrganOx Metra device. Each graft had one or more elements outside of established criteria (age >50; BMI >30, non-metropolitan). The functional warm ischaemic times were 12,16,27 and cold ischaemic times were 5h, 5h15min, and 7h4min respectively. NMP duration was >6 (range 9 – 17.5) hours. Recipient MELD score ranged from 18-31.
Results: Each liver met pre-established criteria for implantation during NMP: lactate clearance within two hours, glucose utilisation within 6 hours, pH maintenance >7.2, satisfactory haemodynamic flows (portal vein 0.9 – 1.2 L/min, hepatic artery 0.5 – 0.6 L/min). Immediate graft function was unanimously observed following implantation.
Conclusion: The OrganOx Metra using a “back-to-base” approach has enabled the safe use of three DCD grafts outside of established Australasian criteria. Whilst early graft dysfunction can be successfully predicted, the impact of NMP on ischaemic biliopathy rates is yet to be established. Nevertheless, this technology undoubtedly improves transplant logistics and should enable a safer expansion of the DCD program across Australasia.
CHARACTERISATION OF TISSUE-RESIDENT T CELLS BY TRANSPLANTATION
PROSSER Amy1,2, HUANG Wen Hua3, LIU Liu1, DE BOER Bastiaan4, WATSON Monalyssa1,2, DART Sarah1,2, LUCAS Andrew1, JEFFREY Gary1, DELRIVIERE Luc3,5, KALLIES Axel6, LUCAS Michaela1,7
1School of Medicine, University of Western Australia, Perth, 2School of Human Sciences, University of Western Australia, Perth, 3School of Surgery, University of Western Australia, Perth, 4Department of Anatomical Pathology, Fiona Stanley Hospital, 5WA Liver & Kidney Transplant Service, Sir Charles Gairdner Hospital, Perth, 6Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, 7Immunology Department, Sir Charles Gairdner Hospital, Perth
Introduction: Tissue-resident (TR) T cells are located in all tissues tested thus far and exhibit rapid responses to stimulation. Organ transplantation involves not only transfer of organ tissue, but of TR T cells as well. Infiltration of the transplanted organ by recipient-derived lymphocytes is also likely to result in alloreactive TR T cells in the organ. Phenotypic characterisation of TR T cells is incomplete, as there appear to be marked subset and context differences in marker expression.
Methods: Using orthotopic liver transplants between congenically matched mouse strains, we have characterised donor and recipient T cells after transplantation. In depth phenotyping by flow cytometry was performed with 19 markers related to memory, activation, exhaustion, transcription factors, and chemokine and co-inhibitory receptors.
Results: Donor-derived T cell subsets exhibit varying degrees of tissue-residency within the liver after transplantation. Subsets which were retained to a higher degree displayed a distinct TR phenotype, as opposed to the heterogeneous phenotypes of low retention subsets. All markers, including those classically associated with tissue-residency were expressed to varying degrees in a subset-dependent manner. Proportions of infiltrating recipient T cell subsets became phenotypically similar to retained donor-derived TR T cells, indicating their residency within the transplanted organ.
Conclusions: A ‘one-size fits all’ descriptive phenotype of TR T cells does not reflect the true heterogeneity of these cells. Subset-specific differences in expression of all markers examined herein confirms the potential for varying localisation, retention and function of each cell type, warranting further investigation.
INTERLEUKIN-6 RECEPTOR BLOCKADE IMPROVES SURVIVAL AND REDUCES GRAFT-VERSUS-HOST DISEASE IN HUMANISED MICE TREATED WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE
MILES Nicole1,2,3, ADHIKARY Sam1,2,3, GERAGHTY Nicholas1,2,3, SLUYTER Ronald1,2,3, ALEXANDER Stephen4, WATSON Debbie1,2,3
1School of Chemistry and Molecular Bioscience, Faculty of Science, Medicine and Health, University of Wollongong, 2Illawarra Health and Medical Research Institute, 3Molecular Horizons, University of Wollongong, 4Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney
INTRODUCTION: Graft-versus-host disease (GVHD) is a major complication of donor stem cell transplantation, where donor immune cells in the graft attack host tissues. We have shown depletion of proliferating immune cells using post-transplant cyclophosphamide (PTCy) can reduce signs of GVHD in humanised mice. However regulatory T cells (Tregs) are reduced over time. Interleukin-6 receptor (IL6R) blockade is known to reduce activated T cells and increase Tregs.
AIM: To investigate the effect of adding IL6R blockade to PTCy on GVHD development in humanised mice.
METHODS: NOD-SCID-IL2Rγnull mice were injected (i.p.) with 20 x 106 human peripheral blood mononuclear cells (day 0). PTCy (33mg/kg) was injected (days 3, 4) and tocilizumab (n = 6) or control IgG antibody (n = 3) (0.5mg/mouse) twice a week for 4 weeks. Mice were monitored for clinical signs of GVHD for 10 weeks. Histological damage to target organs and serum cytokines were assessed.
RESULTS: Tocilizumab, which blocks human IL6R, did not affect human T cell engraftment (CD4+, CD8+), or the proportion of Tregs (CD4+CD25+CD127lo), but increased CD39hi Tregs. Humanised mice treated with tocilizumab demonstrated lower clinical scores (Toc; 4.2±0.8 vs Ctl; 8.3±0.3), (p < 0.05) and prolonged survival (Toc; median survival time (MST) >70 days vs Ctl; MST, 53.5 days), (p < 0.05). Tocilizumab mice showed reduced histological damage to the gut and skin. Tocilizumab did not affect human serum cytokine levels (hIFN-γ, TNF-α, IL-6, IL-10, IL-2).
CONCLUSION: Additional therapy using tocilizumab reduces GVHD in humanised mice treated with PTCy, and further studies are warranted.
LOW-DOSE INTERLEUKIN-2 INCREASES HUMAN REGULATORY T CELLS IN HUMANISED MICE WITH GRAFT-VERSUS-HOST DISEASE TREATED WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE
ADHIKARY Sam1,2, GERAGHTY Nicholas1,2, SLUYTER Ronald1,2, ALEXANDER Stephen3, WATSON Debbie1,2
1Immunology and Cell Signalling Group, Illawarra Health and Medical Research Institute, 2School of Chemistry and Molecular Bioscience, University of Wollongong, 3Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney
INTRODUCTION: Graft-versus-host disease (GVHD) is a life threatening complication of donor stem cell transplantation where reactive donor T cells in the graft attack the host. We have shown that post-transplant cyclophosphamide (PTCy) depletes reactive donor cells and significantly reduces GVHD in humanised mice. In humans, low-dose interleukin (IL)-2 reduces GVHD by boosting regulatory T cells (Tregs).
AIM: To investigate the effect of combinational treatment of PTCy and low-dose IL-2 on GVHD in humanised mice.
METHODS: NOD-SCID-IL2Rγnull mice were injected (i.p.) with 20 x 106 human peripheral blood mononuclear cells (day 0), followed by 33 mg/kg PTCy (days 3 and 4) and 0.3 IU IL-2 (or PBS) (day 0-5, then thrice weekly). Mice were monitored for clinical GVHD for 10 weeks, with flow cytometric assessment of human cell engraftment, qPCR analysis of regulatory genes and H&E assessment of damage to target organs.
RESULTS: Engraftment of hCD45+ leukocytes were similar between PTCy+PBS- and PTCy+IL-2-mice (P>0.05), the majority being hCD3+ T cells in each group (P=0.75). Both groups demonstrated similar hCD4+:hCD8+ T cell ratios (P=0.561), however PTCy+IL-2-mice showed significantly greater hCD4+hCD25+hCD127lo Tregs (P=0.045). PTCy+PBS- and PTCy+IL-2-mice demonstrated similar survival (MST=65 days vs. 53 days, respectively), (P=0.613), which was prolonged compared to IL-2-mice (MST=38 days) (P<0.05 for both). Finally, PTCy+PBS- and PTCy+IL-2-mice demonstrated reduced infiltrating liver leukocytes compared to IL-2-mice (P<0.05 for both), but similar relative expression of splenic human interferon-γ, hFoxP3 and hIL-17 (P>0.05 for all)
CONCLUSION: This study indicates that combined treatment of PTCy with low-dose IL-2 increases human Tregs that survive long-term in humanised mice.