Search

BACKGROUND: Antibody-mediated rejection (ABMR) poses a barrier to long-term graft survival and is one of the most challenging events after kidney transplantation. Removing donor specific antibodies (DSA) through therapeutic plasma exchange (PLEX) is a cornerstone of antibody depletion but has inconsistent effects. Imlifidase is a treatment currently utilized for desensitization with near-complete inactivation of DSA both in the intra- and extravascular space. METHODS: This was a 6-month, randomized, open-label, multicenter, multinational trial conducted at 14 transplant centers. Thirty patients were randomized to either imlifidase or PLEX treatment. The primary endpoint was reduction in DSA level during the 5 days following the start of treatment. RESULTS: Despite considerable heterogeneity in the trial population, DSA reduction as defined by the primary endpoint was 97% for imlifidase compared to 42% for PLEX. Additionally, imlifidase reduced DSA to noncomplement fixing levels, whereas PLEX failed to do so. After antibody rebound in the imlifidase arm (circa days 6-12), both arms had similar reductions in DSA. Five allograft losses occurred during the 6 months following the start of ABMR treatment-four within the imlifidase arm (18 patients treated) and one in the PLEX arm (10 patients treated). In terms of clinical efficacy, the Kaplan-Meier estimated graft survival was 78% for imlifidase and 89% for PLEX, with a slightly higher eGFR in the PLEX arm at the end of the trial. The observed adverse events in the trial were as expected, and there were no apparent differences between the arms. CONCLUSION: Imlifidase was safe and well-tolerated in the ABMR population. Despite meeting the primary endpoint of maximum DSA reduction compared to PLEX, the trial was unsuccessful in demonstrating a clinical benefit of imlifidase in this heterogenous ABMR population. TRIAL REGISTRATION: EudraCT number: 2018-000022-66, 2020-004777-49; ClinicalTrials.gov identifier: NCT03897205, N

Background In Australia, Lupus Nephritis (LN) affects a culturally diverse population of patients. We established the Lupus Nephritis Australian Registry (LUNAR) to better understand the population of patients receiving Myfortic and other immunosuppressants, and to analyse the safety and efficacy of the treatments they received. Methods A non-interventional, multicentre, registry of patients with biopsy-proven ISN/RPS class III, IV or V LN, treated with Myfortic or other immunosuppressants, was established. We collected baseline demographic and 6-monthly follow-up data over a 5-year period (2013-2018), including clinical data, laboratory tests and safety outcomes. Results 149 patients were enrolled in LUNAR across 8 sites, with 83.7% female and a mean age of 38.8 years. Most patients were Caucasian (45.2%) - patients of Asian ethnicity (29.6%) and Aboriginal/Torres Strait Islander or Maori/Pacific Islander descent (10.4%) were significantly over-represented compared to the general population. The mean and median duration of SLE was 8.6 and 6 years, respectively (range 0-42 years), and of LN was 5.4 and 3.9 years, respectively (range 0-30 years). Most patients had class IV LN on their initial kidney biopsy (59.3%), with 21.5% having class III and 11.1% having class V LN. Immunosuppressants used prior to screening included corticosteroids (68.9%), mycophenolate mofetil ((MMF) 61.5%), Myfortic (41.5%) and cyclophospha-mide (32.6%). At enrolment or during the study, most patients were treated with Myfortic (76.3%), MMF (65.2%) and/or hydroxychloroquine (67.4%). Rituximab and azathio-prine were each started in 8.9% of patients during the study period. Kidney function was stable/improved for most patients over the study period and mycophenolate-based therapy was well-tolerated. Conclusions LUNAR is the first study outlining the demographics, outcomes and practice patterns in the management of patients with LN in Australia.

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 rapid allograft loss. Previous studies have shown that this risk may be mitigated with 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 SLKT recipients peri-operatively and describe a profound sustained depletion of all DSAs from the time of liver anastomosis with no extra desensitisation therapy required. CASE PRESENTATION: Two patients underwent SLKT and received our centre's standard renal transplant immunosuppression with basiliximab and methylprednisolone for induction therapy and prednisolone, mycophenolate and tacrolimus for maintenance therapy. HLA antibody samples were collected pre-operatively, and immediately post-liver and post-kidney revascularisation, and then regularly in the post-transplant period. Complement Dependant Cytotoxicity (CDC) crossmatches were also performed. Both patients were highly sensitised with a PRA over 97%. One patient had a positive B- and T-cell crossmatch pre-transplant. These positive CDC crossmatches became negative and the level of pre-formed DSAs reduced profoundly and rapidly, within 3 h post-liver revascularisation. The reduction in pre-formed DSAs, regardless of subclass, was seen immediately post-liver revascularisation, before implantation of the renal allografts. No significant reduction in non-donor specific HLA-antibodies was observed. Both patients maintained good graft function with no rejection on kidney allograft protocol biopsies performed at 10-weeks post-transplant. CONCLUSIONS: These cases support the protective immunoregulatory role of the liver in the setting of SLKT, with no extra desensitisation treatment given pre-operatively for these highly sensitised patients.

In 2016, the Transplantation Society of Australia and New Zealand, with the support of the Australian Government Organ and Tissue authority, commissioned a literature review on the topic of infectious disease transmission from deceased donors to recipients of solid organ transplants. The purpose of this review was to synthesize evidence on transmission risks, diagnostic test characteristics, and recipient management to inform best-practice clinical guidelines. The final review, presented as a special supplement in Transplantation Direct, collates case reports of transmission events and other peer-reviewed literature, and summarizes current (as of June 2017) international guidelines on donor screening and recipient management. Of particular interest at the time of writing was how to maximize utilization of donors at increased risk for transmission of human immunodeficiency virus, hepatitis C virus, and hepatitis B virus, given the recent developments, including the availability of direct-acting antivirals for hepatitis C virus and improvements in donor screening technologies. The review also covers emerging risks associated with recent epidemics (eg, Zika virus) and the risk of transmission of nonendemic pathogens related to donor travel history or country of origin. Lastly, the implications for recipient consent of expanded utilization of donors at increased risk of blood-borne viral disease transmission are considered.

Background: Primary oxaloses are rare genetic disorders that result in hepatic overproduction of oxalate. Primary hyperoxaluria type1(PH1) is themost common and severe form. Clinical manifestations range from renal calculi to progressive renal impairment and systemic deposition of oxalate. Supportive measures may slow kidney disease progression but many cases develop end stage renal disease(ESRD). Combined liver-kidney transplantation may be curative. Case Report: A 65yo male had developed ESRD in 1990 and underwent deceased-donor kidney transplantation in Holland in 2000. The transplant failed within a week, histology revealed oxalate crystals and a diagnosis of PH1 was made by genetic analysis revealing compound pyridoxine-sensitive mutations in the AGXT gene. The patient returned to haemodialysis for 8 years then presented to our unit for simultaneous kidney-liver transplantation( SLK). Aiming to prevent early disease recurrence, Continuous Renal Replacement Therapy(CRRT) was performed during surgery followed by daily CRRT for nine days. Liver allograft functionwas achieved, however the kidney experienced delayed graft function. A renal biopsy showed only acute tubular necrosis and intermittent haemodialysis was continued for a further week by which time kidney function was evident. The patient was discharged on day 26, creatinine 178umol/L. On day 29, creatinine was 202umol/L and a renal biopsy revealed focal oxalate crystals affecting 10% of kidney. A Repeat biopsy at day 39 showed progressive oxalate deposition. Daily dialysis was re-established followed by slow recovery of kidney allograft function. Conclusion(s): Data surrounding transplantation for primary hyperoxyluria are limited to small case series. Risk of disease recurrence caused by renal excretion of residual systemic oxalate may occur despite SLK preventing further production. More data on how to assess oxalate burden and prevent recurrence are required.

Background and Aims: BK virus is an important cause of renal allograft loss in the renal transplant population. There is limited data regarding intermediate to long-term outcomes in patients with BK viraemia. Effects of routine screening are not well established, with prevalence in prospectively screened cohorts ranging from 11 to 43%. Our aim was to describe the burden of BK viraemia (BKV) and BK nephropathy (BKN) in a large single transplant centre. Method(s): We conducted a retrospective cohort study of 526 patients transplanted between 2008 and 2015, when routine screening (at 3 and 12 months post transplantation) was established. Result(s): 71 patients (13%) developedBKVand 20 (4%) developed BKN during the study period. The median follow-up was 50.9 months (IQR 28.4-82.2) with a minimum follow-up of 12 months. More than 95% of patients were screened for BK at 3 months. All but two patients with BKN had intermediate or high levels of BKV>1000copies/ml. Themajority of patients had basiliximab induction (73%) and maintenance tacrolimus, mycophenolate and prednisolone (94%). Race was strongly associated with BKV (p<0.001), with Asian/ Indian and Aboriginal/Pacific Islander groups both having an increased risk compared to Caucasian (OR Asian/Indian compared to Caucasian 2.49; 95%CI 1.20-5.16). Therewas a trend toward higher rates ofBKV with increasing HLA mismatch (p=0.065). Acute rejection and thymoglobulin use were not associated with BKV (OR 1.16, p=0.751; OR 0.71, p=0.349 respectively). Conclusion(s): BKV was detected in 13%of our cohort and Asian and Indian race was associated with a significantly increased risk. Routine screening for BKV is effective and enables optimal management of immunosuppression to minimise progression.

Background To determine the incremental gains in graft and patient survival under a risk-based, deceased donor kidney allocation compared with the current Australian algorithm. Methods Risk-based matching algorithms were applied to first graft, kidney only recipients (n = 7513) transplanted in Australia between 1994 and 2013. Probabilistic models were used to compare the waiting time, life, and QALYs and graft years between the 8 risk-based allocation strategies against current practice. Results Compared with current practice, Kidney Donor Risk Index-Estimated Posttransplant Survival matching of the lowest 20% of scores reduced median waiting time by 0.64 years (95% confidence interval [CI], 0.52-0.73) for recipients aged 30 years or younger, but increased waiting time by 0.94 years (95% CI, 0.79-1.09) for recipients older than 60 years. Among all age groups, the greatest gains occurred if Kidney Donor Risk Index-Estimated Posttransplant Survival matching of the lowest 30% of scores was used, incurring a median overall gain of 0.63 (95% CI, 0.03-1.25) life years and 0.78 (95% CI, 0.30-1.26) graft years compared with the current practice. A median gain in survival of 1.91 years for younger recipients (aged 30-45 years) was offset by a median reduction in survival (by 0.95 life years) among the older recipients. Prioritization of lower-quality donor kidneys for older candidates reduced the waiting time for recipients older than 45 years, but no changes in graft and patient survivals were observed. Conclusions Risk-based matching engendered a moderate, overall increase in graft and patient survivals, accrued through benefits for recipients 45 years or younger but disadvantage to recipients older than 60 years.Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Aim: To collect and analyse long-term safety and efficacy data in patients with Lupus Nephritis (LN) and to characterise and describe the population of patients receiving Myfortic and other immunosuppressant therapies. Background(s): Long term monitoring of outcomes and safety provides an invaluable opportunity to generate significant insights about the nature of the disease, temporal and treatment induced changes within the natural history of the disease, as well as to pick up early signs of any safety signals that may not be evident with current patient numbers or duration of treatment. Method(s): This non-interventional registry will collect data for up to five years, here we present patient demographics at entry into LUNAR. Result(s): 144 patients are enrolled in LUNAR with 82.6% female and a mean age of 38.8 years. Patients had a mean and median duration of SLE of 8.81 and 7.00 years respectively (range 0-42 years). The mean duration of LN was 5.35 years (range 0.1-30.2 years) with a mean time between SLE and LN of 3.37 years (range 1.0-32.0). Class of LN from biopsy indicated the majority of patients were Class IV (56.3%) and Class III (20.1%). The mean serum creatinine was 89.4 mumol/L (range 34-426 mumol/). The average calculated eGFR was 92 mL/ min/1.73 m2 (range 10-146.7), 57.6% of patients had a calculated eGFR >= 90 mL/min/1.73 m2 and 20.8% between 60-<90 mL/min/1.73 m2. At enrolment 81.25% of patients had a mycophenolate based immunosuppressive therapy with 59.7% Myfortic. There was 46 patients (31.9%) previously treated with cyclophosphamide and 79.2% and 47.9% of patients were concomitantly treated with corticosteroids and hydroxycholorquine. Conclusion(s): LUNAR is the first study in Australia that will examine outcomes in patients treated for LN and may further inform therapeutic decisions regarding management of lupus nephritis.

Aim: To conduct a pilot trial of diet and exercise to determine feasibility and examine outcomes. Background(s): New Onset Diabetes After Transplantation (NODAT) is common and is predictive of increased mortality. We hypothesised that progressive resistance training (PRT) coupled with dietary advice may improve body composition, decrease insulin resistance and reduce NODAT prevalence. Method(s): Kidney recipients were enrolled 6-8 weeks after transplantation (n = 56) across 4 sites. All received basiliximab, tacrolimus, mycophenolate and steroids. All received dietary assessment/advice plus supervised instruction on PRT, followed by unsupervised PRT for 6 months. Assessments included 3-day food diary, anthropometrics, body composition (DEXA), strength testing, OGTT, kidney function, SF-36. Result(s): Fifty-six patients were enrolled; 9 discontinued prematurely (back pain (2), depression (2), lymphoma (1), non-compliance (1), withdrawal of consent (3)). Intention to treat analysis comparing baseline to study-end demonstrated trends toward less diabetes (24.5% v 11.4%) andinsulin resistance (93.5% v 82.6%). HbA1c (5.6 +/- 0.6 v 5.7 +/- 0.6) was unchanged. Despite reductions in measured caloric intake (8791 +/- 2771 KJ v 7691 +/- 2561) and increased physical activity, BMI (24.6 +/- 3.9 v 25.1 +/- 4.5), WHR (0.89 +/- 0.1 v 0.88 +/- 0.1) and body composition (% body fat (28.7 +/- 8.5 v 29.0 +/- 9.0, lean mass (46.1 +/- 9.3 kg v 47.1 +/- 10.2)) were unchanged. Perceived physical health improved with mean baseline SF-36 PCS scores (41.4 +/- 5.9) becoming similar to population norms at month 6 (50.4 +/- 5.0). Conclusion(s): A program of diet and exercise was generally well tolerated and was associated with trends toward improvement, rather than the usual decline, in metabolic parameters post-transplant. A controlled study is warranted.

Aim: To assess the safety, efficacy and outcomes of indigenous and nonindigenous patients treated for LN with Mycophenolate and other immunosuppressive agents within Australia. Background(s): Patients with Systemic lupus erythematosus (SLE) and kidney involvement, particularly WHO class III or IV lupus nephritis (LN), typically have poorer outcomes than those without. Until recently, the management of severe disease has involved corticosteroids and cyclophosphamide for both for induction and maintenance therapy. In 2012 mycophenolate sodium was approved in Australia for induction and maintenance therapy in adult patients with WHO class III, IV or V LN. Method(s): This is an ongoing multicentre, non-interventional study of patients treated forWHOclass III, IV or V LN. Data is to be collected from approximately 200 patients taking mycophenolate sodium and other immunosuppressives over a 5 year period. Observational data capture includes laboratory measures of disease (serum creatinine and complement levels, full blood count, ESR, CRP, anti-dsDNA and urinary estimations of erythrocytes and proteinuria) and histopathology. Result(s): As of 31st March 2014 there is currently 81 patients recruited (41% Caucasian, 8% Aboriginal/Torres Strait Islander, 30% Asian, 20% Other) with 85% of patients female and a mean age of 38 years. 46% of patients are on a mycophenolate sodium regimen, 21% mycophenolate mofetil, 7% azathioprine 3% cyclophosphamide. Patients have a mean SLE disease duration of 9.9 years with a mean duration of LN of 6.15 years. Conclusion(s): LUNAR is the first study in Australia to examine outcomes in patients treated for WHO class III, IV or V LN with Mycophenolate and other immunosuppressive agents.

Background. Interleukin 18 (IL-18) is primarily a macrophage-derived, pro-inflammatory cytokine. As macrophages can act as effector cells in acute rejection, we examined the role of IL-18 in a rat model of acute renal allograft rejection. Methods. Life-sustaining orthotopic DA to Lewis allograft and Lewis-Lewis isograft kidney transplants were performed. In the same model, macrophage-depleted animals, achieved with liposomal-clodronate therapy, were also studied. Macrophage (ED1+) accumulation and IL-18 expression was assessed by immunohistochemistry. CD11b+ cells (macrophages) were isolated from kidney and spleen by micro beads. Real-time PCR was used to assess IL-18 and INF-gamma mRNA expression in tissue and cell isolates. Results. Allografts, but not isografts, developed severe tubulo-interstitial damage and increased serum creatinine by day 5 (P<0.001). Immunohistochemistry revealed a greater ED1+ cell accumulation in day 5 allografts compared with isografts (P<0.001). IL-18 mRNA expression was increased 3-fold in allografts compared to isografts (P<0.001). Accordingly, IL-18 protein was increased in allografts (P<0.001), and was predominantly expressed by ED1+ macrophages. CD11b+ macrophages isolated from allografts had a 6-fold upregulation of IL-18 mRNA expression compared to isograft macrophages (P<0.001). Macrophage depletion resulted in a marked attenuation of allograft rejection, ED1+ and IL-18+ cells were significantly reduced (P<0.05) as was IL-18 mRNA expression (29.28 +/- 2.85 vs 62.48 +/- 3.05, P < 0.001). INF-gamma mRNA expression (P < 0.01) and iNOS (P < 0.001) production were also significantly reduced in the macrophage-depleted animals. Conclusion. This study demonstrates that IL-18 is significantly increased during acute rejection and is principally produced by intra-graft macrophages. We hypothesize that IL-18 upregulation may be an important macrophage effector mechanism during the acute rejection process. © The Author [2005]. Published by Ox