MORTALITY FOLLOWING PRIMARY RENAL ALLOGRAFT FAILURE – A REGISTRY ANALYSIS

WH LIM1,2, S CHADBAN2,3, H PILMORE4, P CLAYTON2,5, SP MCDONALD2,5, G WONG6

1Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth; 2ANZDATA Registry, Adelaide; 3Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney; 4Department of Renal Medicine, Auckland Hospital, Auckland; 5Department of Renal Medicine, Royal Adelaide Hospital, Adelaide; 6Centre for Kidney Research & Department of Renal Medicine, Westmead Hospital, Sydney,

Aim: To determine the association between retransplantation and mortality after primary kidney allograft loss.

Background: The reported estimates of mortality following renal allograft loss has been poorly described, which may reflect the variability in patient characteristics in those who were deemed suitable for retransplantation or remained on dialysis.

Methods: Using ANZDATA registry, the association between study groups (patients who were retransplanted vs. not retransplanted [i.e. remained on dialysis] after allograft loss) and all-cause mortality were examined using Cox regression analysis.

Results: Of 5770 patients with failed primary kidney allografts between 1980-2014, 2330 (40.4%) were retransplanted. Retransplanted patients were younger (mean[SD] 35.4[13.3] vs. 46.5[14.7], p<0.01) at graft loss, but had shorter mean first allograft duration (6.0[6.4] vs. 7.0[7.0], p<0.01) compared to those who were not retransplanted. Of patients who were not retransplanted, 76% died within 5 years of graft loss, compared to 17% in those who were retransplanted (p<0.01). Cardiovascular disease was the most frequent cause of mortality after graft loss for patients who were and were not retransplanted (32% vs. 38%), whereas cancer mortality was almost 4-times as common in patients who were retransplanted (15% vs. 4%; p<0.01). Compared to patients who were not retransplanted, retransplanted patients were less likely to die following graft loss, with adjusted hazard ratio (HR) of 0.22 (95%CI 0.20-0.24). Following exclusion of patients who had died within the first year post-graft loss, the adjusted HR for all-cause mortality was 0.27 (95%CI 0.24-0.30). Conclusions: Following failed kidney allografts, patients who were not retransplanted were at a greater risk of mortality compared to those who were retransplanted, with over 75% of deaths occurring within 5 years of allograft loss

CORRELATION AND AGREEMENT BETWEEN THE NUMBER OF CLASS I AND II EPLET MISMATCHES CALCULATED USING SEROLOGICAL, LOW-INTERMEDIATE AND HIGH RESOLUTION MOLECULAR HUMAN LEUKOCYTE ANTIGEN TYPING METHODS

S FIDLER1, L D’ORSOGNA1, AB IRISH2, J LEWIS3, G WONG4, WH LIM5

1Department of Clinical Immunology, Fiona Stanley Hospital, Perth; 2 Department of Renal Medicine, Fiona Stanley Hospital, Perth; 3Centre for Kidney Research & Department of Renal Medicine, Westmead Hospital, Sydney; 4Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth

Aim: To evaluate the agreement between eplet mismatches calculated by serological and two-digit typing methods compared to high-resolution four-digit typing method.

Background: Structural human leukocyte antigen (HLA) matching at the eplet level can be identified by HLAMatchmaker, but requires the entry of four-digit allele typing, which are often not practicable in donor kidney allocation because of time constraint.

Methods: In a cohort of 264 donor/recipient pairs, the evaluation of measurement error was assessed using intra-class correlation to confirm the absolute agreement between the number of eplet mismatches at class I (HLA-A, -B, C) and II loci (HLA-DQ and -DR) calculated using serological or two-digit molecular typing compared to four-digit molecular typing methods. The proportion of donor/recipient pairs with a difference of >5 eplet mismatches between the HLA typing methods was also determined.

Results: Intra-class correlation coefficients between serological and four-digit molecular typing methods were 0.969 (95% confidence intervals [95%CI] 0.960-0.975) and 0.926 (95%CI 0.899-0.944), respectively; and 0.995 (95%CI 0.994-0.996) and 0.993 (95%CI 0.991-0.995), respectively between two-digit and four-digit molecular typing methods. The proportion of donor/recipient pairs with a difference of >5 eplet mismatches at class I and II loci was 4% and 16% for serological versus four-digit molecular typing methods, and <1% and 2% for two-digit versus four-digit molecular typing methods, respectively.

Conclusions: Compared with serology, there is a high level of agreement in the number of eplet mismatches calculated using two- compared to four-digit molecular HLA-typing methods, suggesting that two-digit typing may be sufficient in determining eplet mismatch load in kidney transplantation.

TEMPORAL TRENDS IN CLINICAL OUTCOMES OF KIDNEY TRANSPLANTATION FROM 1996 TO 2013 IN AUSTRALIA AND NEW ZEALAND

WC YEUNG1,2,3, SV BADVE1,2,3, E PASCOE4, CM HAWLEY4,5,6, PA CLAYTON7,8, SP MCDONALD7,8, WH LIM9, G WONG10,11, SJ CHADBAN12,13, SB CAMPBELL4,5,6, and DW JOHNSON4,5,6.

1Department of Renal Medicine, St. George Hospital, Sydney, Australia; 2Renal and Metabolic Division, The George Institute for Global Health, Sydney, Australia; 3School of Medicine, University of New South Wales, Sydney, Australia; 4Australasian Kidney Trials Network, School of Medicine, University of Queensland, Brisbane, Australia; 5Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia; 6Translational Research Institute, Brisbane, Australia; 7The Australia and New Zealand Dialysis and Transplant Registry, Adelaide, Australia; 8Central Northern Adelaide Renal and Transplantation Service, School of Medicine, University of Adelaide, Adelaide, Australia; 9Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, Australia; 10Centre for Transplant and Renal Research, Westmead Hospital, Sydney, Australia; 11School of Public Health, University of Sydney, Sydney, Australia; 12Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney, Australia; 13Kidney Node, Charles Perkins Centre, University of Sydney, Australia.

Aim: To evaluate temporal trends in clinical outcomes of kidney transplantation using data from the ANZDATA Registry.

Background: In recent years, there have been substantial changes in the practice of kidney transplantation including medical and surgical advances, and donor and recipient selection.  Long-term kidney graft and patient survival in the recent era have not been systematically studied.

Methods: This longitudinal study included all 11,512 children and adults who underwent first living or deceased donor kidney transplant surgery in Australia and New Zealand between January 1, 1996 and December 31, 2013. Trends in all-cause graft loss and patient death across the three transplant eras (era 1: 1996-2001, era 2: 2002-2007, and era 3: 2008-2013) were estimated using time-to-event analysis techniques.

Results: Compared to cohort 1996-2001, patients in cohorts 2002-2007 and 2008-2013 were more likely to be older; have diabetes and coronary artery disease; receive kidneys from older donors, circulatory death and expanded criteria donors; have more HLA mismatches; and receive anti-CD25 monoclonal antibody and be treated with tacrolimus and mycophenolate. Over a median follow-up of 7.7 years, 3,774 grafts were lost and 2,360 patients died. Compared to cohort 1996-2001, all-cause graft and patient survival rates were superior in cohorts 2002-2007 and 2008-2013 for deceased-donor transplants, but not for living-donor transplants.  A significant interaction between survival time and transplant era was observed. The risks of graft loss and death for deceased-donor transplants in recent cohorts were lower than cohort 1996-2001 at all time-points, except the risk of graft loss at 5-year in cohort 2008-2013.

Conclusions: Long-term graft and patient survival outcomes of kidney transplantation have improved in deceased-donor transplants, but remained unchanged in living-donor transplants.

POST RENAL TRANSPLANT EXTRAPULMONARY TUBERCULOSIS IN AN OVERSEAS-BORN AUSTRALIAN

C WILKINSON1,2, D JEGATHEESAN3, G KAN1,2, V MANICKAM1,2, V SRIVASTAVA1,2 , S CAMPBELL3

1The Townsville Hospital, Queensland; 2James Cook University Clinical School, Queensland; 3University of Queensland at the Princess Alexandra Hospital, Queensland

Background:  Post-transplant tuberculosis (PTTB) is not uncommon in endemic tuberculosis (TB) areas. It generally represents reactivation of latent TB and 50-60% of cases occur within 12 months post-transplant. Risk factors include acute transplant rejection, concurrent cytomegalovirus (CMV), and HIV infection. TB in Australia has an incidence of 5-7 cases per 100 000, but amongst overseas-born Australians is 19 per 100 000.

Case report:  A 47 year old Phillipines-born female received a deceased donor renal transplant; CMV positive to negative, for ESKD secondary to IgA nephropathy in 2013.  Pre-transplant TB and HIV screening was negative.  She received basiliximab induction and was maintained on tacrolimus, mycophenolate and prednisolone. There was no early rejection.  She presented in March 2017 with fevers and diarrhoea of 10 days duration but no other positive symptoms.  Radiographic investigations revealed tubo-ovarian collection associated with diffuse abdominal lymphadenopathy and terminal ileum thickening.  She underwent laparoscopic drainage with bilateral salpingectomy and oophorectomy; initial histology showed necrotic granuloma and TB was confirmed on culture.  She was commenced on a regime of rifabutin, isoniazid, pyrazinamide and ethambutol. Rifabutin was pre-emptively used in place of rifampicin to reduce drug interaction with tacrolimus.  Graft function deteriorated in the setting of dehydration contributed by nausea, diarrhoea and oral mucosal HSV co-infection; recovering when oral intake was restored.  Tacrolimus dosing required close monitoring and titration within the first month of treatment.

Conclusion: PTTB is not uncommon in endemic areas and should be considered in at risk patients in non-endemic areas. The above anti-TB regime interacts with tacrolimus however there was no rejection observed.

SPONTANEOUS ATRAUMATIC SPLENIC RUPTURE FOLLOWING INTRAVENOUS IMMUNOGLOBULIN FOR PARVOVIRUS B19 ASSOCIATED PURE RED CELL APLASIA IN A RENAL TRANSPLANT PATIENT – A CASE REPORT

M TIONG1, H NANDURKAR1,2, R WALKER1,2, S WILSON1,2,3

1Alfred Health, Melbourne, Victoria; 2Monash University, Melbourne, Victoria; 3Baker IDI, Melbourne, Victoria

Introduction: Parvovirus B19 (PB19) infection is an uncommon cause of anaemia in solid organ transplant. Persistent cases may be treated with intravenous immunoglobulin (IVIg). We report a case of PB19 associated anaemia in a renal transplant recipient who subsequently developed an atraumatic splenic rupture after administration of IVIg.

Case presentation: A 58 year-old male received his second renal transplant in August 2016 (first transplant in 1985 for chronic glomerulonephritis). He developed progressive anaemia from 6-months post transplant (haemoglobin nadir 57 g/L) requiring transfusion support. Further investigation demonstrated a suppressed reticulocytosis with preserved platelet, myeloid and lymphoid lines, consistent with pure red cell aplasia (PRCA). Plasma PB19 IgM was equivocal with negative IgG serology. Subsequent qualitative PB19 DNA PCR was positive.  Bone marrow biopsy showed features consistent with PB19 associated PRCA.

The patient remained anaemic and subsequently progressed to IVIg infusion (2g/kg in two divided doses, 3 days apart). Following treatment there was recovery of reticulocyte counts with spontaneous increment in haemoglobin levels. Repeat serum PB19 PCR was negative.

The patient re-presented 1-week after IVIg with sudden onset abdominal pain. CT demonstrated spontaneous splenic haemorrhage with evidence of an underlying splenic haemangioma.

Though described, spontaneous atraumatic rupture of splenic haemangioma is quite unusual, with PB19 virus a particularly unusual infective cause. Whilst it is possible that rapid erythrocytosis and splenic erythrocyte aggregation may have contributed to his presentation, IVIg administration itself may trigger splenic sequestration of red-cells and has been associated with spleen rupture in primary cytomegalovirus (but not PB19) infections.

Conclusions: To our knowledge this is the first reported case of spontaneous atraumatic splenic rupture following administration of IVIg for treatment of PB19 associated PRCA.

RESISTANT CYTOMEGALOVIRUS DISEASE IN KIDNEY-PANCREAS TRANSPLANT: TREATMENT WITH PRIMED T-CELL THERAPY

K KABLE1, S SO1, J LI1, L CLANCY2,3, N ROGERS1,2,  E BLYTH2,3,4, B GETTA4, G WONG1,2, P O’CONNELL1, 2, J CHAPMAN 1, 2, D GOTTLIEB2,3,4

1Department of Nephrology, Westmead Hospital, Westmead, New South Wales; 2The Westmead Institute for Medical Research, Australia; 3Sydney Cell and Gene Therapy Laboratory, Westmead Hospital; 4Blood and Marrow Transplant Unit, Australia

Background: Human cytomegalovirus (CMV) infection in transplant patients can lead to devastating invasive disease. Ganciclovir and foscarnet resistance poses a therapeutic dilemma. Adoptively-transferred CMV T-cells have been used in bone marrow transplants, but there has been reluctance to adopt this in solid-organ transplants given the theoretical risks of graft sensitisation and rejection.

Case Report: A 43 year old lady with type 1 diabetes and end stage renal failure received a simultaneous kidney-pancreas transplant in March 2015. She received standard induction therapy, but two weeks post-transplant, she received methylprednisolone and anti-thymocyte globulin for acute rejection. Mycophenolate was subsequently changed to azathioprine for gastrointestinal intolerance.

She received 12 months prophylaxis with valganciclovir as she was the CMV-seronegative recipient of a CMV-seropositive graft. She developed CMV disease three months post cessation and was restarted with treatment dose valganciclovir with improvement in the viral copy number.  Six months later, she developed breakthrough invasive CMV disease and her viral CMV copies continued to rise to 800,000 copies/mL despite reduction in immunosuppression and treatment with IV foscarnet.

Gene mutation testing revealed UL 97 and UL 54 mutations, confirming foscarnet resistance. Novel therapies including maribavir, brincidofovir and letermovir were unavailable. She received a trial of primed IV CMV T-cell therapy in March 2017, and achieved excellent response. Her current CMV copies now below 1000 copies/ml. She has maintained stable graft function with no clinical evidence of rejection.

Conclusions: T-cell therapy may be effective against invasive, resistant cytomegalovirus disease in transplant recipients, without incurring adverse effects including acute rejection and graft loss.

SCEDOSPORIUM APIOSPERMUM BONE INFECTION IN A RENAL TRANSPLANT RECIPIENT

A SIRIWARDANA1, J HOLT1, J GREENSTEIN1

1Department of Renal Medicine, The Wollongong Hospital, Wollongong, NSW

Background: Scedosporium apiospermum is a fungal species that has been rarely reported to cause serious infections in solid organ transplant recipients. 14 cases have been reported among renal allograft recipients between 2000-2015, with a mortality rate of 4/14 (28.6%). Case report: A 45 year old man with end-stage renal failure secondary to crescenteric glomerulonephritis underwent a cadaveric renal transplant in 2015 and was maintained on standard immunosuppression with tacrolimus, mycophenolate sodium and prednisone. Other past medical history included idiopathic thrombocytopaenic purpura and hypertension. 3 months post-transplant, he presented with acute on chronic graft dysfunction with creatinine 235μmol/L and left 4th toe swelling. Left foot X-ray demonstrated soft tissue oedema and MRI identified subcutaneous fluid locules at the level of the middle and proximal phalanges. No clinical improvement was seen despite intravenous antibiotics and repeat MRI 3 weeks later demonstrated rapid progression to osteomyelitis involving the metatarsal head and proximal and distal phalangeal bases. He underwent a left 4th toe amputation. Bone histopathology showed abundant septate fungal hyphae amidst actively inflamed marrow, and culture grew Scedosporium apiospermum and methicillin-resistant Staphylococcus aureus. Therapy with 4 weeks intravenous vancomycin and 6 months oral voriconazole was undertaken, necessitating tacrolimus dose reduction due to voriconazole-tacrolimus drug interactions. He had good clinical recovery, however his course has also been complicated by BK nephropathy which has responded to reduced immunosuppression. Conclusion: Scedosporium apiospermum is an opportunistic pathogen that can cause rare but serious soft tissue infection in immunocompromised patients; treatment in renal allograft recipients may be complicated by drug interactions and have subsequent impacts on graft outcomes.

RHABDOMYOLYSIS SECONDARY TO SEASONAL INFLUENZA VACCINE IN A RENAL TRANSPLANT RECIPIENT

A SIRIWARDANA1, J MURRAY1, T CHIRAKIJJA1, 2, G MANGOS1, 2

1Department of Renal Medicine, St George Hospital, Kogarah, NSW; 2St George and Sutherland Clinical School UNSW, St George Hospital, Kogarah, NSW

Background: Seasonal influenza vaccination is recommended for all renal allograft recipients and is predominantly well tolerated. Very few cases of influenza vaccine-induced rhabdomyolysis, with or without acute kidney injury, have been reported, and only one case in a renal allograft recipient has been described. Case report: A 58 year old male received a quadrivalent influenza vaccine in the primary care setting. Within 24 hours he developed myalgias, marked proximal leg weakness and malaise. Symptoms persisted and he developed dark urine 8 days later resulting in hospitalisation. Past history included cadaveric renal transplant for diabetic nephropathy 8 years prior for which he was on maintenance immunosuppression with cyclosporine and mycophenolate mofetil, type 2 diabetes mellitus, ischaemic heart disease and hypercholesterolaemia on ezetimibe/simvastatin. Admission investigations revealed mildly elevated creatinine of 136μmol/L (baseline 114μmol/L), markedly elevated creatinine kinase of 65,142 IU/L and elevated liver transaminases (ALT 1274 U/L, AST 1916 U/L). Serum potassium, calcium, phosphate and thyroid function were normal. Urine dipstick was strongly positive for blood and protein, however formal microscopy revealed no microscopic haematuria.  A diagnosis of vaccine-related rhabdomyolysis on a background of statin and cyclosporine therapy was made. Statin was withheld and aggressive intravenous fluid therapy was commenced. Creatinine kinase, renal function and liver transaminases improved, and clinical symptoms also improved. The patient reported a similar history of myalgias and weakness shortly after influenza vaccination 3 years prior however he did not present to hospital at this time. Conclusion: This is the second case of influenza vaccine-related rhabdomyolysis in a renal transplant recipient to be described. Clinicians should be aware of this unusual complication which can have potentially damaging effects on allograft function.

THE ADOPT TRIAL: A PHARMACOMETRIC STUDY OF THE BETWEEN-OCCASION VARIABILITY IN FREE MYCOPHENOLIC ACID PHARMACOKINETICS PRIOR TO AND IN THE EARLY PHASE POST KIDNEY TRANSPLANT IN SIXTY PROSPECTIVELY RECRUITED ADULTS AND CHILDREN

D METZ1, A WALKER1, N CRANSWICK1, J KAUSMAN1, N HOLFORD2, F IERINO3

1Royal Children’s Hospital, Melbourne; 2Univerisity of Auckland, Auckland New Zealand; 3 St Vincent’s Hospital, Melbourne

Aim: Provide proof of concept that dosing to free mycophenolic acid (MPA) concentrations will allow optimisation of mycophenolate mofetil (MMF) prior to kidney transplantation and negate the need for repeated AUC estimation in the early months.

Background: The free drug principle, established for a broad range of therapeutic drugs, holds that it is the free drug concentration in plasma most directly linked with biophase concentration and hence drug effect.

To safely perform concentration-controlled dosing of MMF in the initial phase post kidney transplant, repeated AUC estimation is required, because of enterohepatic recycling and time-dependant clearance. However, assuming the free drug principle holds for MPA, as has been shown in vitro, it is likely that much of the increase in MPA exposure over time is related to clinically irrelevant plasma protein binding changes. This would reduce the need for repeated estimation and, we hypothesize, providing an opportunity for dose optimisation prior to kidney transplant.

Methods: The ADOPT trial, completing recruitment in 2017, is a national, multi-site pharmacokinetic trial examining the relationship between total and free MPA pharmacokinetics before and at several points after kidney transplantation, and of covariates known to influence MPA plasma protein binding. Pharmacometric mixed effect modelling will be used for analysis, including examining whether the between-occasion variability in free MPA is small enough to allow for precise concentration-controlled dosing.

Conclusions: If precision and practicality of free MPA dose optimisation can be shown, this would provide a compelling case for a larger interventional trial targeting mycophenolate dose to free MPA concentration. This would overcome the major practical challenges to optimising exposure to mycophenolic acid in the critical early phase post transplantation.

NON-ABO RED BLOOD CELL GROUP ANTIGENS IN RENAL TRANSPLANTATION

P KOTAGIRI1, R MASTERON1, P HUGHES1, M HAEUSLER1, S HOLT1, C HOGAN1

1Royal Melbourne Hospital, Melbourne, Victoria

Background: Blood group antigens are red blood cell surface markers made of either protein or carbohydrate and are defined serologically by an antibody. The role of most are unknown. Antibodies against these antigens cause varying degrees of red blood cell hemolysis. Antibodies against the major ABO blood groups cross-reacts with similar antigens on the kidney causing hyper-acute rejection without therapy. Non-ABO red blood cell antigens can cause transient red blood cell hemolysis due to antigen positive passenger red blood cells. Renal transplant rejection may occur, where the red blood cell antigen is present on the endothelial cells of vasculature or renal epithelium and is structurally immunogenic. Of the common non-ABO red blood cell group antigens, there is evidence of renal expression with the MNS, Lutheran, Lewis, Duffy and Kidd groups.

Case report: We present a case series of renal transplants with mismatched non-ABO red blood cell group antigens and examine the evidence that this can cause rejection. We illustrate the merits of treatments including; increased immunosuppression, plasma exchange and warming of the kidney, to help prevent rejection.

Conclusion: Future studies are required to help delineate the significance of the non-ABO red blood cell antigens and the most effective therapy. More extensive red blood cell antigen and antibody screening pre-transplantation may help identify patients at risk. The use of transfusion matching and antibody depleted FFP may help prevent antibody formation. In the presence of known non-ABO red blood cell antigen mismatch and rejection with no donor specific antibody, there may be a role for testing for non-ABO red blood cell group antibodies.

About ANZSN

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