Identification of risk epitope mismatches associated with de novo donor-specific HLA antibody development in cardiothoracic transplantation.

The development of de novo donor-specific HLA antibodies (dnDSA) after transplantation is associated with graft failure, mortality, and cost. There is no effective therapeutic intervention to prevent dnDSA or ameliorate associated injury. The aims of this study were to identify specific HLA factors associated with dnDSA development and to propose primary prevention strategies that could reduce the incidence of dnDSA without prohibitively limiting access to transplant. The investigation cohort included heart transplant recipients from 2008 to 2015 (n = 265). HLA typing was performed and HLA antibody testing was undertaken before and after transplantation. HLAMatchmaker analysis was performed for persistent dnDSA to identify potentially more immunogenic eplet differences. Validation was performed in recipients of lung transplants from 2008 to 2013 (n = 433). The majority of recipients with dnDSA had antibodies to identical eplet positions on DQ2 and DQ7. A high-risk epitope mismatch (found in DQA1*05 +  DQB1*02/DQB1*03:01(7)) was associated with a 4.2- and 4.9-fold increased risk of dnDSA in heart and lung recipients respectively. HLA electrostatic potential modeling provided a plausible explanation for this observed immunogenicity. A theoretical allocation algorithm avoiding high-risk epitope mismatches was generated and predicted to reduce dnDSA by up to 72% without additional testing, eplet analysis, or cost.

Is big bad or bearable? Long-term renal transplant outcomes in obese recipients.

BACKGROUND: The global obesity epidemic has implications for kidney transplantation. There are conflicting reports regarding the impact of obesity on long-term post-transplant outcomes. AIM: To explore the impact of body mass index (BMI) on long-term outcomes after kidney transplantation. DESIGN: The association between BMI and cardiovascular disease, cancer, post-transplant diabetes mellitus, graft and recipient survival was investigated in recipients who had been transplanted at least ten years previously. METHODS: All consecutive adult renal transplant recipients who received first, deceased donor, transplants between 1986 and 2005 in Northern Ireland were followed-up until 2016. RESULTS: A total of 328 patients were eligible. Of them, 96 were overweight with a BMI 25.0-29.9 kg/m2, and 56 were obese with a BMI exceeding 29.9 kg/m2. Median follow-up time was 16.7 years. In multivariate analysis recipient BMI was associated with the development of post-transplant diabetes mellitus (P=0.003), but not with new cardiovascular disease (P=0.78). Cancer was less common in recipients with a higher BMI (hazard ratio (HR) 0.58, P < 0.001). BMI at the time of transplantation did not significantly influence graft (P=0.28) or recipient survival (P=0.13). CONCLUSIONS: Increased BMI at time of transplantation is associated with an increased risk of post-transplant diabetes mellitus but not new cardiovascular disease or malignancy. Long-term graft and recipient survival is not impacted. Potential recipients should not be excluded from transplantation solely on the basis of obesity, rather it should be considered as one part of an individualized risk stratification, based on comorbidity and considering the risk of death on maintenance dialysis.

Analysis of single nucleotide polymorphisms implicate mTOR signalling in the development of new-onset diabetes after transplantation.

INTRODUCTION: Despite excellent first year outcomes in kidney transplantation, there remain significant long-term complications related to new-onset diabetes after transplantation (NODAT). The purpose of this study was to validate the findings of previous investigations of candidate gene variants in patients undergoing a protocolised, contemporary immunosuppression regimen, using detailed serial biochemical testing to identify NODAT development. METHODS: One hundred twelve live and deceased donor renal transplant recipients were prospectively followed-up for NODAT onset, biochemical testing at days 7, 90, and 365 after transplantation. Sixty-eight patients were included after exclusion for non-white ethnicity and pre-transplant diabetes. Literature review to identify candidate gene variants was undertaken as described previously. RESULTS: Over 25% of patients developed NODAT. In an adjusted model for age, sex, BMI, and BMI change over 12 months, five out of the studied 37 single nucleotide polymorphisms (SNPs) were significantly associated with NODAT: rs16936667:PRDM14 OR 10.57;95% CI 1.8-63.0;p = 0.01, rs1801282:PPARG OR 8.5; 95% CI 1.4-52.7; p = 0.02, rs8192678:PPARGC1A OR 0.26; 95% CI 0.08-0.91; p = 0.03, rs2144908:HNF4A OR 7.0; 95% CI 1.1-45.0;p = 0.04 and rs2340721:ATF6 OR 0.21; 95%CI 0.04-1.0; p = 0.05. CONCLUSION: This study represents a replication study of candidate SNPs associated with developing NODAT and implicates mTOR as the central regulator via altered insulin sensitivity, pancreatic ß cell, and mitochondrial survival and dysfunction as evidenced by the five SNPs. GENERAL SIGNIFICANCE: 1)Highlights the importance of careful biochemical phenotyping with oral glucose tolerance tests to diagnose NODAT in reducing time to diagnosis and missed cases.2)This alters potential genotype:phenotype association.3)The replication study generates the hypothesis that mTOR signalling pathway may be involved in NODAT development.

The clinical course of kidney transplant recipients after 20 years of graft function.

There is a growing population of kidney transplant recipients who have survived 20 years with a functioning graft. This study identified the factors associated with prolonged survival and described the clinical course of recipients after two decades of transplant function. All recipients transplanted in Northern Ireland between 1968 and 1993 were included (n = 706) and data were collected prospectively. At 20 years, 25% had a functioning transplant; in multivariate analysis younger recipient age and living donation were associated with 20-year survival. The median recipient survival beyond two decades was 13.3 years; cancer was the commonest cause of death. De novo malignancy developed in 37% of recipients and cardiovascular disease in 27% after 20 years of graft function. The median graft survival after 20 years was 9.3 years; 69% of graft loss was due to death with a functioning transplant. Advances in kidney transplantation have improved the long-term survival of both graft and recipient. After two decades the majority of patients die with a functioning graft. The focus of management in long-term survivors may need to be on the prevention of cancer and cardiovascular disease to allow further improvements in graft and recipient survival.

Recurrent dense deposit disease after renal transplantation: an emerging role for complementary therapies.

Dense deposit disease is a rare glomerulonephritis caused by uncontrolled stimulation of the alternative complement pathway. Allograft survival after kidney transplantation is significantly reduced by the high rate of disease recurrence. No therapeutic interventions have consistently improved outcomes for patients with primary or recurrent disease. This is the first reported case of recurrent dense deposit disease being managed with eculizumab. Within 4 weeks of renal transplantation, deteriorating graft function and increasing proteinuria were evident. A transplant biopsy confirmed the diagnosis of recurrent dense deposit disease. Eculizumab was considered after the failure of corticosteroid, rituximab and plasmapheresis to attenuate the rate of decline in allograft function. There was a marked clinical and biochemical response following the administration of eculizumab. This case provides the first evidence that eculizumab may have a place in the management of crescentic dense deposit disease. More information is necessary to clarify the effectiveness and role of eculizumab in dense deposit disease but the response in this patient was encouraging. The results of clinical trials of eculizumab in this condition are eagerly awaited.

Further evidence of the increased risk for malignant peripheral nerve sheath tumour from a Scottish cohort of patients with neurofibromatosis type 1.

A recent study, looking at the lifetime risk of developing malignant peripheral nerve sheath tumour (MPNST) in patients with neurofibromatosis type 1 (NF1), estimated the risk to be 8-13%. Prior to this, longitudinal studies had shown that patients with NF1 had a risk of 4-5% of developing MPNST, and cross-sectional studies had found that only 1-2% of patients with NF1 had MPNST. The aim of this study was to estimate the lifetime risk of MPNST in patients with NF1 in southern Scotland, using patient records obtained from the Edinburgh and Glasgow Genetic Units and Scottish Cancer Register. In the period 1993-2002, 14 patients with NF1 were diagnosed with MPNST in a population of 3.5 million. The lifetime risk of MPNST in the Scottish patients with NF1 was calculated to be 5.9-10.3%. This provides further evidence that patients with NF1 are at greater risk of developing MPNST than was previously estimated, and emphasises the importance of educating patients about suspicious symptoms, which may need an urgent medical opinion. The mean age at diagnosis of MPNST (p<0.05) and 5-year survival (p<0.01) were significantly lower in patients with NF1 than in unaffected individuals. This may be due to patients with NF1 presenting later, because the tumour is mistaken for a neurofibroma, or due to MPNST having a more aggressive course in NF1.