Shruti Mittal

Peripheral Blood Sampling for the Detection of Allograft Rejection: Biomarker Identification and Validation

Currently, acute allograft rejection can only be detected reliably by deterioration of graft function confirmed by allograft biopsy. A huge drawback of this method of diagnosis is that substantial organ damage has already taken place at the time that rejection is diagnosed. Discovering and validating noninvasive biomarkers that predict acute rejection, and chronic allograft dysfunction, is of great importance. Many studies have investigated changes in the peripheral blood in an attempt to find biomarkers that reflect changes in the graft directly or indirectly. Herein, we will review the promises and limitations of the peripheral blood biomarkers that have been described in the literature so far.

De novo donor-specific HLA antibodies: biomarkers of pancreas transplant failure.

This study assesses the role of posttransplant HLA antibody monitoring in the surveillance of pancreas transplant recipients. Four hundred thirty‐three pancreas transplants were performed at the Oxford Transplant Centre 2006–2011 (317 simultaneous pancreas kidney [SPK] and 116 isolated pancreas [IP]). HLA antibody monitoring was performed at 0, 6 and 12 months and annually and during clinical events. There was no association between pancreas graft failure and recipient or donor characteristics. Posttransplant antibody status, available for 354 (81.8%) of recipients, demonstrated that 141 (39.8%) developed de novo HLA antibodies, of which 52 (36.9%) were de novo donor‐specific HLA antibodies (DSA) (34 SPK, 18 IP). The development of antibodies to donor HLA, but not to nondonor HLA, was significantly associated with poorer graft outcomes, with 1‐ and 3‐year graft survival inferior in SPK recipients (85.2% vs. 93.5%; 71.8% vs. 90.3%, respectively; log‐rank p = 0.002), and particularly in IP recipients (50.0% vs. 82.9%; 16.7 vs. 79.4%, respectively; log‐rank p = 0.001). In a multivariate analysis, development of de novo DSA emerged as a strong independent predictor of pancreas graft failure (hazard ratio 4.66, p < 0.001). This is the largest study to examine de novo HLA antibodies following pancreas transplantation and clearly defines a high‐risk group in need of specific intervention.

Pancreas Transplantation: Solid Organ and Islet

Transplantation of the pancreas, either as a solid organ or as isolated islets of Langerhans, is indicated in a small proportion of patients with insulin-dependent diabetes in whom severe complications develop, particularly severe glycemic instability and progressive secondary complications (usually renal failure). The potential to reverse diabetes has to be balanced against the morbidity of long-term immunosuppression. For a patient with renal failure, the treatment of choice is often a simultaneous transplant of the pancreas and kidney (SPK), whereas for a patient with glycemic instability, specifically hypoglycemic unawareness, the choice between a solid organ and an islet transplant has to be individual to the patient. Results of SPK transplantation are comparable to other solid-organ transplants (kidney, liver, heart) and there is evidence of improved quality of life and life expectancy, but the results of solitary pancreas transplantation and islets are inferior with respect to graft survival. There is some evidence of benefit with respect to the progression of secondary diabetic complications in patients with functioning transplants for several years.

Validation of the Pancreas Donor Risk Index for use in a UK population.

Pancreas graft failure rates remain substantial. The PDRI can be used at the time of organ offering, to predict one‐year graft survival. This study aimed to validate the PDRI for a UK population. Data for 1021 pancreas transplants were retrieved from a national database for all pancreas transplants. Cases were categorized by PDRI quartile and compared for death‐censored graft survival. Significant differences were observed between the UK and US cohorts. The PDRI accurately discriminated graft survival for SPK and was associated with a hazard ratio of 1.52 (P = 0.009) in this group. However, in the PTA and PAK groups, no association between PDRI quartile and graft survival was observed. This is the largest study to validate the PDRI in a European cohort and has shown for the first time that the PDRI can be used as a tool to predict graft survival in SPK transplantation, but not PTA or PAK transplantation.

Pancreas Transplantation: Past, Present, Future

Diabetes is the pandemic disease of the modern era, with 10% of these patients having type 1 diabetes mellitus. Despite the prevalence, morbidities, and associated financial burden, treatment options have not changed since the introduction of injectable insulin. To date, over 40,000 pancreas transplants have been performed globally. It remains the only known method for restoring glycemic control and thus curing type 1 diabetes mellitus. The aim of this review is to bring pancreatic transplantation out of the specialist realm, informing practitioners about this important procedure, so that they feel better equipped to refer suitable patients for transplantation and manage, counsel, and support when encountering them within their own specialty. This study was a narrative review conducted in October 2015, with OVID interface searching EMBASE and MEDLINE databases, using Timeframe: Inception to October 2015. Articles were assessed for clinical relevance and most up-to-date content, with articles written in English as the only inclusion criterion. Other sources used included conference proceedings/presentations and unpublished data from our institution (Oxford Transplant Centre). Pancreatic transplantation is growing and has quickly become the gold standard of care for patients with type 1 diabetes mellitus and renal failure. Significant improvements in quality of life and life expectancy make pancreatic transplant a viable and economically feasible intervention. It remains the most effective method of establishing and maintaining euglycemia, halting and potentially reversing complications associated with diabetes.

Improving monitoring after pancreas transplantation alone: Fine-tuning of an old technique

Graft survival after pancreas transplantation alone (PTA) is significantly poorer than graft survival after simultaneous pancreas kidney (SPK) and is particularly affected by difficulty in monitoring rejection. Exocrine bladder drainage allows assessment of pancreas graft function as urinary amylase (UA). However, standards for UA collection and interpretation are not well defined. In this study, 21 bladder‐drained PTA recipients were monitored with daily values for UA and urine creatinine (Creat) concentration from post‐transplant 10‐mL samples and 24‐h collections. Clinical events were documented and correlated to UA measurements. UA values were found to increase post‐transplant until day 15, and large interpatient variability was noted (median 12 676 IU/L, range 668–60 369 IU/L). A strong correlation was found total 24‐h UA production and spot UA/Creat ratio (r = 0.80, p < 0.001). UA/Creat ratio showed less variation during episodes of impaired renal function; therefore, urinary amylase baseline was defined as the median UA/Creat ratio after day 15. A > 25% decrease of UA predicted 9/13 (69%) events. We conclude that individual baselines should be set once the values have stabilized after 15 d post‐transplant and that spot UA/Creat measures are reliable, patient friendly and indicate potential events after PTA.

Early postoperative continuous glucose monitoring in pancreas transplant recipients

Continuous glucose monitoring (CGM) is used in people with type 1 diabetes to help with insulin treatment regimens. Its value in whole‐organ pancreas transplantation (PT) is largely unknown. This study aimed to use CGM to assess the metabolic profile of pancreas transplant recipients in the early post‐transplant period. We studied CGM data in 30 PT recipients and related findings to an early oral glucose tolerance test (OGTT). Complete data were available for 26 recipients. Seven days after a PT, normoglycaemia was present 77.9% of the time. Hypoglycaemic events (glucose <3.9 mmol/l) occurred in 10 of 26 (38.5%) of the cohort, but were infrequent (present 1.4% of the time). Hyperglycaemia (glucose >7.8 mmol/l) was present for 20.7% of the study period and correlated with a diagnosis of abnormal glucose tolerance. Whilst normoglycaemia is successfully achieved for the majority of the time after PT, hypoglycaemia can occur. Hyperglycaemia is more common and correlates well with the early postoperative OGTT, which is associated with graft failure. CGM is easier to perform and provides 24‐h data that could inform clinical decision‐making in patients in the postoperative period.

Genetic Variation in Caveolin‐1 Correlates With Long‐Term Pancreas Transplant Function

Pancreas transplantation is a successful treatment for a selected group of people with type 1 diabetes. Continued insulin production can decrease over time and identifying predictors of long‐term graft function is key to improving survival. The aim of this study was to screen subjects for variation in the Caveolin‐1 gene (Cav1), previously shown to correlate with long‐term kidney transplant function. We genotyped 435 pancreas transplant donors and 431 recipients who had undergone pancreas transplantation at the Oxford Transplant Centre, UK, for all known common variation in Cav1. Death‐censored cumulative events were analyzed using Kaplan–Meier and Cox regression. Unlike kidney transplantation, the rs4730751 variant in our pancreas donors or transplant recipients did not correlate with long‐term graft function (p = 0.331–0.905). Presence of rs3801995 TT genotype (p = 0.009) and rs9920 CC/CT genotype (p = 0.010) in our donors did however correlate with reduced long‐term graft survival. Multivariate Cox regression (adjusted for donor and recipient transplant factors) confirmed the association of rs3801995 (p = 0.009, HR = 1.83;[95% CI = 1.16–2.89]) and rs9920 (p = 0.037, HR = 1.63; [95% CI = 1.03–2.73]) with long‐term graft function. This is the first study to provide evidence that donor Cav1 genotype correlates with long‐term pancreas graft function. Screening Cav1 in other datasets is required to confirm these pilot results.

Pre-operative Predictors of Health-Related Quality of Life for Pancreas Transplant Recipients

Pancreas transplantation restores endocrine pancreatic function. Nevertheless, it is also burdened by high perioperative morbidity and mortality. There is a general consensus that surgical risks must be balanced against clinical outcomes as well as post-transplant health-related quality of life. There is currently a paucity of robust evidence on prognostic factors to inform clinical decision making on post-transplantation health-related quality of life resulting in a reliance on anecdotal case studies. It is possible that recipient phenotypes lead to differential treatment effects on post-transplant health-related quality of life Aims The aim of this study is to identify the relative importance of pre-operative recipient and donor factors as possible predictors of post-pancreas transplant health-related quality of life. Methods We use data from a prospective cohort of over 200 pancreas transplant recipients who underwent either simultaneous pancreas kidney (SPK), pancreas transplant alone (PTA) or pancreas transplant after kidney (PAK) at Oxford University Transplant Centre, UK, from 2002 to 2011. A large number of pre-transplant clinical and demographic variables for recipient and donor were linked to recipient post-transplant health-related quality of life, as measured by the EuroQoL EQ-5D-3L instrument. Uncertainty in possible prognostic factors for post-transplant health-related quality of life was accommodated within a Bayesian Model Averaging (BMA) framework with a uniform prior to assess the relative importance of pre-transplant recipient and donor variables. Results The use of a uniform prior within BMA assumes all potential predictors are equally plausible. However, the posterior inclusion probability attached greater weight to a much smaller number of key pre-transplant predictors for post-transplant health-related quality of life. Key variables at recipient level included BMI, pre-existing vascular conditions (Stroke, Peripheral Vascular Disease and Ischaemic Heart Disease/Angina) as well as cause of diabetes. No donor level covariates were identified as important predictors for recipient post-transplant health-related quality of life. Conclusions Recipients with lower BMI and absence of vascular comorbidities had better QoL post-transplant. However, QoL was not affected by donor factors, suggesting that QoL outcomes may be in part determined pre-transplant. This analysis gives insight into factors associated with the best outcomes after pancreas transplantation and will inform the design of a prospective study into the causal effect of pancreas transplantation on health-related quality of life.

Donors after circulatory death pancreas transplantation.

Purpose of review The use of organs from donors after circulatory death (DCD) has become standard practice in solid organ transplantation of most abdominal organs and has been used successfully in some centres for pancreas transplantation. Nevertheless, concerns regarding poor graft outcomes and complications remain. This review aims to discuss the current state of DCD pancreas transplantation and the associated outcomes. Recent findings In many countries, whereas the number of donors after brainstem death (DBD) remains stable, the mean age and BMI have increased making these donors, previously considered to be low risk, now more marginal. Recent meta-analyses have confirmed previous single-centre and registry reports that graft and patient survival after DCD pancreas transplantation are comparable with outcomes using pancreases from DBD donors; DCD pancreas transplantation is now common practice in several countries in Europe, particularly the United Kingdom. Although there have been reports of higher thrombosis rates after DCD pancreas transplantation, the significance of this is difficult to judge as the impact has not been seen in overall graft survival. Summary Pancreas transplantation using DCD organs is well tolerated and feasible when other risk factors are minimized. Although there has been some evidence of an increased risk of thrombosis, this has not translated into a significant difference in graft survival.