Peri‐transplant glycaemic control as a predictor of pancreas transplant survival

The relationship between peri‐transplant glycaemic control and outcomes following pancreas transplantation is unknown. We aimed to relate peri‐transplant glycaemic control to pancreas graft survival and to develop a framework for defining early graft dysfunction.


| INTRODUCTION
Pancreas transplantation is performed as part of the treatment strategy for patients with complex type 1 diabetes mellitus (T1DM). Primary function of the transplanted pancreas is assumed when glycaemic control improves towards normal values. The absence of an improvement in glycaemic control after reperfusion of the pancreas heralds justified concern about potentially catastrophic events resulting in early graft loss. 1,2 Failure of the pancreas within the first 5 days is almost exclusively attributed to technical complications. 2 In our experience, reactive investigation to severe hyperglycaemia post-transplantation seldom leads to graft salvage in cases of significant technical complications. At lower levels, glucose measurement acts as a physiological barometer of both the patient and the transplanted organs. [3][4][5] The factors influencing hyperglycaemia in the early postoperative period are poorly defined, although it has been suggested that postoperative inflammation could mediate stress hyperglycaemia, 5 pancreatic damage 6 and possibly delayed graft function (DGF).
DGF is a poorly defined concept in pancreas transplantation and current definitions are based exclusively on the patient requirement for exogenous insulin (Table 1). [7][8][9][10][11][12] In these definitions, both the time-frame for the assessment post-transplant and the target glucose range that influence insulin initiation vary considerably. Consequently, there is no consensus on the definition of DGF, and reported rates of DGF vary considerably from 0% 10 to 69%. 7 The relationship between peri-transplant glycaemic control and outcomes is unknown. One reason for this might be because of inappropriate or an inadequate interpretation of glucose levels and trends.
There is a tendency to interpret glucose levels either in isolation or as a trend within the context of a short period postoperatively. However, this short-term glucocentric approach has its limitations, i.e. (a) isolated random glucose levels have limited value because they may be explained by transient episodes of high metabolic stress after major surgery, and (b) glucose levels in isolation do not account for individual donor and recipient factors that could contribute to hyperglycaemia.
We hypothesized that peri-transplant glucose levels below those currently used to define graft dysfunction, predict subsequent pancreas transplant graft failure. Our aims were (a) to relate peritransplant glycaemic control to pancreas graft survival, and (b) to develop a framework for defining early graft dysfunction, which is based on glucose levels independently of insulin use, accounts for other causes of hyperglycaemia, predicts graft failure and enables treatment modification.

| METHODS
We analysed retrospective data from consecutive recipients of solid pancreas transplants performed from 2010 to 2015 in our programme.

| Routine practice
In our unit, all recipients of solid pancreas transplants underwent blood glucose measurement at 15-min intervals during the perioperative period starting immediately following reperfusion of the pancreas. Postoperatively, glucose measurements were performed hourly for the first 36 h. Thereafter, patients had their glucose levels measured on average seven times daily depending on the stability of glycaemic control, physiological parameters and postoperative recovery. Capillary blood glucose measurements were analysed using point of care analysers that were standardized and calibrated within a single critical care unit. Exogenous insulin therapy was routinely ceased once blood glucose levels dropped below 10 mmol/L. In patients who stopped exogenous insulin, blood glucose levels above 8 mmol/L prompted an urgent clinical review, including a surgical assessment on intensive care or the ward to identify the cause and treat any complications threatening graft viability. All patients followed a standardized steroid-free immunosuppression regimen, including induction with alemtuzumab, a calcineurin inhibitor and an anti-metabolite.

| Glycaemic control
Data from glucose readings were collected retrospectively from solid pancreas transplant recipients during the first 5 days postoperatively.
The data were explored descriptively and the mean daily glucose levels were used for between-patient comparisons. We quantified the degree of glycaemic control from the area under the glucose level-   Glycaemic variability was assessed using the coefficient of variation (CV), calculated as the standard deviation of average daily glucose levels/mean value over 5 days.

| Definitions
We defined normoglycaemia as a daily mean blood glucose of <7.0 mmol/L. 13 We applied this normoglycaemia threshold to the AUC to define peri-transplant hyperglycaemia as an AUC ≥35 mmol/ day/L over 5 days (   were TNFα 2 pg/mL, IL-6 1 pg/mL and IL-10 5 pg/mL. C-peptide was measured using a bioplex micro-array multi-bead based system (BioRad Life Science Group, Hercules, California, United States) for which the lower limit of detection was 1.0 pg/mL (331 pmol/mL).

| Data analysis
Demographic data from pancreas donors and recipients were first . We calculated that our dataset would provide 86.1% power to detect a 10% reduction in graft failure using a two-way test when statistical significance was assumed at P < .05.

| RESULTS
Between 2010 and 2015, we collected 7606 glucose readings from 123 pancreas transplant recipients [male: 61%; mean ± SD age 41 ± 9 years; body mass index (BMI) 24 ± 4 kg/m 2 ] of which the majority (94%) had received a simultaneous kidney and pancreas transplant. Donors had a mean ± SD age of 33 ± 13 years, BMI of 23 ± 3 kg/m 2 , 55% were men, and 45% required insulin while on intensive care. Donors after brain death comprised 84% of the cohort.
Over the duration of the first 5 days, the glucose AUC was 32.6 (4.  (Table S1).
Non-technical graft failure occurring in transplant recipients   As expected in the early postoperative phase, levels of inflammatory mediators were higher than normal values. There was no relationship between inflammatory mediators and glucose AUC (Table S4).

| DISCUSSION
The main findings in this study have shown that peri-transplant Other potential pathophysiological causes of graft dysfunction include donor quality, glucotoxicity, 20 and inflammation from brain death and during reperfusion. 6 We did not identify any relationship between inflammation and peri-transplant glycaemic control nor glycaemic variability. Donor age and BMI are widely recognized covariates that are strongly associated with both DGF and graft survival. 8,9,12,21,22 This further highlights the inadequacies of current donor selection methodologies and absence of an objective assessment tool to describe pancreatic β-cell function in vivo in the donor and predict post-transplant function at the point of donor selection. 23 Hyperglycaemia causes oxidative stress and glucotoxicity. For pancreatic β-cells, this is a case of 'double jeopardy' because glucoseinduced β-cell damage leads to higher glucose levels, which leads to further β-cell damage. 20 Insulin therapy is a well-recognized strategy, which can ameliorate glucotoxicity and promote β-cell rest in patients with diabetes. 24 However, this is more complicated in pancreas for at least 10 days after transplantation. 25 Peri-transplant insulin therapy is currently the standard of care in islet cell transplantation for this reason but also because its use is associated with higher rates of long-term insulin independence. Although, these data are far from conclusive, we can hypothesize that the benefits of insulin in this setting are in part because of β-cell rest induced in the recently transplanted cells. 25,26 We might speculate that peri-transplant insulin therapy in solid pancreas transplantation could be doubly beneficial by ameliorating glucotoxicity and by providing β-cell rest during a period of heightened insulin resistance.
Hyperglycaemia during TPN use has been shown to be associated with increased hospital complications and mortality. 27 3 and could help strengthen the use of glucose AUC as a metric in pancreas transplantation.

| CONCLUSIONS
In conclusion, we have demonstrated that peri-transplant hyperglycaemia, determined by using the 5-day peri-transplant glucose AUC, predicts graft failure at glucose levels below those currently used to define graft dysfunction in recipients not receiving insulin.
We have shown that peri-transplant hyperglycaemia occurs independently of good C-peptide production and inflammatory processes.
Glucose AUC could be a valuable tool to guide individualized graft monitoring and treatment modification to reduce the impact of hyperglycaemia on graft outcome.

CONFLICT OF INTEREST
The authors declare no potential conflict of interest.

AUTHOR CONTRIBUTIONS
IMS was involved in all aspects of the study and was lead author. ZLT contributed to the data collection and writing. RG was involved in the data collection and writing. HK contributed to the data collection, laboratory analysis, data interpretation and writing. AS was involved in all aspects of the study, but not data collection. CF contributed to the data analysis, statistical oversight and writing. PY was involved in the data collection, data analysis and writing. NAH contributed to the study concept and oversight, and writing. TA was involved in the study concept and oversight writing. MKR was involved in all aspects of the study and was a senior author. DvD contributed to all aspects of the study and was a senior author.