Local Postoperative Graft Inflammation in Pancreas Transplant Patients With Early Graft Thrombosis.

Background: Graft thrombosis is the main cause of early graft loss following pancreas transplantation, and is more frequent in pancreas transplant alone (PTA) compared with simultaneous pancreas-kidney (SPK) recipients. Ischemia-reperfusion injury during transplantation triggers a local thromboinflammatory response. We aimed to evaluate local graft inflammation and its potential association with early graft thrombosis. Methods: In this observational study, we monitored 67 pancreas-transplanted patients using microdialysis catheters placed on the pancreatic surface during the first postoperative week. We analyzed 6 cytokines, interleukin-1 receptor antagonist (IL-1ra), IL-6, IL-8, interferon gamma-induced protein 10 (IP-10), macrophage inflammatory protein 1ß (MIP-1ß), IL-10, and the complement activation product complement activation product 5a (C5a) in microdialysis fluid. We compared the dynamic courses between patients with pancreas graft thrombosis and patients without early complications (event-free) and between PTA and SPK recipients. Levels of the local inflammatory markers, and plasma markers C-reactive protein, pancreas amylase, and lipase were evaluated on the day of thrombosis diagnosis compared with the first week in event-free patients. Results: IL-10 and C5a were not detectable. Patients with no early complications (n = 34) demonstrated high IL-1ra, IL-6, IL-8, IP-10, and MIP-1ß concentrations immediately after surgery, which decreased to steady low levels during the first 2 postoperative days (PODs). Patients with early graft thrombosis (n = 17) demonstrated elevated IL-6 (P = 0.003) concentrations from POD 1 and elevated IL-8 (P = 0.027) concentrations from POD 2 and throughout the first postoperative week compared with patients without complications. IL-6 (P < 0.001) and IL-8 (P = 0.003) were higher on the day of thrombosis diagnosis compared with patients without early complications. No differences between PTA (n = 35) and SPK (n = 32) recipients were detected. Conclusions: Local pancreas graft inflammation was increased in patients experiencing graft thrombosis, with elevated postoperative IL-6 and IL-8 concentrations, but did not differ between PTA and SPK recipients. Investigating the relationship between the local cytokine response and the formation of graft thrombosis warrants further research.

Thromboinflammatory response is increased in pancreas transplant alone versus simultaneous pancreas-kidney transplantation and early pancreas graft thrombosis is associated with complement activation.

Background: Pancreas transplant alone (PTA) recipients are more affected by pancreas graft thrombosis, and graft loss compared to simultaneous pancreas-kidney (SPK) recipients. The pathophysiology is unknown, but an increased immune response has been suggested in the PTA recipients. In this observational study, we compared perioperative thromboinflammation between PTA (n=32) and SPK (n=35) recipients, and between PTA recipients with (n=14) versus without (n=18) early graft thrombosis. Methods: We measured C-reactive protein (CRP), plasma markers of activated coagulation and complement, and cytokines preoperatively and daily during the first postoperative week. Results: Preoperatively, coagulation and complement activation markers were comparable between PTA and SPK recipients, while cytokine concentrations were higher in SPK recipients (TNF, IL-8, IP-10, MCP-1, MIP-1α; all p<0.05). On the first postoperative day, PTA recipients had higher coagulation activation, measured as thrombin-antithrombin complex (TAT), than SPK recipients (p=0.008). In the first postoperative week, PTA recipients showed higher relative cytokine release (IL-6, IL-8, G-CSF, IP-10, MCP-1, and MIP-1α; all p<0.05) while SPK recipients showed higher absolute cytokine concentrations (TNF, IL-1ra, IL-8, MIP-1α, and IL-4; all p<0.05). PTA and SPK recipients showed similar terminal complement complex (TCC, sC5b-9) activation. On the first postoperative day, TCC (OR 1.2 [95% CI 1.0-1.5] for 0.1 CAU/ml increase, p=0.02) and CRP (OR 1.2 [95% CI 1.0-1.3] for 10 mg/L increase, p=0.04) were associated with an increased risk of early graft thrombosis. TCC was specific for graft thrombosis, while CRP increased with several complications. PTA recipients with compared to those without graft thrombosis had higher TCC pre- (p=0.04) and postoperatively (p=0.03). Conclusion: The relative increase in postoperative thromboinflammatory response was more pronounced in PTA recipients. Complement activation was associated with an increased risk of graft thrombosis. This study indicates that innate immune activation rather than elevated levels may affect early postoperative pancreas graft thrombosis. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT01957696, identifier NCT01957696.

Validating the US pancreas donor risk index in a Norwegian population, a retrospective observational study.

OBJECTIVES: Despite advances in immunosuppression and surgical technique, pancreas transplantation is still associated with a significant graft loss rate. The Pancreas Donor Risk Index (PDRI) is a pre-transplant scoring tool derived from a US population. We sought to validate the PDRI in a Norwegian population. METHODS: We retrospectively retrieved donor data for 344 pancreas transplants undertaken in Norway between 2000 and 2019, utilising the Scandiatransplant database, and matched these to the respective recipients. The PDRI score was calculated for each transplanted pancreas, these were then stratified into quintiles. The association between the PDRI quintiles and 1-year graft survival was calculated, and this was repeated for the different types of pancreas transplantation. The association between PDRI as a continuous variable, and graft survival was determined. Donor and recipient data were compared to the original US population. RESULTS: The overall 1-year graft survival was 82.7%. There were no significant differences in survival between the different PDRI quintiles. When viewed as a continuous variable, increased PDRI score was not associated with decreased graft survival. Significant differences between the Norwegian and US populations were found. CONCLUSIONS: When applied to a Norwegian population, the PDRI score was unable to predict 1-year graft survival.

Microdialysis and CO2 sensors detect pancreatic ischemia in a porcine model.

BACKGROUND: Pancreatic transplantation is associated with a high rate of early postoperative graft thrombosis. If a thrombosis is detected in time, a potentially graft-saving intervention can be initiated. Current postoperative monitoring lacks tools for early detection of ischemia. The aim of this study was to investigate if microdialysis and tissue pCO2 sensors detect pancreatic ischemia and whether intraparenchymal and organ surface measurements are comparable. METHODS: In 8 anaesthetized pigs, pairs of lactate monitoring microdialysis catheters and tissue pCO2 sensors were simultaneously inserted into the parenchyma and attached to the surface of the pancreas. Ischemia was induced by sequential arterial and venous occlusions of 45-minute duration, with two-hour reperfusion after each occlusion. Microdialysate was analyzed every 15 minutes. Tissue pCO2 was measured continuously. We investigated how surface and parenchymal measurements correlated and the capability of lactate and pCO2 to discriminate ischemic from non-ischemic periods. RESULTS: Ischemia was successfully induced by arterial occlusion in 8 animals and by venous occlusion in 5. During all ischemic episodes, lactate increased with a fold change of 3.2-9.5 (range) in the parenchyma and 1.7-7.6 on the surface. Tissue pCO2 increased with a fold change of 1.6-3.5 in the parenchyma and 1.3-3.0 on the surface. Systemic lactate and pCO2 remained unchanged. The area under curve (AUC) for lactate was 0.97 (95% confidence interval (CI) 0.93-1.00) for parenchymal and 0.90 (0.83-0.97) for surface (p<0.001 for both). For pCO2 the AUC was 0.93 (0.89-0.96) for parenchymal and 0.85 (0.81-0.90) for surface (p<0.001 for both). The median correlation coefficients between parenchyma and surface were 0.90 (interquartile range (IQR) 0.77-0.95) for lactate and 0.93 (0.89-0.97) for pCO2. CONCLUSIONS: Local organ monitoring with microdialysis and tissue pCO2 sensors detect pancreatic ischemia with adequate correlation between surface and parenchymal measurements. Both techniques and locations seem feasible for further development of clinical pancreas monitoring.

Early detection of anastomotic leakage after pancreatoduodenectomy with microdialysis catheters: an observational Study.

BACKGROUND: Microdialysis catheters can detect focal inflammation and ischemia, and thereby have a potential for early detection of anastomotic leakages after pancreatoduodenectomy. The aim was to investigate whether microdialysis catheters placed near the pancreaticojejunostomy can detect leakage earlier than the current standard of care. METHODS: Thirty-five patients with a median age 69 years were included. Two microdialysis catheters were placed at the end of surgery; one at the pancreaticojejunostomy, and one at the hepaticojejunostomy. Concentrations of glucose, lactate, pyruvate, and glycerol were analyzed hourly in the microdialysate during the first 24 h, and every 2-4 h thereafter. RESULTS: Seven patients with postoperative pancreatic fistulae (POPF) had significantly higher glycerol levels (P < 0.01) in the microdialysate already in the first postoperative samples. Glycerol concentrations >400 µmol/L during the first 12 postoperative hours detected patients with POPF with a sensitivity of 100% and a specificity of 93% (P < 0.001). After 24 h, lactate and lactate-to-pyruvate ratio were significantly higher (P < 0.05) and glucose was significantly lower (P < 0.05) in patients with POPF. CONCLUSION: High levels of glycerol in microdialysate was an early detector of POPF. The subsequent inflammation was detected as increase in lactate and lactate-to-pyruvate ratio and a decrease in glucose (NCT03627559).

Early detection of complications in pancreas transplants by microdialysis catheters, an observational feasibility study.

BACKGROUND: Despite advances in immunosuppression and surgical technique, pancreas transplantation is encumbered with a high rate of complication and graft losses. Particularly, venous graft thrombi occur relatively frequently and are rarely detected before the transplant is irreversibly damaged. METHODS: To detect complications early, when the grafts are potentially salvageable, we placed microdialysis catheters anteriorly and posteriorly to the graft in a cohort of 34 consecutive patients. Glucose, lactate, pyruvate, and glycerol were measured at the bedside every 1-2 hours. RESULTS: Nine patients with graft venous thrombosis had significant lactate and lactate-to-pyruvate-ratio increases without concomitant rise in blood glucose or clinical symptoms. The median lactate in these patients was significantly higher in both catheters compared to non-events (n = 15). Out of the nine thrombi, four grafts underwent successful angiographic extraction, one did not require intervention and four grafts were irreversibly damaged and explanted. Four patients with enteric anastomosis leakages had significantly higher glycerol measurements compared to non-events. As with the venous thrombi, lactate and lactate-to-pyruvate ratio were also increased in six patients with graft surrounding hematomas. CONCLUSIONS: Bedside monitoring with microdialysis catheters is a promising surveillance modality of pancreatic grafts, but differentiating between the various pathologies proves challenging.