Ten Years of Quality Monitoring of Abdominal Organ Procurement in the Netherlands and Its Impact on Transplant Outcome.

In this study, 10 years of procurement quality monitoring data were analyzed to identify potential risk factors associated with procurement-related injury and their association with long-term graft survival. All deceased kidney, liver, and pancreas donors from 2012 to 2022 and their corresponding recipients in the Netherlands were retrospectively included. The incidence of procurement-related injuries and potential risk factors were analyzed. Of all abdominal organs procured, 23% exhibited procurement-related injuries, with a discard rate of 4.0%. In kidneys and livers, 23% of the grafts had procurement-related injury, with 2.5% and 4% of organs with procurement-related injury being discarded, respectively. In pancreas procurement, this was 27%, with a discard rate of 24%. Male donor gender and donor BMI >25 were significant risk factors for procurement-related injury in all three abdominal organs, whereas aberrant vascularization was significant only for the kidney and liver. In the multivariable Cox regression analyses, procurement-related injury was not a significant predictor for graft failure (kidney; HR 0.99, 95% CI 0.75-1.33, p = 0.99, liver; HR 0.92, 95% CI 0.66-1.28, p = 0.61, pancreas: HR 1.16; 95% CI 0.16-8.68, p = 0.88). The findings of this study suggest that transplant surgeons exhibited good decision-making skills in determining the acceptability and repairability of procurement-related injuries.

Presence of hyperemic islets in human donor-pancreata results in reduced islet isolation yield.

When studying histological characteristics of human donor-pancreata, a remarkably high number of hyperemic islets (HIs) were encountered. The abnormalities in these HIs ranged from single/multiple dilated vessels to hemorrhages extending into the exocrine tissue. We aimed to determine the relevance of the presence of HIs in human donor-pancreata for isolation outcome and to identify donor and procurement factors associated with the occurrence of HIs. The presence of HIs was scored semi-quantitatively (HI-, HI+) in 102 human donor-pancreata. Islet isolation was performed in 40 cases. Donor and procurement factors were retrospectively analyzed in 94 donors. HIs were found in 54.6% of all donor-pancreata. However, only 4.5% of all islets in the affected pancreata was hyperemic. The affected pancreata contained slightly more endocrine tissue, but produced significantly lower yields. When corrected for other factors known to influence isolation outcome, the presence of HIs and endocrine content were the only factors significantly influencing isolation outcome. Prolonged ICU stay and pre-procurement hypertension were associated with the presence of HIs. This study is a first indication that the presence of HIs in human donor-pancreata are associated with reduced isolation outcomes and suggest an impact of the procurement procedure and pre-procurement hemodynamic status of the donor on the islet quality. It is tempting to speculate that this contributes to the generally experienced difficulties in obtaining sufficient amounts of human islets.

Applicability and reproducibility of the CPAT-grading system for pancreas allograft thrombosis.

PURPOSE: Although pancreas allograft thrombosis (PAT) incidence has progressively decreased, it remains the most common cause of early graft failure. Currently, there is no consensus on documentation of PAT, which has resulted in a great variability in reporting. The Cambridge Pancreas Allograft Thrombosis (CPAT) grading system has recently been developed for classification of PAT. In this study we aimed to assess the applicability and validate the reproducibility of the CPAT grading system. METHODS: This study is a retrospective cohort study. Selected for this study were all 177 pancreas transplantations performed at our center between January 1 st, 2008 and September 1 st, 2018 were included. RESULTS: A total of 318 Computed Tomography (CT) images was reevaluated according the CPAT system by two local radiologists. Inter-rater agreement expressed in Cohen's kappa was 0.403 for arterial and 0.537 for venous thrombosis. Inter-rater agreement, expressed in the Fleiss' kappa, within clinically relevant thrombosis categories was 0.626 for Grade 2 and 0.781 for Grade 3 venous thrombosis. CONCLUSIONS: Although not perfect, we believe that implementation of the CPAT system would improve current documentation on PAT. However, it is questionable whether identification of a small Grade 1 thrombosis would be relevant in clinical practice. Furthermore, a good quality CT scan, including adequate phasing, is essential to accurately identify potential thrombus and extend after pancreas transplantation.

Similar liver transplantation survival with selected cardiac death donors and brain death donors.

BACKGROUND: The outcome of orthotopic liver transplantation (OLT) with controlled graft donation after cardiac death (DCD) is usually inferior to that with graft donation after brain death (DBD). This study compared outcomes from OLT with DBD versus controlled DCD donors with predefined restrictive acceptance criteria. METHODS: All adult recipients in the Netherlands in 2001-2006 with full-size OLT from DCD (n = 55) and DBD (n = 471) donors were included. Kaplan-Meier, log rank and Cox regression analyses were used. RESULTS: One- and 3-year patient survival rates were similar for DCD (85 and 80 per cent) and DBD (86.3 and 80.8 per cent) transplants (P = 0.763), as were graft survival rates (74 and 68 per cent versus 80.4 and 74.5 per cent; P = 0.212). The 3-year cumulative percentage of surviving grafts developing non-anastomotic biliary strictures was 31 per cent after DCD and 9.7 per cent after DBD transplantation (P < 0.001). The retransplantation rate was similar overall (P = 0.081), but that for biliary stricture was higher in the DCD group (P < 0.001). Risk factors for 1-year graft loss after DBD OLT were transplant centre, recipient warm ischaemia time and donor with severe head trauma. After DCD OLT they were transplant centre, donor warm ischaemia time and cold ischaemia time. DCD graft was a risk factor for non-anastomotic biliary stricture. CONCLUSION: OLT using controlled DCD grafts and restrictive criteria can result in patient and graft survival rates similar to those of DBD OLT, despite a higher risk of biliary stricture.

Early renal ischemia-reperfusion injury in humans is dominated by IL-6 release from the allograft.

The pathophysiology of ischemia/reperfusion (I/R) injury is complex, and current knowledge of I/R injury in humans is incomplete. In the present study, human living-donor kidney transplantation was used as a highly reproducible model to systematically study various processes potentially involved in early I/R injury. Unique, direct measurements of arteriovenous concentration differences over the kidney revealed massive release of interleukin (IL)-6 in the first 30 minutes of graft reperfusion and a modest release of IL-8. Among the assessed markers of oxidative and nitrosative stress, only 15(S)-8-iso-PGF(2alpha) was released. When assessing cell activation, release of prothrombin factor 1 + 2 indicated thrombocyte activation, whereas there was no release of markers for endothelial activation or neutrophil activation. Common complement activation complex sC5b-9 was not released into the bloodstream, but was released into urine rapidly after reperfusion. To investigate whether IL-6 plays a modulating role in I/R injury, a mouse experiment of renal I/R injury was performed. Neutralizing anti-IL-6 antibody treatment considerably worsened kidney function. In conclusion, this study shows that renal I/R in humans is dominated by local IL-6 release. Neutralization of IL-6 in mice resulted in a significant aggravation of renal I/R injury.

Transfer of ureteral carcinoma in a transplanted kidney presenting by early stenosis of the proximal ureter.

A 71-yr-old male kidney transplant recipient suffered from delayed graft function. Eighty days after transplantation complete obstruction of the proximal ureter was observed, complicated by recurrent urinary tract infections. Two months later, the donor kidney was removed because of infectious complications and inadequate arterial perfusion. Histological examination of the removed graft showed signs of rejection as well as a low-grade papillary urothelial cell carcinoma of donor origin in the ureter. The remaining donor ureter was removed subsequently and showed no further signs of malignancy. Follow-up of the patient until 12 months after surgery did not reveal recurrence of the tumor. This case report is the first to describe accidental transfer of urothelial cell carcinoma in the ureter by transplantation, highlighting the possibility of malignancy when early stenosis is not related to the anastomosis. It again emphasizes the need for precise and cautious screening of organ donors, especially those of higher age.

Isolation of the islets of Langerhans from the human pancreas with magnetic retraction.

Low yield and insufficient purity limit the transplantation of human islets of Langerhans. In the rat, a new technique to isolate the islets of Langerhans was developed by intraarterial infusion of iron particles into the islet capillaries. After digestion the iron-loaded islets were purified with magnetic retraction (MR). In the present study, 10 human pancreata not suitable for clinical use were arterially injected with an iron-oxide suspension. After injection a small piece was used for histological analysis, and the tail was intraductally perfused with collagenase and manually digested. The yield was compared with 11 pancreata processed in the standard way. Nine of 10 pancreata were successfully injected with iron-oxide and digested. After MR, enrichment was achieved but the purity was not more than 50%. Similar results between the 2 groups were obtained regarding digestion times (23 +/- 1.1 vs 22.7 +/- 1.5 minutes) and purification yields (1749 +/- 502.1 vs 2111 +/- 501.8 IE/g, P = .6) for the MR vs control groups, respectively. Histological analysis revealed that 60% to 88% of the islets contained iron aggregations with substantially higher concentrations compared with the exocrine tissue. In conclusion, iron-oxide did not influence the isolation outcome before purification. Islet purification with MR gave enrichment but no pure fractions.

Pancreas Transplantation With Grafts From Donors Deceased After Circulatory Death: 5 Years Single-Center Experience.

BACKGROUND: Donation after circulatory death (DCD) pancreas transplantation has been shown to be an additional way to deal with donor organ shortages. The results of 5-year DCD pancreas transplantation are presented. METHODS: A retrospective, single-center analysis (2011-2015) was performed to compare the results of donation after brain death (DBD) to DCD pancreas transplantation. RESULTS: During the study period, 104 pancreas transplantations (83 from DBD and 21 from DCD) were performed. Median Pancreas Donor Risk Index (PDRI) was 1.47, (DBD, 1.61 vs DCD, 1.35; P = 0.144). Without the factor DCD, PDRI from DCD donors was significantly lower (DBD, 1.61 vs DCD, 0.97; P < 0.001). Donor age was the only donor-related risk factor associated with pancreas graft survival (Hazard ratio, 1.06; P = 0.037). Postoperative bleeding and kidney delayed graft function occurred more frequently in recipients from DCD (P = 0.006). However, DCD pancreata had a lower incidence of thrombosis. Kidney and pancreas graft survival were equally good in both groups. CONCLUSIONS: Pancreas transplantation from DCD donors yields comparable results to DBD donors when PDRI of DCD is relatively low. Most DCD donors are younger donors with trauma as cause of death. These DCD pancreas grafts may be a better option to cope with increasing organ shortages than exploring the limits with older (and higher PDRI) DBD donors.

In vivo IgM depletion by anti-mu monoclonal antibody therapy. The role of IgM in hyperacute vascular rejection of discordant xenografts.

Xenoreactive natural antibodies (XNA) and complement activation are thought to be the 2 main factors responsible for the hyperacute vascular rejection (HVR) of discordant xenografts. The aim of this work was to study the role of IgM XNA in the HVR of guinea pig to rat cardiac xenografts, a discordant model. Adult LOU/C rats were depleted of circulating IgM and therefore of IgM XNA using an anti-mu mAb (mouse anti-rat IgM mAb 7 [MARM-7]). Rats were injected with 10 mg and 5 mg of MARM-7 at days -3 and -1, respectively, and guinea pig cardiac xenografts were performed on day 0. Control animals were injected on the same days with 10 mg and 5 mg of anti-alpha mAb (MARA-1) or equivalent volumes of PBS. Xenografts were performed on day 0. Guinea pig cardiac xenograft survival time was significantly prolonged in IgM-depleted animals (62 min, P < 0.01) compared with controls using PBS (18 min) or MARA-1 mAb (12 min). This prolongation was not due to a decrease in the complement activity in IgM-depleted rats, since no significant variation of the C1q, C4, C3, and C5 complement hemolytic activity was observed between control and treated animals before HVR. Prolongation of the xenograft survival time in the MARM-7-treated group was correlated with an undetectable serum level of IgM and IgM XNA and a lack of IgM XNA deposits on the rejected xenograft vascular endothelium. Contrarily, both IgM-depleted and control animals showed C3 deposits on the rejected xenograft vascular endothelium and myocardium, as well as diffuse deposits of IgG2a XNA. Although HVR was not abrogated by the depletion of IgM XNA, our data indicate that IgM is implicated in the HVR and that the anti-mu approach is a potential therapeutic treatment for discordant xenografts. Finally, we suggest that other factors such as IgM-independent activation of complement might be one of the mechanisms responsible for the pathogenesis of HVR in the guinea pig to rat xenograft model.

Preformed antibody and complement rebound after plasma exchange: analysis of immunoglobulin isotypes and effect of splenectomy.

UNLABELLED: Splenectomy (Sx) has been proposed to attenuate post-PE (plasma exchange) rebound of isoagglutinins and xenogenic (XG) antibody (Ab) in both ABO-incompatible allografts and discordant xenografts. This study analyses the qualitative nature and kinetics of serum immunoglobulins as well as complement resynthesis after PE in sham-operated (PE) and splenectomized (PE+Sx) syngeneic LOU/C rats; non-PE sham-operated or splenectomized animals were used as controls. PE was performed in unanesthetized, unheparinized rats. Immunoglobulin isotypes and subclasses (IgM, IgG1, IgG2 alpha, IgG2b) of total circulating Ab were measured pre-PE and up to 21 days post-PE, using ELISA (enzyme-linked immunosorbent assay) and specific mouse antirat monoclonal Ab. Antiguinea-pig (GP) XG Ab (IgM, IgG2a) serum levels were measured using cellular ELISA with cultured GP endothelial cells as targets. Sx alone significantly reduced XG IgM serum levels (p < 0.0001). Maximal rebound of total and XG IgM was observed on day 3 post-PE, reaching 674% and 187% of the pre-PE levels, respectively; these overshoots were entirely suppressed by Sx (p < 0.005 for total IgM; p < 0.0001 for XG IgM). Total IgG2a, IgG2b and IgG1 as well as XG IgG2a serum levels did not show significant overshoot post-PE. The activity of the complement classical pathway (mean +/- SD), assessed by CH50, was decreased at 51 +/- 19% of basal value 15 minutes after PE, and had returned to baseline level by day 2 post-PE with or without Sx. IN CONCLUSION: (1) Six alone significantly reduced XG IgM serum levels; (2) early post-PE Ab rebound was mainly observed for IgM; (3) both total and XG IgM rebound was inhibited by Sx. This suggests that Sx probably removes a significant proportion of IgM producing cells undergoing post-PE stimulation. These data provide a rationale for combining PE with Sx in ABO-incompatible and discordant XG transplantation.

Capillary electrophoresis of some tetracycline antibiotics coupled with reductive fast cyclic voltammetric detection.

The separation and quantitative performance parameters for tetracycline, chlortetracycline and oxytetracycline antibiotics were investigated by capillary zone electrophoresis coupled with fast cyclic voltammetric detection. Optimization of pH and complexation with a boric acid-sodium tetraborate buffer provided good resolution of all compounds. Detection by electrochemical reduction using fast on-line cyclic voltammetric detection with a Hg-film-microm electrode gave detection limits (2 x peak-to-peak baseline noise) of 7 x 10(-7) mol/l for tetracycline and chlortetracycline, and 1.5 x 10(-6) mol/l for oxytetracycline. The influence of electrode material, potential range and scan rate was examined and discussed. Optimal electrochemical detection was obtained at a Hg-film electrode with a waveform that consisted of an initial constant potential of -0.6 V for 200 ms followed by a cyclic voltammetry (CV) scan at 300 V/s from - 0.6 V to a vertex potential of 1.7 V. The analytical signal was obtained by plotting the integrated values of the CV current from each applied waveform as a function of time. The calibration plot (peak areas) for each separated peak was found to be linear over three-orders of magnitude.

On the electrolytic accumulation of halide ions at hanging mercury drop electrodes.

The process of electrolytic accumulation of halide ions as Hg(2)X(2), at the hanging mercury drop electrode is considered theoretically. The efficiency of this process is explained by considering various chemical reactions of mercury ions with halogens, and the adsorption of Hg(2)X(2). The agreement of these considerations with experimental results obtained by other authors is found to be satisfactory.

Clinical aspects of small-bowel transplantation.

AIM: To update clinical aspects of small-bowel transplantation. METHODS: Critical review of the literature. RESULTS: The two major functions of the small bowel are absorption of food and protection of the body against ingested pathogens. The highly developed immune system of the bowel, necessary for the latter function, prevented successful small-bowel transplantation during the 1960s and 1970s by provoking early and severe rejection of the graft. The introduction of cyclosporin in the 1980s enabled small-bowel transplantation with a moderate success rate. Further improvement of immunosuppressive regimens, especially the introduction of tacrolimus and aggressive surveillance for and treatment of infections, has resulted in a slow but steady improvement of transplant results during the past decade. At this moment, however, long-term parenteral nutrition is still the first-line treatment of the short-bowel syndrome world-wide because of the excellent results with regard to patient survival. CONCLUSION: Although results of small-bowel transplantation are steadily improving, especially due to better immunosuppressive regimens, long-term parenteral nutrition is still the first-line treatment of short-bowel syndrome.

Exchange of best practices within the European Union: surgery standardization of abdominal organ retrieval.

Considering the growing organ demand worldwide, it is crucial to optimize organ retrieval and training of surgeons to reduce the risk of injury during the procedure and increase the quality of organs to be transplanted. In the Netherlands, a national complete trajectory from training of surgeons in procurement surgery to the quality assessment of the procured organs was implemented in 2010. This mandatory trajectory comprises training and certification modules: E-learning, training on the job, and a practical session. Thanks to the ACCORD (Achieving Comprehensive Coordination in Organ Donation) Joint Action coordinated by Spain and co-funded under the European Commission Health Programme, 3 twinning activities (led by France) were set to exchange best practices between countries. The Dutch trajectory is being adapted and implemented in Hungary as one of these twinning activities. The E-learning platform was modified, tested by a panel of Hungarian and UK surgeons, and was awarded in July 2013 by the European Accreditation Council for Continuing Medical Education of the European Union of Medical Specialists. As a pilot phase for future national training, 6 Hungarian surgeons from Semmelweis University are being trained; E-learning platform was fulfilled, and practical sessions, training-on-the-job activities, and evaluations of technical skills are ongoing. The first national practical session was recently organized in Budapest, and the new series of nationwide selected candidates completed the E-learning platform before the practical. There is great potential for sharing best practices and for direct transfer of expertise at the European level, and especially to export this standardized training in organ retrieval to other European countries and even broader. The final goal was to not only provide a national training to all countries lacking such a program but also to improve the quality and safety criteria of organs to be transplanted.

Reuse of auxiliary liver grafts in second recipients with chronic liver disease.

We describe the first cases of reuse of auxiliary liver grafts for orthotopic transplantation in chronic liver disease. A reduced liver graft (segments 2, 3, half of 4) was first transplanted auxiliary for acute liver failure using a new technique. After regeneration of both native liver and graft, the auxiliary graft was removed and immunosuppression discontinued in the first recipients. After informed consent of donors and recipients, both auxiliary grafts were then orthotopically transplanted into second recipients. Both grafts function normally. Reuse of auxiliary grafts may help to reduce the shortage or liver grafts available for transplantation.