Unlocking the post-transplant microenvironment for successful islet function and survival.

Islet transplantation (IT) offers the potential to restore euglycemia for patients with type 1 diabetes mellitus (T1DM). Despite improvements in islet isolation techniques and immunosuppressive regimes, outcomes remain suboptimal with UK five-year graft survivals (5YGS) of 55% and most patients still requiring exogenous insulin after multiple islet infusions. Native islets have a significant non-endocrine component with dense extra-cellular matrix (ECM), important for islet development, cell survival and function. Collagenase isolation necessarily disrupts this complex islet microenvironment, leaving islets devoid of a supporting framework and increasing vulnerability of transplanted islets. Following portal venous transplantation, a liver injury response is potentially induced, which typically results in inflammation and ECM deposition from liver specific myofibroblasts. The impact of this response may have important impact on islet survival and function. A fibroblast response and ECM deposition at the kidney capsule and eye chamber alongside other implantation sites have been shown to be beneficial for survival and function. Investigating the implantation site microenvironment and the interactions of transplanted islets with ECM proteins may reveal therapeutic interventions to improve IT and stem-cell derived beta-cell therapy.

Jejunal or Ileal Exocrine Drainage in Pancreas Transplantation: Impact on Gastrointestinal Function.

OBJECTIVES: Pancreas transplant can have serious complications requiring salvage pancreatectomy, and surgical approaches should be carefully considered, with jejunal or ileal anastomoses most often employed. The jejunum may reduce gastrointestinal disturbance, whereas the ileum is more immunogenic. Proximal gastrointestinal anastomoses pose challenges with salvage pancreatectomy and creation of high-output stoma, often in the context of end-stage renal failure. Here, we compared outcomes between these techniques. MATERIALS AND METHODS: We retrospectively analyzed patient records of simultaneous pancreas and kidney transplants at a single center between 2013 and 2015, with follow-up to 2020. RESULTS: Our center performed 86 simultaneous pancreas and kidney transplants during the study period; 10 patients were excluded because of incomplete records of anastomosis type. Of included recipients, 59.2% were men (mean age 41.5 ± 8.4 y), 72.4% were donors after brain death, and 98.7% had received a first pancreas transplant. Forty-three simultaneous pancreas and kidney transplants were performed with ileal anastomosis and 33 with jejunal anastomosis. We found no significant differences in recipient or donor factors or immunosuppression regimen between anastomosis groups and no significant differences in overall patient, pancreas, or kidney graft survival or in gastrointestinal complications. Hospital length of stay was higher with ileal anastomosis (median 14 vs 19 days; P < .05), as was cold ischemic time (median 8:48 vs 9:31 hours; P < .05). Three patients required salvage pancre-atectomy and loop ileostomy formation with multiorgan support, prolonged intensive care unit stay, relaparotomy, and/or laparostomy. CONCLUSIONS: Long-term outcomes were comparable between our patient groups. Catastrophic complica-tions occur in a minority of cases, requiring salvage surgery. More complications occurred with ileal anastomosis, but this approach allows graft pancreatectomy and formation of loop ileostomy, avoiding a more proximal stoma in clinically unstable patients. Further studies are needed to examine the impact of enteric anastomosis site.

Kidney Transplantation From Hepatitis-C Viraemic Donors:Considerations for Practice in the United Kingdom.

Background: Donor hepatitis-C (HCV) infection has historically represented a barrier to kidney transplantation (KT). However, direct-acting antiviral (DAA) medications have revolutionised treatment of chronic HCV infection. Recent American studies have demonstrated that DAA regimes can be used safely peri-operatively in KT to mitigate HCV transmission risk. Methods: To formulate this narrative review, a comprehensive literature search was performed to analyse results of existing clinical trials examining KT from HCV-positive donors to HCV-negative recipients with peri-operative DAA regimes. Results: 13 studies were reviewed (11 single centre, four retrospective). Outcomes for 315 recipients were available across these studies. A sustained virological response at 12 weeks (SVR12) of 100% was achieved in 11 studies. One study employed an ultra-short DAA regime and achieved an SVR12 of 98%, while another achieved SVR12 of 96% due to treatment of a missed mixed genotype. Conclusion: HCV+ KT is safe and may allow increased utilisation of organs for transplantation from HCV+ donors, who often have other favourable characteristics for successful donation. Findings from US clinical trials can be applied to the United Kingdom transplant framework to improve organ utilisation as suggested by the NHSBT vision strategy "Organ Donation and Transplantation 2030: meeting the need".

SOX9 is required for kidney fibrosis and activates NAV3 to drive renal myofibroblast function.

Renal fibrosis is a common end point for kidney injury and many chronic kidney diseases. Fibrogenesis depends on the sustained activation of myofibroblasts, which deposit the extracellular matrix that causes progressive scarring and organ failure. Here, we showed that the transcription factor SOX9 was associated with kidney fibrosis in humans and required for experimentally induced kidney fibrosis in mice. From genome-wide analysis, we identified Neuron navigator 3 (NAV3) as acting downstream of SOX9 in kidney fibrosis. NAV3 increased in abundance and colocalized with SOX9 after renal injury in mice, and both SOX9 and NAV3 were present in diseased human kidneys. In an in vitro model of renal pericyte transdifferentiation into myofibroblasts, we demonstrated that NAV3 was required for multiple aspects of fibrogenesis, including actin polymerization linked to cell migration and sustained activation of the mechanosensitive transcription factor YAP1. In summary, our work identifies a SOX9-NAV3-YAP1 axis involved in the progression of kidney fibrosis and points to NAV3 as a potential target for pharmacological intervention.

Right iliac fossa kidney: Differential diagnoses.

A right iliac fossa kidney is rarely encountered by the general clinician but multiple diagnoses should be considered.

Isiris™ for Ureteric Stent Removal in Renal Transplantation: An Initial Single-Centre Experience of 150 Cases.

Background. Ureteric stent insertion is performed at the time of renal transplant to minimise the risk of post-operative urological complications, including anastomotic leak and ureteric stenosis or obstruction. Transplant ureteric stent removal (TUSR) has historically been performed via flexible cystoscopy, predominantly in a theatre setting. Isiris™ is a single-use cystoscope with integrated grasper designed for removal of ureteric stents. We report our initial experience. Methods. A retrospective analysis of a contemporaneously maintained database was performed with review of case notes from October 2017 to September 2018. TUSR was performed by surgical middle grades with a single nurse assistant. Results. One hundred and fifty ureteric stents were removed in transplant recipients (mean age 50.2 years, SD ± 15.2; 61.3% male). 91.3% (n = 137) of cases were performed in the outpatient clinic. Median time to TUSR was 42 days (IQR 30-42). 147 attempts at removal were successful. One urinary tract infection (UTI) was reported following TUSR. Use of the Isiris™ for TUSR corresponds to a £63,480 saving in this cohort compared to conventional practice. This value is conservative and does not include income that has been gained from the reallocation of operating theatre capacity. Conclusion. Isiris™ can safely be employed for the timely performance of non-complicated TUSR. Isiris™ releases this procedure from the confines of the operating theatre to the outpatient clinic. This reduces the resource burden for healthcare providers and may result in improved patient satisfaction. The environmental implications of disposable healthcare equipment require consideration. Evaluation of Isiris™ TUSR for encrustation is required.

Should End-of-Life Preferences Be Discussed Routinely before High-Risk Surgery?

Encapsulating peritoneal sclerosis (EPS) is a rare but devastating complication of peritoneal dialysis. It is characterized by peritoneal neovascularization, fibrosis, and calcification ultimately leading to intestinal obstruction and eventual failure. Surgery for EPS has a mortality approaching 50% and most patients require some form of postoperative life-sustaining therapy (LST) during their admission. A 43-year-old gentleman with progressive EPS and significant comorbidities was assessed for enterolysis after a failed first attempt at another center. Because of his comorbidities, postoperative mortality was quoted above 50%. The patient favored surgery to improve his survival and quality of life, but was reluctant to receive prolonged LST in the event of failure of surgical therapy. The surgical team, in conjunction with a palliative care physician, therefore held extensive discussions with the patient and his partner regarding LST and its limitations. Clinical parameters to trigger a transition to palliative care were identified and agreed. Limitations on LST that are directly expressed by patients can represent a contraindication to surgery for many surgeons. Surgical Buy-In is a concept described as a perceived contract, or covenant, between the patient and clinician regarding implied consent for postoperative LST. Currently, preoperative discussions regarding limitations of LST are infrequent, and there can be reticence among patients and surgeons to have these conversations, leading to dissatisfaction on behalf of the patient and their family. After the Montgomery legal ruling, the provision and perception of informed consent are particularly pertinent. The palliative care physician is uniquely placed to contribute to such discussions as part of the surgical multidisciplinary team.