Improving Liver Graft Function Using CD47 Blockade in the Setting of Normothermic Machine Perfusion.

BACKGROUND: Toward the goal of using more livers for transplantation, transplant centers are looking to increase the use of organs from "marginal" donors. Livers from these donors, however, have been shown to be more susceptible to preservation and reperfusion injury. METHODS: Using a porcine model of donation after circulatory death, we studied the use of antibody-mediated CD47 blockade to further improve liver graft function undergoing normothermic machine perfusion. Livers from 20 pigs (5 per group) were brought under either 30 or 60 min of warm ischemia time followed by the administration of CD47 monoclonal antibody (CD47mAb) treatment or immunoglobulin G control antibodies and 6 h of normothermic extracorporeal liver perfusion. RESULTS: After 6 h of normothermic extracorporeal liver perfusion, CD47mAb-treated livers with 30 or 60 min warm ischemia time had significantly lower alanine transaminase levels and higher bile production compared with their respective control groups. Blockade of the CD47 signaling pathway resulted in significantly lower thrombospondin-1 protein levels, lower expression of caspase-3, and higher expression of phosphorylated extracellular signal-regulated kinase. CONCLUSIONS: These findings suggested that CD47mAb treatment decreases ischemia/reperfusion injury through CD47/thrombospondin-1 signaling downregulation and the presence of necrosis/apoptosis after reperfusion and could increase liver regeneration during normothermic perfusion of the liver.

The learning curve of deceased donor liver transplant during fellowship training.

Liver transplantation (LT) is a complex operation that most transplant surgeons learn in fellowship. Training varies as there is lack of objective data that can be used to standardize teaching. We performed a retrospective review of our adult LT database with aim of looking at fellow's experience. Using American Society of Transplant Surgery cutoff of, at least 45 LT during fellowship, data for first 45 LT were compared to LT 45-90. Fellow's cases were also clustered in sequential groups of 15 LT and analyzed to estimate the learning curve (LC). Comparison of LT 1-45 with LT 46-90 showed significantly lower total operative times (TOT) (324 vs. 344 min) and warm ischemia times (WIT) (28 vs. 31 min) in the 45-90 group. Rates of biliary complications (23.8% vs. 16.4%) and bile leaks alone (10.3% vs. 5.5%) were significantly higher for first 45 LT. Analysis of fellows experience in sequential clusters of 15 LT showed decreasing TOT, WIT, biliary complications and rates of unplanned return to the OR with progression of fellowship. This study validates the current ASTS requirement of at least 45 LT. LC generated using these data can help individualize training and optimize outcomes through identification of areas in need of improvement.

Incisional hernia after liver transplantation: Risk factors, management strategies and long-term outcomes of a cohort study.

INTRODUCTION: Incisional hernias (IH) develop in up to 40% of liver transplant (LT) recipients and can contribute to considerable morbidity. MATERIALS AND METHODS: A single center retrospective review of a prospectively maintained LT database was conducted to identify all patients diagnosed with IH after LT during a 13-year study period (2003-2015). Analyzed data included patient demographics, LT details, incidence and timing of IH, risk factors, management strategies and long-term outcomes. RESULTS: During the 13-year study period, IH was diagnosed in 16.7% (163/976) of LT recipients after a median of 19.6 months (range 6.7-49.5 months) from transplant surgery. Identified risk factors for developing IH included male gender (p < 0.001) while acute cellular rejection (ACR) was found to be negatively associated with the risk of developing IH (p = 0.014). Acute incarceration/strangulation was seen in 4 patients with IH while the remaining (n = 159) presented with non-emergent symptoms. Surgical repair was undertaken in 70/163 (43%) IH patients after medical optimization when possible (open repair 83%, mesh use 90%). IH recurrence rate was 14.3% (10/70) with comparable rates in no-mesh and with-mesh repairs (42.9% vs. 11.3%; p = 0.057) and open (15.8%) and laparoscopic (9.1%) approaches (p = 0.68). CONCLUSION: IH is a late complication following LT and male gender is a consistent predictive marker. Acute presentation is infrequent and elective repair can be planned in most patients allowing for risk factor optimization to ensure promising long-term outcomes.

Enhanced immunosuppression improves early allograft function in a porcine kidney transplant model of donation after circulatory death.

It remains controversial whether renal allografts from donation after circulatory death (DCD) have a higher risk of acute rejection (AR). In the porcine large animal kidney transplant model, we investigated the AR and function of DCD renal allografts compared to the non-DCD renal allografts and the effects of increased immunosuppression. We found that the AR was significantly increased along with elevated MHC-I expression in the DCD transplants receiving low-dose immunosuppression; however, AR and renal function were significantly improved when given high-dose immunosuppressive therapy postoperatively. Also, high-dose immunosuppression remarkably decreased the mRNA levels of ifn-g, il-6, tgf-b, il-4, and tnf-a in the allograft at day 5 and decreased serum cytokines levels of IFN-g and IL-17 at day 4 and day 5 after operation. Furthermore, Western blot analysis showed that higher immunosuppression decreased phosphorylation of signal transducer and activator of transcription 3 and nuclear factor kappa-light-chain-enhancer of activated B cells-p65, increased phosphorylation of extracellular-signal-regulated kinase, and reduced the expression of Bcl-2-associated X protein and caspase-3 in the renal allografts. These results suggest that the DCD renal allograft seems to be more vulnerable to AR; enhanced immunosuppression reduces DCD-associated AR and improves early allograft function in a preclinical large animal model.

Assessment and optimization of liver volume before major hepatic resection: Current guidelines and a narrative review.

Post hepatectomy liver failure (PHLF) remains a significant cause of morbidity and mortality after major liver resection. Although the etiology of PHLF is multifactorial, an inadequate functional liver remnant (FLR) is felt to be the most important modifiable predictor of PHLF. Pre-operative evaluation of FLR function and volume is of paramount importance before proceeding with any major liver resection. Patients with inadequate or borderline FLR volume must be considered for volume optimization strategies such as portal vein embolization (PVE), two stage hepatectomy with portal vein ligation (PVL), Yttrium-90 radioembolization, and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). This paper provides an overview of assessing FLR volume and function, and discusses indications and outcomes of commonly used volume optimization strategies.

Anti-CD47 monoclonal antibody therapy reduces ischemia-reperfusion injury of renal allografts in a porcine model of donation after cardiac death.

We investigated whether blockade of the CD47 signaling pathway could reduce ischemia-reperfusion injury (IRI) of renal allografts donated after cardiac death (DCD) in a porcine animal model of transplantation. Renal allografts were subjected to 30 minutes of warm ischemia, 3.5 hours of cold ischemia, and then perfused with a humanized anti-CD47 monoclonal antibody (CD47mAb) in the treatment group or HTK solution in the control group (n = 4/group). The animals were euthanized five days after transplantation. At the time of reperfusion, indocyanine green-based in vivo imaging showed that CD47mAb-treated organs had greater and more uniform reperfusion. On post-transplant days 3-5, the treatment group had lower values compared to the control for creatinine and blood urea nitrogen. Histological examination of allograft tissues showed a significant decrease of acute tubular injury in the CD47mAb-treated group compared to control. Compared to the control group, CD47mAb treatment significantly decreased genes expression related to oxidative stress (sod-1, gpx-1, and txn), the inflammatory response (il-2, il-6, inf-g, and tgf-b), as well as reduced protein levels of BAX, Caspase-3, MMP2, and MMP9. These data demonstrate that CD47mAb blockade decreases IRI and subsequent tissue injury in DCD renal allografts in a large animal transplant model.

Long-term outcomes of living-related small intestinal transplantation in children: A single-center experience.

Pediatric patients with irreversible intestinal failure present a significant challenge to meet the nutritional needs that promote growth. From 2002 to 2013, 13 living-related small intestinal transplantations were performed in 10 children, with a median age of 18 months. Grafts included isolated living-related intestinal transplantation (n=7), and living-related liver and small intestine (n=6). The immunosuppression protocol consisted of induction with thymoglobulin and maintenance therapy with tacrolimus and steroids. Seven of 10 children are currently alive with a functioning graft and good quality of life. Six of the seven children who are alive have a follow-up longer than 10 years. The average time to initiation of oral diet was 32 days (range, 13-202 days). The median day for ileostomy takedown was 77 (range, 18-224 days). Seven children are on an oral diet, and one of them is on supplements at night through a g-tube. We observed an improvement in growth during the first 3 years post-transplant and progressive weight gain throughout the first year post-transplantation. Growth catch-up and weight gain plateaued after these time periods. We concluded that living donor intestinal transplantation potentially offers a feasible, alternative strategy for long-term treatment of irreversible intestinal failure in children.

Liver Transplantation for Advanced Hepatocellular Carcinoma after Downstaging Without Up-Front Stage Restrictions.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) continues to increase dramatically worldwide. Liver transplantation (LT) is now the standard and optimal treatment for patients with HCC in the setting of cirrhosis, but only for tumors within Milan criteria. In patients presenting beyond Milan criteria, locoregional therapy (LRT) can downstage to within Milan criteria for consideration for LT. Although controversial, the current study aims to evaluate the outcomes of LT in patients presenting with advanced-stage HCC who underwent downstaging and compare these outcomes with those of patients who met Milan criteria at presentation. STUDY DESIGN: Our protocol does not set a priori limitations as long as HCC is confined to the liver. In this retrospective study between January 1, 2002 and December 31, 2014, we reviewed outcomes associated with 284 patients who presented within Milan criteria and patients who presented with more-advanced stage tumor who were potential transplantation candidates. The patients with advanced disease were then subdivided into those who were within or beyond University of California San Francisco criteria. Imaging, details of LRT, recurrence, and survival were compared between the groups. RESULTS: Sixty-three of 210 (30%) eligible patients were downstaged and underwent transplantation; 14 additional downstaged and listed patients were withdrawn for the following reasons: death while waiting (n = 4), disease progression (n = 8), development of other malignancy (n = 1), and declined LT (n = 1). Twelve patients underwent resection after downstaging and did not require LT. Survival for patients who were downstaged was similar to those who were within Milan criteria initially. Recurrence of HCC at 5 years was similar between groups (10.9% vs 10.8%; p = 0.84). CONCLUSIONS: Patients with beyond-Milan criteria HCC who are otherwise candidates for LT should undergo aggressive attempts at downstaging without a priori exclusion. This highly selective approach allows for excellent long-term results, similar to patients presenting with earlier-stage disease.

Single Center Experience With Robotic Kidney Transplantation for Recipients With BMI of 40 kg/m2 Or Greater: A Comparison With the UNOS Registry.

BACKGROUND: Obesity represents a barrier to kidney transplantation, but the increasing prevalence among renal failure patients has forced some centers to carefully consider such candidates. Morbidly obese patients may be at increased risk of delayed graft function, higher postoperative complications, and inferior graft outcomes. Nevertheless, mortality on the waiting list remains significantly higher than after transplant. We have applied minimally invasive surgery to perform kidney transplant in individuals with body mass index (BMI) of 40 kg/m or greater. We compared our results to the national United Network of Organ Sharing database. METHODS: The United Network of Organ Sharing registry was reviewed for adult living donor kidney transplant recipients with BMI of 40 kg/m or greater performed from September 2009 to December 2014. We compared transplants performed with robotic technique (RKT) versus patients performed with open surgery at all US centers including our own (open kidney transplant). Subgroup analysis in patients with BMI of 45 kg/m or greater was conducted. We compared outcomes including patient and graft survival, renal function, and technical complications. RESULTS: Robotic kidney transplantation group had a significantly higher mean BMI overall. The 1-year patient and graft survival rates were similar between groups. Renal function was also similar at 6, 12, and 36 months. Thrombosis caused 1.3% of the graft losses in open kidney transplant and 0% in the RKT group. Interestingly, 52.8% of the overall experience in patients with BMI of 45 kg/m or greater was performed with the robotic technique. CONCLUSIONS: Robotic surgery offers similar patient and graft survivals with comparable renal function to open technique. Robotic kidney transplantation permits transplantation in extreme BMI categories without additional technical complications. Further studies are required to establish the role of RKT for obese candidates but preliminary data are encouraging.

The use of bovine pericardial patch for vascular reconstruction in infected fields for transplant recipients.

Infectious vascular complications affecting transplant recipients may lead to severe morbidity and graft loss. This is a retrospective review of vascular repair with bovine pericardial patch (BPP) in infected fields for immunosuppressed patients. BPP was used as either a patch or an interposition graft. Five cases of arterial reconstruction in infected fields using BPP were performed. There were no complications related to bleeding, thrombosis, or recurrent infection. In our limited experience, the use of BPP as a vascular patch is successful, and it represents an alternative when vascular reconstruction is needed in the context of infected fields.

Simultaneous Living Donor Kidney and Parathyroid Allotransplantation: First Case Report and Review of Literature.

BACKGROUND: Congenital hypoparathyroidism can be severely debilitating for patients, leading to renal failure at young age. Parathyroid transplantation may represent a permanent parathyroid replacement therapy. In patients already on immunosuppression for other organ transplant, there is little additional risk involved with parathyroid allotransplantation. METHODS: Robotic assisted transaxillary single parathyroidectomy is performed on a living donor also donating a kidney to her sibling. RESULTS: Recipient total serum PTH levels became detectable after 3 days from the procedure and maintained for 9 months after transplant with minimal calcium supplementation after the procedure. Literature review and previous results are summarized. CONCLUSIONS: Obtaining a parathyroid gland and a kidney from the same donor reduces the exposure to different HLA antigens. The combined procedure using minimally invasive surgery is safe, with the additional cosmetic advantage and convenience for the willing donor. In the setting of need for immunosuppression, additional transplantation to treat the cause is safe and justified in the recipients.

Bocio amiloide en paciente con fibrosis quística / Amyloid goiter in a patient with cystic fibrosis

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