Srikanth Reddy

Normothermic Perfusion: A New Paradigm for Organ Preservation

Objective:Transplantation of organs retrieved after cardiac arrest could increase the donor organ supply. However, the combination of warm ischemia and cold preservation is highly detrimental to the reperfused organ. Our objective was to maintain physiological temperature and organ function during preservation and thereby alleviate this injury and allow successful transplantation. Background Data:We have developed a liver perfusion device that maintains physiological temperature with provision of oxygen and nutrition. Reperfusion experiments suggested that this allows recovery of ischemic damage. Methods:In a pig liver transplant model, we compared the outcome following either conventional cold preservation or warm preservation. Preservation periods of 5 and 20 hours and durations of warm ischemia of 40 and 60 minutes were tested. Results:After 20 hours preservation without warm ischemia, post-transplant survival was improved (27%–86%, P = 0.026), with corresponding differences in transaminase levels and histological analysis. With the addition of 40 minutes warm ischemia, the differences were even more marked (cold vs. warm groups 0% vs. 83%, P = 0.001). However, with 60 minutes warm ischemia and 20 hours preservation, there were no survivors. Analysis of hemodynamic and liver function data during perfusion showed several factors to be predictive of posttransplant survival, including bile production, base excess, portal vein flow, and hepatocellular enzymes. Conclusions:Organ preservation by warm perfusion, maintaining physiological pressure and flow parameters, has enabled prolonged preservation and successful transplantation of both normal livers and those with substantial ischemic damage. This technique has the potential to address the shortage of organs for transplantation.

Liver transplantation from non–heart‐beating donors: Current status and future prospects

Liver transplantation is the treatment of choice for many patients with acute and chronic liver failure, but its application is limited by a shortage of donor organs. Donor organ shortage is the principal cause of increasing waiting lists, and a number of patients die while awaiting transplantation. Non–heart‐beating donor (NHBD) livers are a potential means of expanding the donor pool. This is not a new concept. Prior to the recognition of brainstem death, organs were retrieved from deceased donors only after cardiac arrest. Given the preservation techniques available at that time, this restricted the use of extrarenal organs for transplantation. In conclusion, after establishment of brain death criteria, deceased donor organs were almost exclusively from heart‐beating donors (HBDs). To increase organ availability, there is now a resurgence of interest in NHBD liver transplantation. This review explores the basis for this and considers some of the published results. (Liver Transpl 2004;10:1223–1232.)

Non-heart-beating donor porcine livers: the adverse effect of cooling.

Normothermic preservation has been shown to be advantageous in an experimental model of preservation of non‐heart‐beating donor (NHBD) livers, which have undergone significant warm ischemic injury. The logistics of clinical organ retrieval might dictate a period of cold preservation prior to warm perfusion. We have investigated the effects of a brief period of cold preservation on NHBD livers prior to normothermic preservation. Porcine livers were subjected to 60 minutes of warm ischaemia and then assigned to following groups: Group W (n = 5), normothermic preservation for 24 hours; and Group C (n = 6), cold preservation in University of Wisconsin solution for 1 hour followed by normothermic preservation for 23 hours (total preservation time, 24 hours). Synthetic function (bile production and factor V production) and cellular damage were compared on the ex vivo circuit during preservation. There was no significant difference in the synthetic function of the livers (bile production and factor V production). Markers of hepatocellular damage (alanine aminotransferase and aspartate aminotransferase release), sinusoidal endothelial cell dysfunction (hyaluronic acid), and Kupffer cell injury (β‐galactosidase) were significantly higher in Group C. The histology of the livers at the end of perfusion was similar. In conclusion, a brief‐period cold preservation prior to normothermic perfusion maintains the synthetic function and metabolic activity but results in significant hepatocellular damage, sinusoidal endothelial cell dysfunction, and Kupffer cell injury. Transplant studies are required to establish whether livers treated in this way are viable for transplantation. (Liver Transpl 2005;11:35–38.)

Remote Revascularization of Abdominal Wall Transplants Using the Forearm

Primary abdominal wall closure following small bowel transplantation is frequently impossible due to contraction of the abdominal domain. Although abdominal wall transplantation was reported 10 years ago this, technique has not been widely adopted, partly due to its complexity, but largely because of concerns that storing the abdominal allograft until the end of a prolonged intestinal transplant procedure would cause severe ischemia‐reperfusion injury. We report six cases of combined small bowel and abdominal wall transplantation where the ischemic time was minimized by remotely revascularizing the abdominal wall on the forearm vessels, synchronous to the intestinal procedure. When the visceral transplant was complete, the abdominal wall was removed from the forearm and revascularized on the abdomen (n = 4), or used to close the abdomen while still vascularized on the forearm (n = 2). Primary abdominal wall closure was achieved in all. Mean cold ischemia was 305 min (300–330 min), and revascularization on the arm was 50 min (30–60 min). Three patients had proven abdominal wall rejection, all treated successfully. Immediate revascularization of the abdominal wall allograft substantially reduces cold ischemia without imposing constraints on the intestinal transplant. Reducing storage time may also have benefits with respect to ischemia‐reperfusion‐related graft immunogenicity.

Abdominal Wall Transplantation: Skin as a Sentinel Marker for Rejection

Abdominal wall transplantation (AWTX) has revolutionized difficult abdominal closure after intestinal transplantation (ITX). More important, the skin of the transplanted abdominal wall (AW) may serve as an immunological tool for differential diagnosis of bowel dysfunction after transplant. Between August 2008 and October 2014, 29 small bowel transplantations were performed in 28 patients (16 male, 12 female; aged 41 ± 13 years). Two groups were identified: the solid organ transplant (SOT) group (n = 15; 12 ITX and 3 modified multivisceral transplantation [MMVTX]) and the SOT‐AWTX group (n = 14; 12 ITX and 2 MMVTX), with the latter including one ITX‐AWTX retransplantation. Two doses of alemtuzumab were used for induction (30 mg, 6 and 24 h after reperfusion), and tacrolimus (trough levels 8–12 ng/mL) was used for maintenance immunosuppression. Patient survival was similar in both groups (67% vs. 61%); however, the SOT‐AWTX group showed faster posttransplant recovery, better intestinal graft survival (79% vs. 60%), a lower intestinal rejection rate (7% vs. 27%) and a lower rate of misdiagnoses in which viral infection was mistaken and treated as rejection (14% vs. 33%). The skin component of the AW may serve as an immune modulator and sentinel marker for immunological activity in the host. This can be a vital tool for timely prevention of intestinal graft rejection and, more important, avoidance of overimmunosuppression in cases of bowel dysfunction not related to graft rejection.

Current state of abdominal wall transplantation.

Purpose of reviewPrimary closure of the abdominal wall remains one of the early challenges of intestinal transplantation. Our aim is to review the role of abdominal wall transplantation in achieving tension-free closure of the abdomen. Recent findingsIn total, 38 full-thickness vascularized abdominal wall transplants, six partial-thickness vascularized and 17 partial-thickness nonvascularized rectus facia grafts have been reported worldwide. Different techniques have been described. The most popular choice seems to be the full-thickness vascularized abdominal wall allograft, where the anastomosis is performed either in a micro- or macrovascular fashion. Temporary ‘remote’ revascularisation of the allograft has been performed in some cases onto the recipients forearm vessels when there is a long anticipated cold ischaemia time (>5 h). Preliminary data suggest that the abdominal wall skin rejection might be an early predictor of intestinal rejection. Vascularized and nonvascularized rectus fascia may be effective when there is inadequate healthy muscle/fascia but sufficient skin cover. SummarySeveral centres have already proved the technical and immunologic feasibility of partial or full-thickness abdominal wall transplantation. It is an effective option to achieve primary abdominal closure following intestinal transplantation and in its full-thickness form, it may be useful for monitoring rejection in visceral organs.

A meta-analysis of CXCL12 expression for cancer prognosis

Background:CXCL12 (SDF1) is reported to promote cancer progression in several preclinical models and this is corroborated by the analysis of human tissue specimens. However, the relationship between CXCL12 expression and cancer survival has not been systematically assessed.Methods:We conducted a systematic review and meta-analysis of studies that evaluated the association between CXCL12 expression and cancer survival.Results:Thirty-eight studies inclusive of 5807 patients were included in the analysis of overall, recurrence-free or cancer-specific survival, the majority of which were retrospective. The pooled hazard ratios (HRs) for overall and recurrence-free survival in patients with high CXCL12 expression were 1.39 (95% CI: 1.17–1.65, P=0.0002) and 1.12 (95% CI: 0.82–1.53, P=0.48) respectively, but with significant heterogeneity between studies. On subgroup analysis by cancer type, high CXCL12 expression was associated with reduced overall survival in patients with oesophagogastric (HR 2.08; 95% CI: 1.31–3.33, P=0.002), pancreatic (HR 1.54; 95% CI: 1.21–1.97, P=0.0005) and lung cancer (HR 1.37; 95% CI: 1.08–1.75, P=0.01), whereas in breast cancer patients high CXCL12 expression conferred an overall survival advantage (HR 0.5; 95% CI: 0.38–0.66, P<0.00001).Conclusions:Determination of CXCL12 expression has the potential to be of use as a cancer biomarker and adds prognostic information in various cancer types. Prospective or prospective–retrospective analyses of CXCL12 expression in clearly defined cancer cohorts are now required to advance our understanding of the relationship between CXCL12 expression and cancer outcome.

Validation of the Pancreas Donor Risk Index for use in a UK population.

Pancreas graft failure rates remain substantial. The PDRI can be used at the time of organ offering, to predict one‐year graft survival. This study aimed to validate the PDRI for a UK population. Data for 1021 pancreas transplants were retrieved from a national database for all pancreas transplants. Cases were categorized by PDRI quartile and compared for death‐censored graft survival. Significant differences were observed between the UK and US cohorts. The PDRI accurately discriminated graft survival for SPK and was associated with a hazard ratio of 1.52 (P = 0.009) in this group. However, in the PTA and PAK groups, no association between PDRI quartile and graft survival was observed. This is the largest study to validate the PDRI in a European cohort and has shown for the first time that the PDRI can be used as a tool to predict graft survival in SPK transplantation, but not PTA or PAK transplantation.

Chronic Intestinal Failure After Crohn Disease: When to Perform Transplantation

IMPORTANCE Because of the severity of disease and additional surgery, Crohn disease (CD) may result in intestinal failure (IF) and dependency on home parenteral nutrition (HPN). Defining the indication and timing for intestinal transplantation (ITx) is challenging. OBJECTIVES To determine the limitations of conventional surgery and to facilitate the decision making for transplantation. DESIGN, SETTING, AND PARTICIPANTS Data were collected prospectively and obtained by retrospective review of medical records from all patients with CD who were assessed for ITx in Oxford, United Kingdom, and Berlin, Germany, from October 10, 2003, through July 31, 2013. Patients were considered suitable for ITx if a diagnosis of irreversible IF was established and life-threatening complications under HPN were unresolvable. Twenty patients with CD and IF, established on HPN, were evaluated for ITx. The mean (SD) age at CD onset was 17.8 (9.8) years. On first diagnosis, most patients had a stricturing CD. By the time of referral, most had a combination of stricturing and fistulizing disease. INTERVENTIONS New scoring system: a modification of the American Gastroenterology Association guidelines for ITx. Modifications are related to CD-specific issues that potentially lead to a poorer outcome and are based on the findings of the study to determine the expected benefit from ITx. MAIN OUTCOMES AND MEASURES A scoring system that would alert the physician to the severity of the patients CD and trigger early referral for ITx. This system may translate into better long-term outcomes for patients with CD. In addition, the Karnofsky performance status score was used to compare pretransplantation and posttransplantation outcomes. RESULTS Ten patients underwent ITx, 4 were on the waiting list, and 4 were unavailable for follow-up. One patient was taken off the waiting list because of severe deterioration. One patient underwent conventional stricturoplasty and did not need transplantation. Among the transplant recipients, 17 (85%) had a stoma or enterocutaneous fistula, and the mean (SD) residual bowel length was 71.5 (38) cm. A total of 80% of transplant recipients had life-threatening catheter infections, and 13 (65%) had a significant decrease in the estimated glomerular filtration rate. At a mean (SD) follow-up of 27.6 (36.1) months for transplant recipients, the patient and graft survival is 80%, and their Karnofsky performance status score increased by a mean of 18.6%. CONCLUSIONS AND RELEVANCE Intestinal transplantation is a suitable treatment option for patients with CD and IF. It should be considered before any additional attempts at conventional surgery, which may cause eligible patients to miss this opportunity through perioperative complications. The suggested scoring system enables the physician to identify patients who may benefit from transplantation before HPN-associated secondary organ failure.

Intestinal transplantation: a review

Purpose of review The purpose of this article is to review the existing literature on the current indications, surgical techniques, immunosuppressive therapy and outcomes following intestinal transplantation (ITx). Recent findings Over recent years, ITx has become a more common operation with approximately 2500 procedures carried out worldwide by 2014. It is reserved for patients with intestinal failure and who have developed complications of home parenteral nutrition or who have a high risk of dying from their underlying disease. Recent advances such as the improvement in survival rates, not only for isolated small bowel transplants but also following inclusion of a liver graft in combined liver-small bowel transplant, and the utility of citrulline as a noninvasive biomarker to appreciate acute rejection herald an exciting shift in the field of ITx. Summary With advancements in immunosuppressive drugs, induction regimens, standardization of surgical techniques and improved postoperative care, survival is increasing. In due course, it will most likely become as good as remaining on home parenteral nutrition and as such could become a viable first-line option.