Bloodstream infections among intestinal and multivisceral transplant recipients.

OBJECTIVE: To examine the etiologies, risk factors, and microbiology of bloodstream infections (BSIs) among intestinal and multivisceral transplant recipients in the 2-year post-operative period. METHODS: A retrospective medical record review of adult intestinal or multivisceral transplant recipients between 2003 and 2015. Descriptive statistics were used to describe cohort data. Logistic regression was used to assess factors related to BSIs using a backward selection process. RESULTS: One-hundred and six intestinal or multivisceral transplants were performed in 103 individuals. Fifty-eight percent (n = 62) developed a BSI in the 2-year post-operative period with a median time to first BSI of 53 days (interquartile range [IQR] 15, 169). The majority of BSIs were catheter related 38% (n = 58) when the source was known. Common microbiological isolates included enterococcus 20% (n = 36/174), coagulase-negative staphylococcus 14% (n = 23), and 12% Klebsiella spp (n = 21). Forty-seven percent (n = 17) of the enterococci were resistant to vancomycin, and 14% (n = 10/70) of the gram negatives were extended spectrum beta-lactamase (ESBL) producers. In adjusted analyses, (OR: 0.200 95% CI: 0.2, 0.514, P = .009) men were less likely to have a BSI. Transplant recipient age, allograft type, comorbidities, rejection, and length of stay were not noted to be risk factors for development of BSIs in our cohort. Mortality at 2-years post-transplant was similar for those who did not develop a BSI and those that developed infection, P = .5028. CONCLUSIONS: BSIs are a common complication of intestinal transplantation, and central venous catheters were a common source. Interventions such as early catheter removal should be implemented to prevent infections in this population. Female sex association with BSI requires further investigation.

Immunologic Complications and Graft Survival in Crohn's Disease and NOD2 Mutant Non-Crohn's Disease Adult Recipients Following Intestine Transplantation.

BACKGROUND: Despite improved outcomes in the modern era of targeted immunotherapy, intestinal failure and chronic parenteral nutrition remains a significant burden for patients with Crohn's disease (CD) worldwide. Transplantation is a key component of management when a patient with CD suffers from life-threatening complications of parenteral nutrition. Nucleotide-binding oligomerization domain 2 (NOD2) mutation is a risk factor for both development of CD and intestinal allograft rejection. METHODS: A retrospective review of a prospectively maintained database of intestinal transplants at a single center from 2003 to 2015 was conducted. Eleven adult patients with CD were identified and were compared with 103 adult control recipients. A sub-analysis was performed comparing the 11 CD recipients to the 13 NOD2 mutant non-CD recipients. RESULTS: Patient and allograft characteristics were similar between the CD and control recipients. Although overall rejection-free survival was not significantly different, patients with CD suffered from more frequent, earlier, and more severe rejection compared with control patients. The onset, severity, and frequency of rejection was comparable between patients with CD and NOD2 mutant non-CD patients. There was a trend toward lower 5-year allograft survival for CD compared with control recipients (33% versus 63.3%; P = 0.19) and NOD2 mutant non-CD recipients (33% versus 57.14%; P = 0.41). CONCLUSIONS: Patients with CD remain a challenging population in intestine transplantation, and NOD2 mutant non-CD patients appear to have a similar immunologic phenotype. These high-risk recipients may require specialized immunosuppression protocols and management at experienced transplant centers.

Intra-abdominal infections among adult intestinal and multivisceral transplant recipients in the 2-year post-operative period.

BACKGROUND: Intestinal and multivisceral transplantations are treatment options for patients with intestinal failure. Transplantation is often complicated by abdominal and/or bloodstream infections in the post-operative period. METHODS: A retrospective chart review of all adults who underwent intestinal or multivisceral transplantation at our institution from 2003 to 2015 was performed. Data were collected for 2 years post transplant. RESULTS: A total of 106 intestinal or multivisceral transplants were performed in 103 patients. The median age at the time of transplant was 44 (IQR: 34-52) with 55% (n = 58) male and 45% (n = 48) female. There were 46 (43%) intra-abdominal infections post transplant among the 103 patients, and six transplant recipients (13%) developed concurrent bloodstream infections. The median time to first intra-abdominal infection was 23 days (IQR: 10-48). For those with organisms isolated in culture, forty-seven percent of the isolates were gram negative, 39% gram positive, 7% anaerobes, and 7% yeast. The most common isolates were enterococci at 28%, E. coli at 14%, and Klebsiella spp at 13%. Sixty-three percent of the enterococci were vancomycin-resistant enterococci (VRE), and 22% of the gram-negative isolates were extended spectrum beta-lactamases (ESBLs). Patients with intra-abdominal infections had longer hospital post-transplant length of stays at a median of 35 days (IQR: 25-48) vs 23 days (IQR: 17-33) for those without infections, P = .0012. There was no difference in all-cause mortality in patients with or without intra-abdominal infections, P = .654. CONCLUSIONS: Intra-abdominal infections are common in intestinal or multivisceral transplant recipients, but despite this complication, we found no increased risk of mortality. These transplant recipients are also at risk for infection with drug-resistant organisms.

Visceral transplantation in patients with intestinal-failure associated liver disease: Evolving indications, graft selection, and outcomes.

Intestinal failure (IF)-associated liver disease (IFALD) is widely recognized as a lethal complication of long-term parenteral nutrition. The pathophysiology of IFALD is poorly understood but appears to be multifactorial and related to the inflammatory state in the patient with IF. Visceral transplant for IFALD includes variants of intestine, liver, or combined liver-intestine allografts. Graft selection for an individual patient depends on the etiology of IF, abdominal and vascular anatomy, severity of IFALD, and potential for intestinal rehabilitation. The past decade has witnessed dramatic improvement in the management of IFALD, principally due to improved lipid emulsion formulations and the multidisciplinary care of the patient with IF. As the recognition and treatment of IFALD continue to improve, the requirement of liver-inclusive visceral grafts appears to be decreasing, representing a paradigm shift in the care of the patient with IF. This review highlights the current indications, graft selection, and outcomes of visceral transplantation for IFALD.

Impact of early reoperation on graft survival after liver transplantation: Univariate and multivariate analysis.

BACKGROUND: Data on rate, risk factors, and consequences of early reoperation after liver transplantation are still limited. STUDY DESIGN: Single-center retrospective analysis of data of 428 patients, who underwent liver transplantation in period between January 2009 and December 2014. Univariate and multivariate analysis were used to study the risk factors of early reoperation and its impact on graft survival. RESULTS: Of 428 patients, 74 (17.3%) underwent early reoperation. Of them, 46 (62.2%) underwent reoperation within the first week and 28 (37.8%) underwent reoperation later than 1 week after transplantation. With multivariate analysis, significant risk factors of early reoperation included pretransplant ICU admission, previous abdominal surgery and diabetes. Early reoperation itself was not found to be an independent predictor of graft loss. However, early reoperation later than 7 days from transplant was found to be independent predictor of graft loss (odds ratio [OR] = 5.125; 95% CI, 1.358-19.552; P = .016). In our series, other independent predictors of graft loss were MELD score (P = .010) and operative time (P = .048). CONCLUSIONS: This analysis demonstrates that early reoperations later than a week appear to negatively impact the graft survival. The timing of early reoperation should be a focus of additional studies.

The use of vascular homografts in pediatric small bowel transplantation: Single-center experience over a decade.

Intestinal transplantation in children has evolved with more isolated small intestine transplants being performed compared to combined liver-intestine transplants. Consequently, surgical techniques have changed, frequently requiring the use of vascular homografts of small caliber to revascularize the isolated small intestine, the impact of which on outcomes is unknown. Among 106 pediatric intestine and multivisceral transplants performed at our center since 2003, 33 recipients of an isolated small intestine graft were included in this study. Outcome parameters were thrombotic complications, graft, and patient survival. A total of 29 of 33 (87.9%) patients required arterial and/or venous homografts from the same donor, mainly iliac or carotid artery and iliac or innominate vein, respectively (donor's median age 1.1 years [2 months to 23 years], median weight 10 kg [14.7-48.5]). Post-transplant, there were three acute arterial homograft thromboses and one venous thrombosis resulting in two peri-operative graft salvages and two graft losses. Three of four thromboses occurred in patients with primary hypercoagulable state, including the two graft losses. Overall, at a median of 4.1 years (1-10.2) from transplant, 29 of 33 (88%) patients are alive with 26 of 33 (79%) functioning grafts. The procurement of intact, size-matched donor vessels and the management of effective post-transplant anticoagulation are critical.

Lymphatic Leak After Intestinal Transplantation: Aspects of the Donor Technique.

The rich component of lymphatics makes the intestine prone to leaks of lymph after transplantation secondary to their transection during procurement. We describe our technique for isolation and ligation of the small lymphatics at the root of the mesentery during the procurement of the small intestine and report our experience with the management of lymphatic leaks posttransplant.

The impact of intercenter sharing on the outcomes of pediatric split liver transplantation.

BACKGROUND: Split liver transplantation allows for expansion of the pool of organs available for pediatric liver transplantation. The impact of sharing segments of the same liver between centers has not been studied. STUDY DESIGN: Retrospective analysis of 24 pediatric split liver transplant cases in a recent cohort. We evaluated the outcomes of pediatric recipients who shared organs with adult patients in our own center (group A) compared to recipients who shared organs with adult patients in other centers. (group B). RESULTS: One-, 3-, and 5-year graft survival for group A was 100%, 100%, and 100% vs 83%, 71%, and 57% for group B (P = .039). Postoperative complications included biliary complications (41.7% in group A vs 50% in group B, P = .682), vascular complications (8.3% in group A vs 41.7% in group B, P = .059), and postoperative bleeding (16.7% in group A vs 25% in group B, P = .615). High-grade Clavien-Dindo complications were 0% in group A vs 33.3% in group B, P = .028. CONCLUSIONS: Organ sharing between centers appears to be associated with significantly poorer graft survival. Possible explanations include greater procurement-related injury or suboptimal vessel distribution. Future larger studies focused on this area may be helpful to formulate policy considerations.

Deceased organ donation for transplantation: Challenges and opportunities.

Organ transplantation saves thousands of lives every year but the shortage of donors is a major limiting factor to increase transplantation rates. To allow more patients to be transplanted before they die on the wait-list an increase in the number of donors is necessary. Patients with devastating irreversible brain injury, if medically suitable, are potential deceased donors and strategies are needed to successfully convert them into actual donors. Multiple steps in the process of deceased organ donation can be targeted to increase the number of organs suitable for transplant. In this review, after describing this process, we discuss current challenges and potential strategies to expand the pool of deceased donors.

Modified technique for aortic cross-clamping during liver donor procurement.

Undue tension on the donor vessels during organ procurement is associated with intimal dissection, which can form the nidus for the thrombosis of the hepatic artery (HA) and graft loss. According to the US OPTN database, 143 grafts were discarded in the last 15 yr due to vascular damage during procurement. The most common technique to expose the supraceliac aorta is dissection between the left lateral segment of the liver and the esophagus-stomach. In obese donors, due to restricted space and in pediatric donors where the vessels are very delicate and this space is very small, the replaced or accessory left HA(R/A LHA) is prone to damage if approached conventionally. We describe a technique for the exposure of the supraceliac aorta in which the aorta is approached from the left side behind the gastroesophageal junction that does not require division of the gastrohepatic ligament. From May 2007 to May 2013, 104 liver procurements were performed. Eighty-nine (85.6%) were adults, and 15 (14.4%) were pediatric donors. Twenty-three (22.1%) had R/A LHA. No donor organ suffered any damage. One adult recipient with R/A LHA suffered HA thrombosis not related to it. In summary, this technical modification offers improved safety during cadaveric procurement and increases the ease.

Infections in intestinal and multivisceral transplant recipients.

Intestinal and multivisceral transplantation has become an effective treatment option for patients with intestinal failure. More potent immunosuppressive therapy has resulted in a decreased incidence of acute rejection and has improved patient survival. However, infectious complications can cause significant morbidity both before and after transplantation. In comparison with other solid organ transplant recipients, these patients experience higher rates of acute allograft rejection, thus requiring higher levels of immunosuppression and escalating the risk of infection. This article reviews the most common infectious disease complications encountered, and proposes a potential temporal association for types of infections in this patient population.

Nucleotide oligomerization domain 2 polymorphisms in patients with intestinal failure.

BACKGROUND: Nucleotide oligomerization domain 2 (NOD2) has been associated with intestinal immunity after the discovery that its polymorphisms are linked to Crohn's disease (CD). Intestinal failure (IF) represents a wider spectrum of diseases where intestinal homeostasis has been disrupted. AIM: To evaluate the prevalence of NOD2 mutations in a population with IF as well as its association with the different conditions causing this problem. METHODS: One hundred ninety-two consecutive patients with IF and 103 healthy controls were genotyped for the three most common NOD2 polymorphisms. Genotypes were compared between the groups and were related to the entities causing IF. RESULTS: A high percentage (26%) of patients had at least one of the three most common NOD2 polymorphisms, while only a 4.8% of healthy controls had a mutant genotype. In patients with IF, specific mutations for the 702W, 908R and 1007fs alleles were 11, 5 and 12.5%, respectively, compared with 0.9% (P = 0.0003), 1.9% (P = 0.1) and 1.9% (P = 0.001) in the control group. If we consider patients with any cause of IF other than CD, the percentage is still as high as 18.8%, with specific mutation frequencies of 7.6% (702W; P = 0.01), 5.8% (908R; P = 0.1) and 8.2% (1007fs; P = 0.002). We could not establish an association between a NOD2 mutant genotype with any other specific clinical condition other than CD. CONCLUSION: Our finding supports the importance of NOD2 in the maintenance of intestinal immune homeostasis and may be important to a variety of intestinal stressors.

Intestinal transplantation: a review.

Parenteral nutrition is a life-saving therapy for patients with intestinal failure. Intestinal transplantation is now recognized as a treatment for patients who develop complications of parenteral nutrition and in whom attempts at intestinal rehabilitation have failed. Patients with parenteral nutrition related liver disease will require a liver graft typically part of a multivisceral transplant. Isolated intestinal transplants are more commonly performed in adults while multivisceral transplants are most commonly performed in infants. Isolated intestinal transplants have the best short-term outcome, with over 80 % survival at 1 year. Patients requiring multivisceral transplants have a high rate of attrition with a 1 year survival less than 70 %. Prognostic factors for a poor outcome include patient hospitalization at the time of transplant and donor age greater than 40 years while systemic sepsis and acute rejection are the major determinant of early postoperative outcome. For patients surviving the first year the outcome of transplantation of the liver in addition to intestine affords some survival advantage though long-term outcome does not yet match other abdominal organs. Outcomes for intestinal retransplantation are poor as a result of immunology and patient debility. Overall intestinal transplantation continues to develop and is a clear indication with cost and quality of life advantages in patients with intestinal failure that do not remain stable on parenteral nutrition.

Paired kidney donor exchanges and antibody reduction therapy: novel methods to ameliorate disparate access to living donor kidney transplantation in ethnic minorities.

BACKGROUND: Currently ethnic minority patients comprise 60% of patients listed for kidney transplantation in the US; however, they receive only 55% of deceased donor renal transplants and 25% of living donor renal transplants. Ethnic disparities in access to kidney transplantation result in increased morbidity and mortality for minority patients with end-stage renal disease. Because these patients remain dialysis dependent for longer durations, they are more prone to the development of HLA antibodies that further delay the possibility of receiving a successful kidney transplant. STUDY DESIGN: Two to 4 pretransplant and post-transplant plasma exchanges and i.v. immunoglobulin were used to lower donor-specific antibody levels to less than 1:16 dilution; cell lytic therapy was used additionally in some cases. Match pairing by virtual cross-matching was performed to identify the maximal exchange benefit. Sixty candidates for renal transplantation were placed into 4 paired kidney exchanges and/or underwent antibody reduction therapy. RESULTS: Sixty living donor renal transplants were performed by paired exchange pools and/or antibody reduction therapy in recipients whose original intended donors had ABO or HLA incompatibilities or both (24 desensitization and 36 paired kidney exchanges). Successful transplants were performed in 38 ethnic minorities, of which 33 were African American. Twenty-two recipients were white. Graft and patient survival was 100% at 6 months; graft function (mean serum creatinine 1.4 g/dL) and acute rejection rates (20%) have been comparable to traditional live donor kidney transplantation. CONCLUSIONS: Paired kidney donor exchange pools with antibody reduction therapy can allow successful transplant in difficult to match recipients. This approach can address kidney transplant disparities.

Liver allograft outcomes after laparoscopic-assisted and minimal access live donor hepatectomy for transplantation.

BACKGROUND: The critical shortage of deceased organ donors has led to live-donor hepatectomy as an alternative donor option for transplantation. Although laparoscopic hepatectomy has been well described for management of liver tumors and can be performed safely, few studies have examined early recipient allograft outcomes after laparoscopic live-donor hepatectomy. We describe our initial experience with laparoscopic-assisted and minimal-access donor hepatectomy and its potential as a safe alternative with graft function comparable with open resection in live-donor liver transplantation. METHODS: We performed a retrospective analysis of our past 30 successive live-donor transplants between 2005 and 2009. Fifteen allografts were procured by standard open live-donor (OLD) hepatectomy, and 15 by laparoscopic-assisted (LALD) or minimal-access (MA) live-donor hepatectomy. Left lateral segment grafts were subcategorized and analyzed further. RESULTS: Mean donor age, sex, and liver anatomy were comparable between donor groups. Early graft function as measured by peak total bilirubin level, aspartate aminotransferase level, alanine aminotransferase level, and international normalized ratio on postoperative days 2, 7, 30, and 90 were similar between groups, although the international normalized ratio was slightly more increased on postoperative day 7 in LALD grafts (1.75 ± .45 vs 1.28 ± .16; P = .02). Perioperative allograft biliary (2 of 15 vs 0 of 15; P = .48) and vascular (3 of 15 vs 1 of 15; P = .6) complication rates also were comparable between OLD and LALD/MA grafts. One-year graft and patient survival for LALD/MA was 100% compared with 93% for OLD. CONCLUSIONS: Our experience shows that LALD or MA live-donor hepatectomy is a safe procedure and produces early graft function comparable with standard OLD hepatectomy. Multicenter, larger-volume experience will determine the widespread application of this technique.

Utilization of donors who have suffered cardiopulmonary arrest and resuscitation in intestinal transplantation.

BACKGROUND: Cardiopulmonary resuscitation (CPR) of a person destined to become an organ donor has been associated with overall poor donor quality, especially for the intestinal donor, as splanchnic vasoconstriction that is intended to preserve coronary and cerebral blood flow may result in clinically relevant intestinal ischemia. Outcomes of recipients who receive intestine grafts that have suffered CPR are unknown. We sought to analyze our clinical experience in using intestinal grafts from donors who suffered cardiopulmonary arrest and resuscitation and to evaluate the outcome of recipients of organs coming from resuscitated donors when compared with recipients of nonresuscitated donors. METHODS: We retrospectively analyzed the donor and recipient charts of all of our intestinal transplants with regard to the performance of donor CPR. RESULTS: Sixty-seven intestinal transplants were performed in 65 patients from November 2003 to December 2007. Twelve donors (18%) were identified as having suffered cardiac arrest and subsequent CPR. Mean duration of CPR was 19.3+/-12.7 min. Terminal laboratory profiles of CPR donors and non-CPR donors were similar. Of the 12 resuscitated grafts, two were used for multivisceral, one for a modified multivisceral, seven for liver-intestine, and two for isolated intestinal transplant. There were no significant differences in outcome parameters such as operative time, blood use, ventilation days, length of stay, time to enteral independence, rejection, enteric bacteremia, and survival between the 12 resuscitated grafts and the 55 nonresuscitated grafts. CONCLUSION: A donor history of cardiac arrest should not automatically exclude the use of the intestine graft for transplantation.

Frontiers in nephrology: immune tolerance to allografts in humans.

Vascularized allografts are rejected unless some indefinite modification to the recipient's immune system is made. This modification is typically achieved through the long-term administration of immunosuppressive drugs. Patients thus trade their end-stage organ failure for dependence on daily drug therapy and the accompanying chronic condition of immunodeficiency. However, it is clear from studies in experimental animals that rejection can be prevented through the use of several therapeutic approaches, including donor hematopoietic cell infusion, chimerism, T cell depletion, and/or co-stimulation blockade. Successfully treated animals avoid rejection beyond the period of therapy without a phenotype of chronic immunosuppression and are thus considered to be tolerant of their grafts. Although intriguing, this success in animals has yet to be reproducibly translated to the clinic, and human transplant recipients remain tethered to immunosuppressive drugs with rare exceptions. This article provides an overview of the existing, largely anecdotal, clinical experience with organ allograft tolerance. It reviews the various approaches that are being applied in pilot human trials and suggests avenues for future clinical investigation.

Diagnostic tools for monitoring kidney transplant recipients.

Recent advancements in immunobiology have introduced several new diagnostic tools for monitoring kidney transplant recipients. These have been added to more established tests that, although imperfect, remain important benchmarks of diagnostic utility. Both new and old tests can be characterized with regard to their practicality, and as to whether they detect aberrant function or define the cause of dysfunction. Unfortunately, no current test is both practical and specific to a particular disease entity. Accordingly, the diagnosis of graft dysfunction remains dependent on the proper use and interpretation of many studies. This article reviews the current assays that have been evaluated in the clinic for the diagnosis of renal allograft-related diseases. These are limited to assays based on routinely obtainable samples such as blood, biopsy tissue, and urine. Newer studies are presented, along with more mundane assays, to highlight the practical use of studies regardless of their degree of mechanistic sophistication.

Isolation of hepatocytes from livers from non-heart-beating donors for cell transplantation.

One of the limitations to hepatocyte transplantation is the restricted availability of donor liver tissue. The aim of this study was to evaluate livers from non-heart-beating donors (NHBDs) as a source of hepatocytes for cell transplantation. A total of 20 livers/segments obtained from NHBD were perfused under good manufacturing practices using a standard collagenase digestion method. The donor liver median warm ischemia time was 15 minutes (range, 11-40 minutes), and cold ischemia time was 13 hours (range, 6-30 hours) prior to cell isolation. The cell viability of the hepatocytes obtained was 52% (1-81%), with a yield of 2.2 x 10(6)(0.2-29.7 x 10(6)) cells per gram of tissue. There was a significant negative correlation between hepatocyte viability and length of both warm ischemia (r = -0.544, P = 0.013) and cold ischemia (r = -0.510, P = 0.022). Preliminary experiments were performed on the viability testing of NHBD livers based on digestion of needle biopsies with collagenase and assessment of the hepatocytes produced. Two of the NHBD cell preparations, which had been cryopreserved, were used as part of a series of cell infusions for hepatocyte transplantation. A 3.5-yr-old girl with Crigler-Najjar syndrome type I received 9.7 x 10(8) NHBD hepatocytes (viability on thawing, 65%), and a 4-month-old boy with inherited clotting factor VII deficiency received 5.0 x 10(8) hepatocytes (viability, 57%). In conclusion, hepatocytes suitable for cell transplantation can be obtained from NHBD livers. Higher viability values may be obtained if both warm and cold ischemia times of donor liver can be reduced prior to processing.