Graft-versus-host disease after multiorgan transplantation

A rat model of multiorgan transplantation (MOTx) including the liver, pancreas, duodenum, and variable segments of small bowel (SB) was used to ascertain whether graft-versus-host disease (GVHD) could be produced by this procedure. Rats receiving an isogeneic multiorgan transplant (MOT) survived more than 150 days. MOTx was then performed in the Lewis to (Lewis x Brown Norway) LBNF1 semiallogeneic combination, ensuring unidirectional GVHD. En bloc transplantation of the liver, pancreas, duodenum, and entire jejunum provoked lethal GVHD in all animals, and the mean time to recipient death (MT) was 16.5 +/- 0.43. When only one-half of the jejunum was included in the MOT, lethal GVHD similarly occurred in 100% of animals and the MT was 18 +/- 0.86. Finally, when only liver, pancreas, and duodenum were transplanted, the incidence of lethal GVHD was reduced to 50% (P less than 0.1). In those rats that died of GVHD, MT was 16 +/- 0.33. Fifty percent of the rats in this group, however, recovered from a milder form of GVHD and survived more than 150 days. These results demonstrate that MOTx induces GVHD and that the lethality of this process correlates with the inclusion of the SB in the graft and thus, with the overall amount of transplanted lymphoid tissue.     

De novo malignancies after intestinal and multivisceral transplantation

BACKGROUND: Maintenance immunosuppression required after organ transplantation creates a permissive environment in which cancer cells can proliferate because of lack of natural immunologic surveillance. With more than a decade of clinical experience, this report is the first to address the risk of de novo cancer after intestinal transplantation. METHODS: A total of 168 consecutive intestinal transplant recipients (86 children and 82 adults) were studied, of whom 52% were male and 91% were white. Surveillance, Epidemiology, and End Results data was used to count expected rates of de novo cancers in the general population matched for age, sex, and length of follow-up. RESULTS: With a mean follow-up of 47+/-41 months, 7 (4.2%) patients developed nonlymphoid de novo cancer, with a cumulative risk of 3% at 5 years and 28% at 10 years. Of these malignancies, one was donor-driven adenocarcinoma. With 0.58 being the expected rate of malignancy for the general population, the risk among intestinal recipients was 8.7 times higher (P =0.01). Such morbidity was significantly higher (50 times) among younger patients (<25 years), with a slight male preponderance. Induction immunosuppression was associated with early onset of de novo cancer. Patient survival after diagnosis of de novo cancer was 72% at 1 year, 57% at 2 years, and 29% at 5 years. CONCLUSION: With conventional immunosuppression, intestinal recipients are at a significantly higher risk of developing de novo cancer when compared with the general population. Thus, a novel tolerogenic immunosuppressive strategy has been recently implemented to reduce the lifelong need for immunosuppression.     

The clinical spectrum of neurologic disorders after intestinal and multivisceral transplantation

?ivkovi? SA, Eidelman BH, Bond G, Costa G, Abu‐Elmagd KM. The clinical spectrum of neurologic disorders after intestinal and multivisceral transplantation.
Clin Transplant 2009: DOI: 10.1111/j.1399‐0012.2009.01065.x
© 2009 John Wiley & Sons A/S. Abstract: Background: Intestinal transplantation has evolved into an effective therapy for patients with intestinal failure and the inability to be maintained on total parenteral nutrition. Long‐term heavy immunosuppression and complex systemic disturbances increase the risk of the neurologic complications. Methods: This retrospective analysis identified the post‐transplant neurologic complications in adult patients who underwent intestinal transplantation at the University of Pittsburgh Medical Center between May 1990 and August 1998. The recipients received 28 isolated intestine, 17 composite liver‐intestine, and nine multivisceral allografts. Results: With a median follow‐up of 25 months, 46 of 54 recipients (68%) developed headaches (n = 27; 50%), encephalopathy (n = 23; 43%), seizures (n = 9; 17%), neuromuscular disorders (n = 4; 7%), opportunistic CNS infections (n = 4; 7%), and ischemic stroke (n = 2; 4%). Conclusions: Under high maintenance immunosuppression, intestinal transplant recipients were at high risk for neurologic complications. Future studies are needed to describe post‐transplant neurologic complications with modern immunosuppression protocols.     

Fluid management of patients undergoing intestinal and multivisceral transplantation

Small bowel transplantation can be associated with large fluid shifts due to massive blood loss, dehydration, vascular clamping, long ischemia times, intraoperative visceral exposure, intestinal denervation, ischemic damage, and lymphatic interruption. Fluid management is the major intra- and postoperative problem after small bowel and multiple organ transplantation, because of the highly variable fluid and electrolyte needs of the transplant recipient. Third-space fluid requirements can be massive; inadequate replacement leads to end-organ dysfunction, particularly renal failure. Several liters of fluid may be required in the initial 24 to 48 hours postoperatively to simply maintain an adequate central pressure to provide a satisfactory urine output. During this time patients may develop extensive peripheral edema, which dissipates over the next few days as the fluids are mobilized and requirements stabilize. Based on our experience in 29 cases of intestinal transplantation and 4 cases of multivisceral transplantation, we have herein described the intraoperative fluid management and hemodynamic changes. Our study confirmed a large quantity of fluid administration during and after small bowel transplantation that required adequate volume monitoring.     

Intestinal and multivisceral transplantation after abdominal trauma

SUMMARY: BACKGROUND Some trauma victims who survive acute illness develop lingering, debilitating syndromes that are incompatible with any semblance of normalcy. Intestinal failure, in particular, exacts a high price in terms of quality of life. Total parenteral nutrition (TPN) has served these patients well, but complications limit its long-term therapeutic effect. Consequently, transplantation is emerging as a life-saving therapy for some patients with the short gut syndrome.METHODS We reviewed eight adult and two pediatric recipients of intestinal and multivisceral transplants after severe abdominal trauma. Background demographics, type of abdominal trauma, transplant procedure, postoperative complications, and survival rates were appraised. This group was also compared with 47 nontrauma recipients of intestinal transplants performed during the same period.RESULTS Four patients (40%) died postoperatively (postoperative days 7, 53, 87, and 91) as a result of multiple organ failure after graft pancreatitis (n = 1), viral encephalitis (n = 1), and sepsis after severe rejection (n = 2). Six patients (60%) are alive (postoperative days 52-1,783). All are off TPN. The 4-year patient survival was 58%, with no significant difference between trauma and nontrauma patients.CONCLUSION Intestinal and multivisceral transplantation are viable options for the treatment of irreversible intestinal failure associated with severe trauma. Surviving patients are TPN independent and have a satisfactory quality of life.     

Bacterial infections after intestine and multivisceral transplantation

BACKGROUND: The frequency of bacterial infections (BI) in intestinal transplant (IT) patients is high with sepsis being the leading cause of death after this procedure. We herein report our experience with major BI to ascertain the incidence, microbiological and clinical factors, risk factors and outcome. MATERIALS AND METHODS: 124 patients (72 children and 52 adults) received 135 grafts: namely, 39 isolated intestine, 33 liver-intestine and 63 multivisceral. Only major BI were considered, namely, those associated with serious morbidity/mortality requiring specific therapy. Patient data were retrieved from computerized databases, flow-charts, and medical records. RESULTS: 92.7% patients showed BI. There were 327 episodes, representing 2.6 episodes/patient (2.8/patients with infection): 193 episodes of bacteremia (1.7/patient with BI) including 29.5% due to catheter related sepsis, 16.5% from abdominal source, 5.7% from respiratory origin and 4.1% from the wound. The organ locations includes 46 respiratory infections, 33 intraabdominal abscesses or infected fluid collections, 8 diffuse peritonitis, 34 wound infections and other miscellaneous sites: empyema, soft tissue infections, cholangitis em leader etc. Median time of infection was nine days after surgery (mean 22+/-3 days), with 67.7% patients having at least one BI before the end of the first month. Infection was present in 76.2% of the 63 deceased patients. An infectious episode during month 1, a clinically manifest abdominal infection and a positive intraabdominal culture had negative impacts on patient survival. CONCLUSIONS: BI are common and early complications after IT. The high rate of bacteremia, line sepsis and abdominal and respiratory infections reflect the recipient's condition, with chronic deterioration superimposed with the effects of prolonged abdominal visceral surgery.     

Monitoring of the intestinal mucosal perfusion using laser Doppler flowmetry after multivisceral transplantation

BACKGROUND: Graft endothelium constitutes a prime target during acute rejection. Infiltration of T cells, monocytes, and enhanced endothelial-leukocyte interactions result in microvascular impairment and altered perfusion. MATERIALS AND METHODS: We measured mucosal blood flow using a laser Doppler flowmeter in three patients undergoing multivisceral transplantation. Thirty-seven measurements were performed through the ileostomy over the first 4 weeks posttransplantation. Most measurements were performed within a 24-hour interval from endoscopy and biopsy. RESULTS: Mucosal perfusion increased throughout the first postoperative week and eventually stabilized around levels specific for each patient. Mucosal perfusion remained stable during graft pancreatitis, but decreased 35% to 55% from baseline (the average value of the previous measurements) during acute rejection and sepsis. During the first week posttransplantation there was a gradual increase in mucosal perfusion, which might reflect regeneration after reperfusion injury. Increased mucosal perfusion did not seem to correlate with rejection or other adverse clinical events. A sudden decrease in mucosal perfusion of 30% or more compared to the previous measurements was associated with septic episodes and/or rejection.     

Graft-versus-host disease in solid organ transplantation

Graft-versus-host disease is well recognized in bone marrow transplantation, but has only recently been described in solid organ transplantation. Two such cases in liver graft recipients, proven by the demonstration of donor type HLA antigens in the peripheral blood and marrow on tissue typing, are described in this paper. The literature on this subject is reviewed and the treatment discussed. It is postulated that there is an order of risk of development of graft-versus-host disease depending on the amount of viable lymphoid tissue included with the transplanted organ as follows: small bowel>heart-lung>liver>kidney>heart. It seems likely that this condition has been substantially underdiagnosed in the past and that greater awareness of the possibility of graft-versus-host disease in solid organ recipients will lead to the recognition of further cases and allow appropriate treatment to be promptly instituted.     

Graft-versus-host disease in solid organ transplantation

Abstract. Graft-versus-host disease is well recognized in bone marrow transplantation, but has only recently been described in solid organ transplantation. Two such cases in liver graft recipients, proven by the demonstration of donor type HLA antigens in the peripheral blood and marrow on tissue typing, are described in this paper. The literature on this subject is reviewed and the treatment discussed. It is postulated that there is an order of risk of development of graft-versus-host disease depending on the amount of viable lymphoid tissue included with the transplanted organ as follows: small bowel > heartlung > liver > kidney > heart. It seems likely that this condition has been substantially underdiagnosed in the past and that greater awareness of the possibility of graft-versus-host disease in solid organ recipients will lead to the recognition of further cases and allow appropriate treatment to be promptly instituted.     

Induction immunosuppression with thymoglobulin and rituximab in intestinal and multivisceral transplantation

BACKGROUND: Induction immunosuppression is now a common practice after intestinal and multivisceral transplantation. We report our experience in 27 adult recipients who received rituximab and rabbit antithymocyte globulin (rATG) in combination as induction agents. MATERIAL AND METHODS: Twenty-seven adult patients received 29 intestinal transplants between July 2004 and March 2007. All patients received induction immunosuppression therapy with rATG, rituximab, and steroids. Tacrolimums and a steroid taper were used for maintenance therapy. Patient and graft survival, episodes of rejection as well as posttransplant lymphoproliferative disease (PTLD) and graft-versus-host disease were analyzed. RESULTS: One-year patient and graft survival was 81% and 76%, respectively. Thirteen patients (48%) experienced 19 episodes of acute rejection (9 mild episodes, 2 moderate, and 8 severe). Patients with a multivisceral graft experienced less episodes of severe acute rejection (1 of 19, 5%) when compared with isolated intestinal transplants and modified multivisceral transplants (7 of 10, 70%). Two patients had episodes of skin graft-versus-host disease that responded to steroid boluses. PTLD was not seen in our series. Two patients developed cytomegalovirus enteritis. CONCLUSIONS: The combination of rATG and rituximab was an effective induction therapy in our preliminary data. The number and severity of rejection episodes increased when the liver was not included as part of the graft. An immunosuppression regimen including rATG, rituximab, and steroids may have a protective effect against PTLD and chronic rejection.     

Infectious complications after multivisceral transplantation in adults

It is thought that multivisceral transplantation requires high levels of immunosuppression and therefore, patients run an increased risk of infection. We retrospectively reviewed our center's experience with clinically relevant infectious complications. PATIENTS: Between 2000 and 2005, 10 adult patients underwent multivisceral transplantation. Two immunosuppression protocols were used: between 2000 and 2003, a high immunosupression protocol (six patients; daclizumab induction, tacrolimus trough levels >20 ng/mL and steroids) and an immunomodulatory, low imunosuppression scheme from 2003 onward (four patients; ATG induction, tacrolimus levels 5 to 10 ng/mL, no steroids). Standard antimicrobial prophylaxis consisted of vancomycin, meropenem, and amphotericin B. Cytomegalovirus (CMV) prophylaxis was used in all but first two cases. Donor and recipient CMV status were D+/R+ (n = 7), D+/R- (n = 2), D-/R+ (n = 1). RESULTS: The median follow-up period was 627 days (range, 19 to 2207 days). A total of 47 infectious episodes were recorded in all patients (range 1 to 14 per patient). The etiology was bacterial in 32 (69%), viral in 8 (17%), and fungal in 7 (14%) cases. The most frequent were catheter related (n = 13) followed by respiratory (n = 7), intraabdominal (n = 6), and wound infections (n = 5). Symptomatic viral infection of the graft (CMV gastritis or enteritis, adenoviral enteritis) was also encountered. Epstein-Barr virus was transiently detected in the serum of nine patients, one of whom later developed posttransplant lymphoproliferative disorder (PTLD). Three deaths all among patients receiving high immunosuppression were owing to infectious complications: pulmonary PTLD at 4 months posttransplantation, ruptured mycotic aneurysm after 8 weeks, and sepsis after 3 weeks. CONCLUSIONS: Infections accounted for a high morbidity after multivisceral transplantation, representing the leading cause of mortality. Exhaustive monitoring, early antimicrobial intervention, and lower immunosuppression may improve the outcome.     

Graft-versus-host disease associated with intestinal transplantation in the rat. Host immune function and general histology

Graft-versus-host disease was studied on the 10th and 14th postoperative days in Lewis x Brown Norway F1 rats (LBN-F1) receiving Lewis accessory heterotopic intestinal allografts. LBN-F1 isograft recipients and LBN-F1 rats were used as controls. The rats were injected with sheep erythrocytes five days before sacrifice. Rats with graft-versus-host disease had progressive loss of the normal architecture of the lymphoid organs. Skin, liver, colon, and salivary glands were infiltrated with immunoblasts and had patchy areas of necrosis. Concurrent with these changes, there were significant, progressive reductions in hemolytic titers, splenocyte plaque-forming counts, viable splenocytes, and the in-vitro splenocyte response to stimulation with concanavalin A. Graft-versus-host disease following intestinal allotransplantation damages the host's lymphoid tissues, producing profound immunosuppression. This finding has implications for clinical intestinal transplantation.     

Intestinal and multivisceral transplantation

Intestinal and multivisceral transplantation can be a lifesaving treatment for patients with complications from the treatment of intestinal failure. However, the indications for this highly specialized treatment are broadening and include other such indications as patients with acute abdominal vascular catastrophes as well as patients with previously unresectable benign intra-abdominal tumours. Since the first successful multivisceral transplant in the late 1980s, the field has expanded and more than 4000 transplants have taken place worldwide and outcomes continue to improve. However, complications are still commonplace and multivisceral and intestinal transplant recipients are more likely to suffer from the complications of transplantation than any other solid organ transplant group. The most important complications are rejection and sepsis, with sepsis remaining the leading cause of death in this patient group. That said the outcomes for intestine alone transplants have improved to such a degree that they are close to that of intestinal failure patients on long-term parenteral nutrition and therefore we may be entering an era where intestinal transplantation will be offered as an alternative to parenteral nutrition for patients with intestinal failure.     

Intestinal and multivisceral transplantation

Intestinal and multivisceral transplantation represents an important treatment option for patients with intestinal failure. Early attempts were hindered by technical and immunological complications. However, significant developments in immunosuppressive therapy have led to marked improvements in outcomes in recent years. The main indications for intestinal transplantation are life-threatening complications or unacceptable quality of life on total parenteral nutrition (TPN), or following evisceration for extensive intra-abdominal tumours. In suitable patients, in the absence of significant liver disease, an isolated intestinal graft is appropriate. A combined liver and intestinal transplant is indicated in patients with significant liver disease, almost always as a result of long-term TPN. Pathology affecting the foregut may require more extensive grafts, including the stomach, duodenum and pancreas. Multivisceral transplantation is technically demanding. The transplant recipient has frequently undergone multiple previous laparotomies and may present with multiple stomata, fistulae, collections, distortion of intra-abdominal anatomy and significant contraction of the abdominal cavity. The most important early complications are acute rejection and sepsis, which frequently occur together. In the long term, chronic rejection and malignancy are the leading causes of graft loss and mortality and immunosuppression related renal impairment a major source of morbidity. It is hoped that ongoing improvements in intestinal and multivisceral transplantation may eventually justify its use as a primary alternative to long-term TPN.