Immunologic challenges in small bowel transplantation.

Since the introduction of tacrolimus, small-bowel and multivisceral transplantion has increased to 100-200/year in the United States. The intestine carries more passenger lymphocytes than other organs, and bidirectional trafficking of lymphocytes and other immunocytes begins as soon as the vascular clamp is released. Because of ischemia-reperfusion injury and exposure to ligands for Toll-like receptors from the lumen, the innate immune system of the graft is activated, causing inflammation which must be brought under control by regulatory cells. Inclusion of the liver in the allograft favors graft acceptance, but the mechanism of this effect has not been determined. Anti-HLA and other anti-donor antibodies clearly play a major role in determining the long-term fate of the graft, as reflected in 5-year graft survival. Development of new (de novo) HLA antibodies and/or increases in their titers or function-especially the ability to bind C1q and activate complement increase the risk of graft loss. Monitoring antidonor antibody production and the use of new therapies including complement inhibitors will contribute to increasing success of SBT.

Preformed and de novo donor specific antibodies in visceral transplantation: long-term outcome with special reference to the liver.

Despite improvement in early outcome, rejection particularly chronic allograft enteropathy continues to be a major barrier to long-term visceral engraftment. The potential role of donor specific antibodies (DSA) was examined in 194 primary adult recipients. All underwent complement-dependent lymphocytotoxic crossmatch (CDC-XM) with pre- and posttransplant solid phase HLA-DSA assay in 156 (80%). Grafts were ABO-identical with random HLA-match. Liver was included in 71 (37%) allografts. Immunosuppression was tacrolimus-based with antilymphocyte recipient pretreatment in 150 (77%). CDC-XM was positive in 55 (28%). HLA-DSA was detectable before transplant in 49 (31%) recipients with 19 continuing to have circulating antibodies. Another 19 (18%) developed de novo DSA. Ninety percent of patients with preformed DSA harbored HLA Class-I whereas 74% of recipients with de novo antibodies had Class-II. Gender, age, ABO blood-type, cold ischemia, splenectomy and allograft type were significant DSA predictors. Preformed DSA significantly (p < 0.05) increased risk of acute rejection. Persistent and de novo HLA-DSA significantly (p < 0.001) increased risk of chronic rejection and associated graft loss. Inclusion of the liver was a significant predictor of better outcome (p = 0.004, HR = 0.347) with significant clearance of preformed antibodies (p = 0.04, OR = 56) and lower induction of de novo DSA (p = 0.07, OR = 24). Innovative multifaceted anti-DSA strategies are required to further improve long-term survival particularly of liver-free allografts.

Rotavirus infection in adult small intestine allografts: a clinicopathological study of a cohort of 23 patients.

Rotavirus enteritis (RVE) is increasingly recognized as a cause of small bowel allograft dysfunction but its significance in adult patients is unknown. We have studied 23 adult small bowel transplant patients aged 19.8-59 years (mean = 38.2 years), who were presented with diarrhea and tested positive for rotavirus by enzyme-linked immunosorbent assay methods. Serial follow-up biopsies, as well as clinical data, are documented and analyzed. These patients were followed up for an average of 168 days (range 33-534 days). Mean time of rotavirus diagnosis from transplant day was 794 days (range 38-2907 days). Self-limited diarrhea lasting 6-13 days (mean = 9 days) was the main presentation. Sixteen (69.6%) patients developed acute cellular rejection either concurrently with (i.e. six patients) or after (10 patients) RVE, often characterized by prominent mucosal plasmacytosis at an average of 22 days (range 0-94 days) from the day RVE was diagnosed. One-third of patients with acute rejection (i.e. five out of 16) required muromonab-CD3 rescue therapy. Two patients experienced graft loss (one from chronic rejection, another from sepsis). Rotavirus infection is a cause of diarrhea in adult small bowel transplant patients. The infection appeared to trigger cellular rejection that was associated with mucosal plasmacytosis, and sometimes required aggressive rescue therapy.

An innovative sphincter preserving pull-through technique with en bloc colon and small bowel transplantation.

This report describes a new innovative pull-through technique of hindgut reconstruction with en bloc small bowel and colon transplantation in a Crohn's disease patient with irreversible intestinal failure. The approach was intersphincteric and the anastomosis was established between the allograft colon and the recipient anal verge with achievement of full nutritional autonomy and anal continence.

Treatment of tardive dyskinesia with levetiracetam in a transplant patient.

OBJECTIVE: To describe successful treatment of tardive dyskinesia with levetiracetam. BACKGROUND: Tardive dyskinesia is a late-onset movement disorder caused by exposure to dopamine receptor blocking agents, most commonly neuroleptics. Metoclopramide is frequently used to treat gastrointestinal dysmotility. It has antidopaminergic properties, and is estimated to be responsible for two-thirds of drug-related movement disorders. DESIGN/METHODS: Case report. RESULTS: A 68-year-old woman presented with a history of intestinal transplantation (12 years ago; short gut syndrome related to bowel resection for rectal carcinoma) and renal transplantation (1 year ago; diabetes). She developed involuntary movements with stereotypic oro-buccal-lingual dyskinesias and right-sided choreiform movements. Her Abnormal Involuntary Movement Scale score (AIMS) score was 27. She has been treated with metoclopramide for gastrointestinal dysmotility for more than 10 years and was diagnosed with tardive dyskinesia. Treatment with levetiracetam 250 mg orally b.i.d. led to a significant improvement of abnormal movements within a week. Her AIMS score decreased to 8. DISCUSSION: Tardive dyskinesia may be quite disabling and options include withdrawal of offending medication, or use of tetrabenazine or reserpine. Several reports also suggested improvement of tardive movement disorders with levetiracetam. In our patient, levetiracetam relieved symptoms of tardive dyskinesia and allowed continuous use of metoclopramide. Larger studies are needed to confirm its efficacy.

Granulomatous amebic encephalitis in a multivisceral transplant recipient.

A 40-year-old man with multivisceral allograft developed acutely right-sided numbness 9 months after transplantation. Cranial magnetic resonance imaging (MRI) showed a small left parietal lesion, and cerebrospinal fluid analysis was unremarkable. Stereotactic brain biopsy was non-diagnostic. The patient continued to deteriorate, developed cerebral edema and died at 13 days after the onset of symptoms. Unexpectedly, autopsy demonstrated acanthamebic encephalitis. This case highlights diagnostic difficulties encountered with amebic encephalitis and expands the spectrum of opportunistic central nervous system (CNS) infections in solid and visceral organ transplant recipients.

Endovascular repair of an aortoduodenal fistula.

PURPOSE: To demonstrate the utility of endovascular stent-graft repair for the management of an unusual aortoduodenal fistula. METHODS AND RESULTS: A 23-year-old man with an aortoduodenal fistula secondary to tumor necrosis was treated with a Corvita endoluminal stent-graft after several failed surgical attempts to repair the defect. At 2-year follow-up, the patient was clinically and radiographically devoid of any evidence of occult stent-graft infection. CONCLUSIONS: This case illustrates the usefulness of endovascular repair for the treatment of a primary aortoduodenal fistula. Endovascular repair should be included in the armamentarium for the management of difficult aortoduodenal fistulas.

Intestinal transplantation in children with chronic intestinal pseudo-obstruction.

BACKGROUND: Children with chronic intestinal pseudo-obstruction (CIPO) often require total parenteral nutrition (TPN) which puts them at risk of liver failure and recurrent line infections. Intestinal transplantation has become a therapeutic option for TPN dependent children with intestinal failure who are failing management with TPN. AIMS: To investigate the outcome of children with CIPO referred for intestinal transplantation. METHODS: A retrospective review was carried out of records and diagnostic studies from 27 patients with CIPO referred for intestinal transplantation. RESULTS: Five children were not listed for transplantation: two because of parental decision, two because of suspicion of Munchausen syndrome by proxy, and one because he tolerated enteral nutrition. Six are still TPN dependent and awaiting transplantation. Eight children died awaiting transplantation. Eight children underwent transplantation. Three died (two months, seven months, and four years after transplant). Five children are alive with a median follow up of 2.6 years (range two months to six years). All transplanted children were able to tolerate full enteral feedings. The postoperative course was complicated by dumping syndrome, Munchausen syndrome by proxy, narcotic withdrawal, and uncovering of achalasia. Conclusion-Intestinal transplantation may be a life saving procedure in children with CIPO. Early referral and thorough pretransplant evaluation are keys to successful transplantation.

Ten years of experience with patients with chronic active liver disease variceal bleeding: ablative versus selective decompressive therapy.

BACKGROUND: Variceal hemorrhage is an added major threat to survival in patients with chronic active liver disease (CALD). The hemodynamic consequences of surgical therapy and the continued activity of the underlying liver disease both contribute to the hepatic dysfunction and determine patient survival. METHODS: Two hundred and seventy two consecutive cases of (Child A or B) variceal bleeding with chronic hepatitis were surgically treated during a 10-year period. Histologic chronic active hepatitis (CAH) was documented in 160 (59%) patients, whereas chronic persistent hepatitis (CPH) was evident in 112 (41%). The applied surgical procedure was distal splenorenal shunt (DSRS) in 99 (36%) patients, splenectomy and gastroesophageal devascularization (SGD) in 108 (40%), and splenectomy with left gastric ligation (SLGL) in 65 (24%) patients. The preoperative data base obtained on these patients was matched comparing the three surgical modalities within each pathologic group (p > 0.05). RESULTS: The operative mortality was low among the patients with CAH (DSRS, 5.1%; SGD, 4.2%) with no deaths occurring in the CPH group. Among the individuals with CAH, recurrent variceal hemorrhage occurred significantly (p < 0.05) more often after SLGL (26%) and SGD (17%) than after DSRS (5%). Sclerotherapy rescued 93% (SGD) and 70% (SLGL) of the patients with rebleeding. DSRS significantly (p < 0.05) increased the risk of encephalopathy (28%) compared with SGD (4.2%) and SLGL (8%). The morbidity rates were quite low among the patients with CPH with no significant (p > 0.05) differences noted when the three surgical modalities were compared. Both groups experienced a significant (p < 0.05) increase in aspartate aminotransferase levels after the three procedures with a significant (p < 0.05) increase in bilirubin level occurring only after DSRS. The 5-year survival rate for the patients with variceal bleeding with CAH was 76% (DSRS), 73% (SGD), and 88% (SLGL). The leading causes of death were liver failure after DSRS (70%), variceal hemorrhage after SLGL (60%), and equally divided between septicemia (43%) and liver failure (43%) after SGD. The patients with CPH had a better 5-year survival of 89% (DSRS) and 100% (nonshunt operation). CONCLUSIONS: These data showed that (1) CALD is common among cases of variceal bleeding; (2) elective surgical treatment of variceal hemorrhage in patients with Child A or B CALD has a low operative mortality; (3) SLGL backed up by sclerotherapy is a better surgical alternative to either selective shunt or SGD in patients with active hepatitis, and (4) both DSRS and nonshunt operation are equally good surgical options for patients with CPH.

Efficacy of hepatic transplantation in patients with primary sclerosing cholangitis.

Controlled trials to assess the therapeutic benefit of orthotopic hepatic transplantation (OHTx) for primary sclerosing cholangitis (PSC) cannot be justified in view of improvement of patient survival after this operation since 1981. However, the actual patient survival with OHTx can be compared with the Mayo model estimated survival probabilities without OHTx. This model, which encompasses physical, biochemical and histopathologic parameters of PSC, was constructed from a study of 392 conservatively treated PSC patients at five international centers in England and North America. We compared the actual survival of 216 adult patients with the diagnosis of advanced PSC who underwent hepatic replacement with the expected survival estimated by the Mayo PSC natural history model, "the simulated control technique." OHTx was performed at the University of Pittsburgh and Mayo Medical Center between 5 December 1981 and 26 December 1990. The mean (plus or minus standard deviation) post-OHTx follow-up period was 34 +/- 25 months (range of zero to 104 months). Before transplantation, biliary or portal hypertensive operation, or both, was performed upon 104 patients. At operation, the mean age of recipients was 42.1 +/- 11.3 years and the mean value of total serum bilirubin was 13.3 +/- 13.0 milligrams per deciliter. Extensive septal fibrosis and cirrhosis were histologically documented in 97 percent of the patients, with splenomegaly in 63 percent. Immunosuppressive therapy was based primarily on cyclosporin in 184 recipients and FK-506 in 32. Within six months, the Kaplan-Meier survival probability after OHTx (0.89) already was higher than predicted by the Mayo model (0.83). At five years, the Kaplan-Meier actual survival with OHTx was 0.73 compared with 0.28 expected Mayo model survival. The overall increased survival rate with transplantation was statistically significant (chi-square equals 126.6; p < 0.001). At all risk stratifications, OHTx significantly improved survival with a p value of 0.031 (low risk), 0.001 (moderate risk) and < 0.001 (high risk). Thus, OHTx is effective therapy for PSC. Disease gravity and unsuspected cholangiocarcinoma in the excised native liver adversely influenced short and long term survival rates after transplantation, respectively.

Should both schistosomal and nonschistosomal variceal bleeders be disconnected?

Splenopancreatic disconnection (SPD) was conceived and implemented as a technical addition to distal splenorenal shunt (DSRS) to maintain its selectivity and preserve portal perfusion. The proposed hemodynamic and metabolic stability of hepatocytes after DSRS-SPD should improve survival. In this nonrandomized study, 145 consecutive (Child A/B) variceal bleeders were electively subjected to selective shunt with DSRS in 93 and DSRS-SPD in 52 patients. The 2 groups were similar before surgery with a mean follow up of 24 +/- 12 (DSRS) and 27 +/- 14 (DSRS-SPD) months. DSRS-SPD had an operative mortality of 3.8%. Postoperative pancreatitis occurred in 7.7% after DSRS-SPD and 3.2% after DSRS alone, with schistosomal hepatic fibrosis representing 86% of morbid cases. Shunt patency was high and recurrent variceal hemorrhage was low in both groups. Clinical encephalopathy was significantly reduced after DSRS-SPD (p less than 0.05). The addition of SPD significantly reduced both the incidence of chronic hyperbilirubinemia in the schistosomal patients (p less than 0.05) and the difference between the changes in total serum bilirubin in all patients (p = 0.001). Portal perfusion was preserved after DSRS-SPD in all of the angiographically-studied patients. The overall survival was 84% after DSRS and 88% after DSRS-SPD. The schistosomal patients showed an incidence of 95% and 96% survival after DSRS and DSRS-SPD, respectively. DSRS-SPD was able to improve survival (92%) better than DSRS (77%) among well-matched nonschistosomal patients. These data show: (1) DSRS-SPD still has low operative mortality and a high patency rate with a low incidence of recurrent variceal hemorrhage, (2) DSRS-SPD maintains portal perfusion, achieves better survival, and reduces the incidence of encephalopathy, especially in patients with nonalcoholic cirrhosis and mixed liver disease, (3) in the schistosomal population, DSRS-SPD reduces the incidence of chronic hyperbilirubinemia but increases the risk of postoperative pancreatitis.