Hepatic artery thrombosis in infants. A comparison of whole livers, reduced-size grafts, and grafts from living-related donors.

Hepatic artery thrombosis (HAT) is a major cause of patient morbidity and graft loss in pediatric liver transplantation (OLT). Although some grafts may be salvaged by arterial thrombectomy and reconstruction, many patients require retransplantation. Patient survival is reduced by HAT. It has been suggested that the incidence of HAT may be altered by the use of reduced-size grafts (RSG). We analyzed our series of infants receiving OLT to determine the frequency of HAT in full-size OLT, cadaveric RSG, and living-related RSG. The role of arterial anastomotic technique in the development of HAT was also examined. Between 10/1/84 and 12/7/90 433 liver transplants were performed. During this period 100 patients between 3 months and 2 years of age (mean 13 months) received 134 liver grafts. The mean weight at the time of transplant was 7.9 kg. (range: 1.9-15 kg). Of the 134 grafts, 60 were whole livers, 61 were cadaveric RSGs, and 13 were living-related RSGs. The cadaveric RSGs were 9 right lobe grafts, 21 left lobe grafts, and 31 left lateral segment grafts. Twenty-seven of the cadaveric RSGs were from split livers, while the other 34 were simple reductions. All 13 living-related RSGs were left lateral segments. HAT occurred in 15 of 60 (25%) whole livers, 9 of 61 (15%) cadaveric RSGs, and 3 of 13 (23%) of the living-related-donor RSGs (P = NS). Subdividing the cadaveric RSGs revealed that HAT occurred in 3 of 9 (33%) right lobe grafts, 3 of 21 (14%) left lobe grafts, and 3 of 31 (10%) left lateral segment grafts (P = NS). The site of the arterial anastomosis in the recipient correlated with the incidence of HAT (hepatic artery 21/86 [24%], celiac axis 1/9 [11%], aorta 2/32 [6%], P = 0.06). In conclusion, it appears that use of a cadaveric left lobe or left lateral segment graft and an aortic arterial anastomosis reduces the risk of hepatic artery thrombosis in liver transplant recipients less than 2 years of age.

Tacrolimus therapy for refractory acute renal allograft rejection: definition of the histologic response by protocol biopsies.

UNLABELLED: Protocol biopsies were performed to define the histologic response to tacrolimus therapy in patients with refractory acute renal allograft rejection. Renal allograft biopsies were performed at defined intervals after initiation of tacrolimus therapy. Protocol biopsies were performed before tacrolimus therapy (within 48 hr of initiation of therapy) and after 1 week of therapy. If the 1-week biopsy did not show rejection reversal, repeat protocol biopsies were obtained at 1- to 2-week intervals, until histologic reversal was observed. Additional biopsies were obtained at 4 weeks and at 8-12 weeks after initiation of tacrolimus therapy. Indicated biopsies were also performed to evaluate increases in serum creatinine. A total of 92 biopsies were performed in 23 patients (average 4.0 biopsies/ patient). Biopsies were performed in each patient immediately before starting tacrolimus therapy (23 biopsies), and 69 biopsies (3.0 biopsies/patient) were performed during tacrolimus therapy. Rejection diagnosis was based on strict Banff criteria. Pretacrolimus biopsies demonstrated mild acute rejection in 64% of patients and moderate acute rejection in 36%. One week after initiation of tacrolimus therapy, protocol biopsies revealed the following: no rejection (60%), improvement (13%), no change (20%), and worsening rejection (7%). Histologic changes at 1 week did not correlate with changes in renal function, as 63% of patients that showed histologic improvement or reversal during the first 2 weeks of therapy did not show improvement in serum creatinine. A lack of histologic improvement (or worsening) at 1 week was demonstrated in a significant proportion of patients (27%); increased tacrolimus dosing provided rejection reversal or improvement in 1-2 weeks in each of these patients. Recurrent rejection was diagnosed on eight biopsies in seven patients, however six episodes were diagnosed by protocol biopsies alone (i.e., in the absence of an elevation in serum creatinine). Delayed improvement in renal function, despite histologic reversal, was likely due to physiologic effects of tacrolimus (i.e., afferent arteriolar vasoconstriction), as histologic evidence of tacrolimus toxicity was not observed during the first 2 weeks of therapy. Histologic evidence of tacrolimus nephrotoxicity (nodular arteriolar hyalinosis) was found in 21% (15 of 69) of biopsies in 39% of patients (9 of 23) at a median time of 60 days (range 12-150 days). Tacrolimus dose and blood levels (by IMx assay) did not correlate with development of clinically silent or clinically evident nephrotoxicity. IN CONCLUSION: 1) protocol biopsies provide information that allows individualization of tacrolimus rejection therapy, 2) histologic resolution of rejection often precedes biochemical improvement, 3) histologic evidence of tacrolimus nephrotoxicity is seldom observed in the first 2 weeks of therapy, and 4) clinically silent recurrent rejection and clinically silent tacrolimus nephrotoxicity are observed with significant frequency during tacrolimus therapy for refractory renal allograft rejection.

Comparison of pancreas transplantation with portal venous and enteric exocrine drainage to the standard technique utilizing bladder drainage of exocrine secretions.

Although bladder drainage of pancreatic exocrine secretions has been reported to decrease morbidity and improve pancreas allograft survival, significant complications remain associated with this technique. Furthermore, this technique requires systemic venous drainage of pancreas allografts. Evidence suggests that portal venous drainage of pancreas grafts prevents hyperinsulinemia and improves lipoprotein composition. This report documents our initial experience with portal venous and enteric exocrine drainage of pancreas allografts (portal/enteric technique) and compares it with the standard technique of systemic venous and bladder exocrine drainage (systemic/bladder technique). Patient and allograft survival, as well as allograft function, were comparable for the two procedures. There were no significant technical complications in this pilot series. Enteric exocrine drainage was associated with a significant reduction in the incidence of acidosis and dehydration when compared with bladder drainage (P<0.005). The portal/enteric technique also avoided reoperation for enteric conversion, as was required by 33% of patients in the systemic/bladder group. The incidence and outcome of allograft rejection were similar for the two techniques. These data suggest that combined pancreas/kidney transplantation with portal venous and enteric exocrine drainage is safe and results in outcomes similar to the standard technique, while eliminating many complications of bladder drainage. These findings should encourage additional studies to determine the consequences of portal venous drainage.

Portal vein thrombosis and stenosis in pediatric liver transplantation.

The aim of this study was to determine the outcome of venous conduits used in living donor liver transplantation (LDLT). We analyzed the portal vein complications in 66 LDLT recipients and 48 cadaveric reduced-size liver transplant (RLT) recipients performed from November 1989 through January 1995. Three different venous conduits were utilized in the LDLT recipients: Group 1, reconstructed vein from the living donor, n=18; Group 2, cadaveric cryopreserved iliac vein, n=37; and Group 3, cadaveric cryopreserved femoral vein, n=11. Overall, 47 percent of the patients were less than one year of age; the age distribution was not significantly different among the groups. The incidence of early thrombosis was significantly greater in LDLT Group 1, (33%) than any of the other groups (LDLT Group 2, 8%; LDLT Group 3, 9%; and RLT, 4%:P<0.0005 vs. reduced graft and < 0.03 vs. other LDLT groups). The incidence of late portal vein stenosis or thrombosis was significantly higher in the LDLT Group 2, (51%) than any of the other groups (LDLT 1, 16%; LDLT Group 3, 9%; RLT 4%;P<0.005 vs. cadaveric and < 0.02 vs. LDLT Group 1 and LDLT Group 3). Five year arterial graft and patient survival for patients who have experienced portal vein thrombosis or stenosis is 61% and 67%, respectively, versus 67% and 71% for those patients who have not experienced portal vein pathology, P=ns. Based on this experience, we recommend avoiding the use of cryopreserved iliac vein for portal vein reconstruction in liver transplantation. Every effort should be taken to eliminate the need for venous conduits in liver transplantation. If venous conduits must be utilized, cryopreserved femoral veins seem to provide superior patency rates. Careful clinical and ultrasonopraphic monitoring of patients at high risk for late venous thrombosis permits therapy with excellent graft and patient survival.

Use of polytetrafluoroethylene patch for temporary wound closure after pediatric liver transplantation.

Despite numerous options for pediatric transplantation, closure of the abdominal wall after liver transplantation is occasionally difficult, resulting in increased abdominal pressure and possible vascular compromise. Since 1990, we have utilized a 2-mm thick sheet of polytetrafluoroethylene (PTFE) to overcome this situation in 21 transplants for 17 patients. The median age was 0.9 months. Ten of the 21 transplants utilized full-size grafts. The donor to recipient weight ratio was 1.7+/-1.2. Cadaveric left lateral segments were used in 8 of 21 transplants (weight ratio, 7.4+/-5.9), living donor left lateral segments were used in 3 of 21 transplants (weight ratio, 13.2+/-6.7). We were able to remove 14 of 21 patches with one additional operation, whereas 4/21 patches required two operations and 3/21 required three operations. Reoperations identified two cases of hepatic artery thrombosis not previously identified by duplex ultrasonography. There were no technical problems or adverse effects associated with the use of the PTFE patch. After patch removal, the fascia was closed with a nonabsorbable suture and the skin was allowed to close by secondary intention. There were no wound infections, portal vein thrombosis, or fluid and electrolyte abnormalities. PTFE is a safe, temporary alternative to primary wound closure in liver transplantation when the size of the graft or intestinal and graft edema does not allow conventional closure of the abdomen. Infectious, fluid/electrolyte, or ventilatory complications were not noted. The necessity of a second-look operation is useful in assessing the graft and vascular patency. The majority of patches can be removed within the first postoperative week.

Long-term outcome of kidney-pancreas transplant recipients with good graft function at one year.

To assess the long-term outcome of kidney/pancreas transplantation, patients were identified who had good graft function at one year posttransplant and a minimum of 3 years' follow-up. Fifty recipients from 1987-92 met these criteria. Records were reviewed for graft survival, graft function, readmissions, and medical complications. Psychosocial adjustment and quality of life were assessed using the SCL-90-R and SIP surveys, respectively. Patient, kidney, and pancreas survivals were 94%, 86%, and 85% at five years (Kaplan-Meier), with a mean follow-up of 4.3 years. The 3 deaths were due to 2 sudden arrests at home (presumed to be cardiac events) and 1 episode of sepsis. Other graft losses were due to rejection, except for one case of sepsis. The remaining patients are normoglycemic (glucose 92 +/- 23 mg/dl) and have a creatinine of 1.8 +/- 0.6 mg/dl. Mortality after the first year was 0.9%/year. Estimated kidney and pancreas half-lives were 15 +/- 2 and 23 +/- 7 years, respectively. Hospitalization, acute rejection, graft pancreatitis, dehydration, and severe infections all decreased dramatically after the first year. While CMV was the most common infection in the first year, foot infections predominated thereafter. Retinal hemorrhage was infrequent. Sudden death (presumably cardiac) was the chief cause of mortality, while peripheral vascular disease resulted in several amputations. Fractures were common, suggesting the need for increased attention to bone demineralization. Psychosocial and quality of life evaluations were within normal limits. In conclusion, most complications specifically related to transplantation occur in the first year, but underlying disease renders these patients susceptible to a variety of cardiovascular, bone, and other disorders.

Tacrolimus for primary treatment of steroid-resistant hepatic allograft rejection.

Twelve patients who experienced steroid-resistant rejection after primary liver transplantation while receiving cyclosporine-based therapy were converted to tacrolimus without receiving OKT3 or additional steroids. The indications for conversion were ongoing biopsy-confirmed rejection. All patients had received one course of high-dose intravenous steroids, which failed to reverse the rejection episode. No other antirejection therapy was given. Tacrolimus was initiated to reverse rejection and for maintenance therapy. The tacrolimus target level was 15-20 ng/ml (whole blood, IMX). All 12 patients had rapid reversal of the rejection episode and did not experience recurrent rejection (mean follow-up: 8.2 +/- 1.2 months). The mean bilirubin level dropped from 6.1 mg/dl at the initiation of tacrolimus therapy to 4.4 mg/dl by day 7 of therapy, 2.5 mg/dl by day 14, and 1.5 mg/dl by day 21 (P < 0.003). Serum glutamic pyruvic transaminase demonstrated a similar response. The serum creatinine level was unchanged at 1.5 mg/dl. No major adverse reactions were noted in this group of patients. Patient and graft survival rates were 100%. Four of the eight patients with a follow-up of >4 months are no longer receiving steroid therapy. Tacrolimus is effective as the primary therapy for the treatment of steroid-resistant rejection and provides a rapid and sustained biochemical response. Patients with mild to moderate rejection may be safely converted from cyclosporine to tacrolimus without an additional steroid bolus or OKT3 therapy. Early "preemptive" conversion to tacrolimus prior to the use of additional steroids or OKT3 may decrease overall rejection therapy requirements. This approach has promise for improved graft survival and fewer infectious and immunologic complications.

Posttransplant lymphoproliferative disease in pediatric liver transplantation. Interplay between primary Epstein-Barr virus infection and immunosuppression.

The incidence, risk factors, and outcome of posttransplant lymphoproliferative disease (PTLD) were examined for 298 children undergoing liver transplantation. The overall incidence of PTLD was 8.4% (25 of 298). Intensity of immunosuppression was found to be a major risk factor for the development of PTLD. Cyclosporine and tacrolimus when used as primary immunosuppression were associated with the development of PTLD in 4.3% and 6.6% of cases (P=NS). OKT3 and tacrolimus, when used as rescue therapy for steroid-resistant rejection, were associated with a comparable increase in the risk of developing PTLD (10.9% and 11.1%, P=NS). Patients requiring both OKT3 and tacrolimus to treat refractory rejection were at significantly increased risk for PTLD (28.1% vs. 4.3% or 6.6%, P<0.0001). PTLD was more common in patients who received transplants for Langerhans cell histiocytosis relative to other indications for transplantation (66% vs. 8.4%, P=0.0005). The data also support an association between primary Epstein-Barr virus (EBV) infections following transplantation and the development of PTLD. While only three patients were EBV seropositive before transplantation (14%), 19 patients were EBV seropositive at the time of diagnosis of PTLD (90%), confirming a high incidence of primary EBV infections in patients with PTLD (21 patients had both pre- and posttransplant EBV serologies). In this series, PTLD was associated with a mortality rate of 60%, and 12 of the 15 patients who died had persistent tumor at the time of death. Five of the 13 patients rendered disease-free developed ductopenic rejection. Of the four with severe liver dysfunction, two have undergone successful retransplantation and are alive without evidence of PTLD. In conclusion, intense immunosuppression using OKT3 and tacrolimus as rescue agents was associated with a significant increase in the incidence of PTLD. Primary EBV infection after transplantation further accentuated this risk. Independent of these risk factors, patients with Langerhans cell histiocytosis were at significantly increased risk for PTLD. The identification of high-risk patients should allow the development of protocols to screen patients for primary EBV infections and early indications of PTLD, as well as the institution of preemptive antiviral and antitumor therapies.