Oscar Bronsther

The Incidence, Timing, and Management of Biliary Tract Complications After Orthotopic Liver Transplantation

ObjectiveThis study analyzed the incidence and timing of biliary tract complications after orthotopic liver transplantation (OLTx) in 1792 consecutive patients. These results were then compared with those of previously reported series. Finally, recommendations were made on appropriate management strategies. Summary Background DataTechnical complications after OLTx have a significant impact on patient and graft survival. One of the principle technical advances has been the standardization of techniques for biliary reconstruction. Nonetheless, biliary complications still occur. A 1983 report from the University of Pittsburgh reported biliary complications in 19% of all transplants, and an update in 1987 reported biliary complications in 13.2% of transplants. MethodsThe medical records of all patients who underwent liver transplantation and were hospitalized between January 1, 1988 and July 31, 1991 were reviewed. The case material consisted of the medical records of 217 patients treated for 245 biliary complications. ResultsPrimary biliary continuity was established by either choledochocholedochostomy over a T-tube (C-C, n = 129) or a Roux-en-Y choledochojejunostomy with an internal stent (C-RY, n = 85). The overall incidence for biliary complication in this large series was 11.5%. Strictures (n = 93) and bile leak (n = 58) were the most common complications (69.6%). Most billary complications (n = 143, 66%) occurred within the first 3 months after surgery. In general, leaks occurred early, and strictures developed later. Bile leaks were equally frequent in both C-C and C-RY (27.1% and 25.9%, respectively); strictures were more common after a C-RY type of reconstruction (36.4% and 52.9%, respectively). Twenty-one patients died, an incidence of 9.6%. Fifteen of the 21 biliary-related deaths were among patients treated for rejection before the recognition of biliary tract pathologic findings. ConclusionsProgress has been made on improving the result of biliary reconstruction after OLTx. Nonetheless, patients continue to experience biliary complications after OLTx, and these complications cause considerable loss of grafts and life. If significant additional improvement in patient and graft survival are to be obtained, the technical performance of OLTx must continue to improve.

EXPERIENCE WITH LIVER AND KIDNEY ALLOGRAFTS FROM NON-HEART-BEATING DONORS

Given the shortage of cadaveric organs, we began a study utilizing NHBD for OLTx and KTx. There were 24 NHBD between January 1989 and September 1993. These donors were divided into 2 groups: uncontrolled NHBD (G1) (n=14) were patients whose organs were recovered following a period of CPR; and controlled NHBD (G2) (n=10) were patients whose organs were procured after sustaining cardiopulmonary arrest (CA) following extubation in an operating room setting. Eight kidneys and 5 livers were discarded because of macroscopic or biopsy findings. In G1, 22/27 (81.5%) kidneys were transplanted; 14/22 (64%) developed ATN; 20/22 (95%) recipients were off dialysis at the time of discharge. With a mean follow-up of 32.7± 21.1 months, sixteen (73%) kidneys are still functioning, with a mean serum creatinine of 1.7±0.6 mg/dl. The one-year actuarial patient and graft survivals are 95% and 86%. In G2, 17/20 (85%) kidneys were transplanted; 13/17 (76%) kidneys experienced ATN. All patients were off dialysis by the time of discharge. With a mean follow-up of 17.6±15.4 months, twelve (70%) kidneys are still functioning, with a mean serum creatinine of 2.5±2.1 mg/dl. The one-year actuarial patient and graft survivals are 94% and 82%, respectively. In G1, 6/10 (60%) livers were transplanted; 3/6 (50%) livers functioned, the other 3 patients required ReOLTx in the first week postoperatively because of PNF(n=2) and inadequate portal flow (n=1). Two functioning livers were lost due to HAT (n=1) and CMV hepatitis (n=1). In G2, 6/7 (85.7%) livers were transplanted. All the livers (100%) functioned. 2 patients required ReOLTx for HAT at 0.9 and 1.0 months. Both patients eventually died. One patient with a functioning liver died 2 months post OLTx. The remaining 3 patients are alive and well at 27 months of follow-up. This study shows that the procurement of kidneys from both uncontrolled and controlled NHBD leads to acceptable graft function despite a high incidence of ATN. The function of liver allografts is adequate in the controlled NHBD but suboptimal in the uncontrolled NHBD, with a high rate of PNF.

The adverse impact on liver transplantation of using positive cytotoxic crossmatch donors

Because of the liver grafts ability to resist cytotoxic antibody-mediated rejection, it has become dogma that the conventional transplant crossmatch used to avoid hyperacute rejection of other organs is irrelevant to the liver. We examined this hypothesis in a consecutive series of adult primary liver recipients treated with FK506 and low-dose steroids. Twenty-five of 231 (10.8%) patients received a liver from a cytotoxic-positive crossmatch donor (more than 50% of donor T lymphocytes were killed by dithiothreitol-pretreated recipient serum). The outcome was compared with that of 50 negative crossmatch patients who had their transplantations just before and after the crossmatch positive cases. The one-year graft and patient survivals were 56% and 68%, for positive and 82% and 86% for negative crossmatch patients (P = 0.004, P = 0.03, respectively). The difference between patient and first graft survival was accounted for by retransplantation, which was 4 times more frequent in the positive-crossmatch cases. Histologically, failed allografts obtained at the time of retransplantation revealed a spectrum of pathologic findings related to vascular injury. This study showed a higher difficulty of intraoperative blood product management, a degraded prognosis, and a poorer average quality of ultimate graft function when liver transplantation was performed against positive cytotoxic crossmatches. In such patients for whom crossmatch-negative donors may never be found because of the broad extent and intensity of sensitization, special therapeutic strategies perioperatively must be evolved if results are to improve.

Single-center experience with primary orthotopic liver transplantation with FK 506 immunosuppression.

OBJECTIVE The efficacy for primary orthotopic liver transplantation of a new immunosuppressive agent, FK 506 (tacrolimus, Prograf, Fujisawa USA, Deerfield, IL), was determined. SUMMARY BACKGROUND DATA After 3 years of preclinical research, a clinical trial of FK 506 for orthotopic liver transplantation was begun in February 1989, first as a rescue therapy for patients with intractable rejection with conventional immunosuppression, then as a primary drug. METHODS Between August 1989 and December 1993, 1391 recipients (1188 adult and 203 pediatric) of primary liver allografts were treated with FK 506 from the outset. Results from these patients were analyzed and compared with those of 1212 historical control patients (971 adult and 241 pediatric) given cyclosporine-based immunosuppression. RESULTS Actuarial survival at 4 years was 86.2% with FK 506 versus 65.5% with cyclosporine in the pediatric patients (p < 0.0000) and 71.4% versus 65.5% in the adults (p < 0.0005). The need for retransplantation was reduced significantly for FK 506 patients. Four-year graft survival was 77.0% with FK 506 versus 48.4% with cyclosporine in the pediatric patients (p < 0.0000), and 61.9% with FK 506 versus 51.4% with cyclosporine in the adult recipients (p < 0.0000). Regression analysis revealed that reduction in mortality or graft loss from uncontrollable rejection, sepsis, technical failure, and recurrent original liver disease were responsible for the improved results with FK 506 therapy. CONCLUSIONS FK 506 is a potent and superior immunosuppressive agent for orthotopic liver transplantation.

Treatment of cyclosporin-induced haemolytic uraemic syndrome with FK506

Sir,—Haemolytic uraemic syndrome (HUS) is a well-recognised complication of cyclosporin therapy in organ transplantation.1-4 It has usually been treated by a switch to azathioprine. We report the first use of FK506 in the management of this complication. A 33-year-old man had liver transplantation in January, 1989, for end-stage liver disease due to chronic active hepatitis. Recovery was complicated by acute tubular necrosis which required haemodialysis for 3 weeks. He was discharged 7 weeks postoperatively with normal liver function, normal haematological profile, serum creatinine 2·4 mg/dl, and blood urea nitrogen (BUN) 24 mg/dl. His daily medications were cyclosporin 600 mg, azathioprine 75 mg, acyclovir 200 mg, and trimethoprim 80 mg plus sulphamethoxazole 400 mg. 7 months postoperatively, he became anaemic with a haematocrit of 14·7%, platelet count of 29 000/μl, and white cell count 5800/μ1. Total bilirubin rose to 5·7 mg/dl, creatinine to 5·0 mg/dl, and BUN to 69 mg/dl. His cyclosporin level, which was therapeutic, was 713 ng/ml (TDX method). A blood smear revealed microangiopathic haemolytic anaemia. The urine contained trace protein and the sediment had 1-3 hyaline casts per high-power field. The patient was afebrile and without major complaints. Because of the microangiopathic haemolytic anaemia, thrombocytopenia, and renal failure, cyclosporin-induced HUS was diagnosed. When the platelet count and haematocrit continued to fall for 2 days after admission, azathioprine and cyclosporin were discontinued. FK506 was started at 8 mg daily (0·15 mg/kg) intravenously and changed to 16 mg pet day orally after 3 days. Within 24 h of the start of FK506 the platelet count had increased to 130 000/μl, and by the seventh day it was 420 000/μl (figure). The haematocrit rose progressively, starting on day 6. Renal function initially worsened but also began to improve on day 7 of FK506 therapy. Dialysis was not required. Total bilirubin fell promptly (figure). The patient was discharged after a week, and a week after this his serum creatinine was 4·2 mg/dl and platelet count 420000/μl. Hospital course of patient with cyclosporin-induced HUS After discharge, the dose of FK506 was arbitrarily halved. 4 weeks later HUS abruptly recurred with thrombocytopenia, hyperbilirubinaemia, and acute renal failure. The oral FK506 dose was restored to 16 mg daily, with resolution of the HUS within a few days and during the ensuing 6 weeks. This patient quickly recovered from cyclosporin-induced HUS without the need for p1asmapheresis or other ancillary therapy. Cyc1opsorin-induced HUS is often fatal1-4 and poor control of graft rejection accompanies the discontinuation of cyclosporin. In our patient the offending immunosuppressive agent was replaced by a more potent one.5 Cyclosporin and FK506 both inhibit interleukin-2 production and binding and selectively suppress T-cell function. However, the two drugs have a completely different chemical structure, and this may explain the salutary effects of FK506 in cyclosporin-induced HUS. Rapid recovery, as seen in this case, has been uncommon. Gradual improvement of the haematological picture has been the usual course as cyclosporin is cleared from the plasma with or without plasmapheresis. Cyclosporin-induced endothelial cell injury is the probable proximate event in the pathogenesis of HUS in most cases. However, autoimmune haemolytic anaemia has also been described.6,7 The ancil1ary manoeuvres used to treat cylosporin-induced HUS are directed at immune mechanisms. FK506, the most potent immunosuppressant yet used clinically,5,8 may exert its effect not only by substituting for cyclosporin but also by treating the primary immunological origin of this disorder.

THE LIVER TRANSPLANT WAITING LIST : A SINGLE-CENTER ANALYSIS

At this transplant center 1340 patients were entered on the liver transplant waiting list during the first 25 months (October 1987 to November 1989) after the initiation of the UNOS allocation system for liver grafts. Of these 972 (72.5%) of the patients received a graft, 120 (9.0%) died waiting for a graft, 109 (8.1%) remained on the active list as of the study endpoint of December 15, 1989, 123 (9.2%) were withdrawn from candidacy, and 16 (1.2%) received a transplant at another center. A total of 1201 patients were candidates for a first graft. Of the 812 primary candidates who received a graft, 64.8% received their graft within one month of entry on the waiting list. Of the 109 primary candidates who died before a graft could be found, 79.0% died within a month of entry onto the waiting list. At time of transplantation, 135 (16.6%) primary recipients of a graft were UNOS class 1, 326 (40.1%) were UNOS class 2, 190 (23.4%) were UNOS class 3, and 161 (19.8%) were UNOS class 4. Actuarial survival rates (percentage) at 6 months for recipients in UNOS class 1, class 2, class 3, and class 4 were 88.7 +/- 2.9, 82.6 +/- 2.1, 78.4 +/- 3.2, and 68.4 +/- 3.9, respectively (P less than 0.001). At the time of death of recipients who failed to get a graft, 6 (5.5%) were UNOS class 1, 14 (12.8%) were UNOS class 2, 23 (21.1%) were UNOS class 3, and 66 (60.6%) were UNOS class 4. These results indicate that a high proportion of liver transplant candidates are in urgent need of a graft and that the UNOS system succeeds in giving these patients high priority. However patient mortality on the waiting list and after transplantation would lessen significantly if more patients with end-stage liver disease were referred to the transplant center in a timely manner before their condition reaches the point where the probability of survival is diminished.

Can adenine nucleotides predict primary nonfunction of the human liver homograft

Sixty-eight primary liver grafts were analyzed to see whether adenine nucleotides (AN: ATP, ADP, and AMP) or purine catabolites (PC: adenosine, inosine, hypoxanthine, and xanthine) of tissue or effluent can predict primary graft nonfunction. AN, PC, and nicotinamide adenine dinucleotide, oxidized form (NAD+) of the tissue before (pretransplant) and after graft reperfusion (post-transplant) and of the effluent were analyzed. The graft outcome was classified into two groups (group A: successful, n=64; group B: primary nonfunctioning, n=4). No significant differences were observed in pretransplant measurements between groups A and B, whereas ATP, ADP, total AN, total AN+total PC (T) and NAD+, in post-transplant tissues, were significantly higher in group A. Xanthine in the effluent was significantly higher in group B than in group A. ATP, ADP, total AN, T, and NAD+ in post-transplant tissue were significantly associated with primary graft nonfunction by logistic regression analysis.

Sonography: A useful tool to detect the mechanical causes of renal transplant dysfunction

The purpose of this study was to evaluate the utility of sonography in distinguishing between mechanical and nonmechanical causes for renal transplant dysfunction.

Total hepatectomy and liver transplant for hepatocellular adenomatosis and focal nodular hyperplasia.

Extensive hepatocellular adenomatosis (HA) and focal nodular hyperplasia (FNH) represent a proliferation of hepatic cells that occurs most frequently in women. These lesions are uncommon in the pediatric age group, accounting for 2% of pediatric hepatic tumors, and are extremely rare in males. The etiology of HA and FNH has been correlated with the use of oral contraceptives. We report to the best of our knowledge the first series of patients treated with OLTx for HA and FNH (five cases). All these patients had lesions involving at least 90% of the hepatic parenchyma and all underwent major hepatic surgery before OLTx because of life threatening complications. One patient died in the immediate postoperative period following retransplantation for primary non-function of the first OLTx. Four out of five patients are currently alive from 4.1 to 9.6 years after OLTx. Our results justify the use of OLTx for symptomatic patients with HA and FNH who cannot be treated with conventional hepatic resections.

Neuroendocrinology of chronic renal failure and renal transplantation

Neuroendocrine activity in normal subjects was compared to patients with chronic renal failure on maintenance hemodialysis (CRF-HD) and to cyclosporinetreated renal transplantation (RT) recipients in an effort to further define the mechanisms underlying their associated fluid, electrolyte, and hemodynamic abnormalities. To evaluate neuroendocrine function in CRF and RT patients, plasma levels of angiotensin II (A-II), vasopressin (AVP), atrial natriuretic peptide (ANP), neuropeptide Y, neuropeptide Y (NPY), epinephrine (E), and norepinephrine (NE) were measured before and after HD and RT. Plasma concentrations of A-II, AVP, ANP, and NPY were significantly elevated in patients with CRF. HD did not produce a significant change in plasma concentrations of AVP, ANP, NPY, E, or NE. NE plasma levels, but not E levels, increased pre- and post-HD. A-II plasma levels were elevated basally in CRF patients and significantly increased following HD. Following RT, plasma levels of A-II, AVP, NPY, and creatinine decreased significantly over the first week, but AVP and NPY did not normalize. Plasma levels of ANP were elevated during the first month, then decreased to normal levels in RT patients. NE levels, but not E levels, were elevated both pre- and post-RT. Despite antihypertensive treatment, the group mean arterial pressure increased post-RT from 100±4.4 to 116± 3.7 mmHg by POD 6.