Raymond Pollak

OUTCOMES OF 385 ADULT-TO-ADULT LIVING DONOR LIVER TRANSPLANT RECIPIENTS: A REPORT FROM THE A2ALL CONSORTIUM

Objective:The objective of this study was to characterize the patient population with respect to patient selection, assess surgical morbidity and graft failures, and analyze the contribution of perioperative clinical factors to recipient outcome in adult living donor liver transplantation (ALDLT). Summary Background Data:Previous reports have been center-specific or from large databases lacking detailed variables. The Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) represents the first detailed North American multicenter report of recipient risk and outcome aiming to characterize variables predictive of graft failure. Methods:Three hundred eighty-five ALDLT recipients transplanted at 9 centers were studied with analysis of over 35 donor, recipient, intraoperative, and postoperative variables. Cox regression models were used to examine the relationship of variables to the risk of graft failure. Results:Ninety-day and 1-year graft survival were 87% and 81%, respectively. Fifty-one (13.2%) grafts failed in the first 90 days. The most common causes of graft failure were vascular thrombosis, primary nonfunction, and sepsis. Biliary complications were common (30% early, 11% late). Older recipient age and length of cold ischemia were significant predictors of graft failure. Center experience greater than 20 ALDLT was associated with a significantly lower risk of graft failure. Recipient Model for End-stage Liver Disease score and graft size were not significant predictors. Conclusions:This multicenter A2ALL experience provides evidence that ALDLT is a viable option for liver replacement. Older recipient age and prolonged cold ischemia time increase the risk of graft failure. Outcomes improve with increasing center experience.

A Study Of Treatment Compliance Following Kidney Transplantation

Kidney transplantation is a successful treatment for end-stage renal disease. We studied demographic and psychosocial variables that relate to compliance behaviors following renal transplant. One hundred and five renal allograft recipients, with a minimum of 18 months follow-up, were studied. A biographical questionnaire, the Center for Epidemiologic Studies Depression Scale, the Multidimensional Health Locus of Control Scale, and the Social Support Appraisals Questionnaire were used as measuring instruments. Specifically for this study, we designed a Health Belief Model Questionnaire, a Patient and Provider Relationship Questionnaire, a Compliance Self-Report Questionnaire, and a Self-Efficacy Questionnaire. Compliance was determined by cyclosporine whole blood levels >30 ng/ml, maintenance of ideal body weight (<20% gain), and percentage of missed clinic visits (<20%). Data was analyzed using discriminant analysis, Pearsons correlation, and chi-square. Four groups were identified, i.e., overall compliant (n=25), noncompliant with diet (n=29), noncompliant with medication (n=27), and overall noncompliant (n=29). No patient missed >20% of clinic visits. Discriminant function analysis distinguished patients who were compliant from those who were not. Males were more likely to be noncompliant with medication, whereas females were more likely to be noncompliant with diet. Noncompliance was also associated with increased numbers of prescribed medications, depression, black race, locus of control attributed to powerful others, unemployment, as well as the perceived amount of social and family support. Patients with failed grafts (n=14) were more depressed (P<0.05), perceived less benefit from the treatment regimen (P<0.01), and had less confidence in their care providers (P<0.05) than those recipients of successful grafts (n=91). In conclusion, this study identifies a number of psychosocial and demographic variables that impact on patient compliance behaviors after renal transplant. Interventional strategies to obviate noncompliance will need to consider these heterogeneous variables in order to maximize long-term renal allograft survival.

Reduced inter- and intrasubject variability in cyclosporine pharmacokinetics in renal transplant recipients treated with a microemulsion formulation in conjunction with fasting, low-fat meals, or high-fat meals

This cross-over study compared the pharmacokinetic parameters obtained from cyclosporine (CsA) concentration-time profiles after administration of the corn oil-based soft gel cap (CsA-GC) with those with the microemulsion (CsA-ME) gel cap. Neither the fasting state nor the coadministration of a low- or high-fat breakfast affected the pharmacokinetics of CsA presented in either formulation. Comparisons of the three sets of pharmacokinetic parameters--namely, after fasting or after low-fat or after high-fat diets--demonstrated the CsA-ME formulation to display greater intraindividual reproducibility of the C0 and C12 trough levels (TLs), Cmax, tmax, and area under the concentration-time curve (AUC) than the CsA-GC formulation. Although the degree of interindividual variation in AUC, Cmax and tmax after CsA-ME administration was slightly, but significantly, less than after CsA-GC administration, there was no difference between the two formulations in terms of the customarily monitored C0 or C12 TL values. CsA-ME showed higher correlation coefficients of drug exposure (AUC) with C12 than CsA-GC (0.910 versus 0.712). However, CsA-ME administration resulted in only modest improvement over CsA-GC administration in the relationships between drug dose and C0, C12, or AUC--namely, 0.645 versus 0.496, 0.611 versus 0.517, and 0.700 versus 0.501, respectively. Correlation analysis between individual timed samples and AUC determinations revealed that CsA-ME requires significantly less frequent blood monitoring for prediction of total drug exposure than does CsA-GC. Although the clinical utility of this reproducible pharmacokinetic behavior remains to be demonstrated in the de novo transplant setting, the markedly reduced intraindividual variation produced by administration of CsA-ME will likely improve the accuracy of pretransplant prediction of, and reduce the frequency of subsequent adjustments in, CsA doses.

The preperitoneal approach and prosthetic buttress repair for recurrent hernia. The evolution of a technique.

Repair of recurrent groin hernias is associated with a high incidence of repeat recurrences (2-19%). Reported herein is a 10-year experience of the management of recurrent groin hernias through the use of the preperitoneal approach with the addition of a reinforcing prosthetic mesh buttress. Two hundred and three recurrent groin hernias in 195 patients (192 men, three women) were treated between July 1975 and October 1986. The preperitoneal approach to the inguinal region was performed under regional anesthesia to define the nature of the recurrent hernia. Initial experience in a randomized trial between the use of local endogenous tissue repair versus endogenous repair with a prosthetic polypropylene mesh buttress demonstrated superiority of the latter in reducing repeat recurrences of anatomically defined direct or combined recurrent hernias. Pure indirect and femoral recurrences did not mandate mesh reinforcement. Long-term follow-up was available for 115 hernias (56%) in 102 patients (52.3%) over a period of 6 months to 10 years. Eight patients had repeat recurrences a mean of 30 +/- 22 months after repair. Six recurrences (four direct, two indirect) occurred in an early experience, when no mesh was used. Two recurrences (one indirect and one lateral to the mesh) representing 1% of all hernias (1.7% of those followed-up) have occurred after routine use of the mesh buttress, with the last re-recurrence seen in December 1982. Three ventral hernias (1.5%) occurred at the wound of entry, but none have occurred since placement of the mesh was modified to cover this wound. There were five (2.5%) wound infections and one (0.5%) hydrocele with no re-recurrences. It is concluded that the preperitoneal approach to recurrent groin hernias, together with the appropriate use of a reinforcing mesh buttress, is safe, allows anatomic definition of the hernial defect, and is followed by few repeated recurrences. The evolution of this approach during the last 10 years has made it the procedure of choice for the management of all recurrent groin hernias at the University of Illinois College of Medicine.

Prevention of Acute Graft Rejection by the Prostaglandin E1 Analogue Misoprostol in Renal-Transplant Recipients Treated with Cyclosporine and Prednisone

Prostaglandins of the E series have been shown to have immunosuppressive properties. To study the effects of the prostaglandin E1 analogue misoprostol on renal function and graft rejection after transplantation, we conducted a randomized, double-blind, placebo-controlled trial in 77 renal-allograft recipients. The subjects received misoprostol (200 micrograms four times daily by mouth; n = 38) or placebo (n = 39) for the first 12 weeks after transplantation, in addition to standard immunosuppression with cyclosporine and prednisone. They were then observed for an additional four weeks after the drug or placebo was discontinued. Treatment with misoprostol was associated with a significant improvement in renal function as judged by the mean (+/- SEM) serum creatinine concentration (128 +/- 7 vs. 158 +/- 11 mumol per liter after 12 weeks; P = 0.03) and creatinine clearance (84 +/- 6 vs. 69 +/- 5 ml per minute per 1.73 m2 of body-surface area; P = 0.05). There was a significant reduction in the incidence of acute rejection in the group treated with misoprostol as compared with the placebo group (10 of 38 vs. 20 of 39; P = 0.02), and there was less need for rehospitalization after transplantation (4 +/- 1 days with misoprostol vs. 10 +/- 2 days for placebo; P = 0.03). Although blood levels of cyclosporine did not differ significantly between the groups, they tended to be higher in the misoprostol group, as did the incidence of acute nephrotoxicity due to cyclosporine (13 of 38 vs. 8 of 39). Infectious complications tended to be fewer in the misoprostol-treated group (14 of 38 vs. 21 of 39). We conclude that misoprostol improves renal function and safely reduces the incidence of acute rejection in renal-transplant recipients treated concurrently with cyclosporine and prednisone.

The pharmacokinetics of a microemulsion formulation of cyclosporine in primary renal allograft recipients

This study was a randomized, double-blind, 12-week comparison of the pharmacokinetics, safety, and tolerability of two cyclosporine (CsA) formulations, cyclosporine emulsion capsules and oral solution for microemulsion and cyclosporine, in the postoperative management of renal transplant patients. Of the 101 patients, aged 18 to 65, who entered the study, 89 were evaluable for pharmacokinetics. Initial dosage was 10 mg/kg per day, administered twice daily in two equal doses. Dosages were adjusted to achieve target CsA concentrations. The pharmacokinetic (PK) parameters (dose-normalized) of greatest interest were maximum blood concentration (C(max)/dose), time to reach maximum concentration (t(max), area under the blood concentration-vs.-time curve (AUC/dose), and trough blood concentrations (Co h/dose). The relative CsA bioavailabilty was found to be significantly enhanced with cyclosporine emulsion compared with cyclosporine with a 16% to 31% increase in AUC and a 32% to 42% increase in C(max). Intrapatient variability of PK parameters was significantly lower with cyclosporine emulsion than with cyclosporine for AUC, C(oh), t(max), and C(max) in many instances. This indicates a more consistent, rapid, and more complete total absorption of CsA. Despite higher CsA C(max) levels and AUCs with cyclosporine emulsion, safety and tolerability (detailed in a parallel report) were comparable to those of cyclosporine. The PK advantages of cyclosporine emulsion over cyclosporine are either independent of food conditions or possibly reflective of more consistent absorption of CsA with cyclosporine emulsion. The findings suggest that de novo use of cyclosporine emulsion may simplify and improve management of organ transplant recipients and that the PK advantages of cyclosporine emulsion may translate into clinical benefits.

Hepatocyte transplantation for the low-density lipoprotein receptor-deficient state. A study in the Watanabe rabbit.

The Watanabe heritable hyperlipidemie (WHHL) rabbit reproduces human familial hypercholesterolemia due to a congenital low-density lipoprotein receptor deficiency and is characterized by elevated serum LDL. cholesterol levels and early atherosclerosis. We attempted to transplant normal allogeneic hepatocytes into WHHL rabbits without chronic immunosuppression to cure the LDL receptor—deficient state. Livers from normal New Zealand White (NZW) rabbits were digested by intraportal perfusion of collagenase solution. Pure hepatocytes (PH) were obtained by Percoll gradient separation and nonpareuchymal (NP) liver cells by pronase digestion. PH and NP were incubated with fluorescein isothiocyanate-monoclonal anti—rabbit class I, anti-ciass II, and anti-T cell antibodies and subjected to flow eytometry analysis. PH and NP were also used as stimulators in one way mixed lymphocyte-hepatoeyte cultures (MLHC), before and after ultraviolet B light (UVB) exposure. Intraportal and intrasplenic injection of allogeneic PH were also performed in homozygous WHHL rabbits. PH were attached to collagen-coated dextran microcarriers (mc-PH) for intraperitonealimjeetion. Recipient control and transplanted WHHL rabbits received a single dose of eyclosporine subcutaneously (10 mg/kg/s.e.) at the time of transplantation. PH were mainly class I-positive (77.6%) and class II-negative (5.9%), while 31.5% of NP cells were class II-positive, In MLHC, PH did not stimulate proliferation, (stimulation index: 0.97 ± 0.21), unlike NP (SI: 23.7). This latter response was abrogated by prior exposure of NP to UVB light. Intraportal injection of PH (n = 4) reduced serum LDL eholesterol to 60% of baseline, an effect lasting 2—3 weeks, and dose-dependent. Intraperitoneal mc-PH, 4 x 108 (n = 4), reduced serum LDL cholesterol levels to 45% of baseline more than 4 weeks posttransplant (P = 0.04). We conclude that transplantation of normal allogeneic NZW rabbit mc-PH reduces serum LDL cholesterol levels in homozygous WHHL rabbits without chronic immunosuppression. Longitudinal studies will establish if less atherosclerosis develops in mc-PH WHHL reeipients than sham controls.

The relationship between flow cytometer crossmatch results and subsequent rejection episodes in cadaver renal allograft recipients

Flow cytometry (FC) T and B cell crossmatches were done retrospectively for 38 cadaver renal transplant recipients (29 first and 9 retransplants—minimum follow-up 12 months) using both current pretransplant serum and peak-reactive sera. An increase in median fluorescence intensity (channel shift) and/or an increase in the number of donor T and/or B cells binding antibody in test sera occurred in 23 cases. These 23 patients experienced a greater number of reversible rejection episodes as compared with patients with negative FC crossmatches (65% vs. 33%), P= 0.031. Graft outcome, however, was not different in the two groups. Thus, a positive FC crossmatch allows for the detection of subliminal levels of donor presensitization and is associated with a greater number of rejection episodes. A positive FC crossmatch is not predictive of ultimate graft loss.

The Natural History of and Therapy for Perirenal Fluid Collections Following Renal Transplantation

Fluid collections following renal transplantation are not rare and may be associated with serious complications. We studied the incidence, clinical features, pathology and treatment outcome of perirenal fluid collections after kidney transplantation. Between January 1977 and June 1985, 386 consecutive renal transplants were performed at our university. All allografts were studied with B-mode ultrasonography together with a renal scan in the immediate post-transplant period, at 6-month intervals or when clinically indicated. Symptomatic fluid collections, those associated with rejection episodes and those containing more than 50 to 100 ml. fluid were aspirated under sonographic control via aseptic techniques. There were 190 fluid collections (49 per cent) observed during followup (2 to 11 years). Of these collections 98 (51 per cent) were estimated to be less than 50 ml. in volume, were clinically insignificant and resulted in no morbidity. A total of 92 collections was aspirated with 1 aspiration being diagnostic and therapeutic in 57 instances (serous or serosanguinous fluid). The 35 collections remaining were revealed to be lymphoceles on biochemical grounds. Of 13 lymphoceles associated with rejection episodes 8 resolved on initial aspiration. Of the recurrent lymph collections 27 were treated with repeated aspiration, tetracycline sclerotherapy or an operation (10 were treated with marsupialization into the peritoneal cavity). No large collections of urine or blood were detected and 1 infected lymphocele required external drainage. No renal allograft was lost as a result of a fluid collection and over-all graft survival was not affected by the development of perirenal fluid collections. We conclude that perirenal fluid collections are detected commonly in the post-transplant period using B-mode ultrasonography. The majority of these collections are small and will require careful observation only or they will resolve with a single aspiration. Aggressive diagnostic and therapeutic measures are used only for those collections that are symptomatic or result in allograft dysfunction. A rational approach to the diagnosis and treatment of peritransplant fluid collections is described in the form of an algorithm.

Complications of groin hernia repair.

This review concerns itself with the recognition and treatment of the common and rare complications of groin hernia (direct, indirect, and femoral) repair. Preoperative complications such as incarceration and intestinal obstruction, operative complications such as hemorrhage and nerve severance, and postoperative complications such as compression of the femoral vein and urinary retention are discussed.