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Forty-three whole-pancreas transplantations with pancreaticocystostomy were performed. Eighteen patients received pancreas transplants after previously receiving living-related kidney transplants, 18 patients received simultaneous kidney and pancreas transplants, and seven patients received pancreas transplants after previously receiving cadaver kidney transplants. All patients were immunosuppressed with quadruple immunosuppression including antilymphocyte globulin, prednisone, cyclosporine, and azathioprine. Overall graft survival for pancreas transplants is 73.1%. In the group with pancreas after living-related kidney, 1-year graft survival was 50% for the pancreas and 95.4% for the kidney. In the pancreas after cadaver kidney group, pancreas and kidney survival rates were 100% at 1 year, and in the simultaneous pancreas and kidney group, pancreas 1-year graft survival was 87.5% and kidney transplant survival was 93.8%. Overall patient survival at 1-year is 95.6%. Technical complications occurred in 21 patients. These included wound infections, intra-abdominal abscess formation, bleeding, and disruption of the pancreaticocystostomy. We believe that pancreas transplantation can now be performed with acceptable graft and patient survival.

A retrospective analysis of our renal transplant population between 1981 and 1987 was undertaken to study the natural history of posttransplant hypercalcemia and to review indications and recommendations regarding the timing of parathyroidectomy. During this period, 1158 renal transplant procedures were performed in 1025 patients, with 819 allografts (71%) functioning currently. Posttransplant hypercalcemia greater than 10.5 mg/dl was associated with a longer duration of dialysis and developed in 227 patients, with onset of hypercalcemia occurring in 90% of these patients by 1 year. In 69% of these patients, spontaneous resolution of the hypercalcemia occurred between 6 months and 7 years after transplantation. A total of 42 patients with asymptomatic hypercalcemia are currently being followed up, with a mean serum calcium level of 11.0 +/- 0.41 mg/dl and a mean follow-up interval of 3.3 +/- 1.6 years since transplantation. Nine symptom-free patients with moderate hypercalcemia (12.0 to 12.4 mg/dl) more than 1 year after transplantation were identified. Five of these patients had spontaneous resolution of the hypercalcemia between 2 and 7 years. Fifteen patients with posttransplant hyperparathyroidism (6.6%) required parathyroidectomy--11 for symptomatic and four for asymptomatic hyperparathyroidism. One patient had symptomatic hyperparathyroidism despite the presence of normocalcemia. One symptom-free patient with significant hypercalcemia (serum calcium level, 14.7 mg/dl) underwent parathyroidectomy 3 months after transplantation. The remaining three symptom-free patients had serum calcium determinations of greater than or equal to 12.5 mg/dl more than 1 year after renal transplantation. Patients with pretransplant and posttransplant hypercalcemia required parathyroidectomy more frequently than did patients with only posttransplant hypercalcemia (18% versus 3.0%; p less than 0.001). An unusual finding was the occurrence of a single adenoma in two patients, which represents sporadic primary hyperparathyroidism in the patient undergoing renal transplantation rather than tertiary hyperparathyroidism. We recommend a conservative approach to posttransplant hypercalcemia, with surgery reserved for patients with symptomatic disease and patients with asymptomatic persistent hypercalcemia greater than or equal to 12.5 mg/dl more than 1 year after transplantation.

The data presented demonstrate that combined kidney-pancreas grafting can be performed with excellent patient and graft survival. Current long-term studies at our center investigating the effect of pancreas transplantation on diabetic retinopathy and comprehensive quality of life assessment will address the question of whether pancreas transplantation can be considered an effective and therapeutic procedure.

The complications of long-term steroid immunosuppression are well known. During a 12-month period, 52 living-donor renal transplant recipients were entered into a protocol of intentional early steroid withdrawal. Selection criteria were primary living-related renal transplants in HLA-identical (12) or one-haplotype match (40) patients. The study population consisted of 25 diabetics (48.1%) with a mean age of 32.4 years. All patients received preoperative blood transfusions (3 donor-specific in haplotype-matched, 3 random in HLA-identical recipients). Immunosuppression consisted of cyclosporine, azathioprine, and corticosteroids, with deliberate steroid withdrawal after two weeks. Forty-six patients (88.5%) were successfully tapered off steroids, while the six protocol failures (11.5%) were due to early rejection or leukopenia that prevented steroid withdrawal. Twenty-three patients (50%) subsequently were returned to steroid therapy for rejection (21) or leukopenia (2). Inadequate immunosuppression precipitated six rejection episodes and were preventable, while the remaining 15 were true breakthrough crises. The overall rejection rate was 50%, with 92.3% of initial rejection episodes occurring within five weeks of steroid withdrawal. Rejection episodes were responsive to steroid therapy alone in 73.2% of cases. No graft loss from rejection has occurred after a mean follow-up interval of 8.5 months. At present, 33 patients (63.5%) are off steroids. In HLA-identical recipients, all but one successfully completed the protocol and 75% are currently steroid-free. In haplotype-matched patients, 87.5% completed the protocol and 60% are steroid-independent. Comparison with well-matched control groups on steroids failed to reveal any difference in graft or patient survival, rejection, infection, or mean serum creatinine level. No discriminating risk factors could be identified that were predictive of steroid withdrawal success or failure. In select patients, early steroid withdrawal can be accomplished without jeopardizing graft function. Long-term follow-up is required to assess the risk-benefit ratio of steroid withdrawal upon immunosuppressive morbidity.

A new solution (UW solution) was used for flushing and storage of 17 livers before transplantation. In 9 cases the preservation times exceeded 10 hours (mean 12.7, range 11-20) but all left hospital with good liver function.

Orthotopic liver transplantation has become an accepted form of therapy for advanced liver disease. Over a 44-month period, we performed 27 liver transplants in 25 pediatric recipients, including 14 infants (mean age, 7.2 months; mean weight, 5.9 kg) and 11 children (mean age, 9.0 years; mean weight, 34.8 kg). Indications for transplantation were biliary atresia (16), tyrosinemia (3), chronic hepatitis with cirrhosis (2), fulminant hepatic failure (2), and one patient each with Wilson's disease and primary hepatoma. Eighteen patients (72%) had undergone a previous laparotomy, including 19 Kasai procedures in 13 patients with biliary atresia. The average time on the waiting list was 26.8 days (range, 1 to 60), and no patients died while awaiting transplantation. Mean preservation time was 6.9 hours (range, 2 to 13.5), employing cold storage with Collin's solution (16), or more recently, UW solution (11). Urgent liver transplantation was performed in seven cases (25.9%), although at present, we perform liver transplantation as a scheduled semielective procedure with extended preservation times in stable patients. The recipient hepatectomy and orthotopic liver transplantation were performed by standard techniques, with venous bypass used in three cases. Biliary reconstruction was performed with a Roux limb in 16 and via choledochocholedochostomy in ten cases, while arterial reconstruction was end-to-end hepatic artery in 21, and aorto-aortic anastomosis in the remaining six. Two hepatic artery thromboses (7.4%) and two biliary complications (7.4%) occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

A major problem in vascularized pancreas transplantation is the lack of reliable methods for the early diagnosis and effective treatment of allograft rejection. Over a 2-year period, 54 rejection episodes occurred in 31 patients (13 isolated pancreas, 18 simultaneous pancreas-kidney recipients) with pancreaticoduodenocystostomy. A total of 253 radionuclide pancreas examinations were performed (mean 8.4 per patient) utilizing 99mtechnetium-DTPA. Computer analysis generated a quantitative measure of blood flow to the allograft caused the technetium index (TI). Rejection episodes were characterized as isolated pancreas (22), combined pancreas-kidney (16), or isolated renal (16) allograft rejection in combined engraftments. The majority of rejection episodes occurred early (within 3 months of transplant, N = 47) and were more responsive than late rejection to anti-rejection therapy (89.4% vs 42.9%, P = 0.01). Mean urinary amylase (UA) levels and TI during normal allograft function were 29,398 U/l and 0.55%, while levels heralding rejection were 6,528 U/l and 0.40%, respectively (P less than 0.05). The treatment of rejection based upon renal dysfunction or combined renal and pancreas dysfunction resulted in significantly higher graft salvage with a lower incidence of hyperglycemia when compared to isolated pancreas allograft rejection. Of the 11 patients who developed hyperglycemia, 8 (72.7%) ultimately lost their pancreas grafts (P less than 0.001). Following therapy, a TI above 0.3% was associated with 97.4% graft survival, while levels below 0.3% resulted in a 70% rate of graft loss (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

With refinements in surgical techniques and increased clinical experience, there has been a resurgence of interest in vascularized pancreas transplantation. From December 1986 to April 1988, 30 whole-organ vascularized pancreas transplants with pancreatico duodenocystostomy were performed simultaneously with renal transplantation. The recipient population consisted of 20 men and ten women, with a mean age of 34.7 years (range of 25-53 years). The mean duration of insulin-dependent diabetes mellitus (IDDM) was 22.6 years (range of 10-37 years). The mean pancreas preservation time was 8.7 hours (range 3-19 years). All patients were immediately insulin-independent. Simultaneous pancreas-kidney engraftment was performed to both iliac fossae via a lower midline incision (n = 28) or through a bilateral lower abdominal incision (n = 2). The mean operating time was 5.9 hours, and packed cell transfusion requirement was 1.3 units. The mean length of hospital stay was 27.4 days. Recipients averaged 2.3 admissions (1-7), with ten patients (34.4%) requiring only one hospital admission. Postoperative immunosuppression consisted of cyclosporine, prednisone, azathioprine, and Minnesota antilymphoblast globulin (MALG). A total of 49 episodes of rejection occurred in 26 patients. Actuarial patient survival rate at two years is 96.3%. The kidney and pancreas survival rates for the same time interval is 94.0% and 84.0%, respectively. Mean serum creatinine at present is 1.75 mg/dl. In conclusion, renal transplantation in concert with pancreas transplantation has a dramatic positive impact on pancreas allograft survival. Combined engraftment does not appear to jeopardize renal allograft functional survival. In view of these results, simultaneous pancreas-kidney transplantation appears to be the treatment of choice for Type I diabetic patients.

With advances in clinical immunosuppression, results in organ transplantation continue to improve. During a 52-month period, 507 cadaver renal transplants were performed, including 435 primary and 72 nonprimary transplants. All patients were managed with quadruple immunosuppression (prednisone, azathioprine, sequential MALG and cyclosporine). Our experience is divided into pre-OKT3 (n = 228) and OKT3 (n = 279) eras. All kidneys were harvested locally and preserved with pulsatile machine perfusion. The mean duration of preservation was 30.1 hours, with an organ utilization rate of 98.1%. The preservation-related dialysis rate was 13.6%, and primary nonfunction occurred in 8 kidneys (1.6%). Actuarial patient survival in primary and secondary transplant recipients was 90% at 3 years. Overall primary graft survival was 81.6% and nonprimary graft survival, 61.1%. However, the current OKT3 era is characterized by improved patient survival (98% vs 90%, p = 0.001) and primary graft survival (91% vs 80%, p = 0.002) at 1 year when compared with the previous era. Forty-nine patients have received OKT3 therapy, with 31 grafts (63.3%) successfully rescued. Cadaveric renal transplantation with machine preservation, quadruple therapy, and OKT3 rescue is associated with excellent early graft function, reduced acute rejection, and improved patient and allograft survival, even in high-risk recipients.

Kidney transplantation for the treatment of end-stage renal disease has been limited by an inadequate number of donor organs. Because of the enormous impact kidney transplantation can have for patients, the authors have performed 40 living-unrelated donor renal transplantations using a donor-specific transfusion protocol since 1981. Ten additional patients were entered but became sensitized. Donors included 23 wives, seven husbands, six friends, and four individuals related by marriage. Type I diabetes was the most common indication for transplantation (45%). Despite 36 rejections in 24 patients (27 of 36 [75%] in the early postoperative period), only two grafts failed because of rejection. Twenty-one of these rejections responded to high-dose prednisone alone; the remainder required antilymphocyte globulin therapy or plasmapheresis. Sixteen patients had no acute rejections. Three other grafts were lost, including two deaths: one myocardial infarction (with a functioning graft), and one death secondary to a postoperative cecal perforation. One graft was lost from infarction after percutaneous nephrostomy placement. Of 40 grafts, 34 were functioning with a mean serum creatinine of 1.7 mg/dL (at a mean follow-up time of 27 months). Actuarial patient and graft survival were 94% and 89%, respectively, at 3 years. Living-unrelated renal transplants are an acceptable alternative to cadaver transplants, with excellent graft and patient survival.

Two technical modifications have been suggested for whole-pancreas transplantation with bladder drainage. The duodenal button technique (DB [Madison]) and the duodenal segment technique (DS [Iowa]) are the most commonly performed procedures (1,2). From December 1985 until May 1988 we performed 32 combined pancreas-kidney transplants using DB and DS techniques in 17 and 15 patients, respectively. Bladder leaks, pancreatitis, bleeding episodes, and surgically related infections were all decreased with the duodenal segment technique. Metabolic acidosis was more common with DS but was easily managed with oral sodium bicarbonate. The one-year actuarial graft survival with DB is less when compared with DS (76.1% vs. 87.5%). Three technical graft losses occurred with DB vs. none with DS. One graft was lost in each group to rejection. Our results indicate that the duodenal segment technique of bladder implantation adds safety to whole-pancreas transplantation and must now be considered the procedure of choice.

1. Quadruple immunosuppression yields excellent early renal allograft survival in primary renal transplant recipients when compared with non-primary renal transplant recipients. Although significant, the difference between primary and nonprimary recipients at 5 years has narrowed considerably (8%). 2. No beneficial effect of HLA or DR matching was noted in this study in primary transplant recipients. However, a trend toward improved graft survival was noted when patients with greater than or equal to 3 antigens matched or less than 3 antigens mismatched were compared to their counterparts. Further analysis of variables related to graft loss is required before statements regarding this trend can be made. 3. Significantly better results in nonprimary renal transplantation continues to be seen in DR matched recipients. Additionally, the use of OKT3 rather than ALG in DR matched recipients has resulted in a 92.3% 3-year allograft survival despite over half of these patients being highly sensitized. 4. Further follow-up of 2 high-risk groups of patients (diabetics and elderly patients) revealed significant decreases in patient survival at 5 years. This difference was not apparent in our earlier results (3-year follow-up) published in Clinical Transplants 1987. Despite this difference, we believe renal transplantation should continue to be offered to diabetic and elderly patients without other contraindications to transplantation. 5. The availability of the monoclonal antibody OKT3 during the CsA era has resulted in a trend toward improved patient and graft survival when compared with patients in the CsA pre-OKT3 era. This trend toward improved survival is also seen in the high-risk diabetic recipients.

Advanced age has been a relative contraindication to kidney transplantation because of the likelihood of increased morbidity and mortality in the geriatric population. However, the introduction of cyclosporine has improved renal allograft survival rates dramatically, and higher-risk patients are now being successfully transplanted. With the introduction of cyclosporine in 1983, we have performed 36 cadaveric renal transplants in 34 recipients 60 years of age or older, including 34 primary and 2 retransplants. Most of the patients (88%) were on dialysis prior to transplantation and 29% had ASCVD. Three-year actuarial patient and allograft survival are 91% and 74%, respectively. Surgical complications were infrequent, and postoperative rejection episodes were less frequent than in younger patients but were more likely to lead to graft loss. Medical complications, especially infection, were common after transplantation but easily managed. Cadaveric renal transplantation with cyclosporine immunosuppression is a safe and effective therapeutic modality that is no longer contraindicated in elderly patients.

Since the introduction of OKT3 at our center in January 1986, we have performed 246 cadaveric renal transplants (220 primary, 26 nonprimary). All patients received quadruple immunosuppression consisting of prednisone, azathioprine, and the sequential use of Minnesota antilymphoblast globulin (MALG) and cyclosporine. OKT3 (Orthoclone OKT3) therapy was reserved for corticosteroid- and/or ALG-resistant rejection. Of the 246 patients, 138 developed one or more rejection episodes (56.1%). Ninety-seven (70.3%) were successfully reversed with prednisone and/or ALG, whereas 41 (29.7%) required additional treatment with OKT3. Initial graft salvage occurred in 34 (82.9%) patients treated with OKT3, but rejection recurred in 18 (52.9%) and was successfully reversed in only 6 patients. However, the rate of recurrent rejection was much lower in patients given OKT3 early (14%), shortly after it was apparent that high-dose corticosteroid therapy was proving ineffective, than in patients who received OKT3 after a prolonged or second course of corticosteroids (64%) or ALG (60%). Graft survival after a mean follow-up interval of 11 months in all OKT3-treated patients was 54%. One or more infections occurred in 19 (46%) patients treated with OKT3. Patients developing infections following OKT3 therapy received significantly larger total doses of prednisone during graft rejection (46.3 mg/kg vs. 27.9 mg/kg, P less than .05) than OKT3-treated patients who did not develop infectious complications. Our experience shows that use of OKT3 for treatment of corticosteroid- and/or ALG-resistant rejection is associated with a high rate of recurrent rejection, except when given early, as soon as it is clear that high-dose corticosteroid therapy is not reversing the rejection episode. It further suggests that prolonged administration of high-dose corticosteroids and possibly ALG for the treatment of rejection prior to beginning OKT3 greatly increases the rate of infection following OKT3 therapy.

The studies reported here describe the successful propagation of variola virus in spinner cultures of mammalian cells, and the factors which influence its growth. Five established cell lines were used for the propagation of variola virus in a spinner culture system. Low doses of virus did initiate an infection but virus yields did not approach those obtained when an intermediate inoculum was used. Although the nonviable cell population remained low during the course of infection with an intermediate amount of virus, with an inoculum of 10(5) infectious units per ml or higher, the percentage of nonviable cells increased rapidly and by the sixth day after infection the population was totally nonviable. Intracellular replication of variola virus occurred early and rapidly in a spinner culture of guinea pig lung cells, whereas the liberation of virus into the suspending medium was a more gradual process. Several complete medium changes tend to maintain a suitable environment for the infected cell culture resulting in fairly high and constant viral titers over a period of 7 days.