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Biomedical subjects

D E Sutherland

Publications and source records attributed to D E Sutherland.

At least 667 records · Page 37Linked to original sources
PubMed1982

Combined immunosuppressive therapy with cyclosporin A and azathioprine. A synergistic effect in three of four experimental models.

Cyclosporin A (Cy A) by itself is limited in its clinical application by its dose-related liver and kidney toxicity. Combining Cy A with prednisone allows lower doses of Cy A to be used, but the side effects of steroids are cumulative. Thus, we tested the effect of Cy A and various drug-dose combinations with azathioprine (AZA) in four different models. The one that gave the best results with the least toxicity was 1.25 mg of Cy A plus 15 mg of AZA for islet allotransplantation in rats across a minor histocompatibility barrier and for heterotopic heart allotransplantation in rats across a major histocompatibility barrier. In the latter, using the same strain of rats, no significant effect can be shown in rat pancreas allotransplantation. In canine renal allografts, only one dose combination (5 mg of Cy A plus 2.5 mg of AZA) was tested, but it was synergistic. Cy A may potentiate the myelosuppressive effect of AZA, and the dose may have to be adjusted to avoid this problem.

Animals↗
PubMed1982

Improved patient and primary renal allograft survival in uremic diabetic recipients.

From January 1968 to December 1981, 470 uremic diabetic patients received primary renal allografts at the University of Minnesota. Until 1979, the patient and graft survival rates were less good in diabetic than in nondiabetic recipients. Since 1979, the results in diabetics have been at least equal to those achieved in nondiabetic patients. Two-year actuarial patient and graft survival rates in diabetic renal allograft recipients were, respectively, 71 and 66% from 1968 to 1976 (n = 156), 78 and 64% from 1976 to 1979 (n = 187), and 88 and 82% from 1979 to 1981 (n = 127). Improved survival rates were seen in all donor source and recipient age categories. For comparison, the 2-year patient and graft survival rates in nondiabetic renal allograft recipients who received transplants between 1979 and 1981 (n = 162) were 92 and 79%. Changes associated with improved survival rates included performance of pretransplant splenectomy on all patients except those receiving grafts from HLA-identical siblings, deliberate transfusions of blood from greater than or equal to 5 random donors at least 1 month before transplantation, intensive insulin therapy for diabetic management post-transplant, and less vigorous treatment of repetitive rejection episodes. The current results show that diabetic recipients are no longer at higher risk than nondiabetics for graft or patient loss, at least during the first 2 years after transplantation.

Adolescent↗
PubMed1982

Experience with 49 segmental pancreas transplants in 45 diabetic patients.

Forty-nine pancreas transplants were performed in 45 patients between July 23, 1978 and May 14, 1982, 18 from related donors. Currently (June 1982), 13 patients have functioning grafts and are insulin independent between 1 and 46 months after transplantation, 5 for more than 1 year. Nineteen patients lost graft function between 1 and 7 months. Sixteen grafts failed for technical reasons. Eight patients died between 1 and 21 months from infections or preexisting complications or for unknown reasons, three with functioning grafts. Actuarial 1-year graft survival is 24% and patient survival is 84%. A variety of techniques were used to handle exocrine secretions of 41 hemipancreas segmental grafts, 4 extended segmental grafts, and 4 whole pancreas grafts. Currently, 3 of 14 duct-open, 0 of 2 duct-ligated, 0 of 4 prolamine-injected, 6 of 19 silicone rubber-injected, and 4 of 10 jejunal anastomosed pancreatic grafts are functioning. Of 33 technically successful allografts, 5 in 12 conventionally immunosuppressed and 8 in 21 cyclosporin A (Cy A)-immunosuppressed recipients are functioning. Most technically successful grafts that failed were not biopsied or removed. In those that were biopsied, fibrosis was a dominant feature in all but one patient. In this patient endocrine and exocrine tissue was normal except for the absence of insulin-positive (beta) cells in the islets and an increase in glucagon-positive (alpha) cells, in contrast to the normal appearance of alpha and beta cells in islets at the time of the pancreas transplant. Currently, we perform pancreas transplants in diabetic patients who have previously received kidney transplants and therefore already require immunosuppression. For nonuremic patients, we perform pancreas transplant only if it is judged that their complications of diabetes exceed, or predictably will exceed, the potential side effects of chronic immunosuppression.

Adult↗
PubMed1982

Report of International Human Pancreas and Islet Transplantation Registry Cases through 1981.

According to cases reported to the new International Human Pancreas and Islet Transplantation Registry, 190 pancreas transplants in 178 patients were performed worldwide between December 16, 1966, and December 31, 1981. Currently (March 1982), 19 patients have functioning pancreas grafts and are insulin-independent, 9 for more than 1 yr. All of the patients with currently functioning grafts were transplanted after 1977. Since 1970, 76 islet transplants have been attempted in 71 patients, of which almost all failed and no patients are currently insulin-independent. Although the technical problems with pancreas transplants are not entirely solved, the major cause of graft failure has been rejection. The need for antirejection therapy has limited the application of pancreas transplantation to diabetic renal allograft recipients or to nonuremic patients whose complications of diabetes are, or predictably will be, worse than the side effects of chronic immunosuppression. Pancreas transplantation can, however, be performed with expectation of long-term success in some patients with current surgical and immunosuppressive methods.

Adult↗
PubMed1982

Cyclosporin A for immunosuppression: observations in rat heart, pancreas, and islet allograft models and in human renal and pancreas transplantation.

Cyclosporin A (CsA) is a unique immunosuppressive cyclic polypeptide that is currently being used, either alone or in combination with low-dose prednisone, to treat recipients of renal or pancreas allografts in clinical trials. CsA is very effective in preventing rejection of heart and renal allografts in rodents, but in nontoxic doses does not consistently prevent rejection of pancreas and islet allografts. Therefore, we tested low-dose CsA in various combinations with low-dose prednisone, azathioprine, or total lymphoid irradiation in rat heart, pancreas, and islet allograft models. Several combinations are synergistic and when administered continuously can indefinitely prevent rejection of heart allografts, but only delay rejection of pancreatic allografts, transplanted across a major histocompatibility barrier, CsA by itself prolonged the survival of islet allografts transplanted across a minor, but not a major, histocompatibility barrier. CsA and azathioprine had a synergistic effect in the minor histocompatibility barrier islet transplant model, but, in the nontoxic combinations tested, could not prevent rejection indefinitely. A randomized prospective trial comparing standard immunosuppressive therapy (ALG, prednisone, and azathioprine), with CsA and low-dose prednisone for clinical renal allotransplantation is ongoing at the University of Minnesota. Current actuarial 1-yr graft survival is 93% for CsA-treated patients (N = 48) and 81% for conventionally treated patients (N = 52). Patient survival is 98% for CsA and 100% for conventionally treated patients. A pilot trial of CsA in the clinical pancreas transplant program at the University of Minnesota is also underway. Since 1978, 46 pancreas transplants have been performed in 43 patients. Of 30 technically successful pancreatic allografts, 5 of 12 recipients treated with conventional immunosuppression and 6 of 18 recipients treated with CsA currently have functioning grafts and are insulin independent between 1 and 44 months after transplantation. The results of metabolic studies are similar in conventional and CsA-treated patients with functioning pancreas grafts. Since pancreas grafts may fail for reasons other than rejection, further observations are needed to ascertain the role of CsA in clinical pancreas transplantation.

Adolescent↗
PubMed1982

Cyclosporin A in renal transplantation: a prospective randomized trial.

Cyclosporin A combined with prednisone was compared with standard immunosuppressive therapy (antilymphoblast globulin, prednisone, and azathioprine) in a prospective randomized trial of 100 mismatched, living related donor and cadaveric renal transplants. The results demonstrated cyclosporin A plus prednisone to be an effective immunosuppressive regimen for renal transplantation. The actuarial graft survival at 1 year was 93% for patients treated with cyclosporin A and 81% for patients treated with conventional immunosuppression. Patient survival was 98% for the cyclosporin A group and 100% for the conventional group. Cyclosporin A-treated patients had fewer rejection episodes and fewer infections complications including a marked decrease in the incidence of posttransplant cytomegalovirus infection. The side effects of cyclosporin A were mild, but nephrotoxicity caused by cyclosporin A was frequent and significant. Nephrotoxicity was reversible and managed by decreasing the daily cyclosporin A dose. It is concluded that the combination of cyclosporin A plus prednisone provides an excellent alternate immunosuppressive regimen for renal transplants as compared with conventional therapy. The consequences of long-term administration of cyclosporin A are at present unknown.

Adolescent↗
PubMed1982

Long-term preservation of segmental pancreas autografts.

Clinical pancreas transplantation is logistically difficult because of uncertainty concerning how long pancreas grafts can be preserved. We studied the viability of canine segmental (tail) pancreatic autografts transplanted after 24 to 72 hours of hypothermic preservation in either modified Collins' solution or modified silica gel filtered dog plasma (SGF). All grafts stored for 24 to 48 hours functioned immediately (plasma glucose less than 140 mg/dl in recipients). Grafts that failed did so between 2 and 7 days, and five dogs died with functioning grafts. The long-term functional success rate was 80% for fresh transplants; 67% and 40% for grafts stored in Collins' solution for 24 and 48 hours, respectively; and 75%, 75%, and 30% for grafts stored in SGF for 24, 48, and 72 hours, respectively. If technical failures are excluded. 50% of grafts stored in Collins' solution and 100% of grafts stored in SGF for 48 hours functioned long term. K values for the intravenous glucose tolerance test at 2 weeks in dogs with functioning grafts ranged from -1.44% to -1.78% and were similar in all groups. In conclusion, pancreatic grafts can be preserved for 48 hours by simple cold storage, but SGF is more reliable than Collins' solution (P = 0.015). Four human pancreas grafts were stored in SGF for 7 to 22 hours, one with and three without prior warm ischemia, and all three of the latter functioned after transplantation.

Animals↗
PubMed1982

Hepatic resection for secondary neoplasms.

Despite recent advances in chemotherapy, patients with hepatic metastases treated nonsurgically continue to have a dismal survival rate. Using our experience with surgical resection of pulmonary metastases as a model, we have adopted an aggressive surgical approach to secondary hepatic neoplasms. Hepatic resection for metastatic disease in 64 patients undergoing 75 celiotomies resulted in a cumulative survival rate of 45% at 2 years and 34% at 5 years. Operative procedures included 37 wedge resections, 20 segmentectomies, 16 lobectomies, and 2 total hepatectomies in preparation for liver allograft transplantation. The operative mortality rate (less than 30 days) was significant (20%). The most favorable prognosis was associated with Wilms tumor (4 patients) and colorectal carcinomas (29), the 2-year survivals being 80% and 67%, respectively. Long-term survivors include patients with Wilms (17 and 14 years), leiomyosarcoma (12 years), and colorectal (11 and 10 years) primary tumors. Thirty patients with synchronous resections of the primary tumor and the hepatic resections had 2- and 5-year survival rates of 29% and 26%, whereas 34 patients with metachronous resections had survival rates of 64% and 30%. Eighteen patients underwent resections of multiple hepatic metastases with a survival rate essentially no worse than that of patients with isolated metastases, but careful case selection may have played an important role in the outcome. The extent of hepatic resection was primarily dictated by location and number of metastases. More extensive resections were not associated with a higher long-term survival rate but did have a higher operative mortality. We conclude that an aggressive surgical approach in the treatment of metastatic disease confined to the liver offers a chance for long-term survival and significant palliation in selected patients whose primary tumor is controlled.

Actuarial Analysis↗