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Biomedical subjects

D E Sutherland

Publications and source records attributed to D E Sutherland.

At least 577 records · Page 32Linked to original sources
PubMed1985

Circadian toxicology of cyclosporin.

Cyclosporin (Cs), a cyclic nonpolar undecapeptide of fungal origin, has potent immunosuppressive and antiparasitic activities, and renal and hepatic toxicities, the mechanisms of which are not worked out. Many nephrotoxins and hepatotoxins are predictably more or less harmful, depending upon the circadian stage at which they are administered. In order to find treatment schedules that might damage the animal least, the toxicity of 20 mg kg-1 day-1 of Cs given intraperitoneally was studied at six different circadian stages in adult male Lewis rats. Cs toxicity was gauged by body temperature decline, body weight loss, and survival time. Rectal temperatures over a 24-hr span during the 2 days prior to the first death revealed that rats treated during darkness were 1.6 +/- 0.3 degree C cooler than vehicle-treated controls, whereas rats treated during the light span were only 0.4 +/- 0.2 degree C cooler than controls (p less than 0.01). Rats treated in darkness lost twice as much weight compared to those treated in light (20 +/- 2 versus 10 +/- 2%, p less than 0.01). Rats receiving daily Cs in the dark span lived an average of 28 +/- 5 days compared with 44 +/- 4 days for animals getting Cs during the light span (p less than 0.05). Three separate nonspecific measures of drug toxicity confirmed that there was substantial circadian stage dependence to Cs toxicity. The safest time for the drug in rats was 2 to 10 hr after lighting onset, a time when rats are usually beginning their diurnal rest and/or sleep span.

Animals↗
PubMed1985

Results of the Minnesota randomized prospective trial of cyclosporine versus azathioprine-antilymphocyte globulin for immunosuppression in renal allograft recipients.

Between September 26, 1980 and June 8, 1984, 246 splenectomized, transfused renal allograft recipients were randomized to treatment with either cyclosporine (CsA)-prednisone (n = 131) or azathioprine (Aza)-prednisone-antilymphocyte globulin (n = 115). On December 31, 1984, actuarial patient survival rates at three years were 89% in the CsA group and 90% in the Aza group, and the corresponding graft survival rates were 82% and 79% (statistically insignificant differences). The results were also compared separately in diabetic and nondiabetic patients and in recipients of related and cadaver donor grafts; only in the subgroup of diabetic recipients of cadaver kidneys were the differences in graft survival rates significantly different between CsA- and Aza-treated patients. The incidence of posttransplant acute tubular necrosis was similar in CsA- and Aza-treated patients (33% v 27%), but the duration was significantly longer in CsA- than in Aza-treated recipients (15.7 +/- 18.4 v 7.7 +/- 3.0 days). Rejection episodes and infections (particularly CMV) occurred significantly less frequently in CsA- than in Aza-treated patients. Mean serum creatinine levels were significantly higher in CsA- than in Aza-treated recipients (2.0 +/- 0.6 v 1.5 +/- 0.5 mg/dl). Treatment of hypertension and hyperkalemia was required significantly more frequently in the CsA-treated patients than in the Aza-treated patients. Initial mean hospitalization time was significantly shorter in the CsA group than in the Aza group (15.6 +/- 9.5 v 19.8 +/- 10.7 days). In the CsA group, 19% of the patients were switched to Aza and 35% had Aza added to their regimen with a concomitant lowering of the CsA dose because of nephrotoxicity. The results of our randomized trial are at variance with those of others in that the graft survival rates in our trial were not different between CsA and Aza-treated patients, primarily because our conventionally-treated patients had a higher graft survival rate than in the other trials. The advantages of CsA (fewer rejection episodes, fewer infections, shorter hospitalization) outweigh the disadvantages (higher serum creatinine, more hypertension), and thus we believe it should be used in most renal allograft recipients, perhaps in combination with Aza so that a lower dose of CsA can be used and the side effects minimized--a regimen that we are currently evaluating.

Adolescent↗
PubMed1985

A single institution, randomized, prospective trial of cyclosporin versus azathioprine-antilymphocyte globulin for immunosuppression in renal allograft recipients.

Between September 26, 1980 and December 31, 1983, 230 splenectomized, transfused renal allograft recipients were randomized to treatment with either cyclosporin-prednisone (N = 121, 68 diabetic and 53 nondiabetic recipients; 73 cadaver and 48 related donor grafts) or azathioprine-prednisone-antilymphocyte globulin (N = 109, 61 diabetic and 48 nondiabetic recipients; 69 cadaver and 40 related donor grafts). The results were analyzed on March 31, 1984. Actuarial patient survival rates at 2 years were 88% in the cyclosporin and 91% in the azathioprine groups (p = 0.649). Graft survival rates at 2 years were 82% in all cyclosporin and 77% in all azathioprine-treated recipients (p = 0.150); the corresponding figures in the recipients of related donor grafts were 87% vs. 83% (p = 0.656), and in the recipients of cadaver donor grafts were 78% vs. 73% (p = 0.178). The 2-year graft survival rates were 81% in cyclosporin and 74% in azathioprine-treated diabetic recipients (p = 0.150) and 83% in cyclosporin and 81% in azathioprine-treated nondiabetic recipients (p = 0.604). Within the cyclosporin and azathioprine treatment groups, the differences in graft survival rates between diabetic and nondiabetic recipients were not significant (p = 0.822 and 0.423, respectively). Although there were no significant differences in graft survival rates, the cumulative incidence of rejection episodes within the first post-transplant year was significantly lower in the cyclosporin (34%) than in the azathioprine (60%) treated recipients (p = 0.001). In recipients of technically successful cadaver kidney grafts, the incidence of acute tubular necrosis (ATN) was 31% in cyclosporin and 30% in azathioprine-treated recipients (p = 0.822). Graft survival rates in azathioprine- and cyclosporin-treated recipients who did or did not undergo ATN were 72% vs. 89% (p = 0.011). The mean (+/- S.D.) serum creatinine levels (mg/dl) at 1 year were higher in cyclosporin (2.0 +/- 0.6) than in azathioprine (1.5 +/- 0.5) treated recipients (p = less than 0.001). A reduction in cyclosporin dose because of nephrotoxicity was required in 96 of the cyclosporin-treated patients (70%), and 25 were switched to treatment with azathioprine (21%). The incidence of all infections in cyclosporin-treated patients was approximately half of that in azathioprine-treated patients, and only nine per cent of the cyclosporin-treated patients were diagnosed to have cytomegalovirus infections during the first post-transplant year vs. 28% in azathioprine-treated patients (p = 0.002).(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1985

CT of pancreas transplantation.

Thirty-eight abdominal CT examinations obtained on 20 patients after pancreas transplantation were reviewed to determine the CT findings associated with pancreas transplantation and to assess the clinical utility of CT in this setting. Visualization of the transplanted pancreas was variable and was strongly influenced by adequacy of gastrointestinal opacification with contrast material. In four cases, linear high-density material was present within the graft, which, depending upon the surgical technique for handling exocrine secretions, represented either pancreaticojejunal stents or silicone within the pancreatic duct. Abdominal fluid collections were identified in 19 patients and were the most common complication identified by CT. Four of these collections were drained percutaneously. The major value of CT in pancreas transplantation is the identification and management of abdominal fluid collections in patients with abdominal pain and fever.

Abscess↗
PubMed1985

Relevance of adenosine deaminase to organ transplantation.

We have presented a discussion on the relevance of ADA to organ transplantation with regard to whether or not purine analogue inhibitors of ADA can prevent allograft rejection, and whether or not cells with high ADA activity may be involved in the rejection of allografts. It is clear that ADA inhibitors do have a modest amount of immunosuppressive activity. The potentiation of this modest effect by the addition of a deoxyadenosine analogue supports studies by others suggesting that it is the metabolism of deoxyadenosine and the presence of this compound as a substrate that is biochemically responsible for the immunosuppressive effects observed. In other studies that we are currently conducting, we have found that the ADA inhibitor EHNA causes a rapid and severe depletion of ATP in resting murine lymphocytes and that EHNA potentiates a similar effect of the new immunosuppressive agent cyclosporine in the same model. Investigations are currently underway to see if ADA inhibitors may potentiate the immunosuppressive effect of cyclosporine in vivo. It appears that cells with high ADA activity that are detectable in the peripheral blood mononuclear cells of renal allograft patients may indeed be involved in the rejection of allografts. However, from murine studies allogeneic cells alone do not seem to generate the appearance of these cells nearly as strongly as infection with murine cytomegalovirus. It must be determined if the ADA-rich cells that appear at the time of CMV infection are involved in viral functions or are the ontologic appearance of cytotoxic T cells representing the host's response to the antigens of the virus. The attack of these host cells against allograft cells infected with the virus may then explain the long-standing observation that viral infections seem to trigger allograft rejection responses.

Adenine↗
PubMed1985

Alterations in immunological reactivity in encephalomyocarditis virus-induced murine diabetes. I. Defective primary IgM plaque forming cell responses to sheep erythrocytes: correction by islet cell transplantation.

Increasing data suggest a possible viral aetiology of juvenile onset, insulin-dependent diabetes mellitus. The M variant of the encephalomyocarditis (EMC) virus infects murine pancreatic beta cells and causes a diabetes like syndrome in susceptible strains of mice. Abnormalities in immunological function have been documented in patients with diabetes mellitus and in spontaneous, streptozotocin-induced and alloxan-induced diabetes in animals. The present study documents a significant impairment of the ability of mice with EMC virus (M variant)-induced diabetes to generate a direct, IgM PFC response after in vivo immunization with sheep erythrocytes. This abnormality appears to be a direct consequence of the diabetic state and not EMC virus infection, per se, since mice infected with EMC virus that do not become diabetic have normal direct PFC responses and islet cell transplantation, which cures the diabetes, corrects the defect in PFC responsiveness.

Animals↗
PubMed1985

Effects of cyclosporine on the renin-angiotensin-aldosterone system and potassium excretion in renal transplant recipients.

To evaluate the mechanism of cyclosporine-induced hyperkalemia, the renin-angiotensin-aldosterone system and renal potassium clearance were compared in ten renal transplant recipients treated with cyclosporine and treated with azathioprine. After stimulation by a low-sodium diet and furosemide, cyclosporine-treated patients demonstrated lower plasma renin activity when supine (1.9 +/- 0.3 v 7.8 +/- 1.4 ng/mL/hr) and after standing (3.0 +/- 0.7 v 12.2 +/- 1.5 ng/mL/hr). Supine plasma aldosterone levels tended to be lower in cyclosporine-treated patients, (4.8 +/- v 10.5 +/- 2.6 ng/dL), although standing plasma aldosterone levels were not different (10.8 +/- 3.0 v 12.3 +/- 2.0 ng/dL). After administration of 0.75 mEq of potassium chloride per kilogram of body weight, cyclosporine-treated patients excreted 52% +/- 7.1% of the potassium load in six hours compared with excretion of 67% +/- 7.0% by the azathioprine-treated patients, although there was no difference in plasma aldosterone levels in response to the potassium load in the two groups. These data suggest that cyclosporine causes suppression of plasma renin activity and a tubular insensitivity to aldosterone, both of which may impair potassium excretion.

Adult↗
PubMed1985

Recurrent diabetes mellitus in the pancreas iso- and allograft. A light and electron microscopic and immunohistochemical analysis of four cases.

Four patients with type 1 diabetes mellitus received segmental pancreatic grafts. The donors were HLA-identical twins in three patients and an HLA-identical sibling in one. Each patient had normal glucose metabolism in the posttransplantation period but impaired graft function developed after 6 to 12 weeks. Complete loss of function developed in three patients. The fourth patient received immunosuppressive therapy but continues to require a low dose of insulin 15 months following transplantation. Pancreatic graft biopsy at the time of declining graft function in three patients revealed a mononuclear cell infiltrate centered upon islets consisting of variable numbers of T11 (pan T), OKT8 (suppressor-killer), OKT9 (transferrin receptor), OKT10 (activated), and HLA-DR-reactive mononuclear cells, as well as 63D3 and OKM1 reactive monocytes. Biopsies obtained following loss of graft function revealed resolution of the inflammatory process and selective destruction of all islet beta-cells in two patients, whereas graft biopsy in one patient demonstrated a mononuclear cell infiltrate in islets containing demonstrable beta-cells but no infiltrate in islets without beta-cells. Following immunosuppressive therapy the fourth patient showed resolution of the insulitis and destruction of beta-cells in 70% of the islets. The variable numbers of beta-cells observed in the remaining islets likely account for the relatively low amount of exogenous insulin required by this patient. There was no immunohistologic evidence of humoral mediated immune reaction in any of the biopsies. It is postulated that selective beta-cell destruction was a consequence of cell-mediated immunity leading to recurrent diabetes mellitus.

Adult↗
PubMed1985

One institution's experience with pancreas transplantation.

The University of Minnesota has the largest experience with pancreas transplantation of any institution, with 130 cases since 1966, including 116 in 98 patients between July 1978 and June 1985. Currently, 30 patients are insulin-independent, 19 for greater than one year, the longest for seven years. One-year patient and graft survival rates overall are 87% and 30%, respectively. Of 98 recipients, 49 had had previous kidney transplants, while 49 had not, and currently most of the pancreas recipients do not have uremia and have not had a kidney transplant but have early complications of diabetes. A total of 44 of the grafts were procured from related and 72 from cadaver donors. Although 32 of the 116 grafts (28%) failed for technical reasons, the most common cause of graft failure has been rejection. Various immunosuppressive regimens have been used in attempts to reduce the rejection rate, and one combination, low-dose cyclosporine-azathioprine-prednisone (triple therapy), has been particularly effective, with a one-year functional survival rate of 73% in recipients of technically successful grafts from human leukocyte antigen-mismatched cadaver or related donors (N = 20). The pancreas graft survival rates have improved gradually (43% for 1984 to 1985, N = 30; versus 27% for 1978 to 1983, N = 86) for transplants from both related and cadaver donors. Metabolic studies from most recipients with functioning grafts (insulin-independent) show normal or nearly normal results. Preliminary observations on secondary complications suggest a more favorable course in recipients whose grafts have functioned long term than in those whose grafts failed early.

Actuarial Analysis↗
PubMed1985

Pancreas transplantation--registry report and a commentary.

From December 1966 through December 1984, there were 561 pancreas transplants reported to the American College of Surgeons/National Institutes of Health Organ Transplant Registry, including 60 from 1966 through June 1977, 206 from July 1977 through December 1982 and 295 from January 1983 through December 1984. One-year graft function-survival rates (insulin-independent) in each of the three periods were 3%, 20% and 40%, and the corresponding patient survival rates were 40%, 72% and 77%. Currently 140 patients have functioning grafts, 76 for more than one year. Of the transplants since July 1977, one-year graft survival rates according to technique are 41% for enteric drainage (N = 155), 30% for polymer injection (N = 260) and 29% for urinary drainage (N = 47). Pancreas graft survival rates at one year according to whether or not the recipients have had a kidney transplant were 35% for recipients of simultaneous grafts (N = 281), 28% in recipients of a pancreas after a kidney (N = 112) and 26% in recipients of a pancreas only who did not have uremia (N = 106); corresponding patient survival rates were 69%, 83% and 83%. Overall, one-year pancreas graft survival rates according to whether the patients did or did not have end-stage diabetic nephropathy were 33% versus 25% and the corresponding patient survival rates were 73% versus 84% (P < .01). Patient survival rates were significantly higher in those without than in those with end-stage diabetic nephropathy. An analysis of technically successful grafts according to principal immunosuppressant showed one-year function rates of 46% in 258 cyclosporine-treated recipients and 26% in 143 azathioprine-treated recipients. Pancreas graft survival rates have progressively improved and the procedure has become safer with advances in surgical technique and immunosuppression. Pancreas transplantation is currently applicable to patients with diabetes mellitus whose complications are, or predictably will be, more serious than the possible side effects of long-term immunosuppression.

Diabetes Mellitus↗