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Biomedical subjects

D E Sutherland

Publications and source records attributed to D E Sutherland.

At least 415 records · Page 23Linked to original sources
PubMed1989

Pancreas-transplant outcome in relation to presence or absence of end-stage renal disease, timing of transplant, surgical technique, and donor source.

The differences in pancreas-transplant outcome according to recipient status, surgical approach, and donor source are illustrated by an analysis of results at one institution with experience in several categories. From July 1978 to January 1988, 210 pancreas transplants were performed, and 67 grafts are still functioning, the longest for 9.7 yr. Since October 1984, a uniform immunosuppressive protocol has been used, antilymphocyte globulin, cyclosporin, azathioprine, and prednisone for induction and the last three drugs for maintaining antirejection therapy. During this period, 110 pancreas transplants were performed, 62 in nonuremic non-kidney transplants, 28 in recipients of a previous kidney, and 20 simultaneous with a kidney; 64 with bladder and 43 with enteric drainage; and 25 from related and 85 from cadaver donors. The overall patient survival rate at 1 yr was 91%, and there were no significant differences between the various categories. Graft survival rates, however, differed between the various categories created by combinations of the above variables. With bladder drainage, 1-yr function rates were 58% (n = 30), 47% (n = 15), and 77% (n = 19) in recipients of a pancreas transplant alone, a pancreas after a kidney, or a simultaneous pancreas-kidney transplant; with enteric drainage, 1-yr function rates were 33% (n = 32) and 36% (n = 11) in the pancreas transplant alone and pancreas after kidney categories (enteric drainage was not done in double-transplant patients).(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗
PubMed1989

Metabolic effect of hemipancreatectomy in donors. Preoperative prediction of postoperative oral glucose tolerance.

Between November 1977 and January 1987, 55 transplantations of pancreas segments from living donors related to their recipients were performed at the University of Minnesota. A preliminary analysis of metabolic test results in donors tested 1 yr after hemipancreatectomy showed an increase in mean glucose and a decrease in mean insulin values during oral glucose tolerance tests (OGTTs) in 18 donors, a 14% increase in the mean of the mean glucose levels during 24-h metabolic profiles in 12 donors, and a decrease of 45% in the mean 24-h urinary C-peptide excretion in 21 donors. Including the studies performed postdonation, 11 of 31 (35%) donors developed an abnormal OGTT result. In a retrospective analysis, preoperative results of intravenous glucose tolerance tests (IVGTTs) and cortisone-stimulated OGTTs were found to be statistically significant predictors of an abnormal OGTT after hemipancreatectomy. The mean of the 5- to 50-min IVGTT insulin values was the best predictive test. With the cutoff value set at 62 microU/ml, this test result had a sensitivity of 100%, a specificity of 83%, and a positive predictive value of 75% for identifying donors who developed an abnormal OGTT. The sum of the 5- and 10-min IVGTT insulin (cutoff 140 microU/ml) had a sensitivity of 100%, a specificity of 67%, and a predictive value of only 60%, whereas the delta-insulin had values of 86, 71, and 60%, respectively. Both the IVGTT mean insulin and the sum of the 5-min and 10-min insulin test results were 100% predictive of an abnormal test (0% risk), but the IVGTT mean insulin excluded the lowest proportion of otherwise suitable donors (a low "false-alarm" rate). The IVGTT mean insulin can be used to identify or exclude potential donors who would develop an abnormal OGTT result should hemipancreatectomy be performed.

Glucose Tolerance Test↗
PubMed1989

Effect of immunodepletion of MHC class II-positive cells from pancreatic islets on generation of cytotoxic T-lymphocytes in mixed islet-lymphocyte coculture.

In vitro manipulation of pancreatic islets to decrease islet immunogenicity before transplantation has largely been directed at eliminating the major histocompatibility complex (MHC) class II-positive passenger leukocytes from the islets. The mixed islet-lymphocyte coculture (MILC) system was used to quantitate the efficacy of immunodepletion of MHC class II-positive cells from pancreatic islets in terms of reducing immunogenicity. With these experiments we compared the in vitro immunogenicity of MHC class II-depleted islets with untreated islets. B10.BR (H-2k) islets were treated with anti-Iak alloserum followed by complement. This treatment successfully eliminated MHC class II-positive cells from the islets, as demonstrated by indirect immunofluorescence techniques. Depleted islets generated slightly lower amounts of allospecific cytotoxic T-lymphocyte (CTL) activity when exposed to C57BL/6 (H-2b) splenocytes in the MILC than untreated control islets. Although the amount of CTL generated by the depleted islets was slightly less than that generated by untreated islets, there was significant stimulation of CTL by the MHC class II-depleted islets. Therefore, the presence or absence of MHC class II cells within the islet is unlikely to be the decisive factor contributing to islet immunogenicity.

Animals↗
PubMed1989

Generation of allospecific cytolytic T-lymphocytes stimulated by pure pancreatic beta-cells in absence of Ia+ dendritic cells.

A murine mixed islet-lymphocyte coculture system (MILC) was used to quantitate the immunogenicity of a pure population of pancreatic beta-cells to more clearly define whether stimulator major histocompatibility complex (MHC) class II-positive dendritic cells are a major component leading to islet immunogenicity. Pancreatic beta-cells express MHC class I antigen but not class II antigen. These experiments compared the in vitro immunogenicity of fluorescence-activated cell sorted (FACS-IV) pure beta-cells (MHC class I-positive cells only) relative to unpurified dispersed islet cells (MHC class I-positive cells and class II-positive cells). The results demonstrated the surprising finding that pure DBA/2J (H-2d) pancreatic beta-cells stimulated a strong cytotoxic T-lymphocyte (CTL) response when exposed to C57BL/6 (H-2b) allosplenocytes in the MILC, similar to DBA/2J nonpurified dispersed islet cells. Furthermore, the stimulation of CTL by both purified beta-cells and nonpurified dispersed islet cells was blocked by addition of MHC-specific anti-class I monoclonal antibody directed against stimulator MHC antigen. The data imply that the highly immunogenic MHC class II-positive passenger leukocytes present in the islets were not necessary for the generation of the immune response in the presence of MHC class I-positive beta-cells. Although most of the pretreatment regimens attempting to decrease islet immunogenicity have been directed at eliminating the MHC class II-positive passenger leukocytes from the islets, this work suggests that modulation of MHC class I antigen may be an important approach.

Animals↗
PubMed1989

Results of pancreas-transplant registry.

From December 1966 to March 1988, 1394 pancreas transplants were reported to the International Pancreas Transplant Registry. For the 1129 cases since 1982, the overall 1-yr graft and recipient survival rates were 46 and 82%, respectively. When analyzed according to the three most common duct-management techniques, polymer injection (n = 324), intestinal drainage (n = 282), and bladder drainage (n = 462), the 1-yr function rates were 47, 45, and 54%, respectively. The graft survival rates were also similar, whether whole (n = 492) or segmental (n = 634) grafts were transplanted (47 vs. 46% at 1 yr). Graft survival rates according to preservation times were 49, 42, and 43% at 1 yr for those stored less than 6 h (n = 694), 6-12 h (n = 237), and greater than 12 h (n = 89), respectively. Immunosuppressive regimens that included both cyclosporin and azathioprine were associated with significantly (P less than .03) higher graft survival rates than those that included only one of the drugs, with 1-yr graft survival rates for technically successful grafts of 67, 54, and 39% for patients treated with azathioprine plus cyclosporin (n = 602), cyclosporin without azathioprine (n = 201), and azathioprine without cyclosporin (n = 44). Pancreas-graft survival rates differed according to whether a kidney was or was not transplanted and according to the timing of the transplant: 53, 40, and 32%, respectively, at 1 yr for cases in which a simultaneous kidney was transplanted (n = 685), a kidney had previously been transplanted (n = 201), or a kidney had never been transplanted (n = 202).(ABSTRACT TRUNCATED AT 250 WORDS)

Graft Survival↗
PubMed1989

Recurrence of disease in pancreas transplants.

In a series of 200 pancreas transplants with 6 mo to less than 9 yr of follow-up, recurrence of disease was identified as the cause of graft failure in 8 cases, all in non- or minimally immunosuppressed recipients of transplants from identical twin (n = 3) or HLA-identical sibling (n = 5) donors. Recurrence of disease was defined as selective loss of beta-cells; other endocrine cell types persisted and appeared normal within the islets of the graft. Isletitis was present in islets with residual beta-cells during the evolution of the process in all nonimmunosuppressed and in some immunosuppressed recipients, but isletitis resolved in all cases in which beta-cell destruction was complete and also resolved in some cases in which residual beta-cells were retained after the introduction of or an increase in immunosuppression. Recurrence of disease can be prevented by immunosuppression, and 2 recipients of identical twin grafts and 12 recipients of grafts from HLA-identical siblings had functioning grafts as of March 1988, the longest greater than 7 yr. The process has not been observed in patients in whom full-dose immunosuppression has been used, including HLA-identical siblings, and this may be the reason no cases of recurrence of disease have been identified in recipients of cadaveric grafts. Alternatively, the observations are consistent with, but not proof of, the hypothesis that recurrence of disease (autoimmune isletitis leading to diabetes) is a major histocompatibility complex-restricted phenomenon.

Graft Rejection↗
PubMed1989

Glucose homeostasis and insulin secretion in human recipients of pancreas transplantation.

To ascertain the consequences of pancreas transplantation with systemic venous drainage on glucose homeostasis and insulin secretion, glucose and insulin responses to intravenous glucose were compared in 10 recipients and 15 normal control subjects. There were no differences in fasting glucose levels or intravenous glucose disappearance rates. However, basal insulin levels and acute insulin responses to glucose were threefold greater in the recipients. It is not clear whether this consequence of hyperinsulinemia in the recipients is due to the abnormal circulatory drainage, the lack of autonomic input, or concurrent immunosuppressive drug therapy.

Blood Glucose↗
PubMed1989

Long-term study of normal kidneys transplanted into patients with type I diabetes.

We examined the rate of development of the lesions of diabetic nephropathy in transplanted kidneys residing for 6-14 yr in type I (insulin-dependent) diabetic kidney-allograft recipients. Although each recipient had end-stage diabetic nephropathy with his/her own kidneys, there was marked variability in the rate of development of mesangial expansion observed in the transplanted kidneys. The progression of glomerular pathology, including widening of the glomerular basement membrane and expansion of the mesangium, did not correlate significantly with several potential risk factors (e.g., donor source--cadaver or living related, histocompatibility match, age of the recipient or donor, age at onset of diabetes, duration of diabetes before renal failure, immunosuppressive drug dose, blood pressure, and severity of lesions of chronic rejection). However, there was a direct albeit imprecise relationship between the index of mesangial expansion at the final biopsy and the index of glycemic control (r = .61, P less than .01). These observations suggest that currently unknown factor(s) may modulate the progression of diabetic renal disease, even in a population that had uniformly demonstrated nephropathy risk. Our data support the hypothesis that in addition to glycemic control per se, there are risk factors intrinsic to the kidney itself.

Adolescent↗
PubMed1989

Mean glomerular volume and rate of development of diabetic nephropathy.

We studied kidney glomerular structure and function in two groups of type I (insulin-dependent) diabetic subjects with 14-16 yr (group 1, n = 16) and 24-26 yr (group 2, n = 13) duration of diabetes and compared them to a group of 18 nondiabetic subjects with similar age ranges. Within each diabetic group, subjects were selected for normal kidney function (urinary albumin excretion less than 40 mg/24 h, normal blood pressure, creatinine clearance greater than 90 ml.min-1.1.73 m-2) or for nephropathy (urinary albumin excretion greater than 200 mg/24 h). Morphometric analysis of glomeruli revealed a significantly larger mean glomerular volume in subjects with nephropathy (group 2). Mesangial volumes were significantly greater in the nephropathic than the normoalbuminuric diabetic subjects in each group, but filtration surface per glomerulus was constant among all subjects. The percentage of sclerosed glomeruli was also significantly increased in the nephropathic subjects compared with the subjects with normal kidney function, in whom sclerosed glomeruli did not exceed 8%. In addition, there was a significant correlation between percentage of globally sclerosed glomeruli and glomerular volume in group 2 (rs = .79, P less than .01) but not group 1 (rs = -.20, NS) subjects. Thus, glomerular size or individual capacity for glomerular expansion may determine the rate of progression of the loss of kidney function in subjects destined to develop diabetic nephropathy.

Adolescent↗
PubMed1989

Physiological and clinical correlates of cardiorespiratory reflexes in diabetes mellitus.

Cardiorespiratory reflexes (CRRs) were studied by measuring heart-rate (HR) variation during 6 breaths/min respiration (delta R6) and Valsalva maneuver (VR) in 145 healthy and 417 type I (insulin-dependent) diabetic subjects. HR variation with breathing at 12 breaths/min and ventilatory response to hypercapnia/hypoxia were measured in fewer subjects. CRR results were compared with symptoms of autonomic dysfunction, the neurological examination, nerve conduction studies, and quantitative sweat testing. The objective was to compare the sensitivity of various methods of characterizing diabetic patients and to use this information when staging patients for clinical therapeutic trials. CRR responses were age dependent in both populations. Either delta R6 or VR was abnormal in 74% of diabetic patients, delta R6 being more sensitive. CRRs correlated well with the presence of symptoms of autonomic dysfunction, abnormalities on the neurological examination, results of nerve conduction studies, and sweating activity in the feet of the same patients. However, both CRRs and sweating were abnormal in a high proportion of patients without any clinical manifestations of neuropathy. The ventilatory reflex response to moderate hypercapnia/hypoxia was also measured. It was normal in most of the diabetic patients tested, including many with severe reduction of CRRs. We conclude from the combined results of CRR, ventilatory response, and other studies that the causative factors for abnormal CRR may not be confined to the vagus nerves, and that in most instances, the depressed CRR may be due to a decrease in the efficacy of sensorimotor nerve conduction around the reflex arc.

Adolescent↗
PubMed1989

Successful transplantation of canine islets of Langerhans after 24 hours cold-storage.

Utilizing the intrasplenic canine islet autograft model, it was possible to examine the effect of cold-storage of pancreatic tissue, both prior to and following dispersion, on functional outcome. A control group of dogs receiving freshly prepared autografts (n = 8) obtained durable euglycaemia in 75% of cases; the mean K value at two weeks being -1.70 (Standard Deviation (sd) = 0.06). In the first experimental group, animals (n = 8) were transplanted following 24 hours of whole pancreas cold-storage in silica gel fractionated plasma (SGF) using intraductal perfusion prior to preservation. None of these animals obtained euglycaemia; the transplanted material having a significantly reduced insulin content compared with controls (p = 0.0006). In the second experimental group, animals (n = 6) were transplanted following 24 hours of dispersed pancreatic tissue storage in SGF. This resulted in an 83% incidence of durable euglycaemia; the mean K value at two weeks being -1.60 (sd = 0.3). The glucose decay curve improved with time in this group and at three months the mean K value was -2.00 (sd = 0.38); this value being significantly superior to that of the control animals (K = -1.34, sd = 0.34, p less than 0.05). We conclude that while storage of the whole pancreas prior to islet isolation remains problematic, it is possible to reliably preserve dispersed pancreatic tissue for 24 hours by simple cold-storage, as assessed by the functional outcome of intrasplenic autografting in the dog model. These findings have important clinical implications.

Amylases↗
PubMed1989

Pancreas transplantation: report from the International Registry and a preliminary analysis of United States results from the New United Network for Organ Sharing (UNOS) Registry.

This report contains information on analysis of 2,292 pancreas transplants worldwide reported to the International Pancreas Transplant Registry from 1966 through 1989, with 1-year recipient survival rates improving from 39% to 71% to 80% to 87% and 1-year graft survival rates from 5% to 26% to 40% to 56% for 1966 to 1977 (n = 64), 1977 to 1983 (n = 336), 1984 to 1985 (n = 364), and 1986 to 1989 (n = 1,220) cases, respectively. The last 2 eras were combined for analyses of multiple variables. In the analyses of all world cases for the 1984 to 1989 period (n = 1,604), the most important finding was the influence of HLA-DR matching or mismatching on pancreas graft survival rates; 1-year function rates for grafts in recipients matched for 2, 1, or 0 DR antigens with the donor were 73% (n = 52), 53%, (n = 468), and 48% (n = 67) (p less than 0.005 for all comparisons). Likewise, in an analysis of 1984 to 1989 cases according to DR mismatching, the 1-year graft survival rates with 0, 1, or 2 DR mismatches were 63% (n = 128), 50% (n = 583), and 49% (496) (p less than 0.02). An analysis of the 1986 to 1989 era cases worldwide confirms the trend in the period analysis for bladder drainage (BD) to be associated with significantly higher graft survival rates than intestinal drainage or duct injection, at 1-year being 59% (n = 656), 47% (n = 97), and 54% (n = 210). Likewise, for the 1986 to 1989 era, worldwide 1-year pancreas graft functional survival rates were significantly higher in recipients of simultaneous-pancreas/kidney transplants (SPK) than in recipients of pancreas-after-kidney (PAK) or a pancreas-transplant-alone (PTA); 63% (n = 865), 45% (n = 186), and 37% (n = 165). In a new analysis of the United States cases reported to the UNOS Registry from October 1, 1987 through June 30, 1989, 1-year patient and graft survival rates were 91% and 69%. Almost all United States cases reported to the UNOS Registry during 1987 to 1989 were with BD (n = 324).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1989

Results of pediatric kidney transplantation at the University of Minnesota.

In all, 473 renal transplants were performed at the University of Minnesota in 386 children 1-17 years old between August 14, 1963 and December 31, 1988. Standard immunosuppressive protocols, pretransplant blood transfusions, and discontinuation of routine splenectomy have led to improving graft and patient survival rates. Children receiving living-related donor kidneys had better graft and patient survival rates, compared to cadaver kidneys. Graft and patient survival rates were better in children who received primary grafts, compared to retransplants. Children who received DST plus conventional immunosuppression had poorer graft survival, compared to quadruple immunosuppression during the same era. Recently, 1-year graft survival rates with quadruple immunosuppression are equal for children receiving primary, living-related donor or cadaver kidneys. Graft and patient survival rates in children 1-4 years old are identical to those in children 5-17 years old. Age no longer appears to be a risk factor for children undergoing kidney transplantation. Good patient and graft survival rates can be achieved at centers specializing in kidney transplantation for small children. Currently, transplantation is the treatment of choice for all children who are candidates for renal replacement therapy.

Adolescent↗