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Biomedical subjects

R D Guttmann

Publications and source records attributed to R D Guttmann.

At least 109 records · Page 6Linked to original sources
PubMed1986

Insulin-dependent diabetes mellitus is associated with genes that map to the right of the class I RT1.A locus of the major histocompatibility complex of the rat.

Previous studies have demonstrated that the presence of at least one u-haplotype of the rat major histocompatibility complex (MHC), RT1, is a necessary but not sufficient condition for the development of overt diabetes mellitus. The present studies were undertaken to determine which portion of the RT1 gene complex is necessary for the occurrence of diabetes. We crossed hooded diabetic rats (RT1.AuBuDu) with PVGr8 rats (RT1.AaBuDu). F1 animals were mated to give 82 F2 animals and backcrossed with the hooded diabetics to produce 41 backcross animals. Diabetes occurred in animals with all three possible RT1.A genotypes. The diabetes was similar to that seen in BB rats and in hybrid strains developed from them. An immunoregulatory defect was marked by decreased percentage of peripheral blood lymphocytes staining with w3/25 monoclonal antibody, by an increased percentage of peripheral blood lymphocytes binding a mouse ascites control protein, and by decreased responsiveness of peripheral blood lymphocytes to stimulation by concanavalin A. We conclude that the u-allele of the class I A-locus gene product is not necessary for susceptibility to the development of diabetes in the rat. Therefore, either genes coding for the class II products of the u-haplotype or genes in linkage disequilibrium with these genes and mapping to the right of the A locus provide the permissive condition. Furthermore, the data suggest, but do not prove, that the u-haplotype derived from a strain remote from the BB rat can confer this susceptibility to the development of diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Genetics of the spontaneous diabetic syndrome. Interaction of MHC and non-MHC-associated factors.

The occurrence of the spontaneous insulin-dependent diabetic syndrome in the rat is the result of several genetic susceptibilities. There is a requirement for the u haplotype of the rat major histocompatibility complex (MHC), RT1. More specifically this requirement is for genes mapping to the right of the RT1 A locus, which codes for class I products. Furthermore, u haplotypes from inbred strains other than the BB rat can provide this permissive u haplotype. Diabetes occurs in animals with either one or two u haplotype and the diabetic syndrome is similar in its characteristics. In addition to the requirement for the MHC genes, there are abnormalities of the immune system of the various diabetes-prone strains, which are present in animals that develop overt disease. These abnormalities segregate independently of the RT1 and interaction between the susceptibilities is necessary for the manifestation of the complete clinical syndrome.

Alleles↗
PubMed1985

Transplantation and home hemodialysis: their cost-effectiveness.

Transplantation and home hemodialysis treatments have been available to treat patients with end stage renal disease for several years but it is not clear which approach is most cost-effective. This study compared the costs of hemodialysis and transplantation for comparable patients using the marginal cost methodology. Sixteen patients in a home program were matched with 16 patients in a transplantation program for sex, age, primary disease and other medical diseases. Questionnaires and a chart review allowed the accounting of all health services received in hospitals, offices or at home, and provided indicators of treatment effectiveness. The impact of the additional services generated by choosing one treatment over the other (difference between the two programs) was evaluated in terms of personnel, equipment and supplies. Survival and rehabilitation were similar in the two groups. However, for each year of follow-up, transplantation was considerably less expensive than home dialysis. These results suggest that transplantation is the most cost-effective way to treat end stage renal failure, at least for the subgroup of patients equally eligible for either transplantation or home dialysis.

Actuarial Analysis↗
PubMed1985

Transplantation versus dialysis in diabetic patients with renal failure.

Studies suggesting that transplantation is better than dialysis for diabetic patients with renal failure may be biased by the more favorable pretreatment prognosis of transplanted patients. Therefore, to provide a fairer comparison we controlled for pretreatment clinical state, categorized treatment received, and assessed mortality, major morbid events, and hospitalization in 51 diabetic patients who began therapy between 1970 and 1980. Fourteen patients were treated by transplantation and 37 by dialysis. The mean waiting period for transplantation was 5 months. The average age of transplanted patients was 40.9 years and of dialyzed patients 59.6 years. When we controlled for this age disparity and other factors (duration of diabetes and heart failure) that affect prognosis in end-stage renal disease (ESRD), the mortality with both transplantation and dialysis was similar to that expected from the overall mortality rate of the 51 study patients. Treatment received had no effect on mortality; the observed deaths compared with deaths expected from pretreatment status were 8 and 7.3 for transplantation and 30 and 30.7 for dialysis. We also compared major morbid events (blindness, amputation, stroke, severe heart failure, and myocardial infarction) and hospitalization in transplanted patients with the 24 dialyzed patients who survived long enough (5 months) to be eligible for transplantation. The number of major morbid events was 2.7 per 10 patient-years in the transplanted group and 3.4 in the dialyzed group. Hospitalization was 151.3 d/yr in transplanted patients and 55.6 d/yr in dialyzed patients (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Chronic hepatitis in end-stage renal disease: comparison of HBsAg-negative and HBsAg-positive patients.

To determine the outcome of chronic hepatitis in ESRD we studied all 358 renal transplant recipients and 295 hemodialysis patients treated for greater than 1 year since 1970. The incidence of chronic hepatitis (elevated SGOT for greater than 1 year) was 15% (N = 54) in transplanted and 3.4% (N = 10) in dialysis patients. Forty-eight percent (26) of transplanted and 50% (5) of dialysis patients were HBsAg positive. In the transplanted group, the clinical outcome of chronic hepatitis was significantly better in HBsAg-negative compared to HBsAg-positive patients; 11% died, none from liver disease, and 32% remitted after a mean follow-up from start of liver disease of 77.3 +/- 8.2 months, whereas in the HBsAg-positive group 54% (14) died, nine from liver disease, and one remitted after a follow-up of 90.2 +/- 8.9 months. Adverse prognostic factors (age, duration of diabetes, and heart disease) present before ESRD treatment began were similar in both groups, as was duration of follow-up. Only 14% (2/14) of HBsAg-negative patients progressed to chronic active hepatitis on liver biopsy compared to 71% (15/21) of HBsAg-positive patients. Histological stability in those with serial biopsies occurred in 66% (4/6) of HBsAg-negative patients, but in only 18% (13/16) of HBsAg-positive patients with a similar duration of follow-up. No dialysis patients died from liver disease. We conclude that chronic hepatitis occurs more frequently in transplanted than dialyzed patients, and that HBsAg-negative chronic hepatitis has a more benign, clinical, and histological outcome than chronic HBsAg-positive hepatitis in renal transplant recipients.

Female↗
PubMed1985

The role of azathioprine reduction in late renal allograft failure.

A group of 123 patients who had functioning renal transplants for more than 5 years were studied to discover whether prolonged reduction of azathioprine could predispose to late allograft failure. From the point of entry into the study (5 years after transplantation), the 5-year cumulative graft survival among living-related-donor recipients was 91.7%, and among non-living-related-donor recipients it was 84.8%. The azathioprine dose was reduced in 21 patients, for medical reasons, below 100 mg/day for more than one year when serum creatinine was stable and less than 2 mg/dl. Eight patients subsequently required dialysis. In the control group of 35 patients (transplanted in the same years, with serum creatinine that was similar at the same time posttransplantation to that of those who had azathioprine reduced) only 1 patient required dialysis. The likelihood of dialysis was significantly greater in those who had azathioprine reduced compared with those who did not (chi 2 = 12.0, P less than 0.001). No patient who had azathioprine reduced because of low white cell counts or chronic hepatitis subsequently required dialysis. It was concluded that a prolonged reduction of the azathioprine dose may predispose to late allograft failure.

Adult↗
PubMed1985

The impact of renal transplantation on the course of hepatitis B liver disease.

To establish the impact of transplantation on the course of chronic hepatitis B liver disease we performed a prospective study of the clinical and pathological sequelae of hepatitis B disease in all 22 patients who had renal allografts that functioned for more than 1 year and who were hepatitis B surface antigen (HBsAg)-positive following transplantation. No patient converted to HBsAg-negative. During a mean follow-up of 83 months serial liver biopsies were performed in 20 patients and 1 liver biopsy was available in the remaining 2 patients. Eleven patients died of liver disease, 5 of whom died of hepatic failure, 3 with hepatoma, 2 of gastrointestinal hemorrhage, and 1 of ascites with pleuroperitoneal fistula. Aggressive liver disease was observed in the vast majority of patients: 12 ultimately developed cirrhosis, (mean follow-up 81 months), 6 chronic active hepatitis (mean follow-up 93 months), 3 chronic persistent hepatitis (mean follow-up 89 months), and in 1 patient the presence of HB virus in hepatocytes was the sole morphologic alteration (follow-up 42 months). There was a marked tendency to progression in that 82% of patients with virus only, reactive hepatitis, or chronic persistent hepatitis on initial biopsy subsequently developed chronic active hepatitis or cirrhosis. For comparison, 10 HBsAg-positive patients whose renal failure had been treated by hemodialysis were also studied over a comparable period. Four patients converted to the negative state. Biochemical evidence of persistent liver dysfunction occurred in only 1 patient and no patient has died from complications of liver disease. We conclude that in the immunosuppressed renal transplant patient HB infection often results in the development of cirrhosis, leading to death from hepatoma and hepatic failure. This course is worse than that in dialysis patients. Renal transplantation of HBsAg-positive patients with end-stage renal failure may be inadvisable.

Aspartate Aminotransferases↗
PubMed1985

Structural studies of the class II histocompatibility antigens of the ACI rat.

The class II antigens of the ACI rat were studied using both conventional alloantisera and monoclonal antibodies. By sequential immunoprecipitation experiments and cell binding studies, alloantisera were shown to contain antibodies to both the RT1.B and the RT1.D gene products. Using one- and two-dimensional gel electrophoresis, the structures of these gene products were shown to be distinguishable. The importance of these differences for the immune response and antigen presentation is discussed.

Animals↗
PubMed1985

Association of spontaneous thyroiditis with the major histocompatibility complex of the rat.

Overt insulin-dependent diabetes mellitus in the rat is associated with the u haplotype of the rat major histocompatibility complex (MHC), RT1. Thyroiditis of sufficient severity to result in elevation of TSH levels is seen in Buffalo rats (RT1b). In order to examine the association of autoimmune thyroid disease with MHC gene products, we have crossed inbred Buffalo rats with diabetic BB rats and examined the RT1 genotype, the histology of thyroid and pancreatic tissue, and two indices of thyroid function. The data indicate that animals having pancreatic lymphocytic infiltration and insulinopenic overt diabetes mellitus had at least one RT1u haplotype. All but one animal having severe histological thyroid lymphocytic infiltration had at least one RT1b haplotype. Rats with severe thyroiditis had higher mean TSH levels than rats with normal histology or rats with mild thyroiditis. We conclude that gene products of the rat MHC affect the severity of spontaneous organ-specific autoimmune disease in terms of clinically apparent as well as tissue inflammatory disease.

Animals↗
PubMed1985

HNK-1+ (Leu-7) and other lymphocyte subsets in long-term survivors with renal allotransplants.

At 5 or more years after renal transplantation, 42 patients were studied for their lymphocyte subsets to Leu-1, Leu-2, Leu-3, and Leu-7. It was found that, in this group of patients who ranged from 25 to 60 years of age, there was a significant decrease in the number of T helper cells and a decrease in the absolute level of T lymphocytes, with no significant change in the number of T suppressor cells. On a relative basis, the helper/suppressor ratio was decreased in patients when compared with normal persons. This was due to an increase in the relative numbers of suppressor cells. It was demonstrated that the Leu-7+ subset, which marks the NK population, was significantly elevated, in relative proportion, in peripheral blood when compared with controls. This was not seen on an absolute basis. The age-dependence of the relative numbers of Leu-7+ cells was seen in the normal control population and in the transplant cohort. There was no significant correlation between lymphocyte subset measurements and delayed-type hypersensitivity skin tests in the transplant population. A finding of interest is that 6 of the patients who had been treated for malignant disease during their posttransplant course had significantly higher numbers of Leu-7+ cells on a relative basis. In 5 of these patients, for whom data was available on absolute numbers, there was also a highly significant difference in the absolute numbers of Leu-7+ cells in these treated and surviving allograft recipients. It is speculated that this finding may suggest that an increase in Leu-7+ cells marks posttransplant patients who have a successful outcome following the treatment of malignancy, for which they are at increased risk.

Adult↗
PubMed1985

Two-color immunofluorescence and flow cytometry analysis of lymphocytes in long-term renal allotransplant recipients: identification of a major Leu-7+/Leu-3+ subpopulation.

Using two-color immunofluorescence with fluorescein isothiocyanate (FITC)- and phycoerythrin (PE)-labeled monoclonal antibodies to human lymphocyte antigens and flow cytometry, we studied lymphocyte subsets in 16 long-term renal allotransplant recipients at risk for a mean of 78 +/- 15 mo. The absolute number of Leu-1+, Leu-2a+, and Leu-3a+ lymphocytes is significantly decreased compared with a control population, whereas Leu-7+ and Leu-15+ subsets remain unchanged despite standard chronic immunosuppression (azathioprine and prednisone). Within the Leu-7+ subset, we found various phenotypes. Doubly fluorescent lymphocytes Leu-7+/Leu-1+ and Leu-7+/Leu-2a+ are not significantly different in the transplant population compared with a normal control population. The Leu-7+/Leu-3a+ subpopulation is seen to be significantly elevated, and the Leu-7+/Leu-15+ subpopulation decreases significantly. The relationship between the modification of these two phenotypes within the Leu-7 subset may be an important correlate of decreased NK cell activity in long-term renal allotransplant recipients. These Leu-7+/Leu-3a+ cells, normally less than 1% of peripheral blood lymphocytes, have no known functional activity.

Adult↗
PubMed1984

Immune dysfunction in diabetes-prone BB rats. Interleukin 2 production and other mitogen-induced responses are suppressed by activated macrophages.

Spleen cells of diabetes-prone BB Wistar rats were found to generate excessively low proliferative responses, and interleukin 2 (IL-2) levels in response to T-dependent mitogens. This abnormality was not due solely to abnormal T cell numbers since: (a) addition of BB spleen cells of BB splenic macrophages to normal major histocompatibility complex (MHC)-matched Wistar Furth (WF) spleen cells resulted in severe suppression of concanavalin A (Con A)-, phytohemagglutinin (PHA)-, and pokeweed mitogen (PWM)-mediated proliferation, and IL-2 production; (b) macrophage depletion from BB spleen cells, but not B cell or T cell depletion, removed completely the suppressive effects of BB cells on WF cells; (c) macrophage depletion greatly enhanced the response of BB lymphocytes to T-dependent mitogens. Although suppressor macrophages could also be found in the spleen of WF control rats they were present in much smaller numbers than in the spleen of BB rats. The suppressive effect of BB macrophages was partially reduced by addition of the prostaglandin synthetase inhibitor indomethacin to cultures. Furthermore, indomethacin (but not catalase or PMA) considerably augmented IL-2 secretion of Con A-stimulated BB spleen cells, but had little effect on WF spleen cells. In contrast, prostaglandins E1 and E2 (PGE1 and PGE2) suppressed IL-2 production. While IL-2 secretion was severely depressed in BB rats unstimulated and lipopolysaccharide (LPS)-stimulated IL-1 secretion by splenic macrophages was normal. BB macrophages did not inactivate IL-2. Low IL-2 production and macrophage-mediated suppression were features of all BB rats tested.

Animals↗
PubMed1984

The clinical and pathological course of hepatitis B liver disease in renal transplant recipients.

A prospective study of the clinical and pathological sequelae of hepatitis B disease in 22 immunosuppressed renal transplant patients is reported. All patients had allografts that functioned for more than 1 year, and all were hepatitis B surface antigen (HBsAg)-positive following transplantation. None of the 18 patients who had serial HBsAg tests converted to HBsAg negative. Serial liver biopsies were performed in 19 patients and one liver biopsy was available in the remaining three patients. Follow-up ranged from 12 to 93 months. Seven patients ultimately developed cirrhosis, 6 developed chronic active hepatitis, 5 developed chronic persistent hepatitis, and in 4 the presence of HB virus in hepatocytes was the sole morphologic alteration. The initial liver biopsy was not an accurate predictor of ultimate severity of liver disease because 5 of the 12 patients with virus only or chronic persistent hepatitis subsequently developed chronic active hepatitis or cirrhosis. Clinical liver dysfunction occurred in 8 patients, all of whom had chronic active hepatitis or cirrhosis. Three patients died with hepatic failure and 2 with hepatoma. The risk of death from liver disease in HBsAg-positive renal transplant patients was 5% per patient-year. For comparison, 10 HBsAg-positive patients whose renal failure had been treated by hemodialysis were also studied over a comparable period. Biochemical evidence of persistent liver dysfunction recurred in 1 patient only; 4 patients converted to the HBsAg-negative state; and no patient has died from complications of liver disease. We conclude that in the immunosuppressed renal transplant patient HB infection often results in the development of chronic active hepatitis, leading to cirrhosis and death from hepatoma and hepatic failure.

Adolescent↗
PubMed1984

Glomerular sclerosis in a renal isograft and identical twin donor. A family study.

Loss of renal mass has been associated with the development of glomerular sclerosis in animals and human beings. The pathophysiology of this renal injury is unknown, but glomerular sclerosis in animals can be aggravated or accelerated following exposure to nephrotoxic antibodies, puromycin aminoglycoside or renal irradiation. We describe here the outcome of the first renal transplant performed in the British Commonwealth. Glomerular sclerosis occurred in identical twins who were kidney donor and recipient, renal failure occurring 14 and 16 years after transplantation, respectively. Examination of these twins and all living immediate family members showed that six of the seven family members (both twins, their mother, and three sisters) had increased concentrations of circulating immune complexes, decreased total hemolytic complement, and low or borderline concentrations of C4. Only twins with single kidneys had detectable renal disease. Other preexisting causes of renal disease in these twins that would account for the glomerular sclerosis could not be identified. We suggest that a familial immune defect contributed to the development of glomerular sclerosis in these twins who were predisposed to renal disease due to loss of renal mass.

Adolescent↗
PubMed1984

The diagnostic and prognostic value of renal allograft biopsy.

We prospectively studied 89 patients to assess the diagnostic use of renal allograft biopsy in the first three months after transplantation. These biopsies were done in patients in whom diagnosis was not clear or clinical rejection was deemed to be severe. Clinical diagnosis at initial biopsy was compared with the morphological diagnosis. To determine if morphological data improved the prognostic usefulness of the clinical data, we performed multiple logistic regression relating clinical variables at initial biopsy and histological changes in the transplant to the outcome of 120 patients one year after biopsy. The clinical and morphological diagnosis differed in 41 of 89 patients (46%). Of 120 patients in the prognostic study, 35 returned to dialysis during the first year following transplantation. Using multiple logistic regression, a categorical variable that took into account both the serum creatinine and its rate of change before biopsy was the best clinical predictor of return to dialysis. Further increase in chi 2 occurred with type of donor, number of transfusions, and age. Using the clinical variables we produced an index, from 0 to 1 to predict outcome. Only 8 had index less than 0.2, of whom 7 returned to dialysis. The best morphological predictor of outcome was interstitial hemorrhage. Further increase in chi 2 was obtained with vascular endothelial proliferation, glomerular endothelial swelling, and glomerular necrosis. With an index derived from the morphological variables only 11 had index less than 0.2, of whom 9 returned to dialysis. Combining both clinical and morphological data, the best predictor of return to dialysis was interstitial hemorrhage, followed by creatinine, glomerular endothelial swelling, and type of donor. Using both clinical and morphological variables we produced another index to predict outcome. A group of 65 patients had index greater than 0.8, of whom 63 (94%) did not return to dialysis, and 18 patients had index less than 0.2, 17 of whom returned to dialysis. The remaining 12 patients in the dialysis group and 15 in the nondialysis group had indices greater than 0.2 less than 0.8. We conclude that a transplant biopsy yields important diagnostic and prognostic information. Unexpected diagnoses were made in 46% of cases. The addition of morphological data to the clinical data available at time of biopsy greatly improved the prediction of return to dialysis.

Biopsy↗