How to improve results for second renal allografts.
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Biomedical subjects
Publications and source records attributed to M Garovoy.
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212 cyclosporine-treated recipients of mismatched first cadaveric renal allografts are evaluated with respect to the effect of pretransplant random blood transfusions. It is determined that transfusions do not effect patient survival or morbidity. Pretransplant random blood transfusions correlate with significantly improved allograft success. There is also a trend, although not statistically significant, for further improvement of allograft survival with increasing numbers of transfusions. The transfusion effect is not related to the time at which the transfusions are given up to 2 years prior to transplantation. Transfused patients have a higher percent reactive antibody (PRA) than untransfused patients, but this does not cause them to wait for a cadaveric allograft significantly longer than the untransfused patients. Rejections are less severe in transfused patients. It is concluded that cyclosporine-treated recipients of first cadaveric renal allografts benefit from pretransplant blood transfusions.
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DST provides excellent graft survival in one- and zero-haplotype-matched donor-recipient pairs as well as a trend towards improving graft survival in HLA-identical matches; serum creatinine levels are good in functioning grafts; Imuran coverage does appear to decrease DST sensitization to the blood donor in nonsensitized patients undergoing a first transplant, which encourages early DST and transplantation in this group; flow cytometry has been extremely helpful in excluding subliminal anti-class 1 antigen activity in patients with positive B warm crossmatches alone; DST, in itself, does not appear to preclude subsequent cadaveric transplantation in patients sensitized to their blood donor; and the family history of the blood donor is known, with essentially no risk to the recipients of hepatitis, AIDS, etc. In regards to the issue of whether DST or Cs is better, both have merits, and one must be aware of the circumstances that relate to the optimum application of each therapy. Only a prospective study of DST- and Cs-treated patients with a long-term follow-up will probably resolve the issue of the optimum regimen for one-haplotype-matched living related donor-recipient pairs. The ultimate strategy may involve the selective use of each regimen for the most appropriate circumstances.
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It has been suggested that a low dose of prednisone initially given post-transplant, besides producing lower patient morbidity, is as effective as high dose regimens in providing positive graft and satisfactory patient outcome. In 1981 and 1982, we prospectively and randomly studied 77 cadaveric kidney recipients who received a high dose (2.0 mg/kg body weight) (H) and 66 who received a low dose of prednisone (0.5 mg/kg body weight) (L) at the time of transplant. Mean time to the first rejection episode was 9.7 +/- 13.8 and 13.3 +/- 12.9 days in the L and H groups, respectively; 10.6% and 15.6% of the patients in the L and H groups, respectively, never had a rejection episode. Among subjects younger than 45 years, graft and patient survival was better for those treated with the high dose (N = 60, 63.9% vs 32.2%, P = 0.032, and 100% vs 88.4%, P = 0.027, respectively) than for those treated with the low dose (N = 46). Patient and graft response to H and L was similar for patients older than 45. Morbidity was similar for both the L and H groups.
Recent advances in cellular immunology have enabled us to delineate numerous lymphocyte subsets and activation stages using monoclonal antibody techniques. lymphocyte subsets and activation stages using monoclonal antibody techniques. We have used a fluorescence activated cell sorter (FACS) and newer monoclonal antibodies to study lymphocyte subpopulations and activation stages of T lymphocytes in intraocular fluids and peripheral blood of uveitis patients. T lymphocytes predominated in aqueous and vitreous. A statistically significant correlation was observed between the T lymphocyte subsets in aqueous and peripheral blood. No correlation was seen between the intravitreal lymphocyte subsets and peripheral blood. Many intraocular lymphocytes are present in the aqueous secondary to a blood ocular barrier breakdown. Using an anti-interleukin-2 (IL-2) receptor monoclonal antibody as a marker for T-cell activation, activated lymphocytes were found in intraocular and peripheral blood of both idiopathic and non-idiopathic uveitis. A statistically significant correlation was found between in vivo lymphocyte activation and clinical uveitis activity. In uveitis, lymphocyte activation in the eye paralleled levels found in the blood. Systemic and intraocular lymphocyte activation occurs in both idiopathic uveitis as well as in systemic syndromes associated with intraocular inflammation. It is possible that idiopathic uveitis is a systemic disease.
Two-hundred three children 1 to 16 years of age received kidney transplants during a 20-year period, 100 from living donors and 103 from cadaver donors. The overall survival rate was 79%. Actuarial patient and kidney survival rates at 15 years were 79% and 52%, respectively, for recipients of living donor kidneys and 57% and 19%, respectively, for recipients of cadaver donor kidneys. One of two children who received transplants in 1964 was alive 20 1/2 years later. Twenty-nine children had kidneys that had functioned more than 10 years; their mean serum creatinine concentration was 1.7 mg/dL and 24 were fully rehabilitated. Eighteen were more than 2 SD below the mean height of normal children, however. Comparison of survival rates during successive 5-year intervals showed significant improvement in patient survival during the 20-year period and smaller improvements in kidney survival after 1979. Patient survival after living donor transplants during the last 10 years was 100%, and kidney survival during the last 5 years was 92%. Improvement was attributed to the effect of experience, as well as to changes in immunosuppressive therapy in 1972 and the introduction of donor-specific transfusions in 1978.
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Two hundred thirty-nine transplants have been performed following donor-specific blood transfusions (DSTs) since 1978. Graft and patient survival in 1- and 0-haplotype-matched transplants with DST pretreatment is comparable to HLA-identical results through 4 years. Graft survival in 174 consecutive nondiabetic, non-HLA-identical DST recipients shows that the transfusion effect persists for at least 4 years, with graft survival of 88 +/- 3% at that time, compared with 83 +/- 4% in the concurrent HLA-identical group. Graft function, as determined by serum creatinine, was the same in both groups. Graft and patient survival in 20 0-haplotype matched pairs with DST pretreatment is 100% at 2 years. Low-dose Imuran coverage during DST administration (n = 91) was compared with a concurrent group with no Imuran (n = 93). Imuran had its maximum effect in patients undergoing their first transplant and with a pre-DST PRA less than 10% (12% vs. 21% sensitization rate in the no-Imuran group). Imuran did not appear to confer any beneficial effect in primary transplants with high PRAs and in patients undergoing a second or third transplant. The majority of patients formally excluded from transplantation because of a post-DST positive B-warm crossmatch can now be successfully transplanted with the use of flow cytometry analysis to rule out previously undetectable low levels of anti-T-lymphocyte antibodies. Of 62 patients with a positive B-warm crossmatch alone since 1982, 73% had a subsequent negative fluorescence-activated cell sorter (FACS) crossmatch permitting transplantation. Preliminary results of a DST and cyclosporine treatment study are described. In conclusion, a long-term immunologic effect of DST has been confirmed and the indications and considerations for optimum use of the DST protocol have been more clearly defined.
Most family members who are evaluated as kidney donors for children have high reactivity in a mixed lymphocyte culture test and are thus excluded from donation. Fifty children, most of whom had highly reactive mixed lymphocyte cultures with their donors, were challenged with three blood transfusions from their donors before transplantation and were tested for the development of lymphocytotoxic antibodies. Ten children (20%) became sensitized and had a positive T-cell or B-cell crossmatch. Sensitization occurred less frequently in children treated with azathioprine during donor-specific transfusions (11%) than in those not treated (26%), but the difference was not significant. Thirty-seven children received renal transplants from their blood donors after the donor-specific transfusions. There were no deaths, and only two patients had kidney failure. Actuarial kidney survival was 93% after 6 years. The use of donor-specific transfusion has increased the number of related-donor transplants performed and the results have been highly successful.
The chance of achieving successful kidney transplants in diabetic patients was previously limited because few of them had optimally-matched (2-haplotype) related donors. Hence, transplants were usually not carried out until renal failure had already occurred. The application of donor-specific transfusions (DSTs) prior to transplantation to poorly matched donor-recipient pairs (1-haplotype) has been associated with a high success rate for type-I diabetic recipients in our center. The rate of graft survival for 35 consecutive transplants in this category was 88%, 80%, and 73% at 1, 2, and 5 years, respectively. Furthermore, the rate of patient survival was 94%, 90%, and 90% at 1, 2, and 5 years. These patient and graft survival data were without significant difference when compared with the corresponding data for 142 optimally-matched (2-haplotype) related transplants performed without DSTs for nondiabetic recipients, and also when compared with the corresponding data for 130 poorly matched (1 or 0-haplotype) related transplants involving nondiabetic recipients who were prepared for transplantation with DSTs. These good results with DSTs in diabetic recipients emphasize that earlier transplantation utilizing poorly matched related donors should be seriously considered for diabetic patients even before the onset of renal failure, as long as the transplants are carried out in association with DSTs.
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Prospective pretreatment with deliberate DST has afforded MLC reactive related donor-recipient pairs enhanced opportunity for successful transplantation. The sensitization rate in patients receiving DST prior to primary transplantation was 30%, but this sensitization has been generally specific and narrow-those patients developing a positive DSXM do not appear to be jeopardized regarding later cadaver transplantation. Graft survival rates in 86 recipients of kidneys from their blood donors are 95% (1-year) and 93% (2-year). This graft survival rate appears to outweigh the minimal risk of possible unfavorable sensitization. Potentially unsuccessful transplants in immunologically disparate related donor-recipient pairs can be avoided, and the transplants actually performed have enhanced prospects of success.
Two cases of recurrent lupus erythematosus involving renal transplants are described. Neither case showed changes of transplant rejection. The clinical course, serologic tests, and renal histopathologic findings remarkably paralleled those seen during each patient's primary disease presentation. Typical and severe extrarenal manifestations of dermatitis, pleuritis, and polyarthritis were noted before renal allograft lupus involvement. Rapid renofunctional deterioration was halted in one patient by plasmapharesis. In the second patient a more protracted course involving the allograft is anticipated. Although previous experiences suggest that lupus disease activity "burns out" after the development of chronic renal failure, findings from these two cases argue against this presumption. Longer periods of transplant follow-up may show more recurrence of lupus erythematosus.
Evidence has been sought for a genetically determined predisposition among children with juvenile rheumatoid arthritis (JRA) who are also at particular risk for the development of inflammatory eye disease.45 unrelated Caucasian patients (41 female) with early-onset pauciarticular JRA were human leukocyte antigen (HLA) types. 28 of the study group were found to be HLA-DRw5 compared with 16 of 84 controls (X(2), 24.3, P = <0.001). 9 patients were HLA-DRw8 compared with 4 of 84 controls (X(2), 7.51, P = <0.01). Iritis developed in 24 of the 45 children studied, 17 of whom were typed as HLA-DRw5 when compared to controls (X(2), 26.76, P = <0.001) and 6 with iritis typed as HLA-DRw8 (X(2), 9.10, P = <0.01). Antinuclear antibody was found in the serum of 17 of the 28 patients typing as HLA-DRw5 compared with 4 of the 17 who did not have this antigen (X(2), 5.88, P = <0.02). No such association was seen in patients with HLA-DRw8. In a study of linked genes, a delta value of 0.090 was found for HLA-DRw5 with HLA-B12, of 0.070 for DRw5 with HLA-Cw4, and a value of 0.050 for DRw5 and HLA-Bw35. This suggests a linkage disequilibrium between HLA-DRw5 and these two B series alleles, a conclusion which was supported by haplotype analysis in families of 11 of the disease probands. HLA-DRw5 has not previously been reported to be increased in any rheumatic disease group. It is proposed that HLA-DRw5 is a genetic marker defining those at risk for early-onset pauciarticular JRA with iritis.