Bruce O. Barger

Improved survival of primary cadaveric renal allografts in blacks with quadruple immunosuppression.

Black recipients of cadaveric kidneys have been shown to have a lower rate of allograft survival than whites. Data were reviewed from 642 primary cadaveric transplants: results in 276 patients (163 white and 113 black) (group 1) who had received triple therapy (azathioprine-CsA-prednisone, 1985–87) were compared with those in 366 patients (180 white and 186 black) (group 2) receiving quadruple immunosuppres-sion (MALG-azathioprine-CsA-prednisone, 1987–90). Blacks in group 2 had better patient (97% vs. 91%, P=0.03) and graft (77% vs. 55%, P=0.0002) survival at 1 year than in group 1. There was no difference in these parameters among whites in either group. Racial differences in graft survival noted in group 1 disappeared in group 2. While HLA BDR matching improved in group 2 patients (P=0.0001), whites received better matched kidneys than blacks in both groups (P=0.001). HLA matching was associated with improved graft survival only in white recipients of 4 BDR-matched kidneys. In group 1, more blacks than whites had at least one episode of acute rejection (76% vs. 57%, P=0.001); blacks also lost more grafts to acute and chronic rejection. In group 2, there were no racial differences in the number of rejection episodes or immunologic graft losses. Of 14 potential variables examined by parametric analysis, only quadruple therapy significantly reduced risk of graft loss in blacks. Quadruple immuno-suppression improved primary cadaveric renal allograft survival in black recipients, abrogating previously noted racial differences.

Host Factors in Juvenile Periodontitis

This study was undertaken to determine whether defects in leukocyte function or in genes at the MHC play a role in the etiology of either localized (LJP) or generalized (GJP) juvenile periodontitis. Thirteen LJP and five GJP patients (ranging in age from 13 to 22 years) and their matched controls were compared with respect to selected leukocyte functions and HLA phenotypic frequencies. The results of these studies indicated that there were significant decreases in the phagocytic and chemotactic abilities of polymorphonuclear leukocytes (PMN) in both LJP and GJP. All JP patients displayed intrinsic cell defects in chemotaxis compared with controls; in addition, some patients displayed multiple defects, including those which were serum-associated. Also, there appeared to be a significant association between JP and HLA-DR2 and HLA-A33 phenotypes. Fifty percent of the JP patients were HLA-DR2-positive, whereas only six percent of the matched controls were positive. Thirty-six percent of JP patients were HLA-A33-positive, whereas none of the controls was positive. The association seen with DR2 may be due to sampling, since there were no significant differences between the JP cases and a larger unmatched control sample which was not evaluated for periodontal disease. We conclude from these data that increased susceptibility of some patients to a very aggressive and destructive form of periodontal disease (JP) is based on defects in PMN responsiveness. Further investigations are necessary to determine whether these defects are under genetic control.

Evidence for Genetic Admixture as a Determinant in the Occurrence of Insulin-dependent Diabetes Mellitus in U.S. Blacks

SUMMARY In recent years, it has been proposed that genetic admixture may have played a role in the increased frequency of insulin-dependent diabetes mellitus (IDDM) in young U.S. blacks relative to African blacks. In support of this proposal, the similar associations of specific markers of the major histocompatibility complex (MHC) with IDDM in U.S. blacks with respect to U.S. whites have been cited. To determine whether racjal admixture was a factor in the increased prevalence, we did three analyses of admixture. In the first we used nine genetic markers (ABO, Rh, Fy, Hp, Gc, PI, OR, Tfr, and Gm) and determined that there was significantly greater than zero genetic contribution from whites in our sample of U.S. black IDDM patients (9.6 ± 2.3%, P < 0.01) when a sample of U.S. blacks without IDDM was used as one “parental” population. In the next two analyses, we estimated the amounts of genetic contribution from whites in the U.S. blacks with and without IDDM using reported gene frequencies for West African blacks for four genetic markers (ABO, Rh, Fy, and Hp). The estimate of admixture (21.4 ± 2.8%) for the black IDDM sample was greater than that for the U.S. black controls (17.9 ± 2.3%), although the difference was not significant. Our estimate of genetic contribution from whites, 21.4% for black IDDM patients, supports the assumptions of 20% admixture which MacDonald and Rotter and Hodge used to test their respective models for the inheritance of IDDM. These results support the hypothesis that admixture with the white population is, in part, responsible for the increase in prevalence of IDDM seen in U.S. blacks.

Renal retransplantation : the role of race, quadruple immunosuppression, and the flow cytometry cross-match

To assess the impact of quadruple immunosuppression in black and white recipients of cadaver kidney retransplants, we reviewed data from 178 second or subsequent renal allografts performed at our center between 1985 and 1991. Sixty-six black and 102 white recipients were divided into 3 groups: groups 1 and 2 consisted of patients with a negative complement-dependent cytotoxicity (CDC) T cell cross-match, receiving triple drug therapy (CsA-AZA-prednisone) and quadruple immunosuppressive therapy (quad therapy; Minnesota antilymphoblast globulin-CsA-AZA-prednisone), respectively. Group 3 patients also received quad therapy, but, in addition to a negative CDC cross-match, had a negative T cell flow cytometry cross-match (FCXM). Black and white patients in groups 1 and 2 experienced similar graft survival at 1 year, ranging from 47% to 63% (P = NS). In group 3, 1-year graft survival in whites, but not blacks, improved to 82%, with fewer grafts lost to immunologic causes in the first 90 days after transplant. A parametric analysis of potential risk factors identified a significant effect of better HLA-DR matching (P = 0.0005) on improved graft survival, with previous mismatched antigens (P = 0.04), female donor (P = 0.002), and short duration of previous graft (P = 0.05) as risk factors for graft loss. Race and immunosuppressive protocol did not affect graft survival. In group 3, blacks received fewer well-matched kidneys than whites (P = 0.05), which may have contributed to poorer outcomes for black recipients. Nine of 10 patients undergoing retransplantation with a negative CDC cross-match and a positive T cell FCXM suffered graft loss at a median of 26 days after transplant. Thus, quad therapy did not enhance graft survival for either black or white patients undergoing cadaveric retransplantation. Immunologic considerations, including HLA-DR matching and the FCXM, continue to exert a strong influence on outcomes in these high-risk recipients.

A Comparison of OKT3 Monoclonal Antibody and Corticosteroids in the Treatment of Acute Renal Allograft Rejection

The monoclonal antibody OKT3 (Ortho Pharmaceutical, Raritan, NJ) was utilized in two separate protocols for treatment of acute renal allograft rejection in patients receiving cyclosporine, azathioprine, and prednisone for maintenance immunosuppression. In Group I, 54 patients received steroids for primary treatment of acute rejection with OKT3 used for resistant rejections and second rejection episodes. In Group II, 34 patients received OKT3 as primary treatment of acute rejection while steroids were used for rescue and second rejection episodes. OKT3 successfully reversed 82% of initial acute rejection episodes in Group II as compared with a 63% reversal with steroids in Group I. Rescue treatment was required in only 15% of Group II patients compared with 33% of Group I patients. Overall patient survival was 96% and 94%, respectively, for steroid primary and OKT3 primary treatments. Allograft survival at 3 months was identical, 74% in both groups. Based on allograft survival data, OKT3 is equally effective either as primary treatment for allograft rejection, or for rescue therapy if initial corticosteroid treatment fails.

Important risk factors of allograft survival in cadaveric renal transplantation. A study of 426 patients

Multiple risk factors contribute to the allogrnft survival of patients who have cadaveric renal transplantation. A retrospective review of 19 such factors in 426 patients identified race, DR match, B + DR match, number of transplants, and preservation time to have a significant influence. The parametric analysis confirmed the effect to be primarily in the early phase, i.e., first 6 months. All patients received cyclosporine with other methods of immunosupprcssion resulting in an overall 1-year graft survival rate of 66%. The overall 1-year graft survival rate in the white race was 73% and in the black race was 57% (p = 0.002). Allograft survival and DR match showed white recipients with a 1 DR match to have 75% survival at 1 year compared with 57% in the black patient (p = 0.009). If HLA B + DR match was considered, the white recipient allograft survival increased to 76%, 84%, and 88% for 1, 2, and 3 match kidneys by parametric analysis. Patients receiving first grafts had better graft survival (68%) than those undergoing retransplantation (58%) (p = 0.05). Organ preservation less than 12 hours influenced allograft survival with a 78% 1-year survival rate compared with 63% for kidneys with 12–18 hours of preservation. Despite the benefits of B + DR typing, short preservation time, and first transplants to the white recipient, the allograft survival in the black recipient remained uninfluenced by these parameters.

Successful renal allografts in recipients with crossmatch-positive, dithioerythritol-treated negative sera. Race, transplant history, and HLA-DR1 phenotype.

Graft survival was examined in 15 renal allograft recipients from a group of 20 patients with IgM autolymphocytotoxic antibody that could be removed in a crossmatch assay using a reducing agent, dithioerythritol (DTE). The significant differences in this group of 20 patients compared with end-stage renal disease (ESRD) patients lacking autolymphocytotoxic antibodies included an increased frequency of black patients (P = 0.002), a lack of previous transplants (P = 0.003), and an increased frequency of the HLA-DR1 phenotype (P = 0.0001). Sex and the number of transfusions did not appear significant, whereas the cause of ESRD was primarily systemic lupus erythematosus. Fifteen of the 20 patients were transplanted against a positive donor crossmatch. Eleven were recipients of cadaveric kidneys, nine of which are still functioning for periods ranging from 0.5 to 40 months. Two fo the cadaveric recipients died with functional grafts. Four received living-related donor transplants, one of which was lost to acute rejection one month posttransplant, while the remaining three have survived 1.5, 9, and 21 months, respectively. Fourteen patients had immediate allograft function with no hyperacute rejection and only one case of acute tubular necrosis (ATN) was found. In summary, a negative crossmatch using DTE-treated, autologous reactive recipient sera may identify a group of patients who can be transplanted with minimal concern for hyperacute rejection or ATN. In addition to cause of ESRD, race, transplant history, and HLA-DR phenotype may further define this group of transplant candidates having IgM autolymphocytotoxic antibody. Extrapolation of these conclusions to transplant candidates lacking autolymphocytotoxic antibodies is not warranted.

Risk Factors for Gestational Diabetes in Black Population

In a long-term longitudinal study of gestational diabetes mellitus in Black women, risk factors that were identified were age, obesity, a family history of diabetes, and the presence of hypertension. Poor predictors were a history of a previous large-for-date infant, parity, and age at first pregnancy. The prevalence of smooth muscle and nuclear autoantibodies was higher in gestational diabetic subjects. Gestational diabetic subjects who required insulin for glycemic control were more obese, had a lower frequency of the Bf-F phenotype and a higher frequency of the Bf-F1 phenotype, and had a lower frequency of the type 2 allele at the polymorphic locus adjacent to the insulin gene. Restriction-fragmentlength polymorphisms flanking the insulin and apolipoprotein A-l and C-MI genes, although not associated with gestational diabetes mellitus, may be associated with hyperlipidemia and subsequent atherosclerosis.

Population genetic analyses of insulin dependent diabetes mellitus using HLA allele frequencies.

In order to try to detect heterogeneity within insulin dependent diabetes mellitus (IDDM) and to distinguish a mode of inheritance of IDDM, population genetic analyses were performed using HLA allele frequencies. HLA‐A and ‐B typing performed on 231 IDDM individuals and 268 controls from the southeastern U.S. showed significant increases with IDDM in A2, B8, B15 and B18, and significant decreases in Aw23, B7, B14 and B17. The combination of HLA‐B8/B15 showed a greatly increased risk (RR = 25.5). Between the 120 IDDM individuals and 123 controls HLA‐DR typed, HLA‐DR3 and ‐DR4 were significantly increased among the IDDM group and DR2 and DR7 were decreased. The risk for DR3/4 was 29.2. It appeared that the B15 association was secondary to the DR4, but the B8/DR3 association showed no difference. Using the method of Curie‐Cohen, no significant increases in risk were found for the B8/B15 or DR3/DR4 heterozygotes when compared to the respective homozygotes. Using the method of Thomson and Bodmer, the dominant mode of inheritance was excluded for DR4 only. There was a significant increase in B15 and DR4 in those with onset before age 20. No significant differences were found among the DR phenotypes with respect to season.

The effect of erythropoietin and blood transfusions on highly sensitized patients on a single cadaver renal allograft waiting list

The effects of EPO on transfusion requirements and HLA allosensitization were studied in a group of 145 sensitized patients on a single cadaveric renal allograft waiting list. All patients included in the study had PRA levels greater than 40% and at least six months of follow-up after the general availability of EPO. A total of 108 (74%) of these patients received EPO during the study period while 37 (26%) did not. The EPO patients had a much higher incidence of prior transfusions than the non-EPO patients (64% vs. 39% P less than 0.05). During the follow-up period, there was a marked reduction in transfusion incidence in the patients who received EPO from 64% to 14% (P less than 0.05). A lesser and nonsignificant reduction in incidence of transfusions was seen in the non-EPO-EPO patients. Analysis of PRA levels in the EPO and non-EPO groups demonstrated a reduction in PRA levels over time but there was no difference between the two groups. When the patients were divided by the need for transfusions in the follow-up period, a comparison of these two groups demonstrated significant differences. At the six-month follow-up point, patients in the nontransfused group had a significantly lower mean PRA than the transfused patients (49% vs. 62%, respectively, P less than 0.05). Furthermore, a greater number of patients in the nontransfused group had PRA declines greater than or equal to 15% compared with the nontransfused group (56/46% vs. 4/15%, respectively; P = .007). Stepwise logistic regression analysis of possible risk factors for persistent high PRA levels demonstrated that continued transfusion was the only significant factor. This study suggests that the institution of EPO therapy in sensitized patients on a single cadaveric waiting list can result in substantial reduction in the need for on-going transfusions. However, the decline in PRA levels appears to be more closely tied to the avoidance of transfusion rather than to the specific institution of EPO therapy.