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PURPOSE: Iron overload unexplained by dietary or medicinal iron excess, transfusion, or sideroblastic anemia has been described infrequently in Americans of African descent. The purpose of this study was to characterize iron overload attributable to excessive iron absorption in African Americans. PATIENTS AND METHODS: In a community hematology and medical oncology practice during the interval 1990 to 1993, we identified and evaluated a series of cases comprised of 6 men and 1 woman, with a mean age of 55 +/- 14 (SD) years (range 33 to 69). Data on clinical features, serum iron parameters, liver and body iron stores, evaluations of anemia, human leukocyte antigen (HLA) typing, and family studies were analyzed. RESULTS: Among our patients, the serum iron parameters were: iron concentration 26 +/- 13 mumol/L, transferrin saturation 59 +/- 21%, and ferritin concentration 1,588 +/- 1,053 micrograms/L. Clinical abnormalities observed included weakness and fatigue, decreased libido and impotence, hepatopathy, arthropathy, diabetes mellitus, hypogonadotrophic hypogonadism, and hyperpigmentation. Hepatic parenchymal cell iron deposits were increased in each of the 6 patients studied, and Kupffer cell iron deposits were prominent in 4. The occurrence of iron overload was verified by liver iron quantification and therapeutic phlebotomy. Four subjects had alpha-thalassemia minor; 2 others had hemoglobin S and C traits. No proband had HLA-A3 positivity. Four probands had other family members with iron overload. CONCLUSIONS: In comparison with Caucasians with hemochromatosis, our patients have slightly lower mean values of serum iron concentration and transferrin saturation, more Kupffer cell iron deposits, a higher incidence of thalassemia and hemoglobinopathy, and infrequent positivity for HLA-A3. Iron overload in African Americans appears to be more similar to that in certain sub-Saharan African natives than to hemochromatosis.

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BACKGROUND AND METHODS: Seventy-six heart transplants in 73 patients were studied for the formation of lymphocytotoxic panel-reactive antibodies after transplantation. Treatment of patient serum with dithioerythritol was used to discriminate between antibodies of the immunoglobulin M and immunoglobulin G isotypes. Human leukocyte antigen specificities of immunoglobulin G panel reactive antibodies were determined by the pattern of reactivity with the cell panel used in the panel-reactive antibodies determinations. A total of 465 panel-reactive antibodies determinations were made during the first year after transplantation. RESULTS: Mean panel-reactive antibodies values were highest during the first posttransplantation month. Positive dithioerythritol-treated panel-reactive antibodies values were rare after the first month after transplantation. Multivariable analysis indicated that previous pregnancy and positive cytomegalovirus serologic analysis predicted a higher dithioerythritol-treated panel-reactive antibodies within the first 3 months. No decrease in actuarial survival, increase in cumulative rejection episodes, or increase in the incidence of coronary artery disease at 1 year was seen in patients with a standard panel-reactive antibodies greater than 10% or among patients with dithioerythritol-treated panel-reactive antibodies greater than 0%. A significant and major increase in rejection-related death or retransplantation occurred among 11 patients in whom donor human leukocyte antigen specific antibodies of the immunoglobulin G isotype were detected during the first posttransplantation year (p = 0.02). Two of the 11 patients died of refractory rejection and 3 and 6 months after transplantation, whereas one patient underwent retransplantation for refractory rejection at 13 months and subsequently died. CONCLUSIONS: (1) Posttransplantation serial standard panel-reactive antibodies or dithioerythritol-treated panel-reactive antibodies are not predictive of rejection-related mortality unless the specificity is determined to be antidonor HLA; (2) routine dithioerythritol-treated panel-reactive antibodies studies are advisable during the first month after transplantation, and, if positive (> 10%), antidonor human leukocyte antigen specificity should be determined; (3) detection of recipient immunoglobulin G anti-donor human leukocyte antigen antibodies after heart transplantation identifies a group at high risk for serious allograft rejection and should prompt more intensive rejection surveillance and consideration for additional immunotherapy.

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Many studies have demonstrated the usefulness of flow cytometry crossmatching (FC-XM) for selection of regraft recipients, and more recently this assay has been shown to correlate with allograft survival in primary cadaveric transplant patients. The need now exists for a practical antibody screening procedure which uses the same methodology. We describe here a simple and sensitive method to screen for HLA antibodies by FC using a pool of 6 cells selected to cover the 14 serological crossreacting groups defined by Rodey. Screenings of 367 sera (255 primary transplant sera, 112 regraft sera) received for monthly antibody testing were performed by both pooled cell FC and complement-dependent cytotoxicity (CDC) assays. Forty of these sera were also FC-screened using a panel of 16 individual cells for comparison with the pooled cell FC screenings. Analysis indicated a strong correlation between the pooled FC-PRA and the individual cell panel FC-PRA (P = .0001) with mean values of 60% and 73%, respectively. Only 2 of the 40 sera screened by both FC methods resulted in PRAs that differed by > 40%. The majority (82%) of the primary patients did not exhibit HLA antibodies by CDC--however, 22% of the CDC negative patients were positive by flow cytometry. Females were more likely to be positive by FC (35%) than males (16%) (P = .0001). Similarly, black patients were more likely to have FC-demonstrable antibodies (28%) than white candidates (14%) (P = .014). The regraft patients who tested positive by either or all methods had a mean PRA for CDC, pooled FC-PRA, and individual cell FC-PRA of 40, 75, and 85, respectively. FC-PRA proved to be a more sensitive technique in both primary and regraft patients.

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HLA mismatch has been shown to influence survival after heart transplantation. No large multicenter study has examined the effect of HLA mismatch on cardiac allograft rejection. HLA mismatch and other potential risk factors for rejection were analyzed in data from 27 institutions (1719 patients) participating in the Cardiac Transplant Research Database between January 1, 1990, and June 30, 1992. Complete HLA information on the A, B, and DR loci was available for both donor and recipient in 1190 patients. Of these, 619 (52%) had five or six mismatches; 68 (6%) had zero, one, or two mismatches. The mean number of mismatches was 4.4 and did not differ, regardless of donor-recipient race match (4.3 versus 4.8, p = 0.19). According to multivariate analysis, risk factors for time to first rejection included younger recipient age (p < 0.0001), female gender of both donor and recipient (p < 0.0006), number of HLA mismatches (p = 0.013) and black recipient race (p < 0.004). Patients with zero, one, or two mismatches (n = 67) had a 54% freedom from rejection at 1 year versus 36% for patients with three or more mismatches (n = 1005, p = 0.02). HLA mismatch number did not affect time to first rejection or rejection frequency among black patients. Risk factors (by multivariate analysis) for death or retransplantation because of rejection included female recipient gender (p = 0.008) and black recipient race (p = 0.006). The probability of rejection-related death or retransplantation by 2 years was 0% with zero, one, or two HLA mismatches versus 5% for three to six mismatches (p = 0.14). These findings should stimulate further investigation of methods to clarify the HLA effect in heart transplantation and eventually the use of HLA typing in donor-recipient selection.

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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.

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The impact of the United Network for Organ Sharing mandatory sharing policy on a large transplant center procuring kidneys primarily from caucasians while serving a pool of prospective recipients composed mainly of blacks is described. This policy requires that all 6-antigen-matched and phenotypically identical donor kidneys be shipped to the appropriately matched recipients. The study consisted of 49 kidneys from 25 cadaveric donors; one kidney was unusable. In general, the 33 recipients of the mandatorily shared kidneys were caucasian (94%), unsensitized (70%), and first-time transplants (73%). Allograft survival for the 24 first-time recipients was 100% (mean graft survival = 11.3 months). Of the 9 regraft kidneys, 2 have failed (mean graft survival = 11.9 months) due to chronic rejection. In comparison, the 16 paired kidneys transplanted into non-6-antigen-matched recipients exhibited a 1-year graft survival of 80% versus 92% for the 33 recipients of mandatorily shared kidneys (P = 0.01). These 16 recipients were composed of more blacks (38%), fewer regrafts (6%), and most were unsensitized (75%). All 25 cadaveric donors were caucasians with very common HLA types. Thus, kidneys provided by the UNOS mandatory sharing policy had excellent allograft survival, and the recipients were largely unsensitized caucasians receiving their first kidney. The low number of blacks receiving allografts under this policy may be due to two factors. First, the histocompatibility differences between black recipients and the primarily caucasian cadaveric donor pool limit the number of kidneys available to blacks. Secondly, blacks do not have access to the best-matched kidneys, in part due to few black donors, their best source for well-matched kidneys. Thus, the mandatory sharing program is of clear benefit to the recipients of these well-matched kidneys; however, for a local program servicing a waiting list composed of 64% blacks the policy has been of limited value. In contrast, over 50% of local cadaveric transplants are into black recipients in a waiting time of 197 days, one third the national average for blacks. In conclusion, this study supports efforts to improve graft survival through matching but emphasizes the need to broaden our efforts in all areas of research and organ procurement to serve the entire recipient population, regardless of race.

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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.

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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 immunosuppression (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 immunosuppression improved primary cadaveric renal allograft survival in black recipients, abrogating previously noted racial differences.

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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.

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In conclusion we find that white cadaveric recipients of renal allografts have clearly benefited from the use of CsA. Matching for the major histocompatibility antigens, especially HLA-B + DR, is also associated with improved allograft survival in whites. For black cadaveric recipients there was no significant improvement in allograft survival with the use of CsA nor with matching for HLA. In contrast, for recipients of LRD kidneys both races appear to benefit from the use of CsA over conventional therapy. Consequently, it is clear that with the excellent allograft survival in LRD black recipients that matching can have a significant beneficial effect. However, the differences in survival between the races of cadaveric recipients suggest that for blacks the use of CsA cannot overcome the inherent genetic or physiologic differences that may exist. These results suggest that blacks should be targeted for concentrated study, the benefits of which would be to increase our understanding of potential factors influencing allograft survival in a group that comprises an increasingly larger proportion of candidates on waiting lists throughout the United States. 1. Overall renal allograft survival in CsA-treated black recipients is significantly lower than in comparable white recipients. The major period of allograft loss is in the first 6 months after which the rates of allograft loss for blacks and whites are similar. 2. There was a 12% increase in allograft survival in CsA-treated cadaveric recipients compared to pre-CsA-treated recipients. Allograft survival in white recipients has increased 15% whereas for black recipients there was only a 5% improvement over the azathioprine-prednisone treatment group. 3. Overall, there was a significantly improved graft survival for primary transplants compared to retransplants. Renal allograft survival in black CsA-treated recipients of primary transplants was significantly lower than in comparable whites, whereas there was no significant difference in graft survival between black and white recipients of retransplants. 4. Allograft survival rates in black and white recipients of kidneys from living-related donors were not significantly different from each other in either the non-CsA or the CsA immunotherapy group. 5. Overall there was improved allograft survival with increased matching for HLA-DR or B + DR compared to a zero match in CsA-treated recipients. Significantly, the effect of matching for HLA-DR or B + DR was seen only in white recipients.(ABSTRACT TRUNCATED AT 400 WORDS)

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