Impact of race on renal transplant outcome

The influence of race on the outcome of cadaver renal transplantation (CRT) continues to be controversial even in the cyclosporine era. The present study examines the effect of race in 343 adult CRT performed from 1/1/82 through 10/1/88 with regard to the incidence of delayed function (DF), graft survival (GS), and patient survival (PS). Blacks constituted 38% of the patients. A history of nephrosclerosis secondary to hypertension was more common in blacks, with 51% (67/130) vs. 8% (17/213) in whites, while glomerulonephritis and Type 1 diabetes mellitus were more common in whites. There was no significant difference in the number of HLA (A,B,DR) matches or DR mismatches between whites and blacks. With azathioprine immunosuppression DF was more common in blacks than in whites, 54% (14/26) vs. 20% (11/55) respectively (P less than 0.01). The higher incidence of DF in blacks than in whites on Aza was associated with a significantly lower dose of intraoperative albumin, 0.25 g/kg vs. 0.44 g/kg, respectively (P less than 0.01). Of the Aza treated black recipients who had DF, 79% (11/14) had graft loss within three months, significantly worse than 25% (3/12) with graft loss when immediate function was present (P less than 0.005). Currently, all patients receive at least 0.80 g/kg of albumin intraoperatively and CsA quadruple induction therapy. With the current regimen, black and white recipients of primary CRT recipients have a comparable low incidence of DF of 18% and 22%, respectively. However, DF remains high among repeat black or white recipients: 33% (10/30) and 57% (8/14), respectively. The incidence of rejection within 30 days was similar for black and white recipients during the Aza and CsA eras, 62% vs. 75% and 34% vs. 42% respectively. GS and PS at three months for blacks on Aza were 54% and 89%, respectively, reflecting the corresponding high incidence of DF. This compares with 71% and 97% GS and PS for whites on Aza. Blacks and whites receiving CsA had equivalent 1-year GS and PS: 76% and 92%, respectively. We conclude that, in our center during the Aza era, blacks had a higher incidence of DF and lower GS than whites. With our current intraoperative fluid replacement and CsA immunosuppression, the incidence of DF and GS and PS are equivalent in black and white recipients.     

Ethnic disparity in clinical outcome after heart transplantation is abrogated using tacrolimus and mycophenolate mofetil-based immunosuppression

BACKGROUND: Black American heart transplant recipients receiving cyclosporine-based primary immunoprophylaxis suffer higher rates of allograft rejection with hemodynamic compromise, infections, and posttransplant coronary artery disease. We examined the hypothesis that a combination of tacrolimus and mycophenolate mofetil "resurrects" clinical outcome of black Americans to those seen in white heart transplant recipients. METHODS: Sixty-three adult primary heart transplant recipients were included in this study. Twenty black American and 21 white patients who received tacrolimus-based primary immunoprophylaxis were enrolled in this prospective, observational parallel cohort investigation. A separate group of 22 black American patients were randomly allocated to receive cyclosporine-microemulsion-based primary prophylaxis and served as the control population for assessing outcomes in the black American group. Adjunctive immunosuppression included mycophenolate mofetil and corticosteroids. The primary end-point was the freedom from allograft rejection requiring treatment at 1 year. Secondary end-points included rejection with hemodynamic compromise, and patient or graft survival. Adverse events evaluated included development of infections requiring hospitalization and nonimmunological outcomes including hyperlipidemia, hypertension, and diabetes mellitus (new onset or worsened). RESULTS: Tacrolimus-treated black American patients had greater freedom from allograft rejection requiring treatment at 1 year than those treated with cyclosporine (64% vs. 37%, P=0.01). No differences were noted between tacrolimus-treated black Americans and whites in the primary end point (64% and 67% respectively, P=nonsignificant [NS]). Tacrolimus-based immunosuppression was associated with better 1-year survival in black Americans compared with cyclosporine (95% vs. 73%, P=0.04), and this end point was similar to that achieved in tacrolimus-treated white heart transplant recipients (95%). No differences in infection rates were noted among either group. Cyclosporine-treated black Americans suffered more hyperlipidemia and worse hypertension than tacrolimus-treated patients. CONCLUSIONS: Compared with cyclosporine, an immunosuppressive strategy using tacrolimus in black Americans achieves superior efficacy with regard to allograft rejection, higher allograft survival, and similar safety. Furthermore, tacrolimus-based immunosuppression is similar in immunological efficacy and safety in black Americans and in white heart transplant recipients.     

The impact of the UNOS mandatory sharing policy on recipients of the black and white races--experience at a single renal transplant center.

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.     

Possible contribution of pretransplant immune responder status to renal allograft survival differences of black versus white recipients.

Black end-stage renal disease patients may present as an immunologically higher-risk group for renal allograft transplantation than white ESRD patients. To test this hypothesis, we correlated graft survivals in 124 black and 241 white cyclosporine-prednisone-treated primary cadaveric renal allograft recipients with pre-Tx nonspecific immune responder status (strong vs. weak immune responders), donor-recipient-specific MLC responsiveness, HLA match, and blood transfusion (BT) history. One-, 2- and 3-year patient survival rates of 95%, 94%, and 94% were identical for both groups. However, the 1-, 2-, 3-year graft survival rates for white recipients of 82%, 79%, and 75% were significantly higher than the 70%, 62%, and 55% rates for black recipients (P less than 0.01 for each, respectively). Pre-Tx nonspecific immune response values for blacks were significantly (P less than 0.01) higher than for whites (38% vs. 28% for active T cell; 1.8 vs. 1.3 for TH:TS ratio; 28,581 c.p.m. vs. 14,870 c.p.m. for spontaneous blastogenesis; and a stimulation index (SI) of 34 vs. 20 for panel mixed lymphocyte culture). Additionally, the specific recipient-donor MLC (SI) for black recipients was significantly greater than the specific recipient-donor MLC for white recipients (MLC SI of 40 vs. 18, P less than 0.01). Blacks present as pre-Tx strong immune responders with a greater frequency than whites (90% vs. 66%, P less than 0.01). Moreover, black strong responders experience a poorer 1-year graft survival than white strong responders (67% vs. 80%, P less than 0.01). Even though the pre-Tx BT histories of white and black ESRD patients studied herein were comparable, the immunoregulatory effect of pre-Tx BT was different in white vs. black patients. A significant reduction in TH:TS ratio was observed when comparing 0 vs. 1-4 pre-Tx white patient BT groups, whereas significant changes in TH:TS ratios were not observed until after comparing 0 vs. greater than or equal to 5 pre-Tx black patient BT groups. HLA matching and pre-Tx BT had no impact on improving the graft survivals of these CsA-Pred-treated white or black recipients. These data, therefore, support the hypothesis that black recipients present as an immunologically higher-risk group than white recipients.     

The beneficial effect of blood transfusion and the DR 1 gene dose on renal transplant outcome in blacks

We performed a retrospective analysis of the factors determining renal allograft survival in 70 black recipients from a single center and 1212 black recipients from multicenter registry data. One and two-year graft survival in single-center blacks was comparable to the result achieved in the general population (81% and 77%, respectively). Two-year graft survival in multicenter blacks was significantly worse than nonblacks (73% versus 55%, respectively; P less than 0.01). Graft survival in untransfused blacks receiving cyclosporine was no better than the result achieved during the azathioprine era. A beneficial effect upon graft survival was seen in blacks transplanted at the centers that have consistently displayed the best overall allograft survival over the years. Matching for HLA antigens was consistently poorer in blacks compared with whites and did not confer additive benefit over cyclosporine and blood transfusion. Our data indicate that cyclosporine immunosuppression, blood transfusion, and individual center expertise contribute significantly toward optimal transplant outcome in the higher-risk black end-stage renal disease population.     

Effect of race on renal transplant outcome

Renal transplant outcome was compared in whites and blacks at a single center. All recipients transplanted between 1984 to 1991 were included in this study. White and black recipients were followed for a mean period of 37.6 (1-96) months. The age, sex, follow-up period, immunosuppressive protocol, number of retransplants, HLA mismatches and etiology of renal disease were comparable in the two races. Overall graft survival was lower in black recipients (p=0.0300). Graft survival in all cadaver (p=0.0520) and primary cadaver (p=0.1430) transplants was lower in blacks, though this was not statistically significant. Percentage of graft losses during the follow-up was higher in black 53/108 (49%), than white recipients 82/257 (32%)(p=0.002), as were cadaver graft losses due to rejection, 39/92 (42%) in blacks, 54/190 (28%) in whites (p=0.02). There was no significant difference in graft losses due to rejection between races in the 1 yr post transplant, but there were significantly more graft losses after 1 yr in blacks 16/83 (19%) compared to whites (16/156(10%)(p=0.05). In cadaver grafts functioning for 6 months, subsequent survival was lower in black recipients (p=0.0418). There was lower patient survival in blacks during the mean follow-up period of 37.6 months (1-96). In conclusion, lower graft survival in blacks can be partially explained by fewer LRD transplants in black recipients. Persistent lower graft survival in all black recipients and significantly more losses due to rejection beyond 1 yr may be related to immunological differences, poor compliance, or a combination of both.     

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

Multiple risk factors contribute to the allograft 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 immunosuppression 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.     

Age-matching in renal transplantation.

BACKGROUND: So far, the combined influence of donor age and recipient age on renal allograft survival has not been investigated sufficiently. In this retrospective single-centre study we analysed whether the influence of donor age and recipient age on renal allograft survival are dependent on each other. METHODS: Data from 1269 cadaveric renal allograft transplantations were evaluated. Paediatric donors (<15 years) and paediatric recipients (<15 years) were excluded. Donors and recipients were divided by age: young donors (yd, 55 years, n=176), young recipients (yr, 55 years, n=211). Functional and actual long-term graft survival (8 years) within the four resulting groups was determined: yd/yr (n=926), yd/or (n=167), od/yr (n=132), and od/or (n=44). RESULTS: Univariate analysis showed that long-term graft survival of both, kidneys from young donors (functional, 66.1 vs 52.2%, P=0.004; actual, 53.3 vs 46.2%, P=0.065) and kidneys from old donors (functional, 68.7 vs 22.5%, P=0.07; actual, 57.1 vs 20.8%, P=0.15) was better in old recipients as compared to young recipients. Multivariate regression analysis revealed that actual graft survival of kidneys from old donors was significantly reduced in young recipients (od/yr) as compared to all other groups (P=0.001; RR, 1. 97; 95% CI, 1.32-2.94). In this group of patients, graft loss was mainly due to acute (33.7%) and chronic (24.0%) rejection. CONCLUSION: Transplantation of kidneys from 'old' donors into 'young' recipients should be avoided, and these kidneys should be given to age-matched recipients.     

Benefits of quadruple immunosuppressive therapy in recipients of living related donor kidneys. A review of 855 operations.

Eight hundred fifty-five living related donor transplant recipients were analyzed according to 15 potential risk factors with regard to patient and graft survival according to immunosuppression. Group I, 1968 to 1983, (n = 440 patients) received azathioprine and prednisone; group II, 1984 to 1987, (n = 229 patients) received triple therapy--azathioprine, prednisone, and cyclosporine; and group III, 1988-1991, (n = 186 patients), quadruple therapy--azathioprine, prednisone, cyclosporine, and Minnesota antilymphocyte globulin. Three important risk factors included immunosuppression, tissue typing, and race. Groups II and III had improved allograft survival over group I (p = 0.03). Patients with two haplotype matches had similar survival in all three groups. Kidney survival in one-haplotype-matched recipients improved in group II and was equal to that of the two-haplotype-matched patients in group III. Cyclosporine improved allograft survival in both races when combined with azathioprine and prednisone. Quadruple therapy improved early survival in one-haplotype black patients, even though long-term results remained better in whites. Cyclosporine did not improve graft survival in two-haplotype recipients. The addition of cyclosporine and quadruple therapy did not increase morbidity and mortality rates.     

Cadaveric renal transplantation in the cyclosporine and OKT3 eras

With advances in clinical immunosuppression, results in organ transplantation continue to improve. During a 52-month period, 507 cadaver renal transplants were performed, including 435 primary and 72 nonprimary transplants. All patients were managed with quadruple immunosuppression (prednisone, azathioprine, sequential MALG and cyclosporine). Our experience is divided into pre-OKT3 (n = 228) and OKT3 (n = 279) eras. All kidneys were harvested locally and preserved with pulsatile machine perfusion. The mean duration of preservation was 30.1 hours, with an organ utilization rate of 98.1%. The preservation-related dialysis rate was 13.6%, and primary nonfunction occurred in 8 kidneys (1.6%). Actuarial patient survival in primary and secondary transplant recipients was 90% at 3 years. Overall primary graft survival was 81.6% and nonprimary graft survival, 61.1%. However, the current OKT3 era is characterized by improved patient survival (98% vs 90%, p = 0.001) and primary graft survival (91% vs 80%, p = 0.002) at 1 year when compared with the previous era. Forty-nine patients have received OKT3 therapy, with 31 grafts (63.3%) successfully rescued. Cadaveric renal transplantation with machine preservation, quadruple therapy, and OKT3 rescue is associated with excellent early graft function, reduced acute rejection, and improved patient and allograft survival, even in high-risk recipients.     

Declining Influence of Race on the Outcome of Living-Donor Renal Transplantation

A racial disparity in graft survival for renal transplant recipients has been documented for both cadaveric and living-donor transplants. In the present single-center study we analyzed graft survival by race for recipients of living-donor kidney transplants in three eras: 1985-89, 1990-94, and 1995-2000. There was an intensification of the immunosuppressant regimen beginning in 1996, such that all patients received cyclosporine or tacrolimus with mycophenolate and prednisone. Graft survival was analyzed using the Cox proportional hazards model. There were 79 black recipients and 210 white recipients with no difference in mean age, degree of HLA matching, or proportion of recipients with diabetes as the cause of end-stage renal disease. Using all data from 1985 to 2000, graft survival was significantly better for whites vs. blacks adjusted for age, gender, diabetes, era of the transplant, and haplotype match (p = 0.05). However, when analyzed by era, there was a temporal trend for a progressive decrease in the racial disparity in graft survival. In confirmation of this effect, there was a significant race-era interaction (p = 0.01) on multivariable Cox proportional hazards analysis. The most recent data from the United States Renal Data System (USRDS) show a similar decrease in the racial difference in 1-year graft survival. We conclude that the influence of race on living-donor graft survival is diminishing over time.     

Survival of cadaveric renal allografts in Hispanic as compared with Caucasian recipients

Evaluation of allograft survival rates revealed a significantly better overall graft survival in Hispanic (n = 66) as compared with Caucasian (n = 38) recipients of primary cadaveric renal transplants. There were no significant differences between the Hispanic and Caucasian cadaveric recipient groups in terms of patient survival, pretransplant transfusion status, immunosuppressive protocols, rejection therapy, mean age, or frequency of diabetes mellitus. Cadaveric donor ethnic origin (i.e., Caucasian or Hispanic) did not significantly alter graft survival rates in either recipient ethnic group. Although Caucasian patients with splenectomies had better cadaveric graft survival than Caucasian graft recipients without splenectomies (P = .02), splenectomy had no significant effect on the renal allograft survival rate in Hispanics. Other factors that were evaluated and found not to correlate significantly with cadaveric graft survival rates were donor recipient HLA matching (A, B, or DR), and panel reactivities of recipient pregraft serum samples. In contrast to the superior cadaveric renal allograft survival in Hispanic as compared with Caucasian recipients, 1-haplotype-matched or 2-haplotype-matched living-related renal allografts had comparable graft survival rates in Caucasian and Hispanic recipients. These results indicate that Hispanics without splenectomy enjoy a cadaveric renal allograft survival rate superior to nonsegregated populations (treated with conventional immunosuppression) reported elsewhere.     

An evaluation of HLA cross-reactive group matching on graft survival in deceased donor kidney recipients

Since September 20, 1999, our organ procurement organization (OPO) serving an ethnically diverse local distribution area has allocated kidneys using a cross-reactive group (CREG)-based variance. This variance awards 7 points for 0-CREG,0-DR mismatches and 6 points for 0-A,B mismatches in addition to points given for waiting time (3) and panel-reactive antibodies (PRA) > or = 80% (3). Previously, we have shown that awarding points for 0-CREG,0-DR mismatches in kidney allocation improves the access to HLA-matched transplants for racial groups, especially for the black race. In this study, we evaluated if there are outcome benefits as well. One- and 3-year uncensored graft survival data and analyses for the influence of HLA mismatching on graft outcome in black and nonblack recipients were provided by Scientific Registry of Transplant Recipients (SRTR). Overall, 1-year graft survival was 87.4% and not significantly different for blacks (86.1%, n = 467) vs nonblacks (88.8%, n = 730); 3-year graft survival was 74.6% and significantly lower P = .0001 for blacks (68.5%, n = 480) vs nonblacks (78.4%, n = 765). No significant advantage was observed for either the black or nonblack recipients in any of the HLA-mismatched categories, including the 0-CREG,0-DR mismatch group. An HLA matching effect also was not seen when data were stratified for patients nonsensitized (PRA < or = 10%) and sensitized (PRA > 10%) at the time of transplantation, except for the improved graft survival in sensitized nonblack recipients of 0- A,B,DR-mismatched grafts. Of the patients who lost their grafts and returned to the waiting list for retransplantation, the 0-A,B,DR mismatched were the least sensitized group (6%, n = 16), and there was a trend for less sensitization in the 0-CREG,0-DR-mismatched group (33%, n = 9), compared to those with other HLA mismatches (68%, n = 137). Thus, based on 1-year and 3-year follow-up data, there are no apparent graft outcome benefits for either CREG matching or conventional HLA matching in our service area, except for sensitized nonblack recipients receiving 0-A,B,DR-mismatched grafts. Such benefits may become more apparent with longer follow-up.     

Long-term results of a controlled prospective study with transfusion of donor-specific bone marrow in 57 cadaveric renal allograft recipients

Experimental studies have shown that antilymphocyte globulin combined with transfusion of donor-specific bone marrow cells can induce partial tolerance to allograft tissue. We have adapted these protocols to clinical use and present the results of 57 cadaveric renal allograft recipients who received Minnesota ALG followed by the transfusion of cryopreserved donor-specific bone marrow. A group of 54 patients received the contralateral kidney and similar immunosuppression without the marrow transfusion and serve as controls. Both groups received quadruple immunosuppression with MALG, cyclosporin, azathioprine, and prednisone. In the bone marrow group, after a 10-14 day induction course of ALG, cryopreserved marrow was transfused on the seventh day after the last dose of ALG. The median follow-up in both groups is 16 months, (range 2.5-33 months). Six grafts have been lost in the bone marrow group, (three rejections, 2 deaths [Cr 2.0, 2.3], 1 recurrent disease). In the control group 16 grafts have been lost (13 rejections, 3 deaths [Cr 1.7, 2.5, 3.0]). Five patients in the control group have biopsy-proved chronic rejection compared to one in the bone marrow group. 17 patients in the bone marrow group have been tapered off the prednisone, and three of these patients have had mild late rejection episodes without graft loss. The two groups were compared for differences in the number of rejection episodes, estimated renal plasma flow, glomerular filtration rate, and urine protein. No differences were found. The allograft survival of the bone marrow group was significantly greater (P less than .01) than the control group. The graft survival rates for the bone marrow group at 12 and 18 months were 90% (confidence limits [CL] 85-94) and 85% (CL 78-90), respectively. In the the control group the 12 and 18 month allograft survival rates were 71% (CL 63-78) and 67% (CL 58-74), respectively. The survival in the control group was similar to our overall transplant experience with quadruple therapy. Mixed lymphocyte culture analysis shows a trend to diminished donor-specific responsiveness in the bone marrow group. The use of cryopreserved donor-specific bone marrow is associated with improved allograft survival in cadaveric kidney allograft recipients. However, a more effective induction protocol is needed to reduce the overall number of rejection episodes.     

Progress in renal transplantation. A single center study of 3359 patients over 25 years.

OBJECTIVE: The study analyzed 3359 consecutive renal transplant operations for patient and graft survival, including living related, cadaveric, and living unrelated patients. The analysis was separated into three groups according to immunosuppression and date of transplant. SUMMARY BACKGROUND DATA: Improvements in renal transplantation in the past 25 years have been the result of better immunosuppression, organ preservation, and patient selection. METHODS: A single transplant center's experience over a 25-year period was analyzed regarding patient and graft survival. Potential risk factors included patient demographics, tissue typing, donor characteristics, number of transplants, acute and chronic rejection, acute tubular necrosis, primary disease, and malignancy. RESULTS: The primary cause of graft loss was rejection. Improvement in cadaveric graft survival since 1987 with quadruple therapy was not apparent in living donor patients. Race continued to be a negative factor in graft survival. Avoiding previous mismatched antigens and the use of flow cytometry improved allograft survival. The leading cause of death in the past 7 years in cadaveric recipients was cardiac (52%). CONCLUSIONS: Improved graft survival in the past 25 years was related to 1) advances in immunosuppression, 2) better methods of cytotoxic antibody detection, and 3) human lymphocyte antigen match.     

The contribution of adhesion molecule expression in donor kidney biopsies to early allograft dysfunction.

BACKGROUND: Renal allograft rejection is associated with the expression of adhesion molecules on vascular endothelial and tubular epithelial cells. METHODS: To assess whether the number of cell adhesion molecules expressed in donor kidneys can predict early rejection or delayed graft function, kidney biopsies from 20 living and 53 cadaveric kidney donors were obtained before engraftment into the recipients and the expression of the cell adhesion molecules intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and endothelial leukocyte adhesion molecule (E-selectin) were determined by immunohistochemistry. RESULTS: All biopsies from living donors showed significantly lower expression of ICAM-1 and VCAM-1 compared to biopsies from cadaveric donors. There was no difference in the expression of adhesion molecules on tubular cells between transplants with primary function compared to allografts with early rejection in living donated kidneys (ICAM-1: 2+/-8 vs. 3+/-8%; VCAM-1: 9+/-7 vs. 1+/-1%), as well as in cadaveric kidneys (ICAM-1: 38+/-29 vs. 39+/-38%; VCAM-1: 55+/-27 vs. 48+/-29%). The expression of ICAM-1 molecules on tubular cells was determined to be a predictor for the occurrence of delayed graft function in cadaveric kidneys (ICAM-1: 65+/-24* vs. 38+/-29% delayed graft versus primary graft function). No delayed graft function occurred in recipients of living donated kidneys. CONCLUSIONS: These data suggest that adhesion molecule expression in donor biopsies is not a predictor for early allograft rejection, but can be used as a marker for the development of postischemic acute renal allograft failure.     

Renal allograft outcomes in African American versus Caucasian transplant recipients in the tacrolimus era

METHODS: Between January 1995 and December 1999, 185 kidney transplants were performed with tacrolimus (TAC)-based immunosuppression including 120 African American (AA, 65%) and 65 Caucasian recipients (C, 35%). Mean follow-up was 34 months. The AA group was characterized by a higher incidence of renal disease due to hypertension (72% AA vs 37% C, P <.001), pretransplant dialysis (95% AA vs 82% C, P =.003), waiting time (1.9 years AA vs 1.1 years C, P =.02), cadaveric donation (88% AA vs 68% C, P =.01), HLA mismatching (mean 3.5 AA vs 2.4 C, P <.001), and delayed graft function (DGF; 50% AA vs 22% C, P =.001). RESULTS: The 5-year actuarial patient and graft survival rates were 96% AA versus 83% C (P = NS) and 83% AA versus 75% C, (P = NS), respectively. The incidence of acute rejection (21% AA vs 12% C, P = NS) and mean time to acute rejection (12 months AA vs 11 months C) were similar. Although the incidence of chronic allograft nephropathy (CAN) was comparable (7% AA vs 5% C), the mean time to CAN was shorter in AA recipients (18 months AA vs 37 months C, P =.03). CONCLUSIONS: These results suggest marked improvement in post-transplant outcomes in the TAC era in patients with multiple immunologic risk factors including AA ethnicity, cadaveric donor source, DGF, and HLA mismatching.     

Outcomes at 7 years post‐transplant in black vs nonblack kidney transplant recipients administered belatacept or cyclosporine in BENEFIT and BENEFIT‐EXT

Clinical outcomes are generally worse for black vs nonblack renal allograft recipients. In BENEFIT and BENEFIT‐EXT, recipients were randomized to belatacept more intense‐based, belatacept less intense‐based, or cyclosporine‐based immunosuppression. At year 7, belatacept was associated with superior graft survival vs cyclosporine in BENEFIT (recipients of living or standard criteria deceased donor kidneys); belatacept was associated with similar graft survival vs cyclosporine in BENEFIT‐EXT (recipients of extended criteria donor kidneys). In both studies, renal function was superior for belatacept‐treated vs cyclosporine‐treated patients. Seven‐year outcomes were examined by race post hoc in each study. The effect of race and treatment on time to death or graft loss was compared using Cox regression. The interaction between treatment and race was also considered. Glomerular filtration rate (GFR) was estimated from months 1 to 84 using a repeated‐measures model. In total, 8.3% (55/666) and 13.1% (71/543) of patients in BENEFIT and BENEFIT‐EXT, respectively, were black. Time to death or graft loss was similar in blacks and nonblacks. For both subgroups, estimated mean GFR increased over 7 years for belatacept, but declined for cyclosporine. Outcomes were similar in belatacept‐treated black and nonblack patients. Due to the small number of black patients, these results must be interpreted with caution.     

Improved renal function in sirolimus-treated renal transplant patients after early cyclosporine elimination

BACKGROUND: Sirolimus (Rapamune; SRL) in combination with cyclosporine (CsA) reduces the incidence of acute rejection episodes in renal allograft recipients. This study evaluated whether renal function could be improved by elimination of CsA from an SRL-based regimen. METHODS: This phase 2, open-label, controlled, randomized study was conducted at 17 centers in the United States and Europe. Two hundred forty-six first cadaveric renal allograft recipients were enrolled, and 197 were randomized to full-dose CsA (microemulsion) plus fixed-dose SRL (2 mg/day; group A, n=97) or reduced-dose CsA plus concentration-controlled SRL (troughs 10-20 ng/mL; group B, n=100). Most patients with acute tubular necrosis-delayed graft function that resolved later than posttransplantation day 7 were not randomized but were assigned to a third group (nonrandomized, n=49) and received up to 5 mg per day of SRL as part of their individualized treatment regimen. All patients received standard doses of corticosteroids. At the end of posttransplantation month 2, eligible patients (those not treated for rejection within 3 weeks) in group B had CsA tapered and eliminated over the subsequent 4 to 6 weeks. RESULTS: At 12 months after transplantation, renal function was significantly better in the CsA-elimination arm. In patients who were on therapy and who had not experienced an acute rejection episode before month 6, serum creatinine level was significantly lower (1.38 mg/dL vs. 1.82 mg/dL, P < 0.001) and calculated glomerular filtration rate (Nankivell method) was significantly higher (73.5 mL/min vs. 57.1 mL/min, P < 0.001) in group B than in group A. In the intention-to-treat population, rates of biopsy-confirmed acute rejection at 12 months were similar between groups A and B (18.6% vs. 22.0%, respectively; P = 0.598). In addition, graft survival (92.8% and 95.0%) and patient survival (96.9% and 96.0%) rates at 12 months were not significantly different between groups A and B, respectively. Furthermore, there were no significant differences between black and nonblack recipients within treatment groups in terms of rejection rates and graft survival at 12 months. Black recipients in group B had better serum creatinine levels at 12 months compared with black recipients in group A (1.55 mg/dL vs. 2.69 mg/dL, respectively, P = 0.011), as did nonblack recipients in group B compared with nonblack recipients in group A (1.53 mg/dL vs. 1.75 mg/dL, respectively, P = 0.055). Black patients in group A had higher mean serum creatinine levels (2.69 mg/dL) than nonblack patients in group A (1.75 mg/dL, P = 0.028). Hypertension, edema, hypomagnesemia, and dyspnea were reported significantly less frequently in patients randomly assigned to undergo CsA elimination compared with patients in group A (P < 0.05); group B patients had a significantly greater (P < 0.05) incidence of abnormal liver function tests, diarrhea, hypokalemia, and thrombocytopenia. CONCLUSION: Concentration-controlled SRL with early elimination of CsA is safe and results in improved renal function. Reduced exposure to CsA does not result in a clinically significant increase in the incidence of acute rejection episodes. This is true for both black and nonblack recipients. SRL may be used to reduce the exposure of renal allograft recipients to the nephrotoxic effects of CsA.     

Immunosuppression without calcineurin inhibition: optimization of renal function in expanded criteria donor renal transplantation

Abstract: Introduction: To assess the efficacy of calcineurin inhibitor (CNI)‐free immunosuppression vs. calcineurin‐based immunosuppression in patients receiving expanded criteria donor (ECD) kidneys. Patient and methods: Thirteen recipients of ECD kidneys were enrolled in this pilot study and treated with induction therapy and maintained on sirolimus, mycophenolate mofetil (MMF) and prednisone. A contemporaneous control group was randomly selected comprised of 13 recipients of ECD kidneys who had been maintained on CNI plus MMF and prednisone. Results: For the study group vs. the control group, two‐yr graft survival was 92.3% vs. 84.6% (p = NS), two‐yr patient survival was 100% vs. 92.3% (p = NS) and the acute rejection rates were 23% vs. 31% (p = NS), respectively. Renal function was significantly better in the study group compared with control up to the six‐month mark, after which, it remained numerically but not statistically significant. Complications were more common in the study group, but serious adverse events requiring discontinuation were rare. Conclusion: This pilot study demonstrates that CNI‐free regimens can be safely implemented in patients receiving ECD kidneys with excellent two‐yr patient and graft survival and good renal allograft function. Longer follow‐up in larger randomized controlled trials are necessary to establish these findings.