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Late Acute Rejection is More Prevalent Among African-American Renal Allograft Recipients and is Frequently Associated With Allograft Loss
Late Acute Rejection is More Prevalent Among African-American Renal Allograft Recipients and is Frequently Associated With Allograft Loss E.M. Vasquez, E. Benedetti, and R. Pollak
L
ATE acute rejection (LAR) episodes following renal transplantation have been reported to be readily reversible with antirejection treatment and are commonly associated with medication noncompliance and suboptimal cyclosporine (CyA) bloods levels.1–3 Our clinical experience with a rather large African-American population has led us to suspect that African-American race may be an additional risk factor for the development of LAR. The purpose of this analysis was to assess the effect of African-American race on the prevalence and clinical outcome of LAR among renal allograft recipients.
MATERIALS AND METHODS We retrospectively reviewed the medical records of all HLAmismatched renal allograft recipients transplanted during a 10-year period to identify those patients with LAR. All patients included in this analysis must have received sustained CyA and prednisone 6 azathioprine-based therapy following transplantation. Patients experiencing allograft failure within the first 6 months of transplant and patients lost to follow-up were excluded from this analysis. For purposes of this analysis, LAR was defined as acute rejection occurring more than 6 months posttranasplant. The immunosuppressive regimens utilized at our center have been previously described.4 In brief, patients were maintained on CyA from the time of transplant. CyA doses were titrated to maintain blood levels between 150 to 200 ng/mL (high-performance liquid chromatography [HPLC]) for the first 2 months posttransplant, 100 to 150 ng/mL between 2 and 6 months posttransplant, and 50 to 100 ng/mL beyond 6 months posttransplant. Prednisone at a dose of 1 mg/kg/d was initiated on the first postoperative day and tapered over 6 months to a dose of 0.2 mg/kg/d. Patients receiving triple therapy received azathioprine at a dose of 1 to 2 mg/kg/d. All episodes of LAR were documented by percutaneous needle biopsy and were evaluated to determine the histologic severity of acute rejection and for evidence of concurrent chronic rejection. Chronic rejection was defined by findings of interstitial fibrosis, glomerular sclerosis, and intimal proliferation or vascular occlusion. Rejections were treated initially with intravenous bolus doses of methylprednisolone (500 mg/d for 3 days) or oral prednisone (2 mg/kg/d rapidly tapered to 0.3 mg/kg/d). Patients with known noncompliance were routinely admitted to the hospital and treated with methylprednisolone boluses. Patients resistant to corticosteroid therapy or those with moderate to severe rejection on histology received either antithymocyte globulin Þ antilymphocyte globulin (ATG/ALG; 15 to 20 mg/kg/d 3 10 days) or OKT3 (5 mg/d 3 10
days). The response to antirejection treatment was assessed in all patients. Clinical response to antirejection therapy was assessed as complete (return to prerejection serum creatinine level 6 10%) or partial (decline in serum creatinine level, but still above prerejection baseline). Treatment failures were defined by a progressive decline in renal function evidenced by a persistent increase in serum creatinine level following antirejection treatment or allograft failure requiring the initiation of chronic dialytic treatment (hemodialysis or chronic ambulatory peritoneal dialysis). Patients with LAR were divided into two groups, the AA group consisting of 27 African-American patients and the non-AA group consisting of 17 non-African American patients. Within each group the following parameters were also evaluated: (1) rejection episodes were evaluated for the time of occurrence posttransplant; (2) history of one or more early rejection episodes; (3) time of allograft loss; and (4) medication noncompliance. Medication noncompliance was defined as an unexpectedly low CyA blood level (,50 ng/mL HPLC) based on prior levels and/or dosage titration. Patients who admitted missing multiple doses of CyA were also defined as noncompliant. AA and non-AA patients were compared with respect to age, sex, type of transplant (cadaveric vs livingrelated), number of transplants, HLA match, and level of panelreactive antibodies. Statistical analysis was performed utilizing the Student’s t test and chi-square testing as appropriate. Statistically significant differences were defined by a P , .05.
RESULTS
There were 274 valuable patients receiving sustained CyA, prednisone, 6 azathioprine-based therapy. The incidence of LAR in our patient population was 16%. Of those patients with LAR, 61.5% (27 of 44) were AA and 38.6% (17 of 44) were non-AA (P , .05). The demographic and immunologic characteristics of the two groups are compared in Table 1. Mean time to LAR was 345 6 253 days in AA vs 348 6 235 days in non-AA (P . .05). In both AA and non-AA, LAR was associated with medication noncompliance and chronic rejection in approximately 50% of cases (P . .05; see Table 1). LAR was preceded by an early acute rejection episode in 55.6% of AA and in 58.8% of non-AA From the University of Illinois at Chicago, Chicago, Illinois Address reprint requests to Eva M. Vasquez, PharmD, BCPS, University of Illinois at Chicago, College of Pharmacy, 833 S Wood St (m/c 886), Chicago, IL 60612.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)00196-1
Transplantation Proceedings, 30, 1173–1175 (1998)
1173
1174
VASQUEZ, BENEDETTI, AND POLLAK Table 1. Comparison of the AA Group and the Non-AA Group
Mean age (y 6 SD) Sex (M/F) Primary/retransplant (n) Donor (cadaveric/living-related) PRA .30% (n) HLA match (A/B/DR) 0 1 2 Time to LAR (d 6 SD) Biopsy findings (n)* Acute rejection Acute 1 chronic rejection Histologic severity of acute rejection (n)* Mild/moderate Severe Response to therapy (n)† Complete Partial None Noncompliance (n)
AA (n 5 27)
Non-AA (n 5 17)
P
36.9 6 13.0 20/7 22/5 26/1 2
33.8 6 14.2 7/10 16/1 16/1 4
..05 ..05 ..05 ..05 ..05 ..05
16/11/9 9/14/15 2/2/3 345 6 253
9/8/5 7/7/8 1/2/4 348 6 235
..05
10 17
8 8
..05 ..05
25 2
14 2
..05 ..05 5.06
10 7 10 14
9 6 2 7
..05
Abbreviations: PRA, panel-reactive antibody. *Biopsy result not available for one patient in the non-AA group. † P 5 .06 for comparison of AA and non-AA patients with no response to therapy.
(P . .05). The characteristics of LAR are compared in Table 1. AA tended to respond less to antirejection treatment compared to non-AA (37% failure rate in AA vs 11% failure rate in non-AA; P 5 .06). LAR was associated with immediate graft loss (within 1 month of LAR) in 26% of AA compared with 6% of non-AA (P 5 .09). Overall, 70% of AA with LAR subsequently lost their grafts compared to 35% of non-AA (P , .05). Mean time to graft loss following LAR was 338 6 381 days in AA patients vs 637 6 389 days in non-AA patients (P . .05).
DISCUSSION
The adverse impact of AA race on renal allograft survival remains somewhat controversial. While this group of patients has been identified as a high-risk population with poor allograft outcomes, the exact reasons for inferior survival rates noted in this population remain ill defined. It has been argued that socioeconomic issues such as level of education, unemployment, and lack of familial support contribute to noncompliance with medications and clinic visits which can culminate in acute rejection and subsequent allograft loss.5,6 Other factors which have been noted to influence long-term allograft outcome include HLA matching and inherent racial differences in immunologic responsiveness.7,8 Kerman et al8 have demonstrated that AA exhibited a stronger immune response when compared to Caucasian transplant recipients. We and others have previously demonstrated that AA renal allograft recipients ex-
hibit an increased rate of early acute rejection.9,10 However, the impact of AA race on the development of LAR has not been previously investigated. LAR episodes following renal transplantation are commonly associated with medication noncompliance, suboptimal CyA bloods levels, and are generally readily reversible with antirejection treatment.1–3 In our heterogenous patient population, LAR occurred at a greater frequency in AA vs non-AA recipients. LAR was observed in 61.5% of AA compared to 38.6% of non-AA. LAR was not always associated with medication noncompliance in our study population. This observation supports the hypothesis that a greater intrinsic immune responsive state may be a primary determinant of long-term allograft outcome in AA. In agreement with previous reports,1–3 LAR in non-AA was associated with an 89% reversal rate. However, among AA, the response rate to antirejection treatment was only 63%. Moreover, these episodes of rejection were frequently associated with graft loss. The basis for the relative differences in response rates in LAR between AA and non-AA remains to be defined. While the presence of chronic irreversible rejection might have been expected to contribute to some degree to the overall response rate, this did not appear to be an important factor in our patient population, as there was a similar frequency of chronic rejection in the non-AA group as in the AA group with a 90% reversal rate in the non-AA group. In conclusion, while medication noncompliance may contribute to the development of LAR in approximately 50% of patients, AA race appears to be an independent risk factor. Our findings indicate that LAR is more prevalent in
LATE ACUTE REJECTION
1175
AA patients. Furthermore, these rejection episodes tend to be less responsive to antirejection treatment and are frequently associated with allograft loss.
6. Schweizer RT, Rovelli M, Palmeri D, et al: Transplantation 55:51, 1993
REFERENCES
8. Kerman RH, Kimball PM, Van Buren CT, et al: Transplantation 51:338, 1991
1. Prieto C, Pulido F, Rodriguez-Paternina E, et al: Transplant Proc 24:35, 1992 2. Johnson HK: Transplant Proc 18(suppl 1):198, 1986 3. Rao KV, Rose JK: Transplantation 40:631, 1985 4. Vasquez EM, Pollak R: Transplantation 60:885, 1995 5. Butkus DE, Meydrech EF, Raju SS: N Engl J Med 327:840, 1992
7. Starzl TE, Demetris AJ, Trucco M: Transplant Proc 25:2450, 1993
9. Benedetti E, Freels SA, Coady NT, et al: Am J Surg 172:56, 1996 10. Katznelson S, Gjertson DW, Cecka JM: In Cecka JM, Terasaki PI (eds): Clinical Transplants 1995. Los Angeles, Calif: UCLA Tissue Typing Laboratory; 1996, p 379
L
ATE acute rejection (LAR) episodes following renal transplantation have been reported to be readily reversible with antirejection treatment and are commonly associated with medication noncompliance and suboptimal cyclosporine (CyA) bloods levels.1–3 Our clinical experience with a rather large African-American population has led us to suspect that African-American race may be an additional risk factor for the development of LAR. The purpose of this analysis was to assess the effect of African-American race on the prevalence and clinical outcome of LAR among renal allograft recipients.
MATERIALS AND METHODS We retrospectively reviewed the medical records of all HLAmismatched renal allograft recipients transplanted during a 10-year period to identify those patients with LAR. All patients included in this analysis must have received sustained CyA and prednisone 6 azathioprine-based therapy following transplantation. Patients experiencing allograft failure within the first 6 months of transplant and patients lost to follow-up were excluded from this analysis. For purposes of this analysis, LAR was defined as acute rejection occurring more than 6 months posttranasplant. The immunosuppressive regimens utilized at our center have been previously described.4 In brief, patients were maintained on CyA from the time of transplant. CyA doses were titrated to maintain blood levels between 150 to 200 ng/mL (high-performance liquid chromatography [HPLC]) for the first 2 months posttransplant, 100 to 150 ng/mL between 2 and 6 months posttransplant, and 50 to 100 ng/mL beyond 6 months posttransplant. Prednisone at a dose of 1 mg/kg/d was initiated on the first postoperative day and tapered over 6 months to a dose of 0.2 mg/kg/d. Patients receiving triple therapy received azathioprine at a dose of 1 to 2 mg/kg/d. All episodes of LAR were documented by percutaneous needle biopsy and were evaluated to determine the histologic severity of acute rejection and for evidence of concurrent chronic rejection. Chronic rejection was defined by findings of interstitial fibrosis, glomerular sclerosis, and intimal proliferation or vascular occlusion. Rejections were treated initially with intravenous bolus doses of methylprednisolone (500 mg/d for 3 days) or oral prednisone (2 mg/kg/d rapidly tapered to 0.3 mg/kg/d). Patients with known noncompliance were routinely admitted to the hospital and treated with methylprednisolone boluses. Patients resistant to corticosteroid therapy or those with moderate to severe rejection on histology received either antithymocyte globulin Þ antilymphocyte globulin (ATG/ALG; 15 to 20 mg/kg/d 3 10 days) or OKT3 (5 mg/d 3 10
days). The response to antirejection treatment was assessed in all patients. Clinical response to antirejection therapy was assessed as complete (return to prerejection serum creatinine level 6 10%) or partial (decline in serum creatinine level, but still above prerejection baseline). Treatment failures were defined by a progressive decline in renal function evidenced by a persistent increase in serum creatinine level following antirejection treatment or allograft failure requiring the initiation of chronic dialytic treatment (hemodialysis or chronic ambulatory peritoneal dialysis). Patients with LAR were divided into two groups, the AA group consisting of 27 African-American patients and the non-AA group consisting of 17 non-African American patients. Within each group the following parameters were also evaluated: (1) rejection episodes were evaluated for the time of occurrence posttransplant; (2) history of one or more early rejection episodes; (3) time of allograft loss; and (4) medication noncompliance. Medication noncompliance was defined as an unexpectedly low CyA blood level (,50 ng/mL HPLC) based on prior levels and/or dosage titration. Patients who admitted missing multiple doses of CyA were also defined as noncompliant. AA and non-AA patients were compared with respect to age, sex, type of transplant (cadaveric vs livingrelated), number of transplants, HLA match, and level of panelreactive antibodies. Statistical analysis was performed utilizing the Student’s t test and chi-square testing as appropriate. Statistically significant differences were defined by a P , .05.
RESULTS
There were 274 valuable patients receiving sustained CyA, prednisone, 6 azathioprine-based therapy. The incidence of LAR in our patient population was 16%. Of those patients with LAR, 61.5% (27 of 44) were AA and 38.6% (17 of 44) were non-AA (P , .05). The demographic and immunologic characteristics of the two groups are compared in Table 1. Mean time to LAR was 345 6 253 days in AA vs 348 6 235 days in non-AA (P . .05). In both AA and non-AA, LAR was associated with medication noncompliance and chronic rejection in approximately 50% of cases (P . .05; see Table 1). LAR was preceded by an early acute rejection episode in 55.6% of AA and in 58.8% of non-AA From the University of Illinois at Chicago, Chicago, Illinois Address reprint requests to Eva M. Vasquez, PharmD, BCPS, University of Illinois at Chicago, College of Pharmacy, 833 S Wood St (m/c 886), Chicago, IL 60612.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)00196-1
Transplantation Proceedings, 30, 1173–1175 (1998)
1173
1174
VASQUEZ, BENEDETTI, AND POLLAK Table 1. Comparison of the AA Group and the Non-AA Group
Mean age (y 6 SD) Sex (M/F) Primary/retransplant (n) Donor (cadaveric/living-related) PRA .30% (n) HLA match (A/B/DR) 0 1 2 Time to LAR (d 6 SD) Biopsy findings (n)* Acute rejection Acute 1 chronic rejection Histologic severity of acute rejection (n)* Mild/moderate Severe Response to therapy (n)† Complete Partial None Noncompliance (n)
AA (n 5 27)
Non-AA (n 5 17)
P
36.9 6 13.0 20/7 22/5 26/1 2
33.8 6 14.2 7/10 16/1 16/1 4
..05 ..05 ..05 ..05 ..05 ..05
16/11/9 9/14/15 2/2/3 345 6 253
9/8/5 7/7/8 1/2/4 348 6 235
..05
10 17
8 8
..05 ..05
25 2
14 2
..05 ..05 5.06
10 7 10 14
9 6 2 7
..05
Abbreviations: PRA, panel-reactive antibody. *Biopsy result not available for one patient in the non-AA group. † P 5 .06 for comparison of AA and non-AA patients with no response to therapy.
(P . .05). The characteristics of LAR are compared in Table 1. AA tended to respond less to antirejection treatment compared to non-AA (37% failure rate in AA vs 11% failure rate in non-AA; P 5 .06). LAR was associated with immediate graft loss (within 1 month of LAR) in 26% of AA compared with 6% of non-AA (P 5 .09). Overall, 70% of AA with LAR subsequently lost their grafts compared to 35% of non-AA (P , .05). Mean time to graft loss following LAR was 338 6 381 days in AA patients vs 637 6 389 days in non-AA patients (P . .05).
DISCUSSION
The adverse impact of AA race on renal allograft survival remains somewhat controversial. While this group of patients has been identified as a high-risk population with poor allograft outcomes, the exact reasons for inferior survival rates noted in this population remain ill defined. It has been argued that socioeconomic issues such as level of education, unemployment, and lack of familial support contribute to noncompliance with medications and clinic visits which can culminate in acute rejection and subsequent allograft loss.5,6 Other factors which have been noted to influence long-term allograft outcome include HLA matching and inherent racial differences in immunologic responsiveness.7,8 Kerman et al8 have demonstrated that AA exhibited a stronger immune response when compared to Caucasian transplant recipients. We and others have previously demonstrated that AA renal allograft recipients ex-
hibit an increased rate of early acute rejection.9,10 However, the impact of AA race on the development of LAR has not been previously investigated. LAR episodes following renal transplantation are commonly associated with medication noncompliance, suboptimal CyA bloods levels, and are generally readily reversible with antirejection treatment.1–3 In our heterogenous patient population, LAR occurred at a greater frequency in AA vs non-AA recipients. LAR was observed in 61.5% of AA compared to 38.6% of non-AA. LAR was not always associated with medication noncompliance in our study population. This observation supports the hypothesis that a greater intrinsic immune responsive state may be a primary determinant of long-term allograft outcome in AA. In agreement with previous reports,1–3 LAR in non-AA was associated with an 89% reversal rate. However, among AA, the response rate to antirejection treatment was only 63%. Moreover, these episodes of rejection were frequently associated with graft loss. The basis for the relative differences in response rates in LAR between AA and non-AA remains to be defined. While the presence of chronic irreversible rejection might have been expected to contribute to some degree to the overall response rate, this did not appear to be an important factor in our patient population, as there was a similar frequency of chronic rejection in the non-AA group as in the AA group with a 90% reversal rate in the non-AA group. In conclusion, while medication noncompliance may contribute to the development of LAR in approximately 50% of patients, AA race appears to be an independent risk factor. Our findings indicate that LAR is more prevalent in
LATE ACUTE REJECTION
1175
AA patients. Furthermore, these rejection episodes tend to be less responsive to antirejection treatment and are frequently associated with allograft loss.
6. Schweizer RT, Rovelli M, Palmeri D, et al: Transplantation 55:51, 1993
REFERENCES
8. Kerman RH, Kimball PM, Van Buren CT, et al: Transplantation 51:338, 1991
1. Prieto C, Pulido F, Rodriguez-Paternina E, et al: Transplant Proc 24:35, 1992 2. Johnson HK: Transplant Proc 18(suppl 1):198, 1986 3. Rao KV, Rose JK: Transplantation 40:631, 1985 4. Vasquez EM, Pollak R: Transplantation 60:885, 1995 5. Butkus DE, Meydrech EF, Raju SS: N Engl J Med 327:840, 1992
7. Starzl TE, Demetris AJ, Trucco M: Transplant Proc 25:2450, 1993
9. Benedetti E, Freels SA, Coady NT, et al: Am J Surg 172:56, 1996 10. Katznelson S, Gjertson DW, Cecka JM: In Cecka JM, Terasaki PI (eds): Clinical Transplants 1995. Los Angeles, Calif: UCLA Tissue Typing Laboratory; 1996, p 379