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Early graft dysfunction developed within one week after renal allograft
Early Graft Dysfunction Developed Within One Week After Renal Allograft S.C. Kim, H.J. Jang, S.K. Kim, T.H. Kim, E.S. Yoo, J.G. Jung, and D.J. Han
T
HE EARLY posttransplant period is critical for the short and long-term outcome of renal allografts. It has been reported that more than one third of cadaveric allografts showed primary nonfunction or some degree of dysfunction.1 The so-called complex syndrome of early graft dysfunction (EGDF) includes functional impairment owing to poor donor conditions, inadequate organ preservation, rejection episodes, and drug toxicity. The clinical course of the transplanted kidney with EGDF is variable and unpredictable. Humoral factors have been reported by many authors to be a major cause of EGDF, but the interpretation of histologic findings is difficult.2 Owing to the absence of reliable clinical and laboratory methods, the cause of EDGF is undetermined in most cases. We investigated the risk factors and clinical outcomes of EGDF in renal allografts. MATERIALS AND METHODS Between January 1991 and August 1998, we examined 30 patients with EGDF among 750 (548 living donors and 202 cadaveric donors) renal allograft recipients. Mean age was 33.5 years and the male-to-female ratio was 17:13. 15 patients (2.7%) received organs from living donors and 15 (7.4%) from cadaveric donors. EGDF was defined as either grafts that did not function at all after transplant or grafts that failed because of any other functional impairment within 1 week, excluding mechanical factors, with or without hemodialysis. Cyclosporine (CyA), prednisolone, and azathioprine were used as standard triple immunosuppression. Patients with acute graft rejection were treated with solumedrol pulse therapy initially and with OKT3 monoclonal antibody (MAb) as a second line antirejection therapy until October 1998. From November 1998, FK 506 and/or mycophenolate mofetil (MMF, CellCept) were used as rescue therapy in EGDF for solumedrolresistant graft rejection or for replacing CyA because of acute tubular damage. Students t and chi-square tests were used to compare the variables, graft survival was analyzed using the Kaplan-Meier method and compared by log-rank test, and risk factor for grant survival was analyzed by regression analysis.
than grafts from living donors (40.0% vs 15.2%, P ⬍ .05). Donor type (living or cadaveric) was the most independent risk factor among several (age, sex, HLA matching, pretransplant transfusion, transplantation). On histological examination of the transplanted kidney, acute vascular rejection (AVR), either humoral or cell mediated, was present in nine cases, acute tubulointerstitial cellular rejection (ATIR) in five, CyA toxicity in three, acute tubular necrosis (ATN) in two, and other nonspecific histology in three. EGDF developed 1.75 days (mean) after transplant in ATN, 2.3 in AVR, and 4.5 in ATIR. Peak serum creatinine was 9.7 mg/dL in ATN, 9.8 in AVR, and 4.9 in ATIR. Increment of serum creatinine per day revealed 0.46 mg/dL in ATN, 1.2 in AVR, and 0.93 in ATIR. Solumedrol pulse therapy was effective in three cases of ATIR. However, OKT3 therapy was in vain in treatment of five cases of AVR and two cases of severe ATN. FK 506 and/or MMF was effective in 12 of 13 cases (92.3%) of ATN. These 12 cases included 4 cases of AVR (100%), 2 of ATIR (100%), and 6 of CyA toxicity and ATN (100%). The 5-year graft survival rate was 37% in patients with EGDF and 84% in patients without EGDF. DISCUSSION
With respect to the pathogenesis of EGDF, in some studies, such as the US Renal Data System3 or Europe Multicenter Study Group,4 immunologic factors were neglected. Cold ischemic time has been identified as the most important single factor. However, our study, in which cold ischemic time was less than 24 hours in most cases, demonstrated that immunologic reasons, especially AVR, can be a leading cause of EGDF. The higher incidence of AVR in EGDF in cadaveric compared with living donors suggests that previous harvest injury to the donor organ can lead to acute accelerated rejection. Feucht et al5 reported that the humoral immune system contributes to EGDF in about 50% of cases. Changes in the histology of the transplanted
RESULTS
The mean onset of EGDF was 3.2 days after transplant. Fifteen were from living donors and 15 were from cadaveric donors (2.7% vs 7.4%, P ⬍ .05). Of 71 graft failures during the study period, 17 (22.8%) were associated with EGDF. Renal grafts from cadaveric donors were more vulnerable
From the Departments of Surgery (S.C.K., H.J.J., S.K.K., T.H.K., D.J.H.) and Pathology (E.S.Y., J.G.J.), Ulsan University and Asan Medical Center, Seoul, Korea. Address reprint requests to Dr S.C. Kim, Department of Surgery, Asan Medical Center, 388-1, Poongnap-dong, Songpaku, Seoul 138-736, Korea.
0041-1345/00/$–see front matter PII S0041-1345(00)01477-9
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1886
Transplantation Proceedings, 32, 1886–1887 (2000)
EARLY GRAFT DYSFUNCTION
kidney from ATN or AVR implicate the difficulties in differential diagnosis of EGDF in renal allografts. Even though not major differences, we can see some comparative factors such as early onset of ATN, more increment of serum creatinine in AVR, and a preponderance of cadaveric donors in ATN and AVR. The efficacy of OKT3 for reversal of AVR was disappointing in our series in contrast to the successful outcome of FK 506 and/or MMF rescue therapy. It may represent the superiority of FK 506 over OKT3 with respect to preventing antibody-mediated humoral rejection. FK 506 as a second line rescue therapy for solumedrol-resistant AVR showed an excellent reversal rate in our series as reported by some authors. Our data on the reversal of ATN to normal renal function implicate the possibility that FK 506 therapy could be an excellent strategy for controlling rejection during the ATN period, minimizing the lethal OKT3-related pulmonary complications. In conclusion, in cadaveric donor kidney transplants, a more prudent preoperative approach is mandatory due to the vulnerability to EGDF from complex preoperative risk
1887
factors. AVR can be the most serious problem due to difficulties in diagnosis and treatment, especially in antibody-mediated rejection. In addition, FK 506 and/or MMF might be a more efficient immunosuppressive strategy in the treatment of AVR and prevention of rejection during the period of ATN compared with conventional OKT3 antibody therapy.
REFERENCES 1. United States Renal Data System 1991 Annual Data Report: Am J Kidney Dis 18:61, 1991 2. Feucht HE, Lederer SR, Kluth B: Transplantation 65:757, 1998 3. Ojo AO, Wolfe RA, Held DJ, et al: Transplantation 63:968, 1997 4. Koning OHJ, Ploeg RJ, Van Bockel JM, et al: Transplantation 63:1620, 1997 5. Feucht HE, Schneeberger H, Hillebrand G, et al: Kidney Int 43:1333, 1993
T
HE EARLY posttransplant period is critical for the short and long-term outcome of renal allografts. It has been reported that more than one third of cadaveric allografts showed primary nonfunction or some degree of dysfunction.1 The so-called complex syndrome of early graft dysfunction (EGDF) includes functional impairment owing to poor donor conditions, inadequate organ preservation, rejection episodes, and drug toxicity. The clinical course of the transplanted kidney with EGDF is variable and unpredictable. Humoral factors have been reported by many authors to be a major cause of EGDF, but the interpretation of histologic findings is difficult.2 Owing to the absence of reliable clinical and laboratory methods, the cause of EDGF is undetermined in most cases. We investigated the risk factors and clinical outcomes of EGDF in renal allografts. MATERIALS AND METHODS Between January 1991 and August 1998, we examined 30 patients with EGDF among 750 (548 living donors and 202 cadaveric donors) renal allograft recipients. Mean age was 33.5 years and the male-to-female ratio was 17:13. 15 patients (2.7%) received organs from living donors and 15 (7.4%) from cadaveric donors. EGDF was defined as either grafts that did not function at all after transplant or grafts that failed because of any other functional impairment within 1 week, excluding mechanical factors, with or without hemodialysis. Cyclosporine (CyA), prednisolone, and azathioprine were used as standard triple immunosuppression. Patients with acute graft rejection were treated with solumedrol pulse therapy initially and with OKT3 monoclonal antibody (MAb) as a second line antirejection therapy until October 1998. From November 1998, FK 506 and/or mycophenolate mofetil (MMF, CellCept) were used as rescue therapy in EGDF for solumedrolresistant graft rejection or for replacing CyA because of acute tubular damage. Students t and chi-square tests were used to compare the variables, graft survival was analyzed using the Kaplan-Meier method and compared by log-rank test, and risk factor for grant survival was analyzed by regression analysis.
than grafts from living donors (40.0% vs 15.2%, P ⬍ .05). Donor type (living or cadaveric) was the most independent risk factor among several (age, sex, HLA matching, pretransplant transfusion, transplantation). On histological examination of the transplanted kidney, acute vascular rejection (AVR), either humoral or cell mediated, was present in nine cases, acute tubulointerstitial cellular rejection (ATIR) in five, CyA toxicity in three, acute tubular necrosis (ATN) in two, and other nonspecific histology in three. EGDF developed 1.75 days (mean) after transplant in ATN, 2.3 in AVR, and 4.5 in ATIR. Peak serum creatinine was 9.7 mg/dL in ATN, 9.8 in AVR, and 4.9 in ATIR. Increment of serum creatinine per day revealed 0.46 mg/dL in ATN, 1.2 in AVR, and 0.93 in ATIR. Solumedrol pulse therapy was effective in three cases of ATIR. However, OKT3 therapy was in vain in treatment of five cases of AVR and two cases of severe ATN. FK 506 and/or MMF was effective in 12 of 13 cases (92.3%) of ATN. These 12 cases included 4 cases of AVR (100%), 2 of ATIR (100%), and 6 of CyA toxicity and ATN (100%). The 5-year graft survival rate was 37% in patients with EGDF and 84% in patients without EGDF. DISCUSSION
With respect to the pathogenesis of EGDF, in some studies, such as the US Renal Data System3 or Europe Multicenter Study Group,4 immunologic factors were neglected. Cold ischemic time has been identified as the most important single factor. However, our study, in which cold ischemic time was less than 24 hours in most cases, demonstrated that immunologic reasons, especially AVR, can be a leading cause of EGDF. The higher incidence of AVR in EGDF in cadaveric compared with living donors suggests that previous harvest injury to the donor organ can lead to acute accelerated rejection. Feucht et al5 reported that the humoral immune system contributes to EGDF in about 50% of cases. Changes in the histology of the transplanted
RESULTS
The mean onset of EGDF was 3.2 days after transplant. Fifteen were from living donors and 15 were from cadaveric donors (2.7% vs 7.4%, P ⬍ .05). Of 71 graft failures during the study period, 17 (22.8%) were associated with EGDF. Renal grafts from cadaveric donors were more vulnerable
From the Departments of Surgery (S.C.K., H.J.J., S.K.K., T.H.K., D.J.H.) and Pathology (E.S.Y., J.G.J.), Ulsan University and Asan Medical Center, Seoul, Korea. Address reprint requests to Dr S.C. Kim, Department of Surgery, Asan Medical Center, 388-1, Poongnap-dong, Songpaku, Seoul 138-736, Korea.
0041-1345/00/$–see front matter PII S0041-1345(00)01477-9
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1886
Transplantation Proceedings, 32, 1886–1887 (2000)
EARLY GRAFT DYSFUNCTION
kidney from ATN or AVR implicate the difficulties in differential diagnosis of EGDF in renal allografts. Even though not major differences, we can see some comparative factors such as early onset of ATN, more increment of serum creatinine in AVR, and a preponderance of cadaveric donors in ATN and AVR. The efficacy of OKT3 for reversal of AVR was disappointing in our series in contrast to the successful outcome of FK 506 and/or MMF rescue therapy. It may represent the superiority of FK 506 over OKT3 with respect to preventing antibody-mediated humoral rejection. FK 506 as a second line rescue therapy for solumedrol-resistant AVR showed an excellent reversal rate in our series as reported by some authors. Our data on the reversal of ATN to normal renal function implicate the possibility that FK 506 therapy could be an excellent strategy for controlling rejection during the ATN period, minimizing the lethal OKT3-related pulmonary complications. In conclusion, in cadaveric donor kidney transplants, a more prudent preoperative approach is mandatory due to the vulnerability to EGDF from complex preoperative risk
1887
factors. AVR can be the most serious problem due to difficulties in diagnosis and treatment, especially in antibody-mediated rejection. In addition, FK 506 and/or MMF might be a more efficient immunosuppressive strategy in the treatment of AVR and prevention of rejection during the period of ATN compared with conventional OKT3 antibody therapy.
REFERENCES 1. United States Renal Data System 1991 Annual Data Report: Am J Kidney Dis 18:61, 1991 2. Feucht HE, Lederer SR, Kluth B: Transplantation 65:757, 1998 3. Ojo AO, Wolfe RA, Held DJ, et al: Transplantation 63:968, 1997 4. Koning OHJ, Ploeg RJ, Van Bockel JM, et al: Transplantation 63:1620, 1997 5. Feucht HE, Schneeberger H, Hillebrand G, et al: Kidney Int 43:1333, 1993