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Recovery of Graft Function Early Posttransplant Determines Long-Term Graft Survival in Deceased Donor Renal Transplants
Recovery of Graft Function Early Posttransplant Determines Long-Term Graft Survival in Deceased Donor Renal Transplants M. Hassanain, J.I. Tchervenkov, M. Cantarovich, P. Metrakos, S. Paraskevas, D. Keith, D. Baran, M. Fernandez, R. Mangel, and P. Chaudhury ABSTRACT Introduction. Because kidneys show remarkable resilience and can recover function, we examined the impact on long-term graft survival in deceased donor renal transplants of both immediate graft function (IGF) and the rate of renal function recovery over the first 3 months after transplantation. Methods. We included all cadaveric renal transplants from 1990 to 2007 (n ⫽ 583). Delayed graft function (DGF) was defined as the need for dialysis in the first 7 days posttransplant. Slow graft function (SGF) and IGF were defined by serum creatinine falls of ⬍20% or ⬎20% in the first 24 hours posttransplant respectively. Recovery of renal function was expressed as either the best creatinine clearance (CrCl) in the first 3 months post–renal transplantation (BCrCl3mos) as calculated using the Cockcroft-Gault formula or as a percentage of actual versus expected value (as calculated from the donors’ CrCl at procurement). Results. There were 140 (23.6%) subjects who received extended criteria donor (ECD) organs. The overall graft survival at 1 and 5 years was 87.8% and 74%, respectively. The 5-year graft survivals for patients with IGF, SGF, and DGF were 85%, 76%, and 54%, respectively (P ⬍ .02). ECD kidneys showed twice the DGF rate (49% vs 23%, P ⬍ .001). BCrCl-3mos of ⬍30 mL/min displayed a 5-year graft survival of 34%; 30 to 39 mL/min, 72%; 40 to 49 mL/min, 85%; and ⬎50 mL/min, 82% (P ⬍ .001). Similarly, a recovery within 90% of expected CrCl in the first 3 months posttransplant correlated with 5-year graft survival of 81%; a recovery of 70% to 90%, with 65%; and a recovery of ⬍70%, with 51% (P ⬍ .001). Conclusion. Early graft function in the first 3 months showed a significant impact on long-term graft survival after deceased donor renal transplantation.
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IDNEY TRANSPLANTATION from diseased donors can be complicated with up to 40% of patients developing delayed graft function (DGF). Patients experiencing DGF are at increased risk for acute rejection and for inferior graft survival. Multiple donor and recipient characteristics have been identified as risk factors for DGF. Creatinine clearance (CrCl) at the time of donation is one important factor that affects donor selection and kidney allocation. Moreover, CrCl in the postoperative period has been used as an indirect marker of long-term graft survival in studies of immunosuppression protocols.1–3 Kidneys show remarkable resilience, recovering function even after prolonged periods of DGF. Recovery from DGF reflects an important intrinsic characteristic of the transplanted kidney. In this study, we examined the impact on 0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2008.10.046 124
long-term graft survival of both early graft function and the rate of recovery after transplantation among deceased donor renal transplantations. PATIENTS AND METHODS We included all cadaveric renal transplants performed at our center between 1990 and 2007. Immunosuppression induction consisted of thymoglobulin (85%; median 18.5 vials), methylpredFrom the Departments of Surgery (M.H., J.I.T., M.C., P.M., S.P., M.F., P.C.) and Medicine (M.C., D.K., D.B., R.M.), McGill University, Montreal, Quebec, Canada. Address reprint requests to Dr Mazen Hassanain, MBBS, McGill University, Department of Surgery, 687 Pine Avenue West, Montreal, Quebec H3A1A1, Canada. © 2009 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 41, 124 –126 (2009)
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nisolone, and mycophenolate mofetil (51%) or azathioprine (47%). Calcineurin inhibitors (tacrolimus 55% or cyclosporine 45%) were introduced when adequate kidney function was achieved within the first 30 postoperative days, namely, a serum creatinine below ⬍ 3.0 mg/dL. Expanded criteria donors (ECDs) were defined according to United Network for Organ Sharing criteria. All other donors were considered to be standard criteria donors (SCDs). DGF was defined as anyone who required a form of dialysis in the first week after transplantation. Slow graft function (SGF) was defined as a functioning kidney with a serum creatinine fall of less than 20% from baseline in the first 24 hours after transplantation. Immediate graft function (IGF) was defined as a functioning kidney with a serum creatinine fall of more than 20% from baseline in the first 24 hours after transplantation. Recovery of renal function (RFR) was expressed in two ways, as the best CrCl in the first 3 months post–renal transplantation (BCrCl-3mos) as calculated using the Cockcroft-Gault formula or as a percentage of actual CrCl versus the expected value as calculated by the donors’ CrCl at procurement. Data for graft survival were non-death-censored. Kaplan-Meier curves were used for graft survival analysis.
RESULTS
Five hundred eighty-three (583) patients were included in the analysis. Of these, 140 patients (23.6%) received kidneys from ECDs. IGF was present in 50.3% of the patients, SGF in 19.8%, and DGF in 29.1%. ECD kidneys had twice the DGF rate (49%) compared with SCD kidneys (P ⬍ .001). Overall graft survival at 1 and 5 years was 87.8% and 74%, respectively. Patients with IGF showed a 5-year graft survival of 85%, whereas patients with SGF or DGF experiment 5-year survivals of 76% and 54%, respectively (P ⬍ .02). There was no difference in the impact of early graft function or 5-year graft survival between ECD and SCD kidneys. RFR showed an impact on 5-year graft survivals and projected half-lives. BCrCl-3mos ⬍ 30 mL/min displayed 1and 5-year graft survivals of 47% and 34%; BCrCl-3mos values between 30 and 39 mL/min, 92% and 72%; BCrCl3mos values between 40 and 49 mL/min, 98% and 85%. While BCrCl-3mos value of ⬎ 50 mL/min showed 1- and 5-year survivals of 96% and 82% (Table 1, Fig 1). Similar results were observed with the percentage of CrCl. A recovery of 90% or more of expected CrCl in the first 3 months posttransplant was associated with graft survivals at 1 and 5 years of 94% and 81%; recovery of 70%
to 90%, 91% and 65%; while less than 70%, 63% and 51% (Table 1, Fig 2). The projected half-lives for these kidneys was 10 months for BCrCl-3mos ⬍ 30 mL/min; 9.5 years for 30 to 39 mL/min; 13.5 years for 40 to 49 mL/min; and 13 years for more than 50 mL/min (P ⬍ .001). Similar results were observed when tested for the percentage of CrCl, as the half-lives for kidneys with 90% or more recovery was 12.5 years; 70% to 90%, 10.5 years; and less than 70%, 5.5 years (P ⬍ .001). The differences in survival between the groups using either classification were significant. Surprisingly, there was no difference in survival between the group achieving CrCl between 40 and 49 mL/min and those achieving CrCl higher than 50 mL/min (Table 1). DISCUSSION
DGF is generally defined as the need for dialysis after transplantation. It has been attributed to numerous immunologic and nonimmunologic factors. DGF reduces longterm graft survival,4 – 6 with a reported increased incidence among ECD. IGF showed the best long-term graft survival, which was significantly different from SGF and DGF. ECD use did not predict a poorer graft survival. The choice of 3 months to calculate renal function recovery was based on trials correlating long-term outcomes with histology.7,8 The kidney undergoes a stage of repair posttransplantation; however, existing data suggest incomplete recovery after acute injury.8,9 Kidney function recovery reflected an improved CrCl to 40 mL/min, resulting in excellent long-term graft survival. Unexpectedly, CrCl ⬎ 50 mL/min did not change long-term survivals. The explanation may be related to other comorbidities. This draws attention to the need to control and treat other related comorbidities while micromanaging a stable functioning kidney. It is also important to notice that CrCl ⬎ 30 mL/min showed acceptable long-term graft survival, drawing the attention to the need for tight management of these patients. Similarly, kidneys achieving a CrCl ⬍ 30 mL/min did not last long (half-life of 10 months). We may want to think of relisting these patients or looking for a living donor to minimize their immunosuppression or eventual time on dialysis. Kidney recovery in the first 3 months strongly predicted long-term outcomes. This also showed the importance of preventing further injury to the kidney during the early postoperative course.
Table 1. One- and 5-Year Graft Survival in Relation to Creatinine Clearance at 3 Months Posttransplant and Kidney Function Recovery
Half-lives (mos/y) 1-y graft survival (%) 5-y graft survival (%)
BCrCl-3mos ⬍30 mL/min
BCrCl-3mos 30–39 mL/min
BCrCl-3mos 40–49 mL/min
BCrCl-3mos ⬎50 mL/min
Recovery ⬍70%
Recovery 70%–90%
Recovery ⬎90%
10/0 47 34
113/9.5 92 72
161/13.5 98 85
156/13 96 82
65/5.5 63 51
125/10.5 91 65
149/12.5 94 81
BCrCl-3mos, best creatinine clearance in the first 3 mo posttransplantation.
126
In conclusion, early graft function in the first 3 months showed a significant impact on long-term graft survival after deceased donor renal transplantation. Renal function recovery above 70% or CrCl clearance of more than 40 mL/min at 3 months posttransplantation were associated with excellent projected half-lives. REFERENCES 1. Moore PS, Farney AC, Sundberg AK, et al: Dual kidney transplantation: a case-control comparison with single kidney transplantation from standard and expanded criteria donors. Transplantation 83:1551, 2007 2. Lee BM, Yoon SN, Oh CK, et al. Fractional creatinine clearance of the donated kidney using Cockcroft-Gault formula as a predictor of graft function after living donor transplantation. Transplant Proc 38:1974, 2006 3. Stratta R, Rohr M, Sundberg A, et al: Intermediate-term outcomes with expanded criteria deceased donors in kidney transplantation: a spectrum or specter of quality? Ann Surg 243:594, 2006
HASSANAIN, TCHERVENKOV, CANTAROVICH ET AL 4. Quiroga I, McShane P, Koo DD, et al: Major effects of delayed graft function and cold ischaemia time on renal allograft survival. Nephrol Dial Transplant 21:1689, 2006 5. Ojo AO, Wolfe RA, Held PJ, et al: Delayed graft function: risk factors and implications for renal allograft survival. Transplantation 63:968, 1997 6. Koning OH, Ploeg RJ, van Bockel JH, et al: Risk factors for delayed graft function in cadaveric kidney transplantation: a prospective study of renal function and graft survival after preservation with University of Wisconsin solution in multi-organ donors. European Multicenter Study Group. Transplantation 63:1620, 1997 7. Kuypers DR, Chapman JR, O’Connell PJ, et al: Predictors of renal transplant histology at three months. Transplantation 67: 1222, 1999 8. Nankivell BJ, Fenton-Lee CA, Kuypers DR, et al: Effect of histological damage on long-term kidney transplant outcome. Transplantation 71:515, 2001 9. Gwinner W, Hinzmann K, Erdbruegger U, et al: Acute tubular injury in protocol biopsies of renal grafts: prevalence, associated factors and effect on long-term function. Am J Transplant 8:1684, 2008
K
IDNEY TRANSPLANTATION from diseased donors can be complicated with up to 40% of patients developing delayed graft function (DGF). Patients experiencing DGF are at increased risk for acute rejection and for inferior graft survival. Multiple donor and recipient characteristics have been identified as risk factors for DGF. Creatinine clearance (CrCl) at the time of donation is one important factor that affects donor selection and kidney allocation. Moreover, CrCl in the postoperative period has been used as an indirect marker of long-term graft survival in studies of immunosuppression protocols.1–3 Kidneys show remarkable resilience, recovering function even after prolonged periods of DGF. Recovery from DGF reflects an important intrinsic characteristic of the transplanted kidney. In this study, we examined the impact on 0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2008.10.046 124
long-term graft survival of both early graft function and the rate of recovery after transplantation among deceased donor renal transplantations. PATIENTS AND METHODS We included all cadaveric renal transplants performed at our center between 1990 and 2007. Immunosuppression induction consisted of thymoglobulin (85%; median 18.5 vials), methylpredFrom the Departments of Surgery (M.H., J.I.T., M.C., P.M., S.P., M.F., P.C.) and Medicine (M.C., D.K., D.B., R.M.), McGill University, Montreal, Quebec, Canada. Address reprint requests to Dr Mazen Hassanain, MBBS, McGill University, Department of Surgery, 687 Pine Avenue West, Montreal, Quebec H3A1A1, Canada. © 2009 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 41, 124 –126 (2009)
EARLY RECOVERY OF GRAFT FUNCTION
125
nisolone, and mycophenolate mofetil (51%) or azathioprine (47%). Calcineurin inhibitors (tacrolimus 55% or cyclosporine 45%) were introduced when adequate kidney function was achieved within the first 30 postoperative days, namely, a serum creatinine below ⬍ 3.0 mg/dL. Expanded criteria donors (ECDs) were defined according to United Network for Organ Sharing criteria. All other donors were considered to be standard criteria donors (SCDs). DGF was defined as anyone who required a form of dialysis in the first week after transplantation. Slow graft function (SGF) was defined as a functioning kidney with a serum creatinine fall of less than 20% from baseline in the first 24 hours after transplantation. Immediate graft function (IGF) was defined as a functioning kidney with a serum creatinine fall of more than 20% from baseline in the first 24 hours after transplantation. Recovery of renal function (RFR) was expressed in two ways, as the best CrCl in the first 3 months post–renal transplantation (BCrCl-3mos) as calculated using the Cockcroft-Gault formula or as a percentage of actual CrCl versus the expected value as calculated by the donors’ CrCl at procurement. Data for graft survival were non-death-censored. Kaplan-Meier curves were used for graft survival analysis.
RESULTS
Five hundred eighty-three (583) patients were included in the analysis. Of these, 140 patients (23.6%) received kidneys from ECDs. IGF was present in 50.3% of the patients, SGF in 19.8%, and DGF in 29.1%. ECD kidneys had twice the DGF rate (49%) compared with SCD kidneys (P ⬍ .001). Overall graft survival at 1 and 5 years was 87.8% and 74%, respectively. Patients with IGF showed a 5-year graft survival of 85%, whereas patients with SGF or DGF experiment 5-year survivals of 76% and 54%, respectively (P ⬍ .02). There was no difference in the impact of early graft function or 5-year graft survival between ECD and SCD kidneys. RFR showed an impact on 5-year graft survivals and projected half-lives. BCrCl-3mos ⬍ 30 mL/min displayed 1and 5-year graft survivals of 47% and 34%; BCrCl-3mos values between 30 and 39 mL/min, 92% and 72%; BCrCl3mos values between 40 and 49 mL/min, 98% and 85%. While BCrCl-3mos value of ⬎ 50 mL/min showed 1- and 5-year survivals of 96% and 82% (Table 1, Fig 1). Similar results were observed with the percentage of CrCl. A recovery of 90% or more of expected CrCl in the first 3 months posttransplant was associated with graft survivals at 1 and 5 years of 94% and 81%; recovery of 70%
to 90%, 91% and 65%; while less than 70%, 63% and 51% (Table 1, Fig 2). The projected half-lives for these kidneys was 10 months for BCrCl-3mos ⬍ 30 mL/min; 9.5 years for 30 to 39 mL/min; 13.5 years for 40 to 49 mL/min; and 13 years for more than 50 mL/min (P ⬍ .001). Similar results were observed when tested for the percentage of CrCl, as the half-lives for kidneys with 90% or more recovery was 12.5 years; 70% to 90%, 10.5 years; and less than 70%, 5.5 years (P ⬍ .001). The differences in survival between the groups using either classification were significant. Surprisingly, there was no difference in survival between the group achieving CrCl between 40 and 49 mL/min and those achieving CrCl higher than 50 mL/min (Table 1). DISCUSSION
DGF is generally defined as the need for dialysis after transplantation. It has been attributed to numerous immunologic and nonimmunologic factors. DGF reduces longterm graft survival,4 – 6 with a reported increased incidence among ECD. IGF showed the best long-term graft survival, which was significantly different from SGF and DGF. ECD use did not predict a poorer graft survival. The choice of 3 months to calculate renal function recovery was based on trials correlating long-term outcomes with histology.7,8 The kidney undergoes a stage of repair posttransplantation; however, existing data suggest incomplete recovery after acute injury.8,9 Kidney function recovery reflected an improved CrCl to 40 mL/min, resulting in excellent long-term graft survival. Unexpectedly, CrCl ⬎ 50 mL/min did not change long-term survivals. The explanation may be related to other comorbidities. This draws attention to the need to control and treat other related comorbidities while micromanaging a stable functioning kidney. It is also important to notice that CrCl ⬎ 30 mL/min showed acceptable long-term graft survival, drawing the attention to the need for tight management of these patients. Similarly, kidneys achieving a CrCl ⬍ 30 mL/min did not last long (half-life of 10 months). We may want to think of relisting these patients or looking for a living donor to minimize their immunosuppression or eventual time on dialysis. Kidney recovery in the first 3 months strongly predicted long-term outcomes. This also showed the importance of preventing further injury to the kidney during the early postoperative course.
Table 1. One- and 5-Year Graft Survival in Relation to Creatinine Clearance at 3 Months Posttransplant and Kidney Function Recovery
Half-lives (mos/y) 1-y graft survival (%) 5-y graft survival (%)
BCrCl-3mos ⬍30 mL/min
BCrCl-3mos 30–39 mL/min
BCrCl-3mos 40–49 mL/min
BCrCl-3mos ⬎50 mL/min
Recovery ⬍70%
Recovery 70%–90%
Recovery ⬎90%
10/0 47 34
113/9.5 92 72
161/13.5 98 85
156/13 96 82
65/5.5 63 51
125/10.5 91 65
149/12.5 94 81
BCrCl-3mos, best creatinine clearance in the first 3 mo posttransplantation.
126
In conclusion, early graft function in the first 3 months showed a significant impact on long-term graft survival after deceased donor renal transplantation. Renal function recovery above 70% or CrCl clearance of more than 40 mL/min at 3 months posttransplantation were associated with excellent projected half-lives. REFERENCES 1. Moore PS, Farney AC, Sundberg AK, et al: Dual kidney transplantation: a case-control comparison with single kidney transplantation from standard and expanded criteria donors. Transplantation 83:1551, 2007 2. Lee BM, Yoon SN, Oh CK, et al. Fractional creatinine clearance of the donated kidney using Cockcroft-Gault formula as a predictor of graft function after living donor transplantation. Transplant Proc 38:1974, 2006 3. Stratta R, Rohr M, Sundberg A, et al: Intermediate-term outcomes with expanded criteria deceased donors in kidney transplantation: a spectrum or specter of quality? Ann Surg 243:594, 2006
HASSANAIN, TCHERVENKOV, CANTAROVICH ET AL 4. Quiroga I, McShane P, Koo DD, et al: Major effects of delayed graft function and cold ischaemia time on renal allograft survival. Nephrol Dial Transplant 21:1689, 2006 5. Ojo AO, Wolfe RA, Held PJ, et al: Delayed graft function: risk factors and implications for renal allograft survival. Transplantation 63:968, 1997 6. Koning OH, Ploeg RJ, van Bockel JH, et al: Risk factors for delayed graft function in cadaveric kidney transplantation: a prospective study of renal function and graft survival after preservation with University of Wisconsin solution in multi-organ donors. European Multicenter Study Group. Transplantation 63:1620, 1997 7. Kuypers DR, Chapman JR, O’Connell PJ, et al: Predictors of renal transplant histology at three months. Transplantation 67: 1222, 1999 8. Nankivell BJ, Fenton-Lee CA, Kuypers DR, et al: Effect of histological damage on long-term kidney transplant outcome. Transplantation 71:515, 2001 9. Gwinner W, Hinzmann K, Erdbruegger U, et al: Acute tubular injury in protocol biopsies of renal grafts: prevalence, associated factors and effect on long-term function. Am J Transplant 8:1684, 2008