- Email: [email protected]
Delayed Graft Function After Renal Transplantation: An Unresolved Problem
Delayed Graft Function After Renal Transplantation: An Unresolved Problem E. Gavela Martínez, L.M. Pallardó Mateu, A. Sancho Calabuig, S. Beltrán Catalán, J. Kanter Berga, A.I. Ávila Bernabeu, and J. Crespo Albiach ABSTRACT Unlike other areas in renal transplantation, delayed graft function (DGF) remains an apparently unavoidable complication owing to the characteristics of current donors. The aim of this study was to analyze risk factors for DGF in relation to graft and patient survivals. We retrospectively analyzed 507 renal transplant recipients with a median follow-up of 74.83 ⫾ 45.06 months. DGF, which occurred among 189 patients (36.8%) was defined as requirement for dialysis within the first week after transplantation. Donor (P ⫽ .000) and recipient (P ⫽ .000) age were greater in the DGF group without differences in recipient or donor gender, HLA sensitization, or dialysis time before transplantation. Donor factors as the cause of death associated with DGF were secondary cerebrovacular stroke (P ⫽ .002) and hypertensive history (P ⫽ .000). Recipient characteristics associated therewith were higher body mass index (P ⫽ .000), smoking habit (P ⫽ .003), ischemic cardiopathy (P ⫽ .01), and dyslipidemia (P ⫽ .05). Moreover, the DGF group showed longer cold ischemia (P ⫽ .01) and vascular anastomosis (P ⫽ .02) times. On multivariate analysis, recipient age (P ⫽ .00) and smoking habit (P ⫽ .01) together with a donor history of hypertension (P ⫽ .02) were independent risk factors for DGF. No differences were observed in acute rejection incidence (P ⫽ .07) with worse renal function during follow-up (P ⬍ .05). Graft (81% vs 88%; P ⫽ .00) and patient (89% vs 95%; P ⫽ .00) survivals at 5 years were lower among the DGF group. In conclusion, DGF which was associated with factors related to the donor, the recipient, and the surgical times, produced worse graft and patient survivals. Shortening the cold ischemia time seems to be a modifiable variable to reduce DGF. elayed graft function (DGF), a well known complication that affects the kidney allografts in the immediate posttransplantation period, shows an uncertain impact on long-term outcomes.1–5 DGF is the result of an ischemic injury to the graft aggravated by the reperfusion syndrome. It is defined as a form of acute renal failure resulting in posttransplantation oliguria, increased graft immunogenicity and a greater risk of acute rejection episodes.3 Moreover, it is associated with prolonged hospitalization and therefore higher costs of transplantation.6 The reported frequencies (2%–50%2) of DGF after cadaveric kidney transplantation are extremely variable. The variability is atleast partially due to ambiguious definitions of the event. As a consequence, it has been difficult to compare results from clinical trials. Therefore, the evaluation of incidences and risk factors for DGF among transplant centers may help to understand the importance of this complication for
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overall renal transplant outcomes. The aim of the present study was to analyze the risk factors for DGF in relation to graft and patient survivals. PATIENTS AND METHODS This longitudinal retrospective analysis of 507 consecutive renal transplants from November 1996 to March 2010 included, a median follow-up of 74.83 ⫾ 45.06 months. DGF was defined as requirement for dialysis within the first week after transplantation. We excluded kidneys that suffered a vascular thrombosis or were nonviable. The mean recipient age was 50.79 ⫾ 12.69 years (range, From the Servicio de Nefrología, Hospital U. Dr Peset, Valencia, Spain. Address reprint requests to Eva Gavela Martínez, Servicio de Nefrología, Hospital U. Dr. Peset, Av Gaspar Aguilar 90, 46017, Valencia, Spain. E-mail: [email protected]
© 2011 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2011.06.051
Transplantation Proceedings, 43, 2171–2173 (2011)
2171
2172
MARTÍNEZ, MATEU, CALABUIG ET AL
20 –74) including 56.7% men and 43.3% women. The mean donor age was 49.61 ⫾ 18.09 years (range, 0 – 80). Immunosuppression for these subjects included steroids, mycophenolate mofetil (2 g/d initially), and either cyclosporine (5 mg/kg/d) or tacrolimus (0.15 mg/kg/d). The calcineurin inhibitor treatment was initiated either at 72 hours after transplantation, during which induction treatment was delivered using basiliximab or thymoglobulin. We compared the characteristics and evolution of patients who presented with DGF versus recipients free of this complication. The statistical analyses included the chi-square and Mann-Whitney tests. Graft and patient survival curves were calculated using the Kaplan-Meier method with differences estimated by the log rank test. A p value less than 0.05 was considered statistically significant. Multiple linear regression models were employed to identify risk factors for DGF.
RESULTS
DGF was observed in 189 patients (36.8%). Comparing both groups (Table 1), we observed higher donor (54.33 ⫾ 6.45 vs 46.91 ⫾ 18.44 years; P ⫽ .000) and recipient (54.34 ⫾ 11.41 vs 48.63 ⫾ 12.97 years; P ⫽ .000) ages among the DGF group, without differences in gender, HLA sensitization, or dialysis time before transplantation. Donor factors of death due to cerebrovascular stroke (71.7 vs 57.9%; P ⫽ .002) or arterial hypertension history (41.8 vs 26%; P ⫽ .000) were associated with the occurrence of DGF. We observed a greater incidence of DGF among recipients with vascular risk factors, such as a greater body mass index (26.43 ⫾ 4.55 vs 24.70 ⫾ 4.09 kg/m2; P ⫽ .000), a smoking habit (52.3 vs 38.4%; P ⫽ .003), ischemic cardiopathy (13 vs 6.3%; P ⫽ .01), or dyslipidemia (54.2% vs 45.4%; P ⫽ .05). Moreover, the cold ischemia (19.79 ⫾ 4.21 vs 18.72 ⫾ 4.47 hours; P ⫽ .01) and vascular anastomosis times (52.59 ⫾ 17.10 vs 46.81 ⫾ 18.06 hours; P ⫽ .02), were longer among the DGF group. The multivariate analysis showed age (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.02–1.05; P ⫽ .00) and smoking habit of the recipient (OR, 1.89; 95% CI 1.27–2.81; P ⫽ .01) together with donor hypertensive history (OR, 1.66; 95% CI, 1.09 –
2.13; P ⫽ .02) to be independent risk factors for DGF. No differences were observed in the incidence of acute rejection episodes (24.5 vs 17.9%; P ⫽ .07); however, a longer hospital stay after transplantation was observed among the DGF group (18.68 ⫾ 7.62 vs 13.40 ⫾ 6.01 days; P ⫽ .000). Graft survivals at 1 and 5 years, respectively, were 93% vs 97% and 88% vs 81% (P ⫽ .00), and patient survivals (96% vs 99% and 89% vs 95%; P ⫽ .00) were lower in the DGF group. DISCUSSION
Our data have shown long-term relationships between DGF and worse patient and graft survivals consistent with the recent literature.2 The risk of DGF development has been associated with factors related to organ procurement as well as donor and recipient characteristics.1,3,5–7 In our series, not only known factors, such as donor and recipient age, but also cardiovascular risk factors, such as a higher body mass index, smoking habit, dyslipidemia, and ischemic cardiopathy in the recipient, were associated with DGF. A well known risk and potentially modifiable risk factor—longer cold ischemia time—was present in the DGF group, it contributed to the worse results among this group.2,7 DGF has been related to increased graft immunogenicity with an higher risk of acute rejection episodes.2,8 We did not observe a significantly increased occurrence of acute rejection episodes among the DGF group, probably due to the more frequent use of induction treatment with low doses of thymoglobulin or basiliximab in those patients deemed to be at higher risk of this complication, particularly among recipients of kidneys from expanded-criteria donors.9 In conclusion, DGF was a frequent complication among our series of cadaveric renal transplantations; it was followed by reduced graft survival. Some risk factors are nonmodifiable, such as those derived from the increased age and greater prevalence of allografts from expandedcriteria donors. In these circumstances, reducing the cold
Table 1. Demographic Univariate Analysis
Recipient age, y Recipient gender (male), % Dyalisis time, mo Dialysis time (PD/HD), % Diabetes mellitus, % HTA, % Smoking habit, % Isquemic cardiopathy, % BMI, kg/m2 Sensitization, % Donor age, y Donor sex (male), % Donor cause of death due to cerebrovascular stroke, % Donor HTA, % Cold ischemia time, h Vascular anastomosis time, min
No DGF
DGF
P Value
48.63 ⫾ 12.97 56.2 45.35 ⫾ 47.33 15.3/84.7 5.7 87.6 38.4 6.3 24.70 ⫾ 4.09 7.7 46.91 ⫾ 18.44 53.7 57.9 26 18.71 ⫾ 47 46.81 ⫾ 18.06
54.34 ⫾ 11.41 52.2 49.19 ⫾ 41.95 9.4/90.6 10.1 89.3 52.3 13 26.43 ⫾ 4.55 6.6 54.33 ⫾ 6.45 58.7 71.7 41.8 19.86 ⫾ 4.25 52.5 ⫾ 17.1
.000 .66 .32 .06 .07 .57 .003 .01 .000 .62 .000 .27 .002 .000 .01 .02
DELAYED RENAL GRAFT FUNCTION
ischemia time may reduce the incidence of DGF and improve graft survival. Other strategies derived from the use of novel nonnephrotoxic immunosuppressive drugs may allow sparing of calcineurin inhibitors.
REFERENCES 1. Boom H, Mallat M, de Fijter J, et al: Delayed graft function influences, but not survival. Kidney Int 58:859, 2000 2. Yarlagadda S, Coca S, Formica R, et al: Association between delayed graft function and allograft and patient survival: a systematic review and meta-analysis. Nephrol Dial Transplant 24:1039, 2010 3. Perico N, Cattaneo D, Sayegh M, Remuzzi G: Delayed graft function in kidney transplantation. Lancet 364:1814, 2004
2173 4. Shaheen M, Shaheen F, Attar B, et al: Impact of recipient and donor nonimmunologic factors on the outcome of deceased donor kidney transplantation. Transplant Proc 42:273, 2010 5. Jushinskis J, Trushkov S, Bicans J, et al: Risk factors for development of delayed graft function in deceased donor renal transplantation. Transplant Proc 41:746, 2009 6. Anonymous. The high cost of delayed graft function in cadaveric transplantation. Transplantation 51:1115, 1991 7. Gallego E, Ortega A, Llamas F, et al: Short cold ischemic time improves the outcomes of transplants with expanded donor criteria. Nefrologı´a 29:456, 2009 8. Pallardó LM, Sancho A, Capdevila L, et al: Acute rejection and late renal transplant failure: risk factors and prognosis. Nephrol Dial Transplant 19(Suppl 3):38, 2004 9. Gavela E, Sancho A, Escudero V, et al: Induction treatment with low-dose thymoglobulin or basiliximab in renal transplants from older donors. Transplant Proc 40:2900, 2008
D
overall renal transplant outcomes. The aim of the present study was to analyze the risk factors for DGF in relation to graft and patient survivals. PATIENTS AND METHODS This longitudinal retrospective analysis of 507 consecutive renal transplants from November 1996 to March 2010 included, a median follow-up of 74.83 ⫾ 45.06 months. DGF was defined as requirement for dialysis within the first week after transplantation. We excluded kidneys that suffered a vascular thrombosis or were nonviable. The mean recipient age was 50.79 ⫾ 12.69 years (range, From the Servicio de Nefrología, Hospital U. Dr Peset, Valencia, Spain. Address reprint requests to Eva Gavela Martínez, Servicio de Nefrología, Hospital U. Dr. Peset, Av Gaspar Aguilar 90, 46017, Valencia, Spain. E-mail: [email protected]
© 2011 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2011.06.051
Transplantation Proceedings, 43, 2171–2173 (2011)
2171
2172
MARTÍNEZ, MATEU, CALABUIG ET AL
20 –74) including 56.7% men and 43.3% women. The mean donor age was 49.61 ⫾ 18.09 years (range, 0 – 80). Immunosuppression for these subjects included steroids, mycophenolate mofetil (2 g/d initially), and either cyclosporine (5 mg/kg/d) or tacrolimus (0.15 mg/kg/d). The calcineurin inhibitor treatment was initiated either at 72 hours after transplantation, during which induction treatment was delivered using basiliximab or thymoglobulin. We compared the characteristics and evolution of patients who presented with DGF versus recipients free of this complication. The statistical analyses included the chi-square and Mann-Whitney tests. Graft and patient survival curves were calculated using the Kaplan-Meier method with differences estimated by the log rank test. A p value less than 0.05 was considered statistically significant. Multiple linear regression models were employed to identify risk factors for DGF.
RESULTS
DGF was observed in 189 patients (36.8%). Comparing both groups (Table 1), we observed higher donor (54.33 ⫾ 6.45 vs 46.91 ⫾ 18.44 years; P ⫽ .000) and recipient (54.34 ⫾ 11.41 vs 48.63 ⫾ 12.97 years; P ⫽ .000) ages among the DGF group, without differences in gender, HLA sensitization, or dialysis time before transplantation. Donor factors of death due to cerebrovascular stroke (71.7 vs 57.9%; P ⫽ .002) or arterial hypertension history (41.8 vs 26%; P ⫽ .000) were associated with the occurrence of DGF. We observed a greater incidence of DGF among recipients with vascular risk factors, such as a greater body mass index (26.43 ⫾ 4.55 vs 24.70 ⫾ 4.09 kg/m2; P ⫽ .000), a smoking habit (52.3 vs 38.4%; P ⫽ .003), ischemic cardiopathy (13 vs 6.3%; P ⫽ .01), or dyslipidemia (54.2% vs 45.4%; P ⫽ .05). Moreover, the cold ischemia (19.79 ⫾ 4.21 vs 18.72 ⫾ 4.47 hours; P ⫽ .01) and vascular anastomosis times (52.59 ⫾ 17.10 vs 46.81 ⫾ 18.06 hours; P ⫽ .02), were longer among the DGF group. The multivariate analysis showed age (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.02–1.05; P ⫽ .00) and smoking habit of the recipient (OR, 1.89; 95% CI 1.27–2.81; P ⫽ .01) together with donor hypertensive history (OR, 1.66; 95% CI, 1.09 –
2.13; P ⫽ .02) to be independent risk factors for DGF. No differences were observed in the incidence of acute rejection episodes (24.5 vs 17.9%; P ⫽ .07); however, a longer hospital stay after transplantation was observed among the DGF group (18.68 ⫾ 7.62 vs 13.40 ⫾ 6.01 days; P ⫽ .000). Graft survivals at 1 and 5 years, respectively, were 93% vs 97% and 88% vs 81% (P ⫽ .00), and patient survivals (96% vs 99% and 89% vs 95%; P ⫽ .00) were lower in the DGF group. DISCUSSION
Our data have shown long-term relationships between DGF and worse patient and graft survivals consistent with the recent literature.2 The risk of DGF development has been associated with factors related to organ procurement as well as donor and recipient characteristics.1,3,5–7 In our series, not only known factors, such as donor and recipient age, but also cardiovascular risk factors, such as a higher body mass index, smoking habit, dyslipidemia, and ischemic cardiopathy in the recipient, were associated with DGF. A well known risk and potentially modifiable risk factor—longer cold ischemia time—was present in the DGF group, it contributed to the worse results among this group.2,7 DGF has been related to increased graft immunogenicity with an higher risk of acute rejection episodes.2,8 We did not observe a significantly increased occurrence of acute rejection episodes among the DGF group, probably due to the more frequent use of induction treatment with low doses of thymoglobulin or basiliximab in those patients deemed to be at higher risk of this complication, particularly among recipients of kidneys from expanded-criteria donors.9 In conclusion, DGF was a frequent complication among our series of cadaveric renal transplantations; it was followed by reduced graft survival. Some risk factors are nonmodifiable, such as those derived from the increased age and greater prevalence of allografts from expandedcriteria donors. In these circumstances, reducing the cold
Table 1. Demographic Univariate Analysis
Recipient age, y Recipient gender (male), % Dyalisis time, mo Dialysis time (PD/HD), % Diabetes mellitus, % HTA, % Smoking habit, % Isquemic cardiopathy, % BMI, kg/m2 Sensitization, % Donor age, y Donor sex (male), % Donor cause of death due to cerebrovascular stroke, % Donor HTA, % Cold ischemia time, h Vascular anastomosis time, min
No DGF
DGF
P Value
48.63 ⫾ 12.97 56.2 45.35 ⫾ 47.33 15.3/84.7 5.7 87.6 38.4 6.3 24.70 ⫾ 4.09 7.7 46.91 ⫾ 18.44 53.7 57.9 26 18.71 ⫾ 47 46.81 ⫾ 18.06
54.34 ⫾ 11.41 52.2 49.19 ⫾ 41.95 9.4/90.6 10.1 89.3 52.3 13 26.43 ⫾ 4.55 6.6 54.33 ⫾ 6.45 58.7 71.7 41.8 19.86 ⫾ 4.25 52.5 ⫾ 17.1
.000 .66 .32 .06 .07 .57 .003 .01 .000 .62 .000 .27 .002 .000 .01 .02
DELAYED RENAL GRAFT FUNCTION
ischemia time may reduce the incidence of DGF and improve graft survival. Other strategies derived from the use of novel nonnephrotoxic immunosuppressive drugs may allow sparing of calcineurin inhibitors.
REFERENCES 1. Boom H, Mallat M, de Fijter J, et al: Delayed graft function influences, but not survival. Kidney Int 58:859, 2000 2. Yarlagadda S, Coca S, Formica R, et al: Association between delayed graft function and allograft and patient survival: a systematic review and meta-analysis. Nephrol Dial Transplant 24:1039, 2010 3. Perico N, Cattaneo D, Sayegh M, Remuzzi G: Delayed graft function in kidney transplantation. Lancet 364:1814, 2004
2173 4. Shaheen M, Shaheen F, Attar B, et al: Impact of recipient and donor nonimmunologic factors on the outcome of deceased donor kidney transplantation. Transplant Proc 42:273, 2010 5. Jushinskis J, Trushkov S, Bicans J, et al: Risk factors for development of delayed graft function in deceased donor renal transplantation. Transplant Proc 41:746, 2009 6. Anonymous. The high cost of delayed graft function in cadaveric transplantation. Transplantation 51:1115, 1991 7. Gallego E, Ortega A, Llamas F, et al: Short cold ischemic time improves the outcomes of transplants with expanded donor criteria. Nefrologı´a 29:456, 2009 8. Pallardó LM, Sancho A, Capdevila L, et al: Acute rejection and late renal transplant failure: risk factors and prognosis. Nephrol Dial Transplant 19(Suppl 3):38, 2004 9. Gavela E, Sancho A, Escudero V, et al: Induction treatment with low-dose thymoglobulin or basiliximab in renal transplants from older donors. Transplant Proc 40:2900, 2008