- Email: [email protected]
Utilization of Elderly Kidney Donors (>70 Years) Does Not Affect Graft Survival in the Medium Term
Utilization of Elderly Kidney Donors (>70 Years) Does Not Affect Graft Survival in the Medium Term C. Galeano, R. Marcén, S. Jimenez, A. Fernández Rodríguez, H. Sosa, J.J. Villafruela, J.L. Teruel, F.J. Burgos and C. Quereda ABSTRACT Background. The need for organs for renal transplantation has encouraged the use of grafts from increasingly older donors. Earlier studies performed in Spain have shown the suitability of donors aged 60 – 65 years. In this single-center study, we evaluated our results using donors ⬎70 years old. Methods. We evaluated 401 primary transplantations performed from January 2000 to December 2009. Their initial immunosuppression was a tacrolimus-based (n ⫽ 324), cyclosporine-based (n ⫽ 70) or calcineurin inhibitor–free (n ⫽ 7) regimen patients. Recipients were classified according to the donors age: ⬍50 (42.6%); 50 –70 (39.7%) and ⬎70 (17.5%) years. Results. There were no differences in recipient or donor gender, time on dialysis, cold ischemia, delayed graft function, or acute rejection episodes. However, the mean age was higher among patients who received grafts from donors ⬎70 years old; 42.5 ⫾ 12.4 years for ⬍50, 58.1 ⫾ 8.2 years for 50 –70, and 65.7 ⫾ 7.2 years for ⬎70; (P ⫽ .000). The serum creatinine at 12 months was increased according to the age of the donor; 1.4 ⫾ 0.6, 1.8 ⫾ 0.6, 70 and 1.7 ⫾ 0.5 mg/dL, respectively (P ⫽ .001). The graft survival rates at 5 years were 81%, 74%, and 70%, respectively (P ⫽ .519). Upon multivariate analysis only HLA-DR mismatches, delayed graft function, and acute rejection episodes were associated with graft loss. Patient survival rates (86%) at 5 years were similar among recipients from donors aged 50 –70 and ⬎70 years, but higher (96%) for those who received a graft from a donor ⬍50 years (P ⫽ .003). Conclusions. Nearly 20% of donors were ⬎70 years old in our study. Their kidneys displayed excellent short-term outcomes. functioning grafted kidney is the best treatment for end-stage renal disease. Patient survival is better after a kidney transplantation than with dialysis therapy even among older patients.1 With the increased survival of renal patients and the improvements in treatment of chronic kidney diseases, the number of patients awaiting kidney transplantation has increased. Because of the limited supply and the increased demand, the criteria for accepting kidneys have been extended. The use of organs from elderly donors has become a reality. However, there are significant unresolved controversial issues. An adverse impact of increasing donor age on graft and patient outcomes has been described in various studies. It is important to use both clinical and histopathologic criteria to determine grafts are which suitable for transplan-
A
tation. However, some studies suggest that the criteria used at the time of transplantation are not sufficient to predict the graft outcomes.2 It has been proposed that kidneys from older donors can be more immunogenic than those from younger individuals, resulting in an increased incidence of acute interstitial rejection episodes early posttransplantation.3 It will be necessary to analyze the impact of improved immunosuppressive regimens on outcomes of the grafts. From the Nephrology (C.G., R.M., S.J., A.F.R., H.S., J.J.V., J.L.T., C.Q.) and Urology Departments (F.J.B.), Hospital Ramón y Cajal, Madrid, Spain. Address correspondence to Cristina Galeano, MD, Ctra de Colmenar, km 9,100. 28034, Madrid, Spain. E-mail: cgaleanoalvarez@ gmail.com
© 2010 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.2010.08.069
Transplantation Proceedings, 42, 3935–3937 (2010)
3935
3936
GALEANO, MARCEN, JIMENEZ ET AL
Another important question is whether kidneys from older donors must be used only in older recipients. After 4 years of dialysis, older patients experience a longer life expectancy when they receive a graft from an older donor within 2 years of ESRD onset compared with waiting for a standard kidney or a living donor. In contrast, younger patients (⬍39 years) display a longer life expectancy with the other option.4 Earlier studies performed in Spain have shown the suitability of donors aged 60 – 65 years,5 highlighting the need to improve their clinical management. In the present single-center study, we evaluated the results of organs from donors ⬎70 years old, comparing them with those from younger donors. PATIENTS AND METHODS All 401 consecutive primary renal transplants from deceased donors performed in our unit from January 2000 to December 2009 were included in the study. Data regarding recipients, donors, and transplants were collected from an electronic database. Recipient data included age, gender, dialysis modality, time on dialysis, and primary renal disease. Donor data included age, gender, cause of death, and pretransplant histology of the kidney when available. Transplant variables included warm and cold ischemia times, immediate renal function, rejection episodes, patient and graft outcomes and causes of death or graft loss. The glomerular filtration rate (GFR) was estimated using the abbreviated Modification of Diet in Renal Disease equation (eGFR (mL/min/1.73 m2): exp(5.228 ⫺ 1.154 ⫻ ln(SCr) ⫺ 0.203 ⫻ ln(age) ⫺ (0.299 if female) ⫹ 0.192 if African-American). There were 252 male and 149 female patients, whose average age at transplantation was 52.8 ⫾ 13.7 years. The mean time on dialysis was 25.9 ⫾ 23.1 months. The initial immunosuppression was a tacrolimus-based (n ⫽ 324) cyclosporine-based (n ⫽ 70), or a calcineurin inhibitor– free (n ⫽ 7) regimen. Altogether, 42.6% of the patients received a graft from a donor ⬍50, 39.7% from a donor 50 –70, and 17.5% from a donor ⬎70 years old. Kidneys from a donor ⬎65 years-old transplanted only when ⬍20% of glomerulae were sclerotic. Continuous variables are expressed as mean ⫾ SD and categoric ones as percentages. Group comparisons were performed by variance analysis and Kruskal-Wallis tests for parametric and nonparametric continuous data, respectively. The chi-squared test was used to compare categoric variables. Survival data were
assessed with the Kaplan-Meier method and the Cox proportional hazard regression model (univariate and multivariate). A 2-tailed P value of .05 was considered to be statistically significant.
RESULTS
There were no differences among the groups according to recipient gender, time on dialysis, cold ischemia, donor gender, incidence of delayed graft function, or incidence of rejection episodes (Table 1). However, the recipient age was greater among patients who received grafts from donors ⬎70 years (P ⫽ .000). Serum creatinine at 12 months showed increases with donor age: 1.4 ⫾ 0.6 mg/dL for ⬍50; 1.8 ⫾ 0.6 for 50 –70 and 1.7 ⫾ 0.5 for ⬎70; P ⫽ .001. In addition, the eGFR at 3 and 12 months were higher among patients with donor ages below 50 years old (P ⫽ .000). The actuarial graft survival rates at 1, 3, and 5 years, respectively, were 86%, 83%, and 81% for ⬍50-year-old donors; 88%, 83%, and 74% for 50 –70-year-old donors, and 81%, 81% and 70% for ⱖ 70-year-old donors (P ⫽ .519). Upon multivariate analysis, HLA-DR mismatches (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.02–1.75; P ⬍ .050), delayed graft function (HR, 2.07; 95% CI, 1.35–3.19; P ⬍ .001), and perhaps acute rejection (HR 1.62; 95% CI, 0.92–2.85; P ⫽ .093) were the variables associated with graft survival. Ninety-six grafts were lost: 36 in the group of ⬍50 y; 46 in the group of 50 –70, and 14 in the group of ⬎70-year-old donors. No differences were observed in the causes of graft loss among the groups; vascular complications and death with a functioning graft were the main causes of graft loss. Forty-five recipients died during the follow-up: 8 in the ⬍50, 28 in the 50 –70 and 8 in the ⱖ70-year-old donor group. The actuarial patient survival rates at 1, 3, and 5 years, respectively, were 98%, 97%, and 96% for ⬍50 y, 94%, 92%, and 85% for 50 –70, and 90%, 86%, and 86% for ⱖ70-year-old donors (P ⫽ .003). Multivariate analysis showed the variables associated with patient survival to be age at transplant in years (HR, 1.08; 95% CI, 1.04 –1.13; P ⫽ .000), time on dialysis in months (HR, 1.02; 95% CI, 1.01–1.03; P ⫽ .002) and serum creatinine (mg/dL) at 3 months (HR, 1.97; 95% CI, 1.20 – 3.25; P ⫽ .008).
Table 1. Characteristics of the Patients According to Donor Age ⬍50 y
Age (y) Gender (M/F) Time on dialysis (mo) Cold ischemia time (h) ATN (yes/no) Early rejection (yes/no) Immunosuppression TAC CsA ACI free eGFR, 3 m eGFR, 12 m *P ⬍.01 versus donors ⬍50 y.
50–70 y
⬎70 y
P Value
42.5 ⫾ 12.4 104/67 27.1 ⫾ 25.9 17.1 ⫾ 4.4 63/108 18/153
58.1 ⫾ 8.2 106/54 26.9 ⫾ 21.4 17.6 ⫾ 4.4 65/95 23/137
65.7 ⫾ 7.2 42/28 20.9 ⫾ 18.9 16.2 ⫾ 4.8 27/43 6/64
.000 .512 .143 .143 .779 .368
140 28 3 52.0 ⫾ 17.3 58.4 ⫾ 18.7
123 35 2 39.5 ⫾ 14.1* 42.6 ⫾ 13.8*
61 7 2 35.1 ⫾ 9.4* 39.5 ⫾ 9.7*
.237
.000 .000
ELDERLY DONORS AND KIDNEY GRAFT SURVIVAL
DISCUSSION
The 17% prevalence of older donors was higher than that reported from a Spainish study of 3,365 adult patients in which 14.8% of donors were ⬎60 years4 old5. The increased prevalence of donors ⬎70 years old represents the acceptance of expanded-criteria donors to address the problem of the growing waiting list. Moreover, data have recently been reported regarding patient and graft outcomes of recipients of transplanted kidneys from donors aged ⬎75 years.2,6. Collini et al6 have shown that in Tuscan transplant centers as many as 20% of all donations in 2006 were obtained from individuals ⬎75 years of age. Graft survival was excellent in our series compared with other studies. In the Eurotransplant Senior Program (ESP), in which kidneys from donors aged ⱖ65 years were given to recipients aged ⱖ65 years, the graft survival at 5 years was 47%.7 In the United Network of Organ Sharing Database, it was 44%.8 These outcomes were far from our 71% rate. Differences in the characteristics of the populations may in part explain these results. Our study showed 7–11% lower short-term graft survival in recipients of kidney donor from age ⱖ50 years than in the younger set, but the difference was not significant. An important point was the lack of difference in graft survival between kidneys coming from 50 –70-year-old donors and those from donors aged ⬎70 years. These findings differ from other multicenter studies showing significantly lower graft survival.5,8 Nevertheless, donor age was not a risk factor for short-term graft loss in the multivariate analysis. When we compared 3 groups categorized by donor age, no differences were observed in the time on dialysis, the prevalence of delayed graft function, or rejection episodes or in the initial immunosuppression. Some authors have reported an increased incidence of rejection episodes among kidneys from older donors. It has been suggested that older-donor kidneys are more immunogenic than those from young donors.3 Because there were no differences in cold ischemia times, HLA mismatches, or immunosuppres-
3937
sion regimens, our acceptance of older donors was not accompanied by efforts to minimize any negative impact of factors that could influence early graft function or rejection incidences. Graft function at 3 and 12 months was significantly worse among recipients transplanted from older donors. Similar results have been observed in earlier studies; kidneys from older donors have been associated with increased serum creatinine values at 3 and 12 months.5 In conclusion, our data showed that old transplanted kidneys into old recipients display an excellent short-term graft outcomes. However, worse graft function is the price to be paid. The results of this retrospective single-center study should be interpreted with caution until we have a broader experience with larger patient sample and longer follow-up. REFERENCES 1. Heldal K, Hartmann A, Grootendorst DC, et al: Benefit of kidney transplantation beyond 70 years of age. Nephrol Dial Transplant 25:1680, 2010 2. Foss A, Heldal K, Scott H, et al: Kidney from deceased donors more than 75 years perform acceptably after transplantation. Transplantation 87:1437, 2009 3. de Fijter JW, Mallat MJK, Doxiadis II, et al: Increased immunogenicity and cause of graft loss of old donor kidneys. J Am Soc Nephrol 12:1538, 2001 4. Schold JD, Meier-Kriesche HU: Which renal transplant candidates should accept marginal kidneys in exchange for a shorter waiting time on dialysis? Clin J Am Soc Nephrol 1:532, 2006 5. Oppenheimer F, Aljama P, Asensio C, et al: The impact of donor age on the results of renal transplantation. Nephrol Dial Transplant 19(Suppl 3):iii11, 2004 6. Collini A, Kalmar P, Dhamo A, et al: Renal transplant from very old donors: how far can we go? Transplantation 87:1830, 2009 7. Frei U, Noeldeke J, Machold-Fabrizi V, et al: Prospective age-matching in elderly kidney transplant recipients— 5-year analysis of the Eurotransplant Senior Program. Am J Transplant 8:50, 2008 8. Chavalit-Dhamrong D, Gill J, Takemoto S, et al: Patient and graft outcomes from deceased kidney donors age 70 years and older: an analysis of the Organ Procurement Transplant Network of Organ Sharing database. Transplantation 85:1573, 2008
A
tation. However, some studies suggest that the criteria used at the time of transplantation are not sufficient to predict the graft outcomes.2 It has been proposed that kidneys from older donors can be more immunogenic than those from younger individuals, resulting in an increased incidence of acute interstitial rejection episodes early posttransplantation.3 It will be necessary to analyze the impact of improved immunosuppressive regimens on outcomes of the grafts. From the Nephrology (C.G., R.M., S.J., A.F.R., H.S., J.J.V., J.L.T., C.Q.) and Urology Departments (F.J.B.), Hospital Ramón y Cajal, Madrid, Spain. Address correspondence to Cristina Galeano, MD, Ctra de Colmenar, km 9,100. 28034, Madrid, Spain. E-mail: cgaleanoalvarez@ gmail.com
© 2010 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.2010.08.069
Transplantation Proceedings, 42, 3935–3937 (2010)
3935
3936
GALEANO, MARCEN, JIMENEZ ET AL
Another important question is whether kidneys from older donors must be used only in older recipients. After 4 years of dialysis, older patients experience a longer life expectancy when they receive a graft from an older donor within 2 years of ESRD onset compared with waiting for a standard kidney or a living donor. In contrast, younger patients (⬍39 years) display a longer life expectancy with the other option.4 Earlier studies performed in Spain have shown the suitability of donors aged 60 – 65 years,5 highlighting the need to improve their clinical management. In the present single-center study, we evaluated the results of organs from donors ⬎70 years old, comparing them with those from younger donors. PATIENTS AND METHODS All 401 consecutive primary renal transplants from deceased donors performed in our unit from January 2000 to December 2009 were included in the study. Data regarding recipients, donors, and transplants were collected from an electronic database. Recipient data included age, gender, dialysis modality, time on dialysis, and primary renal disease. Donor data included age, gender, cause of death, and pretransplant histology of the kidney when available. Transplant variables included warm and cold ischemia times, immediate renal function, rejection episodes, patient and graft outcomes and causes of death or graft loss. The glomerular filtration rate (GFR) was estimated using the abbreviated Modification of Diet in Renal Disease equation (eGFR (mL/min/1.73 m2): exp(5.228 ⫺ 1.154 ⫻ ln(SCr) ⫺ 0.203 ⫻ ln(age) ⫺ (0.299 if female) ⫹ 0.192 if African-American). There were 252 male and 149 female patients, whose average age at transplantation was 52.8 ⫾ 13.7 years. The mean time on dialysis was 25.9 ⫾ 23.1 months. The initial immunosuppression was a tacrolimus-based (n ⫽ 324) cyclosporine-based (n ⫽ 70), or a calcineurin inhibitor– free (n ⫽ 7) regimen. Altogether, 42.6% of the patients received a graft from a donor ⬍50, 39.7% from a donor 50 –70, and 17.5% from a donor ⬎70 years old. Kidneys from a donor ⬎65 years-old transplanted only when ⬍20% of glomerulae were sclerotic. Continuous variables are expressed as mean ⫾ SD and categoric ones as percentages. Group comparisons were performed by variance analysis and Kruskal-Wallis tests for parametric and nonparametric continuous data, respectively. The chi-squared test was used to compare categoric variables. Survival data were
assessed with the Kaplan-Meier method and the Cox proportional hazard regression model (univariate and multivariate). A 2-tailed P value of .05 was considered to be statistically significant.
RESULTS
There were no differences among the groups according to recipient gender, time on dialysis, cold ischemia, donor gender, incidence of delayed graft function, or incidence of rejection episodes (Table 1). However, the recipient age was greater among patients who received grafts from donors ⬎70 years (P ⫽ .000). Serum creatinine at 12 months showed increases with donor age: 1.4 ⫾ 0.6 mg/dL for ⬍50; 1.8 ⫾ 0.6 for 50 –70 and 1.7 ⫾ 0.5 for ⬎70; P ⫽ .001. In addition, the eGFR at 3 and 12 months were higher among patients with donor ages below 50 years old (P ⫽ .000). The actuarial graft survival rates at 1, 3, and 5 years, respectively, were 86%, 83%, and 81% for ⬍50-year-old donors; 88%, 83%, and 74% for 50 –70-year-old donors, and 81%, 81% and 70% for ⱖ 70-year-old donors (P ⫽ .519). Upon multivariate analysis, HLA-DR mismatches (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.02–1.75; P ⬍ .050), delayed graft function (HR, 2.07; 95% CI, 1.35–3.19; P ⬍ .001), and perhaps acute rejection (HR 1.62; 95% CI, 0.92–2.85; P ⫽ .093) were the variables associated with graft survival. Ninety-six grafts were lost: 36 in the group of ⬍50 y; 46 in the group of 50 –70, and 14 in the group of ⬎70-year-old donors. No differences were observed in the causes of graft loss among the groups; vascular complications and death with a functioning graft were the main causes of graft loss. Forty-five recipients died during the follow-up: 8 in the ⬍50, 28 in the 50 –70 and 8 in the ⱖ70-year-old donor group. The actuarial patient survival rates at 1, 3, and 5 years, respectively, were 98%, 97%, and 96% for ⬍50 y, 94%, 92%, and 85% for 50 –70, and 90%, 86%, and 86% for ⱖ70-year-old donors (P ⫽ .003). Multivariate analysis showed the variables associated with patient survival to be age at transplant in years (HR, 1.08; 95% CI, 1.04 –1.13; P ⫽ .000), time on dialysis in months (HR, 1.02; 95% CI, 1.01–1.03; P ⫽ .002) and serum creatinine (mg/dL) at 3 months (HR, 1.97; 95% CI, 1.20 – 3.25; P ⫽ .008).
Table 1. Characteristics of the Patients According to Donor Age ⬍50 y
Age (y) Gender (M/F) Time on dialysis (mo) Cold ischemia time (h) ATN (yes/no) Early rejection (yes/no) Immunosuppression TAC CsA ACI free eGFR, 3 m eGFR, 12 m *P ⬍.01 versus donors ⬍50 y.
50–70 y
⬎70 y
P Value
42.5 ⫾ 12.4 104/67 27.1 ⫾ 25.9 17.1 ⫾ 4.4 63/108 18/153
58.1 ⫾ 8.2 106/54 26.9 ⫾ 21.4 17.6 ⫾ 4.4 65/95 23/137
65.7 ⫾ 7.2 42/28 20.9 ⫾ 18.9 16.2 ⫾ 4.8 27/43 6/64
.000 .512 .143 .143 .779 .368
140 28 3 52.0 ⫾ 17.3 58.4 ⫾ 18.7
123 35 2 39.5 ⫾ 14.1* 42.6 ⫾ 13.8*
61 7 2 35.1 ⫾ 9.4* 39.5 ⫾ 9.7*
.237
.000 .000
ELDERLY DONORS AND KIDNEY GRAFT SURVIVAL
DISCUSSION
The 17% prevalence of older donors was higher than that reported from a Spainish study of 3,365 adult patients in which 14.8% of donors were ⬎60 years4 old5. The increased prevalence of donors ⬎70 years old represents the acceptance of expanded-criteria donors to address the problem of the growing waiting list. Moreover, data have recently been reported regarding patient and graft outcomes of recipients of transplanted kidneys from donors aged ⬎75 years.2,6. Collini et al6 have shown that in Tuscan transplant centers as many as 20% of all donations in 2006 were obtained from individuals ⬎75 years of age. Graft survival was excellent in our series compared with other studies. In the Eurotransplant Senior Program (ESP), in which kidneys from donors aged ⱖ65 years were given to recipients aged ⱖ65 years, the graft survival at 5 years was 47%.7 In the United Network of Organ Sharing Database, it was 44%.8 These outcomes were far from our 71% rate. Differences in the characteristics of the populations may in part explain these results. Our study showed 7–11% lower short-term graft survival in recipients of kidney donor from age ⱖ50 years than in the younger set, but the difference was not significant. An important point was the lack of difference in graft survival between kidneys coming from 50 –70-year-old donors and those from donors aged ⬎70 years. These findings differ from other multicenter studies showing significantly lower graft survival.5,8 Nevertheless, donor age was not a risk factor for short-term graft loss in the multivariate analysis. When we compared 3 groups categorized by donor age, no differences were observed in the time on dialysis, the prevalence of delayed graft function, or rejection episodes or in the initial immunosuppression. Some authors have reported an increased incidence of rejection episodes among kidneys from older donors. It has been suggested that older-donor kidneys are more immunogenic than those from young donors.3 Because there were no differences in cold ischemia times, HLA mismatches, or immunosuppres-
3937
sion regimens, our acceptance of older donors was not accompanied by efforts to minimize any negative impact of factors that could influence early graft function or rejection incidences. Graft function at 3 and 12 months was significantly worse among recipients transplanted from older donors. Similar results have been observed in earlier studies; kidneys from older donors have been associated with increased serum creatinine values at 3 and 12 months.5 In conclusion, our data showed that old transplanted kidneys into old recipients display an excellent short-term graft outcomes. However, worse graft function is the price to be paid. The results of this retrospective single-center study should be interpreted with caution until we have a broader experience with larger patient sample and longer follow-up. REFERENCES 1. Heldal K, Hartmann A, Grootendorst DC, et al: Benefit of kidney transplantation beyond 70 years of age. Nephrol Dial Transplant 25:1680, 2010 2. Foss A, Heldal K, Scott H, et al: Kidney from deceased donors more than 75 years perform acceptably after transplantation. Transplantation 87:1437, 2009 3. de Fijter JW, Mallat MJK, Doxiadis II, et al: Increased immunogenicity and cause of graft loss of old donor kidneys. J Am Soc Nephrol 12:1538, 2001 4. Schold JD, Meier-Kriesche HU: Which renal transplant candidates should accept marginal kidneys in exchange for a shorter waiting time on dialysis? Clin J Am Soc Nephrol 1:532, 2006 5. Oppenheimer F, Aljama P, Asensio C, et al: The impact of donor age on the results of renal transplantation. Nephrol Dial Transplant 19(Suppl 3):iii11, 2004 6. Collini A, Kalmar P, Dhamo A, et al: Renal transplant from very old donors: how far can we go? Transplantation 87:1830, 2009 7. Frei U, Noeldeke J, Machold-Fabrizi V, et al: Prospective age-matching in elderly kidney transplant recipients— 5-year analysis of the Eurotransplant Senior Program. Am J Transplant 8:50, 2008 8. Chavalit-Dhamrong D, Gill J, Takemoto S, et al: Patient and graft outcomes from deceased kidney donors age 70 years and older: an analysis of the Organ Procurement Transplant Network of Organ Sharing database. Transplantation 85:1573, 2008