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The Impact of Donor Factors on Early Graft Function in Kidney Transplantation From Donation After Cardiac Death
The Impact of Donor Factors on Early Graft Function in Kidney Transplantation From Donation After Cardiac Death T. Ishimura, M. Muramaki, H. Kishikawa, H. Miyake, K. Tanaka, K. Nishimura, M. Nojima, S. Yamamoto, Y. Ichikawa, and M. Fujisawa ABSTRACT Donation after cardiac death (DCD) has the potential to significantly increase the number of organ donors. In this study, we investigate the influence of several donor parameters on the early graft function in kidney transplantation from DCD donors. We performed 58 kidney transplantations from DCD donors. Recipients were divided into 2 groups according to their graft function: normal graft function (NGF), patients who became be free of hemodialysis within 14 days post-transplantation) and delayed graft function (DGF) group, patients who required hemodialysis for longer than 15 days after transplantation). We compared donor age, sex, cause of death, warm and total ischemic time, duration of anuria (urine volume < 10 mL/h), and low blood pressure (systolic blood pressure < 60 mm Hg), usage of catecholamine and vasopressin, serum creatinine on the day of admission and graft retrieval, serum sodium concentration, and body temperature between 2 groups. The number of recipients in NGF and DGF group was 41 and 17. Univariate analysis revealed that duration of anuria (<24 vs 24 hours) and usage of catecholamine significantly influenced graft function. Duration of anuria was an independent risk factor for early graft function by multivariate analysis. In cadaveric kidney transplantation from DCD donors, there was a trend to poorer early graft function with donors who suffered from anuria for longer than 24 hours before kidney retrieval.
R
ECENTLY, THE CRITICAL SHORTAGE of organ donation has led to worldwide interest in cadaveric kidney transplantation from donation after cardiac death (DCD) [1,2]. Kidneys from DCD donors, unlike those donated after brain death, undergo long warm ischemia before procurement, which results in delayed graft function after transplantation [3]. However, recent reports show that long-term graft function from DCD donors is satisfactory, and such evidence has led transplant surgeons to accept such grafts for their patients [4]. On the other hand, it is fact that organs from DCD donors are inevitably subjected to unfavorable condition such as prolonged low blood pressure, anuria, hypernatremia, and high body temperature before declaration of death by cardiocirculatory arrest with subsequent organ retrieval. Although donor age, cause of death, and history of hypertension are known to be the important donor factors that influence graft function in kidney transplantation by donation after brain death, risk factors in kidney transplantation from DCD donors, including the above-mentioned stress attributed to a prolonged agonal period, are scarcely reported. In this study, we investigate the
influence of several donor parameters on the early graft function in kidney transplantation from DCD donors. PATIENTS AND METHODS From January 1999 to February 2010, we performed 58 cadaveric kidney transplantations from 29 noneheart-beating donors in Hyogo prefecture. The initial immunosuppression protocol consisted of quadruple sequential treatment with azathioprine or mycophenolate mofetil, prednisone, cyclosporine, or tacrolimus and antieinterleukin-2 receptor monoclonal antibody (basiliximab). Recipients were divided into 2 groups according to their graft function, that is, normal graft function (NGF) group (patients who
From the Department of Urology (T.I., M.M., H.M., K.T., M.F.), Kobe University; Department of Urology (H.K., K.N.), Hyogo Prefectural Nishinomiya Hospital; Department of Urology (M.N., S.Y.), Hyogo Medical College; and Joyoejiri Hospital (Y.I.), Kobe, Hyogo, Japan. Address correspondence to Dr. Takeshi Ishimura, Kobe University, Urology, 7-5-1 Kusunokicho ChuokuKobe, Hyogo, Japan. E-mail: [email protected]
0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.11.070
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1064
Transplantation Proceedings, 46, 1064e1066 (2014)
DONOR FACTORS AND EARLY GRAFT FUNCTION became to be free of hemodialysis within 14 days post transplantation) and delayed graft function (DGF) group (patients who required hemodialysis for longer than 15 days after transplantation). We investigated the influence of several donor factors by logistic regression analysis, including age, sex, cause of death, warm and total ischemic time, duration of anuria (defined as urine volume < 10 mL/ h), low blood pressure (defined as systolic blood pressure < 60 mm Hg), usage of catecholamine and vasopressin, serum creatinine on the day of admission and kidney retrieval, serum sodium concentration, and body temperature on early graft function.
RESULTS
Mean donor age was 51.3 14.7. Warm and total ischemic time and duration of anuria and low blood pressure were 5.8 6.0, 767.4 338.1, 606.6 727.4, and 831.8 909.5 minutes, respectively (Table 1). Among 58 recipients, 2 experienced primary nonfunction. In the remaining 56 patients, the average duration of hemodialysis posttransplantation was 13.9 14.5 days. The number of recipients in NGF and DGF group was 41 and 17 (including 2 primary nonfunction cases). Average serum creatinine in 56 patients at 1 year after transplantation was 1.8 0.7 (mg/dL). Univariate analysis reveals that duration of anuria (<24 vs 24 hours) and usage of catecholamine significantly influenced early graft function (Table 2). By multivariate analysis using these 2 parameters, duration of anuria was shown to be an independent risk factor (Table 3). Table 1. Donors and Recipients Demographics Median (MineMax, Average SD)
Donor (n ¼ 29) Age (y) 53 (26e75, 51.3 14.7) Gender (M/F) 40/18 Cause of death (CVD/others) 32/26 Duration of anuria (min)* 307 (0e2225, 606.6 727.4) Duration of low sBP (min)** 435 (0e3255, 831.8 909.5) Warm ischemic time (min) 3 (0e24, 5.8 6. 0) Total ischemic time (min) 715 (276e1747, 767.4 338.1) Catecholamine (yes/no) 40/18 Vasopressin (yes/no) 27/31 Serum Cr on admission (mg/dL) 0.8 (0.4e1.6, 0.9 0.3) Serum Cr at organ retrieval 2.0 (0.3e11.5, 3.1 2.9) (mg/dL) Serum sodium at organ 148 (125e181, 151.9 14.9) retrieval (mEq/L) Body temperature at organ 36.8 (34.0e42.6, 37.0 1.8) retrieval ( C) Recipient (n ¼ 58) Age (y) Gender (M/F) Duration on hemodialysis after 10 (0e90, 13.9 14.5) kidney transplantation (d) Serum Cr at 1 y after 1.7 (0.5e3.9, 1.8 0.7) transplantation Abbreviations: CVD, cardiovascular disease; sBP, systolic blood pressure; Cr, creatinine; Min, minimum; Max, maximum. *Urine volume < 10 mL/h. **Systolic blood pressure < 60 mm Hg.
1065 Table 2. Risk Factors for Early Graft Function: Univariate Analysis
Age (>60/60 y) Gender (M/F) Cause of death (CVD/others) In situ cannulation before cardiac arrest (yes/no) Warm ischemic time (<15/15 min) Total ischemic time (<24/24 h) Duration of anuria (<24/24 h) Duration of low sBP (<24/24 h) Catecholamine (yes/no) Vasopressin (yes/no) Serum Cr on admission (<1.0/1.0 mg/dL) Serum Cr at organ retrieval (>5.0/5.0 mg/dL) Sodium at organ retrieval (>150/150 mEq/L) Body temperature at organ retrieval (>38/38 C)
n
P
22/36 40/18 32/26 42/16 52/6 53/5 46/12 38/20 40/18 12/46 42/16 46/12 34/24 48/10
.35 .28 .34 .10 .97 .63 .003 .06 .05 .10 .65 .71 .54 .95
Abbreviations: CVD, cardiovascular disease; sBP, systolic blood pressure; Cr, creatinine.
DISCUSSION
In Japan, until the organ transplant law revision in 2010, most cadaveric kidney transplantations were performed using kidneys from DCD donors. These DCD donors suffered massive irreversible brain injury and fulfilled the criteria for clinical brain-stem death. In these donors, interval from diagnosis of clinical brain death to natural cessation of cardiopulmonary function tends to be very long [1e4]. It incurs low blood pressure and requires catecholamine administration, which causes anuria or elevation of serum creatinine before kidney retrieval. In addition, most kidneys of such donors are exposed to substantial metabolic and hormonal disturbances, such as abnormal body temperature and hypernatremia, which accompany brain death. To make best use of kidneys from DCD donors, the factors that affect outcome after transplantation need to be understood. We set no absolute cutoff or limitation in donor age, cause of death, duration of low blood pressure, usage of catecholamine or vasopressin, or serum creatinine at retrieval when we determine the application of kidney in transplantation. We basically believe that kidney is available for transplantation if duration of anuria is less than 24 hours. If duration of anuria exceeds 24 hours, other clinical information such as duration of low blood pressure is taken into consideration to decide the indication of kidney graft for transplantation. Kidneys are regarded as not preferable for transplantation if the duration of anuria exceeds 48 Table 3. Analysis of Risk Factors for Early Graft Function
n
Duration of anuria 12/46 (>24/24 h) Catecholamine 39/17 (yes/no)
Multivariate
Univariate P
P
Odds Ratio
95% CI
.003
.017
0.75
0.094e6.01
.05
.25
2.7
0.48e14.6
Abbreviation: CI, confidence interval.
1066
hours. Using these criteria, we performed 58 kidney transplantations from 29 DCD donors. Although some of these donors experienced extremely high body temperature or serum sodium before retrieval, most recipients recovered and only 2 of them had primary nonfunction. By univariate analysis, age, sex, cause of death, warm and total ischemic time, usage of vasopressin, serum creatinine on the day of admission and kidney retrieval, serum sodium concentration, and body temperature had no impact on early graft function. Multivariate analysis revealed that prolonged periods of anuria negatively impacted early graft function, resulting in long-term graft dysfunction. In conclusion, we can utilize kidney from DCD donors although their body temperature, serum sodium, and serum creatinine are elevated abnormally on the day
ISHIMURA, MURAMAKI, KISHIKAWA ET AL
of retrieval unless the period of anuria is less than 24 hours.
REFERENCES [1] D’Alessandro AM, Fernandez LA, Chin LT, et al. Donation after cardiac death: the University of Wisconsin experience. Ann Transplant 2004;9:68. [2] Snoeijs MG, Wiermans B, Christiaans MH, et al. Recipient hemodynamics during noneheart-beating donor kidney transplantation are major predictors of primary non-function. Am J Transplant 2007;7:1158. [3] Sohrabi S, Navarro A, Wilson C, et al. Renal graft function after prolonged agonal time in non-heart-beating donors. Transplant Proc 2006;38:3400. [4] Goldsmith PJ, Pine JK, Ridgway DM, et al. Renal transplantation following donation after cardiac death: impact of duration from withdrawal to asystole. Transplant Proc 2010;42:3966.
R
ECENTLY, THE CRITICAL SHORTAGE of organ donation has led to worldwide interest in cadaveric kidney transplantation from donation after cardiac death (DCD) [1,2]. Kidneys from DCD donors, unlike those donated after brain death, undergo long warm ischemia before procurement, which results in delayed graft function after transplantation [3]. However, recent reports show that long-term graft function from DCD donors is satisfactory, and such evidence has led transplant surgeons to accept such grafts for their patients [4]. On the other hand, it is fact that organs from DCD donors are inevitably subjected to unfavorable condition such as prolonged low blood pressure, anuria, hypernatremia, and high body temperature before declaration of death by cardiocirculatory arrest with subsequent organ retrieval. Although donor age, cause of death, and history of hypertension are known to be the important donor factors that influence graft function in kidney transplantation by donation after brain death, risk factors in kidney transplantation from DCD donors, including the above-mentioned stress attributed to a prolonged agonal period, are scarcely reported. In this study, we investigate the
influence of several donor parameters on the early graft function in kidney transplantation from DCD donors. PATIENTS AND METHODS From January 1999 to February 2010, we performed 58 cadaveric kidney transplantations from 29 noneheart-beating donors in Hyogo prefecture. The initial immunosuppression protocol consisted of quadruple sequential treatment with azathioprine or mycophenolate mofetil, prednisone, cyclosporine, or tacrolimus and antieinterleukin-2 receptor monoclonal antibody (basiliximab). Recipients were divided into 2 groups according to their graft function, that is, normal graft function (NGF) group (patients who
From the Department of Urology (T.I., M.M., H.M., K.T., M.F.), Kobe University; Department of Urology (H.K., K.N.), Hyogo Prefectural Nishinomiya Hospital; Department of Urology (M.N., S.Y.), Hyogo Medical College; and Joyoejiri Hospital (Y.I.), Kobe, Hyogo, Japan. Address correspondence to Dr. Takeshi Ishimura, Kobe University, Urology, 7-5-1 Kusunokicho ChuokuKobe, Hyogo, Japan. E-mail: [email protected]
0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.11.070
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1064
Transplantation Proceedings, 46, 1064e1066 (2014)
DONOR FACTORS AND EARLY GRAFT FUNCTION became to be free of hemodialysis within 14 days post transplantation) and delayed graft function (DGF) group (patients who required hemodialysis for longer than 15 days after transplantation). We investigated the influence of several donor factors by logistic regression analysis, including age, sex, cause of death, warm and total ischemic time, duration of anuria (defined as urine volume < 10 mL/ h), low blood pressure (defined as systolic blood pressure < 60 mm Hg), usage of catecholamine and vasopressin, serum creatinine on the day of admission and kidney retrieval, serum sodium concentration, and body temperature on early graft function.
RESULTS
Mean donor age was 51.3 14.7. Warm and total ischemic time and duration of anuria and low blood pressure were 5.8 6.0, 767.4 338.1, 606.6 727.4, and 831.8 909.5 minutes, respectively (Table 1). Among 58 recipients, 2 experienced primary nonfunction. In the remaining 56 patients, the average duration of hemodialysis posttransplantation was 13.9 14.5 days. The number of recipients in NGF and DGF group was 41 and 17 (including 2 primary nonfunction cases). Average serum creatinine in 56 patients at 1 year after transplantation was 1.8 0.7 (mg/dL). Univariate analysis reveals that duration of anuria (<24 vs 24 hours) and usage of catecholamine significantly influenced early graft function (Table 2). By multivariate analysis using these 2 parameters, duration of anuria was shown to be an independent risk factor (Table 3). Table 1. Donors and Recipients Demographics Median (MineMax, Average SD)
Donor (n ¼ 29) Age (y) 53 (26e75, 51.3 14.7) Gender (M/F) 40/18 Cause of death (CVD/others) 32/26 Duration of anuria (min)* 307 (0e2225, 606.6 727.4) Duration of low sBP (min)** 435 (0e3255, 831.8 909.5) Warm ischemic time (min) 3 (0e24, 5.8 6. 0) Total ischemic time (min) 715 (276e1747, 767.4 338.1) Catecholamine (yes/no) 40/18 Vasopressin (yes/no) 27/31 Serum Cr on admission (mg/dL) 0.8 (0.4e1.6, 0.9 0.3) Serum Cr at organ retrieval 2.0 (0.3e11.5, 3.1 2.9) (mg/dL) Serum sodium at organ 148 (125e181, 151.9 14.9) retrieval (mEq/L) Body temperature at organ 36.8 (34.0e42.6, 37.0 1.8) retrieval ( C) Recipient (n ¼ 58) Age (y) Gender (M/F) Duration on hemodialysis after 10 (0e90, 13.9 14.5) kidney transplantation (d) Serum Cr at 1 y after 1.7 (0.5e3.9, 1.8 0.7) transplantation Abbreviations: CVD, cardiovascular disease; sBP, systolic blood pressure; Cr, creatinine; Min, minimum; Max, maximum. *Urine volume < 10 mL/h. **Systolic blood pressure < 60 mm Hg.
1065 Table 2. Risk Factors for Early Graft Function: Univariate Analysis
Age (>60/60 y) Gender (M/F) Cause of death (CVD/others) In situ cannulation before cardiac arrest (yes/no) Warm ischemic time (<15/15 min) Total ischemic time (<24/24 h) Duration of anuria (<24/24 h) Duration of low sBP (<24/24 h) Catecholamine (yes/no) Vasopressin (yes/no) Serum Cr on admission (<1.0/1.0 mg/dL) Serum Cr at organ retrieval (>5.0/5.0 mg/dL) Sodium at organ retrieval (>150/150 mEq/L) Body temperature at organ retrieval (>38/38 C)
n
P
22/36 40/18 32/26 42/16 52/6 53/5 46/12 38/20 40/18 12/46 42/16 46/12 34/24 48/10
.35 .28 .34 .10 .97 .63 .003 .06 .05 .10 .65 .71 .54 .95
Abbreviations: CVD, cardiovascular disease; sBP, systolic blood pressure; Cr, creatinine.
DISCUSSION
In Japan, until the organ transplant law revision in 2010, most cadaveric kidney transplantations were performed using kidneys from DCD donors. These DCD donors suffered massive irreversible brain injury and fulfilled the criteria for clinical brain-stem death. In these donors, interval from diagnosis of clinical brain death to natural cessation of cardiopulmonary function tends to be very long [1e4]. It incurs low blood pressure and requires catecholamine administration, which causes anuria or elevation of serum creatinine before kidney retrieval. In addition, most kidneys of such donors are exposed to substantial metabolic and hormonal disturbances, such as abnormal body temperature and hypernatremia, which accompany brain death. To make best use of kidneys from DCD donors, the factors that affect outcome after transplantation need to be understood. We set no absolute cutoff or limitation in donor age, cause of death, duration of low blood pressure, usage of catecholamine or vasopressin, or serum creatinine at retrieval when we determine the application of kidney in transplantation. We basically believe that kidney is available for transplantation if duration of anuria is less than 24 hours. If duration of anuria exceeds 24 hours, other clinical information such as duration of low blood pressure is taken into consideration to decide the indication of kidney graft for transplantation. Kidneys are regarded as not preferable for transplantation if the duration of anuria exceeds 48 Table 3. Analysis of Risk Factors for Early Graft Function
n
Duration of anuria 12/46 (>24/24 h) Catecholamine 39/17 (yes/no)
Multivariate
Univariate P
P
Odds Ratio
95% CI
.003
.017
0.75
0.094e6.01
.05
.25
2.7
0.48e14.6
Abbreviation: CI, confidence interval.
1066
hours. Using these criteria, we performed 58 kidney transplantations from 29 DCD donors. Although some of these donors experienced extremely high body temperature or serum sodium before retrieval, most recipients recovered and only 2 of them had primary nonfunction. By univariate analysis, age, sex, cause of death, warm and total ischemic time, usage of vasopressin, serum creatinine on the day of admission and kidney retrieval, serum sodium concentration, and body temperature had no impact on early graft function. Multivariate analysis revealed that prolonged periods of anuria negatively impacted early graft function, resulting in long-term graft dysfunction. In conclusion, we can utilize kidney from DCD donors although their body temperature, serum sodium, and serum creatinine are elevated abnormally on the day
ISHIMURA, MURAMAKI, KISHIKAWA ET AL
of retrieval unless the period of anuria is less than 24 hours.
REFERENCES [1] D’Alessandro AM, Fernandez LA, Chin LT, et al. Donation after cardiac death: the University of Wisconsin experience. Ann Transplant 2004;9:68. [2] Snoeijs MG, Wiermans B, Christiaans MH, et al. Recipient hemodynamics during noneheart-beating donor kidney transplantation are major predictors of primary non-function. Am J Transplant 2007;7:1158. [3] Sohrabi S, Navarro A, Wilson C, et al. Renal graft function after prolonged agonal time in non-heart-beating donors. Transplant Proc 2006;38:3400. [4] Goldsmith PJ, Pine JK, Ridgway DM, et al. Renal transplantation following donation after cardiac death: impact of duration from withdrawal to asystole. Transplant Proc 2010;42:3966.