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Prognostic Value of Absent End-Diastolic Flow Within the First Week Following Renal Transplantation
Prognostic Value of Absent End-Diastolic Flow Within the First Week Following Renal Transplantation S. Ba, J.-M. Halimi, A. Al-Najjar, C. Barbet, M. Buchler, L. Brunereau, Y. Lebranchu, and F. Tranquart ABSTRACT Background. Doppler sonogram of the graft is used as a routine assessment in renal transplantation. When the resistance index (RI) equals 1, absent end-diastolic flow (AEDF) is observed; the prognostic value of AEDF is presently unknown. Patients and Methods. Between 1988 and 1996, 342 patients received a first cadaveric kidney transplant in our ward. AEDF was observed in 30 patients who were compared with 60 controls who showed an RI ⬍ 0.75 within the first 7 days after transplantation. They were matched for year of transplantation (⫾1 year); recipient age (⫾2 years); recipient sex; and HLA antibodies (3 classes: 0%, 1–75%, ⬎75%). The follow-up was 4 years. Results. AEDF was observed at day 1 in 64%, at day 3 in 96%, and at day 7 in 28%. Recipient age, donor age, recipient sex, cold and warm ischemia durations, HLA A, B, and DR mismatches, and cytomegalovirus (CMV) status were not different between the 2 groups. Immediate graft function and 3- to 24-month creatinine levels were better in the control than the AEDF group. However, there was no difference in serum creatinine at 3 and 4 years or in patient and graft survivals during follow-up. Conclusions. AEDF observed within the first week following transplantation is associated with impaired renal functional recovery. However, whether AEDF is a prognostic marker of poor long-term graft function or survival remains to be proven.
O
PTIMAL MANAGEMENT of renal transplants includes an early sonogram to detect complications and avoid irreversible damage. A sonogram provides an easy morphological and functional assessment of the renal transplant.1 The normal renal artery shows forward systolic and diastolic flow due to low distal vascular resistance thereby maintaining high perfusion of the kidney. This vascular resistance is quantified by calculation of Doppler indices, such as the resistance index (RI), which is the ratio of the systolodiastolic difference divided by the systolic velocity. When RI equals 1, there is decreased diastolic velocity corresponding to absent end-diastolic flow (AEDF). RI has a limited sensitivity and specificity: an increased RI may reflect acute rejection, tubular necrosis, vascular thrombosis, ureteral obstruction, or compression; however, RI can also be normal in these situations.2,3 In contrast, the predictive value of AEDF has not been assessed in renal transplantation. Specifically, it is presently unknown whether AEDF early after transplantation predicts a poor outcome. The aim of the present study was to evaluate the predictive value of AEDF for long-term transplant function. © 2009 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 41, 645– 647 (2009)
PATIENTS AND METHODS Between 1988 and 1996, 342 patients received a first kidney transplant in our ward. After harvesting, the kidneys were perfused with Euro-Collins (EC) solution and immediately before transplantation, reperfused with EC solution containing diltiazem (50 mg in 10 mL for 15 minutes). The renal artery was anastomosed end-toside to the external iliac artery in all patients. Each patient received the following immunosuppressive regimen: (1) antithymocyte globulin (Thymoglobuline, Mérieux, France) for the first 14 days and monitored by blood T-lymphocyte counts; (2) prednisone (1 mg/ kg/d) for the first 3 weeks, then reduced to 5 or 10 mg/d over 6 weeks; (3) azathioprine (2.5 mg/kg/d) adjusted subsequently according to white blood cell (WBC) counts; and (4) cyclosporine (6
From the Department of Imaging, INSERM U930-CNRS 2448 (S.B., L.B., F.T.), and Department of Nephrology and Clinical Immunology (J.-M.H., A.A.-N., C.B., M.B., Y.L.), François Rabelais University, CHU Tours, France. Address reprint requests to Jean-Michel Halimi, MD, PhD, Service de Néphrologie-Immunologie Clinique, Hôpital Bretonneau, 2, Bd Tonnellé, 37044 Tours Cedex, France. E-mail: halimi@med. univ-tours.fr 0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2008.12.006 645
646 mg/kg/d) on day 13 posttransplantation adjusted to yield whole blood trough levels of 100 to 200 mg/mL, as measured by a radioimmunoassay (RIA) with monoclonal antibodies. All patients were examined using Doppler sonogram between the first and third days after surgery using an Acuson 128 XP (Mountain View, Calif, United States) with 3.5 and 5 MHz probes. This examination was divided into 2 parts: the first consisted of a morphological examination of the transplant and the second color Doppler imaging with spectral recordings from renal, interlobar, and arcuate arteries. RI was determined in these arteries. AEDF was observed in 30 patients who were matched with 60 controls who showed an RI ⬍ 0.75 within the first 7 days after transplantation based on year of transplantation (⫾1 year), recipient age (⫾2 years), recipient sex, and HLA antibodies (3 classes: 0%, 1–75%, ⬎75%). Complications were reported during the 4-year follow-up. Acute tubular necrosis was defined by occurrence during the first week after surgery, the absence of vascular disease associated with permanent kidney failure, and normalization in 2 to 3 weeks. Results are expressed as percentages or as mean values ⫾ standard deviations. Graft survival rates were computed using the Kaplan-Meier method with comparisons using the log-rank test (Fig 1). Analyses were performed using SAS 8.0 (SAS Institute Inc, Cary, NC, United States); P ⬍ .05 was considered significant.
RESULTS
In the patient group, AEDF was observed at day 1 in 64%, at day 3 in 96%, and at day 7 in 28%. Recipient age, donor age, recipient sex, cold and warm ischemia durations, HLA A, B, and DR mismatches, and cytomegalovirus (CMV) status were not different between the 2 groups (Table 1). During follow-up, 4 deaths were reported: 1 in the exposed and 3 in the control group without a significant difference (relative risk [RR]: 0.670 [0.070 – 6.441]; P ⫽ .728). There were 13 graft losses, 5 in the exposed group and 8 in the control group (RR: 1.36 [0.430 – 4.023]; P ⫽ .630).
BA, HALIMI, AL-NAJJAR ET AL Table 1. Patient Characteristics
Donor age (y) Recipient age (y) Donor sex (% male) Recipient sex (% male) Cold ischemia time (min) Warm ischemia time (min) HLA mismatches A B DR Total Maximal anti-HLA Panel-reactive antibodies (%) Donor cytomegalovirus status (% positive) Recipient cytomegalovirus status (% positive)
AEDF Group (n ⫽ 30)
Controls (n ⫽ 60)
37.4 ⫾ 16.5 48.7 ⫾ 13.0 73 57 1598 ⫾ 477 57 ⫾ 15
36.7 ⫾ 12.0 48.0 ⫾ 14.1 70 58 1440 ⫾ 494 55 ⫾ 22
.960 .812 .742 .880 .210 .170
0.9 ⫾ 0.7 1.2 ⫾ 0.7 1.2 ⫾ 0.6 3.3 ⫾ 1.2 15.1 ⫾ 27.0 4.8 ⫾ 16.6 35
0.9 ⫾ 0.6 1.3 ⫾ 0.7 1.1 ⫾ 0.6 3.3 ⫾ 1.1 27.0 ⫾ 1.9 4.8 ⫾ 16.6 27
.700 .690 .400 .820 .940 .510 .430
60
60
1.000
P
Creatinine levels at 3, 6, 12, and 24 months, time to obtain a daily diuresis ⬎ 1 L, and absence of delayed graft function (DGF 40% vs 23%, P ⫽ .10) were greater in the AEDF group (Table 2); P ⫽ .004, .039, .07, .05, and .10, respectively). The time to achieve a serum creatinine ⬍ 250 mol/L was longer in the exposed group (13.7 ⫾ 5.0 vs 7.8 ⫾ 6.3 days; P ⫽ .0001). The rate of acute tubular necrosis tended to be higher in the AEDF group (RR: 1.714; P ⫽ .1). No difference was noted with regard to acute rejection episodes, renal artery stenosis, or renal vein thrombosis. However, no significant difference in serum creatinine at 36 and 48 months or in the chronic rejection rate at 4 years was noted between the 2 groups (Table 2).
DISCUSSION
Fig 1. Graft survival in patients according to AEDF within the first week following transplantation.
The results of the present study indicated that AEDF observed in the first week following transplantation was associated with impaired renal functional recovery, reduced renal function at 1 and 2 years following transplantation, but not subsequent renal function or reduced graft and patient survival. Numerous risk factors for impaired graft survival have been previously identified, including recipient age, immunity status, cold and warm ischemic durations, and donor CMV status. These factors played no role in our findings. The present results may indicate that early RI assessment may be a marker of subsequent renal function independent of these parameters.4,5 AEDF is the consequence of abnormal vascular conditions in small vessels. AEDF is associated with poor perfusion in areas that play a role in kidney function, such as glomeruli, as illustrated by the initial dysfunction of the transplant. Persistence of dysfunction at 2 years after transplantation favors irreversible cellular lesions during the initial period of transplantation. These observations supported the value of a Doppler examination of transplanted kidneys to assess initial vascu-
PROGNOSTIC VALUE OF ABSENT END-DIASTOLIC FLOW
647
Table 2. Initial and Long-Term Renal Function According to AEDF Within the First Week Following Transplantation
Creatinine at month 3 (mol/L) Creatinine at month 6 (mol/L) Creatinine at month 12 (mol/L) Creatinine at month 24 (mol/L) Creatinine at month 36 (mol/L) Creatinine at month 48 (mol/L) Autonomy (d) Diuresis ⬎ 1000 mL/d (d) Creatinine ⬍ 250 mol/L (d) Chronic rejection at 4 years (%)
AEDF Group (n ⫽ 30)
Controls (n ⫽ 60)
P
153 ⫾ 80 (n ⫽ 29) 133 ⫾ 36 (n ⫽ 28) 132 ⫾ 48 (n ⫽ 28) 135 ⫾ 34 (n ⫽ 27) 137 ⫾ 49 (n ⫽ 26) 125 ⫾ 29 (n ⫽ 22) 5.6 ⫾ 4.0 3.7 ⫾ 4.0 13.7 ⫾ 5.0 38.3
122 ⫾ 39 (n ⫽ 60) 123 ⫾ 68 (n ⫽ 60) 116 ⫾ 34 (n ⫽ 59) 120 ⫾ 38 (n ⫽ 58) 135 ⫾ 104 (n ⫽ 57) 131 ⫾ 91 (n ⫽ 46) 2.6 ⫾ 3.7 2.4 ⫾ 3.4 7.8 ⫾ 6.3 43.3
.004 .039 .07 .05 .828 .851 .0001 .0300 .0001 .7890
lar conditions to identify kidneys with a high risk for long-term failure. AEDF is a frequent situation (9% in our population) which is easy to identify corresponding to dramatic vascular conditions. Should we consider AEDF to be an important event? In a previous study we reported a significant difference in vascular conditions as early as 30 minutes after unclamping between acute tubular necrosis and controls, demonstrating that initial vascular conditions are predictive of early renal function.5 The present study supported the view that AEDF has a short-term predictive value on renal function; however, whether it also has a long-term risk for graft loss remains to be proven.
REFERENCES 1. Taylor KJM, Marks WH: Use of Doppler imaging for evaluation of dysfunction in renal allografts. AJR 155:536, 1990 2. Trillaud H, Merville P, Tran Le linh Q, et al: Color Doppler sonography in early renal transplantation follow-up: resistive index versus power Doppler sonography. AJR 171:1611, 1998 3. Genkins SM, Sanfilippo FP, Carroll BA: Duplex sonography of renal transplants: lack of sensitivity and specificity in establishing pathologic diagnosis. AJR 152:535, 1989 4. Kelcz F, Pozniak MA, Pirsch JD, et al: Pyramidal appearance and resistive index: insensitive and nonspecific sonographic indicators of renal transplant rejection. AJR 155:531, 1990 5. Tranquart F, Lebranchu Y, Haillot O, et al: The use of perioperative Doppler ultrasound as a screening test for acute tubular necrosis. Transpl Int 6:14, 1993
O
PTIMAL MANAGEMENT of renal transplants includes an early sonogram to detect complications and avoid irreversible damage. A sonogram provides an easy morphological and functional assessment of the renal transplant.1 The normal renal artery shows forward systolic and diastolic flow due to low distal vascular resistance thereby maintaining high perfusion of the kidney. This vascular resistance is quantified by calculation of Doppler indices, such as the resistance index (RI), which is the ratio of the systolodiastolic difference divided by the systolic velocity. When RI equals 1, there is decreased diastolic velocity corresponding to absent end-diastolic flow (AEDF). RI has a limited sensitivity and specificity: an increased RI may reflect acute rejection, tubular necrosis, vascular thrombosis, ureteral obstruction, or compression; however, RI can also be normal in these situations.2,3 In contrast, the predictive value of AEDF has not been assessed in renal transplantation. Specifically, it is presently unknown whether AEDF early after transplantation predicts a poor outcome. The aim of the present study was to evaluate the predictive value of AEDF for long-term transplant function. © 2009 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 41, 645– 647 (2009)
PATIENTS AND METHODS Between 1988 and 1996, 342 patients received a first kidney transplant in our ward. After harvesting, the kidneys were perfused with Euro-Collins (EC) solution and immediately before transplantation, reperfused with EC solution containing diltiazem (50 mg in 10 mL for 15 minutes). The renal artery was anastomosed end-toside to the external iliac artery in all patients. Each patient received the following immunosuppressive regimen: (1) antithymocyte globulin (Thymoglobuline, Mérieux, France) for the first 14 days and monitored by blood T-lymphocyte counts; (2) prednisone (1 mg/ kg/d) for the first 3 weeks, then reduced to 5 or 10 mg/d over 6 weeks; (3) azathioprine (2.5 mg/kg/d) adjusted subsequently according to white blood cell (WBC) counts; and (4) cyclosporine (6
From the Department of Imaging, INSERM U930-CNRS 2448 (S.B., L.B., F.T.), and Department of Nephrology and Clinical Immunology (J.-M.H., A.A.-N., C.B., M.B., Y.L.), François Rabelais University, CHU Tours, France. Address reprint requests to Jean-Michel Halimi, MD, PhD, Service de Néphrologie-Immunologie Clinique, Hôpital Bretonneau, 2, Bd Tonnellé, 37044 Tours Cedex, France. E-mail: halimi@med. univ-tours.fr 0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2008.12.006 645
646 mg/kg/d) on day 13 posttransplantation adjusted to yield whole blood trough levels of 100 to 200 mg/mL, as measured by a radioimmunoassay (RIA) with monoclonal antibodies. All patients were examined using Doppler sonogram between the first and third days after surgery using an Acuson 128 XP (Mountain View, Calif, United States) with 3.5 and 5 MHz probes. This examination was divided into 2 parts: the first consisted of a morphological examination of the transplant and the second color Doppler imaging with spectral recordings from renal, interlobar, and arcuate arteries. RI was determined in these arteries. AEDF was observed in 30 patients who were matched with 60 controls who showed an RI ⬍ 0.75 within the first 7 days after transplantation based on year of transplantation (⫾1 year), recipient age (⫾2 years), recipient sex, and HLA antibodies (3 classes: 0%, 1–75%, ⬎75%). Complications were reported during the 4-year follow-up. Acute tubular necrosis was defined by occurrence during the first week after surgery, the absence of vascular disease associated with permanent kidney failure, and normalization in 2 to 3 weeks. Results are expressed as percentages or as mean values ⫾ standard deviations. Graft survival rates were computed using the Kaplan-Meier method with comparisons using the log-rank test (Fig 1). Analyses were performed using SAS 8.0 (SAS Institute Inc, Cary, NC, United States); P ⬍ .05 was considered significant.
RESULTS
In the patient group, AEDF was observed at day 1 in 64%, at day 3 in 96%, and at day 7 in 28%. Recipient age, donor age, recipient sex, cold and warm ischemia durations, HLA A, B, and DR mismatches, and cytomegalovirus (CMV) status were not different between the 2 groups (Table 1). During follow-up, 4 deaths were reported: 1 in the exposed and 3 in the control group without a significant difference (relative risk [RR]: 0.670 [0.070 – 6.441]; P ⫽ .728). There were 13 graft losses, 5 in the exposed group and 8 in the control group (RR: 1.36 [0.430 – 4.023]; P ⫽ .630).
BA, HALIMI, AL-NAJJAR ET AL Table 1. Patient Characteristics
Donor age (y) Recipient age (y) Donor sex (% male) Recipient sex (% male) Cold ischemia time (min) Warm ischemia time (min) HLA mismatches A B DR Total Maximal anti-HLA Panel-reactive antibodies (%) Donor cytomegalovirus status (% positive) Recipient cytomegalovirus status (% positive)
AEDF Group (n ⫽ 30)
Controls (n ⫽ 60)
37.4 ⫾ 16.5 48.7 ⫾ 13.0 73 57 1598 ⫾ 477 57 ⫾ 15
36.7 ⫾ 12.0 48.0 ⫾ 14.1 70 58 1440 ⫾ 494 55 ⫾ 22
.960 .812 .742 .880 .210 .170
0.9 ⫾ 0.7 1.2 ⫾ 0.7 1.2 ⫾ 0.6 3.3 ⫾ 1.2 15.1 ⫾ 27.0 4.8 ⫾ 16.6 35
0.9 ⫾ 0.6 1.3 ⫾ 0.7 1.1 ⫾ 0.6 3.3 ⫾ 1.1 27.0 ⫾ 1.9 4.8 ⫾ 16.6 27
.700 .690 .400 .820 .940 .510 .430
60
60
1.000
P
Creatinine levels at 3, 6, 12, and 24 months, time to obtain a daily diuresis ⬎ 1 L, and absence of delayed graft function (DGF 40% vs 23%, P ⫽ .10) were greater in the AEDF group (Table 2); P ⫽ .004, .039, .07, .05, and .10, respectively). The time to achieve a serum creatinine ⬍ 250 mol/L was longer in the exposed group (13.7 ⫾ 5.0 vs 7.8 ⫾ 6.3 days; P ⫽ .0001). The rate of acute tubular necrosis tended to be higher in the AEDF group (RR: 1.714; P ⫽ .1). No difference was noted with regard to acute rejection episodes, renal artery stenosis, or renal vein thrombosis. However, no significant difference in serum creatinine at 36 and 48 months or in the chronic rejection rate at 4 years was noted between the 2 groups (Table 2).
DISCUSSION
Fig 1. Graft survival in patients according to AEDF within the first week following transplantation.
The results of the present study indicated that AEDF observed in the first week following transplantation was associated with impaired renal functional recovery, reduced renal function at 1 and 2 years following transplantation, but not subsequent renal function or reduced graft and patient survival. Numerous risk factors for impaired graft survival have been previously identified, including recipient age, immunity status, cold and warm ischemic durations, and donor CMV status. These factors played no role in our findings. The present results may indicate that early RI assessment may be a marker of subsequent renal function independent of these parameters.4,5 AEDF is the consequence of abnormal vascular conditions in small vessels. AEDF is associated with poor perfusion in areas that play a role in kidney function, such as glomeruli, as illustrated by the initial dysfunction of the transplant. Persistence of dysfunction at 2 years after transplantation favors irreversible cellular lesions during the initial period of transplantation. These observations supported the value of a Doppler examination of transplanted kidneys to assess initial vascu-
PROGNOSTIC VALUE OF ABSENT END-DIASTOLIC FLOW
647
Table 2. Initial and Long-Term Renal Function According to AEDF Within the First Week Following Transplantation
Creatinine at month 3 (mol/L) Creatinine at month 6 (mol/L) Creatinine at month 12 (mol/L) Creatinine at month 24 (mol/L) Creatinine at month 36 (mol/L) Creatinine at month 48 (mol/L) Autonomy (d) Diuresis ⬎ 1000 mL/d (d) Creatinine ⬍ 250 mol/L (d) Chronic rejection at 4 years (%)
AEDF Group (n ⫽ 30)
Controls (n ⫽ 60)
P
153 ⫾ 80 (n ⫽ 29) 133 ⫾ 36 (n ⫽ 28) 132 ⫾ 48 (n ⫽ 28) 135 ⫾ 34 (n ⫽ 27) 137 ⫾ 49 (n ⫽ 26) 125 ⫾ 29 (n ⫽ 22) 5.6 ⫾ 4.0 3.7 ⫾ 4.0 13.7 ⫾ 5.0 38.3
122 ⫾ 39 (n ⫽ 60) 123 ⫾ 68 (n ⫽ 60) 116 ⫾ 34 (n ⫽ 59) 120 ⫾ 38 (n ⫽ 58) 135 ⫾ 104 (n ⫽ 57) 131 ⫾ 91 (n ⫽ 46) 2.6 ⫾ 3.7 2.4 ⫾ 3.4 7.8 ⫾ 6.3 43.3
.004 .039 .07 .05 .828 .851 .0001 .0300 .0001 .7890
lar conditions to identify kidneys with a high risk for long-term failure. AEDF is a frequent situation (9% in our population) which is easy to identify corresponding to dramatic vascular conditions. Should we consider AEDF to be an important event? In a previous study we reported a significant difference in vascular conditions as early as 30 minutes after unclamping between acute tubular necrosis and controls, demonstrating that initial vascular conditions are predictive of early renal function.5 The present study supported the view that AEDF has a short-term predictive value on renal function; however, whether it also has a long-term risk for graft loss remains to be proven.
REFERENCES 1. Taylor KJM, Marks WH: Use of Doppler imaging for evaluation of dysfunction in renal allografts. AJR 155:536, 1990 2. Trillaud H, Merville P, Tran Le linh Q, et al: Color Doppler sonography in early renal transplantation follow-up: resistive index versus power Doppler sonography. AJR 171:1611, 1998 3. Genkins SM, Sanfilippo FP, Carroll BA: Duplex sonography of renal transplants: lack of sensitivity and specificity in establishing pathologic diagnosis. AJR 152:535, 1989 4. Kelcz F, Pozniak MA, Pirsch JD, et al: Pyramidal appearance and resistive index: insensitive and nonspecific sonographic indicators of renal transplant rejection. AJR 155:531, 1990 5. Tranquart F, Lebranchu Y, Haillot O, et al: The use of perioperative Doppler ultrasound as a screening test for acute tubular necrosis. Transpl Int 6:14, 1993