- Email: [email protected]
Effect of Perioperative Administration of a Drug Regimen on the Primary Function of Human Renal Allografts
Effect of Perioperative Administration of a Drug Regimen on the Primary Function of Human Renal Allografts R.B. Brauer, T. Marx, K. Ulm, and M.J. Stangl ABSTRACT Delayed graft function (DGF) has one of the greatest effects on short- and long-term outcomes of cadaveric renal allografts. Ischemia reperfusion injury in the context of cold ischemia time and acute calcineurin inhibitor (CNI) nephrotoxicity is a major factor predisposing to DGF. A drug regimen consisting of prostaglandin E1 (PGE1) furosemide and dopamine has been used to reduce DGF after kidney transplantation. Prostaglandin E1 has multiple anti-ischemic and tissue-protective abilities, furosemide improves diuresis, and dopamine augments renal blood flow and urinary volume. To evaluate a potential positive effect of this drug regimen on the primary function of cadaveric renal allografts, we performed a retrospective single-center study that compared 100 patients who received this regimen with a control group. The results showed no significant improvement in renal function. In contrast, plasma levels of creatinine and urea were increased in the drug regimen group. Thus, the effectiveness of PGE1 in combination with high-dose furosemide and dopamine in diminishing DGF was not demonstrated in this trial. ELAYED GRAFT FUNCTION (DGF) exerts a most important effect on short- and long-term outcome of graft survival.1 Delayed graft function is defined as urine output less than 500 mL/d; need for dialysis, and serum creatinine levels increased, unchanged, or decreased less than 10% per day on 3 consecutive days in the first week after transplantation. Development of DGF is multifactorial. Ischemia-reperfusion injury of cadaveric donor kidneys contributes largely to development of DGF.2 The numerous anti-ischemic and tissue-protective effects of prostaglandin E1 (PGE1) and its successful therapeutic application in peripheral arterial disease has been demonstrated previously. Therefore, we performed a retrospective study to investigate the therapeutic potential of PGE1 in patients undergoing renal transplantation, and whether perioperative administration of PGE1 in combination with high-dose furosemide improved initial renal function and led to decreased need for postoperative dialysis.
D
PATIENTS AND METHODS In this retrospective single-center study, 100 cadaveric renal allograft recipients, excluding those with specific contraindications, were given PGE1 and high-dose furosemide intraoperatively. Data for the PGE1 group during the first 2 weeks after surgery were compared with those for a control group of 100 individuals. Excluded from the study were recipients younger than 18 years, those with 2 or more transplants, those with living-donor trans-
plants, and those with severe cardiac (ejection fraction ⬍35%) or hepatic (Child-Pugh B or higher) disease. The drug regimen consisted of intravenous (IV) PGE1, 40 g, administered twice a day beginning on day 1 after surgery, and IV furosemide, starting with a loading dose of 250 mg intraoperatively, followed by continuous infusion at 10 mg/h. Administration of PGE1 was stopped in patients with sufficient renal function, that is, decrease in creatinine concentration of more than 15% of the initial value per day and urine output of more than 2000 mL in 24 hours. Otherwise, therapy was continued for up to 10 days after surgery. On average, PGE1 was administered for a mean (SD) of 3.08 (1.69) days. Furosemide was administered for 2.53 (1.80) days. Reasons for withdrawal were complete anuria and polyuria of more than 4000 mL/d. In patients with moderate urine output (⬍1500 mL/d), furosemide was continued until sufficient transplant function was achieved. Patients in the control group did not receive PGE1, but received furosemide once at a maximum dose of 40 mg IV, if required. Parameters analyzed included incidence of postoperative From the Department of Surgery (R.B.B., M.J.S.) and Institut für medizinische Statistik und Epidemiologic (K.U.), Klinikum Rechts der Isar, Technische Universität München, and the Department of Anesthesiology, Klinikum Grosshadern, LudwigMaximilian-Universität (T.M.), Munich, Germany. Address reprint requests to Robert B. Brauer, MD, Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Ismaningerstrasse 22, D-81675 München, Germany. E-mail: [email protected]
© 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.2010.01.057
Transplantation Proceedings, 42, 1523–1525 (2010)
1523
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dialysis, rate of DGF, daily urine output, plasma concentrations of creatinine and urea, and creatinine clearance (Table 1). The immunosuppressive regimen in all patients consisted of a calcineurin inhibitor (cyclosporine), mycophenolate mofetil, and prednisolone. The mean trough blood concentration of cyclosporine (C0) was 165 g/L. Acute rejection episodes were treated with an IV bolus of prednisolone, 500 mg, for 3 days, or in cases of steroid resistance, with either anti-human T-cell immunoglobulin or the monoclonal antibody muromonab CD-3. Statistical analysis was performed using commercially available software (SPSS 15, Inc., Chicago, Illinois). Continuous covariates were analyzed using the Wilcoxon test for paired samples, and the Mann-Whitney test for unpaired samples. Categorical variables were analyzed using the 2 test and the Fisher exact test.
RESULTS
Between the PGE1 and control groups, there were no significant differences insofar as sex (female-male ratio, 35:65 and 34:64 [P ⫽ .88]), incidence of acute rejection (20 vs 17 patients [P ⫽ .72]), and incidence of cytomegalovirus infection (17 vs 24 patients [P ⫽ .29]). However, recipients and donors were significantly older in the PGE1 group (52 vs 47 years [P ⫽ .009] and 52 vs 38 years [P ⬍ .001]). Cold and warm ischemia times were significantly shorter in the PGE1 group (13 hr 18 min vs 20 hr 42min [P ⬍ .001] and 33 vs 34 min [P ⫽ .004). The results are given in Table 1. Insofar as renal function, incidence of DGF (20 patients in each group [P ⫽ 1.00) and number of patients who required postoperative dialysis (19 vs 22 patients [P ⫽ .73]) did not differ significantly between the PGE1 group and the control group. Mean (SD) duration of DGF was longer in the control group than in the PGE1 group (6.20 [4.56] vs 4.25 [4.35] days) [P ⫽ .07). In patients who required postoperative dialysis, the number of treatments until recovery of renal function was 2.63 (1.54) per patient in the PGE1 group vs 3.86 (2.68) in the control group (P ⫽ .17). In the first 2 postoperative weeks, daily urine output was significantly increased in the PGE1 group (Mann-Whitney test per measurement day, P ⱕ .02). In the first 4 postoperative days, laboratory results showed no significant differences for creatinine (P ⱖ .11) and urea (P ⱖ .07) concentrations. Thereafter, concentrations of creatinine (P ⱕ .01) and urea (P ⱕ .02) were significantly lower in the control Table 1. Parameters Considered for Their Influence on Renal Function Variable
PGE1 Group
Control Group
P Value
Female-male ratio Mean patient age, y Mean donor age, y Mean cold ischemia time Mean warm ischemia time, min No. of acute rejection episodes No. of cytomegalovirus infections
35:65 52 52 13 hr 18 min 33
34:66 47 38 20 hr 42 min 34
.88 .009 ⬍.001 ⬍.001 .004
20
17
.72
17
24
.29
Table 2. Distribution of Dialysis and DGF Variable
No. of patients requiring postoperative dialysis No. of dialysis treatments until recovery of renal function, mean No. of patients with DGF Duration of DGF, mean, days
PGE1 Group
19
Control Group
22
P Value
.73
2.63
3.86
.17
20 4.20
20 6.25
1.00 .07
DGF, delayed graft failure
group. After the second postoperative day, creatinine clearance was significantly increased in the control group (P ⱕ .009). The results of renal functional parameters are given in Table 2 and Fig 1. Analysis of the influence of high-dose furosemide on creatinine concentration using the generalized estimating equation showed that longer administration of high-dose furosemide resulted in a higher creatinine concentration (P ⫽ .02). In addition, multivariate linear regression on the dependent variable “Days until renal functional recovery in cases of DGF” showed that there was no influence on outcome of cold and warm ischemia times (P ⫽ .46 and P ⫽ 1.00, respectively), age of patient and donor (P ⫽ .89 and P ⫽ .91, respectively), or PGE1 vs control group (P ⫽ .79). Multivariate logistic regression analysis of the dependent variable “Number of dialysis treatments needed in cases of postoperative dialysis requirement” (1–3 vs 4 –10 treatments) for the same parameters showed similar results. Neither cold nor warm ischemia time (P ⫽ .48 and P ⫽ .36, respectively), patient age, nor PGE1 or control group (P ⫽ .31 and P ⫽ .67, respectively) significantly influenced the outcome. The only factor of influence was donor age. The number of postoperative dialysis treatments was lower in patients who received kidneys from elderly donors.
DISCUSSION
Delayed graft function is a common and severe complication after cadaveric renal transplantation, and has been reported to influence long-term graft survival.1 Experimental studies have revealed that inadequate vasoconstriction in the context of acute calcineurin inhibitor nephrotoxicity is caused in part by increased angiotensin and endothelin activity, enhanced thromboxane synthesis, and decreased synthesis of vasodilating prostaglandins. Prostaglandin E1 protects ischemic tissue by downregulating the inflammatory response of human neutrophils, effectively suppressing chemotaxis and initiating inhibition of cytotoxic enzyme release and decreased adherence of neutrophils to endothelial cells.3,4 In this context, administration of PGE1 seems to be a promising approach to prevent, or at least diminish, DGF. However, the present study failed to demonstrate a positive effect of PGE1 on the primary function
PGE1 IN RENAL TRANSPLANTATION
1525
Fig 1. Mean number of dialysis treatments per patient in those requiring postoperative dialysis, and mean number of days needed to recover renal function in patients with delayed graft function (DGF). The tendency for fewer dialysis treatments and shorter recovery time in the prostaglandin E1 (PGE1) group (n ⫽ 100) is not statistically significant.
of cadaveric renal allografts, as seen by the similar incidence of DGF and postoperative dialysis requirement between the PGE1-treated and control groups. Although there seems to be a tendency to moderate the extent of DGF in the PGE1 group, insofar as duration of DGF and average number of postoperative dialysis treatments, these differences were not significant. The increased plasma concentration of creatinine and decreased creatinine clearance in the PGE1 group can be explained in part by the high-dose furosemide regimen, as the analysis using the generalized estimating equation shows. However, there was no evidence of furosemide influence on urea concentration. Nonetheless, a significant reduction in DGF or dialysis is necessary to justify the clinical use of PGE1. Thus, PGE1 in combination with high-dose furosemide is not an effective
therapy to improve outcome after cadaveric renal transplantation. REFERENCES 1. Ojo AO, Wolfe RA, Held PJ, et al: Delayed graft function: risk factors and implications for renal allograft survival. Transplantation 63:968, 1997 2. Perico N, Cattaneo D, Sayegh MH, et al: Delayed graft function in kidney transplantation. Lancet 364:1814, 2004 3. Ham EA, Soderman DD, Zanetti ME, et al: Inhibition by prostaglandins of leukotriene B4 release from activated neutrophils. Proc Natl Acad Sci U S A 80:4349, 1983 4. Hecker G, Ney P, Schror K. Cytotoxic enzyme release and oxygen centered radical formation in human neutrophils are selectively inhibited by E-type prostaglandins but not by PGI2. Naunyn Schmiedebergs Arch Pharmacol 341:308, 1990
D
PATIENTS AND METHODS In this retrospective single-center study, 100 cadaveric renal allograft recipients, excluding those with specific contraindications, were given PGE1 and high-dose furosemide intraoperatively. Data for the PGE1 group during the first 2 weeks after surgery were compared with those for a control group of 100 individuals. Excluded from the study were recipients younger than 18 years, those with 2 or more transplants, those with living-donor trans-
plants, and those with severe cardiac (ejection fraction ⬍35%) or hepatic (Child-Pugh B or higher) disease. The drug regimen consisted of intravenous (IV) PGE1, 40 g, administered twice a day beginning on day 1 after surgery, and IV furosemide, starting with a loading dose of 250 mg intraoperatively, followed by continuous infusion at 10 mg/h. Administration of PGE1 was stopped in patients with sufficient renal function, that is, decrease in creatinine concentration of more than 15% of the initial value per day and urine output of more than 2000 mL in 24 hours. Otherwise, therapy was continued for up to 10 days after surgery. On average, PGE1 was administered for a mean (SD) of 3.08 (1.69) days. Furosemide was administered for 2.53 (1.80) days. Reasons for withdrawal were complete anuria and polyuria of more than 4000 mL/d. In patients with moderate urine output (⬍1500 mL/d), furosemide was continued until sufficient transplant function was achieved. Patients in the control group did not receive PGE1, but received furosemide once at a maximum dose of 40 mg IV, if required. Parameters analyzed included incidence of postoperative From the Department of Surgery (R.B.B., M.J.S.) and Institut für medizinische Statistik und Epidemiologic (K.U.), Klinikum Rechts der Isar, Technische Universität München, and the Department of Anesthesiology, Klinikum Grosshadern, LudwigMaximilian-Universität (T.M.), Munich, Germany. Address reprint requests to Robert B. Brauer, MD, Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Ismaningerstrasse 22, D-81675 München, Germany. E-mail: [email protected]
© 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.2010.01.057
Transplantation Proceedings, 42, 1523–1525 (2010)
1523
1524
BRAUER, MARX, ULM ET AL
dialysis, rate of DGF, daily urine output, plasma concentrations of creatinine and urea, and creatinine clearance (Table 1). The immunosuppressive regimen in all patients consisted of a calcineurin inhibitor (cyclosporine), mycophenolate mofetil, and prednisolone. The mean trough blood concentration of cyclosporine (C0) was 165 g/L. Acute rejection episodes were treated with an IV bolus of prednisolone, 500 mg, for 3 days, or in cases of steroid resistance, with either anti-human T-cell immunoglobulin or the monoclonal antibody muromonab CD-3. Statistical analysis was performed using commercially available software (SPSS 15, Inc., Chicago, Illinois). Continuous covariates were analyzed using the Wilcoxon test for paired samples, and the Mann-Whitney test for unpaired samples. Categorical variables were analyzed using the 2 test and the Fisher exact test.
RESULTS
Between the PGE1 and control groups, there were no significant differences insofar as sex (female-male ratio, 35:65 and 34:64 [P ⫽ .88]), incidence of acute rejection (20 vs 17 patients [P ⫽ .72]), and incidence of cytomegalovirus infection (17 vs 24 patients [P ⫽ .29]). However, recipients and donors were significantly older in the PGE1 group (52 vs 47 years [P ⫽ .009] and 52 vs 38 years [P ⬍ .001]). Cold and warm ischemia times were significantly shorter in the PGE1 group (13 hr 18 min vs 20 hr 42min [P ⬍ .001] and 33 vs 34 min [P ⫽ .004). The results are given in Table 1. Insofar as renal function, incidence of DGF (20 patients in each group [P ⫽ 1.00) and number of patients who required postoperative dialysis (19 vs 22 patients [P ⫽ .73]) did not differ significantly between the PGE1 group and the control group. Mean (SD) duration of DGF was longer in the control group than in the PGE1 group (6.20 [4.56] vs 4.25 [4.35] days) [P ⫽ .07). In patients who required postoperative dialysis, the number of treatments until recovery of renal function was 2.63 (1.54) per patient in the PGE1 group vs 3.86 (2.68) in the control group (P ⫽ .17). In the first 2 postoperative weeks, daily urine output was significantly increased in the PGE1 group (Mann-Whitney test per measurement day, P ⱕ .02). In the first 4 postoperative days, laboratory results showed no significant differences for creatinine (P ⱖ .11) and urea (P ⱖ .07) concentrations. Thereafter, concentrations of creatinine (P ⱕ .01) and urea (P ⱕ .02) were significantly lower in the control Table 1. Parameters Considered for Their Influence on Renal Function Variable
PGE1 Group
Control Group
P Value
Female-male ratio Mean patient age, y Mean donor age, y Mean cold ischemia time Mean warm ischemia time, min No. of acute rejection episodes No. of cytomegalovirus infections
35:65 52 52 13 hr 18 min 33
34:66 47 38 20 hr 42 min 34
.88 .009 ⬍.001 ⬍.001 .004
20
17
.72
17
24
.29
Table 2. Distribution of Dialysis and DGF Variable
No. of patients requiring postoperative dialysis No. of dialysis treatments until recovery of renal function, mean No. of patients with DGF Duration of DGF, mean, days
PGE1 Group
19
Control Group
22
P Value
.73
2.63
3.86
.17
20 4.20
20 6.25
1.00 .07
DGF, delayed graft failure
group. After the second postoperative day, creatinine clearance was significantly increased in the control group (P ⱕ .009). The results of renal functional parameters are given in Table 2 and Fig 1. Analysis of the influence of high-dose furosemide on creatinine concentration using the generalized estimating equation showed that longer administration of high-dose furosemide resulted in a higher creatinine concentration (P ⫽ .02). In addition, multivariate linear regression on the dependent variable “Days until renal functional recovery in cases of DGF” showed that there was no influence on outcome of cold and warm ischemia times (P ⫽ .46 and P ⫽ 1.00, respectively), age of patient and donor (P ⫽ .89 and P ⫽ .91, respectively), or PGE1 vs control group (P ⫽ .79). Multivariate logistic regression analysis of the dependent variable “Number of dialysis treatments needed in cases of postoperative dialysis requirement” (1–3 vs 4 –10 treatments) for the same parameters showed similar results. Neither cold nor warm ischemia time (P ⫽ .48 and P ⫽ .36, respectively), patient age, nor PGE1 or control group (P ⫽ .31 and P ⫽ .67, respectively) significantly influenced the outcome. The only factor of influence was donor age. The number of postoperative dialysis treatments was lower in patients who received kidneys from elderly donors.
DISCUSSION
Delayed graft function is a common and severe complication after cadaveric renal transplantation, and has been reported to influence long-term graft survival.1 Experimental studies have revealed that inadequate vasoconstriction in the context of acute calcineurin inhibitor nephrotoxicity is caused in part by increased angiotensin and endothelin activity, enhanced thromboxane synthesis, and decreased synthesis of vasodilating prostaglandins. Prostaglandin E1 protects ischemic tissue by downregulating the inflammatory response of human neutrophils, effectively suppressing chemotaxis and initiating inhibition of cytotoxic enzyme release and decreased adherence of neutrophils to endothelial cells.3,4 In this context, administration of PGE1 seems to be a promising approach to prevent, or at least diminish, DGF. However, the present study failed to demonstrate a positive effect of PGE1 on the primary function
PGE1 IN RENAL TRANSPLANTATION
1525
Fig 1. Mean number of dialysis treatments per patient in those requiring postoperative dialysis, and mean number of days needed to recover renal function in patients with delayed graft function (DGF). The tendency for fewer dialysis treatments and shorter recovery time in the prostaglandin E1 (PGE1) group (n ⫽ 100) is not statistically significant.
of cadaveric renal allografts, as seen by the similar incidence of DGF and postoperative dialysis requirement between the PGE1-treated and control groups. Although there seems to be a tendency to moderate the extent of DGF in the PGE1 group, insofar as duration of DGF and average number of postoperative dialysis treatments, these differences were not significant. The increased plasma concentration of creatinine and decreased creatinine clearance in the PGE1 group can be explained in part by the high-dose furosemide regimen, as the analysis using the generalized estimating equation shows. However, there was no evidence of furosemide influence on urea concentration. Nonetheless, a significant reduction in DGF or dialysis is necessary to justify the clinical use of PGE1. Thus, PGE1 in combination with high-dose furosemide is not an effective
therapy to improve outcome after cadaveric renal transplantation. REFERENCES 1. Ojo AO, Wolfe RA, Held PJ, et al: Delayed graft function: risk factors and implications for renal allograft survival. Transplantation 63:968, 1997 2. Perico N, Cattaneo D, Sayegh MH, et al: Delayed graft function in kidney transplantation. Lancet 364:1814, 2004 3. Ham EA, Soderman DD, Zanetti ME, et al: Inhibition by prostaglandins of leukotriene B4 release from activated neutrophils. Proc Natl Acad Sci U S A 80:4349, 1983 4. Hecker G, Ney P, Schror K. Cytotoxic enzyme release and oxygen centered radical formation in human neutrophils are selectively inhibited by E-type prostaglandins but not by PGI2. Naunyn Schmiedebergs Arch Pharmacol 341:308, 1990