389Vol. 9 | No. 1 | Winter 2012 |U R O LO G Y J O U R N A L Effect of Low Dose Dopamine on Early Graft Function in Living Unrelated Kid- ney Donors Hamzeh Hosseinzadeh, Samad Golzari, Mohammad Abravesh, Ata Mahmoodpoor, Davood Aghamohammadi, Afshar Zomorrodi, Parisa Hosseinzadeh Purpose: To evaluate the effect of low-dose dopamine administration on the early function of the kidney in unrelated kidney donors after transplantation. Materials and Methods: In this double-blinded clinical trial, 60 adult kidney do- nors and 60 recipients, younger than 50 years old, were studied. Donors and re- cipients were randomly divided into two groups; group 1 received dopamine 3 µg/ kg/min and group 2 received similar regimen of placebo. During the first 3 days postoperatively, serum levels of urea and creatinine as well as urine output and early kidney function were compared between two groups. Results: Serum levels of creatinine and urea and urine output during the first three days after the operation did not differ statistically significantly between two groups (P = .549, P = .306 and P = .375, respectively). Early kidney function was better significantly in group 1 (5.3 ± 3.2 versus 8.6 ± 8.0 hours; P = .048). Conclusion: Premedication of the kidney transplant donors with low-dose dopa- mine accelerates early kidney function after transplantation, but has no effect on the hemodynamic status and serum levels of creatinine and urea in the donors. Keywords: kidney transplantation, kidney function tests, dopamine, tissue donors Corresponding Author: Ata Mahmoodpoor, MD; FCCM General ICU, Shohada Hospital, El-Goli St., Tabriz, Iran Tel: +98 914 116 0888 E-mail: amahmoodpoor@ yahoo.com Received January 2011 Accepted July 2011 Department of Anesthe- siology, Imam Khomeini Hospital, Faculty of Medi- cine, Tabriz University of Medical Sci- ences, Tabriz, Iran Kidney Transplantation 390 | Kidney Transplantation INTRODUCTION Kidney transplantation is the treatment of choice for patients with end-stage renal disease. Delay in achieving transplanted kidney function after transplantation is a serious problem.(1) Although immunosuppressive medica- tions have been able to prevent acute transplant rejection, chronic nephropathy still exists and dis- turbs the function of transplanted kidneys. There are numerous non-immunologic factors which can affect transplanted kidney function, including hemodynamic instability, manipulations during donor nephrectomy, renal vessels spasm in the do- nor and recipient, duration of cold ischemia, and ischemia and reperfusion-induced injuries. These conditions can lead to pro-inflammatory state and increase immunogenicity of graft, which in turn results in graft dysfunction and rejection.(2-4) Therefore, decreasing organ injury with medical pretreatment of donors may lead to better outcome of the kidney transplantation. Instant urine production has been reported in 90% of the living donor transplantations and 40% to 70% of the cadaveric transplantations.(5) Some studies demonstrated that catecholamine adminis- tration could have protective effects on the trans- planted kidney, reducing acute transplant rejection and increasing long-term survival after transplan- tation.(6-9) Among catecholamines, dopamine has the best effect on survival of transplanted kidneys. Dopamine induces heat shock protein heme oxy- genase enzyme-1,(10) which plays an important role in preventing vascular damage in the transplanted kidney in animal models.(11) Dopamine can protect endothelial cells from oxidative stress with its di- hydroxy-phenolic structure.(12) Although catecho- lamines protect against the increase of inflam- matory molecules, such as intracellular adhesion molecule-1, and cold storage-induced endothelial cell damage,(13,14) there is controversy over protec- tive effects of dopamine in kidney recipients by reviewing current strategies for renal transplanta- tion.(15) The majority of transplantations which are per- formed in Imam Khomeini Hospital in Tabriz are from the unrelated living donors, and delay in achieving kidney function reduces graft survival. This study was aimed to evaluate the effect of low- dose dopamine administration in the living donors on early function of the transplanted kidney. MATERIALS AND METHODS From May 2008 to October 2009, 120 subjects were studied. Sixty kidney donors were rand- omized into two groups, group 1 (n = 30) received 3 µg/kg/min dopamine and group 2 (n = 30) re- ceived similar regimen of placebo. Sixty recipients were allocated in respected groups. Randomiza- tion was done by random block. There were 60 sealed envelopes for each group with the name of dopamine (30) or control (30) inside them. Patients and anesthesiologist were blind to the study. This study was reviewed and approved by the Medical Ethics Committee of Tabriz University of Medical Sciences. Written informed consent was obtained from each participant. Power calculations indicated that a sample of 60 patients and 60 controls would detect a proportion difference of at least 15% between two groups, with a significance (α = 0.05) and a power of 80%. The kidney donors’ conditions and short-term sur- vival after kidney transplantation were compared between the two groups. Blood pressure, central venous pressure, body temperature, end-tidal CO2, and urine output were measured. Furthermore, pulse oximetry and elec- trocardiography were performed. Intravenous anesthesia was performed using remifentanil, propofol, cisatracurium, and a gas mixture of N2O + O2 6 L/min. The administered gas was reduced by 50% every 10 minutes until reaching the flow of 2 L/min. Central venous pres- sure of the patients was maintained between 10 and 12 mmHg. 391Vol. 9 | No. 1 | Winter 2012 |U R O LO G Y J O U R N A L Effect of Dopamine on Early Graft Function | Hosseinzadeh et al Subjects in group 1 received dopamine drip with 3 µg/kg throughout the operation with infusion pump and those in control group received normal saline with the same volume/hour as drip through infusion pump. All donors received manitol 1 g/kg before nephrec- tomy. All kidney recipients received manitol 1 g/kg plus furosemide 1.5 mg/kg before removing arte- rial clamp. During reperfusing, bicarbonate 1 meq/ kg was administered intravenously. Time to diure- sis after removing vascular clamp was recorded. Diuresis below 60 minutes was considered early. All the subjects were followed up for 6 hours af- ter diuresis. The follow-up period was 3 days after the operation. Subjects in each group received the same immunosuppressive regimen. Demographic parameters and cold and warm is- chemia duration were recorded. Serum levels of blood urea nitrogen and creatinine as well as urine volume were recorded before the operation and 12, 24, 36, 40, 60, and 72 hours postoperatively. Data were presented as mean ± standard deviation, fre- quency, and percentage. Data were analyzed with SPSS software (the Sta- tistical Package for the Social Sciences, Version 15.0, SPSS Inc, Chicago, Illinois, USA). Quanti- tative variables were compared using independent samples t test, and categorical variables were com- pared using contingency tables and Chi-Square or Fisher’s Exact test. To compare the changes in the quantitative parameters between two groups, re- peated measures analysis was used. P values less than .05 were considered statistically significant. RESULTS Kidney Donors Demographic characteristics of kidney donors are shown in Table 1. No statistically significant differ- ence was observed between two groups. As shown in Table 2, there were no significant differences re- garding systolic blood pressure (P = .100), mean arterial pressure (P = .547), heart rate (P = .618), SPO2 (P = .413), and body temperature (P = .866) between two groups. Kidney Recipients General quantitative variables in both groups are summarized in Table 1. No statistically signifi- cant difference was observed between two groups. Again, there was no significant difference regard- ing systolic blood pressure (P = .299), mean arte- Table 1. Comparing demographic characteristics in kidney donors and recipients Donors Recipients Variables Intervention group Control group P Intervention group Control group P Mean ± SD Mean ± SD Mean ± SD Mean ± SD Age, y 28.9 ± 5.0 26.9 ± 4.2 .093 37.6 ± 11.7 35.6 ± 9.7 .480 Weight, kg 70 ± 12.3 68.4 ± 11.6 .602 62.4 ± 10.1 62.3 ± 14.4 .983 Duration of anesthesia, h 3.7 ± 0.6 3.6 ± 0.4 .316 5.0 ± 0.8 4.9 ± 0.7 .427 Duration of surgery, h 2.9 ± 0.5 2.9 ± 0.5 .682 4.2 ± 0.7 4.2 ± 0.6 .780 Liquid volume, L 4.6 ± 0.9 4.3 ± 0.7 .056 4.7 ± 1.0 4.9 ± 0.9 .486 Urine , L 0.8 ± 0.4 0.9 ± 0.4 .772 0.3 ± 0.2 0.3 ± 0.2 .480 Bleeding, L 0.3 ± 0.1 0.3 ± 0.1 .184 0.6 ± 0.2 0.6 ± 0.1 .084 Hematocrit, % 43.3 ± 4.4 4 5 ± 4.3 .094 32.4 ± 2.3 33.3 ± 3.8 .118 Body mass index 22.7 ± 2.4 22.2 ± 2.4 .389 Duration of dialysis, month 17 ± 11.2 19.9 ± 0.6 .560 Warm ischemia duration, min 1.3 ± 0.5 1.2 ± 0.5 .552 Cold ischemia duration, min 94 ± 21.6 88.2 ± 17.9 .262 SD indicates standard deviation. 392 | Kidney Transplantation Table 2. Comparing quantities of general variables between two recipient groups Variables Time Intervention group Control group P Mean ± SD Mean ± SD Systolic blood pressure Before surgery 89.8 ± 9.5 88.9 ± 13.8 .761 After induction 84.7 ± 13.1 90.9 ± 12.2 .062 After intubation 96.3 ± 18.7 94.6 ± 15.2 .821 During surgery 92.6 ± 9.0 91.9 ± 11.2 .771 Heart rate Before surgery 80.6 ± 13.5 82.4 ± 10.3 .564 After induction 80.5 ± 12.5 85.1 ± 9.7 .116 After intubation 87.4 ± 16.0 89.7 ± 18.6 .615 During surgery 83.3 ± 9.6 79.4 ± 11.4 .157 SPO2 Before surgery 95.3 ± 1.3 97.9 ± 1.1 .382 After induction 98.6 ± 1.2 98. 8 ± 0.7 .508 After intubation 98.9 ± 1.2 99.1 ±1.0 .561 During surgery 99.4 ± 0.7 99.0 ± 1.2 .115 Body temperature Before surgery 35.9 ± 0.7 35.7 ± 0.6 .239 During surgery 34.6 ± 5.5 35.5 ± 0.5 .350 End-tidal CO2 31.7 ± 4.3 30.1 ± 2.7 .096 SD indicates standard deviation. Table 3. Comparing hemodynamic parameters and vital signs in recipients Variables Time Intervention group Control group P Mean ± SD Mean ± SD Mean arterial pressure Before surgery 102.3 ± 18.1 102.3 ± 12.5 .993 After induction 96.8 ± 17.5 95.1 ± 13.9 .684 After intubation 95.9 ± 20.0 101.4 ± 23.9 .327 During surgery 88.4 ± 12.4 92.5 ± 12.9 .218 Heart rate Before surgery 88.9 ± 17.0 85.8 ± 14.1 .450 After induction 88.5 ± 15.4 86.0 ± 18.1 .561 After intubation 90.2 ± 18.5 86.5 ± 17.3 .418 During surgery 75.8 ± 15.0 73.4 ± 12.3 .502 SPO2 Before surgery 96.7 ± 1.7 96.4 ± 1.5 .373 After induction 97.9 ± 1.0 98.4 ± 1.3 .150 After intubation 98.2 ± 1.1 98.7 ± 0.8 .048 During surgery 98.2 ± 1.3 98.9 ± 0.9 .035 Body temperature Before surgery 36.4 ± 0.5 36.2 ± 0.9 .206 After induction 35.4 ± 5.4 36.2 ± 0.7 .469 During surgery 35.8 ± 1.8 35.9 ± 0.8 .975 Central venous pressure Before surgery 12.6 ± 3.8 11.8 ± 2.9 .387 After induction 13.2 ± 3.2 12.7 ± 3.5 .587 After intubation 13.6 ± 3.3 13.7 ± 3.8 .914 During surgery 13.7 ± 3.1 13.6 ±2 .3 .816 End-tidal CO2 31.9 ± 3.4 31.7 ± 3.0 .810 SD indicates standard deviation. 393Vol. 9 | No. 1 | Winter 2012 |U R O LO G Y J O U R N A L rial pressure (P = .538), heart rate (P = .429), SPO2 (P = .179), body temperature (P = .973), and cen- tral venous pressure (P = .667) (Table 3). Changes in serum levels of creatinine and urea and urine volume during the study in both groups are presented in Table 4. Mean serum level of urea and mean urine volume after 24 hours were signifi- cantly higher in group 1 (P = .367 and P = .480, respectively). There was no statistically significant difference regarding other variables. Studying the variables mentioned above revealed no statistically significant difference between two groups regard- ing serum creatinine (P = .549), serum urea (P = .306), and urine volume (P = .375). The mean time for initiation of diuresis after clamp removal was 5.3 ± 3.2 hours (range, 1 to 13 hours) in group 1 and 8.6 ± 8.0 hours (range, 1 to 29 hours) in group 2 (P = .048). Instant delay function was observed in 1 subject (3.3%) in the interven- tion group and in 2 subjects (6.7%) in the control group. There was no statistically significant differ- ence between two groups in this regard (P = .500). DISCUSSION There are few studies about the effect of low- dose dopamine on transplanted kidney function. Schnuelle and colleagues reported that low-dose dopamine administration in intensive-care unit significantly reduced the probability of acute trans- plant rejection and increased transplanted organ survival.(16) In another study, they also concluded that low-dose dopamine administration in the kid- ney donors reduced the need for hemodialysis after transplantation.(17) In a randomized controlled trial, Grundmann and associates showed a higher urine output in the immediate post transplant period with the use of low dosage of dopamine, without any ef- fect on creatinine clearance.(18) In another study, the effect of low-dose dopamine (5 µ/kg/min) on the kidney donors’ status before transplantation was evaluated. In a 3-year follow-up period, transplant rejection rate was significantly lower in the inter- vention group. Although dopamine administration significantly increased systolic blood pressure in the donors, it was not clinically significant or in- fluential.(19) Low-dose dopamine administration in donors has a positive effect on the recipient status and trans- planted organ survival in all the above-mentioned conditions. However, the method of results evalu- ation and follow-up duration after transplantation are different in our study compared to others. The core objective of the above-mentioned studies was the evaluation of hemodialysis need after trans- plantation. While in our study, we focused on the changes of serum levels of urea and creatinine af- ter transplantation for 3 days, which can directly reflect status of the kidney recipients as core pa- rameters. The study by Schnuelle and colleagues, which has been still the most comprehensive study on the liv- ing kidney donors,(19) had several limitations. The most important drawback in their study is that the researchers and evaluating staff were not blind to the study and the results were obtained according to the patients’ grouping (epinephrine or placebo). In comparison, our study has been carried out as a double-blind study, which can be considered a major advantage. On the other hand, the study by Schnuelle and associates was carried out on brain death donors whereas the present study was carried out on healthy donors in the age range of 20 to 30 years. Considering the intervention and controlled status of brain death cases, generalizing the ob- tained results to the non-brain death living donors might be inaccurate. Furthermore, the status of do- pamine administration during kidney transplanta- tion surgery in the recipients and status of receiv- ing other common medications related to kidney transplantation by donors, such as thyroxin, corti- costeroid, vasopressin, insulin, iron chelator, etc, have not been studied.(20-22) Gottmann and coworkers evaluated the effect of low-dose dopamine (5µ//kg/min) in the kidney Effect of Dopamine on Early Graft Function | Hosseinzadeh et al 394 | donors in rat models. They demonstrated that do- pamine administration in kidney donors improved both short-term and long-term prognoses.(23) As it was mentioned, early kidney function was signifi- cantly better in the intervention group in our study, but no significant effect was observed regarding serum levels of creatinine and urea within three days after transplantation. Novitzky and colleagues and Wood and associates concluded that dopamine administration in the kidney donors only increased systolic blood pressure whereas it had no signifi- cant effect on transplant rejection rates within 30 days and on allograft and patient survival until 36 months after transplantation.(24,25) De Los Angeles and colleagues reported that low- dose dopamine administration (3µg/kg/min) in combination with furosemide in kidney donors had no significant effect on urine output or creati- nine clearance in the recipients after transplanta- tion compared to the placebo.(26) Spicer and associ- ates using Doppler ultrasonography in their study showed that dopamine administration in the kid- ney donors had no significant effect on speed and degree of blood stream in the transplanted tissue.(27) As it can be seen, the results obtained in this field differ greatly. One of the reasons can be the effect of confounding factors on final results, such as the age of donors, the weight of recipients, and cold ischemia duration.(24) In our study, all the above- mentioned factors were matched between two groups. To the best of our knowledge, this study is the first study carried out on non-brain death do- nors. Limitations of our study were the short dura- tion of study, monitoring of kidney function based Kidney Transplantation Table 4. Serum levels of creatinine and urea, and urine volume after transplantation in recipients Variables Time Intervention group Control group P Mean ± SD Mean ± SD Serum creatinine Basic 7.2 ± 3.6 13.8 ± 36.3 .322 After 12 hours 6.5 ± 3.5 5.4 ± 2.0 .139 After 24 hours 4.7 ± 3.2 4.5 ± 2.5 .701 After 36 hours 4.1 ± 2.9 3.5 ± 2.1 .338 After 48 hours 3.3 ± 2.7 2.9 ± 1.9 .605 After 60 hours 2.8 ± 2.4 2.6 ± 1.8 .666 After 72 hours 2.0 ± 2.0 2.6 ± 1.9 .272 Serum urea Basic 84.0 ± 32.6 66.4 ± 26.8 .026 After 12 hours 81.0 ± 27.9 75.8 ± 27.2 .468 After 24 hours 78.0 ± 4.7 70.0 ± 26.2 .367 After 36 hours 80.8 ± 49.3 70.3 ± 27.4 .309 After 48 hours 78.9 ± 52.8 68.4 ± 30.7 .349 After 60 hours 77.3 ± 57.1 68.1 ± 34.4 .450 After 72 hours 68.2 ± 50.3 72.4 ± 35.4 .706 Urine volume, L Basic 0.9 ± 0.9 0.7 ± 0.9 .470 After 12 hours 2.4 ± 2.2 2.9 ±1.9 .359 After 24 hours 2.2 ± 1.8 3.9 ± 2.4 .004 After 36 hours 1.8 ± 1.6 2.2 ± 1.0 .274 After 48 hours 1.8 ± 1.7 2.3 ± 1.6 .306 After 60 hours 3.0 ± 7.6 1.7 ± 1.1 .355 After 72 hours 1.4 ± 0.9 1.9 ± 1.1 .072 SD indicates standard deviation. 395Vol. 9 | No. 1 | Winter 2012 |U R O LO G Y J O U R N A L on early diuresis and urea/creatinine, and short- term patients’ follow-up. CONCLUSION We concluded that low-dose dopamine in the unre- lated kidney donors, compared to the placebo, sig- nificantly increases the speed of diuresis initiation in the recipients after transplantation. Furthermore, it has no statistically significant effect on reducing serum level of creatinine and/or urea in the kidney recipients after transplantation. CONFLICT OF INTEREST None declared. REFERENCES 1. Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortal- ity in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric trans- plant. N Engl J Med. 1999;341:1725-30. 2. Pratschke J, Wilhelm MJ, Kusaka M, et al. Brain death and its influence on donor organ quality and outcome after transplantation. Transplantation. 1999;67:343-8. 3. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991-1045. 4. van der Woude FJ. 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