Objectives: The relation between dopamine infusion and renal hemodynamics and function has not been studied in renal allografts during early recovery. We analyzed the dose response of dopamine infusion on renal blood flow and function in human kidney transplant recipients at reperfusion and during early graft recovery.
Materials and Methods: Phasic and mean renal blood flow was measured by the pulsed Doppler technique using implantable Doppler microprobes in contact with the graft artery. Systemic and renal parameters were recorded on dopamine infusion (0, 3, 5, and 10 μg·kg-1·min-1) immediately after transplant (day 0) in 13 patients and at day 6 in 7/13 patients with early graft recovery. Results are expressed as median and interquartile range between the 25th and 75th percentiles.
Results: At day 0, 3 μg·kg-1·min-1 dopamine did not increase mean renal blood flow over baseline (580 mL/min [219-663 mL/min] vs 542 mL/min [207-686 mL/min]; P = .84). There was an absence of effect with higher dopamine doses, whereas cardiac output, heart rate, and systolic and mean arterial pressure were significantly increased. Urinary sodium excretion, creatinine clearance, and urine output increased dose dependently, with a positive correlation between the increase in urine output and mean arterial pressure (r = 0.48, P < .001). At day 6, 3 μg·kg-1·min-1 dopamine increased mean renal blood flow over baseline (318 mL/min [234-897 mL/min] vs 191 mL/min [173-706 mL/min]; P = .016), with no further increase at higher doses.
Conclusions: Immediately after transplant, kidney grafts with ischemic-reperfusion injury are fully dilated and do not respond to dopamine. The specific renal effects observed are due to systemic hemodynamic status. Vascular responsiveness to a “renal dopamine dose” returns on graft recovery.
Key words : Acute kidney injury, Ischemia-reperfusion injury, Kidney transplant, Renal blood flow, Dopamine
The specific renal effects of dopamine on human volunteers and patients were first described in the early 1960s.1 Unlike other catecholamines, dopamine infused at a low dose increases renal blood flow (RBF), glomerular filtration rate, urine output and urinary sodium excretion.2 On infusion of a so-called renal dose (0.5-3 μg·kg-1·min-1), dopamine primarily activates D1 and D2 receptors, whereas, at higher doses (3-5 μg·kg-1·min-1), dopamine receptor activation is overcome by β-adrenergic stimulation. At even higher doses, stimulation of α-adrenergic receptors occurs. This classification is, however, largely theoretical because receptor activation depends on interindividual variations in receptor densities or affinities.3,4 Moreover, these pharmacologic results were largely obtained on experimental models, with limited systemic or local inflammation, which may modify the ligand-receptor interaction and the targeted cells’ response.
The specific renal effects of dopamine are mostly due to D1 receptors located on afferent arterioles and the interlobular and arcuate arteries that promote vasodilatation,3,5 but they also may be due to dopamine receptors in the glomerulus and renal tubule.6 Because of its specific renal effects, low-dose dopamine has been used to treat cases of suspected renal hypoperfusion and vasoconstriction, 2 factors involved in renal dysfunction and acute tubular necrosis.7-13 Vasoconstriction after ischemia-reperfusion in kidney transplant has been proposed to explain posttransplant kidney dysfunction.14 Although infusion of a “renal dopamine dose” has been suggested to provide better renal tissue perfusion and better preservation of transplant function, so far, there is no clinical evidence either for or against this strategy.15-18 A study looking specifically at renal perfusion by noninvasive transparietal Doppler supports an absence of effect of dopamine on transplanted kidneys in the early phase of reperfusion, which could explain the lack of clinical benefits.19
In this study, we hypothesized that the effect of dopamine on renal transplant blood flow and function may differ according to time after transplant and the resolution of the effects of ischemia-reperfusion injury. Using implantable Doppler microprobes, we investigated the dose-response relationship of titrated dopamine infusion (0, 3, 5, and 10 μg·kg-1·min-1) on systemic hemodynamic and RBF and function in human renal transplant recipients at reperfusion on the day of transplant and during early recovery of graft function.
Materials and Methods
Patients and protocol
This prospective study was conducted in a surgical intensive care unit at a tertiary teaching hospital and was approved by the Institutional Review Board (No. 00003835, Comité de Protection des Personnes Ile-de-France IV). Patients receiving kidney transplants from brain dead donors were enrolled after written informed consent was received. All of the protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration.
Patients were included according to investigator availability and technical feasibility (availability of implantable transducers and adequate surgical conditions). Postoperative anuric patients were excluded from the study, and last hemodialysis was performed within 12 hours before surgery. Transplant was performed under general anesthesia, according to standard protocols used in our institution. Tolerance and efficiency of volemic control were monitored using a pulmonary arterial catheter. During surgery, dopamine was infused at 3 μg·kg-1·min-1. Intravenous furosemide (500 mg) and methylprednisolone acetate (500 mg) were administered before renal arterial clamp release. All grafts were preserved by cold storage using Euro-Collins solution.
The study started immediately after surgery and stabilization in the recovery room (day 0). After clinical and laboratory parameters (central temperature = 36.6 ± 0.6°C, PaO2 = 144 ± 30 mm Hg, PaCO2 = 31 ± 5 mm Hg, mean ± standard deviation) and urine flow stability were checked, the protocol was applied. Four sets of measurements (Figure 1) were performed under successive dopamine infusion rates of 0, 3, 5, 10,μg·kg-1·min-1 via a specific central intravenous line. For each rate of dopamine infusion, there was an initial 10 minutes of equilibration, after which urine was collected over a 20-minute period, a sufficient delay to allow for urine flow variations caused by filtration modification. Urine output was constantly and precisely compensated by a saline solution containing electrolyte concentration adapted to urine excretion. Systemic and renal hemodynamic parameters and blood and urine samples were collected at the end of the 20-minute period (Figure 1). Great care was taken to ensure stability, avoiding any change in ventilation or fluid challenge during data collection. Given the necessity to complete measurements as quickly as possible and the short half-life of dopamine, there was no washout period between each dopamine dose.
At day 6 after the surgical procedure, the same protocol was applied to patients who had grafts that recovered from the initial ischemic-reperfusion injury and who showed early graft function. Patients were divided into either an early or delayed graft function group according to the current definition.20 Delayed graft function was defined as the necessity for dialysis within the first 7 days after renal transplant, whereas early graft function was defined as the absence of dialysis after transplant. Requirement for dialysis was indicated as standard, by nephrologists blinded to measurements, and based on overload or classic metabolic criteria.
Measurement of systemic and renal parameters
The following parameters were measured: heart rate by electrocardiogram recording, systolic and mean arterial pressure using a noninvasive oscillometric blood pressure monitoring device (Dinamap, Critikon, France), right atrial pressure, mean pulmonary arterial pressure, pulmonary capillary pressure, and cardiac output (average of 3 successive random thermodilution measurements in L/min) using a triple lumen Swan-Ganz catheter (CO Computer 9510, Edwards Laboratories, Irvine, CA, USA). End-expiratory intravascular pressures were measured by Hewlett-Packard (Palo Alto, CA, USA) quartz transducers carefully zeroed at the midaxillary level. Renal blood flow was measured by the pulsed Doppler technique using implantable 8-MHz pulsed Doppler microprobes (3 mm wide, 4 mm long); this technique has been previously published and validated.21-23 Briefly, the piezoelectric crystal, glued on a silicone prism fixing the ultrasonographic incidence angle at 60° was implanted at the end of surgery. At the end of the surgical procedure, the Doppler microprobe was sutured to the adventitia of the graft artery 2 cm downstream from the anastomosis to the external iliac artery. The curvilinearity of the probe facilitates the implant and proper alignment with the vessel axis. Four 7-0 sutures, through the arterial adventia and the silicone prism, ensured close contact between the probe and vessel wall and proper alignment with the vessel axis. The probe was connected to a pulsed Doppler flowmeter (Alvar Ultrasound, Cachan, France) via percutaneous abdominal leads. The zero-crossing pulsed Doppler blood flowmeter has been previously described and validated.24 It is able to measure internal vessel diameter and subsequently calculate the vessel section. Mean and phasic cross-sectional blood flow velocities were measured (in cm/s), as well as peak systolic and end diastolic blood flow velocities. Mean RBF, systolic RBF, and diastolic RBF (in mL/min) were calculated with the formula: RBF = (π × vessel diameter2 × velocity × 60)/4, assuming a constant vessel diameter throughout the cardiac cycle. The probes were removed on day 6 or 7 by gentle traction with no adverse events.
The renal resistive index (RI) conventionally25 given by the formula RI = (systolic velocity – diastolic velocity)/systolic velocity was calculated as RI = (systolic RBF – diastolic RBF)/systolic RBF. Urine output was measured by precise time-related collection via an intravesical catheter. Urine and blood samples were collected at the end of each protocol period for urinary sodium and creatinine concentration determination. Excretion rate (urinary sodium excretion = urinary sodium × urinary output) and creatinine clearance were calculated (urine concentration × urine output/plasma concentration). At day 6, Swan-Ganz catheters and urine catheterization had been removed from most patients; therefore, neither measurement of Swan-Ganz parameters nor collection of urine samples was made.
Data for categorical variables were expressed as frequencies and percentages. Continuous variables were expressed as medians with 25th and 75th percentiles, unless stated otherwise. Dopamine dose-response curves on day 0 and day 6 were compared using the Fisher exact test for categorical variables and the Wilcoxon and Friedman tests for continuous paired variables. The relations between changes in urinary output and mean arterial pressure with dopamine were analyzed by linear regression analyses. The correlation was given by Pearson product moment correlation coefficient. All tests were two-tailed at the P = .05 significance level. Analyses were performed using R version 3.1.2 (R Core Team 2014) (R: A language and environment for statistical computing; R Foundation for Statistical Computing, Vienna, Austria; available at http://www.R-project.-org/).
Thirteen patients (5 women and 8 men, median age of 43 y, range 21-80 y) were included at day 0 of renal transplant and for follow-up to day 6. Their clinical characteristics are shown in Table 1. Of note, 3 further patients were enrolled in the study, but dysfunction or wrong positioning of the transducer induced a poor quality Doppler signal and they were excluded from the analyses. No patient had residual diuresis before renal transplant. Median total ischemic time was 37 hours (interquartile range, 35-42 h). Patients with early recovery of graft function (7/13) were investigated again on day 6. The remaining patients were excluded for the second evaluation because of delayed recovery of graft function (n = 5) and absence of a Doppler signal (n = 1). No major event (requiring an intervention) was reported during dopamine infusion.
Hemodynamics and renal function at day 0
In 13 patients, dopamine infusion at day 0 led to a dose-dependent increase in cardiac output, systolic arterial pressure, mean arterial pressure, and mean pulmonary arterial pressure (Table 2). The 3 μg·kg-1·min-1 dopamine dose had no significant effect on baseline mean RBF (580 mL/min [interquartile range, 219-663 mL/min] vs 542 mL/min [interquartile range, 207-686 mL/min]; P = .84) (Figure 2). Only 2 patients experienced a greater than 15% increase in mean RBF at this dose (Figure 3). Higher dopamine infusion rates also had no significant effect on mean RBF (Figure 2), although renal function parameters were dose-dependently improved (sodium excretion, creatinine clearance, and urinary output) (Table 2). The dopamine-induced increase in urinary output was related to the rise in mean arterial pressure (r = 0.48; P < .001) (Figure 4) but not to the marked increase observed in cardiac output (r = -0.07; P = .63).
Hemodynamics at day 6 in early graft function patients
Baseline mean RBF at day 6 did not differ significantly from baseline value at day 0 (191 mL/min [interquartile range, 173-706 mL/min] vs 542 mL/min [interquartile range, 207-686 mL/min]; P = .81) (Table 2) in 7 patients with early graft function. Infusion of 3 μg·kg-1·min-1 dopamine induced a significant increase in mean RBF (318 mL/min [interquartile range, 234-897 mL/min] vs 191 mL/min [interquartile range, 173-706 mL/min]; P = .016) (Figure 2) with no further increase at a higher dopamine infusion rate. All patients experienced an increase in mean RBF > 15%, a proportion significantly different from that observed on day 0 (P < .001) (Figure 3).
Renal resistive index
At day 0, the RI was not modified by dopamine infusion (Table 2), especially for systolic RBF and diastolic RBF (0% [interquartile range, -2%-7%] and 0% [interquartile range, -6%-15%]) when dopamine renal dose was infused. Compared with day 0, day 6 baseline value for RI was significantly increased (0.83 [interquartile range, 0.55-0.93] vs 0.54 [interquartile range, 0.48-0.67]; P = .036), suggesting an increase in renal resistance. At the low dopamine dose infusion rate, systolic RBF increased only by 14% (interquartile range, 12%-28%; P = .036), whereas diastolic RBF increased by 44% (interquartile range, 21%-212%; P = .036). Such a predominant diastolic flow increase explains the decrease in RI from 0.84 to 0.57, suggesting dopamine induced renal vasodilation during the passive diastolic flow.
This study recorded local graft circulation in kidney transplant patients using an implantable Doppler microprobe placed in contact with the implanted artery and compared the data thus obtained with hemodynamic data. The probe gave highly reproducible RBF measurements that could be used to determine the dopamine dose-response curves. A lack of renal vasoreactivity to dopamine was noted immediately after renal transplant. Infusion of a “renal dopamine dose” (3 μg·kg-1·min-1) did not improve renal perfusion at this time. However, urinary output increased with dopamine dose, suggesting that sodium excretion and renal clearance depended on a systemic response to dopamine. The renal functional response was related to the dopamine-induced increase in blood pressure. Six days after transplant, graft vasoreactivity to low-dose dopamine was restored in patients who experienced early recovery of graft function.
This study yields unique information about beat-by-beat systole-diastolic kidney graft blood flow variations. Kidney blood flow was measured with a pulsed Doppler flowmeter linked to a disposable implantable microprobe previously described and validated.21-23 The implanted method has the advantage of eliminating the uncertainty of flow accuracy related to operator training, patient echogenicity, and potential impact of variant ultrasound incidence angle with the vessel axis. The renal graft artery diameter and section were accurately measured with the pulsed Doppler device.24 Cross-sectional blood flow velocity over all of the vessel section was measured after adjustment of the gating pulsed Doppler system, providing highly reproducible flow measurements. Day 0 record of systemic hemodynamic data permitted investigation of the relation between systemic values and renal graft blood flow.
The absence of modifications of RBF values at day 0 during increasing doses of dopamine suggests an absence of vascular reactivity to dopamine. Our study confirms the findings of Spicer and associates19 but using more accurate instrumentation. This nonreactivity may indicate vasoplegia resulting from hypocontractile smooth vessels and/or loss of dopamine receptor response. Such vasodilatation status is supported by a high RBF and a low RI value at day 0 and by the absence of a relation between cardiac output modifications induced by dopamine and RBF. Early kidney graft vasodilatation might be seen to be paradoxical when compared with the more usual vasoconstriction reported previously.14 Having no clear explanation for this paradox, we can only speculate on putative mechanisms. First, the use of a calcium-free solution for graft conservation might have contributed, especially considering the prolonged cold ischemia time. Second, timing of the ischemic-reperfusion vasoconstriction response could appear later on the graft, perhaps several hours later, leading to vasoconstriction. After 6 days, graft vasoreactivity to low-dose dopamine was restored in patients recovering graft function. Low-dose dopamine reduced the RI, with an increase in the diastolic component supporting the vasodilating effect of low-dose dopamine. The “renal dose” of dopamine could not further dilate kidney vessels and failed to increase RBF at day 0. In this condition, graft glomerular filtration and urinary output have to depend on perfusion pressure, that is, mean arterial pressure. Consequently, the increase in sodium excretion observed with a constant urine sodium concentration implies a major role for urinary output and a negligible impact from renal tubules. The glomerulotubular balance appeared also functionally modified because sodium excretion increase did not modify glomerular filtration rate.
To summarize, the kidney graft at day 0 behaves as a “passive filter” depending on the hydrostatic pressure generated by the increase in dopamine dose, according to Guyton’s concept of pressure diuresis.26 Several factors may account for the loss of normal renal vasoreactivity to dopamine immediately after kidney transplant (eg, denervation, ischemia-reperfusion injury, duration of cold ischemia, and quality of the reperfusion technique). Such a loss suggests a modification of “normal” renal vascular tone control, and the dopamine test can be seen as pharmacologically functional. Dopamine administration is not recommended in the early posttransplant period.15-18 Whether delayed administration monitored by the graft vascular tone could benefit graft function is beyond the reach of our study. The dopaminergic pathway may have been transiently disrupted by the release of reactive oxygen species or by calcium homeostasis changes after ischemia followed by reperfusion injury.27,28
The lack of an adaptive response of RBF to an endogenous effector mimics the “vascular paralysis” observed in sepsis. A strength of our study is that it offers a specific target for therapeutic intervention based on vascular regulatory capacity immediately after injury. Maintenance of a minimal systemic pressure might be important during the early posttransplant phase to maintain glomerular filtration rate, sodium excretion, and urinary output.
The use of the RI as a noninvasive tool obtained with Doppler echocardiography has been proposed to assess renal vascular tone in different conditions such as septic shock.25 A threshold of RI has been proposed to detect the risk of acute kidney injury29 and may help to adjust therapeutic modalities for perfusion at the bedside.30 The RBF increase during infusion of a “renal dopamine dose” at day 6 is associated with vasodilatation reflected by RI decrease. Because RI is a ratio, it cannot analyze the diastolic and systolic flow phases separately and does not take into account the mean flow value. Renal RI can then be normal when the flow is proportionally reduced for both systolic anddiastolic components. The measure of systolic and diastolic flows in our study allowed confirmation of dilatation in terms of diastolic blood flow increase.
This study has important limitations. First, evolution of the reactivity of the graft to dopamine between day 0 and day 6 is unknown, because measurements with a progressive dose of dopamine were not part of the protocol during this period. Each pair of donors and recipients is specific regarding the time course of kidney function recovery and does not depend on RBF alone. It is the reason why each patient was chosen as his own control, and a paired statistic test was performed. Second, kidney graft hemodynamic data such as flow and pressure cannot be interpreted in light of metabolism. Changes in oxygen consumption might be part of the RBF modifications, a key adaptation to match energy required by renal function.31 Third, renal RI data were calculated from the velocities in the main renal artery and not in the interlobular arteries as recommended for noninterventional native kidneys. This has to be taken into account when interpreting the data.
In summary, measurement of the absolute phasic and mean arterial blood flow in transplanted kidneys during the early phase after transplant by implantable Doppler microprobes shows a nonresponse to renal dopamine dose initially, which recovered within 6 days. When dopamine renal dose at 6 days increased RBF, this primarily affected the diastolic blood flow component.
Volume : 14
Issue : 2
Pages : 176 - 183
DOI : 10.6002/ect.2015.0181
From the 1Department of Anesthesia and Intensive Care, Groupe
Hospitalier Universitaire Saint-Louis-Lariboisière-Fernand-Widal, Assistance
Publique-Hôpitaux de Paris, 75010; and the 2Inserm Unit 1160, Paris, France
Acknowledgements: Financial support for this study was provided by Assistance Publique–Hôpitaux de Paris. The authors have no conflicts of interest to declare. †Deceased.
Corresponding author: Laurent Jacob, Service d'Anesthésie-Réanimation, Hôpital Saint-Louis
1, avenue Claude Vellefeaux, 75010 Paris, France
Phone: +33 1 4249 4830, +33 1 4249 4831 (office) Fax: +33 1 4249 4833
Figure 1. Protocol Design Scheme Showing Hemodynamic Recording Points and Time of Urine Sampling
Figure 2. Mean Renal Blood Flow as a Function of Dopamine Infusion Rate on Day 0 and Day 6
Figure 3. Individual Vasoreactivity (Percent Increase of Mean Renal Blood Flow Over Baseline) to a Renal Dopamine Dose (3μgákg-1ámin-1) on Day 0 and Day 6
Figure 4. Correlation Between Increase in Urine Output and Mean Arterial Pressure on Dopamine Infusion
Table 1. Patient Clinical Characteristics
Table 2. Hemodynamic and Renal Functional Parameters at Day 0 and Day 6 After Kidney Transplant