Acute tubular necrosis (ATN) is the type of acute renal failure (ARF) encountered most frequently in the intensive care unit. A discussion of the causes of ATN is beyond the scope of this review, but the final common pathway for all of them is an imbalance between oxygen supply and demand at the cellular level. Pathological studies have consistently shown one area of the kidney that is particularly susceptible to necrosis: the outer medullary region. 1 The reasons for this phenomenon are the focus of the present discussion.
The kidney is traditionally divided into two anatomic areas: the cortex and the medulla. The medulla is subdivided into the outer medulla and the inner medulla; the outer medulla represents the beginning of the thick ascending limbs and the inner medulla contains only thin (ascending and descending) limbs and collecting ducts. The outer medulla is divided further still into two morphologically distinct regions: an outer stripe, which contains thick ascending limbs, straight segments of the proximal tubules, and collecting ducts; and an inner stripe, which differs in that it contains descending thin limbs and no proximal tubular segments. 2 These anatomic differences have profound implications for the kidney with respect to susceptibility to ischemia, as described later.
There are two populations of nephrons in the kidney: cortical nephrons (CN) and juxtamedullary nephrons (JMN). These are defined by the location of their glomeruli within the kidney. They exist in a proportion of about seven CNs to one JMN and have been shown to differ structurally. Cortical nephrons have thick, muscular afferent arterioles and are responsive to autoregulation; JM nephrons have thick, muscular efferent arterioles and are not responsive to autoregulation. The entire blood supply to the outer medullary tubular cells originates from the efferent arterioles of JMNs. 3 These efferent arterioles give rise to the descending vasa recta, which in turn give rise to the capillary network and ascending vasa recta, a “hairpin loop” configuration necessary for preservation of the countercurrent mechanism within the medulla (vide infra).
Although the kidney receives approximately 20% of cardiac output, which represents more blood flow per unit weight than any organ in the body, the vast majority of this flow is directed to the cortex for the purpose of filtration and solute reabsorption. 4 In contrast, the medullary region of the kidney is subtended by a low-flow system via the vasa recta and receives only about 6% of renal blood flow (RBF), barely sufficient to meet metabolic requirements. 5 The reason for this is a consequence of the purpose of the medullary region, which is to create an osmolar gradient that permits efficient concentration of the urine by the countercurrent mechanism. At higher rates of flow, the medullary osmotic gradient is washed out, and the ability to concentrate the urine diminishes. 6 The ability to concentrate urine allows for conservation of water; without this, survival on land would not be possible. Thus, the kidney can be thought of as having two major, but separate functions: filtration of the blood (with reabsorption of solute) in the cortex and preservation of water in the medulla. The continuous balance of these two functions provides blood volume and osmolar homeostasis.
Oxygen Supply/Demand Balance
As with blood flow, there is a similar discrepancy between the medullary and cortical regions with regard to oxygen consumption: it is high in the medullary region, where the cells of the thick ascending limb actively reabsorb solute, and low in the cortical area. It is estimated that 70–90% of kidney oxygen consumption is due to tubular solute transport; the net result of the high-demand/low-supply state of the medullary area is a tissue partial pressure of oxygen (PO2) of only 10–20 mm Hg, whereas the cortical PO2, in contrast, is about 50 mm Hg. 7 Thus, the medullary region is nearly hypoxic in its normal physiological state, a consequence of its role in the establishment of the osmotic gradient necessary for urinary concentration.
Because of the precarious state produced by the high-demand/low-supply conditions just described, the kidney has a complex feedback system to defend against ischemic injury. Because oxygen extraction in the outer medulla is maximal at 90%, any additional improvement in oxygen balance to these cells requires either an increase in oxygen delivery or a decrease in oxygen utilization. To this end, there are two mechanisms by which the outer medullary region achieves this: tubuloglomerular feedback and corticomedullary redistribution of flow.
Although intrarenal blood flow is notoriously difficult to study experimentally, there is long-standing agreement among researchers in this field that there is a shift of blood flow from the cortical to the medullary region under conditions of hemorrhage. 2 Although the mechanisms by which this shift occurs are not clear, a few of the likely mediators that have been identified are nitric oxide, prostaglandins (PGI2 and PGE2), and dopamine. The end result is relocation of the filtration process from superficial cortical glomeruli to the deep juxtamedullary glomeruli. This shift serves two functions. First, urinary concentrating capacity is improved, because these nephrons are more efficient in this regard. Second, medullary blood flow improves, a result of increased perfusion to glomeruli, whose efferent arterioles supply the vasa recta. There is a limit to the extent to which medullary blood flow can increase, however. Because this physiological reserve of oxygen supply is limited, the kidney relies primarily on its ability to decrease oxygen demand to prevent ischemia. This phenomenon has been demonstrated experimentally in a canine model of progressive hemorrhage, 8 and it has been shown that, in general, the reduction of cellular work is the most effective means of protection against anoxia. 9
In the outer medullary region, tubular work is due almost entirely to solute reabsorption. To decrease energy expenditure, the kidney uses the tubuloglomerular feedback (TGF) mechanism to decrease solute delivery to the tubular cells. TGF operates as follows: incomplete reabsorption of solute by the tubular cells, as a result of ischemia, increases delivery of solute to the macula densa. These specialized cells sense the increase in solute concentration and send chemical signals to the glomerulus, which increase afferent arteriolar vasoconstriction. This decreases solute filtration and delivery to the tubules, thereby decreasing tubular energy expenditure (secondary to decreased active reabsorption of solute) and effectively allaying cellular hypoxia. Current thinking is that the most important chemical signal in TGF is adenosine, which is produced by the breakdown of adenosine triphosphate in the setting of hypoxia. 10 Adenosine not only mediates afferent arteriolar vasoconstriction, but it also plays a role in increasing medullary blood flow by causing efferent arteriolar dilation.
The net effects of these changes have been shown in elegant studies by Brezis, Heyman, and Fuchs. 4 Using oxygen microelectrodes and laser Doppler ultrasound probes to quantify the microenvironment of the rat kidney in vivo, they described the effect of multiple clinical interventions on medullary oxygenation. Renal toxins such as amphotericin B, nonsteroidal antiinflammatory drugs, intravenous contrast agents, and myoglobin were all shown to decrease medullary PO2, whereas interventions such as loop diuretics 11 and adenosine increased medullary PO2. In the case of the renal toxins, all have been shown to decrease regional blood flow, increase tubular solute absorption, or both. In the case of the loop diuretics, a profound decrease in tubular solute absorption more than offsets a small decrease in medullary blood flow; adenosine has beneficial effects in both delivery and consumption. Of note, a small increase in regional blood flow was shown with dopamine infusion, but the regional PO2 was unaffected, indicating an increase in tubular work. 12
It has been demonstrated in many species that RBF and glomerular filtration rate (GFR) are constant over a wide range of blood pressures. Like most organs, the kidney exhibits autoregulatory behavior in the normal state; this constancy of RBF and GFR is important for the prevention of medullary ischemia. The mechanism of autoregulation is controversial. A number of studies lend support to Bayliss' myogenic theory, 13 which states that the change of arterial resistance in response to changes in vascular wall tension is mediated by smooth muscle. This explanation is insufficient, however, because GFR has been shown to have greater autoregulatory capacity than RBF. The solution appears to have been reached by Aukland and Oien, 14 who proposed a combination of the myogenic and TGF mechanisms to explain GFR autoregulation. According to their model, the myogenic mechanism is operative at the interlobular artery and at the afferent arteriole, whereas TGF operates as a fine control mechanism at the afferent arteriole. Support for this theory has been provided by Holstein-Rathlou, 15 who, through analysis of flow oscillations, showed two separate frequency components within the autoregulatory mechanism. Although this finely tuned autoregulatory mechanism is operative in normal controls, it is lost or markedly diminished in animal models of the ischemically injured kidney. When this occurs, flow becomes linearly related to pressure, 16 and animal studies confirmed that low blood pressure in this setting contributes to recurrent ischemic injury and delays recovery from ARF. 17 In humans, however, improvement in renal function with augmentation of perfusion pressure has not been investigated by prospective, randomized, controlled trials, although clinical series support this practice. 18 Despite this evidence for optimization of hemodynamics in patients with renal ischemia, much more common in current clinical practice is the use of dopamine as a potentially therapeutic modality.
History of Renal Dose Dopamine
Goldberg and colleagues, in 1963, 19 first reported on the clinical use of dopamine. This article was a case series of four patients with severe congestive heart failure (CHF) refractory to standard diuretic therapy. The intention of the study was to take advantage of dopamine's inotropic properties and increase sodium excretion via an increase in cardiac output. To this end, dopamine infusion was titrated to limited increases in heart rate and blood pressure (no more than 15 beats per minute or 30-mm Hg increase in systolic blood pressure above baseline). The average infusion rate that achieved this was 100 μg/min. Surprisingly, sodium excretion increased dramatically with dopamine infusion, whereas previous studies with other sympathomimetics (mephentermine and isoproterenol) in the setting of CHF failed to demonstrate such an effect.
Goldberg and associates supplemented this study with another on the effects of dopamine infusion on GFR, estimated renal plasma flow (RPF), and solute excretion in healthy volunteers and in patients with CHF. 20 In all patients, dopamine infusion was increased to the largest dose possible without increasing heart rate or blood pressure. The finding in normal controls was that GFR, estimated RPF, and solute excretion were increased, but cardiac output was also increased as a result of increased stroke volume. In the CHF patients, only solute excretion was significantly increased; cardiac outputs were not measured in this group. The authors concluded that dopamine decreased renal vascular resistance, because RPF (as measured by clearance of para-aminohippuric acid [PAH]) was increased in the absence of an increase in blood pressure. Accordingly, a study followed in which Goldberg's group used electromagnetic flow probes to measure directly the effects of dopamine infusion on RBF in dogs. 21 Dopamine was given both systemically, titrated to the highest rate that did not cause an increase in blood pressure, and intraarterially to both the renal and femoral arteries. The predominant findings were that (1) RBF increased significantly with systemic injection of dopamine, although it should be noted that cardiac output was not measured; (2) renal arterial injection of dopamine caused a variable response in resistance, with vasodilation occurring at low doses and vasoconstriction at higher doses; (3) femoral arterial injection of dopamine caused only progressive vasoconstriction with escalating doses. On the basis of these results, Goldberg an colleagues posited the existence of a dopamine receptor on the renal vasculature, which was verified in later studies.
Extrapolation from the aforementioned studies led to the conclusion that dopamine at low doses likely had renal protective properties, which in turn led to clinical studies of low-dose dopamine in the perioperative setting as well as in the settings of oliguria and ARF (vide infra). Problematic in the majority of these studies is the question of whether RBF/estimated RPF can be measured accurately; whether this represents an appropriate clinical end point is discussed later.
In the studies of Goldberg and those that followed, estimated RPF was measured by the clearance of PAH. This measurement is an extension of the Fick equation, such that the rate of appearance of a nonabsorbable/nonexcretable substance in the urine is equal to the rate of delivery to the kidney times its filtration fraction:EQUATION
It is apparent from this equation that several conditions need to be met in order for the measurement of RPF to be accurate: (1) urine flow (QUrine) and urine PAH concentration (UPAH) must be measured; (2) renal arterial (APAH) and renal venous PAH concentrations must be measured; (3) the assumption that PAH is neither secreted nor absorbed by the renal tubules must be valid. If all of these conditions are met, then RBF is calculated from estimated RPF by the following equation:EQUATION
Of note is that, in practice, renal venous blood is not sampled because of the technical difficulty of doing so; therefore, the additional assumption is made that 100% of PAH is filtered by the kidney and eliminated in the urine. This assumption has been shown to be invalid; the actual extraction varies from 70–90% in humans. 2 Furthermore, this variation is increased in both renal disease and after interventions that increase RBF, which compounds the difficulty in interpreting estimated RPF by this method. Because of the problems inherent in the PAH method, other techniques for measuring estimated RPF/RBF have been developed, including uptake of radiolabeled microspheres, 22 washout of radioactive inert gases, 23 and the application of magnetic resonance imaging 24 and ultrasound technology. 25 A discussion of the various methods is beyond the scope of this review, but it should be appreciated that each has inherent limitations and that there is currently no definitive method for accurately measuring RBF.
Other Effects of Dopamine on the Kidney
Despite the technical difficulties in quantifying changes in RBF, and the fact that there is currently no study documenting increased RBF in the absence of simultaneously increased cardiac output, the bulk of the evidence to date (using the aforementioned methods as well as angiographic 26 and videographic methods) strongly suggests that exogenously administered low-dose dopamine decreases renovascular resistance. Even if this conclusion is granted, however, it is not clear that increased blood flow at the preglomerular level per se is a useful or even desirable clinical end point. For example, the increased sodium excretion and urine output commonly observed during dopamine infusion is at least in part attributable to activation of dopamine receptors on the renal tubules. 27,28 In fact, there is strong evidence that dopamine is synthesized in the renal cortex, has no effect on autoregulation of RBF, 29 and is regulated by dietary sodium. 30 Current opinion is that dopamine functions endogenously as a natriuretic, and this appears to be its predominant clinical effect with exogenous infusion (vide infra). In addition, there is good evidence that both dopamine 31 and fenoldopam 32 (another DA-1 receptor agonist) infusions inhibit TGF, which, as previously mentioned, is the kidney's main line of defense against ischemia. Given all of these theoretical considerations, it seems most reasonable to limit conclusions about the clinical utility of renal dopamine to evidence gleaned from clinical trials of the drug.
Clinical Trials of Renal Dopamine
Dopamine has been studied in several clinical scenarios: oliguric states, ARF, sepsis, and the perioperative setting. It should be emphasized that, although the dose of dopamine infusion in these trials is usually specified, the plasma levels are not. Given the finding of MacGregor and others 33 that even weight-based dosing of dopamine in normal men does not avoid profound variation of plasma levels among patients, it is impossible to know whether the dopamine infusion in a given patient in a given study is, in fact, renal dose.
Several studies evaluated the effectiveness of low-dose dopamine on volume-replete, oliguric patients. 34 All of these studies involved postsurgical or critically ill patients and a trial of therapy lasting no longer than 12 hours; none of them was controlled. Although all of the studies showed an increase in urine output during the dopamine infusion, two caveats should be noted. First, it has been shown that dopamine does not increase urine output in volume-depleted patients. 35 Second, the dopamine-mediated increase in urine output has been shown to return to baseline by 48 hours after initiation of the infusion. 36 Thus, if dopamine is to be used for the indication of oliguria, it should be recognized that the available data are uncontrolled and limited to volume-replete patients and that the effect diminishes with time. It should also be appreciated that this effect is likely due to the natriuretic effect of dopamine described previously rather than to an improvement in renal function mediated by increased RBF. This has been demonstrated in two separate clinical studies. In a study of 12 postoperative cardiac surgical patients, Hilberman and coworkers 37 titrated either dopamine or dobutamine infusions to conditions of equivalent cardiac output and systemic blood pressure. All patients served as their own control after a 60-minute washout period, and GFR, sodium excretion, and urine output were measured. The investigators found no difference between dopamine and dobutamine with respect to GFR, but dopamine significantly increased diuresis and natriuresis, indicating a “direct tubular inhibition of solute reabsorption.”
In a similar study performed on 18 critically ill patients, Duke and associates 38 studied the effects of dobutamine at 175 μg/minute versus dopamine at 200 μg/minute on the same indices of renal function. The patients served as their own controls and received infusions of placebo, dopamine, or dobutamine in a random, blinded fashion. Cardiac index and mean arterial pressure were slightly higher in the pressor groups than in the placebo group, but the differences between dobutamine and dopamine were not significant. The findings were that dopamine increased sodium excretion and urine output without increasing creatinine clearance, whereas dobutamine increased creatinine clearance (CrCl) and urine output without increasing sodium excretion. The conclusion was that dopamine acted primarily as a diuretic in critically ill patients.
Acute Renal Failure
Studies of renal dopamine in ARF are few, and all are retrospective, uncontrolled, or of small sample size. The largest of these was observational, and it assessed the effect of dopamine on the placebo arm (256 patients) of a renal control trial of atrial natriuretic factor in ARF. 39 The investigators concluded that the use of dopamine did not improve survival or decrease the need for dialysis. Parker and coworkers 40 prospectively evaluated the effects of a 12-hour infusion of dopamine at 2 μg/kg/min on 52 patients with oliguric renal failure, defined as CrCl less than 40 mL/hr and urine output greater than 1 mg/kg/hr. Cardiac output and blood pressure data were not reported, although urine samples were not analyzed if cardiac output was less than 3.0 L/min or systolic blood pressure was less than 100 mm Hg. They found that, on average, dopamine increased CrCl by 3.8 mL/min, a small but significant amount (P < .05), and increased urine output by 30 mL/hr. The conclusions of this study share the weaknesses of other similar studies, namely that the lack of reported change in cardiac output or blood pressure with dopamine infusion makes the mechanism of increased CrCl unclear. In addition, the outcomes of survival and renal recovery, which are the true clinical end points of interest, were not reported. The only randomized, prospective study to date is in the setting of malaria-induced ARF; it examined the effect of combination dopamine/furosemide therapy on renal recovery in eight patients. 41 The authors concluded that treatment shortened recovery from 17 days to 9 days. Because of the absence of properly designed randomized, controlled trials, powered to detect differences in survival or renal recovery, the conclusion of numerous authors is that dopamine should not be used for the treatment of established ARF. 42
Multiple trials have examined the potential beneficial effects of dopamine when given preemptively in the operative setting. Although there are prospective, randomized, controlled trials for this group of patients, none of the trials possess the statistical power to detect an effect on the incidence of renal failure, which is a relatively rare postoperative complication. 43 In a frequently cited study, Baldwin and colleagues 44 randomized 37 patients undergoing elective abdominal aortic aneurysm (AAA) repair to placebo or dopamine for the first 24 hours postoperatively. Crystalloid was administered to maintain urine output greater than 1 mL/kg during the first 24 hours. The study showed no difference in plasma creatinine levels, CrCl, or mortality. Urine volumes were slightly higher in the dopamine group. Two deaths occurred in the dopamine group versus none in the placebo group, and three myocardial infarctions occurred in the dopamine group versus one in the placebo group. In a separate study also examining patients undergoing elective AAA repair (infrarenal cross-clamp), Paul and coworkers 45 prospectively evaluated the effect of renal dopamine and mannitol on renal function when given preclamp and for 40 minutes postclamp. Allocation of patients to treatment and control groups was nonrandom. There was no difference between groups with respect to urine output and CrCl. In another study of patients undergoing AAA repair, Paul and colleagues 45 prospectively evaluated the effects of infrarenal aortic cross-clamping on renal function in 27 patients. Patients were randomized to two treatment groups: saline or dopamine plus mannitol, which were started before clamping. Hemodynamics and pulmonary artery occlusion pressure were maintained at normal values in both groups. GFR, urine output, and fractional excretion of sodium were measured at several set intervals from preinduction to 24 hours postoperatively. The group found that dopamine and mannitol had no effect on any of the measured indices of renal function, except a slight delay in the onset of postclamp decrease in GFR.
In a prospective study in the setting of liver transplantation, Swygert and associates 46 randomized 48 patients to dopamine at 3 μg/kg/min versus placebo for 48 hours. No benefit was seen for dopamine with regard to urine output, GFR, and need for dialysis. Myles and coworkers 47 studied the effect of renal dose dopamine on cardiac surgical patients and saw no benefit with dopamine on urine output, CrCl, or the likelihood of renal insufficiency, despite an increase in cardiac index. DeLosAngeles and others 48 performed a retrospective study to determine the effects of dopamine at 3 μg/kg/min and furosemide, both started preoperatively and continued for 1–2 days, on 20 patients undergoing renal transplantation. No difference was seen between treatment group and the control cohort with respect to urine output or CrCl.
Several studies examined whether dopamine has utility in the treatment of septic shock patients. In a prospective, randomized, double-blind trial, Martin and coworkers 49 assigned 32 patients with hyperdynamic septic shock to dopamine (10–25 μg/kg/min) or norepinephrine (1.5 ± 1.2 μg/kg/min) infusion. In the dopamine group, 5 of 16 patients responded to therapy, as judged by increases in urine output and systemic blood pressure, whereas 15 of 16 responded in the norepinephrine group. Furthermore, in the cross-over phase of the study, 10 of the 11 nonresponders from the dopamine group responded to norepinephrine. Desjars and colleagues 50 reported similar findings in 12 hyperdynamic septic patients in whom dopamine therapy failed to reverse oliguria and hypotension; 11 of 12 patients responded to norepinephrine infusion. In a related animal study, Bersten and Rutten 51 studied the effect of dopamine on unanesthetized sheep made septic by intraperitoneal injection of bacteria. RBF was measured by placing an electromagnetic flow probe on the renal artery; CrCl was also measured. Dopamine increased RBF in healthy sheep but not in septic sheep and failed to increase CrCl or change renal arteriovenous oxygen extraction in either group. In addition, dopamine infusion did not improve the increased RBF achieved with epinephrine infusion.
Side Effects of Dopamine
Justification of the use of dopamine for the indications mentioned previously depends not only on a demonstrated benefit for the kidney, but also on evidence that this benefit outweighed the deleterious effects of the drug. Dopamine has many commonly observed adverse side effects, 52 notably the precipitation of tachyarrhythmias as well as myocardial and gut ischemia. 53 Additionally, it is conceivable that, given the unpredictability of plasma levels of dopamine for a given infusion rate, an intended low dose of dopamine is, in fact, a high dose, with inappropriate activation of alpha receptors and renal vasoconstriction as a consequence in a given patient.
Despite the prevalent use of renal dose dopamine for treatment of oliguria and ARF, as well as for the prevention of these clinical states, little theoretical, laboratory, or clinical evidence exists to support such practice, particularly when dopamine's adverse side effects are considered. The kidney has an extraordinarily complex mechanism for preventing or mitigating its own demise, and efforts to interfere with it should be viewed skeptically. Of proven benefit for renal well-being are the maintenance of normal volume status and blood pressure and avoidance of renal toxins, interventions that are too often ignored. The conclusion of previous authors 42,43,52 that the use of low-dose dopamine be stopped, pending properly powered controlled trials supporting its use, is appropriate given currently available data.
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