Renal actions of dopamine

INTRODUCTION — Dopamine is synthesized within the kidney in the proximal tubule from circulating L-dopa, via the enzyme L-amino acid decarboxylase [1-3]. There are also renal nerves that contain dopamine, although the physiologic significance of these nerves is unclear.

The renal actions of dopamine are discussed here. The use of dopamine in patients with shock is presented elsewhere. (See "Use of vasopressors and inotropes".)

RENAL ACTIONS — Circulating and locally formed dopamine can affect both sodium excretion and renal hemodynamics via activation of the D1-like and D2-like receptors [1,4,5].

Natriuresis — Dopamine is a natriuretic hormone, increasing sodium excretion by diminishing reabsorption, primarily in the proximal tubule [1,2,6,7]. This effect of dopamine appears to involve both of the steps involved in transtubular sodium transport:

●Dopamine, acting via the generation of cyclic AMP, decreases the activity of the Na-H exchanger in the luminal membrane, a transporter that plays an important role in the entry of filtered sodium into the cell [8].

●Dopamine inhibits the Na-K-ATPase pump in the basolateral membrane [1,2,8]. Sodium that has entered the cell from the lumen is normally transported by this pump out of the cell into the peritubular interstitium (and then the peritubular capillary).

In addition to these proximal effects, dopamine can also reduce sodium reabsorption in the collecting tubules. This response may be mediated both by decreased secretion of aldosterone [9] and by diminished activity of the Na-K-ATPase pump in the renal tubular cells [10]. The latter effect appears to be mediated by local prostaglandin generation [10].

The natriuretic effects of dopamine depend in part upon dietary sodium intake. During dietary sodium restriction, the ability of endogenous renal dopamine to inhibit sodium transport is abolished. In addition, intravenous dopamine or fenoldopam (a DA1 receptor agonist) induces natriuresis in subjects consuming a high-sodium diet but not a low-sodium diet. However, administration of an angiotensin-converting enzyme (ACE) inhibitor to individuals on a low-sodium diet restores the natriuretic properties of dopamine, suggesting an interaction between dopamine and the renin-angiotensin system [11].

Vascular effects — Parenteral dopamine has an onset of action within 5 minutes, an elimination half-life of 2 minutes, and, after it is discontinued, a duration of action of less than 10 minutes; varying doses of dopamine have different pharmacodynamic effects [12]. When infused in low doses (0.5 to 2 mcg/kg per minute), dopamine primarily stimulates dopaminergic receptors (DA1 and DA2) in the renal vascular beds, which dilates the interlobular arteries and both the afferent (preglomerular) and efferent (postglomerular) arterioles [6,12,13]. The net effect is a relatively large increase in renal blood flow with a lesser or no elevation in glomerular filtration rate (GFR) [7,14]; the relative lack of increase in GFR is due to the efferent dilatation, which minimizes the rise in intraglomerular pressure. At intermediate doses (2 to 5 mg/kg/min), beta receptors are stimulated, primarily in the myocardium, and norepinephrine is released from sympathetic neurons, increasing heart rate and cardiac output [12]. At higher concentrations (above 5 mcg/kg per minute), dopamine induces renal vasoconstriction, a response that is mediated by activation of the alpha-adrenergic receptors [6,12,13,15].

The increase in kidney perfusion with low-dose dopamine may not be seen in patients with acute tubular necrosis (ATN) [14]. (See "Possible prevention and therapy of ischemic acute tubular necrosis".)

Physiologic role — Although these actions can be readily demonstrated by intravenous infusion [7], the physiologic importance of dopamine remains to be defined. The local production of dopamine is increased by volume expansion [7,16], a finding that is consistent with a role in the ensuing natriuresis. This response is mediated in part by increased activity of L-amino acid decarboxylase, the enzyme that converts L-dopa into dopamine [2]. Also compatible with dopamine being a natriuretic hormone is the observation that administration of a dopamine receptor inhibitor to experimental animals impairs the response to modest volume expansion [17].

CLINICAL UTILITY

Postischemic acute tubular necrosis — The previously mentioned findings have led to the use of low-dose (ie, "renal dose") dopamine both to increase the urine output and to preserve kidney function in oliguric patients at risk for postischemic acute tubular necrosis (ATN). However, such therapy is ineffective and may cause harm, and therefore should not be used. This is discussed in detail separately. (See "Possible prevention and therapy of ischemic acute tubular necrosis".)

Polyuria — Dopamine is frequently administered to maintain the systemic blood pressure in hypotensive patients with sepsis. A rare complication in this setting is the development of a marked natriuresis and diuresis with the urine volume occasionally exceeding 300 to 500 mL/hour despite reduced kidney perfusion [18,19]. The natriuresis presumably reflects the normal inhibitory effect of dopamine on sodium reabsorption; why it may be dramatically enhanced in some septic patients is not clear.

Resistant edema — The role of low-dose dopamine in patients with diuretic-resistant edema is unclear. The best data come from the Renal Optimization Strategies Evaluation in Acute Heart Failure and Reliable Evaluation of Dyspnea in the Heart Failure Network (ROSE) Study in which 241 patients with acute heart failure and kidney dysfunction (estimated glomerular filtration rate [eGFR] of 15 to 60 mL/min/1.73 m²) were randomly assigned to receive dopamine (2 microg/kg/min) or placebo; all patients received diuretic therapy [4]. Compared with placebo, low-dose dopamine had no significant effect on 72-hour cumulative urine volume (8524 versus 8296 mL) or on kidney function measured by cystatin C level (0.12 versus 0.11) [4].

In a post-hoc analysis of the ROSE study, the response to dopamine was found to differ according to ejection fraction [5]. Dopamine-enhanced urine volume and sodium excretion were greater among those with reduced ejection fractions (ie, ≤40 percent) than among those with preserved ejection fraction (ie, >40 percent). These post-hoc findings from the ROSE study were explored in two subsequent trials of patients with acute heart failure and preserved ejection fraction (HFpEF):

●The Diuretics and Dopamine in Heart Failure with Preserved Ejection Fraction (ROPA-DOP) trial assigned 90 patients with HFpEF to intermittent furosemide, continuous furosemide plus low-dose dopamine, or intermittent furosemide plus low-dose dopamine [20]. Compared with intermittent furosemide, the continuous furosemide strategy led to an 11 percent greater rise in serum creatinine at 72 hours and a 25 percent greater relative risk of acute kidney injury (defined as a serum creatinine increase >0.4 mg/dL within 72 hours). The addition of low-dose dopamine did not appear to modify the risk of a diuretic-induced rise in serum creatinine, and there were no significant differences between strategy arms in length of stay or total urine output.

●In another study, treatment with diuretics plus low-dose dopamine was compared with diuretics alone in 100 patients with HFpEF [21]. Low-dose dopamine failed to prevent worsening of estimated GFR from admission to discharge. However, patients in the dopamine arm lost more weight (-1.4 versus 0.9 kg), had a larger diuresis (2072 versus 1690 mL/day), and had shorter hospital stays (3.9 versus 4.8 days). However, mean diuretic doses were relatively modest: 178 and 175 mg of intravenous furosemide daily and 28 and 27 mg of spironolactone daily in the two groups. There were no differences in rehospitalization or mortality during a six-month follow-up.  

Given the conflicting data and the lack of a "kidney-protective" benefit of dopamine, we would not advocate its use to achieve an enhanced diuresis.

DOPAMINE A-1 AGONISTS — It is possible that the renal therapeutic actions of dopamine are obviated because of its nonselective effects upon multiple dopaminergic and adrenergic receptors. For the treatment of acute kidney failure, an ideal agent would selectively activate the renal dopamine A-1 receptor without affecting additional receptors, thereby lowering renal vascular resistance, enhancing natriuresis, and increasing urinary output [22]. Although not ideal, fenoldopam is a relatively selective dopamine A-1 receptor agonist that increases sodium excretion and renal blood flow in normal and hypertensive humans [23].

Studies that have examined the utility of fenoldopam are discussed separately. (See "Possible prevention and therapy of ischemic acute tubular necrosis".)

SUMMARY

●Dopamine is synthesized within the proximal tubule and is also released from renal nerves that contain dopamine. Circulating and locally formed dopamine can affect both sodium excretion and renal hemodynamics (see 'Introduction' above and 'Renal actions' above):

•Dopamine is a natriuretic hormone, increasing sodium excretion by diminishing reabsorption in the proximal tubule and collecting tubule. (See 'Natriuresis' above.)

•When infused in low doses (0.5 to 3 mcg/kg per minute), dopamine dilates the interlobular arteries and both the afferent (preglomerular) and efferent (postglomerular) arterioles. The net effect is a relatively large increase in renal blood flow with a lesser or no elevation in glomerular filtration rate (GFR). At higher concentrations (above 5 mcg/kg per minute), dopamine induces renal vasoconstriction. (See 'Vascular effects' above.)

●Low-dose (ie, "renal dose") dopamine has been used to increase the urine output and to preserve kidney function in oliguric patients at risk for ischemic acute tubular necrosis (ATN). However, such therapy is ineffective and may cause harm, and therefore should not be used. This is discussed in detail separately. (See "Possible prevention and therapy of ischemic acute tubular necrosis", section on 'Experimental and unproven measures for the prevention of ischemic ATN'.)

●It has been proposed that the natriuretic and renal vasodilator activity of dopamine can be used to potentiate the effect of diuretics in patients with resistant edema. However, limited data suggest that dopamine is not beneficial in these patients. (See 'Resistant edema' above.)

●Limited data suggest that fenoldopam, a selective dopamine A-1 receptor agonist, may be beneficial in the prevention or treatment of acute kidney injury. These data, and corresponding recommendations, are discussed separately.