First Experience with Intra-Renal Fenoldopam in a Patient with Heart Failure

Patients with chronic kidney disease have a high prevalence of heart failure. According to the United States Renal Data System, nearly 40% of incident dialysis patients had a clinical diagnosis of heart failure.¹ Furthermore, deterioration in renal function during an episode of cardiac decompensation is commonplace — some deterioration occurs in over 70% of all patients hospitalized for heart failure.² Renal vasoconstriction is the final common pathway for many factors such as drugs, contrast media, and poor pump function that contributes to acute renal insufficiency in hospitalized heart failure patients. Because renal vasodilator or anti-constrictor therapies, such as fenoldopam (a selective dopamine-1 receptor agonist), atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and dopamine have undesirable systemic effects such as hypotension, increased afterload, or tachycardia in heart failure patients, these drugs are often not used in doses that lead to optimal renal effects. In addition, all of the aforementioned drugs also have dose-related diuretic and natriuretic properties which also may not be fully realized due to suboptimal dosing. It is plausible that direct intra-renal arterial infusion of drugs with favorable renal hemodynamic and natriuretic effects may permit the kidneys to be perfused with relatively higher concentrations of such drugs, leading to greater renal effects. Furthermore, because most drugs are eliminated by the kidneys, it is expected that there may be a substantial renal first-pass elimination following intra-renal drug delivery such that systemic exposure to the drug is decreased and unwanted effects of high systemic concentrations are avoided. Recently, Mathur, et al.³ reported that intra-renal infusion of fenoldopam in dogs resulted in 50% lower fenoldopam concentrations compared to the same dose given intravenously. B-type natriuretic peptide (BNP, nesiritide) had an even greater first-pass renal elimination (60–75%).⁴ As a matter of fact, in a recent randomized placebo-controlled trial including patients undergoing angiography,⁵ intra-renal fenoldopam administration at 0.2 mcg/kg/min caused a significant four-fold increase in the glomerular filtration rate compared with intravenous fenoldopam administration at the same dose, as well as placebo. Interestingly, intravenous fenoldopam given at a dose 2 to 4 times higher than the dose used in a larger randomized clinical trial6 was not different than placebo at increasing the glomerular filtration rate. In addition, plasma concentrations of fenoldopam and nadir systolic blood pressures were significantly lower following intra-renal versus intravenous administration.⁵ We performed bilateral renal cannulation and drug infusion in a patient with advanced heart failure using a new bifurcated infusion catheter (Benephit™ Infusion System, FlowMedica, Inc., Fremont, California), shown in Figure 1, as a prelude to clinical use of such a method for managing patients with decompensated heart failure and cardio-renal syndrome. Case Report. This case features a 66-year-old male with chronic renal disease (baseline serum creatinine ~2.0 mg/dL), and a recent finding of severe systolic dysfunction by echocardiography (left ventricular ejection fraction of 20–25%), and inducible ischemia in a stress test. The patient was admitted to our institution for further evaluation and management. His past medical history was also notable for orthostatic hypotension, hypothyroidism, ataxia, depression, and dyslipidemia. The patient had been recently admitted to an outside hospital with a blood pressure of 80/40 mmHg, increased serum creatinine (4.9 mg/dL), and diarrhea. Over 5 days, he improved following treatment with fluid and holding of his angiotensin converting enzyme inhibitor, and his creatinine returned to 1.8 mg/dL. He was transferred to our institution for further evaluation. His cardiac medications included aspirin, carvedilol, enalapril (on hold), midodrine, and simvastatin. The patient complained of orthostatic lightheadedness. Physical examination was remarkable for somewhat cool extremities, a supine blood pressure of 173/60 mmHg, a 2/6 holosystolic murmur best heard at the left lower sternal border, and balance difficulties. The electrocardiogram revealed normal sinus rhythm at a rate of 62 beats per minute and a left bundle-branch block. The patient underwent right and left heart catheterization. The hemodynamic findings are displayed in Table 1. Right arterial femoral access was achieved using the modified Seldinger technique with placement of a standard 6 Fr sheath. Contrast injection through the sheath revealed a severe right common iliac stenosis. Subsequently, an angiographic “road-map” of the renal arteries was obtained with a 5–6 cc hand injection of contrast through a 6 Fr pigtail catheter advanced to the region of the renal arteries. Based on the road map image, the standard sheath was replaced by an appropriate length Benephit System 8 Fr sheath. The patient was noted to have a 75% right renal artery stenosis (Figure 2). The Benephit Infusion System sheath was advanced without difficulty to the region of the renal ostia. Despite the renal artery stenosis, we easily advanced the System’s bifurcated renal catheter through the sheath and were able to cannulate both renal ostia. Fenoldopam 0.2 mcg/kg/min was infused into the renal arteries via the Benephit System Catheter. During the drug infusion, all 6 Fr catheters required for coronary angiography and left heart catheterization were passed through the second port on the system’s sheath (Figure 3). Coronary angiography revealed mild diffuse disease of the left anterior descending artery, with a 95% stenosis of a large first diagonal (D1) branch, and moderate diffuse disease with tandem 50% lesions in the mid-right coronary artery. The Benephit System was left in place to allow 30 minutes of fenoldopam infusion. Right heart catheterization was repeated at the end of the case. Intra-renal fenoldopam resulted in mild afterload reduction, given the moderately antihypertensive dose that was used, and was consistent with reduced systemic exposure following intra-renal delivery (Table 1). No anticoagulation was used. The patient received a total of 65 ml of iodixanol. The patient tolerated the procedure well and there were no complications. The serum creatinine on the following day was 1.7 mg/dL. Discussion. This case highlights the feasibility and ease of bilateral intra-renal fenoldopam infusion in a typical heart failure patient with multiple comorbidities, including peripheral, coronary and renal vascular disease. The availability of an easy-to-use system that allows targeted renal delivery of drugs may widen the therapeutic window for a number of currently available drugs with beneficial renal effects but undesirable systemic effects. In this case we used a higher dose of fenoldopam than that tested in clinical trials with systemic infusion6,7 with good tolerability and minimal systemic effects. There is a high probability that drugs with useful renal properties may be undeservedly relegated to being “not effective” after being tested at subtherapeutic renal doses. For example, the dose of fenoldopam (0.05–0.1 mcg/kg/min) chosen for the CONTRAST trial⁶ had been shown not to affect the glomerular filtration rate in patients with renal insufficiency.^5,8 Another example is nesiritide. It is well known that the effects of nesiritide on urine output and renal hemodynamics are dose-related at infusion rates of 0.015 and 0.030 mcg/kg/min.^9–11 However, a recent small crossover study designed to test the renal effects of nesiritide used a lower dose of 0.01 mcg/kg/min and concluded that nesiritide was not effective in improving renal function or urine output in patients with decompensated heart failure and acute renal functional deterioration.¹² In these two examples, fenoldopam and nesiritide were probably not adequately dosed to maximize renal effects due to fear of dose-related systemic hypotension. In patients with heart failure for whom systemic drug administration may not be tolerated or may be limited by deterioration in renal function, intra-renal drug delivery may offer a means to break out of the vicious cycle of reduced cardiac function, renal dysfunction and refractory volume overload. Additional study is required to define effective and safe intra-renal drug regimens for managing acutely decompensated heart failure with cardio-renal syndrome.

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