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Case Study
D.T., a 78-year-old, black female, presented electively for a redo right renal percutaneous transluminal angioplasty (PTA) after canceling 3 weeks prior, due to the ravages of Hurricanes Katrina and Rita in Louisiana. She noted vague right back pain that she attributed to prior back surgery and muscle straining while evacuating during the hurricanes. Past medical history included diabetes, hypertension, chronic heart failure (CHF), chronic renal insufficiency (CRI) with a prior baseline serum creatinine (CR) of 1.7–1.9 mg/dl, prior bilateral renal artery (RA), celiac, superior mesenteric arterial (SMA) and aortic stents, and severe PVD with a left femoral to posterior tibial bypass graft, with multiple left common femoral artery endarterectomies with complex patch angioplasties. Further history included a primary advanced adenocarcinoma of the right groin, with a radical groin dissection and post-op radiation treatment three years prior, resulting in a patient with limited femoral artery access. She had undergone bilateral RA PTA/stents in 2002 with subsequent bilateral RA ISR diagnosed by ultrasound in June 2005. In August 2005, a repeat left RA PTA was performed by a left brachial artery (BA) approach without complications, and a right RA PTA had been scheduled just prior to the hurricanes for a 80–90% RA ISR (Figure 1A). The patient had 2 right RA stents placed in 2002 for a small distal dissection. The last serum CR (1–2 months prior) was 1.8 mg/dl. The patient was on no nephrotoxic oral medications, and was maintained on daily Plavix and ASA. The preadmission serum CR was 2.3 mg/dl, with a calculated CR clearance (CRCL) of 35 mL/min and she was instructed to preadmit 24 hours prior to the planned RA PTA for oral N-acetylcysteine (NAC) 600 mg po bid and “gentle” hydration with saline and sodium bicarbonate, due to her history of CHF.

Unfortunately, the patient “missed her ride” to the hospital the day before her planned procedure, but “had a ride” the morning of the procedure, so she was instructed to take nothing by mouth (NPO) and “come on in” for her scheduled procedure. A right renal infarction or renal artery occlusion had not been diagnosed preprocedure, and her right RA was patent with 80–90% ISR one month ago. Targeted renal therapy (TRT) utilizing the Benephit Infusion System (FlowMedica, Inc., Fremont, California) for direct bilateral RA fenoldopam (Corlopam, Abbott Laboratories, Abbott Park, Illinois) infusions was introduced to our cath lab two weeks prior and TRT had been used in several prior cases, including 4 BA approach infusions without complications and with favorable outcomes. Since this patient was at high risk for contrast-induced nephropathy (CIN) and had minimal hydration (total of 150 cc preprocedure) without NAC, a strategy for CIN prophylaxis utilizing TRT with the Benephit catheter and fenoldopam was planned that day utilizing a bilateral BA approach.

Simultaneous percutaneous bilateral BA access was accomplished under local anesthesia utilizing a Cook (Cook, Inc., Bloomington, Indiana) needle and bivalirudin (Angiomax, The Medicines Company, Parsippany, New Jersey) was used for anticoagulation. A 5-Fr introducer sheath was inserted from the left BA and 5-Fr Benephit Introducer Sheath from the right BA. Set-up angiography utilizing 10 cc contrast revealed 100% occlusion of the previous (1 month ago) 80–90% right RA ISR (Figure 1B). The left RA was patent without ISR. A decision was made to cannulate the left RA using a single branch of the bifurcated Benephit PV catheter via the right BA and provide unilateral TRT with a fenoldopam 0.4 mcq/kg/min infusion while attempts were made to revascularize the right kidney via the left BA (Figures 1C and 1D).

A 6–Fr Amplatz right coronary guide catheter (Cordis Corporation, Miami, Florida) was used to engage the ostium of the 100% right RA occlusion with the previously placed bilateral RA stents extending 1–2 mm into the aorta (Figure 1D). A 0.035” Magic torque (Boston Scientific, Maple Grove, Minnesota) 260-cm guidewire crossed the occluded RA and a 6-Fr Vista Brite Tip (Cordis Corporation) 90 cm sheath was exchanged over the guidewire (Figure 1D). PTA was performed using a 5.0 x 4.0 cm Invatec (Roncadelle, Italy, distributed by eV3, Inc., Plymouth, Minnesota) Sailor Plus balloon at 8 atmospheres (Figure 1E). The RA ostium was further dilated with a 6.0 x 2.0 cm Sailor Plus balloon with excellent angiographic results. A total of 80 cc iso-osmolar Iopamidol contrast (Isovue, Bracco Diagnostics, Inc., Princeton, New Jersey) was utilized. A right RA angiogram and nephrogram demonstrated no thrombus, with the right RA filling somewhat slower, and “pruned” versus the left RA (Figure 1F). The right periprocedural nephrogram also appeared somewhat smaller than the left by visual estimation.

The Benephit catheter was then repositioned first in the higher right RA and next in the left RA in < 90 seconds. Bilateral RA TRT was initiated with an infusion of the selective D-1 agonist and vasodilator fenoldopam at 0.4 mcq/kg/min (Figures 1G and 1H). The bivalirudin was stopped, a 1000 U bolus of heparin was given, a continuous infusion of 500 U heparin was started through the side ports of both BA sheaths and the ACT kept > 300 seconds. The left BA sheath was maintained for monitoring, and the right BA TRT was continued for 8 hours at the same infusion rate without complications or hypotension. The maintenance of in vitro fertilization (IVF) was 80 cc/hr NS. Diuretics, sodium bicarbonate and NAC were not used. The urine output remained > 100 cc/hr and the Benephit catheter and sheath were pulled at 8 and 10 hours, respectively, as per protocol, without complications. The 24-, 48- and 72-hour serum CR and CRCL were 1.8 mg/dL and 49 mL/min, 1.7 mg/dL and 52 mg/min, and 1.4 mg/dL and 60 mL/min, respectively. At one-month the serum CR and CR CL were maintained at 1.4 mg/dL and 60 mL/min with bilateral RA duplex ultrasound velocities in the normal range. The right kidney size measured 9.0 cm and the left kidney 9.2 cm.

Discussion
The clinical impact of CRI both associated and unassociated with CIN has just recently begun to be recognized. In percutaneous transluminal coronary angioplasty (PTCA) populations, CIN has been associated with increased in-hospital mortality (7.1%–35.7%) as well as increased one-year mortalities of > 35–45% if dialysis is required.^1–3 Little is known of the association of CIN and CRI in the endovascular treatment of PVD, but the known higher incidence of both diabetes and CRI in the older PVD population make it highly likely that the clinical impact of CIN and CRI in the PVD patient is even greater than in coronary patients.⁴ CRI has long been known to be a negative outcomes predictor during major cardiac and vascular surgical procedures. Even mild CRI (CR 1.5 mg/dL) during CABG was associated with an 11.1% versus 3.8% (p < 0.001) 1-year mortality when compared to CABG with normal renal function.^5–7 Likewise, CRI is associated with poorer outcomes in patients with abdominal aortic aneurysm (AAA) and thoracic aortic aneurysm (TAA), and it remains the third most common morbidity after endovascular aneurysm repair (EVAR).^8,9 Only recently have strategies been devised to “upstream” treat these high-risk patients with CRI, diabetes and those at high risk for CIN and worsening renal function during endovascular revascularization procedures.

This novel case demonstrates the potential of both the simultaneous prevention of CIN and the therapeutic vasodilatation effect of TRT with intrarenal (IR) fenoldopam infusion. The patient did not experience hypotension during the 8-hour postprocedure TRT infusion, and the BA sheaths were managed easily and removed without complications. The urine output was well-maintained and both the serum CR and CR CL improved at 24, 48, and 72 hours without bicarbonate, NAC or significant hydration, implicating a favorable response to TRT with IR fenoldopam. The Benephit catheter was easily manipulated in this complex setting of bilateral RA stents and remained safely in place for a total of 10 hours.

Fenoldopam is a short-acting, selective dopamine-1 agonist and vasodilator that is the only agent shown to increase renal cortical and medullary blood flow.¹⁰ The initial favorable clinical reports of intravenous fenoldopam administration in reducing CIN during PTCA were not replicated in the randomized CONTRAST trial.¹¹ Fenoldopam has a first-pass renal metabolism and can cause hypotension at mild to moderate systemic doses. It can be theorized that the CONTRAST trial results were secondary to an inability to deliver therapeutic doses directly to the renal medulla. Direct, high-dose intrarenal infusion of fenoldopam, in concept, has the potential to deliver selective renal vasodilation and increased medullary blood flow with the potential to reduce CIN.

The early clinical experience with fenoldopam and TRT has been encouraging.¹² The completed FEN-01 study validated the feasibility, safety and efficacy of (intrarenal fenoldopan) IR-FEN delivery and validated several key hypotheses about IR-FEN.¹² Thirty-three patients with mild CRI were randomized 2:1 to receive (intravenous fenoldopam) IV-FEN, then IR-FEN versus placebo during PCI. Inulin was used to measure glomerular filtration rate (GFR) and serum FEN levels were measured. In concept, the IR-FEN infusion maximized the favorable hemodynamic benefits of FEN by “targeted” infusion of FEN into the renal arteries. Systemic FEN levels were lower with IR-FEN compared to IV-FEN, due to first-pass renal metabolism and excretion of FEN.

Administration of IR-FEN compared to IV-FEN (0.2 mcg/kg/min) resulted in 30% lower serum levels of FEN. Additionally, there was 45% less reduction in systemic blood pressure with IR-FEN compared to placebo (12 + 3 mmHg versus 23 + 3 mmHg, p < 001). Importantly, GFR was not significantly altered by IV-FEN, but was significantly increased by 25% during IR-FEN (p < 0001 compared to baseline). The increase in GFR after IR-FEN was significantly greater than seen with IV-FEN (25% versus 5%, p < .001). GFR measured two hours after the procedure remained significantly elevated (25% increase) in IR-FEN patients, while GFR in placebo patients declined by 14%. This 25% prolonged increase in GFR with TRT compared to a 14% decrease with placebo has significant clinical implications in not only preventing CIN, but also in multiple clinical scenarios that would benefit from improved GFR.

The Benephit Infusion System has been granted a 510k approval, and is currently commercially available. The system is available with either an 8-Fr dual port or 5-Fr single port introducer sheath, and a separate bifurcated catheter with atraumatic, low-profile infusion arms with tips that can be easily positioned into both renal arteries without the need of guidewires for continuous fluid infusions (Figure 2). We have found the percutaneous BA approach particularly advantageous with the 105-cm Benephit PV system, especially when treating patients with lower extremity PVD and limited vascular access. We have also used both the BA and femoral approach in a wide variety of both endovascular and surgical cases in patients with CRI both with and without risk of CIN. Trials are being initiated with CRI patients at high risk of worsening renal function during CABG, cardiac valve surgery, AAA (open and EVAR), PTCA, and the endovascular treatments of PVD and critical limb ischemia.

Conclusion
Worsening renal function in patients with CRI with or without CIN results in significantly poorer overall outcomes. TRT with IR fenoldopam infusion via the Benephit Infusion System is a novel therapy that has potentially widespread clinical use in many of our cardiovascular patients. This case demonstrates both a novel bilateral BA vascular access with unilateral renal salvage of a totally occluded renal artery and a longer-term therapeutic renal vasodilator strategy utilizing the bifurcated Benephit catheter. It is likely that further experience will identify many creative clinical opportunities to avoid worsening renal function utilizing TRT during endovascular and surgical treatments. Ongoing randomized trials are being conducted in an attempt to validate this promising therapy.