Targeted renal therapy (TRT) with direct intrarenal artery fenoldopam (FEN) infusions were used to treat a multifactorial acute renal failure (ARF) patient with acute limb ischemia, contrast-induced nephropathy (CIN) and sepsis. TRT was initially infused periprocedurally for CIN prophylaxis. Congestive heart failure (CHF), sepsis and ARF developed 48 hours later, requiring dialysis. TRT was restarted during the third dialysis treatment with immediate return of renal function and urine outputs > 100 cc/hour, avoiding further dialysis. Catheter-delivered TRT has shown benefits in CIN prevention by increasing the glomerular filtration rate (GFR) by 25%.¹ We report a multifactorial ARF case in which TRT facilitated “rescue from dialysis”.

Case Report. A 79 year-old diabetic male with several chronically infected diabetic foot ulcers was transferred emergently with a cold, pulseless left leg. The patient arrived fully anticoagulated with an 8 Fr right femoral sheath. During a percutaneous interventional revascularization attempt at the referring facility, the superficial femoral, popliteal and all infrapopliteal arteries developed thrombosis, with resultant acute limb ischemia. N-acetylcysteine, FEN and bicarbonate hydration were not used before transfer, and 240 cc of iso-osmolar contrast was utilized immediately prior to transfer. The patient’s past history included ischemic cardiomyopathy with an ejection fraction of 20% and multiple episodes of CHF. Just 6 months prior to transfer, the patient required 8 weeks of dialysis for ARF precipitated by pneumonitis, CHF, sepsis and CIN during left renal stenting.

Daily dialysis treatments for the next 48 hours removed 7.5 liters fluid volume with the serum Cr and blood urea nitrogen (BUN) level decreasing to 3.0 mg/dL and 63 mg/dL, respectively. The urine output completely stopped during the initial 48-hour dialysis treatments. During the third dialysis treatment on postprocedural day-5, high-dose TRT with FEN (0.5–0.6 ug/kg/minute) was restarted, and a new single-port 5 Fr Benephit Infusion sheath was reinserted from the right femoral artery and the infusion arms of the catheter were again placed into both renal arteries. The treatment strategy was to reestablish direct renal artery vasodilator therapy for 48 hours and increase the GFR by 25% in an effort to minimize dialysis requirements. Within 4 hours of reinstituting TRT, the patient’s urine output increased to 60 cc/hour, the urine color cleared, and the urine output remained 100–200 cc/hour during the second 48 hours of TRT. Lab values after the third dialysis treatment and reinstitution of TRT for 24 hours included serum Cr of 1.9 mg/dL, BUN of 34 mg/dL and hematocrit of 34.5%. The sequence of treatment included the following: peri- and postprocedure day-1 TRT only (CIN prophylaxis); days 3–4 dialysis only (no TRT); day-5 therapeutic TRT (TTRT) with dialysis; day-6 TTRT only (dialysis stopped). The patient did not require further dialysis after the third dialysis treatment and achieved 30-day limb salvage with a serum Cr of 1.4 mg/dL. The patient underwent a similar successful contralateral percutaneous limb salvage procedure with TRT 3 months later with a serum Cr of 1.5 mg/dL.

Discussion. TTRT refers to direct bilateral intrarenal artery therapeutic infusions of fluids that may be potentially applicable to a wide range of clinical conditions including CIN prophylaxis and sepsis. Theoretically, TRT therapy may have benefit in CHF with cardiorenal syndrome and in worsening renal insufficiency during cardiac and vascular surgical procedures.^1–2 The Benephit PV Infusion system is FDA-approved and clinically available and consists of a 5 Fr single-port and 8 Fr dual-port system. The system includes an introducer sheath and infusion catheter with bifurcated low-profile arms that are easily directed into both renal arteries (Figure 2). FEN is a short-acting selective dopamine-1 receptor agonist and vasodilator that is the only agent known to increase renal cortical and medullary blood flow.³ Intravenous FEN has a serum T 1/2 of 5 minutes and can cause systemic hypotension at low doses of 0.05–0.¹ mcq/kg/minute, as demonstrated in the CONTRAST trial.⁴ It can be theorized that the poor CONTRAST trial results comparing intravenous FEN with hydration in CIN prevention were due to an inability to deliver therapeutic FEN doses directly to the renal nephrons. Direct high-dose intrarenal artery infusion of FEN in concept has the potential to deliver selective renal vasodilatation with increased cortical and medullary blood flow, thereby increasing the GFR.^1,3

Tierstein et al recently reported the safety and feasibility of TRT utilizing FEN 0.4 mcq/kg/minute in 33 percutaneous coronary intervention patients at high risk for CIN.¹ Inulin was used to measure GFR and FEN levels were measured. Several key TRT hypotheses were proven. No patient developed CIN, systemic FEN levels were lower with intravenous FEN versus TRT, and GFR was significantly increased with TRT versus intravenous FEN (23.6% versus 4.9%; p < 0.001).¹ The GFR remaind elevated by 25% for 2 hours after discontinuing TRT versus a 14% decrease in GFR in patients receiving placebo.¹ Further ongoing clinical trials are attempting to validate TRT in percutaneous coronary interventions, cardiothoracic and vascular surgery and peripheral endovascular interventions.

Recent data have demonstrated GFR to be a strong predictor of outcomes in patients after acute myocardial infarction, CHF and in overall cardiovascular events in several large population studies.^5–11 Khan et al analyzed the GFR in 6,640 CHF patients and reported the rate of decline in GFR as a strong predictor of increased mortality independent of worsening CHF and baseline kidney function.⁶ Most recently, a decreased GFR of < 60 mL/minute has been found to be a significant predictor of mortality in two cohorts of surgical patients, coronary artery bypass graft surgery (CABG) and endovascular abdominal aortic aneurysm repair (EVAR), further underscoring the clinical need to aggressively treat and preserve renal function.^12–14 Hills et al analyzed 2,067 CABG patients from the United Kingdom and found 37% had a preoperative GFR < 60 ml/minute, and that at mean 2.3-year follow up, GFR was a significant independent predictor of mortality.¹³ Cooper et al reviewed 483,914 CABG patients using the Society of Thoracic Surgeons national database and found preoperative renal insufficiency (RI) to be common, with 51% having mild RI (GFR 60–90 mL/minute), 24% moderate RI (GFR 30–59 mL/minute), and 2% severe RI (< 30 mL/minute).12 Operative mortality increased inversely with declining GFR, from 1.3% (GFR > 90 mL/minute) to 9.3% (GFR < 30 mL/minute), demonstrating GFR as a powerful predictor of CABG operative mortality.¹²

Interestingly, the proposed pathogenesis of ARF associated with CIN and sepsis are similar with the final common pathway leading to intense renal medullary vasoconstriction with the resulting sequelae of a vicious cycle of worsening ischemia, decreased renal medullary blood flow, cellular hypoxia, acidosis, endothelial dysfunction, hypercoagulability, glomerular microvascular thrombosis and acute tubular necrosis.^2,3,18,19 CIN is not uncommon and is now the third leading cause of hospital-acquired ARF.^15,16 The long-term survival of cardiovascular patients who develop ARF and require permanent dialysis is poor, with a 2-year survival rate of < 30%.^5,12,15 In the United States each year, sepsis results in 210,000 deaths, which exceeds the reported deaths due to myocardial infarction.²⁰ ARF occurs in 23–51% of the 700,000 patients yearly who develop sepsis, with a mortality rate of 45–70% resulting in > 200,000 deaths.^18–20 ARF has been shown to occur in 51% of sepsis patients with positive blood cultures.^18–20 The mortality rate from sepsis with ARF is 70% versus 45% with ARF alone, therefore identifying this combination of ARF and sepsis as a major U.S. healthcare issue.^2,20

Morelli et al reported a prospective, double-blind, placebo-controlled, prophylactic, intravenous, low-dose (0.09 mcq/kg/minute) FEN trial in 300 patients with sepsis.² This study demonstrated safety and that the incidence of protocol-defined ARF and length of ICU stay, as well as the increase of serum Cr, were significantly lower in the FEN group. However, the probability of death and the difference in the incidence of severe ARF and dialysis demonstrated only a favorable trend and did not reach statistical significance in this small trial.²

In early sepsis, vasoconstriction with intact tubular function predominates, therefore, it could be theorized that early TTRT with high-dose FEN could potentially be an effective early treatment strategy.² This early interventional TTRT strategy appears reasonable when considering there are no proven early or late therapeutic strategies to prevent dialysis for patients who develop ARF due to CIN, sepsis, or a combination of both, as likely occurred in this patient.

In conclusion, worsening renal function, as estimated or calculated by GFR, is associated with poor outcomes in a wide range of cardiovascular and noncardiovascular patients including sepsis. This single case report does not definitively prove TRT with FEN “rescued” this patient from multifactorial ARF, and it is likely that the early renal recovery was secondary to multiple therapies including TRT. It is, however, intriguing to now have the availability of percutaneous catheter-directed renal artery access for therapeutic infusions capable of significantly increasing the GFR. TRT very likely was clinically important to this patient’s recovery when considering the pathogenesis of ARF in CIN and sepsis, and the increase in GFR associated with TRT. The lack of any effective percutaneous or nonpercutaneous medical interventional therapy in the very large number of patients with rapidly worsening renal function destined for dialysis have lowered our threshold to utilize TTRT in a wide range of clinical scenarios including CIN prevention, coronary and peripheral vascular interventions, CABG, EVAR, CHF and “renal rescue” in sepsis. Pilot and randomized trials are being organized in each of these clinical scenarios, and it is highly likely that other therapeutic infusions besides FEN could also potentially improve clinical outcomes.