Acute Kidney Injury (AKI) commonly complicates

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1 IN THE LITERATURE Brain Natriuretic Peptide Therapy to Prevent Acute Kidney Injury After Cardiac Surgery Commentary on Mentzer RM, Oz MC, Sladen RN, et al: Effects of Perioperative Nesiritide in Patients with Left Ventricular Dysfunction undergoing Cardiac Surgery. The NAPA Trial. J Am Coll Cardiol 49: , 2007 Acute Kidney Injury (AKI) commonly complicates the perioperative management of cardiac surgery patients, particularly in patients with preexisting risk factors such as congestive heart failure (CHF) and chronic kidney disease (CKD). It is increasingly recognized that development of AKI following cardiac surgery portends a poor outcome, so that prevention and aggressive management of this complication are important components of perioperative care in high-risk patients. AKI is common following cardiac surgery, occurring in 7.7% (reported in 1 ) to 42% (reported in 2 ) of patients with previously normal renal function, depending on the definition of AKI used. Even small increments in serum creatinine have been shown to be associated with increased mortality after cardiac surgery and other insults. 2-8 There is emerging evidence that any change in serum creatinine may have important prognostic value post cardiac surgery, including increases barely beyond the limits of assay variability. 4 Specifically, postoperative serum creatinine increments of 20% to 25% are associated with mortality increases from the range of 0% to 1% to the range of 12% to 14%, 5,6 and even increments of 0.1 to 0.3 mg/dl (8.84 to mol/l) are associated with significant increased mortality. 4 A variety of patient characteristics (CKD, advanced age, diabetes mellitus, CHF), operative factors (emergent surgery, prolonged cardiopulmonary bypass time, valvular surgery, repeat coronary artery bypass graft surgery), and postoperative events (vasodilatory or cardiogenic shock, bleeding) are known to increase the risk of AKI following cardiac surgery. 1,3,8 Although it is clear that preoperative CKD is the major patient risk factor for severe AKI following cardiac surgery, preoperative CHF is found to be among the other significant risk factors in every cohort study. Furthermore, patients with postoperative lowcardiac output syndrome, vasodilatory shock, 9 and bleeding are highest risk for postoperative AKI. In summary, the adverse prognostic significance of AKI following cardiac surgery is well established, and although prior CKD is the most significant predictor of severe perioperative AKI, preoperative CHF with or without postoperative ventricular dysfunction with cardiogenic shock are among the other significant predictors of adverse renal outcomes. Although preoperative identification of patients at high risk of AKI is possible, there are no proven interventions to prevent AKI following cardiac surgery. 10,11 Careful monitoring of renal function, appropriate use of fluids, vasoactive drugs, and diuretics to optimize renal function, avoidance of nephrotoxins, and appropriate use of renal replacement therapy are regarded as critical approaches to minimize any potential adverse impact of perioperative renal dysfunction on outcomes. However, the current understanding of the pathogenesis of AKI postcardiotomy is incomplete, with evidence supporting multifactorial roles of insults from intraoperative hypoperfusion, nephrotoxin exposure (heme pigments, inflammatory cytokines, oxidant stress, medications), embolism, and ischemia-reperfusion injury, all superimposed on preexisting CKD and CHF-associated renal hypoperfusion in many cases. 11 The use of vasoactive drugs to provide perioperative circulatory support is among the potentially effective options to prevent or ameliorate AKI after cardiac surgery, and of greatest theoretical utility in patients with preoperative CHF with or without postoperative ventricular dysfunction with cardiogenic shock. Address correspondence to Patrick Murray, MD, University of Chicago Hospitals, Section of Nephrology, MC5100, University of Chicago Hospitals, 5841 S Maryland Ave, Chicago, IL pmurray@medicine.bsd.uchicago.edu 2007 by the National Kidney Foundation, Inc /07/ $34.00/0 doi: /j.ajkd American Journal of Kidney Diseases, Vol 51, No 1 (January), 2008: pp 5-9 5

2 6 Patrick Murray Natriuretic peptides are hormones secreted by the heart in response to volume overload with increased cardiac stretch and other stimuli. Atrial natriuretic peptide (ANP) is a 28-amino acid peptide synthesized by atrial myocytes. Brain natriuretic peptide (BNP) is a 32-amino acid peptide synthesized in the brain and in the heart. ANP and BNP are systemic and renal vasodilators that also inhibit renal tubular sodium reabsorption and renin-angiotensin-aldosterone axis activation. The synthetic natriuretic peptide nesiritide (recombinant BNP) is approved for treatment of symptomatic acute decompensated heart failure. In studies in which subjects received unrestricted standard CHF therapy (diuretics, dobutamine), nesiritide therapy lowered pulmonary capillary occlusion pressure and resolved dyspnea more rapidly than nitroglycerin or placebo, 12,13 and the drug was approved for use in acute decompensated heart failure. More recently, meta-analysis of outcome data from these and some other nesiritide CHF trials generated some controversy and an expert panel concluded that further trial data were needed to discern the effects of nesiritide therapy on renal function and survival in patients with acute decompensated heart failure. The panel also reemphasized that the indication for nesiritide therapy is acute decompensated heart failure, not chronic intermittent therapy or other unproven uses. Finally, they noted that the drug should not be used to improve renal function or to augment or replace diuretic therapy in CHF patients, as there is no conclusive proof of the utility of the drug for these purposes, despite some interesting preclinical and pilot studies suggesting that nesiritide could suppress neurohormonal activation and improve diuretic responsiveness in patients with CHF. 17 Uncontrolled studies using nesiritide for cardiovascular support of patients with CHF undergoing cardiac surgery have suggested beneficial effects on renal function Feldman and colleagues administered nesiritide to 10 consecutive patients following cardiac transplantation with oliguric acute-on-chronic renal insufficiency refractory to escalating inotropic support and diuretics, which resulted in decreased pulmonary artery pressures, higher cardiac output, and improved diuretic responsiveness and glomerular filtration rate (GFR). 18 Salzberg and colleagues infused nesiritide to 14 high-risk patients undergoing mitral valve surgery, and found that this therapy acutely lowered pulmonary artery pressures and was associated with much lower perioperative mortality than predicted by risk factor scoring. 19 Beaver and colleagues retrospectively compared 151 patients who received nesiritide within 3 days after cardiothoracic surgery with 789 who did not, to determine effects on the incidence of acute renal failure requiring dialysis or mortality over a 3-year period. 20 They used multiple logistic regression to determine that nesiritide therapy was associated with a significant reduction of the risk of dialysis or death in those with preoperative serum creatinine values greater than 1 mg/dl ( 88.4 mol/l), but not those with lower serum creatinines. Taken together, the findings of these and other studies suggested that a prospective, randomized trial should be performed to test the hypothesis that nesiritide can improve outcomes after cardiac surgery. WHAT DOES THIS IMPORTANT STUDY SHOW? The Nesiritide Administered Peri-Anesthesia in Patients Undergoing Cardiac Surgery (NAPA) trial was a multicenter, randomized, doubleblind, placebo-controlled trial of nesiritide versus placebo in 303 patients with chronic left ventricular dysfunction (ejection fraction 40%) undergoing cardiac surgery (coronary artery bypass graft with or without mitral valve replacement/repair) using cardiopulmonary bypass. 21 Nesiritide was administered as a 24- to 96-hour infusion of 0.01 g/kg/min. The study had multiple exploratory endpoints, aimed to establish drug safety and efficacy in preparation for a larger trial to establish clinical effectiveness. There were 5 primary endpoints, including 3 renal endpoints (change from baseline to peak serum creatinine by the end of hospital stay or day 14; change from baseline estimated GFR [egfr] as measured by the Modification of Diet in Renal Disease [MDRD] Study equation in the same period; urine output during the initial 24 hours of intensive care unit admission), and 2 hemodynamic endpoints (pulmonary artery pressures; other vasoactive drug use). There were no significant differences between the groups in baseline patient characteristics;

3 In the Literature 7 serum creatinine values were approximately 1.1 mg/dl (97 mol/l), with egfr approximately 80 ml/min/1.73 m 2 (1.33 ml/s/1.73 m 2 ). Of 303 randomized patients, 24 did not receive study drug and 7 more were excluded because they had off-pump surgery. The efficacy analysis was restricted to the 272 randomized patients who received study drug and had cardiopulmonary bypass. The safety analysis, including mortality, included all 279 patients who received study drug, irrespective of cardiopulmonary bypass use. The mean duration of study drug infusion was about 40 hours in both groups. Perioperative renal function quantified by the 3 renal primary endpoints was better in the nesiritide group (peak serum creatinine increase of 0.15 mg/dl [13 mol/l] v 0.34 mg/dl [30 mol/l] in the placebo group, P 0.001; egfr decrease of 10.2 ml/min/1.73 m 2 [ 0.17 ml/s/1.73 m 2 ] v 17.8 ml/min/1.73 m 2 [ 0.30 ml/s/1.73 m 2 ]inthe placebo group, P 0.001; initial 24-h urine output L v L in the placebo group, P 0.001). These trends were more pronounced in the small 62-patient subset with preoperative serum creatinine values greater than 1.2 mg/dl ( 106 mol/l). Although serum creatinine increased postoperatively in both groups, it returned to baseline within 12 hours in the nesiritide group, and remained elevated throughout hospitalization in the placebo group. Use of vasoactive drugs and hemodynamic parameters did not differ significantly between the groups. Adverse events also were similar between the groups, as was 30-day and 180-day mortality (although capture of mortality data was incomplete). Among other secondary endpoints, nesiritide was not associated with any change in mechanical ventilation time or intensive care unit length of stay, but hospital length of stay was significantly shorter in the nesiritide group ( days v days in the placebo group; P 0.04). Thus, it appears that administration of nesiritide infusion during and after cardiac surgery with cardiopulmonary bypass in patients with preoperative left ventricular dysfunction has favorable short-term effects on renal function (as measured by serum creatinine changes, calculated GFR, and urine output). This study also showed that short-term adverse effects were comparable to placebo infusion. HOW DOES THIS STUDY COMPARE TO PRIOR STUDIES? More recently, Bail and colleagues demonstrated that intraoperative BNP improved hemodynamics during experimental cardiopulmonary bypass in a porcine model. 22 Furthermore, a small randomized controlled pilot trial in 40 patients with CKD (estimated creatinine clearance 60 ml/min) undergoing cardiopulmonary bypass demonstrated better preservation of renal function (measured by changes in plasma cystatin C and by estimated creatinine clearance) and less perioperative plasma aldosterone increase in the nesiritide group than in the placebo group. 23 Taken together with these newer data and the prior uncontrolled retrospective studies, the results of the NAPA trial suggest potential utility of nesiritide to prevent or ameliorate AKI during cardiac surgery in high-risk patients with CHF and preserved preoperative renal function. Results from similar studies using the related compound ANP also suggest utility of natriuretic peptide therapy for this indication. Specifically, Sezai and colleagues found that perioperative infusion of ANP improved hemodynamics, neurohormonal activation, and urine output during and after coronary artery bypass graft with cardiopulmonary bypass in 3 small prospective trials Similarly, the use of ANP for early therapy of evolving AKI after cardiac surgery resulted in improved renal function in a recent, small, placebo-controlled randomized pilot study. 27 Of course, ANP previously failed to improve dialysis-free survival in a broader group of hospitalized patients with more severe, established acute tubular necrosis in 2 large randomized trials (the latter restricted to oliguric patients), 28,29 and was unsuccessfully tested to prevent radiocontrast nephropathy 30 or improve the course of delayed graft function following cadaveric renal transplantation. 31,32 WHAT SHOULD CLINICIANS AND RESEARCHERS DO? Although it appears that administration of nesiritide infusion during and after cardiac surgery with cardiopulmonary bypass in patients with preoperative left ventricular dysfunction has favorable shortterm effects on renal function, the prespecified renal endpoints were physiologic measures of drug efficacy, not clinical effectiveness. 33 Serum creatinine changes, calculated GFR, and urine output are

4 8 not proven surrogates; despite their common use as primary endpoints in AKI trials, none of these efficacy measures has been validated to reliably predict the effectiveness of interventions to improve clinical outcomes in prospective trials. 33,34 Until the prophylactic use of nesiritide is proven to improve clinical outcomes after cardiac surgery, such as dialysis-free survival, this should not be accepted as an indication for use of this drug. Although there is a wealth of data associating AKI defined by small increments in serum creatinine with adverse outcomes, no therapy that prevents such creatinine increases has also been shown to improve hard clinical outcomes (dialysis indication/ initiation, survival, dialysis-free survival). The lack of validation of such a surrogate (or others, such as AKI resulting in sustained GFR loss with new or worsening CKD) remains a major obstacle to drug development for AKI prevention and therapy. This study also fails to demonstrate a convincing mechanism of the observed beneficial effects on renal function. It is interesting to speculate that, based upon these results, any renoprotective effect of this vasoactive drug during and after cardiopulmonary bypass is not mediated by effects on systemic perfusion (which was similar in both groups), rather suggesting an effect on regional perfusion, or a pleiotropic phenomenon. However, it should be noted that although a similar proportion of each group received vasoactive drugs, the doses prescribed and an integrated picture of the level of vasoactive drug support required to maintain similar hemodynamic profiles in both groups is not provided in this paper. It is conceivable that occult effects of varying drug and dose combinations on regional perfusion played a role in the results of the study. Finally, the design of the trial was appropriate for phase 2 drug development, including multiple exploratory primary endpoints, and not intended to support any claim of a new indication for the use of nesiritide. The interesting findings of this study provide a strong rationale for a definitive clinical trial to prove utility of nesiritide for renoprotection during cardiac surgery in patients with left ventricular dysfunction. Patrick Murray, MD University of Chicago Hospitals Chicago, Illinois Patrick Murray ACKNOWLEDGEMENTS Support: None. Financial Disclosure: Dr Murray reports having received speaking fees from Scios Inc (the manufacturer of nesiritide) in 2005 and having served as a paid consultant for the company in REFERENCES 1. Mangano CM, Diamondstone LS, Ramsey JG, et al: Renal dysfunction after myocardial revascularization: Risk factors, adverse outcomes, and hospital resource utilization. Ann Intern Med 128: , Tuttle KR, Worrall NK, Dahlstrom LR, et al: Predictors of ARF after cardiac surgical procedures. Am J Kidney Dis 41:76-83, Chertow GM, Lazarus JM, Christiansen CL, et al: Preoperative renal risk stratification. Circulation 95: , Lassnigg AL, Schmidlin D, Mouhieddine M, et al: Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: A prospective cohort study. J Am Soc Nephrol 15: , Ryckwaert F, Boccara G, Frappier J-M, et al: Incidence, risk factors, and prognosis of a moderate increase in plasma creatinine after cardiac surgery. Crit Care Med 30: , Loef BG, Epema AH, Smilde TD, et al: Immediate postoperative renal function deterioration in cardiac surgical patients predicts in-hospital mortality and survival. J Am Soc Nephrol 16: , Leacche M, Rawn JD, Mihalijevic T, et al: Outcomes in patients with normal serum creatinine and with artificial renal support for acute renal failure developing after coronary artery bypass grafting. Am J Cardiol 93: , Conlon PJ, Stafford-Smith M, White WD, et al: Acute renal failure following cardiac surgery. Neph Dial Transplant 14: , Ruel M, Khan TA, Voisine P, et al: Vasomotor dysfunction after cardiac surgery. Eur J Cardiothorac Surg 26: , Tang I, Murray PT: Prevention of perioperative ARF: What works? Best Pract Res ClinAnaesthesiol 18:91-111, Rosner MH, Okusa MD: Acute kidney injury associated with cardiac surgery. Clin J Am Soc Nephrol 1:19-32, Colucci WS, Elkayam U, Horton DP, et al: Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med 343: , Publication Committee for the VMAC Investigators: Intravenous nesiritide vs. nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA 287: , Sackner-Bernstein JD, Kowalski M, Fox M, et al: Short-term risk of death after treatment with nesiritide for decompensated heart failure. A pooled analysis of randomized controlled trials. JAMA 293: , Sackner-Bernstein JD, Skopicki HA, Aaronson KD: Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 111: , 2005

5 In the Literature Topol EJ: Nesiritide not verified. N Engl J Med 353: , Cataliotti A, Boerrigter G, Costello-Boerrigter LC, et al: Brain natriuretic peptide enhances renal actions of furosemide and suppresses furosemide-induced aldosterone activation in experimental heart failure. Circulation 109: , Feldman DS, Ikonomidis JS, Uber WE, et al: Human B-natriuretic peptide improves hemodynamics and renal function in heart transplant patients immediately after surgery. J Card Fail 10: , Salzberg SP, Filsoufi F, Anyanwu A, et al: High-risk mitral valve surgery: perioperative hemodynamic optimization with nesiritide (BNP). Ann Thorac Surg 80: , Beaver TM, Winterstein AG, Shuster JJ, et al: Effectiveness of nesiritide on dialysis or all-cause mortality in patients undergoing cardiothoracic surgery. Clin Cardiol 29:18-24, Mentzer RM, Oz MC, Sladen RN, et al: Effects of perioperative nesiritide in patients with left ventricular dysfunction undergoing cardiac surgery. The NAPA Trial. J Am Coll Cardiol 49: , Bail DHL, Steger V, Heinzelmann U, et al: Administration of brain natriuretic peptide improves cardiac function following operations using extracorporeal circulation in an animal model. Clin Sci 112: , Chen HH, Sundt TM, Cook DJ, et al: Low dose nesiritide and the preservation of renal function in patients with renal dysfunction undergoing cardiopulmonary-bypass surgery: a double-blind placebo-controlled pilot. Circulation 116: , 2007 (suppl 11) 24. Sezai A, Shiono M, Orime Y, et al: Low-dose continuous infusion of human atrial natriuretic peptide during and after cardiac surgery. Ann Thorac Surg 69: , Sezai A, Hata M, Wakui S, et al: Efficacy of low-dose continuous infusion of human atrial natriuretic peptide (hanp) during cardiac surgery. Possibility of postoperative left ventricular remodeling effect. Circ J 70: , Sezai A, Hata M, Wakui S, et al: Efficacy of continuous low-dose hanp administration in patients undergoing emergent coronary artery bypass grafting for acute coronary syndrome. Circ J 71: , Sward K, Valsson F, Odencrants P, et al: Recombinant human atrial natriuretic peptide in ischemic acute renal failure. A randomized placebo controlled trial. Crit Care Med 32: , Allgren RL, Marbury TC, Rahman SN, et al: Anaritide in acute tubular necrosis. Auriculin Anaritide Acute Renal Failure Study Group. N Engl J Med 336: , Lewis J, Salm MM, Chertow GM, et al: Atrial natriuretic factor in oliguric acute renal failure. Anaritide Acute Renal Failure Study Group. Am J Kidney Dis 36: , Sands JM, Neylan JF, Olson RA, et al: Atrial natriuretic factor does not improve the outcome of cadaveric renal transplantation. J Am Soc Nephrol 1: , Ratcliffe PJ, Richardson AJ, Kirby JE, et al: Effect of intravenous infusion of atriopeptin 3 on immediate renal allograft function. Kidney Int 39: , Kurnik BR, Allgren RL, Genter FC, et al: Prospective study of atrial natriuretic peptide for the prevention of radiocontrast-induced nephropathy. Am J Kid Dis 31: , Murray PT, Le Gall JR, Dos Reis Miranda D, et al: Physiologic endpoints (efficacy) for acute renal failure studies. Curr Opin Crit Care 8: , Palevsky PM, Metnitz PG, Piccinni P, et al: Selection of endpoints for clinical trials of acute renal failure in critically ill patients. Curr Opin Crit Care 8: , 2002

Projecting the Effect of Nesiritide on Dialysis and Hospital Mortality in Cardiac Surgery Patientsvhe_

Volume 13 Number 5 2010 VALUE IN HEALTH Projecting the Effect of Nesiritide on Dialysis and Hospital Mortality in Cardiac Surgery Patientsvhe_710 643..648 Jinghua He, MS, Almut G. Winterstein, PhD, Thomas