Journal of the American College of Cardiology Vol. 58, No. 9, by the American College of Cardiology Foundation ISSN /$36.

Transcription

1 Journal of the American College of Cardiology Vol. 58, No. 9, by the American College of Cardiology Foundation ISSN /$36.00 Published by Elsevier Inc. doi: /j.jacc CLINICAL RESEARCH Clinical Trials Results of Low-Dose Human Atrial Natriuretic Peptide Infusion in Nondialysis Patients With Chronic Kidney Disease Undergoing Coronary Artery Bypass Grafting The NU-HIT (Nihon University Working Group Study of Low-Dose hanp Infusion Therapy During Cardiac Surgery) Trial for CKD Akira Sezai, MD, PHD,* Mitsumasa Hata, MD, PHD,* Tetsuya Niino, MD, PHD,* Isamu Yoshitake, MD, PHD,* Satoshi Unosawa, MD, PHD,* Shinji Wakui, MD, PHD,* Haruka Kimura, MD,* Motomi Shiono, MD, PHD,* Tadateru Takayama, MD, PHD, Atsushi Hirayama, MD, PHD Tokyo, Japan Objectives Background Methods Results Conclusions The purpose of this comparative study is to prove the efficacy of the human atrial natriuretic peptide (hanp) in patients with chronic kidney disease (CKD) undergoing coronary artery bypass graft surgery (CABG). CKD is an important risk factor for cardiac surgery. This was a randomized controlled study of 303 patients with CKD who underwent CABG, and were divided into a group who received carperitide infusion and another group without carperitide. The primary endpoints were: 1) the post-operative dialysis-free rate; and 2) serum creatinine (scr) and estimated glomerular filtration rate. The secondary endpoints were: 1) the early post-operative outcome; 2) outcome at 1 year post-operatively; 3) the maximum scr, the rate of increase of scr, and an increase of scr by 0.3 mg/dl compared with the pre-operative value; and 4) ANP and cyclic-guanosine monophosphate levels. The post-operative scr was significantly lower in the hanp group not only in the post-operative acute stage but also in the first year. The maximum Cr and Cr increase rate were significantly lower in the hanp group (p , p ). There was no difference in mortality rate in the first year post-operatively, and fewer cardiac events and patients going on dialysis were found in the hanp group (p and p , respectively). In the post-operative acute stage, carperitide showed cardiorenal protective effects that prevented post-operative cardiac events and initiation of dialysis. Thus, perioperative infusion of low-dose carperitide may have a significant role in management of patients with renal dysfunction undergoing on-pump CABG. (Effectiveness of hanp for Cardiac Surgery in Patients With Moderate to Severe Preoperative Renal Dysfunction Without Dialysis [NU-HIT for CRF]; UMIN ) (J Am Coll Cardiol 2011;58: ) 2011 by the American College of Cardiology Foundation Chronic kidney disease (CKD) is said to have a strong effect on the prognosis of cardiovascular disease (1,2). Patients with CKD have a high rate of invasive treatment such as surgery, and protection of the kidneys is important at all times during procedures. Cooper et al. (3) reported that From the *Department of Cardiovascular Surgery, Nihon University School of Medicine, Tokyo, Japan; and the Department of Cardiology, Nihon University School of Medicine, Tokyo, Japan. This study was supported by a grant for scientific research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (no ), a Nihon University School of Medicine Alumni 60th Anniversary Medical Research Grant, and a Nihon University School of Medicine Foundation 50th Anniversary Medical Research Grant. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received June 20, 2010; revised manuscript received March 18, 2011, accepted March 29, pre-operative renal dysfunction (RD) is an important prognostic factor based on analysis of the database of The Society of Thoracic Surgeons, and stated that the mortality rate of patients with severe RD is 9.3%. Zakeri et al. (4) See page 904 compared patients with mild RD and subjects with normal renal function and found that the operative mortality rate of normal patients was 2.1%, whereas that of mild RD patients was significantly higher at 6.1%. There was also a significant difference (0.8% vs. 5.2%) in the rate of commencing dialysis, and the 3-year survival rate was 93% versus 81%, being significantly lower in the mild RD patients (4). In a

2 898 Sezai et al. JACC Vol. 58, No. 9, 2011 Low-Dose hanp During CABG for CKD August 23, 2011: Abbreviations and Acronyms ANP atrial natriuretic peptide BNP brain natriuretic peptide CABG coronary artery bypass graft surgery CKD chronic kidney disease CPB cardiopulmonary bypass egfr estimated glomerular filtration rate hanp human atrial natriuretic peptide RCT randomized controlled trial RD renal dysfunction % Cr rate of increase of serum creatinine scr serum creatinine 4-year post-operative follow-up study, Yu et al. (5) found that a pre-operative estimated glomerular filtration rate (egfr) of 60 ml/min or less was a more important risk factor for postoperative dialysis than the choice of off-pump or on-pump surgery. We previously performed a randomized controlled trial (RCT) known as the NU-HIT (Nihon University Working Group Study of Low-Dose hanp Infusion Therapy During Cardiac Surgery) trial, in which human atrial natriuretic peptide (hanp [carperitide], Daiichi-Sankyo Pharmaceutical, Tokyo, Japan, and Asubio Pharmaceuticals, Inc., Kobe, Japan) was administered perioperatively for cardiac and renal protection. Because carperitide inhibits the renin-angiotensinaldosterone system and has a potent natriuretic effect, we have found that it can compensate for the adverse effects of extracorporeal circulation and can inhibit left ventricular remodeling (6,7). In an RCT that assessed the early postoperative effects of carperitide in 504 patients with normal pre-operative renal function who underwent coronary artery bypass graft surgery (CABG) in 2009, post-operative maximum Cr and the percent increase of Cr were significantly smaller in the hanp group than in the placebo group. Creatinine clearance decreased by one-third relative to the pre-operative value immediately after surgery, and did not recover to the level just before surgery at 1 week postoperatively in the placebo group whereas the pre-operative level was maintained in the hanp group (8). Few studies have assessed the effects of carperitide in patients undergoing cardiac surgery. Valsson et al. (9) administered carperitide for 30 min to patients with acute renal failure and cardiac failure after cardiac surgery, and found that the urine output, GFR, and renal blood flow increased by 62%, 43%, and 38%, respectively, while renal vascular resistance decreased by 30%. They also performed a larger-scale study, and reported that the need for dialysis was decreased by carperitide, and dialysis-free survival was improved (10). The purpose of this study was to evaluate the impact of perioperative (2.4 days) low-dose carperitide infusion versus placebo on changes in renal function, need for dialysis, and 1-year outcomes in CABG patients with moderate chronic renal insufficiency (egfr 45 to 50 ml min 1 m 2 ). Methods Study protocol. The NU-HIT trial for CKD was a randomized, double-blind, placebo-controlled study of patients with pre-operative CKD (pre-operative egfr 60 ml min 1 m 2 ) who were not on dialysis and underwent CABG with cardiopulmonary bypass (CPB). We excluded patients with cardiogenic shock, dialysis, or offpump CABG. Among the patients undergoing CABG at Nihon University Itabashi Hospital from March 1997 to March 2009, 303 were enrolled in this trial. They were randomized by the lottery method into 2 groups, which were an hanp group who received infusion of carperitide from the initiation of CPB and a placebo group who received infusion of physiological saline (Fig. 1). Because carperitide is approved for treatment of acute cardiac failure in Japan, but not for administration during cardiac surgery, approval for this study was obtained from the ethics committee of Nihon University Itabashi Hospital, the details of the study were explained to subjects, and informed consent was obtained from each patient. This study was registered with the University Hospital Medical Information Network (UMIN). Infusion of carperitide is performed from a starting dose of 0.1 g kg 1 min 1 for acute cardiac failure, but a lower initial dose of g kg 1 min was selected for this study because the subjects did not have cardiac failure. Administration of carperitide or placebo was initiated at the start of CPB. The infusion rate was decreased to 0.01 g kg 1 min 1 at the commencement of oral medication, and then infusion was discontinued after another 12 h. The CPB was performed with nonpulsatile low-temperature perfusion (target rectal temperature 34 C). In all patients, the left internal thoracic artery was anastomosed to the left anterior descending coronary artery, and radial artery and/or saphenous vein grafts were used for other sites. Endpoints. The primary endpoints were: 1) dialysis-free rate at 1 year post-operatively; and 2) the serum creatinine Figure 1 Study Population A total of 303 patients registered in the NU-HIT (Nihon University Working Group Study of Low-Dose hanp Infusion Therapy During Cardiac Surgery) trial for chronic kidney disease (CKD) were randomly assigned to receive human atrial natriuretic peptide (hanp) therapy (hanp group) or placebo therapy (placebo group).

3 JACC Vol. 58, No. 9, 2011 August 23, 2011: Sezai et al. Low-Dose hanp During CABG for CKD 899 (scr) and egfr at 0, 1, and 3 days, 1 week, and 1 month post-operatively. The need for dialysis in patients who had acute renal failure post-operatively was determined by a nephrologist specializing in dialysis according to the following criteria: 1) urine output 400 ml daily despite intravenous administration of furosemide and adequate postoperative fluid infusion; 2) persistent oliguria with an increase of CVP or PCWP; 3) failure to control the serum K level; 4) a persistent increase of scr despite a response to intravenous fluid infusion; and 5) progression of metabolic acidosis. The egfr was calculated according to the method proposed for Japanese persons by the Japanese Society of Nephrology (men: 194 scr age ; women: 194 scr age ) (11). The secondary endpoints were: 1) the early post-operative outcome (operative mortality and complications); 2) outcome at 1 year post-operatively (overall survival rate and cardiac event-free rate), 3) the maximum scr, the rate of increase of scr (% Cr: [maximum scr pre-operative scr]/pre-operative scr 100), and an increase of scr by 0.3 mg/dl compared with the pre-operative value; and 4) ANP and cyclic-guanosine monophosphate (cgmp) levels (on return to intensive care unit, and on postoperative day 1, week 1, and month 1). Post-operative complications were categorized as central nervous system disorders, cardiovascular disorders (low output syndrome, heart failure, perioperative myocardial infarction, and refractory arrhythmia), respiratory failure, acute renal failure (requiring dialysis), gastrointestinal disorders (requirement for higher alimentation such as in patients with gastrointestinal bleeding, ileus, liver dysfunction), infections (septicemia, pneumonia, mediastinitis, and so forth), and other disorders requiring long-term intensive care unit management. In the present study, carperitide or saline administration was discontinued only when the systolic blood pressure could not be maintained at 90 mm Hg using intra-aortic balloon pump. Cardiac events were classified as cardiac failure requiring treatment with cardiotonic agents or assisted circulation for 1 week or longer after surgery, cardiac failure requiring hospital treatment after discharge, perioperative myocardial infarction, recurrence of ischemic heart disease after discharge, arrhythmia requiring treatment to maintain postoperative hemodynamics, and arrhythmia requiring readmission after discharge. Statistical analysis. Data are expressed as mean SD. For parametric and nonparametric data, the significance of differences was determined by using Student s t test and Fisher s exact test, respectively. The statistical analysis for the comparison of scr was performed using the Mann- Whitney U test. Statistical differences were verified by Student t test. Early and late deaths, cardiac events, and initiation of dialysis were subjected to a logistic regression analysis. Interactions were also examined. A p value 0.05 was considered to indicate statistical significance. Other data were analyzed with repeated measures analysis of variance. The overall survival rate, cardiac event-free rate, and dialysis-free rate were determined by the Kaplan-Meier method, and the significance of differences was assessed by the log-rank test. All analyses were conducted with SPSS software (SPSS Inc., Chicago, Illinois). Results Patient enrollment. Initially, 303 patients were enrolled in the NU-HIT trial for CKD, but 3 patients were switched to off-pump CABG, and 15 patients underwent concomitant operations (mitral valve plasty, mitral valve replacement, and graft replacement) in addition to CABG and thus were excluded from the trial, leaving 285 patients. Among these 285 patients, 141 were assigned to the hanp group and 144 formed the placebo group (Fig. 1). All patients were reviewed at our hospital, and none of them was lost to follow-up. Pre-operative baseline patient characteristics showed no significant differences between the 2 groups (Table 1). Surgical procedures and post-operative management, including aortic cross-clamp time, cardiopulmonary bypass time, number of bypasses performed, and mechanical support, are shown in Table 2. There were no significant differences of these parameters between the hanp group and the placebo group. The duration of carperitide infusion was days in the hanp group, whereas physiological saline was infused for days in the placebo group, and the infusion period was significantly shorter in the hanp group (p ). In all patients, administration was discontinued at 12 h after administration of 0.01 g kg 1 min 1 as specified in the protocol. Both carperitide and saline were infused continuously, and administration was not discontinued for reasons such as hypotension in any of the patients. The length of hospital Comparison Table 1 Comparison of Patient Characteristics of Patient Characteristics Age, yrs Male:female ratio 123:18 128: Body surface area, m Diagnosis Acute myocardial infarction 10 8 Old myocardial infarction Unstable angina Stable angina Emergency Risk factor Diabetes mellitus 72 (51%) 70 (49%) Hypertension 100 (71%) 104 (72%) Hyperlipidemia 77 (55%) 80 (56%) Obesity 36 (26%) 30 (21%) Smoking 69 (49%) 58 (40%) Ejection fraction, % Values are mean SD, n, or n (%). hanp human atrial natriuretic peptide.

4 900 Sezai et al. JACC Vol. 58, No. 9, 2011 Low-Dose hanp During CABG for CKD August 23, 2011: Operative Table 2 and Operative Post-Operative and Post-Operative Data Data ACC time, min CPB time, min Bypass Intra-aortic balloon pump Venoatrial bypass hanp administration, day Furosemide dose, mg Dopamine use Dobutamine use Norepinephrine use Hospital stay, days Values are mean SD or n. ACC aortic cross-clamp; CPB cardiopulmonary bypass; hanp human atrial natriuretic peptide. stay was days in the hanp group versus days in the placebo group, being significantly shorter in the hanp group (p ). Primary endpoints. POST-OPERATIVE DIALYSIS. During the early post-operative period, dialysis was required by 1 patient in the hanp group and 8 in the placebo group, and the post-operative dialysis rate was significantly lower in the hanp group (p ). Only 1 patient in the hanp group but 5 patients in the placebo group were placed on dialysis after discharge until 1 year post-operatively. The dialysis-free rate at 1 year post-operatively was 98.6% in the hanp group and 91.6% in the placebo group. The rate for the hanp group was significantly higher than that for the placebo group (p ) (Fig. 2). SERUM CREATININE. Serum creatinine immediately before surgery was mg/dl in the hanp group and mg/dl in the placebo group, showing no difference; but post-operatively, it was mg/dl in the hanp group and mg/dl in the placebo group on the day of the operation, mg/dl in the hanp group and mg/dl in the placebo group on day 1 post-operatively, mg/dl in the hanp group and mg/dl in the placebo group on day 3 post-operatively, mg/dl in the hanp group and mg/dl in the placebo group 1 week post-operatively, mg/dl in the hanp group and mg/dl in the placebo group 1 month post-operatively, mg/dl in the hanp group and mg/dl in the placebo group 6 months post-operatively, and mg/dl in the hanp group and mg/dl in the placebo group 1 year post-operatively. From day 1 post-operatively, the hanp group showed significantly lower values than in the placebo group (p 0.01). ESTIMATED GLOMERULAR FILTRATION RATE. In the same way, egfr was ml min m 2 in the hanp group and ml min m 2 in the placebo group immediately before surgery, ml min m 2 in the hanp group and ml min m 2 in the placebo group on the day of the operation, ml min m 2 in the hanp group and ml min m 2 in the placebo group on day 1 post-operatively, ml min m 2 in the hanp group and ml min m 2 in the placebo group on day 3 post-operatively, ml min m 2 in the hanp group and ml min m 2 in the placebo group 1 week postoperatively, ml min m 2 in the hanp group and ml min m 2 in the placebo group 1 month post-operatively, ml min m 2 in the hanp group and ml min m 2 in the placebo group 6 months post-operatively, and ml min m 2 in the hanp group and ml min m 2 in the placebo group 1 year post-operatively. From day 1 post-operatively, the hanp group showed significantly lower values than the placebo group (p 0.01). Secondary endpoints. EARLY POST-OPERATIVE RESULTS. There were no in-hospital deaths in the hanp group, but 4 patients died in the placebo group. The cause of death was heart failure in 2 patients, and cerebral infarction and arrhythmia in 1 patient each. There was no significant difference of the death rate between the 2 groups (p ) (Table 3). Perioperative complications occurred in 10 patients from the hanp group and 20 patients from the placebo group. There were fewer complications in the hanp group, but the difference was not significant (p ). In the hanp group, 4 patients had heart failure (including 1 with low output syndrome), 2 each had mediastinitis and cerebral infarction, and 1 each had acute renal failure and hemorrhage. In the placebo group, 7 patients had acute renal failure, 5 had heart failure (including 2 with low output syndrome), 3 had cerebral infarction, 2 had refractory arrhythmia, and 1 each had mediastinitis, pneumonia, and gastrointestinal bleeding. Figure 2 Dialysis-Free Rate The dialysis-free rate was significantly higher in the human atrial natriuretic peptide (hanp) group (solid line) than in the placebo group (dashed line).

5 JACC Vol. 58, No. 9, 2011 August 23, 2011: Sezai et al. Low-Dose hanp During CABG for CKD 901 Early Table and 3 Late Early Results and Late Results Death, n Early 0 4 (2.8%) Discharge to 1 yr post-surgery Total Cardiac event, n Dialysis, n Early Discharge to 1 yr post-surgery Total hanp human atrial natriuretic peptide. Figure 4 Data of Serum Creatinine Increase Rate OUTCOME AT 1 YEAR POST-OPERATIVELY. Mortality from discharge until 1 year post-operatively was 1 patient in the hanp group and 2 patients in the placebo group (p ) (Table 3). The causes of death were acute myocardial infarction in the hanp group and heart failure and acute renal failure in 1 patient each in the placebo group. The overall survival rates determined by the Kaplan-Meier method were 99.3% in the hanp group and 95.8% in the placebo group at 1 year post-operatively. No statistically significant differences were observed between the 2 groups (p ) (Fig. 3). Patients with cardiac events within 1 year postoperatively included 25 in the hanp group and 55 in the placebo group. In the hanp group, heart failure occurred in 4 patients, arrhythmia in 19 patients, and ischemic heart disease in 2 patients. In the placebo group, there were 8 patients with heart failure, and 47 with arrhythmia. There were significantly fewer cases in the hanp group (p ). The cardiac event-free rate determined by the Kaplan-Meier method was 82.3% in the hanp group and 61.8% in the placebo group at 1 year post-operatively. The hanp group showed significantly higher event-free rates than the placebo group (p ) (Fig. 3). Creatinine increase was % in the human atrial natriuretic peptide (hanp) group and % in the placebo group, being significantly higher in the placebo group. MAXIMUM CREATININE AND PERCENT INCREASE. The maximum Cr value was mg/dl in the hanp group and mg/dl in the placebo group. The % Cr was % in the hanp group and % in the placebo group, being significantly higher in the placebo group (p , p ) (Fig. 4). The scr increased by 0.3 mg/dl or more compared with the pre-operative value in 36 patients from the hanp group and 85 patients from the placebo group, with significantly fewer patients being affected in the hanp group (p ). Post-operative Cr was 1.3 mg/dl in 76 patients from the hanp group and in 109 patients from the placebo group. The number was significantly smaller in the hanp group (p ). Post-operative Cr was 1.5 mg/dl in 51 patients from the hanp group and 81 patients from the placebo group, and the number was also significantly smaller in the hanp group (p ). However, Cr exceeded 2.0 mg/dl in 20 patients from the hanp group and in 31 patients from the placebo group, showing no significant difference between the 2 groups (p 0.112) (Table 4). Figure 3 Overall Survival Rate and Cardiac Event-Free Rate (A) The overall survival rate showed no significant difference between the 2 groups. (B) The cardiac event-free rate was significantly higher in the human atrial natriuretic peptide (hanp) group (solid lines) than in the placebo group (dashed lines).

6 902 Sezai et al. JACC Vol. 58, No. 9, 2011 Low-Dose hanp During CABG for CKD August 23, 2011: Post-Operative Table 4 Post-Operative Serum Creatinine Serum Creatinine ANP AND CGMP. The ANP increased rapidly in the hanp group to reach almost 10 times the pre-operative value. The ANP immediately before surgery was pg/dl in the hanp group and pg/dl in the placebo group, showing no difference; but post-operatively, the ANP value was pg/dl in the hanp group and pg/dl in the placebo group on the day of the operation, and pg/dl in the hanp group and pg/dl in the placebo group on day 1 post-operatively, indicating that the hanp group was significantly higher than the placebo group (p 0.01). At 1 week post-operatively, it was pg/dl in the hanp group and pg/dl in the placebo group, and the placebo group was significantly higher than the hanp group (p 0.05). There was no significant difference at 1 month post-operatively. The cgmp was pg/dl in the hanp group and pg/dl in the placebo group immediately before surgery, showing no difference; but it was pg/dl in the hanp group and pg/dl in the placebo group on the day of the operation, pg/dl in the hanp group and pg/dl in the placebo group on day 1 post-operatively, and pg/dl in the hanp group and pg/dl in the placebo group at 1 week post-operatively. The value was significantly higher in the hanp group than in the placebo group (p 0.05). Discussion Maximum Cr, mg/dl mg/dl (pre max Cr) 36 (26%) 85 (59%) Cr 1.3 mg/dl 76 (54%) 109 (76%) Cr 1.5 mg/dl 51 (36%) 81 (56%) Cr 2.0 mg/dl 20 (14%) 31 (22%) Cr creatinine; hanp human atrial natriuretic peptide; max maximum; pre pre-operative. This study demonstrated that infusion of carperitide in patients with pre-operative CKD undergoing CABG could improve renal function not only during the acute postoperative period but also up to 1 year post-operatively. Carperitide is not considered to have any long-term pharmaceutical effects, but the cardiorenal protective effects of carperitide in the acute period are considered to result in good long-term effects (avoiding dialysis and cardiac events). It was very clear that the cardiorenal events decreased at 1 year post-operatively. The maximum postoperative Cr and the present increase of scr were significantly lower in the hanp group than in the placebo group, indicating that carperitide was associated with a substantial renoprotective effect. Various studies have investigated the treatment of acute renal failure after cardiac surgery, but few studies have assessed its prevention in patients with CKD, who have a high risk of deterioration of renal function after cardiac surgery and a relatively poor prognosis. In patients undergoing cardiac surgery, CKD is an important risk factor (3,4). The present study is the first RCT to assess the effect of carperitide in CABG patients with CKD, and the results are interesting with regard to management of CKD patients after cardiac surgery. Brown et al. (12) studied 1,391 patients with normal renal function who underwent cardiac surgery and reported that the mortality rate was significantly higher for patients with a % Cr 50% than for those with a% Cr 25%, suggesting that it is necessary to maintain renal function perioperatively. Hobson et al. (13) performed a study of 2,973 patients with normal renal function who underwent cardiothoracic surgery and reported that the 10-year prognosis was poor for patients with post-operative acute renal failure and that it is necessary to improve renal protection during surgery. In the present study, % Cr values were significantly lower in the hanp group than in the placebo group, and perioperative deterioration of renal function could be prevented by starting treatment with carperitide from the time of surgery. To treat acute renal failure after surgery, the efficacy of mannitol, dopamine, and furosemide has been reported, but aggravation of electrolyte abnormalities and deterioration of renal function can also result from forced diuresis (14). Therefore, use of such drugs for prevention of postoperative acute renal failure can be problematic. Conger et al. (15) evaluated coadministration of dopamine and carperitide for acute renal failure and reported that dopamine alone slightly improved the GFR, whereas coadministration of both drugs markedly increased urine output and urinary sodium excretion compared with dopamine alone. Sica et al. (16) performed very interesting research on this point. They conducted a comparative study on acute heart failure patients divided into 3 groups: nesiritide, furosemide, and nesiritide and furosemide concomitantly. In the furosemide group, the urinary sodium excretion rate was significantly higher than in the nesiritide group, but the aldosterone value was significantly lower in the nesiritide group than in the furosemide group, indicating that neurohormonal activation plays an important role in shaping diuretic responsiveness in heart failure patients. At present, carperitide is only available in Japan. Although BNP (nesiritide) cannot be used in Japan, it is a similar peptide product to carperitide that is available in Western countries. Chen et al. (17) reported that in cardiac surgery patients with renal dysfunction, low-dose nesiritide infusion was associated with improvement in post-operative plasma cystatin and aldosterone levels, and improvement in egfr. Ejaz et al. (18) administered nesiritide to 94 patients undergoing high-risk cardiac surgery. They found no differences of mortality and dialysis rates, but the BNP group had a significantly better percent increase of scr and egfr. Mentzer et al. (19) performed the NAPA (Nesiritide Administered Peri-Anesthesia in Patients Undergoing Cardiac Surgery) trial on CABG in patients with low cardiac

7 JACC Vol. 58, No. 9, 2011 August 23, 2011: Sezai et al. Low-Dose hanp During CABG for CKD 903 function and reported that the early post-operative peak value of scr was low and GFR was high in the BNP group, indicating that BNP has effects on post-operative renal function. They also found that the survival rate up to 180 days post-operatively was significantly higher in the BNP group than in the placebo group (19). Our study was different because it was a RCT on hanp and the subjects were CKD patients, but the effects on renal function were similar to those reported in the NAPA trial. The only large-scale studies of carperitide performed so far are a multicenter study of carperitide administration after reperfusion therapy in patients with acute myocardial infarction, the J-WIND (Japan-Working Groups of Acute Myocardial Infarction for the Reduction of Necrotic Damage by ANP) study and our NU-HIT study on cardiac surgery. In the J-WIND study, the hanp group showed a significantly smaller infarct size, greater improvement of cardiac function, and significantly fewer cases of cardiac death and heart failure than the placebo group (20). We showed that carperitide not only provided effective renal protection in the acute stage, but also over the long term. As for renal function, a renoprotective effect was seen in both the acute period and over the long term, based on the results of this study and previous studies. Study limitations. It was clear from the results of this study that carperitide has renoprotective effects. Biomarkers of renal injury, including cystatin C and albuminuria, were not measured, and the renal effects of carperitide were not verified in detail. At present, an RCT measuring biomarkers is in progress, and this point should be clarified in the future. Conclusions The results of this study demonstrated that in CKD patients undergoing CABG, perioperative low-dose carperitide infusion has renal protective effects, enabling patients to avoid dialysis and cardiac events not only during the early postoperative stage but also for as long as 1 year post-operatively. Thus, perioperative infusion of low-dose carperitide may have a significant role in the management of patients with renal dysfunction undergoing on-pump CABG. Acknowledgment The authors thank Dr. Masato Kasahara of the Department of Medicine and Clinical Science, Kyoto University, for his helpful comments on the renal function data in our study. Reprint requests and correspondence: Dr. Akira Sezai, Department of Cardiovascular Surgery, Nihon University School of Medicine, 30-1 Oyaguchi-kamimachi Itabashi-ku, Tokyo , Japan. asezai.med@gmail.com. REFERENCES 1. El Nahas AM, Bello AK. Chronic kidney disease: the global challenge. Lancet 2005;365: Hage FG, Venkataraman R, Zoghbi GJ, Perry GJ, DeMattos AM, Iskandrian AE. The scope of coronary heart disease in patients with chronic kidney disease. J Am Coll Cardiol 2009;53: Cooper WA, O Brien SM, Thourani VH, et al. Impact of renal dysfunction on outcomes of coronary artery bypass surgery: results from The Society of Thoracic Surgeons National Adult Cardiac Database. Circulation 2006;113: Zakeri R, Freemantle N, Barnett V, et al. Relation between mild renal dysfunction and outcomes after coronary artery bypass grafting. Circulation 2005;112:I Yu HY, Li JY, Sun S, et al. Late dialysis rate for coronary artery bypass grafting patients with moderate-to-severe impairment: comparison between off-pump and conventional method. Eur J Cardiothorac Surg 2008;33: Sezai A, Shiono M, Orime Y, Hata H, Negishi N, Sezai Y. Low-dose continuous infusion of human atrial natriuretic peptide during and after cardiac surgery. Ann Thorac Surg 2000;69: Sezai A, Hata M, Niino T, et al. Continuous low-dose infusion of human atrial natriuretic peptide in patients with left ventricular dysfunction undergoing coronary artery bypass grafting: the NU-HIT (Nihon University Working Group Study of Low-Dose hanp Infusion Therapy During Cardiac Surgery for Left Ventricular Dysfunction). J Am Coll Cardiol 2010;55: Sezai A, Hata M, Niino T, et al. Influence of continuous infusion of low-dose human arterial natriuretic peptide on renal function during cardiac surgery: a randomized controlled study. J Am Coll Cardiol 2009;54: Valsson F, Ricksten SE, Hedner T, Lundin S. Effects of atrial natriuretic peptide on acute renal impairment in patients with heart failure after cardiac surgery. Intensive Care Med 1996;22: Swärd K, Valsson F, Odencrants P, Samuelsson O, Ricksten SE. Recombinant human atrial natriuretic peptide in ischemic acute renal failure: a randomized placebo-controlled trial. Crit Care Med 2004; 32: Matsuo S, Imai E, Horio M, et al., for the Collaborators Developing the Japanese Equation for Estimated GFR. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009;53: Brown JR, Cochran RP, Dacey LJ, et al., for the Northern New England Cardiovascular Disease Study Group. Perioperative increases in serum creatinine are predictive of increased 90-day mortality after coronary artery bypass graft surgery. Circulation 2006;114:I Hobson CE, Yavas S, Segal MS, et al. Acute kidney injury is associated with increased long-term mortality after cardiothoracic surgery. Circulation 2009;119: Lassnigg A, Donner E, Grubhofer G, Presterl E, Druml W, Hiesmayr M. Lack of renoprotective effects of dopamine and furosemide during cardiac surgery. J Am Soc Nephrol 2000;11: Conger JD, Falk SA, Yuan BH, Schrier RW. Atrial natriuretic peptide and dopamine in a rat model of ischemic acute renal failure. Kidney Int 1989;35: Sica D, Oren RM, Gottwald MD, Mills RM. Natriuretic and neurohormonal responses to nesiritide, furosemide, and combined natriuretic and furosemide in patients with stable systolic dysfunction. Clin Cardiol 2010;33: Chen HH, Sundt TM, Cook DJ, Heublein DM, Burnett JC Jr. Low dose nesiritide and the preservation of renal function in patients with renal dysfunction undergoing cardiopulmonary-bypass surgery: a double-blind placebo-controlled pilot study. Circulation 2007;116:I Ejaz AA, Martin TD, Johnson RJ, et al. Prophylactic nesiritide dose not prevent dialysis or all-cause mortality in patients undergoing high-risk cardiac surgery. J Thorac Cardiovascular Surg 2009;138: Mentzer RM Jr., Oz MC, Sladen RN, et al., for the NAPA Investigators. Effects of perioperative nesiritide in patients with left ventricular dysfunction undergoing cardiac surgery: the NAPA trial. J Am Coll Cardiol 2007;49: Kitakaze M, Asakura M, Kim J, et al., for the J-WIND Investigators. Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomized trials. Lancet 2007;370: Key Words: atrial natriuretic peptide y cardiac surgery y carperitide y chronic kidney disease y natriuretic peptide.