- Email: [email protected]
Natriuretic Peptides
Journal of the American College of Cardiology © 2011 by the American College of Cardiology Foundation Published by Elsevier Inc.
EDITORIAL COMMENT
Natriuretic Peptides Renal Protective After All?* Guido Boerrigter, MD, John C. Burnett, JR, MD Rochester, Minnesota
Renal dysfunction has emerged as an important independent predictor of adverse outcomes, renal as well as cardiovascular. Renal function is crucially affected by intrinsic renal factors (particularly remaining functional renal mass), hemodynamic function (renal perfusion pressure, renal venous pressure), oxygen delivery, and neurohumoral input. The natriuretic peptides play an important role in cardiovascular homeostasis. The 28-amino acid atrial natriuretic peptide (ANP) and 32-amino acid B-type natriuretic peptide (BNP1–32) are secreted by the heart in response to cardiac stretch and stress. By activating guanylyl cyclase A (GC-A), they exert their pleiotropic actions, which include natriuresis, vasodilation, suppression of renin, angiotensin II, and aldosterone as well as antihypertrophic, antifibrotic, vascular regenerative, and cytoprotective properties (1,2). Given this background, it is no surprise that clinical trials have tested the therapeutic benefit of administering exogenous ANP (approved in Japan as carperitide) and BNP1–32 (approved in the U.S. as nesiritide) in a variety of cardiovascular disease states. That has led to at times promising, neutral, or disconcerting results as it relates to overall benefit and renal function (3–9). See page 897
Sezai et al. (10) in the NU-HIT for CKD trial in this issue of the Journal tested the renal effects of carperitide infused during and after coronary artery bypass graft surgery (CABG) with cardiopulmonary bypass (CPB) in patients (n ⫽ 285) with pre-operative chronic kidney disease (CKD), defined as estimated glomerular filtration rate (eGFR) ⬍60 ml·min⫺1·1.73 m⫺2. Carperitide was initiated at the start of bypass at 0.2 g·kg⫺1·min⫺1, reduced to 0.1 g·kg⫺1·min⫺1 at the beginning of oral medication, and *Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minnesota. This work is supported by National Institutes of Health grants HL36634 and HL76611. Dr. Boerrigter has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Burnett is Chair of the Nile Therapeutics Scientific Advisory Board, and Mayo has licensed cenderitide to Nile Therapeutics.
Vol. 58, No. 9, 2011 ISSN 0735-1097/$36.00 doi:10.1016/j.jacc.2010.12.053
discontinued 12 h thereafter. These investigators report that creatinine levels were lower with carperitide compared to placebo on the first day after surgery, and this effect was still present 1 year later. The same was true for aldosterone until 1 month after surgery. Although there was no significant difference in mortality at 1 year, the study was probably not powered for this endpoint. Fewer patients in the carperitide group had a cardiac event, and, importantly, fewer required dialysis. This study complements 2 similar studies by the same authors with carperitide during and after CPB. In the first, in patients with normal eGFR and left ventricular (LV) function (n ⫽ 504), carperitide decreased creatinine compared to placebo during the 7-day post-operative observation period, and reduced the length of hospital stay (8). However, given the small number of events in this healthier group of patients, carperitide did not significantly reduce mortality (1.6% vs. 2.4%) or the need for dialysis (0% vs. 1.6%). In the other study, patients (n ⫽ 133) were enrolled with LV dysfunction defined as ejection fraction ⱕ35% (9). Carperitide decreased creatinine and increased LV ejection fraction compared to placebo for at least a year after surgery, and reduced perioperative complications and hospital length of stay. While all-cause mortality showed no difference, the carperitide group had fewer cardiac events. Mentzer et al. (5) reported the results of an exploratory randomized trial with nesiritide, the NAPA (Nesiritide Administered Peri-Anesthesia in Patients Undergoing Cardiac Surgery) trial (n ⫽ 279) in patients undergoing CPB. Compared to placebo, nesiritide (0.01 g·kg⫺1·min⫺1, no bolus) improved renal function, increased urine output, shortened hospital length of stay, and reduced 180-day mortality. Ejaz et al. (7) compared a 5-day infusion of nesiritide to placebo in patients (n ⫽ 94) undergoing high-risk cardiac surgery, in 77% for thoracic aortic aneurysm. Although nesiritide reduced creatinine compared to placebo, there were no differences between groups regarding need for dialysis, all-cause mortality, or both at 30 days. Likewise, the hospital length of stay was similar. Of note, per protocol, the dose of nesiritide was to be increased from 0.01 to 0.03 g/kg to maintain post-operative urine output ⬎1 ml·kg⫺1·h⫺1. This algorithm was probably the reason for a significantly increased use of vasopressors in the nesiritide group, and may conceivably have offset some potential benefit of nesiritide therapy. In a small proof of concept trial, we defined the actions of low-dose nesiritide (0.05 ng·kg⫺1·min⫺1) infused for 24 h started at the time of anesthesia in a double-blind placebo-controlled trial of patients with CKD (eGFR ⬍60 ml/min/1.73 m2) undergoing CPB surgery with a focus on cystatin C and aldosterone. We observed a significant decrease in cystatin C with nesiritide compared to placebo and a lowering of aldosterone (6). Taken together, GC-A agonism with both ANP and BNP have shown promising beneficial results in patients undergoing CPB surgery.
Boerrigter and Burnett, Jr Natriuretic Peptide Renal Protection
JACC Vol. 58, No. 9, 2011 August 23, 2011:904–6
What are the potential mechanisms? Given the pleiotropic actions of GC-A agonists, these are likely multifactorial and include suppression of neurohormones such as aldosterone, angiotensin II, and the sympathetic nervous system. Another mechanism could be an improved post-operative LV ejection fraction as was seen in patients with preoperative LV dysfunction indicated above (9). In addition, GC-A activation may have improved renal perfusion and promoted cell survival, thus inhibiting the loss of functional renal tissue. In future studies, assessment of kidney injury markers, such as NGAL and KIM-1, may help to identify whether GC-A activation indeed reduces kidney injury. Most recently at the 2011 meeting of the American Heart Association, the results of a key 7,000-patient clinical trial using nesiritide for acute decompensated heart failure (ADHF) were announced and have relevance to the use of natriuretic peptides as therapeutic agents for cardiorenal disease. This trial, ASCEND (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) (11), was conducted after safety concerns were raised regarding renal function and mortality on the basis of publicly available information on earlier trials with nesiritide for HF (3,4). The ASCEND trial showed that nesiritide for patients with ADHF was safe and, specifically, did not harm renal function. However, it also did not improve survival or reduce rehospitalization and only tended to improve symptomatic status (11). Nesiritide was infused at 0.01 g·kg⫺1·min⫺1; an initial 2 g/kg bolus could be given at the discretion of the investigator, which was the case in approximately 62% of patients. Of note, asymptomatic and symptomatic hypotension occurred more often with nesiritide (21.4% vs. 12.4% and 7.1% vs. 4.0%, respectively). While the demonstration of safety is reassuring, it remains to be seen whether specific groups of acute HF patients can be identified that derive clinically significant benefit from nesiritide. Many more questions remain regarding GC-A agonists as therapeutic agents that need to be addressed in future studies. For example: 1. An important question is whether there are relevant clinical differences between carperitide and nesiritide, for example, as it relates to the incidence and duration of hypotension. 2. Degradation of NPs to an inactive metabolite is probably a multistep process, and some intermediate NP derivatives are likely to have a shorter half-life while still retaining bioactivity. Would it be safer to administer such a NP derivative with short half-life to patients with ADHF so that any developing hypotension would be less sustained? Do any of these endogenous NP derivatives have an activity profile that may be more appropriate for patients in critical hemodynamic condition (12)? For example, BNP3–32, a BNP derivative reported to circulate at higher concentrations than BNP1–32, levels in HF patients was natriuretic but not hypotensive in healthy canines (13).
905
3. Can we modulate the activity of GC-A agonists by combining them with inhibitors of their degradation, e.g., neprilysin inhibitors? Also, can we combine GC-A agonists with phosphodiesterase inhibitors to reduce degradation of the NP’s second messenger cGMP? 4. Should we also target GC-B, the receptor of C-type natriuretic peptide, which has important vascular and renal actions especially at the level of the podocyte (14)? Indeed, the use of a novel dual GC-A and GC-B agonist (cenderitide) designed by our group, which is currently in clinical trials, could have an important role in renoprotection in CPB surgery on the basis of such novel properties. 5. In the case of ADHF, would chronic therapy with NPs after hospital discharge improve survival and reduce rehospitalizations? This strategy is currently being pursued. Specifically, chronic subcutaneous delivery of the above-mentioned cenderitide is being evaluated using the same pump technology used for the treatment of diabetes mellitus. In summary, Sezai et al. (10) remind us that GC-A agonism has shown promising cardiorenal protective effects in several studies, and that it remains an attractive therapeutic target worthy of continuing investigation. Reprint requests and correspondence: Dr. Guido Boerrigter, Cardiorenal Research Laboratory, Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905. E-mail: [email protected].
REFERENCES
1. Boerrigter G, Lapp H, Burnett JC. Modulation of cGMP in heart failure: a new therapeutic paradigm. Handb Exp Pharmacol 2009; (191):485–506. 2. Yamahara K, Itoh H, Chun TH, et al. Significance and therapeutic potential of the natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway in vascular regeneration. Proc Natl Acad Sci USA 2003;100:3404 –9. 3. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA 2005;293:1900 –5. 4. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005;111:1487–91. 5. Mentzer RM Jr., 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 2007;49:716 –26. 6. 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: I134 – 8. 7. Ejaz AA, Martin TD, Johnson RJ, et al. Prophylactic nesiritide does not prevent dialysis or all-cause mortality in patients undergoing high-risk cardiac surgery. J Thorac Cardiovasc Surg 2009;138:959 – 64. 8. Sezai A, Hata M, Niino T, et al. Influence of continuous infusion of low-dose human atrial natriuretic peptide on renal function during cardiac surgery: a randomized controlled study. J Am Coll Cardiol 2009;54:1058 – 64.
906
Boerrigter and Burnett, Jr Natriuretic Peptide Renal Protection
9. 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 Human ANP Infusion Therapy During Cardiac Surgery) for left ventricular dysfunction. J Am Coll Cardiol 2010;55:1844 –51. 10. Sezai A, Hata M, Niino T, et al. 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. J Am Coll Cardiol 2011;58:897–903. 11. Hernandez AF, O’Connor CM, Starling RC, et al. Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure
JACC Vol. 58, No. 9, 2011 August 23, 2011:904–6 Trial (ASCEND-HF). Paper presented at: Late Breaking Clinical Trial, American Heart Association, 2010; Chicago, IL. 12. Ralat LA, Guo Q, Ren M, et al. Insulin-degrading enzyme modulates the natriuretic peptide-mediated signaling response. J Biol Chem 2011;286:4670 –9. 13. Boerrigter G, Costello-Boerrigter LC, Harty GJ, Lapp H, Burnett JC Jr. Des-serine-proline brain natriuretic peptide 3-32 in cardiorenal regulation. Am J Physiol Regul Integr Comp Physiol 2007;292:R897–901. 14. Lisy O, Huntley BK, McCormick DJ, Kurlansky PA, Burnett JC Jr. Design, synthesis, and actions of a novel chimeric natriuretic peptide: CD-NP. J Am Coll Cardiol 2008;52:60 – 8. Key Words: atrial natriuretic peptide y cardiac surgery y chronic kidney disease y natriuretic peptide.
EDITORIAL COMMENT
Natriuretic Peptides Renal Protective After All?* Guido Boerrigter, MD, John C. Burnett, JR, MD Rochester, Minnesota
Renal dysfunction has emerged as an important independent predictor of adverse outcomes, renal as well as cardiovascular. Renal function is crucially affected by intrinsic renal factors (particularly remaining functional renal mass), hemodynamic function (renal perfusion pressure, renal venous pressure), oxygen delivery, and neurohumoral input. The natriuretic peptides play an important role in cardiovascular homeostasis. The 28-amino acid atrial natriuretic peptide (ANP) and 32-amino acid B-type natriuretic peptide (BNP1–32) are secreted by the heart in response to cardiac stretch and stress. By activating guanylyl cyclase A (GC-A), they exert their pleiotropic actions, which include natriuresis, vasodilation, suppression of renin, angiotensin II, and aldosterone as well as antihypertrophic, antifibrotic, vascular regenerative, and cytoprotective properties (1,2). Given this background, it is no surprise that clinical trials have tested the therapeutic benefit of administering exogenous ANP (approved in Japan as carperitide) and BNP1–32 (approved in the U.S. as nesiritide) in a variety of cardiovascular disease states. That has led to at times promising, neutral, or disconcerting results as it relates to overall benefit and renal function (3–9). See page 897
Sezai et al. (10) in the NU-HIT for CKD trial in this issue of the Journal tested the renal effects of carperitide infused during and after coronary artery bypass graft surgery (CABG) with cardiopulmonary bypass (CPB) in patients (n ⫽ 285) with pre-operative chronic kidney disease (CKD), defined as estimated glomerular filtration rate (eGFR) ⬍60 ml·min⫺1·1.73 m⫺2. Carperitide was initiated at the start of bypass at 0.2 g·kg⫺1·min⫺1, reduced to 0.1 g·kg⫺1·min⫺1 at the beginning of oral medication, and *Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minnesota. This work is supported by National Institutes of Health grants HL36634 and HL76611. Dr. Boerrigter has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Burnett is Chair of the Nile Therapeutics Scientific Advisory Board, and Mayo has licensed cenderitide to Nile Therapeutics.
Vol. 58, No. 9, 2011 ISSN 0735-1097/$36.00 doi:10.1016/j.jacc.2010.12.053
discontinued 12 h thereafter. These investigators report that creatinine levels were lower with carperitide compared to placebo on the first day after surgery, and this effect was still present 1 year later. The same was true for aldosterone until 1 month after surgery. Although there was no significant difference in mortality at 1 year, the study was probably not powered for this endpoint. Fewer patients in the carperitide group had a cardiac event, and, importantly, fewer required dialysis. This study complements 2 similar studies by the same authors with carperitide during and after CPB. In the first, in patients with normal eGFR and left ventricular (LV) function (n ⫽ 504), carperitide decreased creatinine compared to placebo during the 7-day post-operative observation period, and reduced the length of hospital stay (8). However, given the small number of events in this healthier group of patients, carperitide did not significantly reduce mortality (1.6% vs. 2.4%) or the need for dialysis (0% vs. 1.6%). In the other study, patients (n ⫽ 133) were enrolled with LV dysfunction defined as ejection fraction ⱕ35% (9). Carperitide decreased creatinine and increased LV ejection fraction compared to placebo for at least a year after surgery, and reduced perioperative complications and hospital length of stay. While all-cause mortality showed no difference, the carperitide group had fewer cardiac events. Mentzer et al. (5) reported the results of an exploratory randomized trial with nesiritide, the NAPA (Nesiritide Administered Peri-Anesthesia in Patients Undergoing Cardiac Surgery) trial (n ⫽ 279) in patients undergoing CPB. Compared to placebo, nesiritide (0.01 g·kg⫺1·min⫺1, no bolus) improved renal function, increased urine output, shortened hospital length of stay, and reduced 180-day mortality. Ejaz et al. (7) compared a 5-day infusion of nesiritide to placebo in patients (n ⫽ 94) undergoing high-risk cardiac surgery, in 77% for thoracic aortic aneurysm. Although nesiritide reduced creatinine compared to placebo, there were no differences between groups regarding need for dialysis, all-cause mortality, or both at 30 days. Likewise, the hospital length of stay was similar. Of note, per protocol, the dose of nesiritide was to be increased from 0.01 to 0.03 g/kg to maintain post-operative urine output ⬎1 ml·kg⫺1·h⫺1. This algorithm was probably the reason for a significantly increased use of vasopressors in the nesiritide group, and may conceivably have offset some potential benefit of nesiritide therapy. In a small proof of concept trial, we defined the actions of low-dose nesiritide (0.05 ng·kg⫺1·min⫺1) infused for 24 h started at the time of anesthesia in a double-blind placebo-controlled trial of patients with CKD (eGFR ⬍60 ml/min/1.73 m2) undergoing CPB surgery with a focus on cystatin C and aldosterone. We observed a significant decrease in cystatin C with nesiritide compared to placebo and a lowering of aldosterone (6). Taken together, GC-A agonism with both ANP and BNP have shown promising beneficial results in patients undergoing CPB surgery.
Boerrigter and Burnett, Jr Natriuretic Peptide Renal Protection
JACC Vol. 58, No. 9, 2011 August 23, 2011:904–6
What are the potential mechanisms? Given the pleiotropic actions of GC-A agonists, these are likely multifactorial and include suppression of neurohormones such as aldosterone, angiotensin II, and the sympathetic nervous system. Another mechanism could be an improved post-operative LV ejection fraction as was seen in patients with preoperative LV dysfunction indicated above (9). In addition, GC-A activation may have improved renal perfusion and promoted cell survival, thus inhibiting the loss of functional renal tissue. In future studies, assessment of kidney injury markers, such as NGAL and KIM-1, may help to identify whether GC-A activation indeed reduces kidney injury. Most recently at the 2011 meeting of the American Heart Association, the results of a key 7,000-patient clinical trial using nesiritide for acute decompensated heart failure (ADHF) were announced and have relevance to the use of natriuretic peptides as therapeutic agents for cardiorenal disease. This trial, ASCEND (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) (11), was conducted after safety concerns were raised regarding renal function and mortality on the basis of publicly available information on earlier trials with nesiritide for HF (3,4). The ASCEND trial showed that nesiritide for patients with ADHF was safe and, specifically, did not harm renal function. However, it also did not improve survival or reduce rehospitalization and only tended to improve symptomatic status (11). Nesiritide was infused at 0.01 g·kg⫺1·min⫺1; an initial 2 g/kg bolus could be given at the discretion of the investigator, which was the case in approximately 62% of patients. Of note, asymptomatic and symptomatic hypotension occurred more often with nesiritide (21.4% vs. 12.4% and 7.1% vs. 4.0%, respectively). While the demonstration of safety is reassuring, it remains to be seen whether specific groups of acute HF patients can be identified that derive clinically significant benefit from nesiritide. Many more questions remain regarding GC-A agonists as therapeutic agents that need to be addressed in future studies. For example: 1. An important question is whether there are relevant clinical differences between carperitide and nesiritide, for example, as it relates to the incidence and duration of hypotension. 2. Degradation of NPs to an inactive metabolite is probably a multistep process, and some intermediate NP derivatives are likely to have a shorter half-life while still retaining bioactivity. Would it be safer to administer such a NP derivative with short half-life to patients with ADHF so that any developing hypotension would be less sustained? Do any of these endogenous NP derivatives have an activity profile that may be more appropriate for patients in critical hemodynamic condition (12)? For example, BNP3–32, a BNP derivative reported to circulate at higher concentrations than BNP1–32, levels in HF patients was natriuretic but not hypotensive in healthy canines (13).
905
3. Can we modulate the activity of GC-A agonists by combining them with inhibitors of their degradation, e.g., neprilysin inhibitors? Also, can we combine GC-A agonists with phosphodiesterase inhibitors to reduce degradation of the NP’s second messenger cGMP? 4. Should we also target GC-B, the receptor of C-type natriuretic peptide, which has important vascular and renal actions especially at the level of the podocyte (14)? Indeed, the use of a novel dual GC-A and GC-B agonist (cenderitide) designed by our group, which is currently in clinical trials, could have an important role in renoprotection in CPB surgery on the basis of such novel properties. 5. In the case of ADHF, would chronic therapy with NPs after hospital discharge improve survival and reduce rehospitalizations? This strategy is currently being pursued. Specifically, chronic subcutaneous delivery of the above-mentioned cenderitide is being evaluated using the same pump technology used for the treatment of diabetes mellitus. In summary, Sezai et al. (10) remind us that GC-A agonism has shown promising cardiorenal protective effects in several studies, and that it remains an attractive therapeutic target worthy of continuing investigation. Reprint requests and correspondence: Dr. Guido Boerrigter, Cardiorenal Research Laboratory, Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905. E-mail: [email protected].
REFERENCES
1. Boerrigter G, Lapp H, Burnett JC. Modulation of cGMP in heart failure: a new therapeutic paradigm. Handb Exp Pharmacol 2009; (191):485–506. 2. Yamahara K, Itoh H, Chun TH, et al. Significance and therapeutic potential of the natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway in vascular regeneration. Proc Natl Acad Sci USA 2003;100:3404 –9. 3. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA 2005;293:1900 –5. 4. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005;111:1487–91. 5. Mentzer RM Jr., 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 2007;49:716 –26. 6. 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: I134 – 8. 7. Ejaz AA, Martin TD, Johnson RJ, et al. Prophylactic nesiritide does not prevent dialysis or all-cause mortality in patients undergoing high-risk cardiac surgery. J Thorac Cardiovasc Surg 2009;138:959 – 64. 8. Sezai A, Hata M, Niino T, et al. Influence of continuous infusion of low-dose human atrial natriuretic peptide on renal function during cardiac surgery: a randomized controlled study. J Am Coll Cardiol 2009;54:1058 – 64.
906
Boerrigter and Burnett, Jr Natriuretic Peptide Renal Protection
9. 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 Human ANP Infusion Therapy During Cardiac Surgery) for left ventricular dysfunction. J Am Coll Cardiol 2010;55:1844 –51. 10. Sezai A, Hata M, Niino T, et al. 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. J Am Coll Cardiol 2011;58:897–903. 11. Hernandez AF, O’Connor CM, Starling RC, et al. Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure
JACC Vol. 58, No. 9, 2011 August 23, 2011:904–6 Trial (ASCEND-HF). Paper presented at: Late Breaking Clinical Trial, American Heart Association, 2010; Chicago, IL. 12. Ralat LA, Guo Q, Ren M, et al. Insulin-degrading enzyme modulates the natriuretic peptide-mediated signaling response. J Biol Chem 2011;286:4670 –9. 13. Boerrigter G, Costello-Boerrigter LC, Harty GJ, Lapp H, Burnett JC Jr. Des-serine-proline brain natriuretic peptide 3-32 in cardiorenal regulation. Am J Physiol Regul Integr Comp Physiol 2007;292:R897–901. 14. Lisy O, Huntley BK, McCormick DJ, Kurlansky PA, Burnett JC Jr. Design, synthesis, and actions of a novel chimeric natriuretic peptide: CD-NP. J Am Coll Cardiol 2008;52:60 – 8. Key Words: atrial natriuretic peptide y cardiac surgery y chronic kidney disease y natriuretic peptide.