rhBNP for Prevention of Cardiac Surgery-Associated Acute Kidney Injury (CSA-AKI)

Официальное название

Perioperative Recombinant Human Brain Natriuretic Peptide for Renal Protection in Cardiac Surgery: the PROTECT-CS Randomized Clinical Trial

Обзор

Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common and serious perioperative complication, independently associated with prolonged hospitalization, increased mortality, and progression to chronic kidney disease. Despite advances in surgical techniques and postoperative care, no widely accepted pharmacological prevention strategy exists. Recombinant human brain natriuretic peptide (rhBNP) exerts vasodilatory, diuretic, and natriuretic effects, reduces cardiac preload and afterload, and has demonstrated safety and efficacy in treating congestive heart failure. Preliminary studies suggest rhBNP may reduce postoperative serum creatinine, increase urine output, and improve renal outcomes; however, large-scale randomized controlled evidence is lacking. The PROTECT-CS trial is a multicenter, prospective, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of perioperative continuous intravenous rhBNP infusion (0.01 μg/kg/min for 48 ± 2 hours) for prevention of AKI in high-risk patients undergoing cardiac surgery with cardiopulmonary bypass. A total of 694 participants will be enrolled across 7 centers in China.

Подробное описание

Acute kidney injury (AKI) is one of the most common and serious complications following cardiac surgery. CSA-AKI is independently associated with short-term adverse outcomes including prolonged ICU stay, increased need for renal replacement therapy, and in-hospital mortality, as well as long-term consequences including progression to chronic kidney disease and elevated cardiovascular mortality. Despite extensive research efforts, current clinical management of CSA-AKI remains largely supportive, and no pharmacological intervention has been established as a standard preventive strategy in international guidelines.

Recombinant human brain natriuretic peptide (rhBNP, generic name: nesiritide) shares structural and biological activity highly similar to endogenous BNP. Its pharmacological properties include arterial and venous vasodilation, promotion of natriuresis and diuresis, reduction of cardiac preload and afterload, and direct improvement of glomerular filtration rate without adversely affecting serum potassium or creatinine. rhBNP has been widely used in Chinese cardiac surgery and critical care centers for perioperative hemodynamic optimization. Published small-sample randomized trials and a recent meta-analysis have suggested potential renal protective benefits of perioperative rhBNP in cardiac surgery patients; however, these studies were limited by small sample sizes, heterogeneous populations, and the use of renal endpoints as exploratory rather than primary outcomes.

The PROTECT-CS trial aims to address this evidence gap. Eligible participants are adults aged ≥18 years scheduled for elective cardiac surgery under cardiopulmonary bypass who have at least one AKI risk factor (age ≥70 years, preoperative renal impairment, type 2 diabetes mellitus, or heart failure). Participants will be randomized 1:1 using a central IWRS system, stratified by study center with a block size of 6, to receive either continuous intravenous rhBNP at 0.01 μg/kg/min or an equivalent volume of normal saline (placebo), initiated from anesthetic induction to the onset of cardiopulmonary bypass and continued for 48 ± 2 hours total. All participants receive standard perioperative care throughout.

The primary endpoint is the incidence of AKI diagnosed per KDIGO criteria within 7 days postoperatively. Secondary endpoints include AKI incidence within 72 hours, AKI duration and severity, need for renal replacement therapy during hospitalization, changes in renal function biomarkers, hemodynamic parameters, diuretic and vasoactive drug use, major adverse kidney events at 30 and 90 days (MAKE-30 and MAKE-90), 30-day all-cause mortality, ICU and hospital length of stay, and total hospitalization costs.

An independent Data Monitoring Committee (DMC) will conduct periodic safety reviews and a pre-planned interim analysis. Adverse drug reactions are graded per NCI-CTCAE Version 5.0. All study data are collected via an electronic data capture (EDC) system and managed in accordance with GCP standards.

Вмешательства

• Препарат Recombinant Human Brain Natriuretic Peptide (rhBNP)
  Continuous intravenous infusion of rhBNP at 0.01 μg/kg/min, initiated at anesthetic induction and continued for 48 ± 2 hours. The infusion rate is consistent with the approved dosage range in the drug prescribing information.
• Препарат Normal Saline (Placebo)
  Continuous intravenous infusion of normal saline at an equivalent volume and rate to the rhBNP arm, initiated at anesthetic induction and continued for 48 ± 2 hours.

Первичные конечные точки

• Incidence of acute kidney injury (AKI) within 7 days postoperatively, diagnosed per KDIGO criteria [Срок оценки: Within 7 days after surgery, or until hospital discharge if earlier]

Вторичные конечные точки (12)

• Incidence of AKI within 72 hours postoperatively, diagnosed according to KDIGO criteria [Срок оценки: Within 72 hours after surgery]
• Duration of AKI by KDIGO criteria [Срок оценки: Within 7 days after surgery, or until hospital discharge if earlier]
• Severity of AKI by KDIGO stage [Срок оценки: Within 7 days after surgery, or until hospital discharge if earlier]
• Incidence of any form of renal replacement therapy (RRT) during the index hospitalization [Срок оценки: During the index hospitalization]
• Change in serum creatinine from preoperative baseline [Срок оценки: 6, 24, 48, and 120 hours and 7 days after surgery]
• Change in urinary creatinine from preoperative baseline [Срок оценки: 6, 24, 48, and 120 hours and 7 days after surgery]
• Change in estimated glomerular filtration rate (eGFR) from preoperative baseline [Срок оценки: 6, 24, 48, and 120 hours and 7 days after surgery]
• Change in pulmonary capillary wedge pressure (PCWP) from post-surgical baseline [Срок оценки: 6, 12, 24, and 48 hours after surgery]
• Change in central venous pressure (CVP) from post-surgical baseline [Срок оценки: 6, 12, 24, and 48 hours after surgery]
• Change in cardiac output (CO) from post-surgical baseline [Срок оценки: 6, 12, 24, and 48 hours after surgery]
• Change in cardiac index (CI) from post-surgical baseline [Срок оценки: 6, 12, 24, and 48 hours after surgery]
• Total intraoperative and postoperative diuretic dose [Срок оценки: From anesthetic induction until hospital discharge]

Критерии участия

Критерии включения

• Age ≥ 18 years
• Scheduled (elective) cardiac surgery requiring cardiopulmonary bypass
• Presence of at least one of the following AKI risk factors:
• Age ≥ 70 years
• Preoperative renal impairment (eGFR ≤ 60 mL/min/1.73 m² or urine protein ≥ +2 at screening)
• Type 2 diabetes mellitus
• Heart failure, defined as NYHA Class II-IV with NT-proBNP ≥ 125 pg/mL at screening; for participants with atrial fibrillation, NT-proBNP ≥ 365 pg/mL is required
• Able to understand and provide written informed consent, and willing and able to comply with all study protocol requirements

Критерии исключения

• Cardiogenic shock
• Severe hypotension (systolic blood pressure ≤ 90 mmHg) at screening
• Restrictive or obstructive cardiomyopathy, pericarditis, or cardiac tamponade
• Preoperative chronic kidney disease stage 4 or higher (eGFR < 30 mL/min/1.73 m²), or renal instability as judged by the investigator
• Known AKI diagnosed per KDIGO criteria within 48 hours prior to surgery
• Receipt of any form of renal replacement therapy within 30 days prior to surgery
• Use of ventricular assist device, intra-aortic balloon pump, or any other mechanical cardiac support device within 7 days prior to surgery
• Chronic hepatic insufficiency (Child-Pugh Class B or C) or hepatic dysfunction (ALT or AST > 2× upper limit of normal \[ULN\], or total bilirubin > 1.5× ULN)
• Active hepatitis B (HBsAg positive with HBV-DNA indicating active viral replication), active hepatitis C (HCV antibody positive with HCV-RNA indicating active viral replication), positive syphilis screen, known HIV infection, or positive HIV test
• Confirmed or treated endocarditis, sepsis, or active infection requiring antibiotic treatment within 30 days prior to surgery
• Requirement for aortic dissection repair, complex congenital heart surgery, emergency surgery, or life-saving surgery
• History of malignant tumor, solid tumor, metastatic tumor, or hematological malignancy within the past 5 years
• Prior organ transplantation or current use of immunosuppressive agents
• Any condition that may conflict with or contraindicate the use of intravenous vasodilator therapy
• Prior adverse reaction to nesiritide (recombinant BNP)
• Participation in any other clinical trial within 30 days prior to surgery
• Pregnant or breastfeeding women
• Any other condition that, in the judgment of the investigator, renders the participant unsuitable for study participation

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Профилактика

Центры проведения

Китай · 1 центр

• Fuwai Hospital, Chinese Academy of Medical Sciences — Пекин

Публикации

• Chen HH, Anstrom KJ, Givertz MM, Stevenson LW, Semigran MJ, Goldsmith SR, Bart BA, Bull DA, Stehlik J, LeWinter MM, Konstam MA, Huggins GS, Rouleau JL, O'Meara E, Tang WH, Starling RC, Butler J, Deswal A, Felker GM, O'Connor CM, Bonita RE, Margulies KB, Cappola TP, Ofili EO, Mann DL, Davila-Roman VG, McNulty SE, Borlaug BA, Velazquez EJ, Lee KL, Shah MR, Hernandez AF, Braunwald E, Redfield MM; NHL PMID 24247300
• Shao J, Wang L, Shao C, Wang Y, Li J, Luo J, Du Z, Hou X. Effects of Perioperative Recombinant Human Brain Natriuretic Peptide in Patients Undergoing Cardiac Surgery: A Systematic Review and Meta-Analysis. Rev Cardiovasc Med. 2025 Sep 18;26(9):36423. doi: 10.31083/RCM36423. eCollection 2025 Sep. PMID 41089773
• Perez-Fernandez X, Ulsamer A, Camara-Rosell M, Sbraga F, Boza-Hernandez E, Moret-Ruiz E, Plata-Menchaca E, Santiago-Bautista D, Boronat-Garcia P, Gumucio-Sanguino V, Penafiel-Munoz J, Camacho-Perez M, Betbese-Roig A, Forni L, Campos-Gomez A, Sabater-Riera J; SIRAKI02 Study Group. Extracorporeal Blood Purification and Acute Kidney Injury in Cardiac Surgery: The SIRAKI02 Randomized Clinical Trial. J PMID 39382234
• Shehabi Y, Balachandran M, Al-Bassam W, Bailey M, Bellomo R, Bihari S, Brown A, Brown A, Collins D, Darlison PR, Li MA, Mandarano R, Sarode V, Pakavakis A; ALBICS AKI Study Investigators. Postoperative 20% Albumin Infusion and Acute Kidney Injury in High-Risk Cardiac Surgery Patients: The ALBICS AKI Randomized Clinical Trial. JAMA Surg. 2025 Aug 1;160(8):835-844. doi: 10.1001/jamasurg.2025.1683. PMID 40498523
• Thielmann M, Corteville D, Szabo G, Swaminathan M, Lamy A, Lehner LJ, Brown CD, Noiseux N, Atta MG, Squiers EC, Erlich S, Rothenstein D, Molitoris B, Mazer CD. Teprasiran, a Small Interfering RNA, for the Prevention of Acute Kidney Injury in High-Risk Patients Undergoing Cardiac Surgery: A Randomized Clinical Study. Circulation. 2021 Oct 5;144(14):1133-1144. doi: 10.1161/CIRCULATIONAHA.120.053029. PMID 34474590
• Jia P, Ji Q, Zou Z, Zeng Q, Ren T, Chen W, Yan Z, Shen D, Li Y, Peng F, Su Y, Xu J, Shen B, Luo Z, Wang C, Ding X. Effect of Delayed Remote Ischemic Preconditioning on Acute Kidney Injury and Outcomes in Patients Undergoing Cardiac Surgery: A Randomized Clinical Trial. Circulation. 2024 Oct 22;150(17):1366-1376. doi: 10.1161/CIRCULATIONAHA.124.071408. Epub 2024 Sep 25. PMID 39319450
• Landoni G, Monaco F, Ti LK, Baiardo Redaelli M, Bradic N, Comis M, Kotani Y, Brambillasca C, Garofalo E, Scandroglio AM, Viscido C, Paternoster G, Franco A, Porta S, Ferrod F, Calabro MG, Pisano A, Vendramin I, Barucco G, Federici F, Severi L, Belletti A, Cortegiani A, Bruni A, Galbiati C, Covino A, Baryshnikova E, Giardina G, Venditto M, Kroeller D, Nakhnoukh C, Mantovani L, Silvetti S, Licheri M PMID 38865168
• 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 Sep 11;116(11 Suppl):I134-8. doi: 10.1161/CIRCULATIONAHA.106.697250. PMID 17846293

Идентификаторы

NCT: NCT07617675 · 2026-3155

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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