AKI - Acute Kidney Injury, Cardiac Surgical Procedures, Cardiopulmonary Bypass
Conditions
Keywords
Recombinant human brain natriuretic peptide, rhBNP, Nesiritide, Acute kidney injury, Cardiac surgery, Cardiopulmonary bypass, Renal protection, Randomized controlled trial, Cardiac surgery-associated acute kidney injury, CSA-AKI
Brief summary
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.
Detailed description
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.
Interventions
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.
DRUGNormal 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.
Sponsors
China National Center for Cardiovascular Diseases
The First Affiliated Hospital of Xiamen University
Guangdong Provincial People's Hospital
Yantai Yuhuangding Hospital
Second Xiangya Hospital of Central South University
First Affiliated Hospital of Chongqing Medical University
Shenzhen Sun Yat-sen Cardiovascular Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The study drug (rhBNP) and placebo (normal saline) are prepared and labeled by an unblinded nurse who is not involved in patient care or outcome assessment. The prepared syringes are identical in appearance. All participants, treating clinicians, investigators, and outcome assessors remain blinded throughout the trial. Emergency unblinding is permitted in cases of medical necessity (e.g., pregnancy, serious adverse event requiring knowledge of treatment allocation) and must be documented in detail.
Intervention model description
Eligible participants are randomized 1:1 to either the rhBNP treatment group or the placebo control group. Both groups receive standard perioperative care. Randomization is performed using a central IWRS, stratified by study center with a block size of 6.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of acute kidney injury (AKI) within 7 days postoperatively, diagnosed per KDIGO criteria | Within 7 days after surgery, or until hospital discharge if earlier | AKI defined per KDIGO 2012 criteria as any of: (1) serum creatinine increase ≥ 0.3 mg/dL (≥ 26.5 μmol/L) within 48 hours; (2) serum creatinine increase to ≥ 1.5 times baseline within 7 days; or (3) urine output \< 0.5 mL/kg/h for ≥ 6 consecutive hours. If a participant is discharged earlier than postoperative day 7, AKI events occurring in-hospital are recorded. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of AKI within 72 hours postoperatively, diagnosed according to KDIGO criteria | Within 72 hours after surgery | — |
| Duration of AKI by KDIGO criteria | Within 7 days after surgery, or until hospital discharge if earlier | Duration of AKI among participants who develop AKI within 7 days postoperatively, recorded in hours from onset to resolution per KDIGO criteria. If a participant is discharged earlier than postoperative day 7, in-hospital AKI events are recorded. |
| Severity of AKI by KDIGO stage | Within 7 days after surgery, or until hospital discharge if earlier | Distribution of participants across KDIGO Stage 1, Stage 2, and Stage 3, based on the maximum stage reached. If a participant is discharged earlier than postoperative day 7, in-hospital AKI events are recorded. |
| Incidence of any form of renal replacement therapy (RRT) during the index hospitalization | During the index hospitalization | Number of participants receiving any form of RRT (intermittent hemodialysis, continuous renal replacement therapy, or peritoneal dialysis) during the surgical hospitalization. |
| Change in serum creatinine from preoperative baseline | 6, 24, 48, and 120 hours and 7 days after surgery | Baseline defined as the last preoperative laboratory result. |
| Change in urinary creatinine from preoperative baseline | 6, 24, 48, and 120 hours and 7 days after surgery | Baseline defined as the last preoperative laboratory result. |
| Change in estimated glomerular filtration rate (eGFR) from preoperative baseline | 6, 24, 48, and 120 hours and 7 days after surgery | Baseline defined as the last preoperative laboratory result. |
| Change in pulmonary capillary wedge pressure (PCWP) from post-surgical baseline | 6, 12, 24, and 48 hours after surgery | Baseline defined as the first measurement obtained after completion of surgery. |
| Change in central venous pressure (CVP) from post-surgical baseline | 6, 12, 24, and 48 hours after surgery | Baseline defined as the first measurement obtained after completion of surgery. |
| Change in cardiac output (CO) from post-surgical baseline | 6, 12, 24, and 48 hours after surgery | Baseline defined as the first measurement obtained after completion of surgery. |
| Change in cardiac index (CI) from post-surgical baseline | 6, 12, 24, and 48 hours after surgery | Baseline defined as the first measurement obtained after completion of surgery. |
| Total intraoperative and postoperative diuretic dose | From anesthetic induction until hospital discharge | Cumulative dose of diuretic agents administered intraoperatively and postoperatively, reported by drug. |
| Total intraoperative and postoperative inotrope dose | From anesthetic induction until hospital discharge | Cumulative dose of inotropic agents administered intraoperatively and postoperatively, reported by drug. |
| Total intraoperative and postoperative vasopressor dose | From anesthetic induction until hospital discharge | Cumulative dose of vasopressor agents administered intraoperatively and postoperatively, reported by drug. |
| Total intraoperative and postoperative vasodilator dose | From anesthetic induction until hospital discharge | Cumulative dose of vasodilator agents administered intraoperatively and postoperatively, reported by drug. |
| Major Adverse Kidney Events at 30 days (MAKE-30) | 30 days after surgery | Composite endpoint defined as the occurrence of any of the following: death from any cause, receipt of renal replacement therapy, or ≥25% decline in eGFR from baseline. |
| Major Adverse Kidney Events at 90 days (MAKE-90) | 90 days after surgery | Composite endpoint defined as the occurrence of any of the following: death from any cause, receipt of renal replacement therapy, or ≥25% decline in eGFR from baseline. |
| All-cause mortality at 30 days | 30 days after surgery | — |
| Total ICU length of stay | Postoperative (From ICU admission until ICU discharge, an average of 3 days) | Total ICU length of stay during the index hospitalization, calculated as the difference between ICU exit time and ICU admission time. For participants with multiple ICU admissions, total ICU length of stay is the sum of all individual ICU stays. |
| Postoperative hospital length of stay during the index hospitalization | Postoperative (From the day of surgery until hospital discharge, an average of 7 days) | Postoperative hospital length of stay during the index hospitalization, calculated as the number of days from the date of surgery to the date of hospital discharge. Days of hospitalization before surgery are not included. |
| Total postoperative medical costs during the index hospitalization | Postoperative (From the day of surgery until hospital discharge, an average of 7 days) | Total postoperative medical costs during the index hospitalization, calculated as the sum of all itemized hospital charges incurred from the date of surgery to the date of hospital discharge (including but not limited to surgical fees, ICU fees, medications, laboratory tests, imaging, nursing care, and bed fees), extracted from the hospital information system (HIS) billing records. Charges incurred before surgery are not included. |
Countries
China
Contacts
CONTACTSheng Liu, MD
CONTACTHeng Zhang, MD
PRINCIPAL_INVESTIGATORSheng Liu
Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Outcome results
None listed