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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
694
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.
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.
Fuwai Hospital, Chinese Academy of Medical Sciences
Beijing, China
Incidence of acute kidney injury (AKI) within 7 days postoperatively, diagnosed per KDIGO criteria
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.
Time frame: Within 7 days after surgery, or until hospital discharge if earlier
Incidence of AKI within 72 hours postoperatively, diagnosed according to KDIGO criteria
Time frame: Within 72 hours after surgery
Duration of AKI by KDIGO criteria
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.
Time frame: Within 7 days after surgery, or until hospital discharge if earlier
Severity of AKI by KDIGO stage
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.
Time frame: Within 7 days after surgery, or until hospital discharge if earlier
Incidence of any form of renal replacement therapy (RRT) 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.
Time frame: During the index hospitalization
Change in serum creatinine from preoperative baseline
Baseline defined as the last preoperative laboratory result.
Time frame: 6, 24, 48, and 120 hours and 7 days after surgery
Change in urinary creatinine from preoperative baseline
Baseline defined as the last preoperative laboratory result.
Time frame: 6, 24, 48, and 120 hours and 7 days after surgery
Change in estimated glomerular filtration rate (eGFR) from preoperative baseline
Baseline defined as the last preoperative laboratory result.
Time frame: 6, 24, 48, and 120 hours and 7 days after surgery
Change in pulmonary capillary wedge pressure (PCWP) from post-surgical baseline
Baseline defined as the first measurement obtained after completion of surgery.
Time frame: 6, 12, 24, and 48 hours after surgery
Change in central venous pressure (CVP) from post-surgical baseline
Baseline defined as the first measurement obtained after completion of surgery.
Time frame: 6, 12, 24, and 48 hours after surgery
Change in cardiac output (CO) from post-surgical baseline
Baseline defined as the first measurement obtained after completion of surgery.
Time frame: 6, 12, 24, and 48 hours after surgery
Change in cardiac index (CI) from post-surgical baseline
Baseline defined as the first measurement obtained after completion of surgery.
Time frame: 6, 12, 24, and 48 hours after surgery
Total intraoperative and postoperative diuretic dose
Cumulative dose of diuretic agents administered intraoperatively and postoperatively, reported by drug.
Time frame: From anesthetic induction until hospital discharge
Total intraoperative and postoperative inotrope dose
Cumulative dose of inotropic agents administered intraoperatively and postoperatively, reported by drug.
Time frame: From anesthetic induction until hospital discharge
Total intraoperative and postoperative vasopressor dose
Cumulative dose of vasopressor agents administered intraoperatively and postoperatively, reported by drug.
Time frame: From anesthetic induction until hospital discharge
Total intraoperative and postoperative vasodilator dose
Cumulative dose of vasodilator agents administered intraoperatively and postoperatively, reported by drug.
Time frame: From anesthetic induction until hospital discharge
Major Adverse Kidney Events at 30 days (MAKE-30)
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.
Time frame: 30 days after surgery
Major Adverse Kidney Events at 90 days (MAKE-90)
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.
Time frame: 90 days after surgery
All-cause mortality at 30 days
Time frame: 30 days after surgery
Total ICU length of stay
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.
Time frame: Postoperative (From ICU admission until ICU discharge, an average of 3 days)
Postoperative hospital length of stay during the index hospitalization
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.
Time frame: Postoperative (From the day of surgery until hospital discharge, an average of 7 days)
Total postoperative medical costs during the index hospitalization
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.
Time frame: Postoperative (From the day of surgery until hospital discharge, an average of 7 days)
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