Amino acid infusion confers kidney protection in people undergoing cardiopulmonary bypass

Continuous infusion of amino acids appears to reduce the risk of acute kidney injury (AKI) in adults undergoing elective cardiopulmonary bypass procedure, as shown in the PROTECTION trial.

In a cohort of 3,511 patients who participated in the study, AKI* occurred within the first week after the procedure in 26.9 percent of those who received an intravenous infusion of amino acids and in 31.7 percent of those who received a Ringer’s solution (placebo; relative risk [RR], 0.85, 95 percent confidence interval [CI], 0.77–0.94; p=0.002). [N Engl J Med 2024;391:687-698]

Most cases of AKI were stage 1, and some were stage 3, including in 1.6 percent of patients in the amino acid group and in 3.0 percent of those in the placebo group (RR, 0.56, 95 percent CI, 0.35–0.87). Kidney replacement therapy was used in 1.4 percent and 1.9 percent of patients in the respective groups, with a median duration of 64 hours. No significant between-group differences were noted in the median duration of mechanical ventilation (11 hours in both groups), median duration of stay in the ICU (30 vs 34 hours), and median duration of stay in the hospital (7 nights in both groups).

In terms of safety events, 4.0 percent of patients in the amino acid group and 3.5 percent in the placebo group underwent surgical revision for bleeding, 6.4 percent and 6.8 percent of patients required mechanical circulatory support, and 33.0 and 30.8 percent had atrial fibrillation, respectively. No adverse drug reactions were documented in either group.

The 30-day mortality rate was 2.8 percent in the amino acid group and 2.8 percent in the placebo.

“AKI is a serious and common complication of cardiac surgery, for which reduced kidney perfusion is a key contributing factor. [Meanwhile,] intravenous amino acids increase kidney perfusion and recruit renal functional reserve,” the investigators said.

“The infusion of amino acids appeared to be safe and effective for the prevention of AKI in patients undergoing cardiac surgery. Moreover, the lower percentage of patients with stage 3 AKI in the amino acid group than in the placebo group implied an effect on AKI severity,” they continued.

These findings are clinically and epidemiologically important, given that 2 million patients undergo heart surgical procedures worldwide every year and that AKI is an independent risk factor for subsequent chronic kidney disease, the investigators pointed out. [Kidney Int 2019;95:160-172]

Study details

PROTECTION was a multinational, double-blind trial conducted at 22 centres in Italy, Singapore, and Croatia. Of the patients who participated in the trial, 1,759 (median age 66 years, 30.1 percent female, 98.4 percent White, median BMI 26 kg/m²) were assigned to the amino acid group and 1,752 to the placebo group (median age 67 years, 30.1 percent female, 98.1 percent White, median BMI 26 kg/m²).

The median dose of amino acids was 1,260 ml, corresponding to 126 g of amino acids. The median duration of infusion was 30 hours in the amino acid group and 31 hours in the placebo group. In both groups, the median infusion rate was 40 ml per hour.

Treatment was discontinued at ICU discharge for most patients (72.1 percent), at initiation of kidney replacement therapy for 0.6 percent of patients, or in error for 1.6 percent. The maximum 72-hour infusion was completed in 22.6 percent of patients. Fourteen patients (0.4 percent) died before the end of the 3-day infusion, and one (<0.1 percent) withdrew consent. Lastly, crossover occurred in four participants.

The investigators acknowledged that PROTECTION had several limitations. “First, we used serum creatinine level alone to diagnose AKI because urinary catheters are typically removed within 48 to 72 hours after surgery. However, adding urinary output confirmed the robustness of our findings in a sensitivity analysis.”

Also, newly identified biomarkers of kidney injury were not measured. Nevertheless, the detection of subclinical AKI was not the objective of the trial, and biomarkers of kidney injury gained more relevance after the Acute Disease Quality Initiative consensus conference in 2020, when the trial was already in progress. [JAMA Netw Open 2022;5:e2212709-e2212709]

Finally, there was no strict protocol for management or prevention of AKI in this trial and lack of data on tubular injury, among others.

*Defined according to Kidney Disease: Improving Global Outcomes 2012 guidelines