Acute kidney injury (AKI) is one of the most frequent complications of cardiac surgery and the cause is complex. Renal hypoperfusion from decreased glomerular filtration rate after cardiopulmonary bypass is a major contributor.1This in combination with exogenous toxins, endogenous metabolites, oxidative stress, bleeding and reperfusion injury can all lead to the patient ending up on renal replacement therapy postoperatively. Unfortunately there is no single preventative intervention for AKI from cardiac surgery. Animal and pilot human studies have shown that amino acid infusion increases renal perfusion, oxygenation and overall GFR. The authors of this study sought to test the hypothesis that intravenous amino acid therapy would lead to a lower occurrence of postoperative AKI when compared to placebo.
Paper: Landoni G. et al. Intravenous amino acid therapy for kidney protection in cardiac surgery a protocol for a multi-centre randomized blinded placebo controlled clinical trial. The PROTECTION trial. Contemp Clin Trials. Epub 2022 Aug 28. PMID: 36038001
Clinical Question:
In patients undergoing cardiac surgery with cardiopulmonary bypass, does the administration of intravenous amino acid therapy lead to lower occurrence of postoperative AKI when compared to placebo?
What They Did:
Double-blind, randomized, placebo controlled trial that ran from October 2019 through January 2024
Multinational study conducted at 22 centers in three European countries
3512 patients were enrolled and before surgery eligible patients were randomly assigned to one of the following two groups
Amino Acid Group: 10% Isopuramin at a dose of 2g/kg/day of ideal body weight from time of operating-room admission to 72 hours after infusion, discharge from the ICU, initiation of renal replacement therapy (RRT) or death (whichever occurred first)
1752 patients in the Placebo Group: Received a blinded continuous infusion of Ringer’s solution at the same rate and according to the same protocol
If enteral or parenteral nutrition was initiated within the first 72 hours, the dose of the amino acid formulary was adjusted
Trial centers provided post-operative monitoring and kidney protection management in accordance with the Kidney Disease: Improving Global Outcomes (KDIGO) AKI guidelines (See Figure 1 below)
The authors also looked at prespecified intraoperative and postoperative adverse effects which included the following:
Cardiogenic shock
Events requiring ICU readmission
Arrhythmia
Need for reintubation
Need for non-invasive ventilation
Adverse neurologic outcome
Myocardial infarction
Wound infection
Sepsis and Septic Shock
Death
A trained investigator unaware of the group assignments performed telephone follow-up at 30, 90 and 180 days after randomization. If a patient could not be contacted, the investigator obtained data by contacting the patient’s surgeons, family medicine physician, city register office or accessing the patient’s hospital electronic records
Figure 1: KDIGO Criteria for AKI Diagnosis (Source: PMID: 27258049)
Inclusion Criteria:
Patients 18 years of age or older
Scheduled to undergo elective cardiac surgery requiring cardiopulmonary bypass
Expected to stay in the ICU for at least one night after undergoing their surgery
Had to have a baseline serum creatinine measured before surgery
Exclusion Criteria:
Preoperative treatment or planned treatment with intermittent or continuous renal replacement therapy
Stage IV or greater chronic kidney disease defined as an estimated glomerular filtration rate of less than 30 mL/min/1.73m2 of body surface area
History of kidney transplantation
Current enrollment into another randomized clinical trial or previous enrollment/randomization into this study
Severe liver disease (defined as a Child-Pugh score > 7 points)
Hypersensitivity or known allergy to one or more of the included amino acids
Pregnant or currently breastfeeding
Congenital alteration of amino acid metabolism
Patient is not expected to survive ICU or hospital discharge
Outcomes:
Primary
Occurrence of AKI within the first week after surgery with AKI defined according to the KDIGO creatinine criteria for stage 1 or greater AKI
Secondary
Severity of AKI according to the KDIGO creatinine criteria
Use and duration of kidney-replacement therapy during hospital stay
ICU duration of stay
Hospital duration of stay
Duration of mechanical ventilation
Death from any cause documented at the time of ICU discharge
Death from any cause at 30, 90 or 180 days after randomization
Results:
1759 patients were enrolled in the Amino Acid Group
1752 patients were enrolled in the Placebo Group
Critical Results:
When comparing the amino acid to the placebo group, there were few occurrences of AKI at all stages. Also important to note is that there were no increase in safety events
None of the secondary outcomes that the authors were looking at were statistically significant
Strengths:
Double-blind, randomized placebo-controlled trial with broad and clear inclusion criteria performed at multiple institutions across three countries adds to external validity
Looks to answer a clinically relevant question regarding a relatively new and emerging therapy
Neither the Italian Ministry of Health nor Baxter (Amino Acid Treatment manufacturer) had any role in the concept or design of the trial
Both amino acid treatment and placebo were delivered in indistinguishable bottles and thus helping with blinding
Patients, physicians, investigators, data collectors and outcome assessors were unaware of the group assessments
Large sample size of enrolled patients with equal number between both groups
Trial intervention is straightforward and would be readily translated into practice. There was also an adjustment made in the dose if enteral or parenteral nutrition was initiated within the first 72 hours
Included patient oriented outcomes such as death at any cause 30, 90 and 180 days after randomization
Had a protocol for obtaining follow-up data if the investigator was unable to reach patient by telephone and there was minimal loss to follow-up
Left all other aspects of perioperative management to the discretion of the attending physicians
Limitations:
Used serum creatinine level alone to diagnose AKI which is a bit isolating, additionally this is a lab oriented outcome, not a patient oriented outcome
Only used one AKI criteria (ie. KDIGO), even though others exist, such as (AKIN and RIFLE)
Did not measure newly identified biomarkers of kidney injury since trial was already in progress
No strict protocol for the management or prevention of AKI
Trial population differs substantially from patients in low and middle-income countries
Overwhelmingly large caucasian population thus lacking patients with a more varied ethnic distribution
Lacked data on tubular injury because no histologically validated markers of hypothetical injury exist
Only obtained creatinine values few days before their surgery as opposed to before hospitalization
Some patients had protocol deviations such as having off-pump surgery
The study was regarding only one type of amino acid formulary
Discussion:
This was a multi-center randomized placebo control trial that served to answer a clinically relevant question regarding a frequently encountered post-cardiac surgery complication
AKI is more than just a rise in creatinine and in clinical critical care settings also requires the provider to factor in urine output. When only using a lab value such as creatinine, the authors are making the end-result more heavily favored to only a lab-oriented outcome.
The authors used only the KDIGO criteria for assessing AKI. There are other good tools out there such as the AKIN and RIFLE criteria. In fact, a prospective cohort study compared all three and found them similar in predicting mortality in critically ill patients2
Overwhelmingly large number of caucasian patients which is to be expected given the trial occurred in three European countries. This does make it difficult to apply the trial findings to a more diversified population such as the United States
The study used Isopuramin 10% as their amino acid treatment which they claim is a “balanced mixture of amino acids”. However, there was no mention of using alternatives or future studies on other amino acid formularies given that 6 others exist3 and whether the benefit was seen with this particular compound.
It’s important to note that there were no significant differences between the two groups in the number of patients with prespecified adverse events. Thus further adding to the well known safety of amino acid infusions
The lack of a diversified patient population in combination with having used only one type of amino acid formulary greatly limits this study’s generalizability. Although amino acid formularies are not expensive, the time, resources and staff needed in introducing them can be substantial. Hospitals should be cautious in deciding to put their efforts towards them when the data from this trial has actually shown that it works in a diversified patient population such as that which exists in the United States.
Author’s Conclusions:
Among adult patients undergoing cardiac surgery, infusion of amino acids reduced the occurrence of AKI.
Our Conclusion:
This multicenter randomized placebo-controlled trial helps add to the knowledge base that amino acid infusions in the context of renal hypoperfusion may exert protective effects and continue to be safe to administer. While the study did show the infusion of amino acids reduced the occurrence of AKI using a single widely accepted criteria, certain methodological flaws limit this study’s overall generalizability to a more diversified patient population. A future study comparing different amino acid formulations to placebo among a varied ethnic patient population receiving cardiac surgery with cardiopulmonary bypass is warranted before this intervention can be streamlined.
Clinical Bottom Line:
The use of amino acid infusions to reduce the occurrence of AKI in cardiac surgery patients receiving cardiopulmonary bypass appeared to be safe and effective for the prevention of AKI. 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. Most of the signal of benefit comes from a reduction in AKI stage 1. A more optimal end-goal would have been patient oriented outcomes such as the need for RRT, death and long term renal outcomes.
Post By:
Mark Ramzy, DO Emergency Medicine Attending and Cardiothoracic Intensivist Clinical Assistant Professor of Emergency Medicine Rutgers Health / RWJBH Community Medical Center, Toms River, NJ Twitter/X: @MRamzyDO
REFERENCES:
Landoni G. et al. Intravenous amino acid therapy for kidney protection in cardiac surgery a protocol for a multi-centre randomized blinded placebo controlled clinical trial. The PROTECTION trial. Contemp Clin Trials. Epub 2022 Aug 28. PMID: 36038001
Levi TM, et al. Comparison of the RIFLE, AKIN and KDIGO criteria to predict mortality in critically ill patients. Rev Bras Ter Intensiva. 2013 Oct. PMID: 24553510
Iacone R, et al. Macronutrients in Parenteral Nutrition: Amino Acids. Nutrients. 2020 Mar 14;. PMID: 32183395
Post Peer Reviewed By: Salim Rezaie, MD (Twitter/X: @Srrezaie)
