A Randomized Trial of Intravenous Amino Acids for Kidney Protection

Landoni G et al. NEJM 2024. DOI: 10.1056/NEJMoa2403769

Clinical Question

• In adult patients scheduled for cardiac surgery with cardiopulmonary bypass does infusion of a balanced solution of amino acids, commencing at the time of surgery, compared with balanced crystalloid alone (Ringer’s Lactate) reduce the incidence of acute kidney injury (AKI)?

Background

• Acute Kidney Injury following cardiac surgery is common and effects ~30% of patients and is thought to be related to changes in renal perfusion
• KDIGO (Kidney Disease: Improving Global Outcomes) defines AKI according to changes in creatinine and/or the presence of oliguria
  • Stage 1 AKI: an increase in the serum creatinine level by at least 26.5 μmol/L during a 48-hour period or a 50% increase from baseline during a 1-week period
  • Stage 2 AKI: a doubling of the baseline serum creatinine level within 1 week
  • Stage 3 AKI: a tripling of the baseline serum creatinine level or the initiation of dialysis, with either occurring within 1 week after the insult (e.g., cardiac surgery)
• Amino Acids, particularly glycine and arginine, have physiological effects on the kidneys:
  • Increased nephron blood flow by decreasing afferent arteriolar resistance
  • Decreased tubuloglomerular feedback activation
  • Increased cortical nitric oxide synthase activity
  • In animal studies, amino acid infusions increased renal perfusion, renal oxygenation, and GFR
• Pilot studies of amino acid infusion in humans following cardiac surgery have suggested potential benefit on renal markers and no safety concerns

Design

• Randomised multi-centre controlled trial with 1:1 concealed allocation to amino acid infusion or balanced crystalloid
• Treating physicians, patients and outcome assessors were blinded to the allocation as the 2 formulations appeared in identical bottles
• Stratification was by site, in variable permuted block sizes
• Written consent was obtained prior to the intervention
• The protocol was published prior to the completion of the study
• An independent data and safety monitoring committee reviewed the data and performed prespecified blinded interim analyses after the enrolment of 25%, 50%, and 75% of the planned number of participants.

Setting

• 3511 patients at 22 centres in three countries (Italy, Croatia, Singapore)
• The study ran from October 2019 to January 2024
• 4931 patients were screened for eligibility. Of these, 3652 provided informed consent (although some had exclusion criteria, had surgery cancelled etc) and 3512 were randomised (one patient subsequently withdrew consent)

Population

• Inclusion:
  • Patients >18 years of age who were scheduled to undergo elective cardiac surgery requiring cardiopulmonary bypass
  • Expected to stay in the intensive care unit (ICU) for at least one night
  • Eligible patients had to have a baseline serum creatinine measurement before surgery (within the last year)
• Exclusion:
  • Preoperative dialysis dependence or planned treatment with intermittent or continuous kidney-replacement therapy
  • Stage IV or greater chronic kidney disease, defined as an estimated glomerular filtration rate (eGFR<30 ml/minute/1.73 m² BSA)
  • Patients not expected to survive
  • Patients with renal transplant
• A sample size of 3500 patients would give the trial 90% power to detect a 20% lower risk of AKI in the amino acid infusion group
• Baseline characteristics well matched at baseline in regard to comorbidities, surgical procedure performed and intraoperative care.
  • Comparing amino acid vs control groups:
    • Median Age: 66 vs 67yrs
    • Female: 30 vs 30%
    • Median pre-op creatinine: 0.96 vs 0.94 mg/dl
    • Median LVEF: 59 vs 60%
    • Cardiac catheterisation < 48 hrs ago: 17.3 vs 18.9%
    • Diabetes: 17.6 vs 19.1 %
    • Pre-operative ARB or ACEi: 51.3 vs 50.5%
    • CABG: 34.8 vs 36.5%
    • Median duration CPB: 93 vs 94 minutes
    • Haemofiltration during CPB: 9.9 vs 9.2%
    • Intraoperative vasoactive/ inotropic drugs: 65.9 vs 63.1%

Intervention

• The amino acid group: continuous infusion of a balanced mixture of amino acids at a dose of 2g/kg/day (up to a maximum of 100 g/day) from the time of CVC insertion in the operating-room. The infusion ran for up to 72 hours, or until discharge from the ICU, initiation of kidney-replacement therapy, or death (whichever occurred first)
• The formulation was Isopuramin 10% (Baxter)
• 1759 were included in the intention-to-treat analysis
• The median duration of the infusion was 30 hours with a median dose of 126g of amino acids. The median infusion rate was 40ml/hr

Control

• The placebo group: continuous infusion of Ringer’s solution at the same rate as the intervention group such that fluid input was identical
• 1752 were included in the intention-to-treat analysis
• The median infusion rate was 40ml/hr

Management common to both groups

• 72.1% stopped the infusion before 72 hours due to ICU discharge, 22.6% completed the maximum of 72 hours of infusion, and 2.7% stopped the infusion early for other reasons (e.g. death, dialysis initiated)
• The pragmatic design allowed for usual postoperative cardiac surgery care
• Postoperative course in the ICU and in the hospital, major outcomes, adverse events, and protocol deviations were documented

Outcome

• Primary outcome: occurrence of AKI within the first week after surgery (defined as a KDIGO creatinine criteria for AKI stage 1 or greater):
  • 474 patients (26.9%) in the amino acid group and in 555 patients (31.7%) in the placebo group
    • RR 0.85 (95% CI 0.77 to 0.94; P=0.002)
    • NNT = 21
  • Stage 1 AKI: 430 (24.4%) vs 492 (28.1%), RR 0.87 (0.78 to 0.97)
  • Stage 2 AKI: 15 (0.9%) vs 11 (0.6%), RR 1.36 (0.63 to 2.95)
  • Stage 3 AKI: 29 (1.6%) vs 52 (3.0%), RR 0.56 (0.35 to 0.87)
• Secondary outcomes:
• Comparing amino acid infusion vs. placebo group
  • No significant difference in
    • Renal Replacement Therapy: 1.4% vs 1.9%, RR 0.73 (0.43-1.22)
    • ICU Length of Stay: 30 vs 34 hours
    • Hospital LOS: 7 vs 7 days
    • No difference in mortality at ICU discharge or day 30, 90 or 180
    • No difference in creatinine at day 30, 90 and 180.
• Subgroup Analysis: Prespecified subgroups
  • Age (≥75 years): Older patients receiving amino acids had less AKI than those receiving placebo: 39% vs 49%, RR 0.8 (0.67-0.95)
  • New York Heart Association class (I or II vs. III or IV): No difference
  • Baseline eGFR (≤60ml/min/1.73m2 BSA): No difference
• Adverse Outcomes: Prespecified adverse events included cardiogenic shock, events requiring ICU readmission, arrhythmia, need for reintubation, need for NIV, adverse neurologic outcome, myocardial infarction, wound infection, sepsis, septic shock, and death
  • There were no differences between groups in adverse outcomes

Authors’ Conclusions

• Continuous amino acid infusion resulted in a significantly lower occurrence of AKI than that with the crystalloid solution, without any effect on adverse events

Strengths

• Allocation concealment, blinding, intention-to-treat analysis, minimal loss to follow-up
• A large, well powered trial with excellent internal validity
• There is biological plausibility that amino acids could provide a protective role of the kidneys
• Cardiac surgery with cardiopulmonary bypass is common with more than 2 million patients worldwide/year
  • There is potential to impact a large global population by influencing renal outcomes in this population as it is known that AKI is associated with increased morbidity and mortality

Weaknesses

• The primary outcome is a serum biomarker, rather than a patient-centred outcome. The clinically meaningful outcomes that were measured, as secondary outcomes (e.g. need for renal replacement therapy, death) were similar between groups
• Most of the signal of benefit in this trial came from reduction in Stage 1 AKI – it is unclear if the amino acids just improve the numbers or if they truly protect the kidneys
• The observed rate of RRT is lower in the amino acid group (although not statistically significant) but this could reflect a lack of power because RRT is a relatively rare event. If this was translated to a larger population, this could be globally important
• An economic analysis would be helpful
• The supplementary material gives outcomes at Day 30, 90 and 180 for serum creatinine levels. There is no difference between groups, suggesting no benefit of amino acid infusion on long term renal function.

The Bottom Line

• This trial shows that amino acids reduce acute kidney injury following cardiac surgery with cardiopulmonary bypass
• However, most of the signal comes from a reduction in AKI Stage 1, and as this biomarker is not a clinically meaningful outcome, I will not change my practice at this stage
• If there were statistically significant reductions in the need for renal replacement therapy or long-term renal function, I would be more inclined to introduce this therapy to my practice

External Links

• article PROTECTION
• further reading Supplementary Material
• further reading Intravenous amino acid therapy for kidney function in critically ill patients: a randomized controlled trial. Doig

Metadata

Summary author: Celia Bradford @celiabradford
Summary date: July 3, 2024
Peer-review editor: George Walker

Picture by: Microsoft CoPilot