Cardiac surgery, particularly those requiring cardiopulmonary bypass (CPB), remains one of the leading causes of hospital-acquired acute kidney injury (AKI), a complication that significantly increases morbidity and mortality. Clinicians have sought pharmacologic strategies to protect the kidneys during and after surgery for years. A new secondary analysis of the PROTECTION trial sheds light on a promising approach: intravenous amino acid infusions.

This large-scale, multinational, randomized controlled trial demonstrates that administering amino acid infusions to patients with chronic kidney disease (CKD) undergoing cardiac surgery significantly reduces the incidence of AKI, even in a population known to have diminished renal functional reserve

Background

AKI occurs in a substantial proportion of patients undergoing cardiac surgery, particularly those involving CPB. The pathophysiology is multifactorial; hemodynamic instability, ischemia-reperfusion injury, inflammation, and exposure to nephrotoxic agents all contribute to renal damage. CKD patients, with preexisting impairments in renal function, are at an even higher risk for AKI, which may lead to long-term dialysis dependence or death.

Renal functional reserve (RFR)—the kidneys’ capacity to increase glomerular filtration in response to stress—is central to this discussion. In CKD patients, RFR is reduced, theoretically limiting the protective effect of interventions like amino acid therapy that work through RFR recruitment.

The PROTECTION trial and secondary analysis

The PROTECTION trial (NCT03709264) was a multinational, randomized, double-blind, placebo-controlled study involving 3,511 adult patients undergoing elective on-pump cardiac surgery. Patients received either:

• A continuous infusion of intravenous amino acids (isopuramin 10%, 2g/kg/day, max 100g/day)
• Or a placebo (Ringer’s solution)
  

The infusion began at operating room admission and continued for up to 72 hours, ICU discharge, or initiation of renal replacement therapy.

This secondary analysis focused specifically on the subgroup of 812 patients with preoperative CKD, defined as an estimated glomerular filtration rate (eGFR) below 60 ml/min/1.73 m². The primary outcome was the incidence of AKI according to KDIGO criteria.

Key findings

1. Significant reduction in AKI

Among CKD patients, the amino acid group had a 43.1% incidence of postoperative AKI, compared to 50.3% in the placebo group. This corresponds to:

• Relative risk reduction: 14%
• Absolute risk reduction: 7%
• Number needed to treat (NNT): 14
  

In comparison, patients without CKD saw a smaller benefit with an NNT of 26, emphasizing that CKD patients derived greater absolute benefit from the same intervention.

2. Reduction in severe AKI

Amino acid infusion more than halved the incidence of stage 3 AKI in CKD patients:

• 2.7% in the amino acid group vs. 5.6% in the placebo group
• Relative risk: 0.48 (P = 0.038)
  

This finding is especially meaningful as stage 3 AKI is closely linked to the need for dialysis and poor long-term outcomes.

3. Improved renal function recovery

By postoperative day 3, CKD patients who received amino acid infusions showed a significantly greater increase in eGFR from baseline:

• Median increase: 12.7% in the amino acid group vs. 6.5% in placebo (P = 0.002)
• Mean increase: 12.7% vs. 6.1% (P = 0.005)
  

This improvement was consistent across all CKD subgroups (eGFR 30–39, 40–49, 50–59 ml/min/1.73 m²), suggesting a robust effect.

4. Trends in renal replacement therapy and mortality

While not statistically significant, trends favored the amino acid group:

• Renal replacement therapy use: 2.2% (amino acids) vs. 3.7% (placebo)
• 30-day mortality: 5.2% in both groups
• 180-day mortality: Slightly higher in the amino acid group, but not statistically significant
  

These findings suggest that amino acids reduce AKI, but their effect on mortality remains unclear.

Clinical implications

This analysis marks a turning point in perioperative renal protection for cardiac surgery patients, especially those with preexisting CKD.

Key takeaways:

• Amino acid infusion should be considered for all CKD patients undergoing cardiac surgery with CPB.
• The intervention is simple, low-cost, and biologically plausible, acting through both RFR recruitment and improved renal perfusion.
• With an NNT of 14, it is a highly efficient strategy, especially in high-risk populations.
  

The findings argue for integrating amino acid therapy into perioperative protocols, particularly for patients with compromised renal function.

Physiologic rationale

The proposed mechanism centers on the recruitment of renal functional reserve, leading to:

• Increased renal blood flow
• Enhanced glomerular filtration
• Improved oxygen delivery to cortical and medullary tissues
  

These effects may prevent injury and promote early renal recovery postoperatively. Importantly, the benefit persists even in CKD patients, suggesting that other mechanisms, such as improved endothelial function or anti-inflammatory effects, may also play a role.

Limitations and future directions

Strengths:

1. Large, multicenter RCT data set.
2. Predefined secondary analysis.
3. Clinically meaningful outcomes.
4. Robustness confirmed by multiple sensitivity analyses.
   

Limitations:

1. As a secondary analysis, the study was not powered specifically for the CKD subgroup.
2. Urine output was not included in AKI diagnosis due to catheter removal.
3. Long-term renal outcomes were not assessed.
4. Biomarkers beyond creatinine were not used to evaluate renal injury or function.
   

These gaps highlight the need for dedicated trials assessing:

1. Long-term renal function post-intervention.
2. Subclinical markers of renal injury.
3. Cost-effectiveness of large-scale implementation.
   

Conclusion

This landmark analysis reveals that intravenous amino acid infusion significantly protects against AKI in cardiac surgery patients with CKD. With meaningful reductions in both overall and severe AKI rates, improved eGFR recovery, and a low number needed to treat, this strategy holds promise as a standard component of perioperative care for high-risk patients. As clinical guidelines evolve to incorporate these findings, the next step is ensuring consistent implementation and extending research into other surgical populations at risk of AKI. Until then, this simple infusion protocol offers an important tool to anesthesiologists, surgeons, and intensivists working to safeguard renal function in vulnerable cardiac surgery patients.

For more information, refer to the full article in Anesthesiology.

Baiardo Redaelli M, Monaco F, Bradic N, Scandroglio AM, Ti LK, Belletti A, Viscido C, Licheri M, Guarracino F, Pruna A, Pisano A, Pontillo D, Federici F, Losiggio R, Serena G, Tomasi E, Silvetti S, Ranucci M, Brazzi L, Cortegiani A, Landoni G, Mastroroberto P, Paternoster G, Gaudino MFL, Zangrillo A, Bellomo R; for the PROTECTION Study Group Collaborators. Amino Acid Infusion for Kidney Protection in Cardiac Surgery Patients with Chronic Kidney Disease: A Secondary Analysis of the PROTECTION Trial. Anesthesiology. 2025 May 1;142(5):818-828.

Read more about kidney injury in our Anesthesiology Manual: Best Practices & Case Management.