Acute kidney injury (AKI) is one of the most frequent complications occurring in the immediate postoperative period of cardiac surgery. Even mild AKI is associated with increased morbidity and mortality. Severe cases often require renal replacement therapy, leading to higher costs, reduced quality of life, and increased long-term mortality.
Animal studies have shown that protein loading may enhance glomerular filtration, introducing the concept of renal functional reserve, which represents the kidneys’ ability to compensate or increase functionality in states of high metabolic demand or intrinsic kidney disease. It has been suggested that this renal functional reserve can be enhanced by protein loading, potentially providing a nephroprotective effect.
The PROTECTION study aimed to confirm or refute the hypothesis that intravenous amino acid therapy decreases the incidence of postoperative AKI compared to a placebo. This international, double-blind, randomized clinical trial included adult patients undergoing elective cardiac surgery with cardiopulmonary bypass (CPB). The amino acid infusion began at the time of surgery and continued for up to 72 hours or until ICU discharge, initiation of renal replacement therapy, or death (whichever occurred first). The patient’s attending physician managed all other aspects of perioperative care. AKI was evaluated based on serum creatinine levels during the first 7 days post-surgery.
The primary outcome was the incidence of AKI within the first postoperative week, defined by KDIGO criteria based on serum creatinine levels. Secondary outcomes included AKI severity per KDIGO criteria, use and duration of renal replacement therapy during hospital stay, ICU and hospital length of stay, mechanical ventilation duration, and all-cause mortality from ICU discharge, hospital discharge, and at 30, 90, and 180 days post-randomization.
A total of 3,511 patients were analyzed. Regarding the primary outcome, a higher incidence of AKI was observed in the placebo group (555 vs. 474 patients; RR = 0.85; 95% CI = 0.77-0.94; p = .002) at hospital discharge. Most patients experienced mild AKI (KDIGO grade I), but significant differences were also observed in severe AKI cases (grade III) between the two groups (29 in the intervention group vs. 52 in the placebo group; RR = 0.56; 95% CI = 0.35-0.87). No statistically significant differences were found for the secondary outcomes, adverse events, or drug reactions.
The authors conclude that amino acid infusion appears to be safe and effective in preventing AKI in cardiac surgery patients. The low incidence of severe AKI (KDIGO grade III) in the amino acid group suggests not only a reduction in AKI incidence but also its severity.
COMMENTARY:
As previously mentioned, AKI is a common complication during the postoperative period of cardiac surgery, associated with high morbidity and mortality, increased costs, prolonged hospital stays, and reduced quality of life.
Regarding the clinical management of postoperative AKI, as explored in this article, I would like to briefly comment on the key aspects of diagnosis and treatment of postoperative AKI.
The KDIGO classification based on diuresis and serum creatinine levels (a substance directly linked to glomerular filtration without tubular secretion or reabsorption) was used for diagnostic purposes. This classification divides AKI into:
KDIGO Classification of Acute Kidney Injury
| Stage | Serum Creatinine (mg/dL) | Urine Output (mL/kg/h) |
| 0 | Increase < 0.3 mg/dL from baseline | ≥ 0.5 mL/kg/h |
| I | Increase > 0.3 mg/dL within 48 hours or 2-2.9 times baseline over 7 days | < 0.5 mL/kg/h for 6-12 hours |
| II | Increase ≥ 2-2.9 times baseline | < 0.5 mL/kg/h for >12 hours |
| III | Increase ≥ 3 times baseline; creatinine ≥ 2.5 mg/dL; renal replacement therapy required | < 0.3 mL/kg/h for 24 hours or anuria > 24 hours |
The main limitation of this scale is that serum creatinine reflects renal function rather than injury. In cases where a drop in glomerular filtration rate is due to hemodynamic disturbances without significant tubular cell damage, the risk of poor outcomes is lower.
To identify patients with renal injury, biomarkers like cystatin C (a sensitive renal function marker) and lipocalin 2 (a marker of injury and a predictor of renal damage in patients without chronic kidney disease) are proposed.
In this study, AKI was diagnosed by serum creatinine levels per KDIGO classification. Therefore, we cannot ascertain whether the amino acid infusion provides functional benefits or actual renal tubular protection. The reduction in grade III AKI suggests a genuine therapeutic effect, although there were no significant secondary outcome differences in functional status, quality of life, or survival.
Currently, effective therapeutic strategies for AKI treatment are lacking, so management focuses on preventive measures.
Intraoperative measures to prevent AKI include avoiding hypotension, maintaining a mean arterial pressure above 65 mmHg, and using propofol, which may have protective effects. Surgical aspects, such as minimizing CPB time, are also considered to reduce AKI risk.
Perioperative preventive strategies include:
- Volume resuscitation: Ensure adequate volume replacement with crystalloids, avoiding colloids like gelatin or albumin due to their association with increased AKI incidence.
- Blood pressure maintenance: Noradrenaline is the vasopressor of choice, with vasopressin or methylene blue as alternatives if hypotension persists.
- Avoidance of nephrotoxins: Discontinue nephrotoxic drugs such as ACE inhibitors, ARBs, or diuretics before surgery.
- Hyperglycemia avoidance: Strict glucose control is recommended.
- Diuretics: No role in AKI prevention or treatment.
These measures are recommended to reduce postoperative AKI incidence in surgical patients. However, in this study, perioperative management was left to the discretion of the attending physician and was not protocolized. Differences in management across multiple centers could have influenced results.
In conclusion, the findings of this study are promising, suggesting that amino acid infusion may serve as a preventive strategy against postoperative AKI with a low risk of complications. Further studies are needed to precisely evaluate renal injury and ensure protocolized perioperative management per current recommendations.
REFERENCES:
Landoni G, Monaco F, Ti LK, Baiardo Redaelli M, Bradic N, Comis M, et al.; PROTECTION Study Group. A Randomized Trial of Intravenous Amino Acids for Kidney Protection. N Engl J Med. 2024 Aug 22;391(8):687-698. doi: 10.1056/NEJMoa2403769.
Ostermann M, Shaw AD. Amino Acid Infusion to Protect Kidney Function after Cardiac Surgery. N Engl J Med. 2024 Aug 22;391(8):759-760. doi: 10.1056/NEJMe2408632.
Pérez Vela JL, Jiménez Rivera JJ, Llanos Jorge C, editores. Cirugía Cardiovascular. Abordaje Integral. Elsevier; 2020.
Joannidis M, Druml W, Forni LG, Groeneveld ABJ, Honore PM, Hoste E, et al. Prevention of acute kidney injury and protection of renal function in the intensive care unit: update 2017 : Expert opinion of the Working Group on Prevention, AKI section, European Society of Intensive Care Medicine. Intensive Care Med. 2017 Jun;43(6):730-749. doi: 10.1007/s00134-017-4832-y.
Meersch M, Schmidt C, Hoffmeier A, Van Aken H, Wempe C, Gerss J, et al. Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: the PrevAKI randomized controlled trial. Intensive Care Med. 2017 Nov;43(11):1551-1561. doi: 10.1007/s00134-016-4670-3. Epub 2017 Jan 21. Erratum in: Intensive Care Med. 2017 Nov;43(11):1749. doi: 10.1007/s00134-017-4735-y.
