Amino acid infusion and renal protection in chronic kidney disease patients undergoing cardiac surgery: physiology meets clinical evidence

Confronting the burden of cardiac surgery-associated acute kidney injury (CSA-AKI)

AKI remains one of the most consequential complications following cardiac surgery with cardiopulmonary bypass (CPB). Its incidence ranges from 20–40% depending on population risk, and even small postoperative rises in serum creatinine translate into markedly higher morbidity, longer hospitalization, and increased mortality (1). The global epidemiology of CSA-AKI underscores a key reality: despite decades of optimization in perfusion, anesthesia, and postoperative care, no pharmacologic renoprotective therapy has achieved broad clinical adoption.

The multinational PROTECTION trial changed this landscape by demonstrating that intravenous amino acid infusion, initiated in the operating room and continued up to 72 hours postoperatively, resulted in a 5% absolute and 15% relative reduction in AKI in 3,511 unselected adult patients undergoing on-pump cardiac surgery (2). This was the first large, randomized evidence that a physiologic intervention—originally conceptualized around the concept of renal functional reserve (RFR)—could yield clinically meaningful renal protection.

But a key question remained unanswered: would such renoprotection extend to patients with chronic kidney disease (CKD), a population defined precisely by reduced nephron number, impaired autoregulation, and diminished RFR?

The secondary analysis by Baiardo Redaelli et al. (3) addresses this important clinical uncertainty. Using data from 812 patients with CKD enrolled in PROTECTION, the authors investigate whether impaired baseline renal function modifies the renoprotective effect of amino acid infusion. Their findings not only offer clinical reassurance but also challenge long-standing assumptions about how amino acids protect the kidneys. This Editorial Commentary situates those findings within the broader physiologic and mechanistic landscape and highlights important limitations and research priorities that now emerge.

Why the kidneys fail during cardiac surgery

The pathophysiology of CSA-AKI is multifactorial (4). Renal hypoperfusion, ischemia-reperfusion injury, inflammation, microvascular dysfunction, hemolysis, and renal medullary hypoxia all contribute to postoperative kidney injury. CPB amplifies these insults through non-pulsatile flow, hemodilution, cytokine release, and altered autoregulatory responses.

A consistent mechanistic theme is medullary hypoxia, which renders the kidney exquisitely sensitive to fluctuations in perfusion and oxygen delivery. Because conventional hemodynamic interventions often fail to restore or maintain adequate microvascular oxygenation, physiologic strategies that directly modulate renal perfusion or oxygen dynamics have become increasingly attractive (5). Intravenous amino acid infusion emerged from this search—not as a traditional drug, but as a physiologic stimulus capable of altering renal hemodynamics and oxygenation.

The classical mechanistic narrative: RFR

The historical rationale for using amino acids to prevent AKI derives from the concept of RFR—the capacity of the kidney to increase glomerular filtration rate (GFR) in response to physiologic stimuli such as dietary protein or amino acid infusion (6). In healthy individuals, this response is mediated by afferent arteriolar vasodilation and increased intraglomerular pressure, facilitated by nitric oxide, prostaglandins, and glucagon (7). When amino acids are infused, GFR rises, renal blood flow (RBF) increases, and urine output often improves. This hyperfiltration response has traditionally been interpreted as a marker of renal “health”, reflecting the capacity of nephrons to adjust to metabolic demands.

RFR is diminished in various common conditions—including aging, diabetes, CKD, hypertension, and prior AKI. Against this backdrop, the concern emerged that amino acid infusion might be less effective in patients with CKD, having reduced nephron number and blunted hyperfiltration capacity. The PROTECTION secondary analysis challenges this expectation.

The CKD subgroup findings: a paradox requiring explanation

The key finding from the CKD subgroup analysis of PROTECTION is that amino acid infusion reduced AKI in CKD patients to a degree comparable to that observed in the overall trial population. The relative reduction in AKI risk was similar, and the absolute reduction—given the higher baseline risk—translated into a number-needed-to-treat (NNT) of approximately 14, substantially more favorable than in the general cohort (NNT 21). Notably, the benefit was observed across CKD strata, with no significant interaction between baseline estimated GFR (eGFR) and treatment effect.

These results create a mechanistic paradox. If amino acids protect primarily by recruiting RFR, and if CKD reduces RFR, then the protective effect should diminish with declining kidney function. Instead, the effect appears preserved. This suggests that amino acid therapy operates through mechanisms that remain functional in CKD and/or are independent of RFR and nephron number. This paradox compels a reevaluation of the classical mechanistic model, shifting attention from GFR augmentation alone toward the broader hemodynamic and oxygenation effects of amino acid infusion.

Interpreting the mechanisms: beyond hyperfiltration

Although amino acid infusion reliably increases GFR, equating hyperfiltration with renoprotection risks substantial oversimplification. Hyperfiltration alone cannot account for the reduction in severe AKI observed in PROTECTION, nor does it explain why patients with CKD—whose hyperfiltration capacity is blunted—experienced a similar magnitude of benefit.

Importantly, hyperfiltration is not inherently protective. In the perioperative environment—marked by fluctuating blood pressure and impaired autoregulation—afferent arteriolar vasodilation may even increase vulnerability rather than protection. When systemic pressure falls, a vasodilated afferent arteriole can transmit hypotensive insults more directly to the glomerular and peritubular circulation (5,8). Such transmitted pressure drops disproportionately threaten the renal medulla, where oxygen tension is already precarious. Illustratively, vasopressin has been shown to increase GFR while simultaneously worsening renal oxygenation in post-cardiac surgery patients (9). Thus, an increase in GFR per se should not be interpreted as evidence of kidney protection.

The classical hyperfiltration response is, however, inseparable from a broader hemodynamic change. Experimental models consistently show that amino acids induce substantial afferent vasodilation, producing a 30–50% increase in total RBF, a parallel rise in GFR, and significant improvements in both cortical and medullary oxygenation (10,11). The central physiologic insight is that renal oxygenation improves not because filtration increases, but because amino acids augment RBF sufficiently to raise oxygen delivery more than oxygen consumption. This hemodynamic signature—rather than hyperfiltration per se—offers a more plausible mechanistic explanation for renal protection.

In addition to effects on RBF and oxygen delivery, amino acids may also modulate renal microvascular tone and reduce susceptibility to ischemic injury through metabolic signaling pathways that are less dependent on nephron number (12,13). These include changes in endothelial nitric oxide availability, prostaglandin-mediated vasoregulation, hormonal signaling, and mitochondrial energetics.

Given these nuances, the postoperative rise in creatinine-based GFR observed with amino acid infusion should not be overinterpreted as structural nephron protection. Rather, the therapy appears to exert a beneficial physiologic profile: increased total RBF, enhanced medullary oxygenation, and greater resilience to hypoperfusion during periods of perioperative instability. These hemodynamic and oxygenation effects—still partly recruitable even in CKD—provide a coherent explanation for the preserved treatment benefit despite reduced renal reserve.

Limitations of the secondary analysis

Although the secondary analysis of the PROTECTION trial offers compelling insights, several limitations warrant careful consideration. First, as in many perioperative AKI studies, urine output data were not collected or incorporated into AKI staging. This omission is significant, because amino acid infusion often increases urine output. Without urine output data, distinguishing between functional and structural changes in renal function becomes difficult. Some cases classified as AKI on the basis of creatinine alone may not reflect the full clinical picture.

Second, the study did not include biomarkers of tubular injury such as NGAL, KIM-1, or TIMP-2·IGFBP7 (14). These biomarkers could have clarified whether amino acids mitigate tubular stress or injury, or whether the observed benefits reflect predominantly hemodynamic changes. Future studies incorporating biomarker panels would greatly enhance mechanistic interpretation.

Third, postoperative increases in eGFR should not be overinterpreted. Hyperfiltration is not necessarily protective in CKD, and whether amino acids exert any long-term influence on kidney function remains unknown. The absence of data on CKD progression represents a major gap, particularly for a population already at high risk of accelerated decline.

Fourth, as a secondary analysis, the study was not powered specifically for CKD subgroups, and residual confounding—although limited by randomization—cannot be entirely excluded. Nevertheless, the consistency of effect across eGFR categories and sensitivity analyses lends robustness to the overall conclusion.

Clinical significance: should amino acids be used in CKD patients?

Given the paucity of effective renoprotective therapies in cardiac surgery, the implications of these findings are substantial. CKD patients represent a disproportionately vulnerable group, with higher rates of AKI, greater progression to severe AKI, and elevated postoperative mortality. The observation that amino acid infusion reduces AKI in this population—and with an absolute benefit greater than in the general cohort—provides a compelling rationale for clinical adoption.

Importantly, the therapy is simple, inexpensive, widely available, and carries a favorable safety profile. Unlike many pharmacologic agents tested for AKI prevention, amino acids have demonstrated a consistent signal of benefit without major adverse effects.

Still, clinicians should remain cautious. The mechanistic underpinnings remain incompletely understood, and data on long-term kidney outcomes are lacking. Amino acid infusion should be embraced as a promising perioperative tool—but not yet viewed as a definitive solution.

Future directions

Several lines of inquiry emerge from this work. Foremost is the need for mechanistic studies capable of distinguishing hemodynamic improvement from structural protection. Trials incorporating biomarker profiling, imaging of renal oxygenation, and detailed hemodynamic monitoring would allow clearer delineation of the relevant pathways. Additionally, studies examining CKD progression after amino acid therapy are urgently needed, particularly in patients with moderate CKD.

Another area of interest is the potential refinement of dosing strategies. CKD patients may require tailored amino acid infusion rates to balance benefits with metabolic considerations. Finally, exploration of whether specific CKD etiologies or phenotypes derive different levels of benefit could guide targeted implementation.

Conclusions

The secondary analysis of the PROTECTION trial provides compelling evidence that intravenous amino acid infusion reduces AKI in patients with CKD undergoing cardiac surgery with CPB. These findings challenge the long-standing assumption that diminished RFR limits therapeutic response and suggest that mechanisms beyond hyperfiltration—potentially related to perfusion, oxygenation, and microvascular signaling—play important roles. Although important limitations remain, the consistency of effect and favorable risk profile position amino acid infusion as a promising addition to perioperative kidney protection strategies in CKD. As the field continues to refine mechanistic understanding and address knowledge gaps, this therapy offers meaningful progress in a domain long characterized by disappointment.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article has undergone external peer review.

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2543/prf

Funding: The article was supported by the funding from Research Foundation - Flanders (FWO) (No. 1102026N).

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2543/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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