Amino acids for renal protection: time to implement in clinical practice

Abstract

Acute kidney injury (AKI) is a common complication observed in both surgical and critical care settings. The PROTECTION trial, published in the New England Journal of Medicine, showed that short-term low-dose infusions of amino acids (AA) reduced the rate of both any-stage and severe AKI in more than 3500 cardiac surgery patients. Its publication resulted in the inclusion of AA in the European guidelines for the management of adult cardiac surgery with cardiopulmonary bypass and changes in clinical practice worldwide. This rapid dissemination has raised practical questions regarding patient selection, formulation choice, dosages, and duration of infusion. In this narrative review, we used the “Wh-questions” framework to provide a clear and structured overview on perioperative AA administration. We outline the historical background of AA-mediated renal protection, the pathophysiological context, and the available AA formulations most commonly used in clinical studies. In addition to the conclusive evidence in cardiac surgery, data supporting potential benefits in other high-risk populations, including urological surgery patients and those receiving temporary mechanical circulatory support, are growing. Importantly, recent insights suggest that clinicians must not exceed a 48-hour infusion. Finally, a reduction in hospitalization costs associated with AA infusions has been demonstrated by a recent health economic analysis. Overall, AA infusions represent a simple, safe, and inexpensive intervention that is effective at reducing AKI. These data further support their immediate adoption in routine clinical practice.

Introduction

The PROTECTION randomized trial, recently published in the New England Journal of Medicine, demonstrated that intravenous amino acids (AA) infusions significantly reduced the rate of acute kidney injury (AKI) in cardiac surgery patients [1]. This landmark study marked a radical change in perioperative medicine by providing, for the first time in medical history, robust evidence of a pharmacological treatment capable of mitigating AKI. Soon after its publication in August 2024, AA infusions for renal protection were included in the European guidelines as the only drug considered for the prevention of AKI in the management of adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) [2].

AKI remains one of the most common and prognostically relevant complications in hospitalized patients [3]. A recent meta-analysis of matched studies showed that patients with AKI are at high risk of developing chronic kidney disease (CKD), requiring dialysis, and death [4]. Prior to the publication of the PROTECTION trial, the preventive and therapeutic landscape of AKI management was limited to the Kidney disease: improving global outcomes (KDIGO) bundle [5]. Short-term low-dose AA infusions have a strong pathophysiological rationale in both preclinical and clinical settings [6]. Indeed, AA recruit renal functional reserve and improve renal hemodynamics, ultimately delivering higher levels of cortical and medullary oxygenation [7].

Following the PROTECTION trial, the concept of AA-mediated renal protection gained remarkable international attention. A growing number of centers worldwide are discussing adoption or formally implementing AA infusion protocols in clinical practice. Furthermore, several secondary analyses have confirmed the magnitude and direction of the beneficial effects of AA on kidney function in patients at a high risk of developing AKI [8–10]. The rapid dissemination and clinical uptake of the results revealed potential heterogeneity in practical and organizational implementation; therefore, clarification is needed to best interpret these highly impactful findings.

As investigators of the PROTECTION trial and several related secondary analyses, in this review we synthesize and discuss all the evidence that has emerged on this topic over the last two years, aiming to support physicians in navigating this evolving field (Fig. 1). To provide a clear and structured overview, the available data are organized using the “Wh-questions” framework (when, why, what, where, how, and how much). This conceptual approach allows for the integration of historical development, physiological rationale, intervention characteristics, clinical settings, practical implementation, and economic impact, translating recent evidence into an accessible and actionable synthesis for clinical practice (Table 1).

Fig. 1.

Evidence for and implementation of amino acids for renal protection. AKI: acute kidney injury, ICU: intensive care unit, RCT: randomized controlled trial, tMCS: temporary mechanical circulatory support.

Table 1.

Key Points on Amino Acids Infusions for Renal Protection using the Wh-questions Framework

Question	Key evidence	Clinical implication
WHEN	Evidence spans more than five decades, culminating in the large PROTECTION randomized trial	Intravenous amino acids reduce AKI in cardiac surgery
WHO	AKI frequently occurs across surgical and critical care populations	Preventive amino acids infusions should not be restricted to selected high-risk groups
WHY	Amino acids recruit renal functional reserve, increasing renal blood flow and glomerular filtration rate	Improved renal oxygen delivery provides biological plausibility for AKI prevention
WHICH	Multiple intravenous amino acids solutions are available worldwide	Evidence supports a class effect rather than the superiority of a specific formulation
WHERE	Conclusive evidence exists in cardiac surgery, with emerging data in other high-risk settings	Amino acids infusions may be broadly implemented in perioperative and critical care practice
HOW	Clinical studies consistently show the efficacy of short-term low-dose amino acids infusions	Start infusions early and for ≤ 48 h; peripheral venous catheters may be employed
HOW MUCH	A health economic analysis shows lower hospitalization costs	Amino acids represent a cost-saving preventive strategy

AKI: acute kidney injury.

WHEN did the evidence on AA infusions for renal protection emerge?

The first randomized trial on this topic was published more than 50 years ago. In 1973, Abel et al. [11] reported the efficacy of “renal failure fluid” as a treatment strategy for AKI. Patients with AKI were randomized to receive either a 1.3% AA solution with glucose or a hypertonic glucose solution alone. The intervention significantly increased survival from renal failure (P = 0.02) [11]. Despite these impressive findings, this topic was largely overlooked for decades.

In 2007, another small randomized trial involving patients with nonoliguric AKI evaluated the effects of different doses of intravenous AA infusions on diuresis. The authors found that a higher AA dose preserved diuresis, improved creatinine clearance, resulted in a less positive fluid balance, and reduced diuretic requirements [12].

Eight years later, a large randomized trial conducted in the intensive care unit (ICU) evaluated the effect of 100 g/day of AA on renal outcomes and found an increased estimated glomerular filtration rate (eGFR) and urinary output compared to the control group [13]. A post-hoc analysis of the same trial that focused on patients with normal renal function at baseline showed reduced mortality at hospital discharge and 90 days after randomization in patients receiving AA [14].

Evidence in various surgical settings has recently increased. Notably, Pu et al. [15] conducted a pilot trial in patients undergoing cardiac surgery, consistently showing beneficial renal effects. Indeed, AA reduced the duration of AKI and increased the mean urinary output per patient per day [15].

Several other pilot studies have uniformly supported the use of AA infusions for renal protection in surgical and critically ill patients; however, none have provided Level I evidence. This body of data underscored the need for a large, international, double-blind, placebo-controlled trial to provide definitive conclusions on this topic [16]. The PROTECTION trial randomized 3511 patients undergoing cardiac surgery with CPB at 22 centers in three countries. Patients received up to 100 g/day of AA infusions or an equal volume of placebo for a median duration of approximately 30 h. Patients in the AA group had a significantly lower incidence of any-stage AKI compared to the placebo group (474/1759 [27%] in the AA group vs. 555/1752 [32%] in the placebo group; relative risk [RR] = 0.85, 95% CI [0.77–0.94], P = 0.002), with a number needed to treat (NNT) of 21. Among secondary outcomes, the investigators found a significant reduction in Stage 3 AKI (29/1759 [1.6%] vs. 52/1752 [3.0%]; RR = 0.56, 95% CI [0.35–0.87]), with no difference in safety outcomes [1]. The need for renal replacement therapy (RRT) was 1.4% and 1.9% in patients in the AA and control groups, respectively.

After a meta-analysis confirmed these findings [17], they were included in the latest guidelines on the management of adult patients undergoing cardiac surgery with CPB [2] and are now informing clinical practice across several centers worldwide, as AA infusions represent the only pharmacological strategy with proven efficacy in protecting renal function in patients at risk of AKI.

WHO are the patients at risk of AKI who may benefit from AA?

AKI is one of the most frequent complications in both perioperative and critical care [18]. Due to its complex and multifactorial pathophysiology, the incidence of AKI depends on the specific settings considered.

Among more than 160 000 surgical hospitalizations in the United States, the overall postoperative rate of AKI was 11.8% [19]. In cardiac surgery, CPB results in reduced renal blood flow and renal medullary hypoxia [20], with reported incidences of up to 40% [21]. The rate of AKI is 15% in major abdominal surgery [22], followed by orthopedic and urological surgery.

In the ICU setting, recent evidence consistently indicates that one in two patients develop AKI, with an absolute risk of more than 15% for the most severe form (KDIGO Stage 3) [23]. Notably, 10% of patients with AKI consequently further progress to acute kidney disease, defined as persistent renal dysfunction lasting up to 90 days [23].

Importantly, even in subclinical cases, AKI can have both short- and long-term consequences [4]. These include accelerated progression to CKD, augmented length of hospital stay, increased need for dialysis, and reduced long-term survival [24]. Thus, AKI should not be interpreted as a self-limiting complication but rather as a clinically relevant event with important implications for patient outcomes and healthcare costs.

Despite its clinical relevance, predicting AKI remains a major challenge in modern medicine. Over the last few decades, several risk scores and predictive models have been described theoretically; however, their real-world performance remains limited [25]. In hospitalized patients, AKI occurrence is often determined by both baseline conditions and acute events. Therefore, a considerable proportion of AKI cases occur among individuals assessed as low risk using predictor tools. This reinforces the urgent need for a simple, widely applicable, and inexpensive preventive strategy.

WHY do AA exert renal protective effects?

Under specific stimuli and conditions, the kidneys have the physiological capability to improve their baseline function by increasing the GFR [26]. The difference between the stimulated GFR and baseline value is known as renal functional reserve, and was first described in the 1980s [27].

The biological plausibility of AA-mediated renal effects relies on a combination of glomerular, tubular, endocrine, and paracrine factors [7]. Sodium and AA are co-transported through the proximal tubule. In the case of AA load, the fluid entering the macula densa has a lower salt concentration, which contributes to a decrease in the activation of tubuloglomerular feedback and afferent arteriolar resistance [28]. This vasodilatory pathway is further enhanced by mediators, such as nitric oxide [29], and prostaglandins [30]. Additionally, AA promote the activation of renal dopamine D3 receptors, as well as systemic hormonal responses involving glucagon and vasopressin [6,31].

As a result, an AA or protein load of 1–2 g/kg body weight increases the GFR by approximately 30%, which is also associated with an increase in renal blood flow [32,33]. These effects equally involve the cortical and medullary regions of the kidney, which receive an oxygen delivery increase of > 20% [34]. Notably, hemodynamic optimization alone does not achieve these results [35].

WHICH AA formulations are currently available for clinical use?

Glycine and arginine appear to play key roles in this process. In the proximal tubule, glycine is a co-agonist of the N-methyl-D-aspartate receptor, directly contributing to the vasodilation previously described [36]. In contrast, arginine is a substrate for nitric oxide synthase, further enhancing its action. Nonetheless, the exact composition of the AA responsible for renal protection is unknown and the ideal formulation remains speculative.

Clinical studies have used various AA solutions for this purpose. In the PROTECTION trial [1], the intervention was represented by Isopuramin 10% (Baxter), whereas in the largest ICU trial [13] and a recent before-after study conducted on urologic surgery [37], Synthamin 10% (Baxter) was used. The main differences consist, for example, in the fact that Isopuramin 10% contains 11.6 g/L of valine and 6.4 g/L of glycine, while Synthamin 10% contains 5.8 g/L and 11.3 g/L of valine and glycine, respectively. However, both AA solutions were found to improve renal outcomes with no detectable side effects. In addition, some trials performed in Japan used Amiparem 10% (Otsuka) [38,39], while other AA solutions that have been investigated include Aminoven 10% (Fresenius) [40], Travasol 10% (Baxter) [41], and Vamin (Fresenius) [42].

Dozens of AA solutions are currently available worldwide, with marked differences among countries in terms of costs and the preparations available (Table 2). These products often differ in composition, concentration, and relative AA proportions. Currently, no comparative evidence identifying the ideal solution for renal protection is available. Thus, based on recent high-quality literature, we suggest an easy algorithm (Fig. 2) be consulted by each institution interested in implementing AA in clinical practice.

Table 2.

Common Intravenous Amino Acids Solutions used Worldwide (in alphabetic order)

Drug name	Pharmaceutical company	L-Arginine (g/L)	Glycine (g/L)	L-Isoleucine (g/L)	L-Leucine (g/L)	L-Valine (g/L)
Aminosyn II 10%	ICU Medical	10.2	5.0	6.6	10.0	5.0
Aminosyn II 15%	ICU Medical	15.3	7.5	9.9	15.0	7.5
Aminosyn-PF 7%	ICU Medical	8.6	2.7	5.3	8.3	4.5
Aminosyn-PF 10%	ICU Medical	12.3	3.9	7.6	12.0	6.7
Aminoven 5%	Fresenius	6.0	5.5	2.5	3.7	3.1
Aminoven 10%	Fresenius	12.0	11.0	5.0	7.4	6.2
Aminoven 15%	Fresenius	20.0	18.5	5.2	8.9	5.5
Amiparem 10%	Otsuka	10.5	5.9	8.0	14.0	8.0
Amiped 10%/Aminoplasmal Paed 10%	B. Braun	9.1	2.0	5.1	7.6	6.1
Amixal 10%/Aminoplasmal	B. Braun	11.5	12.0	5.0	8.9	6.2
Branched-chain amino acid solution 4%	Galenica Senese	Absent	Absent	12.5	15.5	12.0
Branched-chain amino acid solution 4%	Monico	Absent	Absent	12.9	15.7	12.0
Clinisol 15%	Baxter	14.7	10.4	7.5	10.4	9.6
Compound Amino Acid Injection (18AA-II)	Guangdong Otsuka Pharmaceutica	7.9	10.7	5.6	12.5	Absent
Dekamin 8%	Monico	8.7	12.8	3.7	5.9	4.2
Essential amino acids	Bioindustria L.I.M.	Absent	Absent	7.0	7.0	9.0
Essential amino acids	Galenica Senese	4.7	3.4	5.5	11.8	9.7
Essential amino acids 5.3 g/100 mL	Galenica Senese	Absent	Absent	5.6	8.8	6.4
Freamine III 8.5%	Baxter	8.1	Absent	5.9	7.7	5.6
Glamin/Glavamin	Fresenius	11.3	10.3	5.6	7.9	7.3
Inframin 5.3%	Fresenius	Absent	Absent	0.6	0.9	0.6
Isopuramin 3%	Baxter	3.3	1.8	2.3	3.0	3.3
Isopuramin 7%	Baxter	8.2	4.5	5.6	7.4	8.1
Isopuramin 10%a	Baxter	11.7	6.4	8.0	10.6	11.6
Isoram 4%	Baxter	3.2	Absent	6.0	15.0	18.2
Isoren 5.4%	Baxter	Absent	Absent	7.0	7.0	9.0
Isoselect 8%	Baxter	7.8	9.5	7.1	11.84	10.7
Pf-Hiperalamine 10%	Polifarma	9.5	14.0	6.9	9.1	6.6
Plenamine 15%	B. Braun	14.7	10.4	7.4	10.4	9.6
Premasol	Baxter	6.7	7.7	5.3	8.4	5.9
Primene 10%	Baxter	8.4	4.0	6.7	10.0	7.6
ProSol	Baxter	13.4	15.2	10.6	16.8	11.8
Selective amino acids 8 g/100 mL	Galenica Senese	6.0	9.0	9.0	11.0	8.4
Siframin 4%	Fresenius	Absent	Absent	12.5	15.5	12.0
Sintamin	Fresenius	9.7	11.8	7.1	9.2	6.7
Synthamin 10%	Baxter	11.5	11.3	6.0	7.3	5.8
TPH 6%	Baxter	7.3	2.2	4.9	8.4	4.7
Travasol 10%	Baxter	11.5	10.3	6.0	7.3	5.8
Trophamine	B. Braun	12.0	3.6	8.2	14.0	7.8
Vamin 8.5%	Fresenius	8.4	5.9	4.2	5.9	5.5
Vamin 11.4%	Fresenius	11.3	7.9	5.6	7.9	7.3

^aIsopuramin is the only amino acids formulation tested in a phase III randomized controlled trial (PROTECTION).

Fig. 2.

Algorithm for amino acid solution selection for renal protection.

Because the PROTECTION trial [1] is the reference study on this topic, the first choice remains Isopuramin 10% or lower concentrations (e.g., 7%, 3%). If unavailable, alternative AA solutions, such as Synthamin, Travasol, Aminoven, or Amiparem, should be considered as they have been included in recent clinical studies with similar results and no safety concerns [13,37–41]. Any locally available product can also be considered, taking into account institutional practices and costs, as the current evidence suggests efficacy is associated with the class rather than the specific formulation (Fig. 2).

WHERE is the strongest evidence across different settings?

Despite growing evidence of AA-mediated renal protection across multiple clinical settings over the last few decades, the most robust and high-quality results to date have been obtained from cardiac surgery [1]. Cardiac surgery with CPB represents a paradigmatic model of “planned AKI” given that the absence of pulsatile flow, hemodynamic alterations leading to renal hypoperfusion and hypoxia, and inflammatory activation are the main triggering factors for kidney injury [43]. Jeppson et al. [44] conducted the first study in cardiac surgery in 2000, demonstrating that AA infusions could increase renal blood flow and GFR. A reduction in AKI duration, together with increased urinary output through perioperative AA administration, has been documented in cardiac surgery patients expected to undergo at least one hour of CPB [15]. Husain-Syed et al. [45] evaluated the effects of oral protein load in cardiac surgery patients and found reduced serum creatinine levels and increased GFRs at 3 months and 1 year post surgery. The PROTECTION trial [1] provided definitive evidence for the beneficial effects of AA in cardiac surgery, with several subgroup analyses confirming the magnitude and direction of the results in specific patient populations.

First, patients with baseline CKD may have lower renal functional reserve [46], which may compromise the ability of AA to protect against renal injury. However, a pre-specified secondary analysis of the PROTECTION trial in patients with CKD found that any-stage AKI occurred in 174/404 (43.1%) patients in the AA group versus 205/408 (50.3%) controls, corresponding to a significant RR reduction of 14% and an NNT of 14 [8]. Similar to the results of the main publication, Stage 3 AKI was also found to be significantly lower in the intervention group (11/404 [2.7%] vs. 23/408 [5.6%]; RR = 0.48, 95% CI [0.24–0.98], P = 0.038) [8]. Second, among patients who underwent surgery with prolonged CPB, a total of 271/857 (31.6%) patients in the AA group and 346/866 (39.9%) in the placebo group had any-stage AKI (RR = 0.79, 95% CI [0.70–0.90], P < 0.001, NNT=12) [9]. Third, the magnitude and direction of AA-mediated benefits on the kidneys were similar between patients with and without baseline diabetes (interaction P-value for any-stage AKI=0.82) [10]. Of note, a Bayesian analysis showed a 97.5% probability of AKI benefit (RR < 1) when comparing AA infusions with a placebo in patients with diabetes [10].

Temporary mechanical circulatory support (tMCS) is another interesting setting. A recent analysis which involved 232 patients with tMCS, of whom 112 received AA infusions and 120 received Ringer’s solution as a placebo, found that AA reduced any-stage AKI by 27% [47]. Specifically, this study found that for every six patients treated with AA infusions, one AKI episode was avoided (50/112 [44.6%] vs. 73/120 [60.8%]; RR = 0.73, 95% CI [0.57–0.94], P = 0.01, NNT=6) [47].

Given the 50% reduction in the AKI rate after the implementation of AA infusions in high-risk urological surgery patients [37], considering AA administration in non-cardiac and transplant surgery would be reasonable. Patients with ongoing AKI, those considered for weaning from RRT, and those admitted to the ICU should be the focus of further investigations, with special attention paid to the dose and duration of AA infusions.

HOW can AA infusions be implemented in clinical practice?

The use of intravenous AA as a preventive strategy against renal injury is rapidly emerging and has influenced clinical practice in several institutions worldwide. As with any practice-changing intervention, some important practical features must be urgently addressed to avoid misinterpretations and maximize the clinical impact.

The first crucial aspect is the duration of the infusion. In a recently published secondary analysis of the PROTECTION trial, the authors divided patients into the following two subgroups: those undergoing a brief duration of infusion (i.e., a maximum of 48 h) and a prolonged duration of infusion (i.e., between 48 and 72 h). Notably, the effect on AKI was identical in both groups (interaction P = 0.89), though the effect on ICU mortality was significantly different (interaction P = 0.04), with a clear benefit among patients who underwent a brief duration of infusion [48]. One possible explanation may be the side effects caused by urea accumulation during prolonged AA or protein administration [49], which may offset the beneficial effects of short-term AA infusions. From this crucial standpoint, clinicians should consider a maximum AA infusion duration of 48 h for AKI prevention and 24 h for AKI treatment, as patients with ongoing AKI may be even more susceptible to urea accumulation.

Even though no specific AA formulation or concentration has been exclusively recommended, physicians adopting concentrations lower than 10% should avoid increasing the infusion rate to more than 40 mL/h or the duration to more than 48 h, with the aim of reaching the same dose. Indeed, the optimal dosage has not been determined, and current literature suggests that short-term low-dose infusions are sufficient to trigger a protective effect. Moreover, AA solutions have no (or negligible) electrolyte content, and high volumes of these solutions may be difficult to manage outside the ICU.

The optimal time to start an AA infusion is before the insult. However, if an insult has already occurred, early initiation may also be beneficial. More studies are needed to compare the benefits associated with AA infusions for AKI prevention and early AKI treatment.

Another crucial point is the route of administration because central venous catheters (CVCs) are often unavailable in surgical settings, and their positioning has not been indicated for this reason alone. Although CVCs remain the ideal solution for a 10% AA infusion, clinicians can use a standard three-way stopcock to connect and mix AA infusions at 40 mL/h with a 20 mL/h crystalloid solution in the same peripheral line, so that the total osmolarity becomes fully compatible for peripheral infusions. The infusion of products at lower concentrations can be safely administered peripherally.

HOW MUCH is AA-mediated renal protection cost-effective?

For potentially practice-changing interventions, the health economic perspective is of paramount importance. Soon after the publication of the PROTECTION trial, we conducted a health economic evaluation starting with the updated meta-analytic data [17]. The analysis was conducted in five countries (Italy, the United States, the United Kingdom, Australia, and China) and accounted for all hospitalization costs except surgical costs. We found the implementation of AA infusions to be clinically beneficial and cost-effective [50]. The observed per-patient cost savings ranged from $184 (95% CI [−$331 to −$32]) in China to $2,521 (95% CI [−$3,770 to −$1,260]) in the United States, making AA a dominant strategy (cost-saving and cost-effective) across all jurisdictions [50].

Conclusions

The administration of intravenous AA infusions for AKI prevention is supported by robust clinical and economic evidence and represents an easy, safe, and inexpensive intervention. Therefore, we recommend that it should be implemented promptly in routine clinical practice worldwide.