The therapeutic horizon of acute kidney injury in critical care: exploring pathology, promises, pitfalls, and progress

Abstract

Purpose of review

Acute kidney injury (AKI) is among the most common organ failures encountered in critically ill patients, contributing to both short-term and long-term morbidity and mortality. No targeted therapy currently prevents or treats AKI. This review highlights recent advances in its prevention and treatment within critical care.

Recent findings

Increased attention to AKI heterogeneity and subphenotypes, coupled with biomarker-driven research, has deepened understanding of its pathophysiology. Several clinical trials have shown no benefit or were stopped early for futility, yet others report promising therapeutic effects or identify potential interventions. These findings need confirmation in larger prospective studies, and their clinical relevance remains to be established. Continued investigation is required to delineate AKI subphenotypes and develop targeted therapies.

Summary

Several trials already demonstrate encouraging results in specific AKI subphenotypes, supported by growing insight into its complex pathophysiology. Although candidate interventions are still under evaluation, recent progress offers hope for improved preventive and therapeutic strategies in critically ill patients.

INTRODUCTION

Acute kidney injury (AKI) represents one of the most frequently observed organ failures in the intensive-care unit that drives excess short- and long-term morbidities and mortality [1]. Although diagnostic criteria are standardized [2–4], the mechanistic architecture of AKI remains incompletely resolved. Converging data indicate that diverse initiating insults funnel into self-amplifying circuits of hemodynamic dysregulation, systemic and local inflammation, mitochondrial dysfunction, microvascular thrombosis, apoptosis, and, ultimately, maladaptive fibrosis [5–7]. This review surveys the literature with an emphasis on reports published 2024–2025, with particular attention to preventive and therapeutic strategies for AKI (Table 1). 

Table 1.

Overview of studies

Intervention	Control	Study	Study design	Number of patients	Disease or surgery	Most important renal outcome	Comments
Angiotensin II	Placebo	Khanna et al. [8]	RCT	321	Catecholamine-resistant vasodilatory shock	Increased liberation from RRT by day 7
Angiotensin II	Placebo	Chaba et al. [9▪▪]	Post hoc ANALYSIS	203	Catecholamine-resistant vasodilatory shock and stage AKI	lower mortality and more RRT free days in stage 3 AKI. But not in the lower AKI stages
Angiotensin II	Standard of care	NCT05824767	RCT	40	Vasodilatory shock	AKI and RRT	Ongoing
Angiotensin II	Noradrenalin	NCT06615102	RCT	1022	Cardiac surgery	AKI and MAKE90	Ongoing
Vasopressin	Other vasoactive comparator	Nagendran et al. [11]	meta-analysis	1453	Septic shock	A nonsignificant trend toward reduced RRT
Vasopressin	norepinephrine	NCT05568160	RCT	1600	Cardiac surgery	Incidence of stage 2–3 AKI	Ongoing
Terlipressin	Standard of care	Jindal et al. [12▪]	RCT	70	Hepatorenal-syndrome	Reduced AKI incidence at day 3 and 7
Terlipressin	norepinephrine	Olson et al. [13▪]	Meta-analysis	376	Hepatorenal-syndrome	No renal endpoints	Showed lower mortality and greater HRS reversal
Levosimendan	placebo or other inotropic drugs	Zhou et al. [15]	Metanalysis	1345	Cardiac surgery	Reduction of AKI and RRT	no effect in patient with a preserved systolic function
Intravenous amino acid	Placebo	Landoni et al. [17▪▪]	RCT	3511	Cardiac surgery	Increased creatinine clearance and reduced AKI incidence	No effect on long term renal function
High protein provision	Standard protein provision	Bels et al. [18▪]	RCT	935	Critical illness	No difference in AKI incidence
Inorganic nitrate	Placebo	Jones et al. [20▪▪]	RCT	640	Contrast induced AKI	Reduced AKI incidence and increased EGFR after 3 months
SGLT2 inhibitors	Placebo	Wang et al. [21▪]	Meta-analysis	25172	Heart failure	Attenuated AKI risk
SGLT2 inhibitors	DPP-4 inhibitors	Chung et al. [22]	retrospective cohort study	104462	Type 2 diabetes	Lower risk for AKI and RRT
SGLT2 inhibitors	Non SGLT2 inhibitors	Paolisso et al. [23]	Multicenter international registry analysis	646	Type 2 diabetes and PCI	Lower incidence of AKI
Dapagliflozin	Placebo	Heerspink et al. [24]	RCT	4304	Chronic kidney disease	Reduction of a composite outcome consisting of a reduction of EGFR end stage renal failure or death
SGLT2 inhibitors	Non SGLT2 inhibitors	Pan et al. [25▪]	Propensity score matched cohort study	10634	Diabetes type 2 and acute kidney disease	Reduced MAKE
Withdrawal from Empagliflozin	Withdrawal of placebo	Packer et al. [26]	RCT	6799	Heart failure	Decrease of EGFR
Dexmedetomidine	Placebo	Zhang et al. [30▪]	RCT	238	CABG	Reduced incidence of AKI no effect on long term outcomes
Dexmedetomidine	Placebo	Kwon et al. [31▪]	RCT	205	Liver transplantation	Reduced incidence of AKI
Dexmedetomidine	Placebo	Zhao et al. [32▪]	Meta-analysis	2907	Cardiac surgery	Reduced AKI risk
Dexmedetomidine	Placebo	Li et al. [33]	Meta-analysis	2744	Cardiac surgery	Reduced AKI risk
Dexmedetomidine	Placebo	Zhuang et al. [34▪]	meta-analysis	2440	Non cardiac surgery	Reduced AKI risk
Reltecimod	Placebo	Bulger et al. [37]	RCT	290	Necrotizing Soft Tissue Infections	Reduced organ failure including AKI stage 2–3
Reltecimod	Placebo	NCT03403751	RCT	58	Sepsis		Terminated
Ilofotase Alfa	Placebo	Pickers et al. [38]	RCT	380	Sepsis	No effect on <7 days ECC but attenuated MAKE90
Ilofotase Alfa	Placebo	Pickers et al. [39]	RCT	650	Sepsis	attenuated MAKE90
Ilofotase Alfa	Placebo	NCT06168799	RCT	250	Cardiac surgery	Serum creatinine ratio, AKI and MAKE60	Ongoing
TIN816	Placebo	NCT05996835	RCT	320	Sepsis	ECC	Ongoing
TIN816	Placebo	NCT05524051	RCT	98	Cardiac surgery	Serum creatinine ratio	Terminated result expected
Dexamethasone	Placebo	Ng et al. [40]	Meta-analysis	12734	Cardiac surgery	No reduction in AKI
Dexamethasone	Placebo	Dvirnik et al. [41]	Meta-analysis	12666	Cardiac surgery	No effect on renal failure
Dexamethasone	Non Dexamethasone	Van Steenbergen [42▪]	Posthoc analysis	54694	Cardiac surgery	Reduced post operative renal failure
RBT-1	Placebo	Lamy et al. [43▪]	RCT	135	Cardiac surgery	No effect on AKI incidence
RBT-1	Placebo	NCT06021457	RCT	454	Cardiac surgery	A composite including AKI	Completed results expected
Cytosorb	Standard of care	Gräfe et al. [44▪▪]	Retrospective propensity score matched study	44	rhabdomyolysis	Improved renal recovery
OXiris	Placebo	Zheng [46▪]	Retrospective observational study	243	sepsis	No difference in partly or full recovery from RRT
Oxiris	Placebo	Pérez-fernández	RCT	343	Cardiac surgery	Reduction in AKI incidence but no difference in persistent AKI incidence of RRT or serum creatinine values at day 90
NRPT	Placebo	Simic et al. [55]	RCT	24	AKI	No effect on EGFR or creatinine levels
NRPT	Placebo	NCT06521307	RCT	100	Cardiac surgery		Ongoing
Metformin	Non metformin users	Van Moorter et al. [56]	Observational	467	Sepsis	Lower incidence of AKI
Metformin	Placebo	NCT05900284	RCT	80	Sepsis	AKI and renal biomarkers	Ongoing
Ravulizumab	Placebo	NCT05746559	RCT	736	Cardiac surgery	MAKE 90 and AKI incidence	Ongoing
Teprasiran	Placebo	Thielman et al. [61]	RCT	360	Cardiac surgery	Reduced AKI incidence
Teprasiran	Placebo	NCT03510897	RCT	1043	Cardiac surgery	No effect on renal outcomes	Terminated
ANG-3777	Placebo	Ayad et al. [62]	RCT	275	Cardiac surgery	No renal benefit
ANG-3777	Placebo	Vincenti et al. [63▪]	RCT	253	Transplant	No improvement in EGFR need for RRT of graft function.

AKI, acute kidney injury; CABG, coronary artery bypass grafting; CKD, chronic kidney disease; DPP-4i, dipeptidyl peptidase-4 inhibitors; ECC, endogenous creatinine clearance; eGFR, estimated glomerular filtration rate; HRS, hepatorenal syndrome; MAKE, major adverse kidney events; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; RRT, renal replacement therapy; SGLT2i, sodium–glucose cotransporter-2 inhibitors.

Box 1.

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OPTIMIZING RENAL HEMODYNAMICS

Maintaining adequate renal perfusion is the main defense against AKI in clinical practice, where this goal is pursued through use of fluids, vasopressors and drugs that modulate afferent and efferent arteriolar tone (Fig. 1).

FIGURE 1.

Pharmacological modulation of renal and cardiovascular pathways: mechanisms of action. This schematic illustrates the sites of action and proposed mechanisms of various pharmacological agents targeting cardiovascular and renal physiology such as improved glomerular filtration rate, enhanced renal perfusion, reduced oxidative stress, and protection against tubular injury. AMPK, AMP-activated protein kinase; DAMPs, damage-associated molecular patterns; GFR, glomerular filtration rate; HO-1, heme oxygenase-1; ICAM, intercellular adhesion molecule; LPS, lipopolysaccharide; MAC, membrane attack complex; NAD⁺, nicotinamide adenine dinucleotide; ROS, reactive oxygen species; SGLT2, sodium-glucose co-transporter 2; SIRT1, sirtuin 1; VCAM, vascular cell adhesion molecule. Created in BioRender. Research, I. (2025). https://BioRender.com/xtxo317.

Angiotensin II

Exogenous human angiotensin II (AngII) provides catecholamine-sparing vasopressor support and predominantly constricts the renal efferent arteriole, thereby restoring intraglomerular pressure and glomerular filtration rate. In ATHOS-3 (vasodilatory shock patients, n = 321), AngII infusion in a subgroup of patients on renal replacement therapy (RRT) doubled liberation from RRT by day 7 (23% vs. 10%) [8]. Renoprotective effects were also observed in AKI stage 3 patients not on RRT, while no effect on RRT free days were found in lower stages of AKI [9^▪▪]. While a survival benefit of AngII infusion could be predicted from its effect on blood pressure, the renal secondary endpoint was not significantly different between responders and nonresponders (alive and RTT-free at day 7) [odds ratio (OR): 0.93, 95% confidence interval (CI) 0.72–1.20] [10^▪].

A study (NCT05824767) in sepsis patients (n = 590) is in progress, focusing on the ability of renin- and DPP3-levels to predict responsiveness to AngII. Secondary outcomes will include rates of AKI and RRT. A large AngII trial (n = 1022) in patients undergoing cardiac-surgery is also underway, with AKI or death at 72-h as the primary endpoint, and major adverse kidney events up to day 90 (MAKE90) as a secondary endpoint.(NCT06615102).

Vasopressin/terlipressin

Although individual trials were underpowered or did not reach statistical significance, a meta-analysis (n = 1453; patients in septic shock) showed a trend for reduced RTT requirement [11], suggesting an early intrinsic or catecholamine sparing renoprotective window. Confirmation is sought in the NOVACC trial (NCT05568160), randomizing cardiac-surgery patients (n = 1600) to intra-operative vasopressin or norepinephrine and assessing stage 2–3 AKI and 30-day mortality.

Early initiation of terlipressin in acute-on-chronic liver failure(ACLF) with hepatorenal-syndrome(HRS) may exert beneficial renal effects. In the eTerli RCT (HRS-AKI, n = 70) administration of terlipressin 12 h after resuscitation halved AKI at day 3 and 7 (69% vs. 31%) [12^▪]. A subsequent meta-analysis pooling seven trials (n = 376) showed lower mortality and greater HRS reversal with terlipressin, but the confidence intervals for both outcomes included 1, indicating the results were not statistically significant. Renal endpoints were not reported [13^▪]. Taken together, terlipressin in the context of HRS-AKI hints at renoprotection.

Levosimendan

Levosimendan is a calcium-sensitizing inodilator that elevates cardiac output and opens adenosine triphosphate (ATP)-sensitive K⁺ channels resulting in afferent arteriole vasodilation, enhancing renal blood flow and glomerular filtration (GFR) [14]. A meta-analysis of 13 randomized trials (RCTs) (n = 1345) in cardiac surgery patients found a 22% relative reduction in AKI and fewer RRT episodes, whereas no benefit was observed in patients with preserved systolic function [15]. suggesting the renoprotective effect is largely hemodynamic rather than directly kidney-specific.

Intravenous amino-acid loading

Short-term amino-acid loading has shown an increased renal plasma flow and GFR by 20–30% through the renal reserve. Experimental and human studies, including animal ischemia–reperfusion and sepsis models, demonstrate this reflex remains intact in early AKI [16]. In the multicenter PROTECTION trial (n = 3511; cardiac surgery patients), infusion a balanced amino-acid mixture during 72 h vs. placebo resulted in an increase in creatinine clearance and reduced AKI incidence in the first week 27% vs. 32% [relative risk (RR): 0.85 (95% CI 0.77–0.094)] mainly driven by stage-1 AKI, while it did not significantly affect longer-term renal function, RRT rates, or survival [17^▪▪]. Conversely, the PRECISe study (n = 935) demonstrated that increasing enteral protein intake throughout critical illness resulted in a lower health-related quality of life. Renal endpoints were not evaluated, and there was no relevant difference in AKI [18^▪] The data suggest that amino-acid infusions can tap into existing renal functional reserve, mediated by afferent arteriolar dilation and suppression of tubuloglomerular feedback, which remains present in early AKI. However, this does not translate into improved long-term outcomes. Therapeutic efficacy might be more pronounced in cases where afferent dilation is pharmacologically impaired but this has not been clinically studied.

Inorganic nitrate

NO restores renal perfusion and tissue oxygenation after contrast or ischemic AKI by bypassing dysfunctional NO-synthase pathways and delivering NO via the nitrate–nitrite–NO axis. This improves medullary blood flow, limits oxidative damage, and preserves mitochondrial and tubular function [19]. The NITRATE-CIN trial (n = 640) investigated oral inorganic nitrate in patients undergoing coronary angiography and found a reduction in contrast-induced AKI (CI-AKI) (9% vs. 31% in the placebo group), without significant hypotension or methemoglobinemia. At 3 months, patients also showed a statistically significant mean increase in eGFR of 5.2 ml/min/1.73 m² compared to placebo, suggesting a sustained renal benefit [20^▪▪]. To our knowledge, inorganic nitrate has not been tested in critically ill patients.

SGLT2 inhibitors

A meta-analysis (n = 25172) demonstrated that chronic use of SGLT2-inhibitors attenuated the risk of AKI in heart failure patients by 28% RR: 0.72 (95% CI: 0.61–0.85), an effect that was more pronounced in patients that used SGLT2-inhibitors for ≥1 year [21^▪]. A retrospective cohort study using Taiwan's national health insurance data (n = 104 462) found that patients with type-2 diabetes on SGLT2-inhibitors had a 34% lower risk of AKI and 44% lower risk of RRT, compared to those on DPP-4 inhibitors [22]. In the international SGLT2-I AMI PROTECT Registry (n = 646, diabetic patients undergoing PCI for myocardial infarction), SGLT2-inhibitor use was associated with a significantly lower incidence of CI-AKI (5.4% vs. 13%) using a multivariate logistic regression corrected for confounders an OR:0.36 (95% CI: 0.13–0.94) was found [23]. The DAPA-CKD RCT (n = 4304) showed a significant reduction in the kidney-specific composite secondary endpoint, consisting of ≥50% sustained decline in eGFR, end-stage kidney disease, or renal death, with events in 5% of the dapagliflozin group vs. 9% in the placebo group [hazard ratio (HR): 0.56 (95% CI: 0.45–0.68)] [24]. In another retrospective cohort study (n = 10634), MAKE occurred significantly less often in the SGLT2-inhibitor group, affecting 10% compared to 21% in propensity matched controls (AHR: 0.62, 95% CI 0.56–0.69) [25^▪]. Moreover, a pooled analysis of the EMPEROR trials (n = 6799) demonstrated that, following its chronic use, discontinuation of SGLT2-inhibitors, led to a significant decline in eGFR compared to continued use (−2.20 vs. −0.09 ml/min/1.73 m² over 12 weeks), suggesting a sustained renoprotective effect during chronic use. The effect might be explained by improved cardiac function, but it could also be due to renal reserve [26,27^▪▪], attenuation of reactive oxygen species (ROS), inflammation, or prevention of fibrosis [28^▪,29]. Current evidence supports its role as a preventive strategy rather than a therapeutic intervention, limiting its applicability in an acute setting.

MODULATING THE SYSTEMIC CYTOKINE SURGE AND THE VAGUS/SPLENIC AXIS

Dexmedetomidine

Dexmedetomidine, a selective α₂-adrenergic agonist favored for hemodynamically stable sedation, may also exert renoprotective properties. In a double-blinded RCT (n = 238) coronary-artery bypass (CABG) patients demonstrated that dexmedetomidine decreased the incidence of AKI (18% vs. 33%) [30^▪]. In a randomized trial (living-donor liver transplantation, n = 205) dexmedetomidine lowered the incidence of AKI from 50% to 35% [31^▪]. A meta-analysis of 15 randomized cardiac-surgery trials (n = 2907) confirmed a 34% RR reduction (OR: 0.66, 95% CI: 0.48–0.91) [32^▪], while dose-timing analysis of 14 trials (n = 2744) showed that loading doses exceeding 0.5 μg/kg and continuation into the early postoperative period intensified protection RR: 0.54 (95% CI: 0.41–0.70) [33]. In noncardiac surgery patients, a meta-analysis of 23 trials (n = 2440) found a pooled RR: 0.57 (95% CI: 0.40–0.83) [34^▪]. Long-term data are sparse. The CABG trial described above is the only study to follow renal function up to 3 months found a nonsignificant trend towards lower incident chronic kidney disease (CKD) 17% vs. 24% [34^▪]. None of the trials report RRT dependence. Mean arterial pressure did not differ compared to control patients, arguing against a macro-hemodynamic mechanism of action.

Preclinical work indicates that the vagus–spleen reflex may account for dexmedetomidine's renoprotective effects: central α₂ activation augments efferent vagal traffic to the splenic sympathetic nerve, suppressing tumor necrosis factor (TNF) and interleukin (IL)-6 and truncal vagotomy or splenectomy abolishes renoprotection in murine ischemia–reperfusion injury [35]. Second, pathways related to TLR-4 signaling limit ROS and these intracellular effects are ineffective when the vagal–splenic brake is absent, potentially implying that asplenic patients or those with blunted vagal tone may be unlikely to obtain renoprotection or wider immunomodulation (Fig. 2).

FIGURE 2.

A schematic overview of immunomodulatory interventions targeting systemic and localized inflammation to mitigate renal injury, along with their proposed mechanisms of action. DAMPs, damage-associated molecular patterns; IFN-γ, interferon gamma; IL, interleukin; MHC-I, major histocompatibility complex class I; PAMPs, pathogen-associated molecular patterns; TCR, T-cell receptor; Th1 cell, T-helper 1 cell. TNF, tumor necrosis factor. Created in BioRender. Research, I. (2025). https://BioRender.com/kv7tb72.

Reltecimod

Reltecimod is a peptide derived from the CD28 homodimer interface that binds allosterically and selectively attenuates CD28–B7-mediated T-cell co-stimulation without full receptor blockade. This interaction attenuates superantigen docking and downstream inflammatory signaling while preserving counter-regulation and antimicrobial defense (Fig. 2). In mouse models and in vitro studies using human peripheral blood mononuclear cells, reltecimod curtailed early cytokine surges yet maintained immune activity for pathogen clearance [36]. Promising results for reltecimod were observed in a phase 3 trial (n = 290) in necrotizing soft tissue infection patients as resolution of organ dysfunction was achieved in 65% of patients treated with reltecimod, compared to 53% in placebo. This improvement appeared to be driven, by a lower incidence of AKI stage 2–3, with rates of 42% vs. 55% in the placebo group [37]. By contrast, the phase 3 trial in sepsis-associated (SA-AKI) (NCT03403751, n = 58) was terminated for futility, with no meaningful difference in renal outcome.

The renal feed-forward inflammation loop, and breaking out of it

AKI often stems from sepsis or sterile ischemia–reperfusion. During ischemia, danger-associated molecular patterns (DAMPs) are released; in sepsis, circulating pathogen-associated molecular patterns (PAMPs) may enter the kidney. DAMPs and PAMPs initiate inflammation through Toll-like receptors present in tubular cells, particularly TLR4, activating NF-κB/MAPK signaling and cytokine release, endothelial adhesion molecules, immune infiltration, and eventually fibrosis. Simultaneously, ATP released through cell damage or pannexin-1 channels activates purinergic receptors, further escalating inflammation and apoptosis (Fig. 1).

Ilofotase alfa

Ilofotase alfa is a recombinant alkaline phosphatase that exerts detoxifying properties, through dephosphorylating activity. In the phase 2 STOP-AKI trial (n = 300) it did not improve <7 days endogenous creatinine clearance (ECC) but attenuated the MAKE90 incidence (26% vs. 40% in placebo) [38]. A phase 3 study, REVIVAL (n = 650), was terminated because it did not influence its primary survival endpoint, but again attenuated MAKE90 (57% vs. 65%), especially in patients with preexistent CKD [39]. A phase 2 trial in 250 cardiac surgery patients with a serum creatinine ratio as primary outcome is expected to be completed in 2025(NCT06168799).

TIN816

TIN816 is a recombinant form of CD39, which hydrolyzes extracellular ATP/ADP, dampening inflammation and platelet activation. It is being studied in two phase 2 trials. The first looking in patients with SA-AKI (n = 320) (NCT05996835) looking at ECC. The second study at cardiac surgery-associated AKI with the primary outcome of the serum creatinine ratio was terminated after including 98 patients. No results are reported yet (NCT05524051).

Dexamethasone

The use of corticosteroids during cardiac surgery have long been hypothesized to reduce the inflammatory response and thus reduce AKI. Several trials have investigated the use of corticosteroids. Meta-analysis of these trails did not show a reduction in AKI OR: 0.84 (95% CI: 0.68–1.02, n = 12734) [40] or renal failure RR: 0.83 (95% CI: 0.68–1.01, n = 12666) [41]. A posthoc DECS trial analysis (n = 4465), dexamethasone reduced RRT (0.4% vs. 1%) in cardiac surgery patients. Patients with CKD appeared to benefit more. A recent registry with 54 694 cardiac surgery patients linked intraoperative dexamethasone to a reduction in postoperative renal failure OR: 0.57 (95% CI: 0.47–0.70). No trial has reported the effects on MAKE [42^▪].

RBT-1

RBT-1, an agent combining tin protoporphyrin IX and iron sucrose, activates Nrf2 to upregulate HO-1, IL-10, and ferritin. HO-1 products exert antioxidant and vasoregulatory effects. A phase 2 trial (n = 135) confirmed pharmacodynamic activity by upregulation of a composite of several cytoprotective proteins. No significant effect on AKI incidence was observed RR: 0.88 (95% CI: 0.35–2.19) [43^▪]. A phase 3 trial (NCT06021457) in cardiac surgery patients (n = 454) using an composite outcome, including AKI, has completed enrollment with results expected soon.

Devices: Cytosorb and oXiris hemofiltration

The Cytosorb and oXiris are devices aimed to capture different molecules from the blood. In critically ill patients (n = 70) with rhabdomyolysis, a retrospective propensity score matched study found that Cytosorb combined with RRT improved kidney recovery defined as independence RRT on day 30 (31% vs. 11%) [44^▪▪]. A small (n = 4) prospective study confirmed rapid myoglobin removal in rhabdomyolysis patients, but noted early saturation of the adsorber after 8–12 h of treatment, potentially limiting benefit [45^▪]. An observational trial with SA-AKI patients on RRT treated with the oXiris filter (n = 88) vs. placebo (n = 155) showed a potential reduction in inflammation, however no statistical difference in full (60%, vs. 64%) or partial recovery (14% vs. 16%) from RRT [46^▪]. The SIRAKI02 was a RCT in 343 cardiac surgery patient who were treated with either the oXiris filter or standard care. There was significant reduction in CSA-AKI 28% vs. the standard care 39.7% (with an adjusted difference of 10.4% (95% CI: 2.3–18.5). However, among patients with early AKI, there was no difference between the intervention and placebo groups in terms of persistent AKI lasting more than 48 h: 16 patients (41%) in the intervention group vs. 22 patients (39%) in the placebo group. Moreover, there was no significant difference in the incidence of RRT, serum creatinine values up to day 90 or mortality [47^▪▪]. The recently completed TIGRIS trial (NCT03901807) evaluated the use of the Polymyxin B hemoperfusion filter in addition to standard care for patients with sepsis [48]. Importantly, the inclusion criteria required evidence of elevated endotoxin activity, ensuring that treatment was targeted to patients most likely to benefit. A recent press release reported a positive effect on mortality, although no renal outcomes were described. The full trial results are eagerly awaited.

MENDING THE KIDNEY'S ENERGY BUDGET

Renal tubular epithelial cells have abundant mitochondria to support high energy demands, preferentially provided by fatty acid oxidation (FAO). In stress, FAO is decreased and carbohydrate catabolism fails to meet energy demand, ultimately associated with increased development of fibrosis (Fig. 1) [49].

Nicotinamide riboside with pterostilbene therapy

In mouse models of AKI induced by dehydration, prostaglandin inhibition, or contrast injection, supplementation with nicotinamide riboside (NR), alone or in combination with pterostilbene (PT), attenuated tubular damage and limited the rise in serum creatinine [50]. This effect appears to rely on sirtuin activity, as it is absent in a mouse model in which sirtuins were inactivated [51]. SIRT1 and SIRT3 are NAD⁺-dependent deacetylases whose depletion leads to impaired mitochondrial biogenesis, endoplasmic reticulum (ER)-stress and defective autophagy, increased inflammatory signaling, ATP depletion, elevated ROS, and ultimately renal damage [52–54]. In both mice and humans, oral NR replenishes NAD⁺, while oral PT acts as a direct SIRT1 activator and antioxidant [55]. In a randomized, double-blind safety study in 24 hospitalized patients with AKI NRPT raised whole-blood NAD⁺ by ~37% at 48-h without affecting creatinine, eGFR, and had only minor side-effects [56]. A perioperative cardiac surgery trial (n = 100, NCT06521307) is underway with expected completion in 2026.

Metformin

While the mechanism of action of metformin in the prevention of AKI is not fully understood, several studies have shown a potential relationship with the ubiquitous cellular energy master regulator AMP-activated protein kinase (AMPK) decreasing incidence of AKI when activated by metformin and increasing when blocked in sepsis models [57,58]. Potential mechanisms of AMPK-induced protection include, but are not limited to, cellular energy conservation, activation of mitochondrial quality control processes, and inhibition of aerobic glycolysis [59^▪]. A retrospective study of 467 ICU patients with sepsis showed that those who had been taking metformin before ICU admission had a significantly lower incidence of AKI and lower 90-day mortality compared to nonusers [60]. The LiMiT-AKI trial (n = 80, NCT05900284) is an ongoing randomized, placebo-controlled pilot study investigating metformin in septic ICU patients at risk for AKI. The study will focus on the safety of metformin, but also includes renal outcomes such as AKI incidence and kinetics of renal biomarkers. The study is estimated to finish early 2026 [59^▪].

TAMING COMPLEMENT & COAGULATION CROSS-TALK

Complement activation unleashed by ischemia–reperfusion or intravascular hemolysis rapidly coats the renal microcirculation with C3b, liberates the anaphylatoxin C5a, and up-regulates tissue factor and platelet reactivity, thereby locking the kidney into a feed-forward loop of inflammation and micro-thrombosis (Fig. 1) [61].

Ravulizumab

Ravulizumab, a second-generation, long-acting monoclonal antibody against complement C5 delivers complete terminal-pathway blockade up to 8 weeks after a single dose. It is already in clinical use for different indications. Clinical evaluation in the context of AKI is underway. ARTEMIS (NCT05746559) is a phase-3 RCT that will enroll cardiac surgery patients (n = 736) with stage 3–4 CKD to receive a single preoperative infusion of ravulizumab or placebo. The primary outcome is MAKE90 and the secondary outcome is AKI incidence. Complement–coagulation coupling is mechanistically distinct from cytokine-driven injury. Should ARTEMIS demonstrate that C5 blockade converts biochemical benefit into renoprotective effects, ravulizumab would validate the broader strategy of uncoupling complement from coagulation in AKI.

FROM CELL DEATH TO CELL RESCUE

Apoptotic loss of proximal tubular epithelium is a shared consequence of ischemic and toxic AKI, with p53 acting as the critical molecular switch (Fig. 1).

Teprasiran (QPI-1002)

A chemically modified small-interfering RNA that transiently suppresses p53, reduced AKI incidence 37% vs. 50% placebo-treated patients in a phase 2 RCT in cardiac surgery patients (n = 360) [62]. However, the phase-3 AKI-001 trial (NCT03510897) was stopped early (n = 1043) because of futility. Development of the compound was stopped in 2023 after an FDA-mandated futility review.

BB3 (ANG-3777)

ANG-3777 is a low-molecular-weight hepatocyte-growth-factor mimetic that aims to activate the c-Met receptor to promote epithelial proliferation and autophagy. ANG-3777 did not show a renal benefit in a phase 2 trial (NCT02771509) in cardiac surgery patients (n = 275) [63^▪]. In a phase 3 trial (NCT02474667)ANG-3777 also did not improve eGFR or attenuate the need for RRT in kidney transplant recipients with delayed graft function (n = 253) [64^▪]. The development of the program has been discontinued.

CONCLUSION

AKI remains a formidable challenge especially in critically illness. While preventive measures remain cornerstones of current management, emerging therapies now aim to more directly address the underlying mechanisms of AKI. Despite numerous setbacks in late-stage trials, promising therapeutic strategies are currently being investigated. Importantly, it is now acknowledged that multiple barriers hinder progress in research. First, AKI is detected late due to the insensitive biomarker creatinine, which narrows the therapeutic window. To mitigate this, research is shifting focus from scenarios such as sepsis to more controlled, elective setting, like cardiac surgery, where preventive treatment is feasible. Second, the complex, feed-forward nature of AKI pathogenesis combined with the current inability to identify the phenotype of the predominant pathophysiological process in individual patients makes predictive enrichment challenging. Research into biomarkers offers hope to overcome this barrier. The ‘magic bullet’ approach to treat all AKI patients in the same manner did not result in positive clinical effects of tested interventions. Currently, it is increasingly appreciated that different underlining causes for example, sepsis, cardiac surgery, or contrast-induced AKI have distinct mechanisms of injury and therefore may respond differently to different interventions. Even more so, the heterogeneity between these patients does not end there, even within these subgroups the underling mechanism might be variable and different phenotypes of AKI may exist. For example, in sepsis-associated AKI patients, those with a more severe illness and corresponding metabolic biomarkers had a more pronounced therapeutic efficacy of recAP compared to those that who had less severe disturbances in the biomarkers [65]. Recognizing and detecting these different mechanisms should be the first step toward more effective treatment by tailoring therapies to the presumed mechanism of action. The mentioned TIGRIS trial, using the biomarker driven approach to select patient most likely to benefit from the intervention is another illustration of this approach [48]. In the future, the use of biomarkers to identify the mechanism of injury in a specific patient, and tailoring the intervention accordingly, will move us closer to true precision medicine and may ultimately result in robust and clinically significant trial outcomes. Although clinically meaningful improvements, such as an effect on MAKE, have yet to be demonstrated in larger clinical trials, with the first large trails showing positive outcomes of e.g. amino acids administration [17^▪▪] or use of the oXiris filter [46^▪] on AKI incidence, there is steady progress (Table 1). Advances in understanding the mechanisms of renal injury, improvements in early detection, and emerging signals of pharmacological efficacy all contribute to a cautiously optimistic mood.

Acknowledgements

None.

Financial support and sponsorship

This article was not sponsored nor did any of the author receive financial compensation for this article.

Conflicts of interest

P. Pickkers and L. Mourisse received a grant in the past and are currently investigating a product from AM-Pharma. P. Pickkers received travel and consultancy reimbursements from AM-Pharma.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

• ▪ of special interest

• ▪▪ of outstanding interest