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Contents lists available at ScienceDirect

Journal of Intensive Medicine

journal homepage: www.elsevier.com/locate/jointm

Review

New drugs for acute kidney injury

Geoffroy Hariri 1,2, Matthieu Legrand 1,3,∗
1
Department of Anesthesia and Perioperative Care, Division of Critical Care Medicine, UCSF, San Francisco, CA, USA
2
Sorbonne Université, GRC 29, Assistance Publique-Hôpitaux de Paris (AP-HP), DMU DREAM, Département d’anesthésie et réanimation, Institut de Cardiologie, Hôpital
La Pitié-Salpêtrière, Paris, France
3
Investigation Network Initiative Cardiovascular and Renal Clinical Trialist Network, Nancy, France

a r t i c l e i n f o a b s t r a c t

Managing Editor: Jingling Bao Acute kidney injury (AKI) presents a significant challenge in the management of critically ill patients, as it is as-
sociated with increased mortality, prolonged hospital stays, and increased healthcare costs. In certain conditions,
Keywords:
Acute kidney injury such as during sepsis or after cardiac surgery, AKI is one of the most frequent complications, affecting 30 %–50 %
Drugs of patients. Over time, even after the resolution of AKI, it can evolve into chronic kidney disease, a leading global
Critical care cause of mortality, and cardiovascular complications. Despite significant improvement in the care of critically ill
Innovative therapies patients over the past two decades, the incidence of AKI remains stable, and novel approaches aiming at reducing
Targeted care its occurrence or improving AKI outcomes are still mostly lacking. However, recent insights into the pathophys-
iology of AKI within critical care settings have shed light on new pathways for both prevention and treatment,
providing various new therapeutic targets aimed to mitigating kidney injury. These advancements highlight the
intricate and multifaceted nature of the mechanisms underlying AKI, which could explain the challenge of iden-
tifying an effective treatment. Among these targets, modulation of the inflammatory responses and the cellular
metabolism, hemodynamic regulation and enhancement of cellular repair mechanisms, have emerged as promis-
ing options. These multifaceted approaches offer renewed hope for limiting the incidence and severity of AKI in
critically ill patients. Several ongoing clinical trials are evaluating the efficacy of these different strategies and
we are facing an exiting time with multiple therapeutic interventions being tested to prevent or treat AKI. In this
review, we aim to provide a summary of the new drugs evaluated for preventing or treating AKI in critical care
and surgical settings.

Introduction els and urine output changes, enabling timely recognition and
intervention.[3–5] In critical care settings, the incidence of AKI
Acute Kidney Injury (AKI) is a global health concern, affect- remains heterogeneous with a range from 15 % to 60 % de-
ing over 13 million individuals annually and contributing to pending on its definition and the patient’s condition.[6] This
approximately 1.7 million deaths worldwide.[1] From a patho- is a major issue regarding the association between AKI sever-
physiological aspect, AKI is characterized by a rapid decline ity and adverse clinical outcomes, including increased mortal-
in glomerular filtration rate (GFR), manifesting within hours ity rates, prolonged hospital stays, and the risk of the evolu-
or days and evidenced by an abrupt increase in serum creati- tion into chronic kidney disease (CKD).[7 , 8] AKI’s heterogeneity
nine levels. Prior to 2004, the lack of a consensual definition for extends beyond its definition, encompassing diverse etiologies
AKI resulted in a broad spectrum of interpretations, spanning such as cardiac surgery-associated acute kidney injury (CSA-
from slight creatinine elevation to the requirement for renal AKI), sepsis-associated acute kidney injury (SA-AKI) or drug tox-
replacement therapy (RRT).[2] However, the establishment of icity.[9–11] This complexity poses challenges in identifying suit-
classification systems like RIFLE (Risk, Injury, Failure, Loss, and able drug targets and designing effective therapeutic interven-
End-stage renal failure), AKIN (Acute Kidney Injury Network), tions. Despite notable advancements in the management of crit-
and KDIGO (Kidney Disease: Improving Global Outcomes) has ically ill patients in the last two decades, randomized controlled
provided a structured approach based on serum creatinine lev- trials (RCTs) evaluating therapies for the prevention or the treat-

∗
Corresponding author at: Matthieu Legrand, Department of Anesthesia and Perioperative Care, Division of Critical Care Medicine, UCSF, 521 Parnassus Avenue,
San Francisco, CA 94143, USA.
E-mail address: [email protected] (M. Legrand).

https://doi.org/10.1016/j.jointm.2024.08.001
Received 24 April 2024; Received in revised form 30 July 2024; Accepted 5 August 2024
Available online xxx
Copyright © 2024 The Author(s). Published by Elsevier B.V. on behalf of Chinese Medical Association. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Please cite this article as: G. Hariri and M. Legrand, New drugs for acute kidney injury, Journal of Intensive Medicine, https://doi.org/10.1016/j.
jointm.2024.08.001
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Figure 1. Mechanisms of new drugs assessed

in prevention or treatment of acute kidney in-
jury in critical care.
HGF: Hepatocyte growth factor; MSC: Mes-
enchymal Stem Cells.

ment of AKI in critical care settings failed to identify an effective receptors (TLRs), initiating the inflammatory response by
therapeutic intervention. However, recent advancements in un- recruiting pro-inflammatory mediators (e.g., Tumor necrosis
derstanding AKI pathophysiology have elucidated shared mech- factor-𝛼 (TNF-𝛼), interleukins (IL-6 or IL-18)). This innate re-
anisms underlying its development in critically ill patients, in- sponse led to the recruitment of neutrophils and macrophages,
cluding inflammatory responses, metabolic dysfunction, and im- leading to production of pro-inflammatory cytotoxic mediators
paired cellular repair. These advancements have paved the way which amplify cell damage.[14] ALP are ubiquitous hydrolases
for new drugs targeting different mechanisms involved in kid- in humans, playing a role in the dephosphorylation of different
ney injury. Overall, new fields of interventions are emerging to endotoxins, notably lipopolysaccharide (LPS).[15] Dephospho-
offer the most suitable therapy possible to critically ill patients, rylated LPS acts as a TLR-4 antagonist and therefore could
taking into account the timing of renal injury and the patient’s reduce the innate immune response after bacterial activa-
condition. In our review, we aim to provide a comprehensive tion.[16] Another mechanism of ALP is the dephosphorylation of
overview of these new drugs and their primary mechanisms of extracellular adenosine triphosphate (ATP) and adenosine di-
action (Figure 1/ Table 1). phosphate (ADP), inhibiting their pro-inflammatory effect.[17]
A phase 2 trial, the STOP-AKI trial, has been conducted in 301
Inflammation patients with SA-AKI, comparing recombinant ALP (ilofotase
alfa) and placebo.[18] In this trial, ilofotase alfa failed to demon-
Inflammatory pathways are activated after different triggers strate an improvement on 7-days renal function, the primary
occurring in intensive care unit (ICU), such as sepsis or is- outcome. However, the extended analysis up to day 28 showed
chemia/reperfusion injury (IRI). In the early phase of injury, an improvement of creatinine clearance of 18.5 mL/min (95 %
innate response enhances pro-inflammatory cytokine that may confidence interval [CI]: 5.3 to 31.7, P=0.006) and a reduction
trigger organ damage. After this early phase, inflammation may of mortality in patients treated with ilofotase alfa (14.4 % vs.
be involved in non-recovery of the AKI, and partial repair lead- 26.7 %, P=0.02). Based on this promising result, a phase 3
ing to fibrosis and CKD.[12 , 13] Targeting different phases of in- trial was conducted to compare the effectiveness of ilofotase
flammatory response may prevent or limit the kidney. alfa vs. placebo in patients with SA-AKI with 28 days and
all-cause mortality as primary outcome. After enrolling 655
Alkaline phosphatase (ALP) patients, the REVIVAL trial was stopped for futility on this
primary outcome.[19] All-cause mortality was not different in
After activation of inflammatory pathways, damage- both groups at day 28 (27.9 % vs. 27.9 %, P=0.50) or at day
associated molecular patterns are recognized by Toll-like 90 (33.9 % vs. 34.8 %, P=0.47). However, the trial suggests

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Table 1
New drugs assessed for prevention or treatment of AKI in critical care.

Drug Mechanism Target Ongoing RCT Population

Angiotensin II Hemodynamic Renal efferent arteriole NCT05199493 Prevention of CSA-AKI

NCT04592744 Prevention of AKI after liver
transplantation
NCT04901169 Prevention of AKI after liver
transplantation
Vasopressin NCT04602767 Prevention of CSA-AKI
NCT06125184 Prevention of SA-AKI (septic shock)
Levosimendan Renal afferent arteriole NCT02531724 CSA-AKI
NCT01720030 AKI
Reltecimod Immunomodulation CD28 NCT03403751 SA-AKI
Activated vitamin D NF-kb NCT02962102 Prevention of AKI in high-risk patients
ALP TLR-4 NCT06168799 Prevention of CSA-AKI
RBT-1 IRI PROTECT study Prevention of CSA-AKI
TIN816 ATP/ADP NCT05996835 SA-AKI
NCT05524051 Prevention of CSA-AKI
Vitamin B3 vitamers Cellular metabolism NAD+ NCT04750616 Prevention of CSA-AKI
NCT05513807 Delayed renal graft function
NCT04589546 Prevention of SA-AKI (septic shock)
NCT04818216 AKI and COVID-19
ASP1128 PPAR𝛿
SIRT1 NCT04342975 Prevention of AKI after Aortic arch
replacement
Ravulizumab Complement inhibitors C5 NCT05746559 Prevention of CSA-AKI
siRNA (QPI-1002) Apoptosis inhibitors/Cellular P53 NCT02610296 Delayed renal graft function
HGF repair Bcl-2 NCT02771509 Prevention of CSA-AKI
MSC NCT04445220 RRT and COVID-19
NCT04194671 AKI

ADP: Adenosine di-phosphate; ALP: Alkaline phosphatase; AKI: Acute kidney injury; ATP: Adenosine triphosphate; C5: Complement 5; CSA-AKI: Cardiac surgery-
associated acute kidney injury; HGF: Hepatocyte growth factor; IRI: Ischemia-reperfusion injury; MSC: Mesenchymal stem cells; NAD+ : Nicotinamide Adenine
Dinucleotide; NF-𝜅b: Nuclear factor kappa b; PPAR𝛿: Peroxisome proliferator-activated receptor delta; RCT: Randomized controlled trial; RRT: Renal Replacement
therapy; SA-AKI: Sepsis-associated acute kidney injury; siRNA: Small interfering RNA; SIRT1: Sirtuins; TLR-4: Toll-like receptor 4.

a potential benefit of ilofotase alfa in the reduction of Major and resolution of organ dysfunction as assessed by the SOFA
adverse kidney events (MAKE) at day 90 (MAKE90) (56.7 % score. While this trial failed to find a benefit in NSTI success of
vs. 64.6 %, P=0.02). Notably, this benefit primarily stems from treatment with Reltecimod for the primary endpoint (48.6 % vs.
a decrease in the requirement for RRT among patients treated 39.9 %, P=0.14), it shows an improvement in organ dysfunction
with ilofotase alfa (28.2 % vs. 36.4 %). Remarkably, this effect with a reduction of SOFA score at day 14 (65.1 % vs. 52.6 %,
was even more pronounced among patients with pre-existing P=0.04).[24]
altered renal function, implying that enriching the population A phase 3 trial is recruiting patients with confirmed AKI stage
could hold significant promise. An ongoing phase 2 trial aims to 2 or 3 according to the KDIGO criteria (NCT03403751) with
assess the preventive effect of ilofotase alfa on CSA-AKI in 150 confirmed or suspected abdominal sepsis. The primary endpoint
patients undergoing prolonged cardiopulmonary bypass (CPB) is the recovery of AKI at day 28, defined as being alive, free of
with a preoperative estimated GFR between 25 mL/(min·m2 ) dialysis, and with less than 37 % loss of estimated glomerular
and 65 mL/(min·m2 ) (NCT06168799). filtration rate (eGFR) from baseline.

Reltecimod Activated vitamin D

Following the initial immune response, a later injury phase The role of Vitamin D in kidney function has long been de-
is characterized by the recruitment of natural killer T cells and bated, potentially extending beyond its involvement in calcium
macrophages. During this adaptative immune response, CD4+ homeostasis and bone metabolism. Studies suggest that Vitamin
and CD8+ T cells play a role in injury.[12] Reltecimod, a peptide D may mitigate inflammatory and profibrotic pathways relevant
developed by Atox Bio, specifically binds to the co-simulator to kidney disease through various mechanisms.[25–27] In a mice
CD28 on T-cell surface to modulate the inflammatory response model of sepsis-induced AKI, activated vitamin D may downreg-
during sepsis in animal models.[20–22] In patients with necrotiz- ulate the expression of nuclear factor-kappa b (NF-𝜅b) in renal
ing soft tissue infections (NSTI), early Reltecimod injection was tubules, modulating inflammatory responses.[28] Vitamin D in-
associated with an improvement of Sequential Organ Failure As- sufficiency has widely been identified in patients with CKD, and
sessment (SOFA) score at day 14 in a phase 2 trial compared to its supplementation is still debated in this context.[29] While vi-
placebo, without related adverse events.[23] In a phase 3 trial tamin D can be administrated in different forms, its active form
involving 290 patients, Reltecimod injected within 6 h after the Calcitriol (1,25(OH)2D) or its percussor Calcifediol (25(OH)D),
diagnosis of NSTI was compared to placebo. The primary end- a meta-analysis of four prospective studies found that levels of
point was a composite outcome evaluating the efficacy of NSTI Calcitriol rather than Calcifediol were significantly lower in pa-
treatment, including vital status at day 28, extent of debride- tients developing AKI.[30] The formation of calcitriol from cal-
ment at day 14, absence of post-initial operation amputation, cifediol occurs in the proximal renal tubules, which could ex-

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plain the decrease in calcitriol levels during AKI. Moreover, pa- monophosphate (AMP). AMP is then converted to adenosine by
tients with AKI have elevated blood levels of fibroblast growth the surface enzyme ecto-5′-nucleotidase (CD73).[40]
factor 23 (FGF23), an osteocyte-derived hormone that inhibits TIN816 is an engineered, highly active, soluble, and stabi-
vitamin D synthesis.[31] Focusing on critically ill patient, an ob- lized recombinant CD39 developed by NOVARTIS that depletes
servational study will assess the levels of calcifediol, calcitriol, extracellular ATP and ADP into AMP. Recombinant CD39 ap-
parathyroid hormone, and FGF23 in patients with and without pears to reduce inflammation, thrombosis, and promotes tissue
AKI (NCT02869919). In critically ill patients with high risk of repair in preclinical studies.[41 , 42] In human whole blood TIN816
AKI, the phase 2 trial, ACTIVATE-AKI (NCT02962102), has en- dose dependently inhibited ATP/LPS-induced IL-1𝛽 secretion as
rolled 150 patients to assess the preventive effect of calcitriol well as ADP-induced platelet aggregation.
and calcifediol compared to placebo. The first analysis of the Three ongoing trials are now recruiting patients to as-
primary outcome, death within 7 days, did not show significant sess and investigate the effect of TIN816. A pharmacologi-
differences among the three groups, nor did the need for RRT cal trial assesses pharmacokinetic and pharmacodynamic pro-
or changes in serum creatinine levels within the first 7 days. file of 20 patients with SA-AKI after TIN816 administration
(NCT05507437), results are not available yet. The efficacy and
safety of TIN816 for the treatment of SA-AKI will be evaluated in
RBT-1 a trial of 320 patients. Participants will receive different doses
of TIN816 or placebo. The primary endpoint of the trial will
RBT-1, developed by Renibus therapeutic, is a combination be the average of the area under the time-corrected creatinine
drug composed of stannic protoporfin (SnPP) and iron sucrose clearance curve from day 1 to day 8 (NCT05996835). In the set-
(FeS) and may protect from IRI during AKI. Ischemia is char- ting of cardiac surgery, a trial is currently recruiting patients to
acterized by a cessation of nutrient and oxygen supply, lead- assess the potential effect of TIN816 administration during CPB
ing to a halt in ATP production through oxidative phosphory- on prevention of CSA-AKI (NCT05524051). The study aims to
lation, resulting in cytoplasmic accumulation of hydrogen ions enroll 120 patients.
and intracellular acidosis.[32] Adaptive mechanisms lead to an
increase in intracellular calcium concentration that participates
Hemodynamic
in the production of inflammatory cytokines and the activa-
tion of intracellular proteases. These combined factors lead to
A decrease in renal perfusion and low blood pressure can im-
the initiation of apoptosis.[33] Quickly, adaptive antioxidative
pair renal perfusion and contribute to the development of AKI.
mechanisms are surpassed, and free radical production causes
cellular damage. Increased permeability of the mitochondrial
membrane results in the release of cytochrome C into the cy- Angiotensin II
toplasm, leading to apoptosis of damaged cells.[34] Ischemia-
reperfusion thus induces an inflammatory response, oxidative Angiotensin II plays a pivotal role as a hormone in the renin-
stress, and protease activation promoting apoptosis participat- angiotensin-aldosterone system (RAAS). Conditions such as re-
ing to AKI.[35] RBT-1 demonstrates a pharmacological precondi- duced renal perfusion or low arterial blood pressure can trigger
tioning effect in a phase 2 trial involving 135 patients undergo- the activation of RAAS, resulting in the release of angiotensin
ing cardiac surgery with CPB. This effect manifests as a reduc- II and subsequent vasoconstriction. Notably, angiotensin II ex-
tion in IRI biomarkers, achieved through the upregulation of erts a selective vasoconstrictive effect on the renal efferent ar-
anti-inflammatory, antioxidant, and iron scavenging pathways, teriole, thereby enhancing the GFR. Interestingly, several lines
including IL-10, Heme-oxygenase 1, and ferritin. However, RBT- of evidence suggest decreased levels of angiotensin II in criti-
1 administration did not lead to a significant reduction in CSA- cal conditions such as CPB or septic shock.[43 , 44] These low an-
AKI incidence (9 % vs. 14 %, risk difference=−4.9, 95 % CI: giotensin II levels could contribute to the development of AKI.
−19.5 to 9.1).[36] The PROTECT study is an ongoing phase 3 trial Understanding the intricate dynamics of angiotensin II in the
aiming to assess the preventive effect of RBT-1 in 400 patients RAAS provides valuable insights into the pathophysiology of
undergoing cardiac surgery. The primary endpoint is a compos- conditions impacting renal function. During vasoplegic shock,
ite with death, AKI requiring dialysis, ICU length of stay, and a pilot study involving 20 patients found that angiotensin II
30-day cardiopulmonary readmission rates.[37] was associated with a reduction of catecholamine doses and
higher urine output within 8 h after treatment initiation.[45] The
ATHOS-3 trial aimed at evaluating the efficacy of angiotensin
TIN816 II in refractory vasodilatory shock.[46] The primary outcome of
the ATHOS-3 trial was a response with respect to mean arterial
Hypoxic conditions during kidney injury result in the release pressure (MAP) at hour 3 after the start of infusion (69.9 % in
of extracellular ATP. In the extracellular space, ATP acts as a the angiotensin II vs. 23.4 % in the placebo group, odds ratio
pro-inflammatory factor by recruiting leukocytes and promot- (OR)=7.95, 95 % CI: 4.76 to 13.3, P <0.001). Death by day 28
ing the secretion of pro-inflammatory cytokines such as IL-1𝛽 occurred in 75 of 163 patients (46 %) in the angiotensin II group
and IL-18 to the site of injury. Furthermore, the dephosphory- and in 85 of 158 patients (54 %) in the placebo group. In a post
lation of ATP leads to the production of ADP, which in turn hoc analysis of the ATHOS-3 trial in patients requiring RRT, an-
triggers platelet activation and thrombosis, contributing to or- giotensin II was associated with increased 28-day survival (53 %
gan injury[38 , 39] ATP and ADP are enzymatically phosphohy- vs. 30 %, P=0.0012) and a higher rate of RRT discontinuation
drolyzed by ectonucleoside-triphosphate-diphosphohydrolase- at day 7 (38 % vs. 15 %, P=0.0068).[47] The potential beneficial
1 (also known as ectopyrase, CD39), yielding adenosine effect of angiotensin II on blood pressure during liver transplan-

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tation is currently under investigation in two different trials aim- dence of CSA-AKI (34 % vs. 40 %; P=0.14) or RRT requirement
ing to recruit, respectively, 30 (NCT04592744) and 50 patients (9.7 % vs. 12.8 %, P=0.27) in a larger RCT.[57] During sepsis,
(NCT04901169).[48] In the context of cardiac surgery, a feasibil- Levosimendan also failed to show a potential benefit in the pre-
ity study compares the use of angiotensin II to norepinephrine to vention of AKI in a RCT involving 516 patients (45.7 vs. 42 %,
maintain a MAP over 70 mmHg intra-operatively and up to 48 h P=0.45).[58] As the preventive effects of Levosimendan on AKI
post-operatively in 61 patients. In this trial, patients treated with remain unproven, there is growing interest in exploring poten-
angiotensin II had a lower incidence of CSA-AKI, although this tial therapeutic applications of Levosimendan in the context of
difference did not achieve statistical significance (25 % vs. 38 %; established AKI. An ongoing RCT, LEVO-AKI (NCT02531724),
P=0.31).[49] This potential preventive impact of angiotensin II is assessing the potential of Levosimendan in the treatment of
on CSA-AKI will be explored in an upcoming trial focusing on CSA-AKI, while another trial focuses on all patients with AKI
patients requiring vasopressors after cardiac surgery with eleva- (NCT01720030) (LAKIS trial results have not been published).
tion of renin level postoperatively (NCT05199493), a biomarker
suggestive of angiotensin II deficit. Cellular Metabolism

Vasopressin Metabolism impairment in AKI has been increasingly high-

lighted in recent years. The kidney, being an organ with a high
Vasopressin exhibits vasoconstrictor effects by modulat- metabolic demand, relies on ATP for active transport and solute
ing the function of ATP-sensitive potassium channels, nitric reabsorption. Any disruptions in energy availability and utiliza-
oxide production, and enhancing vascular response to cate- tion can result in cellular dysfunction. Emerging evidence in-
cholamines.[50] Unlike norepinephrine, vasopressin acts on the dicates that pathways involving energy metabolism and mito-
renal efferent arterioles and has potential nephroprotective ef- chondrial dysfunction are pivotal contributors to AKI, present-
fects. In ovine model of septic-induced AKI, vasopressin re- ing novel potential targets for therapeutic interventions.
stored MAP but also maintained renal perfusion, leading to sus-
tained improvement in renal function when compared to nore- Vitamin B3 vitamers: niacine, nicotinamide, or nicotinamide
pinephrine.[51] A single double-blind RCT involving 330 patients riboside (NR)
in vasoplegic shock after cardiac surgery demonstrated a reduc-
tion of CSA-AKI with vasopressin compared to norepinephrine Mitochondrial respiration and function are compromised in
(10.3 % vs. 35.8 %; P <0.0001).[52] However, in the context of AKI, leading to a disruption in the de novo biosynthesis of Nicoti-
septic shock, a large multicenter RCT including 409 patients, namide Adenine Dinucleotide (NAD+ ), a factor contributing
vasopressin infusion did not reduce the incidence of AKI com- to the development of AKI. Vitamin B3 includes three forms:
pared to norepinephrine.[53] Moreover, a RCT focusing on 250 Niacin, Nicotinamide (Nam), or NR, which plays a crucial role
patients with septic shock and cancer also reported an absence of in NAD+ production. Poyan Mehr et al.[59] demonstrated that
a significant reduction in AKI when vasopressin was employed NAD+ protects against AKI, highlighting the significance of its
compared to norepinephrine (42.4 % vs. 41.6 %; P=0.98).[54] In biosynthesis and its impairment as a contributing factor in the
2019, an individual patient data meta-analysis including 1453 pathogenesis of AKI. In a phase 1 pilot study involving 41 pa-
patients of four RCT comparing vasopressin to norepinephrine tients in cardiac surgery, they found that administration of Nam
in septic shock found a potential reduction of the need for perioperatively was associated with a 35 % decrease in AKI in-
RRT with vasopressin (risk ratio=0.86, 95 % CI: 0.74 to 0.99). cidence compared to placebo. Building on this finding, a phase
These divergent results underscore the nuanced and context- 2 trial in cardiac surgery is underway to assess the preventive
dependent effects of vasopressin, prompting a careful consid- effect of 3 g of Nam administered on the day of surgery and
eration of its application in distinct clinical scenarios. In car- for 2 days post-surgery compared to placebo in patients at high-
diac surgery, an ongoing RCT aims at comparing vasopressin to risk for CSA-AKI. The study aims to enroll over 300 patients
phenylephrine as first line vasopressor intra-operatively, with (NCT04750616). In the context of renal transplantation, a phase
CSA-AKI as a primary outcome (NCT04602767). In patients with 3 trial will evaluate the effect of perioperative Nam administra-
a history of arterial hypertension and septic shock, a trial will tion on early graft function (NCT05513807). Additionally, in pa-
compare the adjunction of vasopressin to norepinephrine vs. tients with septic shock, a multicenter RCT is underway to evalu-
norepinephrine alone on renal outcome (NCT06125184). ate the preventive effect of 3 days of 1 g Nicotinamide (Nam) on
AKI compared to placebo (NCT04589546). Meanwhile, NR, an-
Levosimendan other form of vitamin B3, is being evaluated in the treatment of
AKI among 28 patients with coronavirus disease 2019 (COVID-
Levosimendan, an inotropic agent, acts by sensitizing tro- 19) in an ongoing RCT (NCT04818216).
ponin C to the action of calcium, thereby improving cardiac
contractility. In addition, the vasodilatory effect of levosimen- ASP1128
dan, in particular in afferent renal arteriole, may participate to
the theoretical benefits of AKI.[55] In cardiac surgery, a meta- Peroxisome proliferator-activated receptor-gamma (PPAR𝛾)
analysis involving 13 small RCTs shows a reduction in the in- is a nuclear hormone receptor that is consistently expressed
cidence of CSA-AKI (OR=0.51, 95 % CI: 0.34 to 0.76) and RRT across the kidney. Various lines of evidence indicate that the
(OR=0.43, 95 % CI: 0.25 to 0.76) when Levosimendan was used activation of PPAR𝛾 can provide kidney protection against IRI,
perioperatively.[56] Contrastingly, the administration of Levosi- primarily through its anti-inflammatory, antioxidant, and anti-
mendan within the 48 h post-surgery did not reduce the inci- apoptotic effects.[60] ASP118, a selective modulator of peroxi-

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some proliferator-activated receptor-delta (PPAR𝛿), has demon- or paroxysmal nocturnal hemoglobinuria, effectively inhibit-
strated the upregulation of PPAR𝛿/fatty acid oxidation target ing complement-mediated thrombotic microangiopathy. During
genes persisting for at least 24 h after administration.[61] This AKI, the efficacy of Ravulizumab was investigated in a pilot RCT
sustained effect holds the potential for providing a renoprotec- involving 13 patients with COVID-19. Patients who were treated
tive impact on IRI. However, when evaluated in cardiac surgery with Ravulizumab had lower dialysis needs 10 days after enroll-
patients at high risk of AKI, as defined by one AKI risk factor and ment (P=0.03) and an upward trend in GFR over 30 days com-
elevated postoperative urinary biomarker (TIMP2) × (IGFBP7) pared to the placebo (P=0.009). However, those findings need to
levels, the trial involving ASP1128 was stopped for futility after be balanced with the very small sample size and high risk of type
enrolling 151 patients. The primary endpoint, the incidence of 1 error and the observation of a higher need for hemodialysis
CSA-AKI at 72 h, did not differ between the treatment and con- by day 30 in patients who received Ravulizumab (18 % vs. 9 %,
trol groups (24.6 % vs. 21 %, P=0.595). Furthermore, ASP1128 P=0.18).[69] A Phase 3 multicenter RCT, the ARTEMIS trial aims
did not show associations with a reduction in AKI severity, a to recruit 736 patients with CKD undergoing cardiac surgery,
decrease in the need for RRT, or a reduction in Major Adverse evaluating the potential benefits of Ravulizumab in preventing
Kidney Events at days 30 and 90.[62] CSA-AKI (NCT05746559).

Sirtuins (SIRT1) Apoptosis Inhibitors/Cellular Repair

Sirtuins, comprising seven members (SIRT1–7), are NAD+ - The nature of apoptosis involvement in AKI remains uncer-
dependent histone deacetylases. The most studied Sirtuin in AKI tain. However, histological evidence confirms the presence of
is SIRT1. Highly expressed in the kidney, especially in the re- apoptosis in tubular cells during AKI.[70] Additionally, animal
nal medulla, SIRT1 deficiency amplifies susceptibility to AKI models of induced AKI have shown that inhibition of apoptosis
in mice.[63] SIRT1 exhibits a multifaceted potential to prevent prevents AKI.[71] At the late stage of AKI, cellular repair mecha-
AKI. Firstly, it can activate PPAR𝛾, promoting mitochondrial nisms are engaged, however, their impairment can prolong AKI
biogenesis and thereby mitigating AKI. Additionally, SIRT1 em- and contribute to partial recovery, potentially leading to CKD.
ploys other mechanisms for AKI protection, including the regu-
lation of apoptosis through the deacetylation of p53, contribut- Small interfering RNA (siRNA) (QPI-1002)
ing to renal cell preservation. Furthermore, SIRT1 acts as an
anti-oxidative agent in tubular cells, supporting its protective ef- QPI-1002, a synthetic siRNA developed by Quark Pharma-
fects against AKI. These intricate pathways highlight the diverse ceuticals, serves to transiently inhibit P53, a tumor suppressor
and comprehensive role of SIRT1 in renal protection.[63–65] In a protein. The role of P53 is multiple in the process and repair
safety clinical trial involving 24 patients, NRPT, a combination of AKI. Following IRI, P53 is secreted and activated. During the
of NR and pterostilbene (PT) acting in synergy on NAD+ and early stages of AKI, P53 may exert a protective effect by inducing
SIRT-1 activation was tested in patients with AKI. In this study, renal tubular cell arrest and reducing cell proliferation. How-
20 patients received NRPT, while 4 patients were administered ever, in cases of prolonged or severe AKI, P53 can trigger tubu-
a placebo. Despite no significant difference in GFR observed lar cell death, exacerbating AKI, and promote autophagy, thus
between the two groups, patients treated with NRPT exhibited impeding renal repair following the initial injury.[72] In mice,
lower Blood Urea Nitrogen (BUN) levels 48 h after treatment.[66] p53 knockout specifically from proximal tubules demonstrated
In light of these promising results, a Phase 2 trial is currently protection against AKI induced by ischemia and cisplatin.[73]
underway to investigate the potential impact of NRPT supple- QPI-1002 was evaluated in different contexts. After renal trans-
mentation. The trial involves administering NRPT 2 weeks be- plantation, QPI-1002 was assessed for its ability to prevent de-
fore aortic arch replacement surgery and continuing for 6 weeks layed graft dysfunction in 327 patients. Although not statisti-
afterward, with the aim of preventing AKI (NCT04342975). cally significant, there was a relative reduction of 30 % in de-
layed graft function observed among patients who received QPI-
Complement Inhibitors 1002 (27.3 % vs. 39.3 %), and a significant improvement in GFR
at day 30 (34.8 mL/(min·1.73 m2 ) vs. 21.1 mL/(min·1.73 m2 ),
Kidney hypoxia and IRI initiate complement activation on the P=0.035).[74] An ongoing trial to confirm this potential bene-
surface of proximal tubular cells by triggering the lectin path- fit on delayed graft dysfunction after renal transplantation is
way. Complement activation leads to the release of anaphylatox- completed with almost 600 patients (NCT02610296), results
ins (C3a and C5a) contributing to interstitial fibrosis. Moreover, are pending. After cardiac surgery, QPI-1002 was assessed for
complement activation plays a significant role in tubular dam- high-risk patients for AKI. QPI-1002 was administered intraop-
age induced by myoglobinuria and hemoglobinuria, as heme can eratively, and the primary endpoint was the incidence of AKI
directly activate complement.[67] based on creatinine levels measured 5 days postoperatively. A
total of 360 patients were enrolled, and the incidence of AKI was
Ravulizumab reduced by 13 % with QPI-1002 (37 % vs. 50 %, P=0.02). Ad-
ditionally, AKI severity and duration were also decreased in pa-
Ravulizumab inhibits the cleavage of C5 into C5a and tients treated with QPI-1002. However, at 90 days, there was no
C5b on the endothelial cell surface, effectively preventing en- significant difference in the incidence of Major Adverse Kidney
dothelial dysfunction resulting from complement activation.[68] Events between the two groups (19.3 % vs. 20.9 %, P=0.71).[75]
This long-acting inhibitor of complement C5 is currently ap- Focusing on MAKE90 as the primary endpoint, a phase 3 clini-
proved for treating atypical hemolytic uremic syndrome (aHUS) cal trial evaluating QPI-1002 for the prevention of CSA-AKI en-

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G. Hariri and M. Legrand Journal of Intensive Medicine xxx (xxxx) xxx

rolling over 1000 patients with high-risk for AKI, was stopped with AKI requiring dialysis assessed the effect of ex vivo admin-
for futility (NCT03510897). istration on another BM-MSC (SB-101). While the sample size
was too small to exhibit clinical differences between groups,
Hepatocyte growth factor (HGF) they found that patients treated with ex vivo BM-MSC had im-
munotherapeutic response triggering accelerated tissue repair
HGF is a pleiotropic protein that participates in injury repair and therefore may have clinical effect.[84] This ex vivo therapy
through the regulation of cell proliferation, survival, and regen- will be evaluated in patients with SARS-CoV-2 infection requir-
eration across various organs, and specifically in the kidney.[76] ing RRT (NCT04445220). Another trial will assess the effect of
AKI triggers the upregulation of cMet expression, the receptor Umbilical cord MSC for the treatment of AKI, aiming to include
of HGF, leading to the formation of the HGF-cMet complex, 100 patients (NCT04194671).
which suppresses apoptosis by activation of Bcl-2, a critical sur-
vival protein.[77] BB3, a small molecule synthesized by Angion Conclusion
Biomedica Corporation (New York, USA) through the reductive
distillation of HGF-like peptides, mimics the biological activity AKI has currently no preventive or therapeutic therapy prov-
of HGF. A preclinical study demonstrated that administration of ing effective with a high level of evidence. However, advance-
BB3 24h after IRI in rats improves survival, mitigates tubular in- ments in understanding the pathophysiology of AKI allow the
jury, BUN and serum creatinine levels, and enhances renal out- development of new strategies targeting various pathways that
put.[78] In a phase 2 study involving 28 patients with low urine are under investigation. Drugs in development exhibit a wide-
output in the 8 h after renal transplant, recovery of urine output ranging impact on pathophysiological processes, from cell death
was more frequent and faster after administration of BB3 (84 % inhibition to inflammation modulation and hemodynamic man-
vs. 50 %, log-rank test: 𝜒 2 =2.799, P=0.09).[79] Interestingly, the agement. With several drugs now in phase 3 trials, the future
authors observe a persistent improvement over time in eGFR in appears bright for AKI prevention and treatment in critically ill
patients who received BB3, from day 14 to 12 months after re- and surgical patients.
nal transplantation. These promising results were explored in a
phase 3 multicenter RCT assessing the impact of BB3 with eGFR Author Contributions
at day 360 after renal transplantation as the primary endpoint.
A total of 248 patients were analyzed, 124 in each group, with- Geoffroy Hariri: Writing – review & editing, Writing – orig-
out any difference on the primary endpoint (eGFR [53.2±2.69] inal draft, Conceptualization. Matthieu Legrand: Writing – re-
mL/(min·1.73 m2 ) vs. [50.2±2.70] mL/(min·1.73 m2 ), P=0.32). view & editing, Conceptualization.
Duration and number of dialysis, delayed graft function, and
acute rejection were similar in both groups. Those results do Acknowledgments
not supporting the interest of BB3 after renal transplantation.[80]
In another context, Angion Biomedica Corporation is conduct- None.
ing a multicenter, randomized, controlled phase 2 trial, Guard
Against Renal Damage (GUARD), assessing the safety and effi- Funding
cacy of BB3 for prevention of CSA-AKI in high-risk AKI patients
undergoing cardiac surgery with CPB (NCT02771509).[81] The This research did not receive any specific grant from funding
primary endpoint will be the mean area under the curve (AUC) agencies in the public, commercial, or not-for-profit sectors.
of the percent increase in serum creatinine above baseline from
H24 to day 6 after surgery, they already enrolled 275 patients.
Ethics Statement

MSC Not applicable.

Mesenchymal Stem Cells (MSC) offer various potential ther- Conflict of Interest
apeutic benefits in the pathophysiology of AKI, contributing to
both the initial injury and the subsequent renal repair processes. Matthieu Legrand is supported by grant R01-GM151494-01
These benefits include immunomodulation, inhibition of apop- from the US National Institutes of Health, and has received con-
tosis, fibrosis, and oxidative stress. Animal studies have demon- sulting fees from Alexion and La Jolla.
strated that MSCs may mitigate AKI by downregulating fac-
tors such as the complement pathway and TNF-𝛼, transform-
Data Availability
ing growth factor beta, while also upregulating others like Bcl-2
and vascular endothelial growth factor, thereby enhancing tubu-
The data sets generated during and/or analyzed during the
lar repair following AKI.[82] A Bone Marrow-MSC (BM-MSC),
current study are available from the corresponding author upon
AC607 (Allocure Inc. Burlington, USA), has been assessed in a
reasonable request.
phase 2 RCT in patients who developed CSA-AKI within 48 h
after the intervention. The primary endpoint was the time to References
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