Acute kidney injury (AKI) is a syndrome with multiple short-term and long-term deleterious effects [1,2]. The past decade was marked by an improvement in the understanding of the cellular and molecular mechanisms involved in AKI . However, there is currently no Food and Drug Administration (FDA)-approved drug for the treatment or prevention of AKI . Barriers to translation of our extensive knowledge of AKI pathogenesis into effective therapeutics are well detailed in the literature [4–6]. This review aims to summarize recent promising agents for the prevention or therapy of AKI (Fig. 1), which include novel agents (Table 1), repurposed drugs (Table 2) and cell-based therapies (Table 3; not further discussed) [7–29]. The detailed pathogenesis of AKI and drug targets still in preclinical development are beyond the scope of this review. Several excellent recent reviews of these topics are referenced [3–9].
Vasoactive drugs: vasopressors, inotropes, vasodilators
Decreased kidney perfusion and microvascular blood flow are critical, well recognized factors in the development of AKI. Sustained, severe kidney hypoperfusion may result in endothelial injury by oxidative stress, alteration to the glycocalyx and reduced capillary blood flow . Several mediators and hormones are implicated in this circulatory dysfunction – including adenosine, nitric oxide and the renin–angiotensin–aldosterone system (RAAS). These mechanisms have led to the development of several therapeutics whose objective is to maintain oxygen and nutrient availability to sustain organ function .
Angiotensin II: Angiotensin II (AII) is a potent vasoconstrictor . In the kidney, it leads to preferential constriction of the efferent arteriole, increasing intraglomerular pressure and filtration fraction. Severe inflammatory states may lead to dysfunction of the RAAS, resulting in a relative lack of AII . Animal models of sepsis demonstrated that AII levels are diminished, which may lead to a decreased transcapillary glomerular pressure gradient and, consequently to AKI. Exogenous infusion of AII increases urine output and improves kidney function [4,34]. Recently, in patients with catecholamine-resistant shock, a phase 3 trial, ‘Angiotensin II for the Treatment of High-Output Shock’ (ATHOS-3), showed that it effectively increased blood pressure, with a trend toward improved survival at 28 days and no increase in AKI-related adverse events . The FDA approved AII for the treatment of vasodilatory shock in 2017. A similar study is underway in a pediatric population (NCT03623529). To date, no study aiming to specifically study the potential renoprotective effects of AII has been published. However, a post-hoc analysis of the ATHOS-3 trial, in patients with AKI requiring renal replacement therapy (RRT), showed a higher 28-day survival and improved day-7 dialysis-free survival in the AII group compared with placebo . The ongoing phase 2 Angiotensin in Septic Kidney Injury Trial evaluates the hemodynamics and urine output in patients with sepsis and AKI exposed to AII (NCT00711789). Another trial is assessing the efficacy of AII in hepatorenal syndrome (ANTHEM Trial, NCT04048707).
Levosimendan: Levosimendan is a calcium sensitizer with inotropic and vasodilatory effects (inodilator). Recently approved for decompensated heart failure in patients with low cardiac output, it improved cardiac contractility without increasing oxygen consumption . However, three large randomized controlled trials (RCTs) and a recent meta-analysis did not demonstrate an improvement in clinical outcomes with levosimendan over conventional inotropic drugs, limiting its routine clinical use . Theoretically, an improvement in cardiac function following its administration could lead to improved renal perfusion and function. In addition, it appears that afferent renal arteriolar vasodilation also plays a role in the potential renoprotective effects of levosimendan [4,37]. Animal models of ischemia-reperfusion and endotoxemia supported this hypothesis . Furthermore, a meta-analysis combining 13 small RCTs on the efficacy of levosimendan in 1345 patients shown a reduction in postoperative AKI, need for RRT, postoperative mortality, days of mechanical ventilation and length of ICU stay . However, a small RCT with primary renal hemodynamic outcomes showed no benefit of levosimendan over dobutamine in patients with cardiorenal syndrome . Two larger RCTs are underway to specifically assess the impact of levosimendan on renal outcomes. The phase 4 ‘Effects of Levosimendan in Acute Kidney Injury after Cardiac Surgery trial’ (LEVOAKI) measures the effect of 210 min infusion of levosimendan versus placebo on renal hemodynamics and glomerular filtration rate (GFR) following cardiac surgeries (NCT02531724). A second RCT is assessing its efficacy on nonsurgical AKI in the ICU (LAKIS, 2012-004979-39).
Atrial natriuretic peptide agonists: Natriuretic peptides (atrial natriuretic peptide – ANP and brain natriuretic peptide – BNP) are endogenous hormones released in response to myocardial stretch and overload, inducing various actions such as natriuresis, kaliuresis, vasodilation and suppression of the RAAS . Currently, nesiritide (a recombinant BNP) is approved for acute heart failure treatment in the USA, while carperitide (a recombinant ANP) is approved in Japan . Renal benefits may also include protective effects on podocytes and arteriolar vasodilation by local RAAS blockade [44,45]. A recent meta-analysis of 1471 patients treated with low-dose carperitide found a trend towards a lower incidence of AKI and RRT initiation in patients at risk of AKI . Ularitide, another recombinant ANP peptide, is currently under investigation in a phase 2 proof-of-concept trial for AKI treatment following cardiovascular surgery (TRUST, 2018-004871-11).
Kidney injury is associated with the release of inflammatory cytokines that attract neutrophils, macrophages and lymphocytes. Inflammation plays a key role in the pathogenesis of AKI and its prognosis. No immunomodulatory interventions have been found effective and approved for the prevention or treatment of AKI to date.
The T-cell costimulatory receptor CD28 is critical to the adaptive immune response. Bacterial toxins may act as superantigens to hyperstimulate the response, inducing a cytokine storm . Reltecimob (formerly AB103) is an immunomodulator that may attenuate the systemic inflammatory response to severe infection [48,49]. As a CD28-mimetic peptide, reltecimob is able to selectively inhibit the direct binding of superantigen to the CD28 receptor on T-helper lymphocytes . Preliminary studies on toxic shock in animal models are associated with improved survival. A phase 2 trial in patients with necrotizing soft tissue infections, showed significantly less global organ dysfunction at 14 days without safety concerns . A phase 3 trial is underway to confirm these results, and secondary outcomes include recovery from AKI by day 28 (ACCUTE, NCT02469857). Another large phase 2 RCT, Reltecimob Efficacy for Acute Kidney Injury Trial, will assess the efficacy and safety of this C28 modulator in patients with abdominal sepsis and AKI. The primary endpoint is complete recovery from KDIGO stage 2 or 3 AKI (NCT03403751; 2018-002547-29).
Alkaline phosphatase is an enzyme expressed along the brush border of the proximal tubule. It has the capacity to reduce inflammation via the dephosphorylation and de-toxification of endotoxin (Lipopolysaccharide), and by dephosphorylation of ATP (which is a proinflammatory mediator) to produce adenosine, which has anti-inflammatory properties [51,52]. A recombinant chimeric alkaline phosphatase (recAP) could potentially exert anti-inflammatory effects and improve kidney function in sepsis, as shown in animal models and early phase trials using a bovine-derived form . Recently, the STOP-AKI trial, using recAP in 301 patients with septic AKI randomized from 53 international sites, confirmed safety. While recAP did not significantly improve short-term (7-day) kidney function (the primary outcome) or need for RRT [54▪▪], there were signals of beneficial effects on both renal function and mortality (dose-dependent) . A large phase 3 RCT of recap in septic AKI is currently in development .
Sphingosine-1-phosphate (S1p) analogues might mitigate endothelial damage and lymphocyte effects in AKI . S1p-receptor activation improves cell survival by a reversible redistribution of lymphocytes, leading to temporary anti-inflammatory and tissue-protective effects . Two analogues have been studied in renoprotection: fingolimod (FTY720) and SEW2871. In animal models exposed to cisplatin and ischemia-reperfusion, FTY720 was found to decrease renal injury biomarkers  and SEW2871 was associated with reduced tubular necrosis, lower serum creatinine and less leukocyte infiltration . Fingolimod was also tested in several small RCTs to prevent acute rejection and delayed graft function  in kidney transplantation, with conflicting results; a meta-analysis is currently underway . Despite potential benefits in renal ischemia-reperfusion injuries, no clinical trial involving S1p analogues on patients at risk of AKI has been registered to date.
∝ Melanocortin stimulating hormone
An ∝-melanocortin stimulating hormone (MSH) agonist, ABT-719 (formerly AP214) also has anti-inflammatory effects. It decreases nitric oxide production, neutrophil adhesion molecule expression and inflammatory cytokines . Small and large animal models showed a protective effect of ∝-MSH agonist in septic and ischemia-reperfusion AKI models . A phase 2 trial of 77 patients undergoing cardiac surgery showed a reduced incidence of AKI when receiving ABT-719 (unpublished, NCT01256372). However, a phase 2b study using ABT-719 in 231 chronic kidney disease (CKD) patients who underwent cardiac surgeries did not lower AKI incidence or kidney injury biomarkers . Potential explanations for these discordant results include the lack of preclinical studies with CKD and other risk factors for AKI , and potentially a ‘U-shaped’ dose–effect relationship, with benefit at moderate doses, but harm at higher doses.
Some hormones play a pivotal role in the mechanism behind the pregnancy-associated immune tolerance. Human chorionic gonadotrophin has been shown to exert these immunomodulatory effects . EA-230, a small tetrapeptide, was developed to replicate these properties. It improved survival in mice and in monkeys with experimental septic shock , and preserved renal function in models of renal ischemia-reperfusion and transplantation [67,68]. A phase 2 RCT is currently being conducted in 180 patients undergoing elective cardiac surgery . The primary outcome is comprised of changes in inflammatory mediators, but secondary outcomes will include serum creatinine and tubular injury biomarkers (EASI-Study, NCT03145220).
Old agents: new trials: dexmedetomidine
Dexmedetomidine, an alpha-2 adrenoreceptor agonist used for its sedative effect, also has hemodynamic and anti-inflammatory properties. Animal studies showed a renoprotective effect in ischemia-reperfusion injuries that may be explained, at least in part, by a reduction of Toll-like receptor 4 and other proinflammatory signals in tubular cells . A similar effect was described in sepsis models, where exposure to dexmedetomidine reduced IL-6, IL-18, TNF∝ as well as serum creatinine and tubular injury biomarkers like kidney injury molecule-1 (KIM-1) . Several single-center RCTs have addressed this question in humans. A recent meta-analysis focusing in postcardiac surgery AKI prevention, including 10 trials and 1575 patients, concluded that dexmedetomidine might reduce the incidence of AKI , but time and dosage must be further evaluated. Other perioperative RCTs aiming to reduce incidence of AKI with this sedative are ongoing in kidney transplantation (NCT03522688) and following vascular surgery (NCT02607163).
Free radical oxygen species (ROS) play a significant role in AKI. Oxidative stress may have deleterious effects on the kidney on several levels: oxidation of proteins, peroxidation of lipids, damage to DNA and even induction of apoptosis . Various disease states associated with AKI may result in free radical formation, including ischemia-reperfusion, contrast nephropathy, sepsis and drug toxicity . Some potential therapies and repurposed drugs that directly target free radicals might prevent or ameliorate AKI.
Iron is critical to the transport of oxygen and a variety of enzymatic reactions. Although iron is essential for life, in its ferrous form it can catalyze conversion of hydrogen peroxide to the toxic hydroxyl radical. A way of restricting this reaction is to favor the passage of free iron, after heme degradation, to ferritin, its protein-bound form. Heme oxygenase-1 (HO-1) can rapidly breakdown toxic free heme to generate three protective antioxidant products: carbon monoxide, biliverdin and ferritin . In animal models of AKI, in addition to reducing oxidative stress, HO-1 also modulates autophagy, inflammations and apoptosis . Heme arginate is a potent inducer of HO-1. In a proof-of-concept phase 2b study, 40 recipients were randomized to receive heme arginate versus placebo during the first 48 h following kidney transplantation. Upregulation of HO-1 was achieved as the primary endpoint, but the study was not powered to assess renal outcomes, despite a trend toward less biomarker-defined tubular injury . A confirmatory phase 3 multicenter RCT recruiting 600 kidney transplant recipients is looking at reduction in delayed graft function (HOT 2 Trial, NCT03646344). Another phase 2 trial aiming to reduce AKI incidence in the context of cardiac surgery is still ongoing (2013-004607-39).
Old agents: new trials: propofol
Propofol is one of the most commonly used medications for induction and maintenance of anesthesia. With its structural resemblance to vitamin E, propofol has been shown to have anti-inflammatory properties . Propofol can also increase levels of bone morphogenetic protein-7 (BMP-7), a potential tubular repair agent discussed below . Indeed, abundant proliferation and a decreased rate of apoptosis was described in human tubular cells treated with propofol in vitro[80,81]. A large retrospective cohort of 4320 patients who underwent colorectal surgeries demonstrated that anesthesia with sevoflurane was associated with a modest increase in AKI incidence when compared with propofol anesthesia . In addition, a prospective RCT conducted in 112 patients who underwent valvular heart surgery using either sevoflurane or propofol reported surprising results: a large reduction of AKI incidence in the group receiving propofol (10.7 versus 37.5%, P = 0.007) . Another small RCT in abdominal aortic aneurysm repair found similar results . Although prior larger prospective studies [85,86] did not show benefit with propofol over volatile anesthetics for AKI in the past, the large treatment effect observed in these both recent studies supports current active research on various surgical populations, including renal transplantation (VAPOR-2 Trial, NCT02727296), orthopedic procedures (NCT03336801) and partial nephrectomies .
P53 is implicated in cell cycle regulation, apoptosis and genomic stability. This pro-apoptotic transcription factor is activated in various AKI causes, including ischemia-reperfusion and cisplatin nephrotoxicity [88,89]. Teprasiran (formerly named QPI-1002), a small interfering RNA (siRNA) developed by Quark Pharmaceuticals, demonstrated rapid and temporary reduction (24–48 h) in p53 gene expression in AKI animal models. The synthetic siRNA was found to be associated with lower serum creatinine and less histological signs of mitochondria disruption and tubular injury . A phase 2 RCT evaluating the efficacy and safety of teprasiran in patients at high risk of AKI following cardiovascular surgery was recently completed. In 341 patients, treatment with a single dose of teprasiran, versus placebo, reduced the primary endpoint of developing AKI within 5 days by 29%, and the duration of AKI . These results were initially presented in 2017 but remain unpublished. However, based on these positive results, a large phase 3 RCT in 1088 patients at risk of AKI following cardiac surgery is ongoing (QRK309, NCT03510897).
Targeting mitochondrial stress
Mitochondria provide energy that is critical to normal kidney functions such as tubular transport and urinary concentration . In the setting of ischemic injury and sepsis, mitochondria undergo changes including alterations in energy metabolism, and increases in ROS with peroxidation of the critical mitochondrial protein, cardiolipin [93,94]. This critical role of mitochondria dysfunction in AKI has led to potential therapies including : first, Targeting antioxidant therapies to the mitochondria using triphenylphosphonium ion conjugated to lipophilic antioxidant molecules, such as MitoQ, TEMPO (MitoTEMPO) or plastoquinone (SkQR1); second, Cardiolipin-targeting peptides such as Szeto-Schiller peptides that stabilize mitochondrial cristae and can prevent apoptosis, ROS and inflammation (elamipretide, discussed below); third, Mitochondrial homing agents such as mitochonic acid-5 that may increase cellular ATP content; fourth, Drugs that promote fatty acid oxidation, including carnitine or acetyl-l-carnitine supplements and peroxisome proliferator-activated receptor (PPAR) α activators such as fenofibrate. Recently, ASP1128, a selective PPARδ modulator received fast-track designation by the FDA for patients at risk of AKI after cardiac surgery (NCT03941483); fifth, Drugs that promote mitochondrial biogenesis such as the PPARγ agonist pioglitazone and the β2-adrenergic agonist formoterol; and sixth, Activators of the major energy-sensing enzyme adenosine monophosphate kinase kinase such as elamipretide.
Cardiolipin is critical in regulating electron transport in the mitochondria as well as in maintenance of mitochondrial structures that support ATP production. Oxidation of cardiolipin leads to mitochondrial damage, impairment of ATP production, ROS production, inflammation and, consequently, initiation of apoptosis . Elamipretide (also known as SS31, MTP-131 or Bendavia) is a mitochondrially targeted tetrapeptide that reduces the production of toxic ROS and stabilizes cardiolipin . In animal models, elamipretide improves energetics and decreases ROS, possibly by stabilizing the mitochondrial membrane and cytochrome-c . Much of the focus on elamipretide has been in neuromuscular diseases due to inherited mitochondrial deficiencies. However, in an early trial in mitochondrial myopathies, elamipretide was not effective in improving muscle function . Elamipretide has also demonstrated potential for attenuating ischemia-reperfusion injury in AKI models, and improving kidney outcomes after experimental percutaneous renal artery angioplasty in renal artery stenosis models . A phase 2a study was performed in patients undergoing stent revascularization for atherosclerotic renal vascular disease where the drug attenuated renal hypoxia developing 24 h after contrast imaging and stent revascularization. Cortical blood flow and estimated GFR (eGFR) increased in the elamipretide group when measured 3 months later suggesting a role of the drug in minimizing procedure-associated ischemic injury . At this time, there are no current registered trials of elamipretide in AKI.
Nicotinamide is incorporated into nicotinamide adenine dinucleotide (NAD)+ and NADP+. NAD+ and NADP+ are coenzymes in a wide variety of enzymatic oxidation-reduction reactions, most notably glycolysis, the citric acid cycle, and the electron transport chain. Recent studies have shown that chronic deficiency of NAD+ can negatively affect several organ systems, while supplementation of NAD+ can extend longevity . Using a metabolomic screen on the urine of mice with AKI induced by ischemia, defects in de novo biosynthesis of NAD+ and elevations of a precursor substance in the pathway of NAD+ biosynthesis, quinolinate were identified . As a marker for defects in this metabolic pathway, elevated urinary levels of quinolinate/tryptophan were a biomarker for prediction of AKI. Following these observations on the importance of NAD+ biosynthesis, a phase I placebo-controlled study using oral nicotinamide to supplement NAD+ levels in patients undergoing cardiac surgery was performed [102▪▪]. Oral nicotinamide was well tolerated, and administration was associated a lower frequency of AKI events. These results will require additional study but suggest that targeting metabolic pathways involved in cellular protection may be a beneficial strategy. A single-center phase II clinical trial to evaluate the efficacy of ‘NAD+ supplementation’ with Basis (Nicotinamide Riboside and Pterostilbene) to prevent AKI in patients undergoing complex aortic aneurysm repair and open aortic arch reconstruction is now recruiting (NCT04342975).
Tubular repair agents
Ischemia-reperfusion models are extensively used to study AKI that may occur in diverse settings. Extensive studies have suggested that renal ischemia-reperfusion triggers a pro-inflammatory cascade that culminates in a tubular epithelial cell response with tubular apoptosis and acute tubular necrosis, resulting in a fall in GFR and AKI [103,104]. Identifying an effective strategy to promote tubular survival and repair is essential for minimizing damage and accelerating functional recovery after AKI.
Hepatocyte growth factor
Hepatocyte growth factor (HGF) is a pleiotropic growth factor with diverse biological roles [105,106]. In models of AKI secondary to various insults including ischemia-reperfusion, cold preservation/transplantation or toxin exposure, administration of recombinant human HGF attenuates injury and augments kidney function [107,108]. These biological actions of HGF are mediated by the tyrosine kinase receptor cMet. HGF administration in the setting of AKI promotes tubular regeneration, mitigates acute tubular necrosis and reduces kidney dysfunction via activation of the cMet-Akt axis and upregulation of cell survival proteins, including Bcl-2 [109–111]. HGF is an attractive target in the development of therapeutics for AKI. However, the short biological half-life of HGF necessitates continuous exogenous administration to achieve a therapeutic effect. Furthermore, administration of HGF, as gene or protein therapy, is impractical in a clinical setting. Thus, there has been a concerted effort to discover HGF-like molecules which would be practical and safe to administer in a clinical setting. BB3 is an HGF-like peptide which emulates the biological activity of HGF and when first administered at 24 h after renal ischemia in rats, improved survival, augmented urine output and reduced increases in serum creatinine and blood urea nitrogen. The kidneys of BB3-treated animals exhibited reduced levels of KIM-1, Neutrophil gelatinase-associated lipocalin and reduced tubular apoptosis and acute tubular necrosis but enhanced tubular regeneration .
BB3 has been renamed ANG-3777 (Angion Biomedica Corporation, San Francisco, California, USA) and is being developed as a potential therapy to activate HGF-related repair pathways post-AKI. In a phase 2 RCT, ANG-3777 was administered to patients with oliguria or slow creatinine reduction (<30% pretransplantation values) over the first 24 h postkidney transplantation . The 19 patients treated with ANG-3777 were more likely to achieve the primary outcome of oliguria resolution by 28 days postkidney transplantation (78.9 versus 44.4% in the placebo group, P = 0.09). In addition, those patients treated with ANG-3777 had lower serum creatinine values and higher eGFRs, and fewer dialysis sessions and hospital days. Further trials of ANG-3777 are ongoing in transplant-associated AKI (NCT02474667) and for postcardiopulmonary bypass AKI (NCT02771509).
Bone morphogenetic protein-7 agonist
Research into the mechanisms of AKI has identified TGF-β and bone morphogenetic protein-7 as key mediators in the processes of kidney fibrosis, inflammation and tubular apoptosis. In these pathways, TGF-β has a primary role in injury, and BMP-7 inhibits TGF-β signaling, thereby protecting the kidney from transforming growth factor-mediated injury . BMP-7 has anti-inflammatory and antifibrotic effects and has been found to be nephroprotective and to promote regeneration of kidney tubules [115,116]. Thus, pharmacological stimulation of the BMP-7 pathway is promising as a therapy for AKI. The compound THR-184 was developed as a synthetic positive modulator of the BMP-7 pathway and in preclinical studies showed promise in exerting anti-inflammatory and antiapoptotic effects in the kidney [117–119]. THR-184 was studied in a multidose RCT in 452 patients scheduled for nonemergent cardiac surgery requiring cardiopulmonary bypass [120▪▪]. The primary endpoint was the proportion of patients developing AKI within 7 days. However, in this study, THR-184 failed to reduce the incidence, severity and duration of AKI postcardiac surgery.
Translation of preclinical candidates into effective pharmacotherapies for the prevention and treatment of AKI has proven challenging. However, several promising candidates with a variety of targets are progressing through early-phase clinical trials, which we anticipate will yield successful therapies soon.
Financial support and sponsorship
Fellowship support for J-.M.C was provided by ’la Société québécoise de Néphrologie’, ’ l’Académie CHUM’ and ’le Fonds de Recherche en Santé du Québec.
Conflicts of interest
J.-M.C and M.H.R have no conflict of interest. P.T.M has received scientific advisory board consultancy fees from AM-Pharma, FAST Biomedical, and Renibus Therapeutics.
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