Preventing the Progression of AKI to CKD: The Role of Mitochondria

AKI concerns up to one half of patients hospitalized in intensive care units and is associated with increased mortality and increased hospital stay independent of comorbidities and severity of the illness.1 In addition to acute repercussions, one of the most dreaded consequences of AKI, even after apparent recovery, is the associated increased risk of CKD in the long term. This association is also observed for mild forms of AKI. Whether AKI is causal for CKD progression or merely identifies patients at higher risk remains debated, but several strands of experimental evidences show that AKI enhances fibrogenesis and thereby, CKD progression risk.2 Despite years of research, no drug has been shown to prevent AKI in patients, whereas numerous therapies have been tested successfully in animal models. This lack of clinical translation has questioned the animal models and preclinical study design of AKI.3 Targeting AKI prevention is also difficult, because the mechanisms involved in various types of AKI differ, making it unlikely that a unique therapy may prevent all AKI types. In addition, identification of patients at risk of AKI is still difficult, and large patient numbers may be treated unnecessarily. Because decreasing the prevalence of CKD is of uttermost importance, a new paradigm has emerged over the last years, refocusing the attention on the transition from AKI to CKD rather than the prevention of AKI itself.2 Indeed, if a treatment may be given after the acute insult, the therapeutic window will be larger, and patients will be easier to identify. Because not all patients are at equal risk of CKD development after AKI, better identification of patients at risk will also be needed to avoid unnecessary treatment. Currently, no drug able to halt the AKI to CKD transition is available in humans. In this perspective, a very interesting aspect of the study by Szeto et al.4 in this issue of the Journal of the American Society of Nephrology is the long (9 months) follow-up after ischemia-reperfusion injury (IRI) in rats. They confirm that AKI is not merely an acute phenomenon but results in long-lasting morphologic and functional consequences. They show that AKI induces an increase in profibrotic and proinflammatory cytokines from 1 to 9 months after an acute injury in rats, leading to progressive increase in glomerulosclerosis and interstitial fibrosis, which are both hallmarks of CKD. They further describe long-lasting signs of endothelial injury as well as damage to capillary loops and podocytes, likely participating in fibrosis and glomerulosclerosis progression. Simultaneously, major alterations of mitochondria, displaying loss of cristae and matrix density, were apparent in endothelial cells, podocytes, and tubular cells by transmission electron microscopy up to 9 months after the injury. Such long follow-up after an ischemic injury has rarely been performed in animal models of AKI and brings crucial information to understanding the AKI to CKD transition. The data presented here are in line with recent data showing that persistence of mitochondrial morphologic alterations and metabolic dysfunctions at 14 days after IRI identify tubuli that will undergo atrophy compared with the ones that will regenerate after an ischemic insult.5 AKI may thus provoke long-term mitochondrial damage, which perpetuates kidney injury, a pathway that seems relevant for potential interventions. Are mitochondria thus a promising target to avoid the AKI to CKD transition? Several pathways are probably involved in the progression of acute kidney lesions to the chronic state and seem common to various AKI types, although IRI remains the most studied model in animals. Hypoxia inducible factor activation before the ischemic injury may alleviate resulting fibrosis. Pharmacologic nuclear factor erythroid 2-related factor 2 (NRF2) activation and alterations of tubular cell cycle are being studied.2 Recently, several groups have reported that energy metabolism and mitochondrial function are altered in various types of AKI, including ischemic and septic ones, and that alterations of key mitochondrial biogenesis regulators drive these acute injuries to become chronic.5–7 Proximal tubular cells are highly metabolic cells relying only on aerobic metabolism. Fatty acid oxidation by mitochondria is a major energy source, and its alteration is involved in various types of AKI and CKD leading to lipid accumulation, ATP depletion, and fibrosis in proximal tubular cells.8 Targeting mitochondria by restoring their metabolism, redox state, and dynamics and enhancing biogenesis all seem promising in preclinical studies in AKI.9 Other than altering metabolism and thereby, tubular cell function, mitochondrial dysfunction has also been reported to induce the inflammasome directly.10 Blocking the proinflammatory reaction seems promising, and a recent study showed that integrin CD11b/CD18 blockade ameliorated fibrosis post-AKI in primates subjected to IRI and unilateral urinary obstruction.11 Because mitochondria seem to play a primary role in AKI and may induce the inflammasome, it made sense to target mitochondria first and determine a potential beneficial effect on inflammation. Szeto-Schiller (SS) peptides are among novel mitoprotective drugs being tested in the field of experimental AKI. SS peptides are synthetic peptides with mitoprotective properties.12 These peptides selectively bind cardiolipin in the mitochondrial inner membrane and protect mitochondrial cristae. Cardiolipin also allows better function of the respiratory chain complexes. Structural studies suggest that the complexes between SS-31 and cardiolipin prevent peroxidase activity and improve mitochondrial respiration and ATP production. Altogether, SS-31 seems to restore mitochondrial structure and function and decrease reactive oxygen species production by mitochondria. In their study, Szeto et al.4 report the presence of inflammasome activation in conjunction with mitochondrial dysfunction late after an ischemic injury. Inflammatory activation was largely improved by restoring mitochondrial function by SS-31, pointing to mitochondrial dysfunction as causal in inflammasome stimulation post-AKI. This observation points to a central role of mitochondria in the proinflammatory and profibrotic response observed in the post-AKI chronic state. SS-31 has been used experimentally in the field of cardiovascular disease and shown to significantly decrease myocardial infarct size and improve heart failure. Several phase 1 and 2 clinical trials are ongoing in cardiovascular and muscle pathologies. SS-31 has been also shown to be beneficial in different types of experimental kidney disease. In IRI, SS-31 administered before the injury ameliorated renal function, decreased tubular injury, and improved tubular cells regeneration.13 In CKD models, SS-31 decreased glomerular and tubular lesions induced by a high-fat diet and diabetes and decreased injury related to aging and urinary tract obstruction.14–16 In larger animals, SS-31 was shown to decrease renal microvascular and fibrotic lesions resulting from atherosclerotic renovascular lesions in pigs.17 Results of a human trial are awaited. All of these observations imply that mitochondrial dysfunction underlies the pathogenesis of several acute kidney diseases and CKDs. This study shows for the first time the beneficial effect of SS-31 not only in AKI prevention but also, on the long-term renal consequences of AKI when administered long enough after the injury and for a limited period of time. Indeed, the peptide was administered 1 month after ischemia-reperfusion for 6 weeks in rats, with apparent complete recovery of renal function. This treatment avoided the development of interstitial fibrosis and glomerulosclerosis, reversed mitochondrial damage in podocytes and tubular cells, improved vessel recovery, and decreased the synthesis of TGF-β, IL-1β, and IL-18 observed until 9 months after the acute injury. The effect of SS-31 on metabolic pathways, such as free fatty acid oxidation, was not described. Although data on renal function and proteinuria would have reinforced the observation, renal structural differences between groups are quite evident. This observation is of major relevance for a potential clinical translation. Indeed, the long follow-up of the study shows that mitochondrial lesions are persistent after AKI, inducing fibrosis even in the case of apparent renal function recovery long after the acute injury. The data suggest that mitochondrial dysfunction is central to the AKI to CKD transition, because targeting mitochondria reverses the proinflammatory and profibrotic phenotype, which is observed in the long-term evolution. Finally, conceptually, the use of a treatment 1 month after the injury and for a limited period of time opens a new window of opportunity for therapeutic intervention if applicable in humans. This suggests that we may have the time to identify patients with persisting mitochondrial dysfunction after an AKI and that we may reverse it pharmacologically, notably with SS peptides. Although the observation is still experimental and needs confirmation in other types of AKI, notably septic AKI (the most frequent form in patients), as well as on renal function parameters, such as GFR and proteinuria, it enlightens new concepts of treatment for AKI to prevent the dreaded progression to CKD. Whether this observation will directly translate into clinical treatment is not certain, because many promising compounds have failed the animal to human transition in the field of AKI. Nevertheless, Szeto et al.4 confirm that we may have to change our approach on AKI treatment, focusing more on the post-AKI phase, where the therapeutic window is larger and the population is more identifiable. Disclosures None.