Metabolic reprogramming and tolerance during sepsis-induced AKI.
Gómez Hernando,Kellum John A,Ronco Claudio
Nature reviews. Nephrology
The host defence against infection is an adaptive response in which several mechanisms are deployed to decrease the pathogen load, limit tissue injury and restore homeostasis. In the past few years new evidence has suggested that the ability of the immune system to limit the microbial burden - termed resistance - might not be the only defence mechanism. In fact, the capacity of the host to decrease its own susceptibility to inflammation- induced tissue damage - termed tolerance - might be as important as resistance in determining the outcome of the infection. Metabolic adaptations are central to the function of the cellular immune response. Coordinated reprogramming of metabolic signalling enables cells to execute resistance and tolerance pathways, withstand injury, steer tissue repair and promote organ recovery. During sepsis-induced acute kidney injury, early reprogramming of metabolism can determine the extent of organ dysfunction, progression to fibrosis, and the development of chronic kidney disease. Here we discuss the mechanisms of tolerance that act in the kidney during sepsis, with particular attention to the role of metabolic responses in coordinating these adaptive strategies. We suggest a novel conceptual model of the cellular and organic response to sepsis that might lead to new avenues for targeted, organ-protective therapies.
The pathology of chronic renal ischemia.
Shanley P F
Seminars in nephrology
Chronic ischemia may cause end stage renal disease, especially in older patients with atherosclerotic renal artery stenosis. Examining the pathology of the ischemic kidney is a fundamental first step toward understanding the mechanisms of this injury. In experimental renal hypoperfusion, there is evidence of a mixture of adaptive responses, tubular and endothelial cell damage and repair events. These processes are reflected in a wide spectrum of morphological changes that include atrophy, focal necrosis, epithelial regeneration, apoptosis, inflammation, interstitial fibrosis, and thrombosis. The most severe damage is seen in the outer medulla, a region with marginal oxygenation even in normal circumstances. In the usual clinical case, the effects of aging, pre-existent hypertension, and the process of atherosclerosis further complicate the pathological picture. Lesions related to these factors include arteriosclerosis, athero-emboli, various types of glomerulosclerosis, and severe tubulointerstitial damage leading to "atubular glomeruli" and regional cortical scarring (nephrosclerosis). In this article, some mechanisms determining the varied and complex pathological findings that may be observed in individual cases are outlined.
Cell cycle arrest and the evolution of chronic kidney disease from acute kidney injury.
Canaud Guillaume,Bonventre Joseph V
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
For several decades, acute kidney injury (AKI) was generally considered a reversible process leading to complete kidney recovery if the individual survived the acute illness. Recent evidence from epidemiologic studies and animal models, however, have highlighted that AKI can lead to the development of fibrosis and facilitate the progression of chronic renal failure. When kidney injury is mild and baseline function is normal, the repair process can be adaptive with few long-term consequences. When the injury is more severe, repeated, or to a kidney with underlying disease, the repair can be maladaptive and epithelial cell cycle arrest may play an important role in the development of fibrosis. Indeed, during the maladaptive repair after a renal insult, many tubular cells that are undergoing cell division spend a prolonged period in the G2/M phase of the cell cycle. These tubular cells recruit intracellular pathways leading to the synthesis and the secretion of profibrotic factors, which then act in a paracrine fashion on interstitial pericytes/fibroblasts to accelerate proliferation of these cells and production of interstitial matrix. Thus, the tubule cells assume a senescent secretory phenotype. Characteristic features of these cells may represent new biomarkers of fibrosis progression and the G2/M-arrested cells may represent a new therapeutic target to prevent, delay or arrest progression of chronic kidney disease. Here, we summarize recent advances in our understanding of the biology of the cell cycle and how cell cycle arrest links AKI to chronic kidney disease.
Novel insights into acute kidney injury-chronic kidney disease continuum and the role of renin-angiotensin system.
Chou Yu-Hsiang,Huang Tao-Min,Chu Tzong-Shinn
Journal of the Formosan Medical Association = Taiwan yi zhi
Acute kidney injury (AKI) is an independent risk factor for chronic kidney disease (CKD). If injury is mild, a repair process can be adaptive and lead to complete renal recovery. However, severe injury will be accompanied by a maladaptive repair which usually leads to nephron loss, fibrosis, vascular rarefaction, and chronic inflammation. Although various mechanisms underlying AKI-CKD transition have been explored, no intervention has been proved effective to block the transition until very recently. A lack of consensus for monitoring renal function and defining renal recovery after AKI should be the reasons for the slow advance in the discovery of a timely pharmacologic treatment to block AKI-CKD transition. Recently, animal studies have shown the activation of renin-angiotensin system (RAS) after AKI. In patients with complete renal recovery after AKI defined as the decrease of serum creatinine level to within 0.3 mg/dL above the baseline, administration of RAS inhibitor can prevent the ensuing CKD. In this review, we will discuss the renal recovery after AKI and the mechanisms underlying AKI-CKD transition. We will then highlight the promising effect of RAS inhibitor on CKD prevention in patients with complete renal recovery from AKI based on the recent clinical evidence.
Role of mast cells in progressive renal diseases.
Holdsworth Stephen R,Summers Shaun A
Journal of the American Society of Nephrology : JASN
Advances in understanding mast cell biology reveal their diverse functional capacity well beyond already established roles in host defense against parasites and allergic disease. Mast cells can initiate, amplify, and direct innate and adaptive immune responses. They also modulate inflammation and regulate immunity. Mast cells potentially induce tissue repair and direct fibrosis; however, they also play other roles in tissue remodeling and repair. Various activation and differentiating signals result in a diverse range of functional phenotypes called "mast cell heterogeneity." Mast cells are significant participants in chronic progressive kidney disease, and their presence is associated with function loss and fibrosis. This suggests a potential role in the fibrotic process, which may involve mast cell activation of local renin-angiotensin systems. Experimental animal studies suggest, however, they do not directly cause renal fibrosis but rather spark inflammation. Evidence for both pro- and anti-inflammatory roles in nephritis is emerging.
Acute kidney injury and chronic kidney disease: From the laboratory to the clinic.
Ferenbach David A,Bonventre Joseph V
Nephrologie & therapeutique
Chronic kidney disease and acute kidney injury have traditionally been considered as separate entities with different etiologies. This view has changed in recent years, with chronic kidney disease recognized as a major risk factor for the development of new acute kidney injury, and acute kidney injury now accepted to lead to de novo or accelerated chronic and end stage kidney diseases. Patients with existing chronic kidney disease appear to be less able to mount a complete 'adaptive' repair after acute insults, and instead repair maladaptively, with accelerated fibrosis and rates of renal functional decline. This article reviews the epidemiological studies in man that have demonstrated the links between these two processes. We also examine clinical and experimental research in areas of importance to both acute and chronic disease: acute and chronic renal injury to the vasculature, the pericyte and leukocyte populations, the signaling pathways implicated in injury and repair, and the impact of cellular stress and increased levels of growth arrested and senescent cells. The importance and therapeutic potential raised by these processes for acute and chronic injury are discussed.
Innate versus adaptive immunity in kidney immunopathology.
Most kidney disorders involve some degree of inflammation, i.e. induction of pro-inflammatory mediators and leukocyte recruitment. But what are the factors that determine inflammation as a trigger or a consequence of kidney injury? Which types of renal inflammation can be targeted by the novel more selective immunosuppressive and anti-inflammatory agents? How to dissect the mechanisms behind innate and adaptive immune responses that are orchestrated inside or outside the kidney but both cause renal immunopathology i.e. renal inflammation? How to dissect leukocytic cell infiltrates into pro-inflammatory leukocytes from anti-inflammatory and pro-regenerative leukocytes? How to dissect leukocytes that support epithelial repair from those that promote renal fibrosis. The term 'renal inflammation' has moved far beyond the descriptive category of 'mixed leukocytic cell infiltrates' as commonly described in kidney biopsies. It is time to face the complexity of renal inflammation to finally benefit from the new age of novel immunomodulatory medicines.
Primary proximal tubule injury leads to epithelial cell cycle arrest, fibrosis, vascular rarefaction, and glomerulosclerosis.
Bonventre Joseph V
Kidney international supplements
Tubular injury has a major etiological role in fibrosis. For many years, this relationship has been dominated by the perception that epithelial cells are transformed into myofibroblasts that proliferate and generate fibrotic matrix-the so-called epithelial-to-mesenchymal transition. Here we focus on mechanisms by which injury to the tubule results in fibrosis because of paracrine mechanisms. Specific injury to the proximal tubule results in inflammation, reversible injury, and adaptive repair if the insult is mild, self-limited in time, and occurs in a background of a normal kidney. Repeated injury, in contrast, leads to maladaptive repair with sustained tubule injury, chronic inflammation, proliferation of interstitial myofibroblasts, vascular rarefaction, interstitial fibrosis, and glomerular sclerosis. During the maladaptive repair process after the renal insult, many tubular cells become arrested in the G2/M phase of the cell cycle. This results in activation of the DNA repair response with the resultant synthesis and secretion of pro-fibrotic factors. Pharmacologic interventions that enhance the movement through G2/M or facilitate apoptosis of cells that otherwise would be blocked in G2/M may reduce the development of fibrosis after kidney injury and reduce the progression of chronic kidney disease.
Repair after nephron ablation reveals limitations of neonatal neonephrogenesis.
Tögel Florian,Valerius M Todd,Freedman Benjamin S,Iatrino Rossella,Grinstein Mor,Bonventre Joseph V
The neonatal mouse kidney retains nephron progenitor cells in a nephrogenic zone for 3 days after birth. We evaluated whether de novo nephrogenesis can be induced postnatally beyond 3 days. Given the long-term implications of nephron number for kidney health, it would be useful to enhance nephrogenesis in the neonate. We induced nephron reduction by cryoinjury with or without contralateral nephrectomy during the neonatal period or after 1 week of age. There was no detectable compensatory de novo nephrogenesis, as determined by glomerular counting and lineage tracing. Contralateral nephrectomy resulted in additional adaptive healing, with little or no fibrosis, but did not also stimulate de novo nephrogenesis. In contrast, injury initiated at 1 week of age led to healing with fibrosis. Thus, despite the presence of progenitor cells and ongoing nephron maturation in the newborn mouse kidney, de novo nephrogenesis is not inducible by acute nephron reduction. This indicates that additional nephron progenitors cannot be recruited after birth despite partial renal ablation providing a reparative stimulus and suggests that nephron number in the mouse is predetermined at birth.
Maladaptive proximal tubule repair: cell cycle arrest.
Bonventre Joseph V
Nephron. Clinical practice
Acute kidney injury (AKI) leads to worsening of chronic kidney disease (CKD), and CKD predisposes to the clinical entity of AKI. The tubules of the kidney play a central role in the fibrotic response, which ultimately leads to progressive kidney disease. The cellular mechanisms responsible for the epidemiological association between AKI and CKD are complex. In order to unravel characteristics of this direct involvement of the tubules, in particular the proximal tubules, we established a model to specifically target injury to the proximal tubule using a genetic approach to express the simian diphtheria toxin (DT) receptor in the proximal tubule. A single administration of DT to the proximal tubule resulted in inflammation, reversible injury, and adaptive repair. By contrast, thrice repeated injury led to maladaptive repair with sustained tubule injury, vascular rarefaction, proliferation of interstitial myofibroblasts, interstitial fibrosis, and glomerular sclerosis. An important feature of the maladaptive repair process after severe injury is the development of cell cycle arrest in G2/M. There is a subsequent activation of the DNA repair response with activation of a secretory phenotype whereby profibrotic factors are released. This insight introduces a number of potential new targets for therapeutic intervention to prevent and/or arrest CKD progression.
Sirtuins in Renal Health and Disease.
Morigi Marina,Perico Luca,Benigni Ariela
Journal of the American Society of Nephrology : JASN
Sirtuins belong to an evolutionarily conserved family of NAD-dependent deacetylases that share multiple cellular functions related to proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammalians express seven sirtuins (SIRT1-7) that are localized in different subcellular compartments. Changes in sirtuin expression are critical in several diseases, including metabolic syndrome, diabetes, cancer, and aging. In the kidney, the most widely studied sirtuin is SIRT1, which exerts cytoprotective effects by inhibiting cell apoptosis, inflammation, and fibrosis together with SIRT3, a crucial metabolic sensor that regulates ATP generation and mitochondrial adaptive response to stress. Here, we provide an overview of the biologic effects of sirtuins and the molecular targets thereof regulating renal physiology. This review also details progress made in understanding the effect of sirtuins in the pathophysiology of chronic and acute kidney diseases, highlighting the key role of SIRT1, SIRT3, and now SIRT6 as potential therapeutic targets. In this context, the current pharmacologic approaches to enhancing the activity of SIRT1 and SIRT3 will be discussed.
Enhancer and super-enhancer dynamics in repair after ischemic acute kidney injury.
Wilflingseder Julia,Willi Michaela,Lee Hye Kyung,Olauson Hannes,Jankowski Jakub,Ichimura Takaharu,Erben Reinhold,Valerius M Todd,Hennighausen Lothar,Bonventre Joseph V
The endogenous repair process can result in recovery after acute kidney injury (AKI) with adaptive proliferation of tubular epithelial cells, but repair can also lead to fibrosis and progressive kidney disease. There is currently limited knowledge about transcriptional regulators regulating these repair programs. Herein we establish the enhancer and super-enhancer landscape after AKI by ChIP-seq in uninjured and repairing kidneys on day two after ischemia reperfusion injury (IRI). We identify key transcription factors including HNF4A, GR, STAT3 and STAT5, which show specific binding at enhancer and super-enhancer sites, revealing enhancer dynamics and transcriptional changes during kidney repair. Loss of bromodomain-containing protein 4 function before IRI leads to impaired recovery after AKI and increased mortality. Our comprehensive analysis of epigenetic changes after kidney injury in vivo has the potential to identify targets for therapeutic intervention. Importantly, our data also call attention to potential caveats involved in use of BET inhibitors in patients at risk for AKI.
Potential approaches to reverse or repair renal fibrosis.
Tampe Desiree,Zeisberg Michael
Nature reviews. Nephrology
The concept of reversing chronic kidney disease (CKD) has been intensively researched over the past decade. Indeed, as the prevalence of end-stage renal disease is constantly on the rise, the lack of established antifibrotic therapies is a considerable unmet need in clinical practice. Now, the possibility of effective antifibrotic treatment has been established in experimental models of CKD and multiple antifibrotic compounds-in kidney disease, as well as in fibrotic diseases of the skin, liver and lung-are being assessed in clinical trials. These strategies target various components of the fibrotic pathway, from signalling molecules that include transforming growth factor-β, phosphatidylinositide 3-kinase and chemokines to microRNAs. Here, we discuss therapeutic concepts to inhibit or even reverse chronic kidney injury and review the leading candidate antifibrotic drugs to be introduced to clinical use.
Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD.
Ferenbach David A,Bonventre Joseph V
Nature reviews. Nephrology
Acute kidney injury is an increasingly common complication of hospital admission and is associated with high levels of morbidity and mortality. A hypotensive, septic, or toxic insult can initiate a cascade of events, resulting in impaired microcirculation, activation of inflammatory pathways and tubular cell injury or death. These processes ultimately result in acutely impaired kidney function and initiation of a repair response. This Review explores the various mechanisms responsible for the initiation and propagation of acute kidney injury, the prototypic mechanisms by which a substantially damaged kidney can regenerate its normal architecture, and how the adaptive processes of repair can become maladaptive. These mechanisms, which include G2/M cell-cycle arrest, cell senescence, profibrogenic cytokine production, and activation of pericytes and interstitial myofibroblasts, contribute to the development of progressive fibrotic kidney disease. The end result is a state that mimics accelerated kidney ageing. These mechanisms present important opportunities for the design of targeted therapeutic strategies to promote adaptive renal recovery and minimize progressive fibrosis and chronic kidney disease after acute insults.