1 4381 117 MITOCHONDRIAL DYSFUNCTION AND THE AKI-TO-CKD TRANSITION. ACUTE KIDNEY INJURY (AKI) HAS BEEN WIDELY RECOGNIZED AS AN IMPORTANT RISK FACTOR FOR THE OCCURRENCE AND DEVELOPMENT OF CHRONIC KIDNEY DISEASE (CKD). EVEN MILDER AKI HAS ADVERSE CONSEQUENCES AND COULD PROGRESS TO RENAL FIBROSIS, WHICH IS THE ULTIMATE COMMON PATHWAY FOR VARIOUS TERMINAL KIDNEY DISEASES. THUS, IT IS URGENT TO DEVELOP A STRATEGY TO HINDER THE TRANSITION FROM AKI TO CKD. SOME MECHANISMS OF THE AKI-TO-CKD TRANSITION HAVE BEEN REVEALED, SUCH AS NEPHRON LOSS, CELL CYCLE ARREST, PERSISTENT INFLAMMATION, ENDOTHELIAL INJURY WITH VASCULAR RAREFACTION, AND EPIGENETIC CHANGES. PREVIOUS STUDIES HAVE ELUCIDATED THE PIVOTAL ROLE OF MITOCHONDRIA IN ACUTE INJURIES AND DEMONSTRATED THAT THE FITNESS OF THIS ORGANELLE IS A MAJOR DETERMINANT IN BOTH THE PATHOGENESIS AND RECOVERY OF ORGAN FUNCTION. RECENT RESEARCH HAS SUGGESTED THAT DAMAGE TO MITOCHONDRIAL FUNCTION IN EARLY AKI IS A CRUCIAL FACTOR LEADING TO TUBULAR INJURY AND PERSISTENT RENAL INSUFFICIENCY. DYSREGULATION OF MITOCHONDRIAL HOMEOSTASIS, ALTERATIONS IN BIOENERGETICS, AND ORGANELLE STRESS CROSS TALK CONTRIBUTE TO THE AKI-TO-CKD TRANSITION. IN THIS REVIEW, WE FOCUS ON THE PATHOPHYSIOLOGY OF MITOCHONDRIA IN RENAL RECOVERY AFTER AKI AND PROGRESSION TO CKD, CONFIRMING THAT TARGETING MITOCHONDRIA REPRESENTS A POTENTIALLY EFFECTIVE THERAPEUTIC STRATEGY FOR THE PROGRESSION OF AKI TO CKD. 2020 2 221 54 ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE TRANSITION. BACKGROUND: ACUTE KIDNEY INJURY (AKI), EVEN IF FOLLOWED BY RENAL RECOVERY, IS A RISK FACTOR FOR THE FUTURE DEVELOPMENT OF CHRONIC KIDNEY DISEASE (CKD) AND END-STAGE RENAL DISEASE (ESRD). IN THE PREVIOUS YEARS, NOVEL INSIGHTS IN THE PATHOPHYSIOLOGY OF CKD PROGRESSION SUGGESTED A CAUSAL LINK BETWEEN AKI AND CKD DUE TO A MALADAPTIVE REPAIR AFTER SEVERE AND REPEATED INJURY. SUMMARY: SEVERAL PATHOLOGICAL MECHANISMS HAVE BEEN PROPOSED TO CONTRIBUTE TO THE PROGRESSION OF AKI AND TRANSITION TO CKD/ESRD INCLUDING HYPOXIA AND MICROVASCULAR RAREFACTION, ALTERATIONS OF RENAL RESIDENT CELL PHENOTYPES AND FUNCTIONS, CELL CYCLE ARREST IN THE G2/M PHASE, PERSISTENT CHRONIC INFLAMMATION, AND DEVELOPMENT OF INTERSTITIAL FIBROSIS, MITOCHONDRIAL FRAGMENTATION, EPIGENETIC CHANGES, ACTIVATION OF RENIN-ANGIOTENSIN SYSTEM (RAS), CELL AND TISSUE SENESCENCE. FURTHERMORE, SEVERAL CLINICAL FACTORS HAVE BEEN IDENTIFIED SUCH AS SEVERITY OF AKI, AGE, AND COMORBIDITIES. THE IDENTIFICATION OF AKI-TO-CKD BIOMARKERS COULD IMPROVE THE EARLY IDENTIFICATION OF AKI PATIENTS WITH HIGHER RISK FOR CKD PROGRESSION. HOWEVER, ALTHOUGH OUR UNDERSTANDING IN THE PATHOPHYSIOLOGY OF AKI-TO-CKD TRANSITION IS SIGNIFICANTLY IMPROVED, NO NOVEL INTERVENTION HAS BEEN VALIDATED. POTENTIAL THERAPEUTIC APPROACHES TO TREAT AKI AND BLOCK THE TRANSITION TO CKD/ESRD HAVE BEEN RECENTLY REPORTED, BUT THEY NEED FURTHER VALIDATIONS. KEY MESSAGES: MALADAPTIVE REPAIR AFTER AKI IS STRONGLY ASSOCIATED TO THE DEVELOPMENT OF CKD AND LONG-TERM CONSEQUENCES. THE PROMPT IDENTIFICATION OF PATIENTS AT HIGHER RISK FOR LATE CKD PROGRESSION AND THE DEVELOPMENT OF NEW THERAPEUTIC INTERVENTIONS REMAIN CRITICAL RESEARCH GOALS. 2018 3 6451 40 THERAPIES TARGETING EPIGENETIC ALTERATIONS IN ACUTE KIDNEY INJURY-TO-CHRONIC KIDNEY DISEASE TRANSITION. ACUTE KIDNEY INJURY (AKI) WAS PREVIOUSLY THOUGHT TO BE A MERELY TRANSIENT EVENT; HOWEVER, RECENT EPIDEMIOLOGICAL EVIDENCE SUPPORTS THE EXISTENCE OF A CAUSAL RELATIONSHIP BETWEEN AKI EPISODES AND SUBSEQUENT PROGRESSION TO CHRONIC KIDNEY DISEASE (CKD). ALTHOUGH THE PATHOPHYSIOLOGY OF THIS AKI-TO-CKD TRANSITION IS NOT FULLY UNDERSTOOD, IT IS MEDIATED BY THE INTERPLAY AMONG MULTIPLE COMPONENTS OF THE KIDNEY INCLUDING TUBULAR EPITHELIAL CELLS, ENDOTHELIAL CELLS, PERICYTES, INFLAMMATORY CELLS, AND MYOFIBROBLASTS. EPIGENETIC ALTERATIONS INCLUDING HISTONE MODIFICATION, DNA METHYLATION, NON-CODING RNAS, AND CHROMATIN CONFORMATIONAL CHANGES, ARE ALSO EXPECTED TO BE LARGELY INVOLVED IN THE PATHOPHYSIOLOGY AS A "MEMORY" OF THE INITIAL INJURY THAT CAN PERSIST AND PREDISPOSE TO CHRONIC PROGRESSION OF FIBROSIS. EACH EPIGENETIC MODIFICATION HAS A GREAT POTENTIAL AS A THERAPEUTIC TARGET OF AKI-TO-CKD TRANSITION; TIMELY AND TARGET-SPECIFIC EPIGENETIC INTERVENTIONS TO THE VARIOUS TEMPORAL STAGES OF AKI-TO-CKD TRANSITION WILL BE THE KEY TO FUTURE THERAPEUTIC APPLICATIONS IN CLINICAL PRACTICE. THIS REVIEW ELABORATES ON THE LATEST KNOWLEDGE OF EACH MECHANISM AND THE CURRENTLY AVAILABLE THERAPEUTIC AGENTS THAT TARGET EPIGENETIC MODIFICATION IN THE CONTEXT OF AKI-TO-CKD TRANSITION. FURTHER STUDIES WILL ELUCIDATE MORE DETAILED MECHANISMS AND NOVEL THERAPEUTIC TARGETS OF AKI-TO-CKD TRANSITION. 2022 4 2034 40 EPIGENETIC CHANGES IN THE ACUTE KIDNEY INJURY-TO-CHRONIC KIDNEY DISEASE TRANSITION. PREVIOUSLY ACUTE KIDNEY INJURY (AKI) HAD BEEN BELIEVED TO BE A TRANSIENT EVENT, AND RECOVERY FROM AKI HAD BEEN THOUGHT TO LEAD TO NO CONSEQUENCES. HOWEVER, RECENT EPIDEMIOLOGICAL STUDIES HAVE SHOWN THAT EVEN IF THERE IS COMPLETE RECOVERY OF THE KIDNEY FUNCTION, AKI CAN EVENTUALLY RESULT IN CHRONIC KIDNEY DISEASE (CKD) AND EVENTUALLY IN END-STAGE KIDNEY DISEASE IN THE LONG TERM. TRANSITION OF AKI TO CKD IS MEDIATED BY MULTIPLE MECHANISMS, INCLUDING ABERRANT CELL CYCLE ARREST AND HYPOXIA. HYPOXIA OF THE KIDNEY IS INDUCED BY RAREFACTION OF THE PERITUBULAR CAPILLARIES AFTER AKI EPISODES, AND INDUCES INFLAMMATION AND FIBROSIS. IT SHOULD ALSO BE NOTED THAT EPIGENETIC CHANGES ARE CLOSELY RELATED TO HYPOXIA, AND EPIGENETIC CHANGES INDUCED BY HYPOXIA, CALLED "HYPOXIC MEMORY" CAN EXPLAIN THE AKI-TO-CKD TRANSITION IN THE LONG TERM AFTER COMPLETE RECOVERY FROM THE INITIAL AKI EPISODE. TARGETING HYPOXIA AND SUBSEQUENT EPIGENETIC CHANGES ARE PROMISING STRATEGIES TO BLOCK THE TRANSITION FROM AKI TO CKD. 2017 5 3466 46 HYPOXIA AS A KEY PLAYER IN THE AKI-TO-CKD TRANSITION. RECENT CLINICAL AND ANIMAL STUDIES HAVE SHOWN THAT ACUTE KIDNEY INJURY (AKI), EVEN IF FOLLOWED BY COMPLETE RECOVERY OF RENAL FUNCTION, CAN EVENTUALLY RESULT IN CHRONIC KIDNEY DISEASE (CKD). RENAL HYPOXIA IS EMERGING AS A KEY PLAYER IN THE PATHOPHYSIOLOGY OF THE AKI-TO-CKD TRANSITION. CAPILLARY RAREFACTION AFTER AKI EPISODES INDUCES RENAL HYPOXIA, WHICH CAN IN TURN PROFOUNDLY AFFECT TUBULAR EPITHELIAL CELLS, (MYO)FIBROBLASTS, AND INFLAMMATORY CELLS, CULMINATING IN TUBULOINTERSTITIAL FIBROSIS, I.E., PROGRESSION TO CKD. DAMAGED TUBULAR EPITHELIAL CELLS THAT FAIL TO REDIFFERENTIATE MIGHT SUPPLY A DECREASED AMOUNT OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND CONTRIBUTE TO CAPILLARY RAREFACTION, THUS AGGRAVATING HYPOXIA AND FORMING A VICIOUS CYCLE. MOUNTING EVIDENCE ALSO SHOWS THAT EPIGENETIC CHANGES ARE CLOSELY RELATED TO RENAL HYPOXIA IN THE PATHOPHYSIOLOGY OF CKD PROGRESSION. ANIMAL EXPERIMENTS SUGGEST THAT TARGETING HYPOXIA IS A PROMISING STRATEGY TO BLOCK THE TRANSITION FROM AKI TO CKD. HOWEVER, THE PRECISE MECHANISMS BY WHICH HYPOXIA INDUCES THE AKI-TO-CKD TRANSITION AND BY WHICH HYPOXIA-INDUCIBLE FACTOR ACTIVATION CAN EXERT A PROTECTIVE EFFECT IN THIS CONTEXT SHOULD BE CLARIFIED IN FURTHER STUDIES. 2014 6 3670 56 INFLAMMAGING AND COMPLEMENT SYSTEM: A LINK BETWEEN ACUTE KIDNEY INJURY AND CHRONIC GRAFT DAMAGE. THE ABERRANT ACTIVATION OF COMPLEMENT SYSTEM IN SEVERAL KIDNEY DISEASES SUGGESTS THAT THIS PILLAR OF INNATE IMMUNITY HAS A CRITICAL ROLE IN THE PATHOPHYSIOLOGY OF RENAL DAMAGE OF DIFFERENT ETIOLOGIES. A GROWING BODY OF EXPERIMENTAL EVIDENCE INDICATES THAT COMPLEMENT ACTIVATION CONTRIBUTES TO THE PATHOGENESIS OF ACUTE KIDNEY INJURY (AKI) SUCH AS DELAYED GRAFT FUNCTION (DGF) IN TRANSPLANT PATIENTS. AKI IS CHARACTERIZED BY THE RAPID LOSS OF THE KIDNEY'S EXCRETORY FUNCTION AND IS A COMPLEX SYNDROME CURRENTLY LACKING A SPECIFIC MEDICAL TREATMENT TO ARREST OR ATTENUATE PROGRESSION IN CHRONIC KIDNEY DISEASE (CKD). RECENT EVIDENCE SUGGESTS THAT INDEPENDENTLY FROM THE INITIAL TRIGGER (I.E., SEPSIS OR ISCHEMIA/REPERFUSIONS INJURY), AN EPISODE OF AKI IS STRONGLY ASSOCIATED WITH AN INCREASED RISK OF SUBSEQUENT CKD. THE AKI-TO-CKD TRANSITION MAY INVOLVE A WIDE RANGE OF MECHANISMS INCLUDING SCAR-FORMING MYOFIBROBLASTS GENERATED FROM DIFFERENT SOURCES, MICROVASCULAR RAREFACTION, MITOCHONDRIAL DYSFUNCTION, OR CELL CYCLE ARREST BY THE INVOLVEMENT OF EPIGENETIC, GENE, AND PROTEIN ALTERATIONS LEADING TO COMMON FINAL SIGNALING PATHWAYS [I.E., TRANSFORMING GROWTH FACTOR BETA (TGF-BETA), P16 (INK4A) , WNT/BETA-CATENIN PATHWAY] INVOLVED IN RENAL AGING. RESEARCH IN RECENT YEARS HAS REVEALED THAT SEVERAL STRESSORS OR COMPLICATIONS SUCH AS REJECTION AFTER RENAL TRANSPLANTATION CAN LEAD TO ACCELERATED RENAL AGING WITH DETRIMENTAL EFFECTS WITH THE ESTABLISHMENT OF CHRONIC PROINFLAMMATORY CELLULAR PHENOTYPES WITHIN THE KIDNEY. DESPITE A GREATER UNDERSTANDING OF THESE MECHANISMS, THE ROLE OF COMPLEMENT SYSTEM IN THE CONTEXT OF THE AKI-TO-CKD TRANSITION AND RENAL INFLAMMAGING IS STILL POORLY EXPLORED. THE PURPOSE OF THIS REVIEW IS TO SUMMARIZE RECENT FINDINGS DESCRIBING THE ROLE OF COMPLEMENT IN AKI-TO-CKD TRANSITION. WE WILL ALSO ADDRESS HOW AND WHEN COMPLEMENT INHIBITORS MIGHT BE USED TO PREVENT AKI AND CKD PROGRESSION, THEREFORE IMPROVING GRAFT FUNCTION. 2020 7 4513 28 MULTI-OMIC APPROACHES TO ACUTE KIDNEY INJURY AND REPAIR. THE KIDNEY HAS A REMARKABLE REGENERATIVE CAPACITY. IN RESPONSE TO ISCHEMIC OR TOXIC INJURY, PROXIMAL TUBULE CELLS CAN PROLIFERATE TO REBUILD DAMAGED TUBULES AND RESTORE KIDNEY FUNCTION. HOWEVER, SEVERE ACUTE KIDNEY INJURY (AKI) OR RECURRENT AKI EVENTS CAN LEAD TO MALADAPTIVE REPAIR AND DISEASE PROGRESSION FROM AKI TO CHRONIC KIDNEY DISEASE (CKD). THE APPLICATION OF SINGLE CELL TECHNOLOGIES HAS IDENTIFIED INJURED PROXIMAL TUBULE CELL STATES WEEKS AFTER AKI, DISTINGUISHED BY A PRO-INFLAMMATORY SENESCENT MOLECULAR SIGNATURE. EPIGENETIC STUDIES HIGHLIGHTED DYNAMIC CHANGES IN THE CHROMATIN LANDSCAPE OF THE KIDNEY FOLLOWING AKI AND DESCRIBED KEY TRANSCRIPTION FACTORS LINKED TO THE AKI RESPONSE. THE INTEGRATION OF MULTI-OMIC TECHNOLOGIES OPENS NEW POSSIBILITIES TO IMPROVE OUR UNDERSTANDING OF AKI AND THE DRIVING FORCES BEHIND THE AKI-TO-CKD TRANSITION, WITH THE ULTIMATE GOAL OF DESIGNING TAILORED DIAGNOSTIC AND THERAPEUTIC STRATEGIES TO IMPROVE AKI OUTCOMES AND PREVENT KIDNEY DISEASE PROGRESSION. 2021 8 2193 49 EPIGENETIC MODIFICATION DRIVES ACUTE KIDNEY INJURY-TO-CHRONIC KIDNEY DISEASE PROGRESSION. ACUTE KIDNEY INJURY (AKI) IS A COMMON CLINICAL CRITICAL DISEASE. DUE TO ITS HIGH MORBIDITY, INCREASING RISK OF COMPLICATIONS, HIGH MORTALITY RATE, AND HIGH MEDICAL COSTS, IT HAS BECOME A GLOBAL CONCERN FOR HUMAN HEALTH PROBLEMS. INITIALLY, RESEARCHERS BELIEVED THAT KIDNEYS HAVE A STRONG ABILITY TO REGENERATE AND REPAIR, BUT STUDIES OVER THE PAST 20 YEARS HAVE FOUND THAT KIDNEYS DAMAGED BY AKI ARE OFTEN INCOMPLETE OR EVEN UNABLE TO REPAIR. EVEN WHEN SERUM CREATININE RETURNS TO BASELINE LEVELS, RENAL STRUCTURAL DAMAGE PERSISTS FOR A LONG TIME, LEADING TO THE DEVELOPMENT OF CHRONIC KIDNEY DISEASE (CKD). THE MECHANISM OF AKI-TO-CKD TRANSITION HAS NOT BEEN FULLY ELUCIDATED. AS AN IMPORTANT REGULATOR OF GENE EXPRESSION, EPIGENETIC MODIFICATIONS, SUCH AS HISTONE MODIFICATION, DNA METHYLATION, AND NONCODING RNAS, MAY PLAY AN IMPORTANT ROLE IN THIS PROCESS. ALTERATIONS IN EPIGENETIC MODIFICATION ARE INDUCED BY HYPOXIA, THUS PROMOTING THE EXPRESSION OF INFLAMMATORY FACTOR-RELATED GENES AND COLLAGEN SECRETION. THIS REVIEW ELABORATED THE ROLE OF EPIGENETIC MODIFICATIONS IN AKI-TO-CKD PROGRESSION, THE DIAGNOSTIC VALUE OF EPIGENETIC MODIFICATIONS BIOMARKERS IN AKI CHRONIC OUTCOME, AND THE POTENTIAL ROLE OF TARGETING EPIGENETIC MODIFICATIONS IN THE PREVENTION AND TREATMENT OF AKI TO CKD, IN ORDER TO PROVIDE IDEAS FOR THE SUBSEQUENT ESTABLISHMENT OF TARGETED THERAPEUTIC STRATEGIES TO PREVENT THE PROGRESSION OF RENAL TUBULAR-INTERSTITIAL FIBROSIS. 2021 9 5370 30 RECENT ADVANCES IN UNDERSTANDING OF CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS DEFINED AS ANY CONDITION THAT CAUSES REDUCED KIDNEY FUNCTION OVER A PERIOD OF TIME. FIBROSIS, TUBULAR ATROPHY AND INTERSTITIAL INFLAMMATION ARE THE HALLMARK OF PATHOLOGICAL FEATURES IN CKD. REGARDLESS OF INITIAL INSULT, CKD HAS SOME COMMON PATHWAYS LEADING CKD TO END-STAGE KIDNEY DISEASE, INCLUDING HYPOXIA IN THE TUBULOINTERSTITIUM AND PROTEINURIA. RECENT ADVANCES IN GENOME EDITING TECHNOLOGIES AND STEM CELL RESEARCH GIVE GREAT INSIGHTS TO UNDERSTAND THE PATHOGENESIS OF CKD, INCLUDING IDENTIFICATIONS OF THE ORIGINS OF RENAL MYOFIBROBLASTS AND TUBULAR EPITHELIAL CELLS UPON INJURY. ENVIRONMENTAL FACTORS SUCH AS HYPOXIA, OXIDATIVE STRESS, AND EPIGENETIC FACTORS IN RELATION TO CKD ARE ALSO DISCUSSED. 2015 10 6299 52 THE PROXIMAL TUBULE IS THE PRIMARY TARGET OF INJURY AND PROGRESSION OF KIDNEY DISEASE: ROLE OF THE GLOMERULOTUBULAR JUNCTION. THERE IS AN ALARMING GLOBAL INCREASE IN THE INCIDENCE OF END-STAGE KIDNEY DISEASE, FOR WHICH EARLY BIOMARKERS AND EFFECTIVE TREATMENT OPTIONS ARE LACKING. LARGELY BASED ON THE HISTOLOGY OF THE END-STAGE KIDNEY AND ON THE MODEL OF UNILATERAL URETERAL OBSTRUCTION, CURRENT INVESTIGATION IS FOCUSED ON THE PATHOGENESIS OF RENAL INTERSTITIAL FIBROSIS AS A CENTRAL MECHANISM IN THE PROGRESSION OF CHRONIC KIDNEY DISEASE (CKD). IT IS NOW RECOGNIZED THAT CUMULATIVE EPISODES OF ACUTE KIDNEY INJURY (AKI) CAN LEAD TO CKD, AND, CONVERSELY, CKD IS A RISK FACTOR FOR AKI. BASED ON RECENT AND HISTORIC STUDIES, THIS REVIEW SHIFTS ATTENTION FROM THE GLOMERULUS AND INTERSTITIUM TO THE PROXIMAL TUBULE AS THE PRIMARY SENSOR AND EFFECTOR IN THE PROGRESSION OF CKD AS WELL AS AKI. PACKED WITH MITOCHONDRIA AND DEPENDENT ON OXIDATIVE PHOSPHORYLATION, THE PROXIMAL TUBULE IS PARTICULARLY VULNERABLE TO INJURY (OBSTRUCTIVE, ISCHEMIC, HYPOXIC, OXIDATIVE, METABOLIC), RESULTING IN CELL DEATH AND ULTIMATELY IN THE FORMATION OF ATUBULAR GLOMERULI. ANIMAL MODELS OF HUMAN GLOMERULAR AND TUBULAR DISORDERS HAVE PROVIDED EVIDENCE FOR A BROAD REPERTOIRE OF MORPHOLOGICAL AND FUNCTIONAL RESPONSES OF THE PROXIMAL TUBULE, REVEALING PROCESSES OF DEGENERATION AND REPAIR THAT MAY LEAD TO NEW THERAPEUTIC STRATEGIES. MOST PROMISING ARE STUDIES THAT ENCOMPASS THE ENTIRE LIFE CYCLE FROM FETUS TO SENESCENCE, RECOGNIZING EPIGENETIC FACTORS. THE APPLICATION OF TECHNIQUES IN MOLECULAR CHARACTERIZATION OF TUBULE SEGMENTS AND THE DEVELOPMENT OF HUMAN KIDNEY ORGANOIDS MAY PROVIDE NEW INSIGHTS INTO THE MAMMALIAN KIDNEY SUBJECTED TO STRESS OR INJURY, LEADING TO BIOMARKERS OF EARLY CKD AND NEW THERAPIES. 2016 11 2293 44 EPIGENETIC REGULATION IN THE ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE TRANSITION. EPIGENETIC MODIFICATIONS HAVE EMERGED AS A NEW, IMPORTANT CONTRIBUTOR TO GENE EXPRESSION REGULATION IN BOTH NORMAL AND PATHOPHYSIOLOGICAL CONDITIONS. EPIGENETICS HAVE BEEN STUDIED IN MANY DISEASES AND CONDITIONS SUCH AS ACUTE KIDNEY INJURY (AKI), A SYNDROME WITH A HIGH PREVALENCE THAT CARRIES A POOR PROGNOSIS WITH INCREASED MORBIDITY AND MORTALITY. IN ADDITION, IT HAS RECENTLY BEEN SHOWN THAT AKI INCREASES THE RISK FOR THE DEVELOPMENT OF CHRONIC KIDNEY DISEASE (CKD). THE SPECIFIC MOLECULAR MECHANISMS BY WHICH AKI INCREASES THE RISK OF CKD AND END STAGE RENAL DISEASE (ESRD) REMAIN UNKNOWN, ALTHOUGH THERE IS NEW EVIDENCE SUPPORTING A ROLE OF EPIGENETIC CHANGES. THE MOST STUDIED EPIGENETIC REGULATIONS IN AKI ARE CHROMATIN COMPACTION, DNA METHYLATION, AND HISTONE ACETYLATION/DEACETYLATION. THESE MODIFICATIONS PREDOMINANTLY INCREASE THE PRODUCTION OF PRO-INFLAMMATORY AND PROFIBROTIC CYTOKINES SUCH AS: MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP-1), COMPLEMENT PROTEIN 3 (C3), TRANSFORMING GROWTH FACTOR BETA (TGF-BETA) THAT HAVE BEEN SHOWN FOR PERPETUATING INFLAMMATION, PROMOTING EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT) AND ULTIMATELY CAUSING RENAL FIBROSIS. A REVIEW OF EPIGENETIC MECHANISMS, THE PATHOPHYSIOLOGY OF AKI AND RECENT STUDIES THAT IMPLICATE EPIGENETIC MODIFICATIONS IN AKI AND IN THE TRANSITION TO CKD ARE DISCUSSED BELOW. 2015 12 2191 47 EPIGENETIC MEMORY CONTRIBUTING TO THE PATHOGENESIS OF AKI-TO-CKD TRANSITION. EPIGENETIC MEMORY, WHICH REFERS TO THE ABILITY OF CELLS TO RETAIN AND TRANSMIT EPIGENETIC MARKS TO THEIR DAUGHTER CELLS, MAINTAINS UNIQUE GENE EXPRESSION PATTERNS. ESTABLISHING PROGRAMMED EPIGENETIC MEMORY AT EACH STAGE OF DEVELOPMENT IS REQUIRED FOR CELL DIFFERENTIATION. MOREOVER, ACCUMULATING EVIDENCE SHOWS THAT EPIGENETIC MEMORY ACQUIRED IN RESPONSE TO ENVIRONMENTAL STIMULI MAY BE ASSOCIATED WITH DIVERSE DISEASES. IN THE FIELD OF KIDNEY DISEASES, THE "MEMORY" OF ACUTE KIDNEY INJURY (AKI) LEADS TO PROGRESSION TO CHRONIC KIDNEY DISEASE (CKD); EPIDEMIOLOGICAL STUDIES SHOW THAT PATIENTS WHO RECOVER FROM AKI ARE AT HIGH RISK OF DEVELOPING CKD. THE UNDERLYING PATHOLOGICAL PROCESSES INCLUDE NEPHRON LOSS, MALADAPTIVE EPITHELIAL REPAIR, INFLAMMATION, AND ENDOTHELIAL INJURY WITH VASCULAR RAREFACTION. FURTHER, EPIGENETIC ALTERATIONS MAY CONTRIBUTE AS WELL TO THE PATHOPHYSIOLOGY OF THIS AKI-TO-CKD TRANSITION. EPIGENETIC CHANGES INDUCED BY AKI, WHICH CAN BE RECORDED IN CELLS, EXERT LONG-TERM EFFECTS AS EPIGENETIC MEMORY. CONSIDERING THE LATEST FINDINGS ON THE MOLECULAR BASIS OF EPIGENETIC MEMORY AND THE PATHOPHYSIOLOGY OF AKI-TO-CKD TRANSITION, WE PROPOSE HERE THAT EPIGENETIC MEMORY CONTRIBUTING TO AKI-TO-CKD TRANSITION CAN BE CLASSIFIED ACCORDING TO THE PRESENCE OR ABSENCE OF PERSISTENT CHANGES IN THE ASSOCIATED REGULATION OF GENE EXPRESSION, WHICH WE DESIGNATE "DRIVING" MEMORY AND "PRIMING" MEMORY, RESPECTIVELY. "DRIVING" MEMORY, WHICH PERSISTENTLY ALTERS THE REGULATION OF GENE EXPRESSION, MAY CONTRIBUTE TO DISEASE PROGRESSION BY ACTIVATING FIBROGENIC GENES OR INHIBITING RENOPROTECTIVE GENES. THIS PROCESS MAY BE INVOLVED IN GENERATING THE PROINFLAMMATORY AND PROFIBROTIC PHENOTYPES OF MALADAPTIVELY REPAIRED TUBULAR CELLS AFTER KIDNEY INJURY. "PRIMING" MEMORY IS STORED IN SEEMINGLY SUCCESSFULLY REPAIRED TUBULAR CELLS IN THE ABSENCE OF DETECTABLE PERSISTENT PHENOTYPIC CHANGES, WHICH MAY ENHANCE A SUBSEQUENT TRANSCRIPTIONAL RESPONSE TO THE SECOND STIMULUS. THIS TYPE OF MEMORY MAY CONTRIBUTE TO AKI-TO-CKD TRANSITION THROUGH THE CUMULATIVE EFFECTS OF ENHANCED EXPRESSION OF PROFIBROTIC GENES REQUIRED FOR WOUND REPAIR AFTER RECURRENT AKI. FURTHER UNDERSTANDING OF EPIGENETIC MEMORY WILL IDENTIFY THERAPEUTIC TARGETS OF FUTURE EPIGENETIC INTERVENTION TO PREVENT AKI-TO-CKD TRANSITION. 2022 13 2788 50 FACTORS AFFECTING THE TRANSITION OF ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE: POTENTIAL MECHANISMS AND FUTURE PERSPECTIVES. ACUTE KIDNEY INJURY (AKI) IS DEFINED AS A RAPID LOSS OF KIDNEY FUNCTION CHARACTERISED BY INFLAMMATION AND CELL DEATH, ULTIMATELY LEADING TO FURTHER FUNCTIONAL AND STRUCTURAL RENAL ALTERATIONS. BASED ON EXPERIMENTAL AND EPIDEMIOLOGICAL PIECES OF EVIDENCE, AKI MAY PROGRESS TO CHRONIC KIDNEY DISEASE (CKD) EVEN AFTER A RECOVERY PERIOD DUE TO MALADAPTIVE REPAIR AND OTHER UNDERLYING MECHANISMS SUCH AS HEIGHTENED WNT SIGNALLING, OVERSTIMULATION OF THE RENIN-ANGIOTENSIN-ALDOSTERONE-SYSTEM (RAAS) PATHWAY, EPIGENETIC ALTERATIONS AND INHIBITION OF HYPOXIA-INDUCIBLE FACTOR (HIF) DEPENDENT DEFENCES. IT HAS BEEN REPORTED THAT RAAS ACTIVATION SUBSEQUENT TO RENAL INSULT MEDIATES INFLAMMATORY AND FIBROTIC MECHANISMS, WHICH ARE A HALLMARK OF CKD. MOREOVER, INTERESTING EVIDENCE REGARDING THE EXPOSURE-DEPENDENT DUAL ROLE OF WNT SIGNALLING IN BOTH INJURY AND REPAIR, EPIGENETIC CHANGES UNDERLYING KIDNEY DISEASE SUGGEST A POTENTIAL THERAPEUTIC ROLE OF THESE PATHWAYS IN AKI TO CKD CONTINUUM. IN ADDITION, THE HYPOXIA-INDEPENDENT RENAL BENEFITS OF ERYTHROPOIETIN SUCH AS ANTI-APOPTOSIS AND TUBULAR REGENERATION ALSO PRESENT AN AUSPICIOUS TARGET WHICH COULD BE USEFUL IN CLINICAL SETTINGS. IN THIS REVIEW, THE SPECIFIC ROLES OF THESE PATHWAYS IN KIDNEY DISEASE, THEIR PATHOLOGICAL MECHANISMS AND THERAPEUTIC STRATEGIES ARE DISCUSSED. MOREOVER, NOTABLE REPORTS CONCERNING STEM CELL THERAPY WHICH HOLD PROMISE IN HALTING AKI-CKD CONTINUUM WILL BE ELABORATED. 2019 14 2195 41 EPIGENETIC MODIFICATION MECHANISMS INVOLVED IN INFLAMMATION AND FIBROSIS IN RENAL PATHOLOGY. THE GROWING INCIDENCE OF OBESITY, HYPERTENSION, AND DIABETES, COUPLED WITH THE AGING OF THE POPULATION, IS INCREASING THE PREVALENCE OF RENAL DISEASES IN OUR SOCIETY. CHRONIC KIDNEY DISEASE (CKD) IS CHARACTERIZED BY PERSISTENT INFLAMMATION, FIBROSIS, AND LOSS OF RENAL FUNCTION LEADING TO END-STAGE RENAL DISEASE. NOWADAYS, CKD TREATMENT HAS LIMITED EFFECTIVENESS UNDERSCORING THE IMPORTANCE OF THE DEVELOPMENT OF INNOVATIVE THERAPEUTIC OPTIONS. RECENT STUDIES HAVE IDENTIFIED HOW EPIGENETIC MODIFICATIONS PARTICIPATE IN THE SUSCEPTIBILITY TO CKD AND HAVE EXPLAINED HOW THE ENVIRONMENT INTERACTS WITH THE RENAL CELL EPIGENOME TO CONTRIBUTE TO RENAL DAMAGE. EPIGENETIC MECHANISMS REGULATE CRITICAL PROCESSES INVOLVED IN GENE REGULATION AND DOWNSTREAM CELLULAR RESPONSES. THE MOST RELEVANT EPIGENETIC MODIFICATIONS THAT PLAY A CRITICAL ROLE IN RENAL DAMAGE INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS, AND CHANGES IN MIRNA LEVELS. IMPORTANTLY, THESE EPIGENETIC MODIFICATIONS ARE REVERSIBLE AND, THEREFORE, A SOURCE OF POTENTIAL THERAPEUTIC TARGETS. HERE, WE WILL EXPLAIN HOW EPIGENETIC MECHANISMS MAY REGULATE ESSENTIAL PROCESSES INVOLVED IN RENAL PATHOLOGY AND HIGHLIGHT SOME POSSIBLE EPIGENETIC THERAPEUTIC STRATEGIES FOR CKD TREATMENT. 2018 15 5660 39 SEX-SPECIFIC EPIGENETIC PROGRAMMING IN RENAL FIBROSIS AND INFLAMMATION. THE GROWING PREVALENCE OF HYPERTENSION, HEART DISEASE, DIABETES, AND OBESITY ALONG WITH AN AGING POPULATION, IS LEADING TO HIGHER INCIDENCE OF RENAL DISEASES IN THE SOCIETY. CHRONIC KIDNEY DISEASE (CKD) IS CHARACTERIZED MAINLY BY PERSISTENT INFLAMMATION, FIBROSIS, AND GRADUAL LOSS OF RENAL FUNCTION LEADING TO RENAL FAILURE. SEX IS A KNOWN CONTRIBUTOR TO THE DIFFERENCES IN INCIDENCE AND PROGRESSION OF CKD. EPIGENETIC PROGRAMMING IS AN ESSENTIAL REGULATOR OF RENAL PHYSIOLOGY AND IS CRITICALLY INVOLVED IN THE PATHOPHYSIOLOGY OF RENAL INJURY AND FIBROSIS. EPIGENETIC SIGNALING INTEGRATES INTRINSIC AND EXTRINSIC SIGNALS ONTO THE GENOME, AND VARIOUS ENVIRONMENTAL AND HORMONAL STIMULI, INCLUDING SEX HORMONES, WHICH REGULATE GENE EXPRESSION AND DOWNSTREAM CELLULAR RESPONSES. THE MOST EXTENSIVELY STUDIED EPIGENETIC ALTERATIONS THAT PLAY A CRITICAL ROLE IN RENAL DAMAGE INCLUDE HISTONE MODIFICATIONS AND DNA METHYLATION. NOTABLY, THESE EPIGENETIC ALTERATIONS ARE REVERSIBLE, MAKING THEM CANDIDATES FOR POTENTIAL THERAPEUTIC TARGETS FOR THE TREATMENT OF RENAL DISEASES. HERE, WE WILL SUMMARIZE THE CURRENT KNOWLEDGE ON SEX-DIFFERENCES IN EPIGENETIC MODULATION OF RENAL FIBROSIS AND INFLAMMATION AND HIGHLIGHT SOME POSSIBLE EPIGENETIC THERAPEUTIC STRATEGIES FOR CKD TREATMENT. 2023 16 1977 33 EPIGENETIC ALTERATIONS IN ACUTE KIDNEY INJURY. ACUTE KIDNEY INJURY (AKI) IS A RISK FACTOR FOR CHRONIC KIDNEY DISEASE AND DEATH. DESPITE PROGRESS MADE IN UNDERSTANDING THE CELLULAR AND MOLECULAR BASIS OF AKI PATHOGENESIS THERE HAS BEEN NO IMPROVEMENT IN THE HIGH MORTALITY RATE FROM THIS DISEASE IN DECADES. EPIGENETICS IS ONE OF THE MOST INTENSIVELY STUDIED FIELDS OF BIOLOGY TODAY AND REPRESENTS A NEW PARADIGM FOR UNDERSTANDING THE PATHOPHYSIOLOGY OF DISEASE. ALTHOUGH EPIGENETICS OF AKI IS A NASCENT FIELD, THE AVAILABLE INFORMATION ALREADY IS PROVIDING COMPELLING EVIDENCE THAT CHROMATIN BIOLOGY PLAYS A CRITICAL ROLE IN THIS DISEASE. IN THIS ARTICLE WE EXPLORE WHAT IS KNOWN ABOUT THE CONTRIBUTION OF EPIGENETIC MECHANISMS TO THE PATHOPHYSIOLOGY OF AKI AND HOW THIS KNOWLEDGE ALREADY IS GUIDING THE DEVELOPMENT OF NEW DIAGNOSTIC TOOLS AND EPIGENETIC THERAPIES. 2013 17 6001 41 THE ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE TRANSITION: A POTENTIAL OPPORTUNITY TO IMPROVE CARE IN ACUTE KIDNEY INJURY. RECENT CONTROLLED TRIALS, EPIDEMIOLOGICAL ANALYSES AND BASIC RESEARCH STUDIES OFFER A COMPREHENSIVE VIEW OF THE SHORT AND LONG-TERM CLINICAL REPERCUSSION OF DE NOVO ACUTE KIDNEY INJURY OR AKI. WHILE MOST POST-AKI PATIENTS RECOVER THEIR BASELINE RENAL FUNCTION, A SIGNIFICANT NUMBER, APPROXIMATELY ~20% OF THOSE AFFECTED, WILL GO ON TO DEVELOP LONG TERM ILLNESS CHARACTERIZED BY AN INCREASE IN LATE STAGE CKD, CARDIOVASCULAR COMPLICATIONS, AND INCREASED DEATH RATES. WHEN AKI OCCURS IN HOSPITALIZED PATIENTS, SELECTED DEMOGRAPHIC AND LABORATORY RESULTS CAN BE INCORPORATED INTO RISK CALCULATORS THAT IDENTIFY THOSE AT HIGHER RISK FOR LONG-TERM COMPLICATIONS. THIS REVIEW TOUCHES ON SOME OF THE SALIENT EPIDEMIOLOGICAL STUDIES OF THE AKI TO CKD TRANSITION. IT ALSO FOCUSES ON CERTAIN RECENT ADVANCEMENTS IN OUR UNDERSTANDING OF THE BIOLOGICAL AND FUNCTIONAL IMPACT OF AKI ON THE RENAL TUBULE REPAIR MECHANISM, AS WELL AS THE IMPORTANT ROLE THAT GENETIC, EPIGENETIC, BIOCHEMICAL AND INFLAMMATORY EVENTS, SEEMINGLY BENEFICIAL TO THE RE-ESTABLISHMENT OF NORMAL RENAL FUNCTION, CAN BE OFFSET BY MEDIATORS OF PROGRESSIVE FIBROSIS AND IRREVERSIBLE STRUCTURAL CHANGES. CHARACTERIZATION OF BASIC PROCESSES THAT MEDIATE THE AKI TO CKD TRANSITION REVEALS PROMISING PHARMACOLOGICAL AND BIOLOGICAL AGENTS THAT HOPEFULLY WILL ONE DAY BE USED IN THE EARLY STAGES OF AKI TO PREVENT ITS DEADLY CONSEQUENCES. 2016 18 5950 39 TARGETING THE PROGRESSION OF CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS A DEVASTATING CONDITION THAT IS REACHING EPIDEMIC LEVELS OWING TO THE INCREASING PREVALENCE OF DIABETES MELLITUS, HYPERTENSION AND OBESITY, AS WELL AS AGEING OF THE POPULATION. REGARDLESS OF THE UNDERLYING AETIOLOGY, CKD IS SLOWLY PROGRESSIVE AND LEADS TO IRREVERSIBLE NEPHRON LOSS, END-STAGE RENAL DISEASE AND/OR PREMATURE DEATH. FACTORS THAT CONTRIBUTE TO CKD PROGRESSION INCLUDE PARENCHYMAL CELL LOSS, CHRONIC INFLAMMATION, FIBROSIS AND REDUCED REGENERATIVE CAPACITY OF THE KIDNEY. CURRENT THERAPIES HAVE LIMITED EFFECTIVENESS AND ONLY DELAY DISEASE PROGRESSION, UNDERSCORING THE NEED TO DEVELOP NOVEL THERAPEUTIC APPROACHES TO EITHER STOP OR REVERSE PROGRESSION. PRECLINICAL STUDIES HAVE IDENTIFIED SEVERAL APPROACHES THAT REDUCE FIBROSIS IN EXPERIMENTAL MODELS, INCLUDING TARGETING CYTOKINES, TRANSCRIPTION FACTORS, DEVELOPMENTAL AND SIGNALLING PATHWAYS AND EPIGENETIC MODULATORS, PARTICULARLY MICRORNAS. SOME OF THESE NEPHROPROTECTIVE STRATEGIES ARE NOW BEING TESTED IN CLINICAL TRIALS. LESSONS LEARNED FROM THE FAILURE OF CLINICAL STUDIES OF TRANSFORMING GROWTH FACTOR BETA1 (TGFBETA1) BLOCKADE UNDERSCORE THE NEED FOR ALTERNATIVE APPROACHES TO CKD THERAPY, AS STRATEGIES THAT TARGET A SINGLE PATHOGENIC PROCESS MAY RESULT IN UNEXPECTED NEGATIVE EFFECTS ON SIMULTANEOUSLY OCCURRING PROCESSES. ADDITIONAL PROMISING AVENUES INCLUDE PREVENTING TUBULAR CELL INJURY AND ANTI-FIBROTIC THERAPIES THAT TARGET ACTIVATED MYOFIBROBLASTS, THE MAIN COLLAGEN-PRODUCING CELLS. 2020 19 5258 37 PROGRESSION OF TUBULOINTERSTITIAL FIBROSIS AND THE CHRONIC KIDNEY DISEASE PHENOTYPE - ROLE OF RISK FACTORS AND EPIGENETICS. ALTHOUGH THE KIDNEY HAS CAPACITY TO REPAIR AFTER MILD INJURY, ONGOING OR SEVERE DAMAGE RESULTS IN SCARRING (FIBROSIS) AND AN ASSOCIATED PROGRESSIVE LOSS OF KIDNEY FUNCTION. HOWEVER, DESPITE ITS UNIVERSAL SIGNIFICANCE, EVIDENCE HIGHLIGHTS A POPULATION BASED HETEROGENEITY IN THE TRAJECTORY OF CHRONIC KIDNEY DISEASE (CKD) IN THESE PATIENTS. TO EXPLAIN THE HETEROGENEITY OF THE CKD PHENOTYPE REQUIRES AN UNDERSTANDING OF THE RELEVANT RISK FACTORS FOR FIBROSIS. THESE FACTORS INCLUDE BOTH THE EXTRINSIC NATURE OF INJURY, AND INTRINSIC FACTORS SUCH AS AGE, GENDER, GENETICS, AND PERPETUAL ACTIVATION OF FIBROBLASTS THROUGH PRIMING. IN MANY CASES AN ADDITIONAL LEVEL OF REGULATION IS PROVIDED BY EPIGENETIC MECHANISMS WHICH INTEGRATE THE VARIOUS PRO-FIBROTIC AND ANTI-FIBROTIC TRIGGERS IN FIBROGENESIS. IN THIS REVIEW WE THEREFORE EXAMINE THE VARIOUS MOLECULAR AND STRUCTURAL CHANGES OF FIBROSIS, AND HOW THEY ARE INFLUENCED BY EXTRINSIC AND INTRINSIC FACTORS. OUR AIM IS TO PROVIDE A UNIFYING HYPOTHESIS TO HELP EXPLAIN THE TRANSITION FROM ACUTE TO CKD. 2017 20 6409 44 THE SIGNALING OF CELLULAR SENESCENCE IN DIABETIC NEPHROPATHY. DIABETIC NEPHROPATHY IS THE LEADING CAUSE OF CHRONIC KIDNEY DISEASE (CKD) IN WESTERN COUNTRIES. NOTABLY, IT HAS A RAPIDLY RISING PREVALENCE IN CHINA. THE PATIENTS, COMMONLY COMPLICATED WITH CARDIOVASCULAR DISEASES AND NEUROLOGIC DISORDERS, ARE AT HIGH RISK TO PROGRESS INTO END-STAGE RENAL DISEASE (ESRD) AND DEATH. HOWEVER, THE PATHOGENIC MECHANISMS OF DIABETIC NEPHROPATHY HAVE NOT BEEN DETERMINED. CELLULAR SENESCENCE, WHICH RECENTLY HAS GAINED BROAD ATTENTION, IS THOUGHT TO BE AN IMPORTANT PLAYER IN THE ONSET AND DEVELOPMENT OF DIABETIC NEPHROPATHY. IN THIS ISSUE, WE GENERALLY REVIEW THE MECHANISMS OF CELLULAR SENESCENCE IN DIABETIC NEPHROPATHY, WHICH INVOLVE TELOMERE ATTRITION, DNA DAMAGE, EPIGENETIC ALTERATIONS, MITOCHONDRIAL DYSFUNCTION, LOSS OF KLOTHO, WNT/BETA-CATENIN SIGNALING ACTIVATION, PERSISTENT INFLAMMATION, AND ACCUMULATION OF UREMIC TOXINS. MOREOVER, WE HIGHLIGHT THE POTENTIAL THERAPEUTIC TARGETS OF CELLULAR SENESCENCE IN DIABETIC NEPHROPATHY AND PROVIDE IMPORTANT CLUES FOR CLINICAL STRATEGIES. 2019