1 2034 87 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 2 4513 27 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 3 3466 54 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 4 4381 40 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 5 6051 28 THE CONTRIBUTION OF HISTONE CROTONYLATION TO TISSUE HEALTH AND DISEASE: FOCUS ON KIDNEY HEALTH. ACUTE KIDNEY INJURY (AKI) AND CHRONIC KIDNEY DISEASE (CKD) ARE THE MOST SEVERE CONSEQUENCES OF KIDNEY INJURY. THEY ARE INTERCONNECTED SYNDROMES AS CKD PREDISPOSES TO AKI AND AKI MAY ACCELERATE CKD PROGRESSION. DESPITE THEIR GROWING IMPACT ON THE GLOBAL BURDEN OF DISEASE, THERE IS NO SATISFACTORY TREATMENT FOR AKI AND CURRENT THERAPEUTIC APPROACHES TO CKD REMAIN SUBOPTIMAL. RECENT RESEARCH HAS FOCUSED ON THE THERAPEUTIC TARGET POTENTIAL OF EPIGENETIC REGULATION OF GENE EXPRESSION, INCLUDING NON-CODING RNAS AND THE COVALENT MODIFICATIONS OF HISTONES AND DNA. INDEED, SEVERAL DRUGS TARGETING HISTONE MODIFICATIONS ARE IN CLINICAL USE OR UNDERGOING CLINICAL TRIALS. ACYL-LYSINE HISTONE MODIFICATIONS (E.G. METHYLATION, ACETYLATION, AND CROTONYLATION) HAVE MODULATED EXPERIMENTAL KIDNEY INJURY. MOST RECENTLY, INCREASED HISTONE LYSINE CROTONYLATION (KCR) WAS OBSERVED DURING EXPERIMENTAL AKI AND COULD BE REPRODUCED IN CULTURED TUBULAR CELLS EXPOSED TO INFLAMMATORY STRESS TRIGGERED BY THE CYTOKINE TWEAK. THE DEGREE OF KIDNEY HISTONE CROTONYLATION WAS MODULATED BY CROTONATE AVAILABILITY AND CROTONATE SUPPLEMENTATION PROTECTED FROM NEPHROTOXIC AKI. WE NOW REVIEW THE FUNCTIONAL RELEVANCE OF HISTONE CROTONYLATION IN KIDNEY DISEASE AND OTHER PATHOPHYSIOLOGICAL CONTEXTS, AS WELL AS THE IMPLICATIONS FOR THE DEVELOPMENT OF NOVEL THERAPEUTIC APPROACHES. THESE STUDIES PROVIDE INSIGHTS INTO THE OVERALL ROLE OF HISTONE CROTONYLATION IN HEALTH AND DISEASE. 2020 6 5420 34 REGULATION OF HYPOXIA-INDUCIBLE FACTOR IN KIDNEY DISEASE. HYPOXIA PLAYS A CRUCIAL ROLE IN THE PATHOPHYSIOLOGY OF ACUTE KIDNEY INJURY (AKI) AND PRESUMABLY ALSO CHRONIC KIDNEY DISEASE (CKD). HYPOXIA-INDUCIBLE FACTOR (HIF) IS THE MASTER TRANSCRIPTION FACTOR THAT REGULATES ADAPTIVE RESPONSES AGAINST HYPOXIA. UNDER HYPOXIC CONDITIONS, HIF ACTIVATES TARGET GENES WITH HYPOXIA-RESPONSIVE ELEMENTS IN THEIR REGULATORY REGIONS. THE HIF ISOFORMS AND REGULATORS OF HIF (I.E. PROLYL HYDROXYLASES) SHOW CELL TYPE-SPECIFIC DISTRIBUTIONS. HYPOXIA IS OBSERVED IN BOTH ISCHAEMIC AND SO-CALLED NON-ISCHAEMIC FORMS OF AKI. IN ADDITION TO THE ACUTE PHASE, HYPOXIA MAY ENSUE DURING THE RECOVERY PHASE OF AKI, POSSIBLY DUE TO THE OXYGEN-CONSUMING PROCESSES OF CELL GROWTH AND PROLIFERATION FOR REPAIR. ALTHOUGH HIF PROTECTS THE KIDNEY AGAINST AKI, INTRINSIC HIF ACTIVATION IS SUBMAXIMAL IN AKI AND FURTHER AUGMENTATION OF HIF AMELIORATES DISEASE MANIFESTATIONS. THE KIDNEY IN CKD ALSO SUFFERS FROM HYPOXIA CAUSED BY MULTIPLE MECHANISMS, INCLUDING SUSTAINED OXYGEN DEMANDS IN THE REMAINING NEPHRONS DUE TO MALADAPTIVE TUBULOGLOMERULAR FEEDBACK. WHETHER HIF IS CHRONICALLY UPREGULATED IN CKD IS CONTENTIOUS. HYPOXIA-INDUCIBLE FACTOR ACTIVATION IS A PROMISING THERAPEUTIC APPROACH TO CKD, BUT EXCESSIVE ACTIVATION OF HIF MAY BE DELETERIOUS. IT IS LIKELY THAT THERE IS A THERAPEUTIC WINDOW OF HIF ACTIVATION IN CHRONIC CONDITIONS. UNDER CERTAIN CIRCUMSTANCES, ANIMALS WITH CKD ARE PROTECTED AGAINST AKI AND THIS MAY BE EXPLAINED BY NON-PHYSIOLOGICAL HYPOXIA OF THE KIDNEY AND SUBSEQUENT HIF EXPRESSION. IN ADDITION, AN ACUTE HYPOXIC INSULT MAY INDUCE LONG-LASTING CHANGES, POSSIBLY INCLUDING EPIGENETIC MODIFICATIONS INDUCED BY HIF. THESE OBSERVATIONS SUGGEST A COMPLEX INTERACTION BETWEEN AKI AND CKD VIA HYPOXIA AND HIF ACTIVATION. 2013 7 221 41 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 8 6451 45 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 9 4016 27 LOW-DOSE HYDRALAZINE PREVENTS FIBROSIS IN A MURINE MODEL OF ACUTE KIDNEY INJURY-TO-CHRONIC KIDNEY DISEASE PROGRESSION. ACUTE KIDNEY INJURY (AKI) AND PROGRESSIVE CHRONIC KIDNEY DISEASE (CKD) ARE INTRINSICALLY TIED SYNDROMES. IN THIS REGARD, THE ACUTELY INJURED KIDNEY OFTEN DOES NOT ACHIEVE ITS FULL REGENERATIVE CAPACITY AND AKI DIRECTLY TRANSITIONS INTO PROGRESSIVE CKD ASSOCIATED WITH TUBULOINTERSTITIAL FIBROSIS. UNDERLYING MECHANISMS OF SUCH AKI-TO-CKD PROGRESSION ARE STILL INCOMPLETELY UNDERSTOOD AND SPECIFIC THERAPEUTIC INTERVENTIONS ARE STILL ELUSIVE. BECAUSE EPIGENETIC MODIFICATIONS PLAY A ROLE IN MAINTAINING TISSUE FIBROSIS, WE USED A MURINE MODEL OF ISCHEMIA-REPERFUSION INJURY TO DETERMINE WHETHER ABERRANT PROMOTER METHYLATION OF RASAL1 CONTRIBUTES CAUSALLY TO THE SWITCH BETWEEN PHYSIOLOGICAL REGENERATION AND TUBULOINTERSTITIAL FIBROGENESIS, A HALLMARK OF AKI-TO-CKD PROGRESSION. IT IS KNOWN THAT THE ANTIHYPERTENSIVE DRUG HYDRALAZINE HAS DEMETHYLATING ACTIVITY, AND THAT ITS OPTIMUM DEMETHYLATING ACTIVITY OCCURS AT CONCENTRATIONS BELOW BLOOD PRESSURE-LOWERING DOSES. ADMINISTRATION OF LOW-DOSE HYDRALAZINE EFFECTIVELY INDUCED EXPRESSION OF HYDROXYLASE TET3, WHICH CATALYZED RASAL1 HYDROXYMETHYLATION AND SUBSEQUENT RASAL1 PROMOTER DEMETHYLATION. HYDRALAZINE-INDUCED CPG PROMOTER DEMETHYLATION SUBSEQUENTLY ATTENUATED RENAL FIBROSIS AND PRESERVED EXCRETORY RENAL FUNCTION INDEPENDENT OF ITS BLOOD PRESSURE-LOWERING EFFECTS. IN COMPARISON, RASAL1 DEMETHYLATION AND INHIBITION OF TUBULOINTERSTITIAL FIBROSIS WAS NOT DETECTED UPON ADMINISTRATION OF THE ANGIOTENSIN-CONVERTING ENZYME INHIBITOR RAMIPRIL IN THIS MODEL. THUS, RASAL1 PROMOTER METHYLATION AND SUBSEQUENT TRANSCRIPTIONAL RASAL1 SUPPRESSION PLAYS A CAUSAL ROLE IN AKI-TO-CKD PROGRESSION. 2017 10 2788 35 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 11 3670 38 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 12 5363 23 RECENT ADVANCES IN DIABETIC KIDNEY DISEASES: FROM KIDNEY INJURY TO KIDNEY FIBROSIS. DIABETIC KIDNEY DISEASE (DKD) IS THE LEADING CAUSE OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE. THE NATURAL HISTORY OF DKD INCLUDES GLOMERULAR HYPERFILTRATION, PROGRESSIVE ALBUMINURIA, DECLINING ESTIMATED GLOMERULAR FILTRATION RATE, AND, ULTIMATELY, KIDNEY FAILURE. IT IS KNOWN THAT DKD IS ASSOCIATED WITH METABOLIC CHANGES CAUSED BY HYPERGLYCEMIA, RESULTING IN GLOMERULAR HYPERTROPHY, GLOMERULOSCLEROSIS, AND TUBULOINTERSTITIAL INFLAMMATION AND FIBROSIS. HYPERGLYCEMIA IS ALSO KNOWN TO CAUSE PROGRAMMED EPIGENETIC MODIFICATION. HOWEVER, THE DETAILED MECHANISMS INVOLVED IN THE ONSET AND PROGRESSION OF DKD REMAIN ELUSIVE. IN THIS REVIEW, WE DISCUSS RECENT ADVANCES REGARDING THE PATHOGENIC MECHANISMS INVOLVED IN DKD. 2021 13 5370 25 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 14 2293 30 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 15 2193 36 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 16 6299 35 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 17 2191 33 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 18 6647 32 UPDATE OF PERICYTES FUNCTION AND THEIR ROLES IN KIDNEY DISEASES. STUDIES HAVE HIGHLIGHTED THE SIGNIFICANT INVOLVEMENT OF KIDNEY PERICYTES IN RENAL FIBROSIS. KIDNEY PERICYTES, CLASSIFIED AS INTERSTITIAL MESENCHYMAL CELLS, ARE EXTENSIVELY BRANCHED, COLLAGEN-PRODUCING CELLS THAT CLOSELY INTERACT WITH ENDOTHELIAL CELLS. THIS ARTICLE AIMS TO PROVIDE AN OVERVIEW OF THE RECENT ADVANCEMENTS IN UNDERSTANDING THE PHYSIOLOGICAL FUNCTIONS OF PERICYTES AND THEIR ROLES IN KIDNEY DISEASES. IN A HEALTHY KIDNEY, PERICYTES HAVE ESSENTIAL PHYSIOLOGICAL FUNCTION IN ANGIOGENESIS, ERYTHROPOIETIN (EPO) PRODUCTION, AND THE REGULATION OF RENAL BLOOD FLOW. NEVERTHELESS, PERICYTE-MYOFIBROBLAST TRANSITION HAS BEEN IDENTIFIED AS THE PRIMARY CAUSE OF DISEASE PROGRESSION IN ACUTE KIDNEY INJURY (AKI)-TO-CHRONIC KIDNEY DISEASE (CKD) CONTINUUM. OUR RECENT RESEARCH HAS DEMONSTRATED THAT HYPOXIA-INDUCIBLE FACTOR-2ALPHA (HIF-2ALPHA) REGULATES ERYTHROPOIETIN PRODUCTION IN PERICYTES. HOWEVER, THIS PRODUCTION IS REPRESSED BY EPO GENE HYPERMETHYLATION AND HIF-2ALPHA DOWNREGULATION WHICH WERE INDUCED BY TRANSFORMING GROWTH FACTOR-BETA1-ACTIVATED DNA METHYLTRANSFERASE AND ACTIVIN RECEPTOR-LIKE KINASE-5 SIGNALING PATHWAY DURING RENAL FIBROSIS, RESPECTIVELY. ADDITIONALLY, AKI INDUCES EPIGENETIC MODIFICATIONS IN PERICYTES, RENDERING THEM MORE PRONE TO EXTRACELLULAR MATRIX PRODUCTION, CELL MIGRATION AND PROLIFERATION, THEREBY CONTRIBUTING TO SUBSEQUENT CAPILLARY RAREFACTION AND RENAL FIBROSIS. FURTHER INVESTIGATION INTO THE SPECIFIC FUNCTIONS AND ROLES OF DIFFERENT SUBPOPULATIONS OF PERICYTES MAY CONTRIBUTE FOR THE DEVELOPMENT OF TARGETED THERAPIES AIMED AT ATTENUATING KIDNEY DISEASE AND MITIGATING THEIR ADVERSE EFFECTS. 2023 19 5925 31 TARGETING EPIGENETIC DNA AND HISTONE MODIFICATIONS TO TREAT KIDNEY DISEASE. EPIGENETICS REFERS TO HERITABLE CHANGES IN GENE EXPRESSION PATTERNS NOT CAUSED BY AN ALTERED NUCLEOTIDE SEQUENCE, AND INCLUDES NON-CODING RNAS AND COVALENT MODIFICATIONS OF DNA AND HISTONES. THIS REVIEW FOCUSES ON FUNCTIONAL EVIDENCE FOR THE INVOLVEMENT OF DNA AND HISTONE EPIGENETIC MODIFICATIONS IN THE PATHOGENESIS OF KIDNEY DISEASE AND THE POTENTIAL THERAPEUTIC IMPLICATIONS. THERE IS EVIDENCE OF ACTIVATION OF EPIGENETIC REGULATORY MECHANISMS IN ACUTE KIDNEY INJURY (AKI), CHRONIC KIDNEY DISEASE (CKD) AND THE AKI-TO-CKD TRANSITION OF DIVERSE AETIOLOGIES, INCLUDING ISCHAEMIA-REPERFUSION INJURY, NEPHROTOXICITY, URETERAL OBSTRUCTION, DIABETES, GLOMERULONEPHRITIS AND POLYCYSTIC KIDNEY DISEASE. A BENEFICIAL IN VIVO EFFECT OVER PRECLINICAL KIDNEY INJURY HAS BEEN REPORTED FOR DRUGS THAT DECREASE DNA METHYLATION BY EITHER INHIBITING DNA METHYLATION (E.G. 5-AZACYTIDINE AND DECITABINE) OR ACTIVATING DNA DEMETHYLATION (E.G. HYDRALAZINE), DECREASE HISTONE METHYLATION BY INHIBITING HISTONE METHYLTRANSFERASES, INCREASE HISTONE ACETYLATION BY INHIBITING HISTONE DEACETYLASES (HDACS, E.G. VALPROIC ACID, VORINOSTAT, ENTINOSTAT), INCREASE HISTONE CROTONYLATION (CROTONATE) OR INTERFERE WITH HISTONE MODIFICATION READERS [E.G. INHIBITS OF BROMODOMAIN AND EXTRA-TERMINAL PROTEINS (BET)]. MOST PRECLINICAL STUDIES ADDRESSED CKD OR THE AKI-TO-CKD TRANSITION. CROTONATE ADMINISTRATION PROTECTED FROM NEPHROTOXIC AKI, BUT EVIDENCE IS CONFLICTING ON DNA METHYLATION INHIBITORS FOR PRECLINICAL AKI. SEVERAL DRUGS TARGETING EPIGENETIC REGULATORS ARE IN CLINICAL DEVELOPMENT OR USE, MOST OF THEM FOR MALIGNANCY. THE BET INHIBITOR APABETALONE IS IN PHASE 3 TRIALS FOR ATHEROSCLEROSIS, KIDNEY FUNCTION BEING A SECONDARY ENDPOINT, BUT NEPHROTOXICITY WAS REPORTED FOR DNA AND HDAC INHIBITORS. WHILE RESEARCH INTO EPIGENETIC MODULATORS MAY PROVIDE NOVEL THERAPIES FOR KIDNEY DISEASE, CAUTION SHOULD BE EXERCISED BASED ON THE CLINICAL NEPHROTOXICITY OF SOME DRUGS. 2018 20 1665 28 DOWNREGULATION OF KIDNEY PROTECTIVE FACTORS BY INFLAMMATION: ROLE OF TRANSCRIPTION FACTORS AND EPIGENETIC MECHANISMS. CHRONIC KIDNEY DISEASE (CKD) IS ASSOCIATED TO AN INCREASED RISK OF DEATH, CKD PROGRESSION, AND ACUTE KIDNEY INJURY (AKI) EVEN FROM EARLY STAGES, WHEN GLOMERULAR FILTRATION RATE (GFR) IS PRESERVED. THE LINK BETWEEN EARLY CKD AND THESE RISKS IS UNCLEAR, SINCE THERE IS NO ACCUMULATION OF UREMIC TOXINS. HOWEVER, PATHOLOGICAL ALBUMINURIA AND KIDNEY INFLAMMATION ARE FREQUENT FEATURES OF EARLY CKD, AND THE PRODUCTION OF KIDNEY PROTECTIVE FACTORS MAY BE DECREASED. INDEED, KLOTHO EXPRESSION IS ALREADY DECREASED IN CKD CATEGORY G1 (NORMAL GFR). KLOTHO HAS ANTI-AGING AND NEPHROPROTECTIVE PROPERTIES, AND DECREASED KLOTHO LEVELS MAY CONTRIBUTE TO INCREASE THE RISK OF DEATH, CKD PROGRESSION, AND AKI. IN THIS REVIEW, WE DISCUSS THE DOWNREGULATION BY MEDIATORS OF INFLAMMATION OF MOLECULES WITH SYSTEMIC AND/OR RENAL LOCAL PROTECTIVE FUNCTIONS, EXEMPLIFIED BY KLOTHO AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA COACTIVATOR-1ALPHA (PGC-1ALPHA), A TRANSCRIPTION FACTOR THAT PROMOTES MITOCHONDRIAL BIOGENESIS. CYTOKINES SUCH AS TWEAK, TNF-ALPHA, OR TRANSFORMING GROWTH FACTOR -BETA1 PRODUCED LOCALLY DURING KIDNEY INJURY OR RELEASED FROM INFLAMMATORY SITES AT OTHER ORGANS MAY DECREASE KIDNEY EXPRESSION OF KLOTHO AND PGC-1ALPHA OR LEAD TO SUBOPTIMAL RECRUITMENT OF THESE NEPHROPROTECTIVE PROTEINS. TRANSCRIPTION FACTORS (E.G., SMAD3 AND NF-KAPPAB) AND EPIGENETIC MECHANISMS (E.G., HISTONE ACETYLATION OR METHYLATION) CONTRIBUTE TO DOWNREGULATE THE EXPRESSION OF KLOTHO AND/OR PGC-1ALPHA, WHILE HISTONE CROTONYLATION PROMOTES PGC-1ALPHA EXPRESSION. NF-KAPPABIZ FACILITATES THE REPRESSIVE EFFECT OF NF-KAPPAB ON KLOTHO EXPRESSION. A DETAILED UNDERSTANDING OF THESE MEDIATORS MAY CONTRIBUTE TO THE DEVELOPMENT OF NOVEL THERAPEUTIC APPROACHES TO PREVENT CKD PROGRESSION AND ITS NEGATIVE IMPACT ON MORTALITY AND AKI. 2016