1 4058 63 MARKERS OF REJECTION OF A LUNG ALLOGRAFT: STATE OF THE ART. CHRONIC LUNG ALLOGRAFT DYSFUNCTION (CLAD) AFFECTS APPROXIMATELY 50% OF ALL LUNG TRANSPLANT RECIPIENTS BY 5 POST-OPERATIVE YEARS AND IS THE LEADING CAUSE OF DEATH IN LUNG TRANSPLANT RECIPIENTS. EARLY CLAD DIAGNOSIS OR IDEALLY PREDICTION OF CLAD IS ESSENTIAL TO ENABLE EARLY INTERVENTION BEFORE SIGNIFICANT LUNG INJURY OCCURS. NEW TECHNOLOGIES HAVE EMERGED TO FACILITATE BIOMARKER DISCOVERY, INCLUDING EPIGENETIC MODIFICATION AND SINGLE-CELL RNA SEQUENCING. THIS REVIEW EXAMINES NEW AND EXISTING TECHNOLOGIES FOR BIOMARKER DISCOVERY AND THE CURRENT STATE OF RESEARCH ON BIOMARKERS FOR IDENTIFYING LUNG TRANSPLANT REJECTION. 2022 2 3013 19 GENETICS AND EPIGENETICS OF CHRONIC ALLOGRAFT DYSFUNCTION IN KIDNEY TRANSPLANTS. CHRONIC ALLOGRAFT DYSFUNCTION IS THE MOST COMMON CAUSE OF ALLOGRAFT LOST. CHRONIC ALLOGRAFT DYSFUNCTION HAPPENS AS A RESULT OF COMPLEX INTERACTIONS AT THE MOLECULAR AND CELLULAR LEVELS. GENETIC AND ENVIRONMENTAL FACTORS BOTH INFLUENCE THE EVOLUTION AND PROGRESSION OF THE CHRONIC ALLOGRAFT DYSFUNCTION. EPIGENETIC MODIFICATION COULD BE CONSIDERED AS A THERAPEUTICALLY MODIFIABLE ELEMENT TO PAUSE THE FIBROSIS PROCESS THROUGH NOVEL STRATEGIES. IN THIS REVIEW, THE PUBMED DATABASE WAS SEARCHED FOR ENGLISH-LANGUAGE ARTICLES ON THESE NEW AREAS. 2016 3 5147 24 POTENTIAL ROLES OF LONG NONCODING RNAS AS THERAPEUTIC TARGETS IN ORGAN TRANSPLANTATION. ORGAN TRANSPLANTATION IS THE MOST PREFERRED TREATMENT OPTION FOR END-STAGE ORGAN DISEASES; HOWEVER, ALLOGRAFT REJECTION IS THE MAJOR HURDLE IN SUCCESSFUL LONG-TERM TRANSPLANT SURVIVAL. IN SPITE OF DEVELOPING BETTER HLA MATCHING AND MORE EFFECTIVE IMMUNOSUPPRESSIVE REGIMEN, ONE-YEAR GRAFT SURVIVAL HAS BEEN INCREASED BY NEARLY 90% AND THE INCIDENCE OF ACUTE REJECTION BY ONE-YEAR POST-TRANSPLANTATION HAS BEEN DECREASED BY 12.2% IN THE LAST DECADES, CHRONIC ALLOGRAFT REJECTION HAS REMAINED AS ONE OF THE MAJOR OBSTACLES TO THE LONG-LASTING SURVIVAL OF THE TRANSPLANTED ALLOGRAFT. THEREFORE, SEEMINGLY PREVENTING THE ALLOGRAFT REJECTION AND INDUCING IMMUNOLOGICAL TOLERANCE AGAINST TRANSPLANTED ALLOGRAFTS IS ONE OF THE PRIMARY GOALS IN TRANSPLANTATION RESEARCH TO ENABLE LONG-LASTING GRAFT SURVIVAL. VARIOUS MECHANISMS SUCH AS LONG NONCODING RNAS (LNCRNAS) HAVE BEEN PROPOSED THAT INDUCE IMMUNE TOLERANCE BY MODULATING THE GENE EXPRESSION AND REGULATING INNATE AND ADAPTIVE IMMUNE RESPONSES DURING TRANSPLANTATION. BESIDES, BECAUSE OF INVOLVEMENT IN REGULATING EPIGENETIC, TRANSCRIPTIONAL, AND POST-TRANSLATIONAL MECHANISMS, LNCRNAS COULD AFFECT ALLOGRAFT STATUS. THEREFORE, THESE MOLECULES COULD BE CONSIDERED AS THE POTENTIAL TARGETS FOR PREDICTION, PROGNOSIS, DIAGNOSIS, AND TREATMENT OF GRAFT REJECTION. IT IS SUGGESTED THAT THE NONINVASIVE PREDICTIVE BIOMARKERS HOLD PROMISE TO OVERCOME THE CURRENT LIMITATIONS OF CONVENTIONAL TISSUE BIOPSY IN THE DIAGNOSIS OF REJECTION. HENCE, THIS REVIEW AIMS TO PROVIDE A COMPREHENSIVE OVERVIEW OF LNCRNAS AND THEIR FUNCTION TO FACILITATE DIAGNOSIS, PROGNOSIS, AND PREDICTION OF THE RISK OF GRAFT REJECTION, AND THE SUGGESTIVE THERAPEUTIC CHOICES AFTER TRANSPLANTATION. 2022 4 3858 20 ISCHEMIA-INDUCED DNA HYPERMETHYLATION DURING KIDNEY TRANSPLANT PREDICTS CHRONIC ALLOGRAFT INJURY. BACKGROUND ISCHEMIA DURING KIDNEY TRANSPLANT CAUSES CHRONIC ALLOGRAFT INJURY AND ADVERSELY AFFECTS OUTCOME, BUT THE UNDERLYING MECHANISMS ARE INCOMPLETELY UNDERSTOOD. IN TUMORS, OXYGEN SHORTAGE REDUCES THE DNA DEMETHYLATING ACTIVITY OF THE TEN-11 TRANSLOCATION (TET) ENZYMES, YIELDING HYPERMETHYLATED GENOMES THAT PROMOTE TUMOR PROGRESSION. WE INVESTIGATED WHETHER ISCHEMIA SIMILARLY INDUCES DNA HYPERMETHYLATION IN KIDNEY TRANSPLANTS AND CONTRIBUTES TO CHRONIC INJURY.METHODS WE PROFILED GENOME-WIDE DNA METHYLATION IN THREE COHORTS OF BRAIN-DEAD DONOR KIDNEY ALLOGRAFT BIOPSY SPECIMENS: A LONGITUDINAL COHORT WITH PAIRED BIOPSY SPECIMENS OBTAINED AT ALLOGRAFT PROCUREMENT (PREISCHEMIA; N=13), AFTER IMPLANTATION AND REPERFUSION (POSTISCHEMIA; N=13), AND AT 3 OR 12 MONTHS AFTER TRANSPLANT (N=5 EACH); A CROSS-SECTIONAL COHORT WITH PREIMPLANTATION BIOPSY SPECIMENS (N=82); AND A CROSS-SECTIONAL COHORT WITH POSTREPERFUSION BIOPSY SPECIMENS (N=46).RESULTS ANALYSIS OF THE PAIRED PREISCHEMIA AND POSTISCHEMIA SPECIMENS REVEALED THAT METHYLATION INCREASED DRASTICALLY IN ALL ALLOGRAFTS ON ISCHEMIA. HYPERMETHYLATION WAS CAUSED BY LOSS OF 5-HYDROXYMETHYLCYTOSINE, THE PRODUCT OF TET ACTIVITY, AND IT WAS STABLE 1 YEAR AFTER TRANSPLANT. IN THE PREIMPLANTATION COHORT, CPG HYPERMETHYLATION DIRECTLY CORRELATED WITH ISCHEMIA TIME AND FOR SOME CPGS, INCREASED 2.6% PER ADDITIONAL HOUR OF ISCHEMIA. HYPERMETHYLATION PREFERENTIALLY AFFECTED AND REDUCED THE EXPRESSION OF GENES INVOLVED IN SUPPRESSING KIDNEY INJURY AND FIBROSIS. MOREOVER, CPG HYPERMETHYLATION IN PREIMPLANTATION SPECIMENS PREDICTED CHRONIC INJURY, PARTICULARLY FIBROSIS AND GLOMERULOSCLEROSIS, 1 YEAR AFTER TRANSPLANT. THIS FINDING WAS VALIDATED IN THE INDEPENDENT POSTREPERFUSION COHORT, IN WHICH HYPERMETHYLATION ALSO PREDICTED REDUCED ALLOGRAFT FUNCTION 1 YEAR AFTER TRANSPLANT, OUTPERFORMING ESTABLISHED CLINICAL VARIABLES.CONCLUSIONS WE HIGHLIGHT A NOVEL EPIGENETIC BASIS FOR ISCHEMIA-INDUCED CHRONIC ALLOGRAFT INJURY WITH BIOMARKER POTENTIAL. 2018 5 3716 14 INHIBITING INFLAMMATION WITH MYELOID CELL-SPECIFIC NANOBIOLOGICS PROMOTES ORGAN TRANSPLANT ACCEPTANCE. INDUCING GRAFT ACCEPTANCE WITHOUT CHRONIC IMMUNOSUPPRESSION REMAINS AN ELUSIVE GOAL IN ORGAN TRANSPLANTATION. USING AN EXPERIMENTAL TRANSPLANTATION MOUSE MODEL, WE DEMONSTRATE THAT LOCAL MACROPHAGE ACTIVATION THROUGH DECTIN-1 AND TOLL-LIKE RECEPTOR 4 (TLR4) DRIVES TRAINED IMMUNITY-ASSOCIATED CYTOKINE PRODUCTION DURING ALLOGRAFT REJECTION. WE CONDUCTED NANOIMMUNOTHERAPEUTIC STUDIES AND FOUND THAT A SHORT-TERM MTOR-SPECIFIC HIGH-DENSITY LIPOPROTEIN (HDL) NANOBIOLOGIC TREATMENT (MTORI-HDL) AVERTED MACROPHAGE AEROBIC GLYCOLYSIS AND THE EPIGENETIC MODIFICATIONS UNDERLYING INFLAMMATORY CYTOKINE PRODUCTION. THE RESULTING REGULATORY MACROPHAGES PREVENTED ALLOREACTIVE CD8(+) T CELL-MEDIATED IMMUNITY AND PROMOTED TOLEROGENIC CD4(+) REGULATORY T (TREG) CELL EXPANSION. TO ENHANCE THERAPEUTIC EFFICACY, WE COMPLEMENTED THE MTORI-HDL TREATMENT WITH A CD40-TRAF6-SPECIFIC NANOBIOLOGIC (TRAF6I-HDL) THAT INHIBITS CO-STIMULATION. THIS SYNERGISTIC NANOIMMUNOTHERAPY RESULTED IN INDEFINITE ALLOGRAFT SURVIVAL. TOGETHER, WE SHOW THAT HDL-BASED NANOIMMUNOTHERAPY CAN BE EMPLOYED TO CONTROL MACROPHAGE FUNCTION IN VIVO. OUR STRATEGY, FOCUSED ON PREVENTING INFLAMMATORY INNATE IMMUNE RESPONSES, PROVIDES A FRAMEWORK FOR DEVELOPING TARGETED THERAPIES THAT PROMOTE IMMUNOLOGICAL TOLERANCE. 2018 6 72 16 A MOLECULAR SIGNATURE FOR DELAYED GRAFT FUNCTION. CHRONIC KIDNEY DISEASE AND ASSOCIATED COMORBIDITIES (DIABETES, CARDIOVASCULAR DISEASES) MANIFEST WITH AN ACCELERATED AGEING PHENOTYPE, LEADING ULTIMATELY TO ORGAN FAILURE AND RENAL REPLACEMENT THERAPY. THIS PROCESS CAN BE MODULATED BY EPIGENETIC AND ENVIRONMENTAL FACTORS WHICH PROMOTE LOSS OF PHYSIOLOGICAL FUNCTION AND RESILIENCE TO STRESS EARLIER, LINKING BIOLOGICAL AGE WITH ADVERSE OUTCOMES POST-TRANSPLANTATION INCLUDING DELAYED GRAFT FUNCTION (DGF). THE MOLECULAR FEATURES UNDERPINNING THIS HAVE YET TO BE FULLY ELUCIDATED. WE HAVE DETERMINED A MOLECULAR SIGNATURE FOR LOSS OF RESILIENCE AND IMPAIRED PHYSIOLOGICAL FUNCTION, VIA A SYNCHRONOUS GENOME, TRANSCRIPTOME AND PROTEOME SNAPSHOT, USING HUMAN RENAL ALLOGRAFTS AS A SOURCE OF HEALTHY TISSUE AS AN IN VIVO MODEL OF AGEING IN HUMANS. THIS COMPRISES 42 SPECIFIC TRANSCRIPTS, RELATED THROUGH IFNGAMMA SIGNALLING, WHICH IN ALLOGRAFTS DISPLAYING CLINICALLY IMPAIRED PHYSIOLOGICAL FUNCTION (DGF) EXHIBITED A GREATER MAGNITUDE OF CHANGE IN TRANSCRIPTIONAL AMPLITUDE AND ELEVATED EXPRESSION OF NONCODING RNAS AND PSEUDOGENES, CONSISTENT WITH INCREASED ALLOSTATIC LOAD. THIS WAS ACCOMPANIED BY INCREASED DNA METHYLATION WITHIN THE PROMOTER AND INTRAGENIC REGIONS OF THE DGF PANEL IN PREPERFUSION ALLOGRAFTS WITH IMMEDIATE GRAFT FUNCTION. PATHWAY ANALYSIS INDICATED THAT AN INABILITY TO SUFFICIENTLY RESOLVE INFLAMMATORY RESPONSES WAS ENABLED BY DECREASED RESILIENCE TO STRESS AND RESULTED IN IMPAIRED PHYSIOLOGICAL FUNCTION IN BIOLOGICALLY OLDER ALLOGRAFTS. CROSS-COMPARISON WITH PUBLICALLY AVAILABLE DATA SETS FOR RENAL PATHOLOGIES IDENTIFIED SIGNIFICANT TRANSCRIPTIONAL COMMONALITY FOR OVER 20 DGF TRANSCRIPTS. OUR DATA ARE CLINICALLY RELEVANT AND IMPORTANT, AS THEY PROVIDE A CLEAR MOLECULAR SIGNATURE FOR THE BURDEN OF "WEAR AND TEAR" WITHIN THE KIDNEY AND THUS AGE-RELATED PHYSIOLOGICAL CAPABILITY AND RESILIENCE. 2018 7 782 21 CELL-FREE MICRORNA-148A IS ASSOCIATED WITH RENAL ALLOGRAFT DYSFUNCTION: IMPLICATION FOR BIOMARKER DISCOVERY. BACKGROUND: CHRONIC ALLOGRAFT DYSFUNCTION (CAD), THE FOREMOST CAUSE OF RENAL GRAFT LOSS WORLDWIDE, IS A SERIOUS CHALLENGE FOR MOST OF THE RECIPIENTS. AS THE EPIGENETIC ERA IS EMERGING, EPIGENETIC BIOMARKERS ESPECIALLY MICRORNAS (MIRNAS) MAY REFLECT THE CURRENT STAGE OF THE DISEASE AND PATIENT'S THERAPY RESPONSE. THE CURRENT STUDY INVESTIGATED THE POTENTIAL SIGNIFICANCE OF CIRCULATING MIRNA-148A IN PREDICTING THE RENAL GRAFT FUNCTION. DESIGN AND METHODS: CIRCULATING MIRNAS WERE ISOLATED FROM 53 PLASMA SAMPLES OF RECIPIENTS WITH HISTOLOGICALLY VALIDATED INTERSTITIAL FIBROSIS AND TUBULAR ATROPHY (IFTA, N = 26), AND RECIPIENTS WITH STABLE GRAFT FUNCTION (SGF, N = 27), AND ALSO HEALTHY INDIVIDUALS ( N = 15). THE LEVEL OF MIRNA-148A WAS EVALUATED BY THE QUANTITATIVE POLYMERASE CHAIN REACTION (QPCR) AND CORRELATED WITH CLINICAL AND HISTOLOGICAL PARAMETERS. RESULTS: SIGNIFICANTLY, MIRNA-148A DECREASED IN IFTA COMPARED WITH SGF SUBJECTS (P < 0.001). MIRNA-148A LEVELS INDICATED A SIGNIFICANT ASSOCIATION WITH SERUM CREATININE LEVELS ( R = 0.451, P = 0.021) AND GLOMERULAR FILTRATION RATE ( R = -0.520, P = 0.006). MIRNA-148A EXPRESSION LEVELS COULD DISCRIMINATE IFTA CASES FROM SGF INDIVIDUALS WITH AN AREA UNDER THE CURVE OF 0.89 ( P < 0.001), 97% SENSITIVITY, AND 72% SPECIFICITY. A NUMBER OF PREDICTED TARGETS THAT MIGHT BE INVOLVED IN CAD BY MIRNA-148A WERE PREDICTED. CONCLUSION: PLASMA CELL-FREE MIRNA-148A CORRELATED WITH RENAL FUNCTION AND HISTOLOGICAL GRADES; THEREFORE, IT MAY BE FURTHER INVESTIGATED AS A NOVEL NONINVASIVE MOLECULAR MARKER OF THE PROGRESSION TO IFTA IN RENAL TRANSPLANT RECIPIENTS; MOREOVER, THE EMERGING BIOMARKER MAY BECOME A THERAPEUTIC TARGET IN THE FUTURE CLINIC. 2019 8 4024 27 LUNG ALLOGRAFT EPITHELIUM DNA METHYLATION AGE IS ASSOCIATED WITH GRAFT CHRONOLOGIC AGE AND PRIMARY GRAFT DYSFUNCTION. ADVANCED DONOR AGE IS A RISK FACTOR FOR POOR SURVIVAL FOLLOWING LUNG TRANSPLANTATION. HOWEVER, RECENT WORK IDENTIFYING EPIGENETIC DETERMINANTS OF AGING HAS SHOWN THAT BIOLOGIC AGE MAY NOT ALWAYS REFLECT CHRONOLOGIC AGE AND THAT STRESSORS CAN ACCELERATE BIOLOGIC AGING. WE HYPOTHESIZED THAT LUNG ALLOGRAFTS THAT EXPERIENCED PRIMARY GRAFT DYSFUNCTION (PGD), CHARACTERIZED BY POOR OXYGENATION IN THE FIRST THREE POST-TRANSPLANT DAYS, WOULD HAVE INCREASED BIOLOGIC AGE. WE CULTURED AIRWAY EPITHELIAL CELLS ISOLATED BY TRANSBRONCHIAL BRUSH AT 1-YEAR BRONCHOSCOPIES FROM 13 SUBJECTS WITH SEVERE PGD AND 15 CONTROLS MATCHED ON AGE AND TRANSPLANT INDICATION. WE MEASURED EPIGENETIC AGE USING THE HORVATH EPIGENETIC CLOCK. LINEAR MODELS WERE USED TO DETERMINE THE ASSOCIATION OF AIRWAY EPIGENETIC AGE WITH CHRONOLOGIC AGES AND PGD STATUS, ADJUSTED FOR RECIPIENT PGD RISK FACTORS. SURVIVAL MODELS ASSESSED THE ASSOCIATION WITH CHRONIC LUNG ALLOGRAFT DYSFUNCTION (CLAD) OR DEATH. DISTRIBUTIONS OF PROMOTER METHYLATION WITHIN PATHWAYS WERE COMPARED BETWEEN GROUPS. DNA METHYLTRANSFERASE (DNMT) ACTIVITY WAS QUANTIFIED IN AIRWAY EPITHELIAL CELLS UNDER HYPOXIC OR NORMOXIC CONDITIONS. AIRWAY EPIGENETIC AGE APPEARED YOUNGER BUT WAS STRONGLY ASSOCIATED WITH THE AGE OF THE ALLOGRAFT (SLOPE 0.38 PER YEAR, 95% CI 0.27-0.48). THERE WAS NO CORRELATION BETWEEN EPIGENETIC AGE AND RECIPIENT AGE (P = 0.96). EPIGENETIC AGE WAS 6.5 YEARS GREATER (95% CI 1.7-11.2) IN SUBJECTS WHO HAD EXPERIENCED PGD, AND THIS EFFECT REMAINED SIGNIFICANT AFTER ADJUSTING FOR DONOR AND RECIPIENT CHARACTERISTICS (P = 0.03). EPIGENETIC AGE WAS NOT ASSOCIATED WITH CLAD-FREE SURVIVAL RISK (P = 0.11). ANALYSIS OF DIFFERENTIAL METHYLATION OF PROMOTERS OF KEY BIOLOGIC PATHWAYS REVEALED HYPOMETHYLATION IN REGIONS RELATED TO HYPOXIA, INFLAMMATION, AND METABOLISM-ASSOCIATED PATHWAYS. ACCORDINGLY, AIRWAY EPITHELIAL CELLS CULTURED IN HYPOXIC CONDITIONS SHOWED SUPPRESSED DNMT ACTIVITY. WHILE AIRWAY METHYLATION AGE WAS PRIMARILY DETERMINED BY DONOR CHRONOLOGIC AGE, EARLY INJURY IN THE FORM OF PGD WAS ASSOCIATED WITH INCREASED ALLOGRAFT EPIGENETIC AGE. THESE DATA SHOW HOW PGD MIGHT SUPPRESS KEY PROMOTER METHYLATION RESULTING IN LONG-TERM IMPACTS ON THE ALLOGRAFT. 2021 9 3495 16 IDENTIFICATION OF MIRNAS POTENTIALLY INVOLVED IN BRONCHIOLITIS OBLITERANS SYNDROME: A COMPUTATIONAL STUDY. THE PATHOGENESIS OF BRONCHIOLITIS OBLITERANS SYNDROME (BOS), THE MAIN CLINICAL PHENOTYPE OF CHRONIC LUNG ALLOGRAFT DYSFUNCTION, IS POORLY UNDERSTOOD. RECENT STUDIES SUGGEST THAT EPIGENETIC REGULATION OF MICRORNAS MIGHT PLAY A ROLE IN ITS DEVELOPMENT. IN THIS PAPER WE PRESENT THE APPLICATION OF A COMPLEX COMPUTATIONAL PIPELINE TO PERFORM ENRICHMENT ANALYSIS OF MIRNAS IN PATHWAYS APPLIED TO THE STUDY OF BOS. THE ANALYSIS CONSIDERED THE FULL SET OF MIRNAS ANNOTATED IN MIRBASE (VERSION 21), AND APPLIED A SEQUENCE OF FILTERING APPROACHES AND STATISTICAL ANALYSES TO REDUCE THIS SET AND TO SCORE THE CANDIDATE MIRNAS ACCORDING TO THEIR POTENTIAL INVOLVEMENT IN BOS DEVELOPMENT. DYSREGULATION OF TWO OF THE SELECTED CANDIDATE MIRNAS-MIR-34A AND MIR-21 -WAS CLEARLY SHOWN IN IN-SITU HYBRIDIZATION (ISH) ON FIVE EXPLANTED HUMAN BOS LUNGS AND ON A RAT MODEL OF ACUTE AND CHRONIC LUNG REJECTION, THUS DEFINITELY IDENTIFYING MIR-34A AND MIR-21 AS PATHOGENIC FACTORS IN BOS AND CONFIRMING THE EFFECTIVENESS OF THE COMPUTATIONAL PIPELINE. 2016 10 2615 22 EPIGENETICS: TIME TO TRANSLATE INTO TRANSPLANTATION. SUBSTANTIAL PROGRESS HAS BEEN MADE IN IDENTIFYING GENETIC LOCI ASSOCIATED WITH MULTIFACTORIAL DISORDERS, INCLUDING VARIANTS THAT SEEM TO IMPACT OUTCOMES FOLLOWING SOLID ORGAN TRANSPLANTATION. DESPITE THESE ADVANCES, MUCH OF THE HERITABILITY AND SUSCEPTIBILITY TO CHRONIC DISEASE PROCESSES REMAINS UNEXPLAINED. EPIGENETIC MODIFICATIONS MAY EXERT THEIR EFFECT INDEPENDENTLY OR COMPLEMENTARY TO GENETIC VARIANTS. EPIGENETIC MODIFICATIONS CAN CHANGE GENE EXPRESSION WITHOUT ALTERING THE DNA SEQUENCE. THESE MODIFICATIONS ARE DYNAMIC, POTENTIALLY HERITABLE, AND CAN BE INDUCED BY ENVIRONMENTAL STIMULI OR DRUGS. THE IMPACT OF EPIGENETIC PHENOMENA ON THE OUTCOMES OF ORGAN TRANSPLANTATION IS CURRENTLY POORLY UNDERSTOOD. EPIGENETIC MODIFICATIONS CAN OCCUR DURING PERIODS OF ILLNESS; THESE MAY PERSIST AND POTENTIALLY INFLUENCE ALLOGRAFT OUTCOMES. EPIGENETIC MECHANISMS INFLUENCE THE ACTIVATION, PROLIFERATION, AND DIFFERENTIATION OF THE IMMUNE CELLS INVOLVED IN ALLOGRAFT REJECTION. THE DONOR'S EPIGENOME MAY ALSO IMPACT TRANSPLANT SURVIVAL, AND INITIAL RESEARCH HAS DEMONSTRATED THAT PERITRANSPLANT CONDITIONS INDUCE RAPID EPIGENETIC MODIFICATION WITHIN THE ALLOGRAFT. FURTHER RESEARCH WILL HELP TO DEFINE THE IMPORTANCE OF EPIGENETIC MODIFICATIONS IN TRANSPLANTATION. THIS WILL POTENTIALLY LEAD TO THE IDENTIFICATION OF USEFUL BIOMARKERS AND THE DEVELOPMENT OF NOVEL PHARMACOTHERAPIES. THIS REVIEW EXPLORES THE NATURE OF EPIGENETIC MODIFICATION IN DISEASE AND THE EMERGING EVIDENCE FOR EPIGENETIC INFLUENCES ON ALLOGRAFT SURVIVAL. 2012 11 1461 16 DISRUPTION OF RCAN1.4 EXPRESSION MEDIATED BY YY1/HDAC2 MODULATES CHRONIC RENAL ALLOGRAFT INTERSTITIAL FIBROSIS. CHRONIC ALLOGRAFT DYSFUNCTION (CAD) IS A MAJOR FACTOR THAT HINDERS KIDNEY TRANSPLANT SURVIVAL IN THE LONG RUN. EPITHELIAL-MESENCHYMAL TRANSITION (EMT) HAS BEEN CONFIRMED TO SIGNIFICANTLY CONTRIBUTE TO INTERSTITIAL FIBROSIS/TUBULAR ATROPHY (IF/TA), WHICH IS THE MAIN HISTOPATHOLOGICAL FEATURE OF CAD. ABERRANT EXPRESSION OF THE REGULATOR OF CALCINEURIN 1 (RCAN1), RECOGNIZED AS AN ENDOGENOUS INHIBITOR OF THE CALCINEURIN PHOSPHATASE, HAS BEEN SHOWN TO BE EXTENSIVELY INVOLVED IN VARIOUS KIDNEY DISEASES. HOWEVER, IT REMAINS UNCLEAR HOW RCAN1.4 REGULATES IF/TA FORMATION IN CAD PATIENTS. HEREIN, AN IN VIVO MOUSE RENAL TRANSPLANTATION MODEL AND AN IN VITRO MODEL OF HUMAN RENAL TUBULAR EPITHELIAL CELLS (HK-2) TREATED WITH TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) WERE EMPLOYED. OUR RESULTS PROVED THAT RCAN1.4 EXPRESSION WAS DECREASED IN VIVO AND IN VITRO, IN ADDITION TO THE UP-REGULATION OF YIN YANG 1 (YY1), A TRANSCRIPTION FACTOR THAT HAS BEEN REPORTED TO CONVEY MULTIPLE FUNCTIONS IN CHRONIC KIDNEY DISEASE (CKD). KNOCKING IN OF RCAN1.4 EFFICIENTLY ATTENUATED CHRONIC RENAL ALLOGRAFT INTERSTITIAL FIBROSIS IN VIVO AND INHIBITED TNF-ALPHA-INDUCED EMT IN VITRO THROUGH REGULATING ANTI-OXIDATIVE STRESS AND THE CALCINEURIN/NUCLEAR FACTOR OF ACTIVATED T CELLS CYTOPLASMIC 1 (NFATC1) SIGNALING PATHWAY. IN ADDITION, SUPPRESSION OF YY1 MEDIATED BY SHRNA OR SIRNA ALLEVIATED TNF-ALPHA-INDUCED EMT THROUGH ABOLISHING REACTIVE SPECIES PARTLY IN AN RCAN1.4-DEPENDENT MANNER. NOTABLY, WE CONFIRMED THAT YY1 NEGATIVELY REGULATED RCAN1.4 TRANSCRIPTION BY DIRECTLY INTERACTING WITH THE RCAN1.4 PROMOTER. IN ADDITION, HISTONE DEACETYLASE 2 (HDAC2) INTERACTED WITH YY1 TO FORM A MULTI-MOLECULAR COMPLEX, WHICH WAS INVOLVED IN TNF-ALPHA-INDUCED RCAN1.4 TRANSCRIPTIONAL REPRESSION. THEREFORE, RCAN1.4 IS SUGGESTED TO BE MODULATED BY THE YY1/HDAC2 TRANSCRIPTION REPRESSOR COMPLEX IN AN EPIGENETIC MANNER, WHICH IS A MEDIATED NEPHROPROTECTIVE EFFECT PARTLY THROUGH MODULATING O2?- GENERATION AND THE CALCINEURIN/NFATC1 SIGNALING PATHWAY. THUS, THE YY1-RCAN1.4 AXIS CONSTITUTES AN INNOVATIVE TARGET FOR IF/TA TREATMENT IN CAD PATIENTS. 2023 12 1048 23 CLINICAL EPIGENETICS AND ACUTE/CHRONIC REJECTION IN SOLID ORGAN TRANSPLANTATION: AN UPDATE. THE LACK OF A PRECISE STRATIFICATION ALGORITHM FOR PREDICTING PATIENTS AT HIGH RISK OF GRAFT REJECTION CHALLENGES THE CURRENT SOLID ORGAN TRANSPLANTATION (SOT) CLINICAL SETTING. IN FACT, THE ESTABLISHED BIOMARKERS FOR TRANSPLANTATION OUTCOMES ARE UNABLE TO ACCURATELY PREDICT THE ONSET TIME AND SEVERITY OF GRAFT REJECTION (ACUTE OR CHRONIC) AS WELL AS THE INDIVIDUAL RESPONSE TO IMMUNOSUPPRESSIVE DRUGS. THUS, IDENTIFYING NOVEL MOLECULAR PATHWAYS UNDERLYING EARLY IMMUNOLOGICAL RESPONSES WHICH CAN DAMAGE TRANSPLANT INTEGRITY IS NEEDED TO REACH PRECISION MEDICINE AND PERSONALIZED THERAPY OF SOT. DIRECT EPIGENETIC-SENSITIVE MECHANISMS, MAINLY DNA METHYLATION AND HISTONE MODIFICATIONS, MAY PLAY A RELEVANT ROLE FOR IMMUNE ACTIVATION AND LONG-TERM EFFECTS (E.G., ACTIVATION OF FIBROTIC PROCESSES) WHICH MAY BE TRANSLATED IN NEW NON-INVASIVE BIOMARKERS AND DRUG TARGETS. IN PARTICULAR, THE MEASURE OF DNA METHYLATION BY USING THE BLOOD-BASED "EPIGENETIC CLOCK" SYSTEM MAY BE AN ADDED VALUE TO THE DONOR ELIGIBILITY CRITERIA PROVIDING AN ESTIMATION OF THE HEART BIOLOGICAL AGE AS WELL AS A PREDICTIVE BIOMARKERS. BESIDES, MONITORING OF DNA METHYLATION CHANGES MAY AID TO PREDICT ACUTE VS CHRONIC GRAFT DAMAGE IN KIDNEY TRANSPLANTATION (KT) PATIENTS. FOR EXAMPLE, HYPERMETHYLATION OF GENES BELONGING TO THE NOTCH AND WNT PATHWAYS SHOWED A HIGHER PREDICTIVE VALUE FOR CHRONIC INJURY OCCURRING AT 12 MONTHS POST-KT WITH RESPECT TO ESTABLISHED CLINICAL PARAMETERS. DETECTING HIGHER CIRCULATING CELL-FREE DNA (CFDNA) FRAGMENTS CARRYING HEPATOCYTE-SPECIFIC UNMETHYLATED LOCI IN THE INTER-ALPHA-TRYPSIN INHIBITOR HEAVY CHAIN 4 (ITIH4), INSULIN LIKE GROWTH FACTOR 2 RECEPTOR (IGF2R), AND VITRONECTIN (VTN) GENES MAY BE USEFUL TO PREDICT ACUTE GRAFT INJURY AFTER LIVER TRANSPLANTATION (LT) IN SERUM SAMPLES. FURTHERMORE, HYPOMETHYLATION IN THE FORKHEAD BOX P3 (FOXP3) GENE MAY SERVE AS A MARKER OF INFILTRATING NATURAL TREG PERCENTAGE IN THE GRAFT PROVIDING THE ABILITY TO PREDICT ACUTE REJECTION EVENTS AFTER HEART TRANSPLANTATION (HTX). WE AIM TO UPDATE ON THE POSSIBLE CLINICAL RELEVANCE OF DNA METHYLATION CHANGES REGULATING IMMUNE-RELATED PATHWAYS UNDERLYING ACUTE OR CHRONIC GRAFT REJECTION IN KT, LT, AND HTX WHICH MIGHT BE USEFUL TO PREVENT, MONITOR, AND TREAT SOLID ORGAN REJECTION AT PERSONALIZED LEVEL. 2021 13 2211 21 EPIGENETIC MODIFICATIONS AND THE DEVELOPMENT OF KIDNEY GRAFT FIBROSIS. PURPOSE OF REVIEW: TO OUTLINE RECENT DISCOVERIES IN EPIGENETIC REGULATORY MECHANISMS THAT HAVE POTENTIAL IMPLICATIONS IN THE DEVELOPMENT OF RENAL FIBROSIS FOLLOWING KIDNEY TRANSPLANTATION. RECENT FINDINGS: THE CHARACTERIZATION OF RENAL FIBROSIS FOLLOWING KIDNEY TRANSPLANTATION HAS SHOWN TGFBETA/SMAD SIGNALING TO PLAY A MAJOR ROLE IN THE PROGRESSION TO CHRONIC ALLOGRAFT DYSFUNCTION. THE ONSET OF UNREGULATED PROINFLAMMATORY PATHWAYS ARE ONLY EXACERBATED BY THE DECLINE IN REGULATORY MECHANISMS LOST WITH PROGRESSIVE PATIENT AGE AND COMORBIDITIES SUCH AS HYPERTENSION AND DIABETES. HOWEVER, SIGNIFICANT DEVELOPMENTS IN THE RECOGNITION OF EPIGENETIC REGULATORY MARKERS UPSTREAM OF ABERRANT TGFBETA-SIGNALING HAS SIGNIFICANT CLINICAL POTENTIAL TO PROVIDE THERAPEUTIC TARGETS FOR THE TREATMENT OF RENAL FIBROSIS. IN ADDITION, DISCOVERIES IN EXTRACELLULAR VESICLES AND THE CHARACTERIZATION OF THEIR CARGO HAS LAID NEW FRAMEWORK FOR THE POTENTIAL TO EVALUATE PATIENT OUTCOMES INDEPENDENT OF INVASIVE BIOPSIES. SUMMARY: THE CURRENT REVIEW SUMMARIZES THE MAIN FINDINGS IN EPIGENETIC MACHINERY SPECIFIC TO THE DEVELOPMENT OF RENAL FIBROSIS AND HIGHLIGHTS THERAPEUTIC OPTIONS THAT HAVE SIGNIFICANT POTENTIAL TO TRANSLATE INTO CLINICAL PRACTICE. 2021 14 6013 28 THE APPLICATIONS OF DNA METHYLATION AS A BIOMARKER IN KIDNEY TRANSPLANTATION: A SYSTEMATIC REVIEW. BACKGROUND: ALTHOUGH KIDNEY TRANSPLANTATION IMPROVES PATIENT SURVIVAL AND QUALITY OF LIFE, LONG-TERM RESULTS ARE HAMPERED BY BOTH IMMUNE- AND NON-IMMUNE-MEDIATED COMPLICATIONS. CURRENT BIOMARKERS OF POST-TRANSPLANT COMPLICATIONS, SUCH AS ALLOGRAFT REJECTION, CHRONIC RENAL ALLOGRAFT DYSFUNCTION, AND CUTANEOUS SQUAMOUS CELL CARCINOMA, HAVE A SUBOPTIMAL PREDICTIVE VALUE. DNA METHYLATION IS AN EPIGENETIC MODIFICATION THAT DIRECTLY AFFECTS GENE EXPRESSION AND PLAYS AN IMPORTANT ROLE IN PROCESSES SUCH AS ISCHEMIA/REPERFUSION INJURY, FIBROSIS, AND ALLOREACTIVE IMMUNE RESPONSE. NOVEL TECHNIQUES CAN QUICKLY ASSESS THE DNA METHYLATION STATUS OF MULTIPLE LOCI IN DIFFERENT CELL TYPES, ALLOWING A DEEP AND INTERESTING STUDY OF CELLS' ACTIVITY AND FUNCTION. THEREFORE, DNA METHYLATION HAS THE POTENTIAL TO BECOME AN IMPORTANT BIOMARKER FOR PREDICTION AND MONITORING IN KIDNEY TRANSPLANTATION. PURPOSE OF THE STUDY: THE AIM OF THIS STUDY WAS TO EVALUATE THE ROLE OF DNA METHYLATION AS A POTENTIAL BIOMARKER OF GRAFT SURVIVAL AND COMPLICATIONS DEVELOPMENT IN KIDNEY TRANSPLANTATION. MATERIAL AND METHODS: A SYSTEMATIC REVIEW OF SEVERAL DATABASES HAS BEEN CONDUCTED. THE NEWCASTLE-OTTAWA SCALE AND THE JADAD SCALE HAVE BEEN USED TO ASSESS THE RISK OF BIAS FOR OBSERVATIONAL AND RANDOMIZED STUDIES, RESPECTIVELY. RESULTS: TWENTY ARTICLES REPORTING ON DNA METHYLATION AS A BIOMARKER FOR KIDNEY TRANSPLANTATION WERE INCLUDED, ALL USING DNA METHYLATION FOR PREDICTION AND MONITORING. DNA METHYLATION PATTERN ALTERATIONS IN CELLS ISOLATED FROM DIFFERENT TISSUES, SUCH AS KIDNEY BIOPSIES, URINE, AND BLOOD, HAVE BEEN ASSOCIATED WITH ISCHEMIA-REPERFUSION INJURY AND CHRONIC RENAL ALLOGRAFT DYSFUNCTION. THESE ALTERATIONS OCCURRED IN DIFFERENT AND SPECIFIC LOCI. DNA METHYLATION STATUS HAS ALSO PROVED TO BE IMPORTANT FOR IMMUNE RESPONSE MODULATION, HAVING A CRUCIAL ROLE IN REGULATORY T CELL DEFINITION AND ACTIVITY. RESEARCH ALSO FOCUSED ON A BETTER UNDERSTANDING OF THE ROLE OF THIS EPIGENETIC MODIFICATION ASSESSMENT FOR REGULATORY T CELLS ISOLATION AND EXPANSION FOR FUTURE TOLERANCE INDUCTION-ORIENTED THERAPIES. CONCLUSIONS: STUDIES INCLUDED IN THIS REVIEW ARE HETEROGENEOUS IN STUDY DESIGN, BIOLOGICAL SAMPLES, AND OUTCOME. MORE COORDINATED INVESTIGATIONS ARE NEEDED TO AFFIRM DNA METHYLATION AS A CLINICALLY RELEVANT BIOMARKER IMPORTANT FOR PREVENTION, MONITORING, AND INTERVENTION. 2022 15 2286 20 EPIGENETIC REGULATION IN KIDNEY TRANSPLANTATION. KIDNEY TRANSPLANTATION IS A STANDARD CARE FOR END STAGE RENAL DISEASE, BUT IT IS ALSO ASSOCIATED WITH A COMPLEX PATHOGENESIS INCLUDING ISCHEMIA-REPERFUSION INJURY, INFLAMMATION, AND DEVELOPMENT OF FIBROSIS. OVER THE PAST DECADE, ACCUMULATING EVIDENCE HAS SUGGESTED A ROLE OF EPIGENETIC REGULATION IN KIDNEY TRANSPLANTATION, INVOLVING DNA METHYLATION, HISTONE MODIFICATION, AND VARIOUS KINDS OF NON-CODING RNAS. HERE, WE ANALYZE THESE RECENT STUDIES SUPPORTING THE ROLE OF EPIGENETIC REGULATION IN DIFFERENT PATHOLOGICAL PROCESSES OF KIDNEY TRANSPLANTATION, I.E., ISCHEMIA-REPERFUSION INJURY, ACUTE REJECTION, AND CHRONIC GRAFT PATHOLOGIES INCLUDING RENAL INTERSTITIAL FIBROSIS. FURTHER INVESTIGATION OF EPIGENETIC ALTERATIONS, THEIR PATHOLOGICAL ROLES AND UNDERLYING MECHANISMS IN KIDNEY TRANSPLANTATION MAY LEAD TO NEW STRATEGIES FOR THE DISCOVERY OF NOVEL DIAGNOSTIC BIOMARKERS AND THERAPEUTIC INTERVENTIONS. 2022 16 5900 21 T-CELL EXHAUSTION IN ORGAN TRANSPLANTATION. EXHAUSTION OF T CELLS OCCURS IN RESPONSE TO LONG-TERM EXPOSURE TO SELF AND FOREIGN ANTIGENS. IT LIMITS T CELL CAPACITY TO PROLIFERATE AND PRODUCE CYTOKINES, LEADING TO AN IMPAIRED ABILITY TO CLEAR CHRONIC INFECTIONS OR ERADICATE TUMORS. T-CELL EXHAUSTION IS ASSOCIATED WITH A SPECIFIC TRANSCRIPTIONAL, EPIGENETIC, AND METABOLIC PROGRAM AND CHARACTERISTIC CELL SURFACE MARKERS' EXPRESSION. RECENT STUDIES HAVE BEGUN TO ELUCIDATE THE ROLE OF T-CELL EXHAUSTION IN TRANSPLANT. HIGHER LEVELS OF EXHAUSTED T CELLS HAVE BEEN ASSOCIATED WITH BETTER GRAFT FUNCTION IN KIDNEY TRANSPLANT RECIPIENTS. IN CONTRAST, REINVIGORATING EXHAUSTED T CELLS BY IMMUNE CHECKPOINT BLOCKADE THERAPIES, WHILE PROMOTING TUMOR CLEARANCE, INCREASES THE RISK OF ACUTE REJECTION. LYMPHOCYTE DEPLETION AND HIGH ALLOANTIGEN LOAD HAVE BEEN IDENTIFIED AS MAJOR DRIVERS OF T-CELL EXHAUSTION. THIS COULD ACCOUNT, AT LEAST IN PART, FOR THE REDUCED RATES OF ACUTE REJECTION IN ORGAN TRANSPLANT RECIPIENTS INDUCED WITH THYMOGLOBULIN AND FOR THE PRO-TOLEROGENIC EFFECTS OF A LARGE ORGAN SUCH AS THE LIVER. AMONG THE DRUGS THAT ARE WIDELY USED FOR MAINTENANCE IMMUNOSUPPRESSION, CALCINEURIN INHIBITORS HAVE A CONTRASTING INHIBITORY EFFECT ON EXHAUSTION OF T CELLS, WHILE THE INFLUENCE OF MTOR INHIBITORS IS STILL UNCLEAR. HARNESSING OR ENCOURAGING THE NATURAL PROCESSES OF EXHAUSTION MAY PROVIDE A NOVEL STRATEGY TO PROMOTE GRAFT SURVIVAL AND TRANSPLANTATION TOLERANCE. 2022 17 3861 14 ISOLATION OF HUMAN ANTIGEN-SPECIFIC REGULATORY T CELLS WITH HIGH SUPPRESSIVE FUNCTION. ADOPTIVE TRANSFER OF REGULATORY T (TREG) CELLS COULD BE AN ALTERNATIVE TO CHRONIC IMMUNOSUPPRESSION FOR PREVENTION OF ALLOGENEIC GRAFT REJECTION. WHILE POLYSPECIFIC TREG CELLS CAN PREVENT IMMUNE RESPONSES UNDER LYMPHOPENIC CONDITIONS, AG-SPECIFIC TREG CELLS ARE NEEDED TO TREAT AUTOIMMUNITY AND GRAFT REJECTION. YET, RELIABLE MARKERS FOR AG-SPECIFIC TREG CELLS ARE MISSING. WE REPORT THAT LATENCY-ASSOCIATED PEPTIDE (LAP) AND GLYCOPROTEIN A REPETITIONS PREDOMINANT (GARP) CAN IDENTIFY HUMAN AG-SPECIFIC TREG CELLS. IN ADDITION, WE SHOW THAT THE DEPLETION OF CD154(+) CELLS FROM LAP(+) OR GARP(+) TREG CELLS INCREASES THE TREG-CELL PURITY TO OVER 90%, AS ASSESSED BY EPIGENETIC ANALYSIS. THESE AG-SPECIFIC TREG CELLS CAN BE ISOLATED MAGNETICALLY AND MIGHT CONTRIBUTE TO THE DEVELOPMENT OF GMP-BASED PROTOCOLS. IN ADDITION, AG-SPECIFIC TREG CELLS ARE FUNCTIONALLY FAR SUPERIOR TO CD4(+) CD25(HIGH) OR CD4(+) CD25(HIGH) CD127(LOW) TREG CELLS IN VITRO AND IN PREVENTING STRONG ALLOREACTIONS IN HUMANIZED MICE. THEY COULD, THEREFORE, HAVE A HIGH THERAPEUTIC POTENTIAL FOR THE CONTROL OF ALLOIMMUNE, AUTOIMMUNE, AND ALLERGIC IMMUNE RESPONSES IN PATIENTS. 2014 18 3856 24 ISCHAEMIA REPERFUSION INJURY: MECHANISMS OF PROGRESSION TO CHRONIC GRAFT DYSFUNCTION. THE INCREASING USE OF EXTENDED CRITERIA ORGANS TO MEET THE DEMAND FOR KIDNEY TRANSPLANTATION RAISES AN IMPORTANT QUESTION OF HOW THE SEVERITY OF EARLY ISCHAEMIC INJURY INFLUENCES LONG-TERM OUTCOMES. SIGNIFICANT ACUTE ISCHAEMIC KIDNEY INJURY IS ASSOCIATED WITH DELAYED GRAFT FUNCTION, INCREASED IMMUNE-ASSOCIATED EVENTS AND, ULTIMATELY, EARLIER DETERIORATION OF GRAFT FUNCTION. A COMPREHENSIVE UNDERSTANDING OF IMMEDIATE MOLECULAR EVENTS THAT ENSUE POST-ISCHAEMIA AND THEIR POTENTIAL LONG-TERM CONSEQUENCES ARE KEY TO THE DISCOVERY OF NOVEL THERAPEUTIC TARGETS. ACUTE ISCHAEMIC INJURY PRIMARILY AFFECTS TUBULAR STRUCTURE AND FUNCTION. DEPENDING ON THE SEVERITY AND PERSISTENCE OF THE INSULT, THIS MAY RESOLVE COMPLETELY, LEADING TO RESTORATION OF NORMAL FUNCTION, OR BE SUSTAINED, RESULTING IN PERSISTENT RENAL IMPAIRMENT AND PROGRESSIVE FUNCTIONAL LOSS. LONG-TERM EFFECTS OF ACUTE RENAL ISCHAEMIA ARE MEDIATED BY SEVERAL MECHANISMS INCLUDING HYPOXIA, HIF-1 ACTIVATION, ENDOTHELIAL DYSFUNCTION LEADING TO VASCULAR RAREFACTION, SUSTAINED PRO-INFLAMMATORY STIMULI INVOLVING INNATE AND ADAPTIVE IMMUNE RESPONSES, FAILURE OF TUBULAR CELLS TO RECOVER AND EPIGENETIC CHANGES. THIS REVIEW DESCRIBES THE BIOLOGICAL RELEVANCE AND INTERACTION OF THESE MECHANISMS BASED ON CURRENTLY AVAILABLE EVIDENCE. 2019 19 3670 21 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 20 3909 19 LIFE AFTER PANCREAS TRANSPLANTATION: REVERSAL OF DIABETIC LESIONS. PURPOSE OF REVIEW: RECIPIENTS OF PANCREAS TRANSPLANTATION BEAR THE BURDEN OF CHRONIC COMPLICATIONS OF DIABETES, BOTH MICROVASCULAR AND MACROVASCULAR. PANCREAS TRANSPLANTATION PROVIDES THE MOST EFFECTIVE METHOD OF GLYCEMIC AND METABOLIC CONTROL. AS TRANSPLANTATION PROVIDES IMMEDIATE RELIEF FROM ACUTE COMPLICATIONS OF DIABETES, THE IMPACT OF A SUCCESSFUL TRANSPLANT ON LONG-TERM COMPLICATIONS IS THE FOCUS OF THIS REVIEW. RECENT FINDINGS: IT IS INCREASINGLY RECOGNIZED THAT A SUCCESSFUL PANCREAS TRANSPLANT MAY SLOW, STABILIZE, OR AMELIORATE THE PROGRESSION OF MACROVASCULAR AND MICROVASCULAR COMPLICATIONS OF DIABETES. NEW UNDERSTANDING OF THE GENETIC AND EPIGENETIC MECHANISMS AND PATHOPHYSIOLOGY OF DIABETIC COMPLICATIONS HAS PROVIDED NEW DATA POTENTIALLY USEFUL FOR PROSPECTIVELY STUDYING THE EFFECT OF PANCREAS TRANSPLANT ON CHRONIC COMPLICATIONS OF DIABETES. SUMMARY: EARLIER CORRECTION OF DIABETES BY PANCREAS TRANSPLANTATION DECREASES CHRONIC COMPLICATIONS. REFINEMENTS IN THE UNDERSTANDING OF THE TISSUE TARGETS OF DIABETES COMPLICATIONS AND NEW DIAGNOSTIC AND IMAGING TOOLS TO MEASURE THEM MAY PROVE USEFUL IN FURTHER STUDYING THE IMPACT OF PANCREAS TRANSPLANTATION ON CHRONIC COMPLICATIONS OF DIABETES. 2014