1 4329 127 MICRORNAS: A NEW AVENUE TO UNDERSTAND, INVESTIGATE AND TREAT IMMUNOGLOBULIN A NEPHROPATHY? IGA NEPHROPATHY (IGAN) IS THE MOST COMMON CAUSE OF PRIMARY GLOMERULONEPHRITIS WORLDWIDE. UP TO 30% OF CASES DEVELOP THE PROGRESSIVE FORM OF THE DISEASE, EVENTUALLY REQUIRING RENAL REPLACEMENT THERAPY. DIAGNOSIS AND RISK STRATIFICATION RELIES ON AN INVASIVE KIDNEY BIOPSY AND MANAGEMENT OPTIONS ARE LIMITED, WITH RECURRENCE FOLLOWING RENAL TRANSPLANTATION BEING COMMON. THUS THE QUEST TO UNDERSTAND THE PATHOPHYSIOLOGY OF IGAN HAS BEEN ONE OF GREAT IMPORTANCE. MICRORNAS (MIRS) ARE SHORT NUCLEOTIDES THAT SUPPRESS GENE EXPRESSION BY HYBRIDIZING TO THE 3' UNTRANSLATED REGION OF MESSENGER RNA (MRNAS), PROMOTING MRNA DEGRADATION OR DISRUPTING TRANSLATION. FIRST DISCOVERED IN 1993, MIRS HAVE SINCE BEEN IMPLICATED IN A NUMBER OF CHRONIC CONDITIONS, INCLUDING CANCER, HEART DISEASE AND KIDNEY DISEASE. THE MOUNTING INTEREST IN THE FIELD OF MIRS HAS LED TO FASCINATING DEVELOPMENTS IN THE FIELD OF NEPHROLOGY, RANGING FROM THEIR ROLES AS BIOMARKERS FOR DISEASE TO THE DEVELOPMENT OF MIR ANTAGONISTS AS AVENUES FOR TREATMENT. THE TRANSLATIONAL POTENTIAL FOR MIRS IN IGAN IS THUS WELL GROUNDED AND MAY REPRESENT A PARADIGM SHIFT IN CURRENT APPROACHES TO THE DISEASE. THIS REVIEW AIMS TO SUMMARIZE THE LITERATURE WITH REGARD TO MIRS AND THEIR ROLES IN IGAN. 2018 2 3095 40 GENOMIC APPROACHES IN THE SEARCH FOR MOLECULAR BIOMARKERS IN CHRONIC KIDNEY DISEASE. BACKGROUND: CHRONIC KIDNEY DISEASE (CKD) IS RECOGNISED AS A GLOBAL PUBLIC HEALTH PROBLEM, MORE PREVALENT IN OLDER PERSONS AND ASSOCIATED WITH MULTIPLE CO-MORBIDITIES. DIABETES MELLITUS AND HYPERTENSION ARE COMMON AETIOLOGIES FOR CKD, BUT IGA GLOMERULONEPHRITIS, MEMBRANOUS GLOMERULONEPHRITIS, LUPUS NEPHRITIS AND AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE ARE ALSO COMMON CAUSES OF CKD. MAIN BODY: CONVENTIONAL BIOMARKERS FOR CKD INVOLVING THE USE OF ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) DERIVED FROM FOUR VARIABLES (SERUM CREATININE, AGE, GENDER AND ETHNICITY) ARE RECOMMENDED BY CLINICAL GUIDELINES FOR THE EVALUATION, CLASSIFICATION, AND STRATIFICATION OF CKD. HOWEVER, THESE CLINICAL BIOMARKERS PRESENT SOME LIMITATIONS, ESPECIALLY FOR EARLY STAGES OF CKD, ELDERLY INDIVIDUALS, EXTREME BODY MASS INDEX VALUES (SERUM CREATININE), OR ARE INFLUENCED BY INFLAMMATION, STEROID TREATMENT AND THYROID DYSFUNCTION (SERUM CYSTATIN C). THERE IS THEREFORE A NEED TO IDENTIFY ADDITIONAL NON-INVASIVE BIOMARKERS THAT ARE USEFUL IN CLINICAL PRACTICE TO HELP IMPROVE CKD DIAGNOSIS, INFORM PROGNOSIS AND GUIDE THERAPEUTIC MANAGEMENT. CONCLUSION: CKD IS A MULTIFACTORIAL DISEASE WITH ASSOCIATED GENETIC AND ENVIRONMENTAL RISK FACTORS. HENCE, MANY STUDIES HAVE EMPLOYED GENETIC, EPIGENETIC AND TRANSCRIPTOMIC APPROACHES TO IDENTIFY BIOMARKERS FOR KIDNEY DISEASE. IN THIS REVIEW, WE HAVE SUMMARISED THE MOST IMPORTANT STUDIES IN HUMANS INVESTIGATING GENOMIC BIOMARKERS FOR CKD IN THE LAST DECADE. SEVERAL GENES, INCLUDING UMOD, SHROOM3 AND ELMO1 HAVE BEEN STRONGLY ASSOCIATED WITH RENAL DISEASES, AND SOME OF THEIR TRAITS, SUCH AS EGFR AND SERUM CREATININE. THE ROLE OF EPIGENETIC AND TRANSCRIPTOMIC BIOMARKERS IN CKD AND RELATED DISEASES IS STILL UNCLEAR. THE COMBINATION OF MULTIPLE BIOMARKERS INTO CLASSIFIERS, INCLUDING GENOMIC, AND/OR EPIGENOMIC, MAY GIVE A MORE COMPLETE PICTURE OF KIDNEY DISEASES. 2018 3 5990 23 TGF-BETA1 PROMOTES EXPRESSION OF FIBROSIS-RELATED GENES THROUGH THE INDUCTION OF HISTONE VARIANT H3.3 AND HISTONE CHAPERONE HIRA. RENAL FIBROSIS IS A HISTOLOGICAL MANIFESTATION THAT OCCURS IN ALMOST EVERY TYPE OF CHRONIC KIDNEY DISEASE. HISTONE VARIANT H3.3 AND ITS CHAPERONE, HISTONE CELL CYCLE REGULATION DEFECTIVE HOMOLOG A (HIRA), SERVE AS EPIGENETIC MARKS THAT REGULATE TRANSCRIPTIONAL ACTIVITY. IN THIS STUDY, WE ASSESSED THE ROLES OF HISTONE H3.3 AND HIRA IN UNILATERAL URETERAL-OBSTRUCTION (UUO) MICE. IN UUO MICE, THE LEVELS OF HISTONE H3.3 AND HIRA WERE SIGNIFICANTLY UPREGULATED IN THE KIDNEYS. THESE UPREGULATED LEVELS WERE DECREASED BY A TGF-BETA1 NEUTRALIZING ANTIBODY. TGF-BETA1 INDUCED HISTONE H3.3 AND HIRA EXPRESSION IN VITRO VIA A SMAD3-DEPENDENT PATHWAY IN NORMAL RAT KIDNEY (NRK)-52E CELLS. ADDITIONALLY, KNOCKDOWN OF HIRA EXPRESSION DECREASED HISTONE H3.3 EXPRESSION AND FIBROGENESIS IN NRK-52E CELLS AFTER TGF-BETA1 STIMULATION. CHROMATIN IMMUNOPRECIPITATION ANALYSIS REVEALED THAT PROMOTERS OF FIBROSIS-RELATED GENES WERE IMMUNOPRECIPITATED WITH BOTH HISTONE H3.3 AND HIRA IN NRK-52E CELLS. LASTLY, IN HUMAN KIDNEY BIOPSIES FROM PATIENTS DIAGNOSED WITH IGA NEPHROPATHY, HISTONE H3.3 AND HIRA IMMUNOSTAINING CORRELATED POSITIVELY WITH AREAS OF FIBROSIS AND ESTIMATED GLOMERULAR FILTRATION RATE. IN CONCLUSION, TGF-BETA1 INDUCES EXPRESSION OF HISTONE H3.3 AND HIRA, WHICH REGULATES EXPRESSION OF FIBROSIS-RELATED GENES. 2018 4 6196 22 THE IMPACT OF THE TH17:TREG AXIS ON THE IGA-BIOME ACROSS THE GLYCEMIC SPECTRUM. SECRETORY IGA (SIGA) IS RELEASED INTO MUCOSAL SURFACES WHERE ITS FUNCTION EXTENDS BEYOND THAT OF HOST DEFENSE TO INCLUDE THE SHAPING OF RESIDENT MICROBIAL COMMUNITIES BY MEDIATING EXCLUSION/INCLUSION OF RESPECTIVE MICROBES AND REGULATING BACTERIAL GENE EXPRESSION. IN THIS CAPACITY, SIGA ACTS AS THE FULCRUM ON WHICH HOST IMMUNITY AND THE HEALTH OF THE MICROBIOTA ARE BALANCED. WE RECENTLY COMPLETED AN ANALYSIS OF THE GUT AND SALIVARY IGA-BIOMES (16S RDNA SEQUENCING OF SIGA-COATED/UNCOATED BACTERIA) IN MEXICAN-AMERICAN ADULTS THAT IDENTIFIED IGA-BIOME DIFFERENCES ACROSS THE GLYCEMIC SPECTRUM. AS TH17:TREG RATIO IMBALANCES ARE ASSOCIATED WITH GUT MICROBIOME DYSBIOSIS AND CHRONIC INFLAMMATORY CONDITIONS SUCH AS TYPE 2 DIABETES, THE PRESENT STUDY EXTENDS OUR PRIOR WORK BY EXAMINING THE IMPACT OF TH17:TREG RATIOS (PRO-INFLAMMATORY:ANTI-INFLAMMATORY T-CELL RATIOS) AND THE SIGA RESPONSE (TH17:TREG-SIGA AXIS) IN SHAPING MICROBIAL COMMUNITIES. EXAMINING THE IMPACT OF TH17:TREG RATIOS (DETERMINED BY EPIGENETIC QPCR LYMPHOCYTE SUBSET QUANTIFICATION) ON THE IGA-BIOME ACROSS DIABETES PHENOTYPES IDENTIFIED A PROPORTIONAL RELATIONSHIP BETWEEN TH17:TREG RATIOS AND ALPHA DIVERSITY IN THE STOOL IGA-BIOME OF THOSE WITH DYSGLYCEMIA, SIGNIFICANT CHANGES IN COMMUNITY COMPOSITION OF THE STOOL AND SALIVARY MICROBIOMES ACROSS GLYCEMIC PROFILES, AND GENERA PREFERENTIALLY ABUNDANT BY T-CELL INFLAMMATORY PHENOTYPE. THIS IS THE FIRST STUDY TO ASSOCIATE EPIGENETICALLY QUANTIFIED TH17:TREG RATIOS WITH BOTH THE LARGER AND SIGA-FRACTIONATED MICROBIOME, ASSESS THESE ASSOCIATIONS IN THE CONTEXT OF A CHRONIC INFLAMMATORY DISEASE, AND OFFERS A NOVEL FRAME THROUGH WHICH TO EVALUATE MUCOSAL MICROBIOMES IN THE CONTEXT OF HOST RESPONSES AND INFLAMMATION. 2021 5 5363 19 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 6 2555 25 EPIGENETICS IN RENAL DISEASES. WITH AGING, PREVALENCE OF OBESITY, HYPERTENSION, DIABETES AND RENAL DISEASES HAVE INCREASED GLOBALLY. OVER THE LAST TWO DECADES, THE PREVALENCE OF RENAL DISEASES HAS BEEN INTENSELY INCREASING. RENAL DISEASE AND RENAL PROGRAMMING ARE REGULATED BY EPIGENETIC MODIFICATIONS LIKE DNA METHYLATION AND HISTONE MODIFICATIONS. ENVIRONMENTAL FACTORS HAVE SIGNIFICANT ROLE IN THE PATHOPHYSIOLOGY OF RENAL DISEASE PROGRESSION. UNDERSTANDING THE POTENTIAL OF EPIGENETIC REGULATION OF GENE EXPRESSION MAY BE USEFUL IN RENAL DISEASE PROGNOSIS, DIAGNOSIS AND PROVIDES NOVEL THERAPEUTIC MEASURES. IN A NUTSHELL, THIS CHAPTER TALKS ABOUT THE ROLE OF EPIGENETIC MECHANISMS-DNA METHYLATION, HISTONE MODIFICATION, AND NONCODING RNA IN DIFFERENT RENAL DISEASES. THESE INCLUDE DIABETIC KIDNEY DISEASE, DIABETIC NEPHROPATHY, RENAL FIBROSIS, ETC. 2023 7 538 35 ATHEROSCLEROSIS AND EPIGENETIC MODIFICATIONS IN CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS ONE OF THE MOST COMMON CHRONIC DISEASES WORLDWIDE, WITH PREVALENCE CURRENTLY PROJECTED AT 10% AND RISING. CARDIOVASCULAR DISEASE IS THE LEADING CAUSE OF MORBIDITY AND MORTALITY IN CKD PATIENTS AND IS INTEGRALLY LINKED WITH ATHEROGENESIS AND VASCULAR STIFFNESS. ESTIMATED GLOMERULAR FILTRATION RATE AND THE LEVEL OF PROTEINURIA ARE NOT ONLY MARKERS OF KIDNEY FUNCTION BUT OF CARDIOVASCULAR RISK, AS WELL. DESPITE THE EFFORTS, CKD PATIENTS STILL EXPERIENCE EXCESSIVE CARDIOVASCULAR BURDEN. MICRORNAS (MIRNAS) ARE SMALL (18-24 NUCLEOTIDES), SINGLE-STRANDED NON-CODING RNAS THAT REGULATE GENE EXPRESSION BY BLOCKING MESSENGER RNA (MRNA) TRANSLATION AND INITIATING DEGRADATION OF MRNA. STUDIES HAVE CONFIRMED THE IMPERATIVE ROLE OF MIRNA DYSREGULATION IN THE PATHOPHYSIOLOGY OF SEVERAL DISEASES, INCLUDING ATHEROSCLEROSIS AND CKD. THIS ARTICLE SUMMARIZES WHAT IS CURRENTLY KNOWN ABOUT THE ROLE OF MIRNAS IN CKD PATIENTS. 2023 8 6075 30 THE DYNAMICS AND PLASTICITY OF EPIGENETICS IN DIABETIC KIDNEY DISEASE: THERAPEUTIC APPLICATIONS VIS-A-VIS. CHRONIC KIDNEY DISEASE (CKD) REFERS TO THE PHENOMENON OF PROGRESSIVE DECLINE IN THE GLOMERULAR FILTRATION RATE ACCOMPANIED BY ADVERSE CONSEQUENCES, INCLUDING FLUID RETENTION, ELECTROLYTE IMBALANCE, AND AN INCREASED CARDIOVASCULAR RISK COMPARED TO THOSE WITH NORMAL RENAL FUNCTION. THE TRIGGERS FOR THE IRREVERSIBLE RENAL FUNCTION DETERIORATION ARE MULTIFACTORIAL, AND DIABETES MELLITUS SERVES AS A MAJOR CONTRIBUTOR TO THE DEVELOPMENT OF CKD, NAMELY DIABETIC KIDNEY DISEASE (DKD). RECENTLY, EPIGENETIC DYSREGULATION EMERGED AS A PIVOTAL PLAYER STEERING THE PROGRESSION OF DKD, PARTLY RESULTING FROM HYPERGLYCEMIA-ASSOCIATED METABOLIC DISTURBANCES, RISING OXIDATIVE STRESS, AND/OR UNCONTROLLED INFLAMMATION. IN THIS REVIEW, WE DESCRIBE THE MAJOR EPIGENETIC MOLECULAR MECHANISMS, FOLLOWED BY SUMMARIZING CURRENT UNDERSTANDINGS OF THE EPIGENETIC ALTERATIONS PERTAINING TO DKD. WE HIGHLIGHT THE EPIGENETIC REGULATORY PROCESSES INVOLVED IN SEVERAL CRUCIAL RENAL CELL TYPES: MESANGIAL CELLS, PODOCYTES, TUBULAR EPITHELIA, AND GLOMERULAR ENDOTHELIAL CELLS. FINALLY, WE HIGHLIGHT EPIGENETIC BIOMARKERS AND RELATED THERAPEUTIC CANDIDATES THAT HOLD PROMISING POTENTIAL FOR THE EARLY DETECTION OF DKD AND THE AMELIORATION OF ITS PROGRESSION. 2022 9 5370 20 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 2579 31 EPIGENETICS OF KIDNEY DISEASE. DNA METHYLATION AND HISTONE MODIFICATIONS DETERMINE RENAL PROGRAMMING AND THE DEVELOPMENT AND PROGRESSION OF RENAL DISEASE. THE IDENTIFICATION OF THE WAY IN WHICH THE RENAL CELL EPIGENOME IS ALTERED BY ENVIRONMENTAL MODIFIERS DRIVING THE ONSET AND PROGRESSION OF RENAL DISEASES HAS EXTENDED OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY OF KIDNEY DISEASE PROGRESSION. IN THIS REVIEW, WE FOCUS ON CURRENT KNOWLEDGE CONCERNING THE IMPLICATIONS OF EPIGENETIC MODIFICATIONS DURING RENAL DISEASE FROM EARLY DEVELOPMENT TO CHRONIC KIDNEY DISEASE PROGRESSION INCLUDING RENAL FIBROSIS, DIABETIC NEPHROPATHY AND THE TRANSLATIONAL POTENTIAL OF IDENTIFYING NEW BIOMARKERS AND TREATMENTS FOR THE PREVENTION AND THERAPY OF CHRONIC KIDNEY DISEASE AND END-STAGE KIDNEY DISEASE. 2017 11 933 30 CHRONIC KIDNEY DISEASE. THE DEFINITION AND CLASSIFICATION OF CHRONIC KIDNEY DISEASE (CKD) HAVE EVOLVED OVER TIME, BUT CURRENT INTERNATIONAL GUIDELINES DEFINE THIS CONDITION AS DECREASED KIDNEY FUNCTION SHOWN BY GLOMERULAR FILTRATION RATE (GFR) OF LESS THAN 60 ML/MIN PER 1.73 M(2), OR MARKERS OF KIDNEY DAMAGE, OR BOTH, OF AT LEAST 3 MONTHS DURATION, REGARDLESS OF THE UNDERLYING CAUSE. DIABETES AND HYPERTENSION ARE THE MAIN CAUSES OF CKD IN ALL HIGH-INCOME AND MIDDLE-INCOME COUNTRIES, AND ALSO IN MANY LOW-INCOME COUNTRIES. INCIDENCE, PREVALENCE, AND PROGRESSION OF CKD ALSO VARY WITHIN COUNTRIES BY ETHNICITY AND SOCIAL DETERMINANTS OF HEALTH, POSSIBLY THROUGH EPIGENETIC INFLUENCE. MANY PEOPLE ARE ASYMPTOMATIC OR HAVE NON-SPECIFIC SYMPTOMS SUCH AS LETHARGY, ITCH, OR LOSS OF APPETITE. DIAGNOSIS IS COMMONLY MADE AFTER CHANCE FINDINGS FROM SCREENING TESTS (URINARY DIPSTICK OR BLOOD TESTS), OR WHEN SYMPTOMS BECOME SEVERE. THE BEST AVAILABLE INDICATOR OF OVERALL KIDNEY FUNCTION IS GFR, WHICH IS MEASURED EITHER VIA EXOGENOUS MARKERS (EG, DTPA, IOHEXOL), OR ESTIMATED USING EQUATIONS. PRESENCE OF PROTEINURIA IS ASSOCIATED WITH INCREASED RISK OF PROGRESSION OF CKD AND DEATH. KIDNEY BIOPSY SAMPLES CAN SHOW DEFINITIVE EVIDENCE OF CKD, THROUGH COMMON CHANGES SUCH AS GLOMERULAR SCLEROSIS, TUBULAR ATROPHY, AND INTERSTITIAL FIBROSIS. COMPLICATIONS INCLUDE ANAEMIA DUE TO REDUCED PRODUCTION OF ERYTHROPOIETIN BY THE KIDNEY; REDUCED RED BLOOD CELL SURVIVAL AND IRON DEFICIENCY; AND MINERAL BONE DISEASE CAUSED BY DISTURBED VITAMIN D, CALCIUM, AND PHOSPHATE METABOLISM. PEOPLE WITH CKD ARE FIVE TO TEN TIMES MORE LIKELY TO DIE PREMATURELY THAN THEY ARE TO PROGRESS TO END STAGE KIDNEY DISEASE. THIS INCREASED RISK OF DEATH RISES EXPONENTIALLY AS KIDNEY FUNCTION WORSENS AND IS LARGELY ATTRIBUTABLE TO DEATH FROM CARDIOVASCULAR DISEASE, ALTHOUGH CANCER INCIDENCE AND MORTALITY ARE ALSO INCREASED. HEALTH-RELATED QUALITY OF LIFE IS SUBSTANTIALLY LOWER FOR PEOPLE WITH CKD THAN FOR THE GENERAL POPULATION, AND FALLS AS GFR DECLINES. INTERVENTIONS TARGETING SPECIFIC SYMPTOMS, OR AIMED AT SUPPORTING EDUCATIONAL OR LIFESTYLE CONSIDERATIONS, MAKE A POSITIVE DIFFERENCE TO PEOPLE LIVING WITH CKD. INEQUITY IN ACCESS TO SERVICES FOR THIS DISEASE DISPROPORTIONALLY AFFECTS DISADVANTAGED POPULATIONS, AND HEALTH SERVICE PROVISION TO INCENTIVISE EARLY INTERVENTION OVER PROVISION OF CARE ONLY FOR ADVANCED CKD IS STILL EVOLVING IN MANY COUNTRIES. 2017 12 5846 30 STUDY PROTOCOL: RATIONALE AND DESIGN OF THE COMMUNITY-BASED PROSPECTIVE COHORT STUDY OF KIDNEY FUNCTION AND DIABETES IN RURAL NEW MEXICO, THE COMPASS STUDY. BACKGROUND: RURAL AREAS IN THE STATE OF NEW MEXICO HAVE BEEN THE "GROUND-ZERO" FOR THE EPIDEMIC OF DIABETIC CHRONIC KIDNEY DISEASE (CKD) IN THE UNITED STATES. HOWEVER, THERE IS LIMITED RESEARCH ABOUT RISK FACTORS OF DIABETIC CKD IN THIS AREA AND SCARCE DATA REGARDING THE PERFORMANCE OF EMERGING MARKERS OF RENAL FILTRATION AND EPIGENETIC BIOMARKERS OF RENAL FUNCTION AND DIABETES IN THIS AREA WITH ITS UNIQUE ETHNIC/RACIAL POPULATION. WE DESIGNED THE COMPASS STUDY AS A COMMUNITY-BASED PROGRAM IN RURAL NEW MEXICO AIMING TO SCREEN FOR CKD AND TO DISCOVER CKD-RELATED TRANSLATIONAL BIOMARKERS. METHODS/DESIGN: THE STUDY INVOLVES A PROSPECTIVE, LONGITUDINAL COHORT DESIGN INVOLVING INDIVIDUALS LIVING IN RURAL NEW MEXICO. PARTICIPANTS UNDERGO A SCREENING FOR KIDNEY DISEASE USING MARKERS OF ABNORMAL RENAL FILTRATION (IMPAIRED GLOMERULAR FILTRATION RATE) OR DAMAGE (ALBUMINURIA). THOSE FOUND TO HAVE CKD ON THE BASIS OF THESE TESTS OR THOSE AT RISK FOR CKD ARE ENROLLED IN A PROSPECTIVE LONGITUDINAL COHORT. WE MEASURE MARKERS OF RENAL FUNCTION, INSULIN RESISTANCE AND EPIGENETICS (MICRORNAS) ON PATIENTS. INDIVIDUALS ARE INVITED TO PARTICIPATE IN INTERVIEWS AND FOCUS GROUPS IN ORDER TO CHARACTERIZE THEIR ATTITUDES TOWARDS RESEARCH AND BARRIERS OR FACILITATORS TO PARTICIPATION IN FUTURE RESEARCH STUDIES ABOUT KIDNEY DISEASE. DISCUSSION: THIS STUDY WILL PROVIDE IMPORTANT DATA ABOUT THE LOCAL EPIDEMIOLOGY OF KIDNEY DISEASE IN A HIGH-RISK RURAL SETTING AND THE UTILITY OF EMERGING RENAL FILTRATION MARKERS (BETA 2 MICROGLOBULIN AND CYSTATIN C), WHILE GENERATING DATA AND METHODS FOR THE ANALYSES OF MICRORNA BIOMARKERS. THE QUALITATIVE RESEARCH SUBPROJECT WILL IDENTIFY FACTORS ASSOCIATED WITH INCREASED WILLINGNESS TO PARTICIPATE IN FUTURE TRANSLATIONAL RESEARCH PROJECTS. WITH ITS GEOGRAPHICAL FOCUS, THIS STUDY WILL ADDRESS A CRITICAL DISPARITY IN KIDNEY DISEASE RESEARCH, WHILE GENERATING NOVEL EPIGENETIC DATA THAT ARE RELEVANT FOR FUTURE STUDIES IN THE GENERAL POPULATION. 2018 13 5329 29 PURINERGIC SIGNALING IN THE LUMEN OF A NORMAL NEPHRON AND IN REMODELED PKD ENCAPSULATED CYSTS. THE NEPHRON IS THE FUNCTIONAL UNIT OF THE KIDNEY. BLOOD AND PLASMA ARE CONTINUALLY FILTERED WITHIN THE GLOMERULI THAT BEGIN EACH NEPHRON. ADENOSINE 5' TRIPHOSPHATE (ATP) AND ITS METABOLITES ARE FREELY FILTERED BY EACH GLOMERULUS AND ENTER THE LUMEN OF EACH NEPHRON BEGINNING AT THE PROXIMAL CONVOLUTED TUBULE (PCT). FLOW RATE, OSMOLALITY, AND OTHER MECHANICAL OR CHEMICAL STIMULI FOR ATP SECRETION ARE PRESENT IN EACH NEPHRON SEGMENT. THESE ATP-RELEASE STIMULI ARE ALSO DIFFERENT IN EACH NEPHRON SEGMENT DUE TO WATER OR SALT PERMEABILITY OR IMPERMEABILITY ALONG DIFFERENT LUMINAL MEMBRANES OF THE CELLS THAT LINE EACH NEPHRON SEGMENT. EACH OF THE ABOVE STIMULI CAN TRIGGER ADDITIONAL ATP RELEASE INTO THE LUMEN OF A NEPHRON SEGMENT. EACH NEPHRON-LINING EPITHELIAL CELL IS A POTENTIAL SOURCE OF SECRETED ATP. TOGETHER WITH FILTERED ATP AND ITS METABOLITES DERIVED FROM THE GLOMERULUS, SECRETED ATP AND ADENOSINE DERIVED FROM CELLS ALONG THE NEPHRON ARE LIKELY THE PRINCIPAL TWO OF SEVERAL NUCLEOTIDE AND NUCLEOSIDE CANDIDATES FOR RENAL AUTOCRINE AND PARACRINE LIGANDS WITHIN THE TUBULAR FLUID OF THE NEPHRON. THIS MINIREVIEW DISCUSSES THE FIRST PRINCIPLES OF PURINERGIC SIGNALING AS THEY RELATE TO THE NEPHRON AND THE URINARY BLADDER. THE REVIEW DISCUSSES HOW THE LUMEN OF A RENAL TUBULE PRESENTS AN IDEAL PURINERGIC SIGNALING MICROENVIRONMENT. THE REVIEW ALSO ILLUSTRATES HOW REMODELED AND ENCAPSULATED CYSTS IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD) AND REMODELED PSEUDOCYSTS IN AUTOSOMAL RECESSIVE PKD (ARPKD) OF THE RENAL COLLECTING DUCT LIKELY CREATE AN EVEN MORE IDEAL MICROENVIRONMENT FOR PURINERGIC SIGNALING. ONCE TRAPPED IN THESE CLOSED MICROENVIRONMENTS, PURINERGIC SIGNALING BECOMES CHRONIC AND LIKELY PLAYS A SIGNIFICANT EPIGENETIC AND DETRIMENTAL ROLE IN THE SECONDARY PROGRESSION OF PKD, ONCE THE REMODELING OF THE RENAL TISSUE HAS BEGUN. IN PKD CYSTIC MICROENVIRONMENTS, WE ARGUE THAT NORMAL PURINERGIC SIGNALING WITHIN THE LUMEN OF THE NEPHRON PROVIDES DETRIMENTAL ACCELERATION OF ADPKD ONCE REMODELING IS COMPLETE. 2008 14 5988 29 TGF-BETA/SMAD AND RENAL FIBROSIS. RENAL FIBROSIS IS CHARACTERIZED BY EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX (ECM) THAT DISRUPTS AND REPLACES FUNCTIONAL PARENCHYMA, WHICH LEADS TO ORGAN FAILURE. IT IS KNOWN AS THE MAJOR PATHOLOGICAL MECHANISM OF CHRONIC KIDNEY DISEASE (CKD). ALTHOUGH CKD HAS AN IMPACT ON NO LESS THAN 10% OF THE WORLD POPULATION, THERAPEUTIC OPTIONS ARE STILL LIMITED. REGARDLESS OF ETIOLOGY, ELEVATED TGF-BETA LEVELS ARE HIGHLY CORRELATED WITH THE ACTIVATED PRO-FIBROTIC PATHWAYS AND DISEASE PROGRESSION. TGF-BETA, THE KEY DRIVER OF RENAL FIBROSIS, IS INVOLVED IN A DYNAMIC PATHOPHYSIOLOGICAL PROCESS THAT LEADS TO CKD AND END-STAGE RENAL DISEASE (ESRD). IT IS BECOMING CLEAR THAT EPIGENETICS REGULATES RENAL PROGRAMMING, AND THEREFORE, THE DEVELOPMENT AND PROGRESSION OF RENAL DISEASE. INDEED, RECENT EVIDENCE SHOWS TGF-BETA1/SMAD SIGNALING REGULATES RENAL FIBROSIS VIA EPIGENETIC-CORRELATED MECHANISMS. THIS REVIEW FOCUSES ON THE FUNCTION OF TGF-BETA/SMADS IN RENAL FIBROGENESIS, AND THE ROLE OF EPIGENETICS AS A REGULATOR OF PRO-FIBROTIC GENE EXPRESSION. 2019 15 2987 26 GENETIC EPIDEMIOLOGY IN KIDNEY DISEASE. FAMILIAL AGGREGATION OF CHRONIC KIDNEY DISEASE AND ITS COMPONENT PHENOTYPES-REDUCED GLOMERULAR FILTRATION RATE, PROTEINURIA AND RENAL HISTOLOGIC CHANGES-HAS LONG BEEN RECOGNIZED. RATES OF SEVERE KIDNEY DISEASE ARE ALSO KNOWN TO DIFFER MARKEDLY BETWEEN POPULATIONS BASED ON ANCESTRY. THESE EPIDEMIOLOGIC OBSERVATIONS SUPPORT THE EXISTENCE OF NEPHROPATHY SUSCEPTIBILITY GENES. SEVERAL MOLECULAR GENETIC TECHNOLOGIES ARE NOW AVAILABLE TO IDENTIFY CAUSATIVE LOCI. THE PRESENT ARTICLE SUMMARIZES AVAILABLE STRATEGIES USEFUL FOR IDENTIFYING NEPHROPATHY SUSCEPTIBILITY GENES, INCLUDING CANDIDATE GENE ASSOCIATION, FAMILY-BASED LINKAGE, GENOME-WIDE ASSOCIATION AND ADMIXTURE MAPPING (MAPPING BY ADMIXTURE LINKAGE DISEQUILIBRIUM) APPROACHES. EXAMPLES OF LOCI DETECTED USING THESE TECHNIQUES ARE PROVIDED. EPIGENETIC STUDIES AND FUTURE DIRECTIONS ARE ALSO DISCUSSED. THE IDENTIFICATION OF NEPHROPATHY SUSCEPTIBILITY GENES, COUPLED WITH MODIFIABLE ENVIRONMENTAL TRIGGERS IMPACTING THEIR FUNCTION, IS LIKELY TO IMPROVE RISK PREDICTION AND TRANSFORM CARE. DEVELOPMENT OF NOVEL THERAPIES TO PREVENT PROGRESSION OF KIDNEY DISEASE WILL FOLLOW. 2017 16 6160 33 THE GENETICS AND PATHOGENESIS OF CAKUT. CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT (CAKUT) COMPRISE A LARGE VARIETY OF MALFORMATIONS THAT ARISE FROM DEFECTIVE KIDNEY OR URINARY TRACT DEVELOPMENT AND FREQUENTLY LEAD TO KIDNEY FAILURE. THE CLINICAL SPECTRUM RANGES FROM SEVERE MALFORMATIONS, SUCH AS RENAL AGENESIS, TO POTENTIALLY MILDER MANIFESTATIONS, SUCH AS VESICOURETERAL REFLUX. ALMOST 50% OF CASES OF CHRONIC KIDNEY DISEASE THAT MANIFEST WITHIN THE FIRST THREE DECADES OF LIFE ARE CAUSED BY CAKUT. EVIDENCE SUGGESTS THAT A LARGE NUMBER OF CAKUT ARE GENETIC IN ORIGIN. TO DATE, MUTATIONS IN ~54 GENES HAVE BEEN IDENTIFIED AS MONOGENIC CAUSES OF CAKUT, CONTRIBUTING TO 12-20% OF THE AETIOLOGY OF THE DISEASE. PATHOGENIC COPY NUMBER VARIANTS HAVE ALSO BEEN SHOWN TO CAUSE CAKUT AND CAN BE DETECTED IN 4-11% OF PATIENTS. FURTHERMORE, ENVIRONMENTAL AND EPIGENETIC FACTORS CAN INCREASE THE RISK OF CAKUT. THE DISCOVERY OF NOVEL CAKUT-CAUSING GENES IS CHALLENGING OWING TO VARIABLE EXPRESSIVITY, INCOMPLETE PENETRANCE AND VARIABLE GENOTYPE-PHENOTYPE CORRELATION. HOWEVER, SUCH A DISCOVERY COULD ULTIMATELY LEAD TO IMPROVEMENTS IN THE ACCURATE MOLECULAR GENETIC DIAGNOSIS, ASSESSMENT OF PROGNOSIS AND MULTIDISCIPLINARY CLINICAL MANAGEMENT OF PATIENTS WITH CAKUT, POTENTIALLY INCLUDING PERSONALIZED THERAPEUTIC APPROACHES. 2023 17 5300 31 PROTEIN METHYLATION IN DIABETIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS DEFINED BY PERSISTENT URINE ABERRATIONS, STRUCTURAL ABNORMALITIES, OR IMPAIRED EXCRETORY RENAL FUNCTION. DIABETES IS THE LEADING CAUSE OF CKD. THEIR COMMON PATHOLOGICAL MANIFESTATION IS RENAL FIBROSIS. APPROXIMATELY HALF OF ALL PATIENTS WITH TYPE 2 DIABETES AND ONE-THIRD WITH TYPE 1 DIABETES WILL DEVELOP CKD. HOWEVER, RENAL FIBROSIS MECHANISMS ARE STILL POORLY UNDERSTOOD, ESPECIALLY POST-TRANSCRIPTIONAL AND EPIGENETIC REGULATION. AND AN UNMET NEED REMAINS FOR INNOVATIVE TREATMENT STRATEGIES FOR PREVENTING, ARRESTING, TREATING, AND REVERSING DIABETIC KIDNEY DISEASE (DKD). PEOPLE BELIEVE THAT PROTEIN METHYLATION, INCLUDING HISTONE AND NON-HISTONE, IS AN ESSENTIAL TYPE OF POST-TRANSLATIONAL MODIFICATION (PTM). HOWEVER, PREVALENT REVIEWS MAINLY FOCUS ON THE CAUSES SUCH AS DNA METHYLATION. THIS REVIEW WILL TAKE INSIGHTS INTO THE PROTEIN PART. FURTHERMORE, BY EMPHASIZING THE CLOSE RELATIONSHIP BETWEEN PROTEIN METHYLATION AND DKD, WE WILL SUMMARIZE THE CLINICAL RESEARCH STATUS AND FORESEE THE APPLICATION PROSPECT OF PROTEIN METHYLTRANSFERASE (PMT) INHIBITORS IN DKD TREATMENT. IN A NUTSHELL, OUR REVIEW WILL CONTRIBUTE TO A MORE PROFOUND UNDERSTANDING OF DKD'S MOLECULAR MECHANISM AND INSPIRE PEOPLE TO DIG INTO THIS FIELD. 2022 18 6575 33 TREATMENT OF DIABETIC KIDNEY DISEASE: CURRENT AND FUTURE. DIABETIC KIDNEY DISEASE (DKD) IS THE MAJOR CAUSE OF END-STAGE KIDNEY DISEASE. HOWEVER, ONLY RENIN-ANGIOTENSIN SYSTEM INHIBITOR WITH MULTIDISCIPLINARY TREATMENTS IS EFFECTIVE FOR DKD. IN 2019, SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITOR SHOWED EFFICACY AGAINST DKD IN CANAGLIFLOZIN AND RENAL EVENTS IN DIABETES WITH ESTABLISHED NEPHROPATHY CLINICAL EVALUATION (CREDENCE) TRIAL, ADDING A NEW TREATMENT OPTION. HOWEVER, THE PROGRESSION OF DKD HAS NOT BEEN COMPLETELY CONTROLLED. THE PATIENTS WITH TRANSIENT EXPOSURE TO HYPERGLYCEMIA DEVELOP DIABETIC COMPLICATIONS, INCLUDING DKD, EVEN AFTER NORMALIZATION OF THEIR BLOOD GLUCOSE. TEMPORARY HYPERGLYCEMIA CAUSES ADVANCED GLYCATION END PRODUCT (AGE) ACCUMULATIONS AND EPIGENETIC CHANGES AS METABOLIC MEMORY. THE DRUGS THAT IMPROVE METABOLIC MEMORY ARE AWAITED, AND AGE INHIBITORS AND HISTONE MODIFICATION INHIBITORS ARE THE FOCUS OF CLINICAL AND BASIC RESEARCH. IN ADDITION, INCRETIN-RELATED DRUGS SHOWED A RENOPROTECTIVE ABILITY IN MANY CLINICAL TRIALS, AND THESE TRIALS WITH RENAL OUTCOME AS THEIR PRIMARY ENDPOINT ARE CURRENTLY ONGOING. HYPOXIA-INDUCIBLE FACTOR PROLYL HYDROXYLASE INHIBITORS RECENTLY APPROVED FOR RENAL ANEMIA MAY BE RENOPROTECTIVE SINCE THEY IMPROVE TUBULOINTERSTITIAL HYPOXIA. FURTHERMORE, NF-E2-RELATED FACTOR 2 ACTIVATORS IMPROVED THE GLOMERULAR FILTRATION RATE OF DKD PATIENTS IN BARDOXOLONE METHYL TREATMENT: RENAL FUNCTION IN CHRONIC KIDNEY DISEASE/TYPE 2 DIABETES (BEAM) TRIAL AND PHASE II STUDY OF BARDOXOLONE METHYL IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND TYPE 2 DIABETES (TSUBAKI) TRIAL. THUS, FOLLOWING SGLT2 INHIBITOR, NUMEROUS NOVEL DRUGS COULD BE UTILIZED IN TREATING DKD. FUTURE STUDIES ARE EXPECTED TO PROVIDE NEW INSIGHTS. 2021 19 2121 34 EPIGENETIC HISTONE MODIFICATIONS IN THE PATHOGENESIS OF DIABETIC KIDNEY DISEASE. DIABETIC KIDNEY DISEASE (DKD), AS THE MAIN COMPLICATION OF DIABETES MELLITUS, IS THE PRIMARY CAUSE OF THE END-STAGE RENAL DISEASE (ESRD) AND THE MOST COMMON CHRONIC KIDNEY DISEASE. OVERALL, 30-40% OF PATIENTS WITH TYPE 1 AND TYPE 2 DIABETES EVENTUALLY DEVELOP DKD. ALTHOUGH SOME DIABETES PATIENTS HAVE INTENSIFIED GLYCEMIC CONTROL, THEY STILL DEVELOP DIABETIC KIDNEY DISEASE. CURRENT TREATMENT METHODS CAN ALLEVIATE BUT DO NOT MARKEDLY HALT DISEASE DEVELOPMENT, RESULTING IN RENAL FAILURE AND SEVERE COMPLICATIONS, EVEN CONTRIBUTING TO ELEVATED MORBIDITY AND MORTALITY RATES. DKD IS A DISEASE WITH INTERACTIONS OF GENES AND THE ENVIRONMENT. EMERGING EVIDENCE INDICATES THAT DKD-ASSOCIATED KEY GENES ARE ALSO REGULATED BY THE EPIGENETIC MECHANISM. RECENTLY, INCREASING RESEARCHES INVOLVING CELLS AND EXPERIMENTAL ANIMALS DEMONSTRATED THAT HISTONE POST-TRANSLATIONAL MODIFICATIONS CAN MEDIATE GENE EXPRESSION, WHICH CORRELATED WITH DIABETIC KIDNEY DISEASE. NOVEL THERAPEUTIC STRATEGIES FOR EPIGENETIC EVENTS COULD BE BENEFICIAL FOR THE EARLY DETECTION AND TREATMENT OF DKD TO PREVENT IT FROM DEVELOPING INTO END-STAGE RENAL DISEASE (ESRD). IN THIS REVIEW, WE DISCUSS PRIOR FINDINGS IN THE FIELD OF HISTONE MODIFICATIONS IN DKD, ESPECIALLY HISTONE ACETYLATION AND HISTONE METHYLATION. WE THEN FOCUS ON RECENT DEVELOPMENTS IN HISTONE ACETYLATION AND METHYLATION INVOLVED IN THE PATHOGENESIS OF DKD. 2021 20 4101 28 MDCT AND MR UROGRAM SPECTRUM OF CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT DIAGNOSED IN ADULTHOOD. OBJECTIVE: CONGENITAL ANOMALIES OF THE KIDNEYS AND URINARY TRACT (CAKUT) ENCOMPASS A SPECTRUM OF ANOMALIES THAT RESULT FROM GENETIC, EPIGENETIC, ENVIRONMENTAL, AND MOLECULAR SIGNAL ABERRATIONS AT KEY STAGES OF URINARY TRACT DEVELOPMENT. CAKUT CAN BE SEEN INCIDENTALLY ON CROSS-SECTIONAL IMAGING OF THE ABDOMEN OR CAN BE A CAUSE FOR ADULT-ONSET CHRONIC KIDNEY DISEASE, POSING NEW CHALLENGES FOR NEPHROLOGISTS, UROLOGISTS, AND RADIOLOGISTS. CONCLUSION: AWARENESS OF CAKUT AND FAMILIARITY WITH THEIR IMAGING FINDINGS PERMIT OPTIMAL PATIENT MANAGEMENT AND THOROUGH WORKUP TO PREVENT HYPERTENSION AND PROGRESSION FROM CAKUT TO RENAL FAILURE. THE PURPOSE OF THIS ARTICLE IS TO REVIEW THE CROSS-SECTIONAL IMAGING FINDINGS OF CAKUT THAT MAY PRESENT IN ADULTHOOD. 2015