1  307 156 ALBUMINURIA DOWNREGULATION OF THE ANTI-AGING FACTOR KLOTHO: THE MISSING LINK POTENTIALLY EXPLAINING THE ASSOCIATION OF PATHOLOGICAL ALBUMINURIA WITH PREMATURE DEATH. TEN PERCENT OF THE ADULT POPULATION HAS CHRONIC KIDNEY DISEASE (CKD), WHICH IS DIAGNOSED WHEN THE GLOMERULAR FILTRATION RATE (GFR) IS BELOW 60 ML/MIN PER 1.73 M(2) OR WHEN ALBUMINURIA IS ABOVE 30 MG/DAY. THE NUMERICAL THRESHOLDS WERE CHOSEN BECAUSE THEY ARE ASSOCIATED WITH AN INCREASED RISK OF CKD PROGRESSION OR PREMATURE DEATH WITHIN A WIDER SCENARIO OF ACCELERATED AGING. INDEED, CKD IS ONE OF THE FASTEST GROWING CAUSES OF DEATH WORLDWIDE. A DECREASED GFR IS ASSOCIATED WITH THE ACCUMULATION OF URAEMIC TOXINS THAT MAY PROMOTE TISSUE AND ORGAN DAMAGE. HOWEVER, CKD MAY BE DIAGNOSED WHEN THE GFR IS COMPLETELY NORMAL, AS LONG AS THERE IS PATHOLOGICAL ALBUMINURIA. A KEY UNANSWERED QUESTION TO STEM THE RISE OF CKD-ASSOCIATED DEATHS IS WHETHER THE ASSOCIATION BETWEEN ISOLATED ALBUMINURIA (WHEN THE GFR IS NORMAL) AND PREMATURE DEATH IS CAUSAL. THE RECENT DEMONSTRATION THAT ALBUMINURIA PER SE DIRECTLY SUPPRESSES THE PRODUCTION OF THE ANTI-AGING FACTOR KLOTHO BY KIDNEY TUBULAR CELLS MAY BE ONE OF THE FIRST STEPS TO ADDRESS THE CAUSALITY OF THE ALBUMINURIA-PREMATURE DEATH-ACCELERATED AGING ASSOCIATION. THIS HYPOTHESIS SHOULD BE TESTED IN INTERVENTIONAL STUDIES THAT SHOULD DRAW FROM TRANSLATIONAL SCIENCE ADVANCES. THUS, THE OBSERVATION THAT ALBUMINURIA DECREASES KLOTHO PRODUCTION THROUGH EPIGENETIC MECHANISMS IMPLIES THAT KLOTHO DOWNREGULATION MAY PERSIST AFTER THE CORRECTION OF ALBUMINURIA, AND INNOVATIVE THERAPEUTIC APPROACHES ARE NEEDED TO RESTORE KLOTHO PRODUCTION. ON THE BASIS OF RECENT LITERATURE, THESE MAY INCLUDE MANIPULATION OF NF-KAPPAB REGULATORS SUCH AS B CELL LYMPHOMA 3 PROTEIN (BCL-3), AND EPIGENETIC REGULATORS SUCH AS HISTONE DEACETYLASES, OR THE REPURPOSING OF DRUGS SUCH AS PENTOXIFYLLINE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2  933  54 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
3 6446  44 THERAPEUTIC INSIGHTS IN CHRONIC KIDNEY DISEASE PROGRESSION. CHRONIC KIDNEY DISEASE (CKD) HAS BEEN RECOGNIZED AS A LEADING PUBLIC HEALTH PROBLEM WORLDWIDE. THROUGH ITS EFFECT ON CARDIOVASCULAR RISK AND END-STAGE KIDNEY DISEASE, CKD DIRECTLY AFFECTS THE GLOBAL BURDEN OF MORBIDITY AND MORTALITY. CLASSICAL OPTIMAL MANAGEMENT OF CKD INCLUDES BLOOD PRESSURE CONTROL, TREATMENT OF ALBUMINURIA WITH ANGIOTENSIN-CONVERTING ENZYME INHIBITORS OR ANGIOTENSIN II RECEPTOR BLOCKERS, AVOIDANCE OF POTENTIAL NEPHROTOXINS AND OBESITY, DRUG DOSING ADJUSTMENTS, AND CARDIOVASCULAR RISK REDUCTION. DIABETES MIGHT ACCOUNT FOR MORE THAN HALF OF CKD BURDEN, AND OBESITY IS THE MOST IMPORTANT PROMPTED FACTOR FOR THIS DISEASE. NEW ANTIHYPERGLYCEMIC DRUGS, SUCH AS SODIUM-GLUCOSE-COTRANSPORTER 2 INHIBITORS HAVE SHOWN TO SLOW THE DECLINE OF GFR, BRINGING ADDITIONAL BENEFIT IN WEIGHT REDUCTION, CARDIOVASCULAR, AND OTHER KIDNEY OUTCOMES. ON THE OTHER HAND, A NEW GENERATION OF NON-STEROIDAL MINERALOCORTICOID RECEPTOR ANTAGONIST HAS RECENTLY BEEN DEVELOPED TO OBTAIN A SELECTIVE RECEPTOR INHIBITION REDUCING SIDE EFFECTS LIKE HYPERKALEMIA AND THEREBY MAKING THE DRUGS SUITABLE FOR ADMINISTRATION TO CKD PATIENTS. MOREOVER, TWO NEW POTASSIUM-LOWERING THERAPIES HAVE SHOWN TO IMPROVE TOLERANCE, ALLOWING FOR HIGHER DOSAGE OF RENIN-ANGIOTENSIN SYSTEM INHIBITORS AND THEREFORE ENHANCING THEIR NEPHROPROTECTIVE EFFECT. REGARDLESS OF ITS CAUSE, CKD IS CHARACTERIZED BY REDUCED RENAL REGENERATION CAPACITY, MICROVASCULAR DAMAGE, OXIDATIVE STRESS AND INFLAMMATION, RESULTING IN FIBROSIS AND PROGRESSIVE, AND IRREVERSIBLE NEPHRON LOSS. THEREFORE, A HOLISTIC APPROACH SHOULD BE TAKEN TARGETING THE DIVERSE PROCESSES AND BIOLOGICAL CONTEXTS THAT ARE ASSOCIATED WITH CKD PROGRESSION. TO DATE, THERAPEUTIC INTERVENTIONS WHEN TUBULOINTERSTITIAL FIBROSIS IS ALREADY ESTABLISHED HAVE PROVED TO BE INSUFFICIENT, THUS RESEARCH EFFORT SHOULD FOCUS ON UNRAVELING EARLY DISEASE MECHANISMS. AN ARRAY OF NOVEL THERAPEUTIC APPROACHES TARGETING EPIGENETIC REGULATORS ARE NOW UNDERGOING PHASE II OR PHASE III TRIALS AND MIGHT PROVIDE A SIMULTANEOUS REGULATORY ACTIVITY THAT COORDINATELY REGULATE DIFFERENT ASPECTS OF CKD PROGRESSION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
4 1665  58 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5 5204  28 PRENATAL PROGRAMMING-EFFECTS ON BLOOD PRESSURE AND RENAL FUNCTION. IMPAIRED INTRAUTERINE NEPHROGENESIS-MOST CLEARLY ILLUSTRATED BY LOW NEPHRON NUMBER-IS FREQUENTLY ASSOCIATED WITH LOW BIRTHWEIGHT AND HAS BEEN RECOGNIZED AS A POWERFUL RISK FACTOR FOR RENAL DISEASE; IT INCREASES THE RISKS OF LOW GLOMERULAR FILTRATION RATE, OF MORE RAPID PROGRESSION OF PRIMARY KIDNEY DISEASE, AND OF INCREASED INCIDENCE OF CHRONIC KIDNEY DISEASE OR END-STAGE RENAL DISEASE. ANOTHER IMPORTANT CONSEQUENCE OF IMPAIRED NEPHROGENESIS IS HYPERTENSION, WHICH FURTHER AMPLIFIES THE RISK OF ONSET AND PROGRESSION OF KIDNEY DISEASE. HYPERTENSION IS ASSOCIATED WITH LOW NEPHRON NUMBERS IN WHITE INDIVIDUALS, BUT THE ASSOCIATION IS NOT UNIVERSAL AND IS NOT SEEN IN INDIVIDUALS OF AFRICAN ORIGIN. THE DERANGEMENT OF INTRAUTERINE KIDNEY DEVELOPMENT IS AN EXAMPLE OF A MORE GENERAL PRINCIPLE THAT ILLUSTRATES THE PARADIGM OF PLASTICITY DURING DEVELOPMENT-THAT IS, THAT TRANSCRIPTION OF THE GENETIC CODE IS MODIFIED BY EPIGENETIC FACTORS (AS HAS INCREASINGLY BEEN DOCUMENTED). THIS REVIEW OUTLINES THE CONCEPT OF PRENATAL PROGRAMMING AND, IN PARTICULAR, DESCRIBES ITS ROLE IN KIDNEY DISEASE AND HYPERTENSION.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6 2982  37 GENETIC CONSIDERATIONS IN PEDIATRIC CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IN CHILDREN IS AN IRREVERSIBLE PROCESS THAT, IN SOME CASES, MAY LEAD TO END-STAGE RENAL DISEASE. THE MAJORITY OF CHILDREN WITH CKD HAVE A CONGENITAL DISORDER OF THE KIDNEY OR UROLOGICAL TRACT ARISING FROM BIRTH. THERE IS STRONG EVIDENCE FOR BOTH A GENETIC AND EPIGENETIC COMPONENT TO PROGRESSION OF CKD. UTILIZATION OF GENE-MAPPING STRATEGIES, RANGING FROM GENOME-WIDE ASSOCIATION STUDIES TO SINGLE-NUCLEOTIDE POLYMORPHISM ANALYSIS, SERVES TO IDENTIFY POTENTIAL GENETIC VARIANTS THAT MAY LEND TO DISEASE VARIATION. GENOME-WIDE ASSOCIATION STUDIES EVALUATING POPULATION-BASED DATA HAVE IDENTIFIED DIFFERENT LOCI ASSOCIATED WITH CKD PROGRESSION. ANALYSIS OF SINGLE-NUCLEOTIDE POLYMORPHISMS ON AN INDIVIDUAL LEVEL SUGGESTS THAT SECONDARY SYSTEMIC SEQUELAE OF CKD ARE CLOSELY RELATED TO DYSFUNCTION OF THE CARDIOVASCULAR-INFLAMMATORY AXIS AND MAY LEAD TO ADVANCED CARDIOVASCULAR DISEASE THROUGH ABNORMAL VASCULAR CALCIFICATION AND ACTIVATION OF THE RENIN-ANGIOTENSIN SYSTEM. SIMILARLY, GENETIC VARIANTS AFFECTING CYTOKINE CONTROL, FIBROSIS, AND PARENCHYMAL DEVELOPMENT MAY MODULATE CKD THROUGH DEVELOPMENT AND ACCELERATION OF RENAL INTERSTITIAL FIBROSIS. EPIGENETIC STUDIES EVALUATE MODIFICATION OF THE GENOME THROUGH DNA METHYLATION, HISTONE MODIFICATION, OR RNA INTERFERENCE, WHICH MAY BE DIRECTLY INFLUENCED BY EXTERNAL OR ENVIRONMENTAL FACTORS DIRECTING GENOMIC EXPRESSION. LASTLY, IMPROVED UNDERSTANDING OF THE GENETIC AND EPIGENETIC CONTRIBUTION TO CKD PROGRESSION MAY ALLOW PROVIDERS TO IDENTIFY A POPULATION AT ACCELERATED RISK FOR DISEASE PROGRESSION AND APPLY NOVEL THERAPIES TARGETED AT THE GENETIC MECHANISM OF DISEASE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7 6652  41 UPDATE ON INFLAMMATION IN CHRONIC KIDNEY DISEASE. BACKGROUND: DESPITE RECENT ADVANCES IN CHRONIC KIDNEY DISEASE (CKD) AND END-STAGE RENAL DISEASE (ESRD) MANAGEMENT, MORBIDITY AND MORTALITY IN THIS POPULATION REMAIN EXCEPTIONALLY HIGH. PERSISTENT, LOW-GRADE INFLAMMATION HAS BEEN RECOGNIZED AS AN IMPORTANT COMPONENT OF CKD, PLAYING A UNIQUE ROLE IN ITS PATHOPHYSIOLOGY AND BEING ACCOUNTABLE IN PART FOR CARDIOVASCULAR AND ALL-CAUSE MORTALITY, AS WELL AS CONTRIBUTING TO THE DEVELOPMENT OF PROTEIN-ENERGY WASTING. SUMMARY: THE VARIETY OF FACTORS CONTRIBUTE TO CHRONIC INFLAMMATORY STATUS IN CKD, INCLUDING INCREASED PRODUCTION AND DECREASED CLEARANCE OF PRO-INFLAMMATORY CYTOKINES, OXIDATIVE STRESS AND ACIDOSIS, CHRONIC AND RECURRENT INFECTIONS, INCLUDING THOSE RELATED TO DIALYSIS ACCESS, ALTERED METABOLISM OF ADIPOSE TISSUE, AND INTESTINAL DYSBIOSIS. INFLAMMATION DIRECTLY CORRELATES WITH THE GLOMERULAR FILTRATION RATE (GFR) IN CKD AND CULMINATES IN DIALYSIS PATIENTS, WHERE EXTRACORPOREAL FACTORS, SUCH AS IMPURITIES IN DIALYSIS WATER, MICROBIOLOGICAL QUALITY OF THE DIALYSATE, AND BIOINCOMPATIBLE FACTORS IN THE DIALYSIS CIRCUIT PLAY AN ADDITIONAL ROLE. GENETIC AND EPIGENETIC INFLUENCES CONTRIBUTING TO INFLAMMATORY ACTIVATION IN CKD ARE CURRENTLY BEING INTENSIVELY INVESTIGATED. A NUMBER OF INTERVENTIONS HAVE BEEN PROPOSED TO TARGET INFLAMMATION IN CKD, INCLUDING LIFESTYLE MODIFICATIONS, PHARMACOLOGICAL AGENTS, AND OPTIMIZATION OF DIALYSIS. IMPORTANTLY, SOME OF THESE THERAPIES HAVE BEEN RECENTLY TESTED IN RANDOMIZED CONTROLLED TRIALS. KEY MESSAGES: CHRONIC INFLAMMATION SHOULD BE REGARDED AS A COMMON COMORBID CONDITION IN CKD AND ESPECIALLY IN DIALYSIS PATIENTS. A NUMBER OF INTERVENTIONS HAVE BEEN PROVEN TO BE SAFE AND EFFECTIVE IN WELL-DESIGNED CLINICAL STUDIES. THIS INCLUDES SUCH INEXPENSIVE APPROACHES AS MODIFICATION OF PHYSICAL ACTIVITY AND DIETARY SUPPLEMENTATION. FURTHER INVESTIGATIONS ARE NEEDED TO EVALUATE THE EFFECTS OF THESE INTERVENTIONS ON HARD OUTCOMES, AS WELL AS TO BETTER UNDERSTAND THE ROLE OF INFLAMMATION IN SELECTED CKD POPULATIONS (E.G., IN CHILDREN).	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
8 3095  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
9 3884  66 KIDNEY DISEASE IN DIABETES. PERSONS WITH DIABETES MAKE UP THE FASTEST GROWING GROUP OF KIDNEY DIALYSIS AND TRANSPLANT RECIPIENTS IN THE UNITED STATES. IN 1985, WHEN THE FIRST EDITION OF DIABETES IN AMERICA WAS PUBLISHED, 20,961 PERSONS WITH DIABETES WERE RECEIVING RENAL REPLACEMENT THERAPY, REPRESENTING 29% OF ALL NEW CASES OF END-STAGE RENAL DISEASE (ESRD). BY 2012, 239,837 PERSONS WITH DIABETES WERE ON RENAL REPLACEMENT THERAPY, ACCOUNTING FOR 44% OF ALL NEW ESRD CASES. THE INCREASED COUNT REFLECTS GROWTH IN DIABETES PREVALENCE AND INCREASED ACCESS TO DIALYSIS AND TRANSPLANTATION. THOSE WITH A PRIMARY DIAGNOSIS OF DIABETES HAVE LOWER SURVIVAL RELATIVE TO OTHER CAUSES OF ESRD, PRIMARILY BECAUSE OF THE COEXISTENT MORBIDITY ASSOCIATED WITH DIABETES, PARTICULARLY CARDIOVASCULAR DISEASES (CVD). WHILE SURVIVAL ON DIALYSIS HAS SLOWLY IMPROVED ACROSS MODALITIES SINCE THE 1990S, IT REMAINS REDUCED IN PERSONS WITH DIABETES, HALF OF WHOM DIE WITHIN 3 YEARS OF BEGINNING DIALYSIS IN THE UNITED STATES. SIMILAR TO PERSONS WITH ESRD IN GENERAL, THE LEADING CAUSES OF DEATH AMONG ADULTS WITH DIABETES WHO STARTED DIALYSIS IN 1995-2009 WERE CVD (58% OF THE DEATHS) AND INFECTIONS (13% OF THE DEATHS). KIDNEY TRANSPLANT RECIPIENTS WITH DIABETES HAVE MUCH BETTER SURVIVAL THAN THOSE ON DIALYSIS, INDICATING A SIGNIFICANT IMPACT OF THE TYPE OF RENAL REPLACEMENT THERAPY (TRANSPLANT VERSUS DIALYSIS) ON LONG-TERM SURVIVAL. KIDNEY FAILURE AFFECTS ABOUT 1% OF PERSONS WITH DIABETES IN THE UNITED STATES. A CONSIDERABLY HIGHER PROPORTION, ABOUT 40%, HAVE LESS SEVERE KIDNEY DISEASE. SINCE THE SECOND EDITION OF DIABETES IN AMERICA WAS PUBLISHED IN 1995, A WEALTH OF NEW INFORMATION HAS CONTRIBUTED SUBSTANTIALLY TO THE UNDERSTANDING OF KIDNEY DISEASE ASSOCIATED WITH DIABETES. IN 2002, THE NATIONAL KIDNEY FOUNDATION'S KIDNEY DISEASE OUTCOME QUALITY INITIATIVE PUBLISHED A UNIFORM DEFINITION OF CHRONIC KIDNEY DISEASE (CKD) AND CLASSIFICATION OF ITS STAGES IRRESPECTIVE OF UNDERLYING CAUSE, THUS PROVIDING A COMMON LANGUAGE FOR DEFINING BOTH THE SEVERITY AND PROGNOSIS OF KIDNEY DISEASE. THE DEFINITION AND CLASSIFICATION OF CKD WERE SUBSEQUENTLY UPDATED AND REFINED BY THE KIDNEY DISEASE: IMPROVING GLOBAL OUTCOMES IN 2012. ACCORDINGLY, CKD IS CLASSIFIED BASED ON BOTH ALBUMINURIA AND GLOMERULAR FILTRATION RATE (GFR) CATEGORIES, AND TOGETHER WITH KIDNEY FAILURE, THESE CONDITIONS ARE COLLECTIVELY REFERRED TO AS CKD, REGARDLESS OF ETIOLOGY. IN ADDITION, THE KIDNEY DISEASE: IMPROVING GLOBAL OUTCOMES RECOMMENDS USING EQUATIONS TO ESTIMATE GFR (EGFR), WHICH INCLUDE THE ROUTINELY OBTAINED VARIABLES SERUM CREATININE, AGE, SEX, AND RACE/ETHNICITY. THE USE OF SERUM CYSTATIN C, AN ENDOGENOUS FILTRATION MARKER LESS INFLUENCED THAN SERUM CREATININE BY VARIATIONS IN MUSCLE MASS, DIET, AND TUBULAR SECRETION, HAS EMERGED AS AN ALTERNATIVE OR AN ADJUNCT TO SERUM CREATININE-BASED EQUATIONS, PARTICULARLY IN PERSONS WITH DIABETES, IN WHOM EARLY KIDNEY DISEASE IS OFTEN CHARACTERIZED BY ELEVATED GFR. SINCE THE LATE 1990S, NEW MOLECULAR MECHANISMS HAVE BEEN DEFINED THAT ARE HELPING TO EXPLAIN THE DEVELOPMENT AND PROGRESSION OF DIABETIC KIDNEY DISEASE. GLOMERULAR STRUCTURAL LESIONS WERE FOUND TO EXPLAIN 95% OF THE VARIABILITY IN ALBUMIN EXCRETION AND 78% OF GFR VARIABILITY. THE LATTER PERCENTAGE INCREASED TO 92% BY ADDING INDICES OF GLOMERULAR-TUBULAR JUNCTION ABNORMALITIES AND INTERSTITIAL EXPANSION TO THE REGRESSION MODELS. PODOCYTE INJURY APPEARS TO PLAY AN ESSENTIAL ROLE IN THE PROGRESSION OF DIABETIC NEPHROPATHY. IN PERSONS WITH EITHER TYPE 1 OR TYPE 2 DIABETES, PODOCYTE CHANGES MAY OCCUR EVEN BEFORE THE INCREASE IN ALBUMINURIA, SUGGESTING THAT DIABETES ITSELF MAY INDUCE PODOCYTE ALTERATIONS. MUCH HAS ALSO BEEN WRITTEN ABOUT THE PROGNOSTIC IMPLICATIONS OF CKD. ELEVATED ALBUMINURIA AND LOW GFR ARE ASSOCIATED WITH ESRD, FATAL AND NONFATAL CVD, AND ALL-CAUSE MORTALITY. A META-ANALYSIS OF 1,024,977 PARTICIPANTS (NEARLY 13% WITH DIABETES) FROM 30 GENERAL POPULATION AND HIGH-RISK CARDIOVASCULAR COHORTS AND 13 CKD COHORTS INDICATED THAT WHILE THE ABSOLUTE RISKS FOR ALL-CAUSE AND CVD MORTALITY ARE HIGHER IN THE PRESENCE OF DIABETES, THE RELATIVE RISKS OF ESRD OR DEATH BY EGFR AND ALBUMINURIA ARE SIMILAR WITH OR WITHOUT DIABETES. THESE FINDINGS UNDERSCORE THE IMPORTANCE OF KIDNEY DISEASE PER SE AS A PREDICTOR OF IMPORTANT CLINICAL OUTCOMES, REGARDLESS OF THE UNDERLYING CAUSE OF KIDNEY DISEASE. NEW BIOMARKERS OF DIABETIC KIDNEY DISEASE APPEAR TO HAVE ADDITIONAL PROGNOSTIC INFORMATION BEYOND THAT PROVIDED BY ALBUMINURIA. THESE MARKERS INCLUDE KIDNEY INJURY MOLECULE 1, LIVER FATTY ACID-BINDING PROTEIN, N-ACETYL-BETA-D-GLUCOSAMINIDASE, NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN, BETA-TRACE PROTEIN, BETA(2)-MICROGLOBULIN, AND TUMOR NECROSIS FACTOR RECEPTORS 1 AND 2. MANY CONCEPTS ABOUT RISK FACTORS FOR CKD ILLUSTRATED IN THIS CHAPTER HAVE NOT CHANGED SINCE 1995, AND WHERE THEY HAVE, THOSE CHANGES ARE DISCUSSED. IN PARTICULAR, MAJOR ADVANCES HAVE BEEN MADE IN ELUCIDATING THE GENETIC AND EPIGENETIC COMPLEXITY OF CKD, WHICH CONTRIBUTED TO DEFINING CELLULAR METABOLIC MEMORY AND THE UNDERSTANDING OF THE LONGLASTING EFFECTS OF STRICT GLYCEMIC CONTROL OBSERVED IN PERSONS WITH TYPE 1 DIABETES OR TYPE 2 DIABETES. IMPROVEMENTS IN THE MANAGEMENT OF PERSONS WITH DIABETES AND CKD HAVE EXTENDED THE TIME COURSE FROM ONSET OF SEVERE ALBUMINURIA TO ESRD AND REDUCED THE OCCURRENCE OF CVD. IN TYPE 1 DIABETES, THE COMBINED DIABETES CONTROL AND COMPLICATIONS TRIAL (DCCT) AND ITS LONG-TERM FOLLOW-UP, THE EPIDEMIOLOGY OF DIABETES INTERVENTIONS AND COMPLICATIONS (EDIC) OBSERVATIONAL STUDY, INDICATED THAT INTENSIVE EARLY METABOLIC CONTROL REDUCED THE RISK OF IMPAIRED GFR BY 50% AND OF CVD OUTCOMES BY 42%, WITH A SPECIFIC 57% DECREASE IN MYOCARDIAL INFARCTION, STROKE, OR DEATH FROM CVD, EFFECTS THAT WERE PARTLY MEDIATED BY THE REDUCED INCIDENCE OF DIABETIC KIDNEY DISEASE. AMONG PERSONS WITH TYPE 2 DIABETES, A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS INDICATED THAT MORE INTENSIVE GLYCEMIC CONTROL (GLYCOSYLATED HEMOGLOBIN [A1C] <7%) WAS ASSOCIATED WITH A SIGNIFICANT 10% REDUCTION IN ALBUMINURIA BUT HAD NO EFFECTS ON MORTALITY, KIDNEY FAILURE, OR OTHER VASCULAR OUTCOMES. THE ACTION TO CONTROL CARDIOVASCULAR RISK IN DIABETES (ACCORD) TRIAL, TARGETING AN A1C LEVEL <6.0% IN THE INTENSIVE INTERVENTION ARM, REPORTED AN INCREASED RISK OF CVD DEATH FOR INTENSIVE VERSUS CONVENTIONAL GLYCEMIC CONTROL, ALTHOUGH IT REMAINS UNCLEAR WHETHER THIS EFFECT WAS RELATED TO MORE HYPOGLYCEMIC EPISODES, THE USE OF ADDITIONAL HYPOGLYCEMIC MEDICINES, OR TO THE TARGET GLYCEMIC LEVEL ITSELF. LIKEWISE, THE MODEST GAINS IN INTERMEDIATE OUTCOMES IN THE INTENSIVE TREATMENT ARMS OF THE ACTION IN DIABETES AND VASCULAR DISEASE: PRETERAX AND DIAMICRON MODIFIED RELEASE CONTROLLED EVALUATION (ADVANCE) AND THE VETERANS AFFAIRS DIABETES (VADT) TRIAL WERE COUNTERBALANCED BY A TWOFOLD TO THREEFOLD HIGHER RISK OF SEVERE HYPOGLYCEMIA. TOGETHER, THESE TRIALS INDICATE THAT GLYCEMIC CONTROL IS EXTREMELY USEFUL UP TO A POINT, BUT MORE AGGRESSIVE GLYCEMIC CONTROL MAY BE HARMFUL. SIMILARLY, FOR BLOOD PRESSURE CONTROL, 2014-2015 RECOMMENDATIONS BY THE GUIDELINE-WRITING GROUPS ENDORSE LESS INTENSIVE AND MORE INDIVIDUALIZED BLOOD PRESSURE TARGETS FOR DIABETES AND CKD THAN IN THE PAST. PERSONS WITH DIABETES AND CKD REQUIRE MULTIDISCIPLINARY MANAGEMENT INVOLVING A COMBINATION OF TREATMENTS AND BEHAVIORAL ADJUSTMENTS TO DELAY PROGRESSION OF CKD AND TO PREVENT THE ASSOCIATED COMPLICATIONS. THE STENO-2 STUDY, A LANDMARK PROSPECTIVE, RANDOMIZED TRIAL IN DENMARK, DEMONSTRATED THAT COMPARED WITH CONVENTIONAL TREATMENT, INTENSIVE MULTIFACTORIAL INTERVENTION LED TO 46% LOWER DEATH RATE, 56% LESS SEVERE ALBUMINURIA, 43% LOWER INCIDENCE OF DIABETIC RETINOPATHY, AND 47% LOWER INCIDENCE OF AUTONOMIC NEUROPATHY DURING THE 13.3-YEAR STUDY PERIOD.	2018	

10 1170  43 CONTRIBUTION OF GENETICS AND EPIGENETICS TO PROGRESSION OF KIDNEY FIBROSIS. CHRONIC KIDNEY DISEASE (CKD) WHICH CAN LEAD TO END-STAGE RENAL FAILURE REMAINS A PRINCIPAL CHALLENGE IN NEPHROLOGY. WHILE MECHANISTIC STUDIES PROVIDED EXTENSIVE INSIGHTS INTO THE COMMON PATHWAYS OF FIBROGENESIS WHICH UNDERLIE THE PROGRESSION OF CKD, THESE PRE-CLINICAL STUDIES FAIL TO FULLY EXPLAIN THE VASTLY DIFFERENT PROGRESSION SLOPES OF INDIVIDUAL PATIENTS. RECENT STUDIES PROVIDE EVIDENCE THAT GENETIC POLYMORPHISMS AND EPIGENETIC VARIATIONS DETERMINE THE INDIVIDUAL SUSCEPTIBILITY OF PATIENTS TO DEVELOP CHRONIC PROGRESSIVE KIDNEY DISEASE. HERE, WE REVIEW RECENT INSIGHTS THAT WERE PROVIDED BY GENOME-WIDE ASSOCIATION STUDIES (GWASS), GENE-LINKAGE STUDIES AND EPIGENOME ANALYSIS. THE PROGRESSION OF CKD TOWARDS END-STAGE RENAL FAILURE REMAINS A PRINCIPAL UNSOLVED PROBLEM IN NEPHROLOGY AS EFFECTIVE THERAPIES AND PREDICTIVE TESTS ARE STILL NOT AVAILABLE [ 1, 2]. CHRONIC PROGRESSIVE KIDNEY DISEASE IS CAUSED BY A WIDE RANGE OF DISEASES, WITH DIABETES MELLITUS, HYPERTENSION AND PRIMARY GLOMERULOPATHIES BEING THE MOST COMMON CAUSES IN THE WESTERN WORLD [ 3]. INFECTIONS, PHYSICAL OBSTRUCTION, INTERSTITIAL NEPHRITIDES AND GENETIC CYSTIC KIDNEY DISEASES ARE ALSO COMMON CAUSES OF END-STAGE RENAL DISEASE (ESRD) [ 3]. REGARDLESS OF THE PRIMARY UNDERLYING DISEASE, CHRONICALLY INJURED KIDNEYS ARE HISTOMORPHOLOGICALLY CHARACTERIZED BY TUBULOINTERSTITIAL FIBROSIS [ 1]. IN FACT, THE EXTENT OF TUBULOINTERSTITIAL FIBROSIS IS THE BEST PREDICTOR FOR KIDNEY SURVIVAL, IRRESPECTIVE OF THE UNDERLYING DISEASE. FOR THIS REASON, FIBROSIS IS CONSIDERED THE COMMON PATHWAY OF CHRONIC PROGRESSIVE KIDNEY DISEASE [ 1]. FIBROGENESIS IS A PATHOLOGICAL SCARRING PROCESS WHICH INVOLVES ACCUMULATION OF ACTIVATED FIBROBLASTS, EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX, FAILED REGENERATION OF TUBULAR EPITHELIUM, MICROVASCULAR RAREFACTION AND (MOSTLY STERILE) INFLAMMATION [ 4]. FIBROGENESIS DEPENDS ON A COMPLEX INTERACTION OF THE INVOLVED CELL TYPES WHICH IS ORCHESTRATED BY AN EXTENSIVE NETWORK OF GROWTH FACTORS AND SIGNALLING PATHWAYS (WHICH ARE REVIEWED EXTENSIVELY ELSEWHERE) [ 1]. IN VIEW OF THE DETAILED MECHANISTIC KNOWLEDGE OF THE PATHWAYS THAT ORCHESTRATE RENAL FIBROGENESIS, IT IS PUZZLING WHY PROGRESSION RATES OF CKD DIFFER DRAMATICALLY AMONG PATIENTS WITH IDENTICAL UNDERLYING DISEASES [ 1, 2]. THE FIBROTIC PATHWAYS ARE KNOWN, BUT THE SWITCHES THAT CONTROL THEIR INTENSITIES AND WHICH DETERMINE THE SPEED AT WHICH FIBROSIS MOVES ALONG THE PROGRESSION SLOPE ARE NOT YET UNDERSTOOD [ 1, 2]. THE CONCEPT THAT GENETIC POLYMORPHISMS ARE THE BASIS FOR INDIVIDUAL PROGRESSION RATES OF CKD IS AN OBVIOUS AND ATTRACTIVE ONE. DISTINCT SUSCEPTIBILITIES OF DIFFERENT MOUSE AND RAT STRAINS TO EXPERIMENTAL CKD ARE A STRONG TESTAMENT OF THE IMPACT OF GENETIC VARIATIONS ON RENAL FIBROGENESIS. IDENTIFICATION OF THE UNDERLYING GENETIC POLYMORPHISMS AND MECHANISTIC PROOF OF THEIR INVOLVEMENT IN THE PROGRESSION OF CKD, HOWEVER, IS AN ONGOING CHALLENGE. THERE ARE TWO BASIC APPROACHES: ONE STRATEGY IS TO PERFORM UNBIASED SCREENING TO IDENTIFY GENES WHICH ARE ASSOCIATED WITH CHRONIC PROGRESSIVE KIDNEY DISEASE AND TO THEN PROVE THEIR MECHANISTIC RELEVANCE IN EXPERIMENTAL STUDIES ('GENOTYPE TO PHENOTYPE APPROACH'). THE SECOND STRATEGY IS TO SELECTIVELY ANALYSE POLYMORPHISMS OF GENES WHICH HAVE BEEN IDENTIFIED IN MECHANISTIC STUDIES AS DRIVERS OF RENAL FIBROGENESIS WITH REGARD TO THEIR ASSOCIATION WITH CKD (PHENOTYPE TO GENOTYPE APPROACH). THE PUZZLING OBSERVATION, HOWEVER, IS THAT GENETIC ANALYSIS AND MECHANISTIC STUDIES SO FAR RARELY COMPLEMENT EACH OTHER. THE CURRENT STATE OF AFFAIRS IS REVIEWED IN MORE DETAIL BELOW.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
11  462  29 ARE ALTERATIONS IN DNA METHYLATION RELATED TO CKD DEVELOPMENT? THE MODIFICATIONS IN GENOMIC DNA METHYLATION ARE INVOLVED IN THE REGULATION OF NORMAL AND PATHOLOGICAL CELLULAR PROCESSES. THE EPIGENETIC REGULATION STIMULATES BIOLOGICAL PLASTICITY AS AN ADAPTIVE RESPONSE TO VARIATIONS IN ENVIRONMENTAL FACTORS. THE ROLE OF EPIGENETIC CHANGES IS VITAL FOR THE DEVELOPMENT OF SOME DISEASES, INCLUDING ATHEROGENESIS, CANCERS, AND CHRONIC KIDNEY DISEASE (CKD). THE RESULTS OF STUDIES PRESENTED IN THIS REVIEW HAVE SUGGESTED THAT ALTERED DNA METHYLATION CAN MODULATE THE EXPRESSION OF PRO-INFLAMMATORY AND PRO-FIBROTIC GENES, AS WELL THOSE ESSENTIAL FOR KIDNEY DEVELOPMENT AND FUNCTION, THUS STIMULATING RENAL DISEASE PROGRESSION. ABNORMALLY INCREASED HOMOCYSTEINE, HYPOXIA, AND INFLAMMATION HAVE BEEN SUGGESTED TO ALTER EPIGENETIC REGULATION OF GENE EXPRESSION IN CKD. STUDIES OF RENAL SAMPLES HAVE DEMONSTRATED THE RELATIONSHIP BETWEEN VARIATIONS IN DNA METHYLATION AND FIBROSIS AND VARIATIONS IN ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) IN HUMAN CKD. THE UNRAVELLING OF THE GENETIC-EPIGENETIC PROFILE WOULD ENHANCE OUR UNDERSTANDING OF PROCESSES UNDERLYING THE DEVELOPMENT OF CKD. THE UNDERSTANDING OF MULTIFACETED RELATIONSHIP BETWEEN DNA METHYLATION, GENES EXPRESSION, AND DISEASE DEVELOPMENT AND PROGRESSION COULD IMPROVE THE ABILITY TO IDENTIFY INDIVIDUALS AT RISK OF CKD AND ENABLE THE CHOICE OF APPROPRIATE DISEASE MANAGEMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12 1883  38 END-STAGE RENAL DISEASE, INFLAMMATION AND CARDIOVASCULAR OUTCOMES. DESPITE MARKED IMPROVEMENTS IN RENAL REPLACEMENT THERAPY DURING THE LAST 30 YEARS, THE AGE-ADJUSTED MORTALITY RATE IN END-STAGE RENAL DISEASE (ESRD) PATIENTS IS STILL UNACCEPTABLY HIGH AND COMPARABLE TO THAT OF MANY MALIGNANCIES. CARDIOVASCULAR DISEASE (CVD) REMAINS THE MAJOR CAUSE OF MORBIDITY AND MORTALITY IN ESRD PATIENTS. HOWEVER, TRADITIONAL RISK FACTORS CAN ONLY PARTIALLY EXPLAIN THE HIGH PREMATURE CARDIOVASCULAR BURDEN IN THIS POPULATION. NONTRADITIONAL RISK FACTORS, INCLUDING PERSISTENT LOW-GRADE INFLAMMATION, ARE CRITICAL IN THE PATHOGENESIS OF ATHEROSCLEROSIS, VASCULAR CALCIFICATION, AND OTHER CAUSES OF CVD AND MAY ALSO CONTRIBUTE TO PROTEIN-ENERGY WASTING AND OTHER COMPLICATIONS IN CHRONIC KIDNEY DISEASE (CKD) PATIENTS. INFLAMMATORY BIOMARKERS, SUCH AS HIGH SENSITIVITY C-REACTIVE PROTEIN AND INTERLEUKIN-6, INDEPENDENTLY PREDICT MORTALITY IN THESE PATIENTS. THE CAUSES OF INFLAMMATION IN CKD ARE MULTIFACTORIAL AND INCLUDE IMBALANCE BETWEEN INCREASED PRODUCTION (DUE TO MULTIPLE SOURCES OF INFLAMMATORY STIMULI SUCH AS OXIDATIVE STRESS, ACIDOSIS, VOLUME OVERLOAD, CO-MORBIDITIES, ESPECIALLY INFECTIONS, GENETIC AND EPIGENETIC INFLUENCES, AND THE DIALYSIS PROCEDURE) AND INADEQUATE REMOVAL (DUE TO DECREASED GLOMERULAR FILTRATION RATE OR IN ESRD PATIENTS, INADEQUATE DIALYTIC CLEARANCE) OF PRO-INFLAMMATORY CYTOKINES. THOUGH THERE ARE CURRENTLY NO ESTABLISHED GUIDELINES FOR THE TREATMENT OF LOW-GRADE INFLAMMATION IN ESRD PATIENTS, SEVERAL STRATEGIES HAVE BEEN PROPOSED, SUCH AS LIFESTYLE MODIFICATIONS, PHARMACOLOGICAL TREATMENT, AND OPTIMIZATION OF DIALYSIS. FURTHER STUDIES ON PATHWAYS INVOLVED IN PATHOGENIC PROCESSES OF INFLAMMATION IN ESRD, AND LONG-TERM EFFECTS OF ANTI-INFLAMMATORY INTERVENTIONS TARGETING PRODUCTION OR REMOVAL OF CYTOKINES OR BOTH ON PREMATURE CVD AND CLINICAL OUTCOMES IN THIS PATIENT GROUP ARE WARRANTED.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
13 6299  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
14 1880  35 EMERGING STRATEGIES TO DISRUPT THE CENTRAL TGF-BETA AXIS IN KIDNEY FIBROSIS. CHRONIC KIDNEY DISEASE (CKD) AFFECTS MORE THAN 20 MILLION PEOPLE IN THE UNITED STATES AND THE GLOBAL BURDEN OF THIS DISORDER IS INCREASING. MANY AFFECTED INDIVIDUALS WILL PROGRESS TO END STAGE KIDNEY DISEASE NECESSITATING DIALYSIS OR TRANSPLANTATION. CKD IS ALSO A MAJOR INDEPENDENT CONTRIBUTOR TO THE RISK OF CARDIOVASCULAR MORBIDITY AND MORTALITY. TUBULOINTERSTITIAL FIBROSIS IS A FINAL COMMON PATHWAY FOR MOST CAUSES OF PROGRESSIVE CKD. CURRENTLY, THERE ARE NO CLINICALLY AVAILABLE THERAPIES TARGETING FIBROSIS THAT CAN SLOW THE DECLINE IN KIDNEY FUNCTION. ALTHOUGH IT HAS LONG BEEN KNOWN THAT TGF-BETA SIGNALING IS A CRITICAL MEDIATOR OF KIDNEY FIBROSIS, TRANSLATING THIS KNOWLEDGE TO THE CLINIC HAS BEEN CHALLENGING. IN THIS REVIEW, WE HIGHLIGHT SOME RECENT INSIGHTS INTO THE MECHANISMS OF TGF-BETA SIGNALING THAT TARGET ACTIVATION OF THIS CYTOKINE AT THE SITE OF INJURY OR SELECTIVELY INHIBIT PRO-FIBROTIC GENE EXPRESSION. MOLECULES DIRECTED AT THESE TARGETS HOLD THE PROMISE OF ATTAINING THERAPEUTIC EFFICACY WHILE LIMITING TOXICITY SEEN WITH GLOBAL INHIBITION OF TGF-BETA. KIDNEY INJURY HAS PROFOUND EPIGENETIC EFFECTS LEADING TO ALTERED EXPRESSION OF MORE THAN A THOUSAND GENES. WE DISCUSS HOW DRUGS TARGETING EPIGENETIC MODIFICATIONS, SOME OF WHICH ARE IN USE FOR CANCER THERAPY, HAVE THE POTENTIAL TO REPROGRAM GENE REGULATORY NETWORKS TO FAVOR ADAPTIVE REPAIR AND PREVENT FIBROSIS. THE LACK OF RELIABLE BIOMARKERS OF KIDNEY FIBROSIS IS A MAJOR LIMITATION IN DESIGNING CLINICAL TRIALS FOR TESTING CKD TREATMENTS. WE CONCLUDE BY REVIEWING RECENT ADVANCES IN FIBROSIS BIOMARKER DEVELOPMENT.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
15 5950  34 TARGETING THE PROGRESSION OF CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS A DEVASTATING CONDITION THAT IS REACHING EPIDEMIC LEVELS OWING TO THE INCREASING PREVALENCE OF DIABETES MELLITUS, HYPERTENSION AND OBESITY, AS WELL AS AGEING OF THE POPULATION. REGARDLESS OF THE UNDERLYING AETIOLOGY, CKD IS SLOWLY PROGRESSIVE AND LEADS TO IRREVERSIBLE NEPHRON LOSS, END-STAGE RENAL DISEASE AND/OR PREMATURE DEATH. FACTORS THAT CONTRIBUTE TO CKD PROGRESSION INCLUDE PARENCHYMAL CELL LOSS, CHRONIC INFLAMMATION, FIBROSIS AND REDUCED REGENERATIVE CAPACITY OF THE KIDNEY. CURRENT THERAPIES HAVE LIMITED EFFECTIVENESS AND ONLY DELAY DISEASE PROGRESSION, UNDERSCORING THE NEED TO DEVELOP NOVEL THERAPEUTIC APPROACHES TO EITHER STOP OR REVERSE PROGRESSION. PRECLINICAL STUDIES HAVE IDENTIFIED SEVERAL APPROACHES THAT REDUCE FIBROSIS IN EXPERIMENTAL MODELS, INCLUDING TARGETING CYTOKINES, TRANSCRIPTION FACTORS, DEVELOPMENTAL AND SIGNALLING PATHWAYS AND EPIGENETIC MODULATORS, PARTICULARLY MICRORNAS. SOME OF THESE NEPHROPROTECTIVE STRATEGIES ARE NOW BEING TESTED IN CLINICAL TRIALS. LESSONS LEARNED FROM THE FAILURE OF CLINICAL STUDIES OF TRANSFORMING GROWTH FACTOR BETA1 (TGFBETA1) BLOCKADE UNDERSCORE THE NEED FOR ALTERNATIVE APPROACHES TO CKD THERAPY, AS STRATEGIES THAT TARGET A SINGLE PATHOGENIC PROCESS MAY RESULT IN UNEXPECTED NEGATIVE EFFECTS ON SIMULTANEOUSLY OCCURRING PROCESSES. ADDITIONAL PROMISING AVENUES INCLUDE PREVENTING TUBULAR CELL INJURY AND ANTI-FIBROTIC THERAPIES THAT TARGET ACTIVATED MYOFIBROBLASTS, THE MAIN COLLAGEN-PRODUCING CELLS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
16 4974  36 PATHOPHYSIOLOGICAL MECHANISMS LEADING TO MUSCLE LOSS IN CHRONIC KIDNEY DISEASE. LOSS OF MUSCLE PROTEINS IS A DELETERIOUS CONSEQUENCE OF CHRONIC KIDNEY DISEASE (CKD) THAT CAUSES A DECREASE IN MUSCLE STRENGTH AND FUNCTION, AND CAN LEAD TO A REDUCTION IN QUALITY OF LIFE AND INCREASED RISK OF MORBIDITY AND MORTALITY. THE EFFECTIVENESS OF CURRENT TREATMENT STRATEGIES IN PREVENTING OR REVERSING MUSCLE PROTEIN LOSSES IS LIMITED. THE LIMITATIONS LARGELY STEM FROM THE SYSTEMIC NATURE OF DISEASES SUCH AS CKD, WHICH STIMULATE SKELETAL MUSCLE PROTEIN DEGRADATION PATHWAYS WHILE SIMULTANEOUSLY ACTIVATING MECHANISMS THAT IMPAIR MUSCLE PROTEIN SYNTHESIS AND REPAIR. STIMULI THAT INITIATE MUSCLE PROTEIN LOSS INCLUDE METABOLIC ACIDOSIS, INSULIN AND IGF1 RESISTANCE, CHANGES IN HORMONES, CYTOKINES, INFLAMMATORY PROCESSES AND DECREASED APPETITE. A GROWING BODY OF EVIDENCE SUGGESTS THAT SIGNALLING MOLECULES SECRETED FROM MUSCLE CAN ENTER THE CIRCULATION AND SUBSEQUENTLY INTERACT WITH RECIPIENT ORGANS, INCLUDING THE KIDNEYS, WHILE CONVERSELY, PATHOLOGICAL EVENTS IN THE KIDNEY CAN ADVERSELY INFLUENCE PROTEIN METABOLISM IN SKELETAL MUSCLE, DEMONSTRATING THE EXISTENCE OF CROSSTALK BETWEEN KIDNEY AND MUSCLE. TOGETHER, THESE SIGNALS, WHETHER DIRECT OR INDIRECT, INDUCE CHANGES IN THE LEVELS OF REGULATORY AND EFFECTOR PROTEINS VIA ALTERATIONS IN MRNAS, MICRORNAS AND CHROMATIN EPIGENETIC RESPONSES. ADVANCES IN OUR UNDERSTANDING OF THE SIGNALS AND PROCESSES THAT MEDIATE MUSCLE LOSS IN CKD AND OTHER MUSCLE WASTING CONDITIONS WILL SUPPORT THE FUTURE DEVELOPMENT OF THERAPEUTIC STRATEGIES TO REDUCE MUSCLE LOSS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
17  538  25 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
18 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
19 5923  40 TARGETING DNA METHYLATION IN PODOCYTES TO OVERCOME CHRONIC KIDNEY DISEASE. THE NUMBER OF PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) IS ON THE RISE WORLDWIDE, AND THERE IS URGENT NEED FOR THE DEVELOPMENT OF EFFECTIVE PLANS AGAINST THE INCREASING INCIDENCE OF CKD. PODOCYTES, GLOMERULAR EPITHELIAL CELLS, ARE AN INTEGRAL PART OF THE PRIMARY FILTRATION UNIT OF THE KIDNEY AND FORM A SLIT MEMBRANE AS A BARRIER TO PREVENT PROTEINURIA. THE ROLE OF PODOCYTES IN THE PATHOGENESIS AND PROGRESSION OF CKD IS NOW RECOGNIZED. PODOCYTE FUNCTION DEPENDS ON A SPECIALIZED MORPHOLOGY WITH THE ARRANGED FOOT PROCESSES, WHICH IS DIRECTLY RELATED TO THEIR FUNCTION. EPIGENETIC CHANGES RESPONSIBLE FOR THE REGULATION OF GENE EXPRESSION RELATED TO PODOCYTE MORPHOLOGY HAVE BEEN SHOWN TO BE IMPORTANT IN THE PATHOGENESIS OF CKD. ALTHOUGH EPIGENETIC MECHANISMS INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS, AND RNA-BASED REGULATION, WE HAVE FOCUSED ON DNA METHYLATION CHANGES BECAUSE THEY ARE MORE STABLE THAN OTHER EPIGENETIC MODIFICATIONS. THIS REVIEW SUMMARIZES RECENT LITERATURE ABOUT THE ROLE OF ALTERED DNA METHYLATION IN THE KIDNEY, ESPECIALLY IN GLOMERULAR PODOCYTES, FOCUSING ON TRANSCRIPTION FACTORS AND DNA DAMAGE RESPONSES THAT ARE CLOSELY ASSOCIATED WITH THE FORMATION OF DNA METHYLATION CHANGES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20 5258  36 PROGRESSION OF TUBULOINTERSTITIAL FIBROSIS AND THE CHRONIC KIDNEY DISEASE PHENOTYPE - ROLE OF RISK FACTORS AND EPIGENETICS. ALTHOUGH THE KIDNEY HAS CAPACITY TO REPAIR AFTER MILD INJURY, ONGOING OR SEVERE DAMAGE RESULTS IN SCARRING (FIBROSIS) AND AN ASSOCIATED PROGRESSIVE LOSS OF KIDNEY FUNCTION. HOWEVER, DESPITE ITS UNIVERSAL SIGNIFICANCE, EVIDENCE HIGHLIGHTS A POPULATION BASED HETEROGENEITY IN THE TRAJECTORY OF CHRONIC KIDNEY DISEASE (CKD) IN THESE PATIENTS. TO EXPLAIN THE HETEROGENEITY OF THE CKD PHENOTYPE REQUIRES AN UNDERSTANDING OF THE RELEVANT RISK FACTORS FOR FIBROSIS. THESE FACTORS INCLUDE BOTH THE EXTRINSIC NATURE OF INJURY, AND INTRINSIC FACTORS SUCH AS AGE, GENDER, GENETICS, AND PERPETUAL ACTIVATION OF FIBROBLASTS THROUGH PRIMING. IN MANY CASES AN ADDITIONAL LEVEL OF REGULATION IS PROVIDED BY EPIGENETIC MECHANISMS WHICH INTEGRATE THE VARIOUS PRO-FIBROTIC AND ANTI-FIBROTIC TRIGGERS IN FIBROGENESIS. IN THIS REVIEW WE THEREFORE EXAMINE THE VARIOUS MOLECULAR AND STRUCTURAL CHANGES OF FIBROSIS, AND HOW THEY ARE INFLUENCED BY EXTRINSIC AND INTRINSIC FACTORS. OUR AIM IS TO PROVIDE A UNIFYING HYPOTHESIS TO HELP EXPLAIN THE TRANSITION FROM ACUTE TO CKD.	2017