1 1170 235 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 2 5258 43 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 3 2982 52 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 4 97 50 A PRIMER ON THE EPIGENETICS OF KIDNEY FIBROSIS. DESPITE EXTENSIVE KNOWLEDGE OF THE VARIOUS MOLECULAR PATHWAYS THAT CONTRIBUTE TO TUBULOINTERSTITIAL FIBROSIS, IT REMAINS AN UNSOLVED QUESTION WHY THE PROGRESSION RATE OF CHRONIC KIDNEY DISEASE VARIES SUBSTANTIALLY FROM PATIENT TO PATIENT, EVEN AMONG PATIENTS WITH COMMON UNDERLYING NEPHROPATHIES AND COMORBIDITIES. POSSIBLE EXPLANATIONS FOR DIFFERENT SUSCEPTIBILITIES OF INDIVIDUAL PATIENTS TO DEVELOP END-STAGE RENAL FAILURE INCLUDE GENETIC OR EPIGENETIC VARIATIONS, WHICH MODIFY HOW INDIVIDUAL PATIENTS RESPOND TO KIDNEY INJURY. HERE WE REVIEW PRINCIPLES OF EPIGENETIC MECHANISMS IN CONTEXT OF CHRONIC KIDNEY DISEASE AND DISCUSS HOW SUCH INSIGHTS MAY BE UTILIZED FOR FUTURE THERAPEUTIC STRATEGIES AND MAY LEAD TO NOVEL DIAGNOSTIC TOOLS IN THE FUTURE. 2012 5 1880 53 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 6 462 39 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 7 5660 42 SEX-SPECIFIC EPIGENETIC PROGRAMMING IN RENAL FIBROSIS AND INFLAMMATION. THE GROWING PREVALENCE OF HYPERTENSION, HEART DISEASE, DIABETES, AND OBESITY ALONG WITH AN AGING POPULATION, IS LEADING TO HIGHER INCIDENCE OF RENAL DISEASES IN THE SOCIETY. CHRONIC KIDNEY DISEASE (CKD) IS CHARACTERIZED MAINLY BY PERSISTENT INFLAMMATION, FIBROSIS, AND GRADUAL LOSS OF RENAL FUNCTION LEADING TO RENAL FAILURE. SEX IS A KNOWN CONTRIBUTOR TO THE DIFFERENCES IN INCIDENCE AND PROGRESSION OF CKD. EPIGENETIC PROGRAMMING IS AN ESSENTIAL REGULATOR OF RENAL PHYSIOLOGY AND IS CRITICALLY INVOLVED IN THE PATHOPHYSIOLOGY OF RENAL INJURY AND FIBROSIS. EPIGENETIC SIGNALING INTEGRATES INTRINSIC AND EXTRINSIC SIGNALS ONTO THE GENOME, AND VARIOUS ENVIRONMENTAL AND HORMONAL STIMULI, INCLUDING SEX HORMONES, WHICH REGULATE GENE EXPRESSION AND DOWNSTREAM CELLULAR RESPONSES. THE MOST EXTENSIVELY STUDIED EPIGENETIC ALTERATIONS THAT PLAY A CRITICAL ROLE IN RENAL DAMAGE INCLUDE HISTONE MODIFICATIONS AND DNA METHYLATION. NOTABLY, THESE EPIGENETIC ALTERATIONS ARE REVERSIBLE, MAKING THEM CANDIDATES FOR POTENTIAL THERAPEUTIC TARGETS FOR THE TREATMENT OF RENAL DISEASES. HERE, WE WILL SUMMARIZE THE CURRENT KNOWLEDGE ON SEX-DIFFERENCES IN EPIGENETIC MODULATION OF RENAL FIBROSIS AND INFLAMMATION AND HIGHLIGHT SOME POSSIBLE EPIGENETIC THERAPEUTIC STRATEGIES FOR CKD TREATMENT. 2023 8 4882 59 OVERVIEW OF THE CELLULAR AND MOLECULAR BASIS OF KIDNEY FIBROSIS. THE COMMON PATHOGENETIC PATHWAY OF PROGRESSIVE INJURY IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) IS EPITOMIZED AS NORMAL KIDNEY PARENCHYMAL DESTRUCTION DUE TO SCARRING (FIBROSIS). UNDERSTANDING THE FUNDAMENTAL PATHWAYS THAT LEAD TO RENAL FIBROSIS IS ESSENTIAL IN ORDER TO DEVELOP BETTER THERAPEUTIC OPTIONS FOR HUMAN CKD. ALTHOUGH COMPLEX, FOUR CELLULAR RESPONSES ARE PIVOTAL. (1) AN INTERSTITIAL INFLAMMATORY RESPONSE THAT HAS MULTIPLE CONSEQUENCES-SOME HARMFUL AND OTHERS HEALING. (2) THE APPEARANCE OF A UNIQUE INTERSTITIAL CELL POPULATION OF MYOFIBROBLASTS, PRIMARILY DERIVED FROM KIDNEY STROMAL CELLS (FIBROBLASTS AND PERICYTES), THAT ARE THE PRIMARY SOURCE OF THE VARIOUS EXTRACELLULAR MATRIX PROTEINS THAT FORM INTERSTITIAL SCARS. (3) TUBULAR EPITHELIAL CELLS THAT HAVE VARIABLE AND TIME-DEPENDENT ROLES AS EARLY RESPONDERS TO INJURY AND LATER AS VICTIMS OF FIBROSIS DUE TO THE LOSS OF THEIR REGENERATIVE ABILITIES. (4) LOSS OF INTERSTITIAL CAPILLARY INTEGRITY THAT COMPROMISES OXYGEN DELIVERY AND LEADS TO A VICIOUS CASCADE OF HYPOXIA-OXIDANT STRESS THAT ACCENTUATES INJURY AND FIBROSIS. IN THE ABSENCE OF ADEQUATE ANGIOGENIC RESPONSES, A HEALTHY INTERSTITIAL CAPILLARY NETWORK IS NOT MAINTAINED. THE FIBROTIC 'SCAR' THAT TYPIFIES CKD IS AN INTERESTING CONSORTIUM OF MULTIFUNCTIONAL MACROMOLECULES THAT NOT ONLY CHANGE IN COMPOSITION AND STRUCTURE OVER TIME, BUT CAN BE DEGRADED VIA EXTRACELLULAR AND INTRACELLULAR PROTEASES. ALTHOUGH TRANSFORMING GROWTH FACTOR BETA APPEARS TO BE THE PRIMARY DRIVER OF KIDNEY FIBROSIS, A VAST ARRAY OF ADDITIONAL MOLECULES MAY HAVE MODULATING ROLES. THE IMPORTANCE OF GENETIC AND EPIGENETIC FACTORS IS INCREASINGLY APPRECIATED. AN INTRIGUING BUT INCOMPLETELY UNDERSTOOD CARDIORENAL SYNDROME UNDERLIES THE HIGH MORBIDITY AND MORTALITY RATES THAT DEVELOP IN ASSOCIATION WITH PROGRESSIVE KIDNEY FIBROSIS. 2014 9 5950 50 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 10 5370 35 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 11 2195 46 EPIGENETIC MODIFICATION MECHANISMS INVOLVED IN INFLAMMATION AND FIBROSIS IN RENAL PATHOLOGY. THE GROWING INCIDENCE OF OBESITY, HYPERTENSION, AND DIABETES, COUPLED WITH THE AGING OF THE POPULATION, IS INCREASING THE PREVALENCE OF RENAL DISEASES IN OUR SOCIETY. CHRONIC KIDNEY DISEASE (CKD) IS CHARACTERIZED BY PERSISTENT INFLAMMATION, FIBROSIS, AND LOSS OF RENAL FUNCTION LEADING TO END-STAGE RENAL DISEASE. NOWADAYS, CKD TREATMENT HAS LIMITED EFFECTIVENESS UNDERSCORING THE IMPORTANCE OF THE DEVELOPMENT OF INNOVATIVE THERAPEUTIC OPTIONS. RECENT STUDIES HAVE IDENTIFIED HOW EPIGENETIC MODIFICATIONS PARTICIPATE IN THE SUSCEPTIBILITY TO CKD AND HAVE EXPLAINED HOW THE ENVIRONMENT INTERACTS WITH THE RENAL CELL EPIGENOME TO CONTRIBUTE TO RENAL DAMAGE. EPIGENETIC MECHANISMS REGULATE CRITICAL PROCESSES INVOLVED IN GENE REGULATION AND DOWNSTREAM CELLULAR RESPONSES. THE MOST RELEVANT EPIGENETIC MODIFICATIONS THAT PLAY A CRITICAL ROLE IN RENAL DAMAGE INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS, AND CHANGES IN MIRNA LEVELS. IMPORTANTLY, THESE EPIGENETIC MODIFICATIONS ARE REVERSIBLE AND, THEREFORE, A SOURCE OF POTENTIAL THERAPEUTIC TARGETS. HERE, WE WILL EXPLAIN HOW EPIGENETIC MECHANISMS MAY REGULATE ESSENTIAL PROCESSES INVOLVED IN RENAL PATHOLOGY AND HIGHLIGHT SOME POSSIBLE EPIGENETIC THERAPEUTIC STRATEGIES FOR CKD TREATMENT. 2018 12 931 40 CHRONIC KIDNEY DISEASE IN CHILDREN AND THE ROLE OF EPIGENETICS: FUTURE THERAPEUTIC TRAJECTORIES. GLOBAL DIFFERENCES IN THE OBSERVED CAUSES OF CHRONIC KIDNEY DISEASE (CKD) IN CHILDREN ARE WELL DOCUMENTED AND ARE ATTRIBUTED TO DISSIMILARITIES IN CLIME, RACE, HEREDITARY, AND ANCESTRY. THUS, FAMILIAL CLUSTERING AND DISPARITIES IN CKD PREVALENCE RATES ACROSS ETHNIC AND RACIAL GROUPS INDICATE THAT THE PROGRESSION OF RENAL DISEASE HAS A STRONG GENETIC COMPONENT. MAMMALIAN STUDIES HAVE DEMONSTRATED A FEASIBLE NEXUS BETWEEN NUTRITION AND NON-GENETIC EXPOSURE (AROUND THE TIME OF CONCEPTION AND IN EPIGENETIC CHANGES) IN THE EXPRESSION OF MAJOR GENES IDENTIFIED IN RENAL ORGANOGENESIS. THE MAJOR CONSEQUENCE IS A REDUCTION IN THE NUMBER OF NEPHRONS, WITH SUBSEQUENT PREDISPOSITION TO HYPERTENSION AND CKD. IDENTIFYING THESE EPIGENETIC CHANGES IS CRUCIAL (DUE TO THEIR POTENTIALLY REVERSIBLE NATURE), AS THEY MAY SERVE AS FUTURE THERAPEUTIC TARGETS TO PREVENT KIDNEY FIBROSIS AND CKD. DESPITE PROGRESS IN THE FIELD OF EPIGENETICS IN ONCOLOGY, RESEARCH IN OTHER SUBSPECIALTIES OF MEDICINE IS LARGELY EXPERIMENTAL WITH FEW EXISTING STUDIES REGARDING THE CLINICAL IMPLICATION OF EPIGENETICS IN RENAL DISEASE. THERAPEUTIC TRAJECTORIES FOR CKD IN CHILDREN BASED ON THE INFLUENCE OF EPIGENETICS MAY EVENTUALLY REVOLUTIONIZE THE MANAGEMENT OF THIS DISEASE. THE AIM OF THE CURRENT NARRATIVE REVIEW IS TO APPRAISE THE ROLE OF EPIGENETICS IN CKD, AND HIGHLIGHT THE POTENTIAL FUTURE THERAPEUTIC PATHWAYS. 2016 13 1604 43 DNA METHYLATION SUSTAINS "INFLAMED" MEMORY OF PERIPHERAL IMMUNE CELLS AGGRAVATING KIDNEY INFLAMMATORY RESPONSE IN CHRONIC KIDNEY DISEASE. THE INCIDENCE OF CHRONIC KIDNEY DISEASE (CKD) HAS RAPIDLY INCREASED IN THE PAST DECADES. A PROGRESSIVE LOSS OF KIDNEY FUNCTION CHARACTERIZES A PART OF CKD EVEN WITH INTENSIVE SUPPORTIVE TREATMENT. IRRESPECTIVE OF ITS ETIOLOGY, CKD PROGRESSION IS GENERALLY ACCOMPANIED WITH THE DEVELOPMENT OF CHRONIC KIDNEY INFLAMMATION THAT IS PATHOLOGICALLY FEATURED BY THE LOW-GRADE BUT CHRONIC ACTIVATION OF RECRUITED IMMUNE CELLS. CUMULATIVE EVIDENCE SUPPORT THAT ABERRANT DNA METHYLATION PATTERN OF DIVERSE PERIPHERAL IMMUNE CELLS, INCLUDING T CELLS AND MONOCYTES, IS CLOSELY ASSOCIATED WITH CKD DEVELOPMENT IN MANY CHRONIC DISEASE SETTINGS. THE CHANGE OF DNA METHYLATION PROFILE CAN SUSTAIN FOR A LONG TIME AND AFFECT THE FUTURE GENES EXPRESSION IN THE CIRCULATING IMMUNE CELLS EVEN AFTER THEY MIGRATE FROM THE CIRCULATION INTO THE INVOLVED KIDNEY. IT IS OF CLINICAL INTEREST TO REVEAL THE UNDERLYING MECHANISM OF HOW ALTERED DNA METHYLATION REGULATES THE INTENSITY AND THE TIME LENGTH OF THE INFLAMMATORY RESPONSE IN THE RECRUITED EFFECTOR CELLS. WE AND OTHERS RECENTLY DEMONSTRATED THAT ALTERED DNA METHYLATION OCCURS IN PERIPHERAL IMMUNE CELLS AND PROFOUNDLY CONTRIBUTES TO CKD DEVELOPMENT IN SYSTEMIC CHRONIC DISEASES, SUCH AS DIABETES AND HYPERTENSION. THIS REVIEW WILL SUMMARIZE THE CURRENT FINDINGS ABOUT THE INFLUENCE OF ABERRANT DNA METHYLATION ON CIRCULATING IMMUNE CELLS AND HOW IT POTENTIALLY DETERMINES THE OUTCOME OF CKD. 2021 14 4389 42 MODELING EPIGENETIC MODIFICATIONS IN RENAL DEVELOPMENT AND DISEASE WITH ORGANOIDS AND GENOME EDITING. UNDERSTANDING EPIGENETIC MECHANISMS IS CRUCIAL TO OUR COMPREHENSION OF GENE REGULATION IN DEVELOPMENT AND DISEASE. IN THE PAST DECADES, DIFFERENT STUDIES HAVE SHOWN THE ROLE OF EPIGENETIC MODIFICATIONS AND MODIFIERS IN RENAL DISEASE, ESPECIALLY DURING ITS PROGRESSION TOWARDS CHRONIC AND END-STAGE RENAL DISEASE. THUS, THE IDENTIFICATION OF GENETIC VARIATION ASSOCIATED WITH CHRONIC KIDNEY DISEASE HAS RESULTED IN BETTER CLINICAL MANAGEMENT OF PATIENTS. DESPITE THE IMPORTANCE OF THESE FINDINGS, THE TRANSLATION OF GENOTYPE-PHENOTYPE DATA INTO GENE-BASED MEDICINE IN CHRONIC KIDNEY DISEASE POPULATIONS STILL LACKS FAITHFUL CELLULAR OR ANIMAL MODELS THAT RECAPITULATE THE KEY ASPECTS OF THE HUMAN KIDNEY. THE LATEST ADVANCES IN THE FIELD OF STEM CELLS HAVE SHOWN THAT IT IS POSSIBLE TO EMULATE KIDNEY DEVELOPMENT AND FUNCTION WITH ORGANOIDS DERIVED FROM HUMAN PLURIPOTENT STEM CELLS. THESE HAVE SUCCESSFULLY RECAPITULATED NOT ONLY KIDNEY DIFFERENTIATION, BUT ALSO THE SPECIFIC PHENOTYPICAL TRAITS RELATED TO KIDNEY FUNCTION. THE COMBINATION OF THIS METHODOLOGY WITH CRISPR/CAS9 GENOME EDITING HAS ALREADY HELPED RESEARCHERS TO MODEL DIFFERENT GENETIC KIDNEY DISORDERS. NOWADAYS, CRISPR/CAS9-BASED APPROACHES ALSO ALLOW EPIGENETIC MODIFICATIONS, AND THUS REPRESENT AN UNPRECEDENTED TOOL FOR THE SCREENING OF GENETIC VARIANTS, EPIGENETIC MODIFICATIONS OR EVEN CHANGES IN CHROMATIN STRUCTURE THAT ARE ALTERED IN RENAL DISEASE. IN THIS REVIEW, WE DISCUSS THESE TECHNICAL ADVANCES IN KIDNEY MODELING, AND OFFER AN OVERVIEW OF THE ROLE OF EPIGENETIC REGULATION IN KIDNEY DEVELOPMENT AND DISEASE. 2018 15 2211 33 EPIGENETIC MODIFICATIONS AND THE DEVELOPMENT OF KIDNEY GRAFT FIBROSIS. PURPOSE OF REVIEW: TO OUTLINE RECENT DISCOVERIES IN EPIGENETIC REGULATORY MECHANISMS THAT HAVE POTENTIAL IMPLICATIONS IN THE DEVELOPMENT OF RENAL FIBROSIS FOLLOWING KIDNEY TRANSPLANTATION. RECENT FINDINGS: THE CHARACTERIZATION OF RENAL FIBROSIS FOLLOWING KIDNEY TRANSPLANTATION HAS SHOWN TGFBETA/SMAD SIGNALING TO PLAY A MAJOR ROLE IN THE PROGRESSION TO CHRONIC ALLOGRAFT DYSFUNCTION. THE ONSET OF UNREGULATED PROINFLAMMATORY PATHWAYS ARE ONLY EXACERBATED BY THE DECLINE IN REGULATORY MECHANISMS LOST WITH PROGRESSIVE PATIENT AGE AND COMORBIDITIES SUCH AS HYPERTENSION AND DIABETES. HOWEVER, SIGNIFICANT DEVELOPMENTS IN THE RECOGNITION OF EPIGENETIC REGULATORY MARKERS UPSTREAM OF ABERRANT TGFBETA-SIGNALING HAS SIGNIFICANT CLINICAL POTENTIAL TO PROVIDE THERAPEUTIC TARGETS FOR THE TREATMENT OF RENAL FIBROSIS. IN ADDITION, DISCOVERIES IN EXTRACELLULAR VESICLES AND THE CHARACTERIZATION OF THEIR CARGO HAS LAID NEW FRAMEWORK FOR THE POTENTIAL TO EVALUATE PATIENT OUTCOMES INDEPENDENT OF INVASIVE BIOPSIES. SUMMARY: THE CURRENT REVIEW SUMMARIZES THE MAIN FINDINGS IN EPIGENETIC MACHINERY SPECIFIC TO THE DEVELOPMENT OF RENAL FIBROSIS AND HIGHLIGHTS THERAPEUTIC OPTIONS THAT HAVE SIGNIFICANT POTENTIAL TO TRANSLATE INTO CLINICAL PRACTICE. 2021 16 4668 43 NEW INSIGHTS INTO MOLECULAR MECHANISMS OF EPIGENETIC REGULATION IN KIDNEY DISEASE. THE NUMBER OF PATIENTS WITH KIDNEY FAILURE HAS INCREASED IN RECENT YEARS. DIFFERENT FACTORS CONTRIBUTE TO THE PROGRESSION OF CHRONIC KIDNEY DISEASE, INCLUDING GLOMERULAR SCLEROSIS, ATHEROSCLEROSIS OF THE RENAL ARTERIES AND TUBULOINTERSTITIAL FIBROSIS. TUBULOINTERSTITIAL INJURY IS INDUCED BY HYPOXIA AND OTHER INFLAMMATORY SIGNALS, LEADING TO FIBROBLAST ACTIVATION. TECHNOLOGICAL ADVANCES USING HIGH-THROUGHPUT SEQUENCING HAS ENABLED THE DETERMINATION OF THE EXPRESSION PROFILE OF ALMOST ALL GENES, REVEALING THAT GENE EXPRESSION IS INTRICATELY REGULATED BY DNA METHYLATION, HISTONE MODIFICATION, CHANGES IN CHROMOSOME CONFORMATION, LONG NON-CODING RNAS AND MICRORNAS. THESE EPIGENETIC MODIFICATIONS ARE STORED AS CELLULAR EPIGENETIC MEMORY. EPIGENETIC MEMORY LEADS TO ADULT-ONSET DISEASE OR AGEING IN THE LONG TERM AND MAY POSSIBLY PLAY AN IMPORTANT ROLE IN THE KIDNEY DISEASE PROCESS. HEREIN WE EMPHASIZE THE IMPORTANCE OF CLARIFYING THE MOLECULAR MECHANISMS UNDERLYING EPIGENETIC MODIFICATIONS BECAUSE THIS MAY LEAD TO THE DEVELOPMENT OF NEW THERAPEUTIC TARGETS IN KIDNEY DISEASE. 2016 17 6299 52 THE PROXIMAL TUBULE IS THE PRIMARY TARGET OF INJURY AND PROGRESSION OF KIDNEY DISEASE: ROLE OF THE GLOMERULOTUBULAR JUNCTION. THERE IS AN ALARMING GLOBAL INCREASE IN THE INCIDENCE OF END-STAGE KIDNEY DISEASE, FOR WHICH EARLY BIOMARKERS AND EFFECTIVE TREATMENT OPTIONS ARE LACKING. LARGELY BASED ON THE HISTOLOGY OF THE END-STAGE KIDNEY AND ON THE MODEL OF UNILATERAL URETERAL OBSTRUCTION, CURRENT INVESTIGATION IS FOCUSED ON THE PATHOGENESIS OF RENAL INTERSTITIAL FIBROSIS AS A CENTRAL MECHANISM IN THE PROGRESSION OF CHRONIC KIDNEY DISEASE (CKD). IT IS NOW RECOGNIZED THAT CUMULATIVE EPISODES OF ACUTE KIDNEY INJURY (AKI) CAN LEAD TO CKD, AND, CONVERSELY, CKD IS A RISK FACTOR FOR AKI. BASED ON RECENT AND HISTORIC STUDIES, THIS REVIEW SHIFTS ATTENTION FROM THE GLOMERULUS AND INTERSTITIUM TO THE PROXIMAL TUBULE AS THE PRIMARY SENSOR AND EFFECTOR IN THE PROGRESSION OF CKD AS WELL AS AKI. PACKED WITH MITOCHONDRIA AND DEPENDENT ON OXIDATIVE PHOSPHORYLATION, THE PROXIMAL TUBULE IS PARTICULARLY VULNERABLE TO INJURY (OBSTRUCTIVE, ISCHEMIC, HYPOXIC, OXIDATIVE, METABOLIC), RESULTING IN CELL DEATH AND ULTIMATELY IN THE FORMATION OF ATUBULAR GLOMERULI. ANIMAL MODELS OF HUMAN GLOMERULAR AND TUBULAR DISORDERS HAVE PROVIDED EVIDENCE FOR A BROAD REPERTOIRE OF MORPHOLOGICAL AND FUNCTIONAL RESPONSES OF THE PROXIMAL TUBULE, REVEALING PROCESSES OF DEGENERATION AND REPAIR THAT MAY LEAD TO NEW THERAPEUTIC STRATEGIES. MOST PROMISING ARE STUDIES THAT ENCOMPASS THE ENTIRE LIFE CYCLE FROM FETUS TO SENESCENCE, RECOGNIZING EPIGENETIC FACTORS. THE APPLICATION OF TECHNIQUES IN MOLECULAR CHARACTERIZATION OF TUBULE SEGMENTS AND THE DEVELOPMENT OF HUMAN KIDNEY ORGANOIDS MAY PROVIDE NEW INSIGHTS INTO THE MAMMALIAN KIDNEY SUBJECTED TO STRESS OR INJURY, LEADING TO BIOMARKERS OF EARLY CKD AND NEW THERAPIES. 2016 18 2286 37 EPIGENETIC REGULATION IN KIDNEY TRANSPLANTATION. KIDNEY TRANSPLANTATION IS A STANDARD CARE FOR END STAGE RENAL DISEASE, BUT IT IS ALSO ASSOCIATED WITH A COMPLEX PATHOGENESIS INCLUDING ISCHEMIA-REPERFUSION INJURY, INFLAMMATION, AND DEVELOPMENT OF FIBROSIS. OVER THE PAST DECADE, ACCUMULATING EVIDENCE HAS SUGGESTED A ROLE OF EPIGENETIC REGULATION IN KIDNEY TRANSPLANTATION, INVOLVING DNA METHYLATION, HISTONE MODIFICATION, AND VARIOUS KINDS OF NON-CODING RNAS. HERE, WE ANALYZE THESE RECENT STUDIES SUPPORTING THE ROLE OF EPIGENETIC REGULATION IN DIFFERENT PATHOLOGICAL PROCESSES OF KIDNEY TRANSPLANTATION, I.E., ISCHEMIA-REPERFUSION INJURY, ACUTE REJECTION, AND CHRONIC GRAFT PATHOLOGIES INCLUDING RENAL INTERSTITIAL FIBROSIS. FURTHER INVESTIGATION OF EPIGENETIC ALTERATIONS, THEIR PATHOLOGICAL ROLES AND UNDERLYING MECHANISMS IN KIDNEY TRANSPLANTATION MAY LEAD TO NEW STRATEGIES FOR THE DISCOVERY OF NOVEL DIAGNOSTIC BIOMARKERS AND THERAPEUTIC INTERVENTIONS. 2022 19 2579 29 EPIGENETICS OF KIDNEY DISEASE. DNA METHYLATION AND HISTONE MODIFICATIONS DETERMINE RENAL PROGRAMMING AND THE DEVELOPMENT AND PROGRESSION OF RENAL DISEASE. THE IDENTIFICATION OF THE WAY IN WHICH THE RENAL CELL EPIGENOME IS ALTERED BY ENVIRONMENTAL MODIFIERS DRIVING THE ONSET AND PROGRESSION OF RENAL DISEASES HAS EXTENDED OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY OF KIDNEY DISEASE PROGRESSION. IN THIS REVIEW, WE FOCUS ON CURRENT KNOWLEDGE CONCERNING THE IMPLICATIONS OF EPIGENETIC MODIFICATIONS DURING RENAL DISEASE FROM EARLY DEVELOPMENT TO CHRONIC KIDNEY DISEASE PROGRESSION INCLUDING RENAL FIBROSIS, DIABETIC NEPHROPATHY AND THE TRANSLATIONAL POTENTIAL OF IDENTIFYING NEW BIOMARKERS AND TREATMENTS FOR THE PREVENTION AND THERAPY OF CHRONIC KIDNEY DISEASE AND END-STAGE KIDNEY DISEASE. 2017 20 2154 41 EPIGENETIC MECHANISMS AND KIDNEY DISEASES. IN RECENT YEARS, MOLECULAR RESEARCH HAS BROUGHT TO LIGHT A SERIES OF MECHANISMS INVOLVED IN THE REGULATION OF GENE FUNCTION WITHOUT ALTERING THE DNA SEQUENCE. THESE MECHANISMS ARE DESCRIBED WITH THE TERM "EPIGENETICS" AND INCLUDE MODIFICATIONS IN THE STRUCTURE OF THE HUMAN GENOME, LEADING TO HERITABLE AND POTENTIALLY REVERSIBLE CHANGES IN GENE EXPRESSION. THERE IS NOW INCREASING EVIDENCE SUGGESTING THAT SEVERAL CHARACTERISTIC FEATURES OF CHRONIC KIDNEY DISEASE SUCH AS HYPERHOMOCYSTEINEMIA, SUBCLINICAL INFLAMMATION, INCREASED OXIDATIVE STRESS AND OTHERS MAY AFFECT THE HUMAN EPIGENOME. IN ADDITION, ANIMAL STUDIES HAVE SUGGESTED A POSSIBLE LINK BETWEEN NUTRITION AND ENVIRONMENTAL EXPOSURE DURING THE PERICONCEPTIONAL PERIOD AND EPIGENETIC CHANGES IN THE EXPRESSION OF MAJOR GENES IMPLICATED IN KIDNEY ORGANOGENESIS; THESE CHANGES RESULT IN A DIMINISHED NUMBER OF NEPHRONS IN THE DEVELOPING KIDNEY, WHICH PREDISPOSES TO AN INCREASED RISK FOR HYPERTENSION AND CHRONIC KIDNEY DISEASE IN FUTURE LIFE. THE UNDERSTANDING OF THE ROLE OF EPIGENETIC PHENOMENA IN THE PATHOGENESIS OF CHRONIC KIDNEY DISEASE OPENS NEW AVENUES FOR FUTURE THERAPEUTIC STRATEGIES, THROUGH THE DEVELOPMENT OF PHARMACEUTICAL AGENTS THAT TARGET DIRECTLY WITH THE CHANGES IN THE HUMAN EPIGENOME. SUCH EPIGENETIC DRUGS ARE ALREADY IN CLINICAL USE FOR THE TREATMENT OF CANCER AS WELL AS UNDER INVESTIGATION FOR THE USE IN OTHER DISEASES. THIS REVIEW WILL SUMMARIZE THE EXISTING DATA ON THE LINK BETWEEN EPIGENETIC MECHANISMS AND CHRONIC UREMIC MILIEU, AS WELL AS THE PROMISING RESULTS OF ONGOING RESEARCH IN THE FIELD OF EPIGENETIC DRUGS THAT COULD REPRESENT ADDITIONAL OPTIONS IN OUR THERAPEUTIC ARMAMENTARIUM FOR PATIENTS WITH CHRONIC KIDNEY DISEASE. 2011