1 5363 65 RECENT ADVANCES IN DIABETIC KIDNEY DISEASES: FROM KIDNEY INJURY TO KIDNEY FIBROSIS. DIABETIC KIDNEY DISEASE (DKD) IS THE LEADING CAUSE OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE. THE NATURAL HISTORY OF DKD INCLUDES GLOMERULAR HYPERFILTRATION, PROGRESSIVE ALBUMINURIA, DECLINING ESTIMATED GLOMERULAR FILTRATION RATE, AND, ULTIMATELY, KIDNEY FAILURE. IT IS KNOWN THAT DKD IS ASSOCIATED WITH METABOLIC CHANGES CAUSED BY HYPERGLYCEMIA, RESULTING IN GLOMERULAR HYPERTROPHY, GLOMERULOSCLEROSIS, AND TUBULOINTERSTITIAL INFLAMMATION AND FIBROSIS. HYPERGLYCEMIA IS ALSO KNOWN TO CAUSE PROGRAMMED EPIGENETIC MODIFICATION. HOWEVER, THE DETAILED MECHANISMS INVOLVED IN THE ONSET AND PROGRESSION OF DKD REMAIN ELUSIVE. IN THIS REVIEW, WE DISCUSS RECENT ADVANCES REGARDING THE PATHOGENIC MECHANISMS INVOLVED IN DKD. 2021 2 1883 24 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 3 3884 37 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 4 6652 23 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 5 3383 20 HNF1B NEPHROPATHY HAS A SLOW-PROGRESSIVE PHENOTYPE IN CHILDHOOD-WITH THE EXCEPTION OF VERY EARLY ONSET CASES: RESULTS OF THE GERMAN MULTICENTER HNF1B CHILDHOOD REGISTRY. BACKGROUND: HNF1B GENE MUTATIONS ARE AN IMPORTANT CAUSE OF BILATERAL (CYSTIC) DYSPLASIA IN CHILDREN, COMPLICATED BY CHRONIC RENAL INSUFFICIENCY. THE CLINICAL VARIABILITY, THE ABSENCE OF GENOTYPE-PHENOTYPE CORRELATIONS, AND LIMITED LONG-TERM DATA RENDER COUNSELING OF AFFECTED FAMILIES DIFFICULT. METHODS: LONGITUDINAL DATA OF 62 CHILDREN PROBANDS WITH GENETICALLY PROVEN HNF1B NEPHROPATHY WAS OBTAINED IN A MULTICENTER APPROACH. GENETIC FAMILY CASCADE SCREENING WAS PERFORMED IN 30/62 CASES. RESULTS: EIGHTY-SEVEN PERCENT OF PATIENTS HAD BILATERAL DYSPLASIA, 74% VISIBLE BILATERAL, AND 16% UNILATERAL RENAL CYSTS AT THE END OF OBSERVATION. CYST DEVELOPMENT WAS NON-PROGRESSIVE IN 72% WITH A MEAN GLOMERULAR FILTRATION RATE (GFR) LOSS OF - 0.33 ML/MIN/1.73M(2) PER YEAR (+/- 8.9). IN PATIENTS WITH AN INCREASE IN CYST NUMBER, THE ANNUAL GFR REDUCTION WAS - 2.8 ML/MIN/1.73M(2) (+/- 13.2), IN THE TOTAL COHORT - 1.0 ML/MIN/1.73M(2) (+/-10.3). A SUBSET OF HNF1B PATIENTS DIFFERS FROM THIS GROUP AND DEVELOPS END STAGE RENAL DISEASE (ESRD) AT VERY EARLY AGES < 2 YEARS. HYPERURICEMIA (37%) WAS A FREQUENT FINDING AT YOUNG AGE (MEDIAN 1 YEAR), WHEREAS HYPOMAGNESEMIA (24%), ELEVATED LIVER ENZYMES (21%), AND HYPERGLYCEMIA (8%) SHOWED AN INCREASED INCIDENCE IN THE TEENAGED CHILD. GENETIC ANALYSIS REVEALED NO GENOTYPE-PHENOTYPE CORRELATIONS BUT A SIGNIFICANT PARENT-OF-ORIGIN EFFECT WITH A PREPONDERANCE OF 81% OF MATERNAL INHERITANCE IN DOMINANT CASES. CONCLUSIONS: IN MOST CHILDREN, HNF1B NEPHROPATHY HAS A NON-PROGRESSIVE COURSE OF CYST DEVELOPMENT AND A SLOW-PROGRESSIVE COURSE OF KIDNEY FUNCTION. A SUBGROUP OF PATIENTS DEVELOPED ESRD AT VERY YOUNG AGE < 2 YEARS REQUIRING SPECIAL MEDICAL ATTENTION. THE PARENT-OF-ORIGIN EFFECT SUGGESTS AN INFLUENCE OF EPIGENETIC MODIFIERS IN HNF1B DISEASE. 2019 6 6648 25 UPDATE ON DIAGNOSIS, PATHOPHYSIOLOGY, AND MANAGEMENT OF DIABETIC KIDNEY DISEASE. DIABETIC KIDNEY DISEASE (DKD) IS A CHRONIC COMPLICATION OF DIABETES MELLITUS WHICH MAY EVENTUALLY LEAD TO END-STAGE KIDNEY DISEASE (ESKD). DESPITE IMPROVEMENTS IN GLYCAEMIC CONTROL AND BLOOD PRESSURE MANAGEMENT WITH RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) BLOCKADE, THE CURRENT THERAPY CANNOT COMPLETELY HALT DKD PROGRESSION TO ESKD IN SOME PATIENTS. DKD IS A HETEROGENEOUS DISEASE ENTITY IN TERMS OF ITS CLINICAL MANIFESTATIONS, HISTOPATHOLOGY AND THE RATE OF PROGRESSION, WHICH MAKES IT DIFFICULT TO DEVELOP EFFECTIVE THERAPEUTICS. IT WAS FORMERLY CONSIDERED THAT ALBUMINURIA PRECEDED KIDNEY FUNCTION DECLINE IN DKD, BUT RECENT EPIDEMIOLOGICAL STUDIES REVEALED THAT A DISTINCT GROUP OF PATIENTS PRESENTED KIDNEY DYSFUNCTION WITHOUT DEVELOPING ALBUMINURIA. OTHER COMORBIDITIES, SUCH AS HYPERTENSION, OBESITY AND GOUT, ALSO AFFECT THE CLINICAL COURSE OF DKD. THE PATHOPHYSIOLOGY OF DKD IS COMPLEX AND MULTIFACTORIAL, INVOLVING BOTH METABOLIC AND HAEMODYNAMIC FACTORS. THESE INDUCE ACTIVATION OF INTRACELLULAR SIGNALLING PATHWAYS, OXIDATIVE STRESS, HYPOXIA, DYSREGULATED AUTOPHAGY AND EPIGENETIC CHANGES, WHICH RESULT IN KIDNEY INFLAMMATION AND FIBROSIS. RECENTLY, TWO GROUPS OF ANTIDIABETIC DRUGS, SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITORS AND GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS, WERE DEMONSTRATED TO PROVIDE RENOPROTECTION ON TOP OF THEIR GLUCOSE-LOWERING EFFECTS. SEVERAL OTHER THERAPEUTIC AGENTS ARE ALSO BEING DEVELOPED AND EVALUATED IN CLINICAL TRIALS. 2021 7 2121 32 EPIGENETIC HISTONE MODIFICATIONS IN THE PATHOGENESIS OF DIABETIC KIDNEY DISEASE. DIABETIC KIDNEY DISEASE (DKD), AS THE MAIN COMPLICATION OF DIABETES MELLITUS, IS THE PRIMARY CAUSE OF THE END-STAGE RENAL DISEASE (ESRD) AND THE MOST COMMON CHRONIC KIDNEY DISEASE. OVERALL, 30-40% OF PATIENTS WITH TYPE 1 AND TYPE 2 DIABETES EVENTUALLY DEVELOP DKD. ALTHOUGH SOME DIABETES PATIENTS HAVE INTENSIFIED GLYCEMIC CONTROL, THEY STILL DEVELOP DIABETIC KIDNEY DISEASE. CURRENT TREATMENT METHODS CAN ALLEVIATE BUT DO NOT MARKEDLY HALT DISEASE DEVELOPMENT, RESULTING IN RENAL FAILURE AND SEVERE COMPLICATIONS, EVEN CONTRIBUTING TO ELEVATED MORBIDITY AND MORTALITY RATES. DKD IS A DISEASE WITH INTERACTIONS OF GENES AND THE ENVIRONMENT. EMERGING EVIDENCE INDICATES THAT DKD-ASSOCIATED KEY GENES ARE ALSO REGULATED BY THE EPIGENETIC MECHANISM. RECENTLY, INCREASING RESEARCHES INVOLVING CELLS AND EXPERIMENTAL ANIMALS DEMONSTRATED THAT HISTONE POST-TRANSLATIONAL MODIFICATIONS CAN MEDIATE GENE EXPRESSION, WHICH CORRELATED WITH DIABETIC KIDNEY DISEASE. NOVEL THERAPEUTIC STRATEGIES FOR EPIGENETIC EVENTS COULD BE BENEFICIAL FOR THE EARLY DETECTION AND TREATMENT OF DKD TO PREVENT IT FROM DEVELOPING INTO END-STAGE RENAL DISEASE (ESRD). IN THIS REVIEW, WE DISCUSS PRIOR FINDINGS IN THE FIELD OF HISTONE MODIFICATIONS IN DKD, ESPECIALLY HISTONE ACETYLATION AND HISTONE METHYLATION. WE THEN FOCUS ON RECENT DEVELOPMENTS IN HISTONE ACETYLATION AND METHYLATION INVOLVED IN THE PATHOGENESIS OF DKD. 2021 8 1642 20 DOES INFLAMMATION AFFECT OUTCOMES IN DIALYSIS PATIENTS? CHRONIC, LOW-GRADE INFLAMMATION IS A COMMON COMORBID CONDITION IN CHRONIC KIDNEY DISEASE (CKD), AND PARTICULARLY IN CHRONIC DIALYSIS PATIENTS. IN THIS REVIEW, WE CONSIDER THE QUESTION OF WHETHER INFLAMMATION AFFECTS OUTCOMES IN DIALYSIS PATIENTS. LEVELS OF PROINFLAMMATORY CYTOKINES, AS WELL AS C-REACTIVE PROTEIN, ARE ELEVATED IN CHRONIC DIALYSIS PATIENTS. MULTIPLE FACTORS LIKELY CONTRIBUTE TO CHRONIC INFLAMMATORY ACTIVATION IN KIDNEY DISEASE PATIENTS INCLUDING THE UREMIC MILIEU, LIFESTYLE AND EPIGENETIC INFLUENCES, INFECTIOUS AND THROMBOTIC EVENTS, THE DIALYSIS PROCESS, AND DYSBIOSIS. INCREASED INFLAMMATORY MARKERS IN BOTH CKD AND CHRONIC DIALYSIS PATIENTS ARE ASSOCIATED WITH ADVERSE CLINICAL OUTCOMES INCLUDING ALL-CAUSE MORTALITY, CARDIOVASCULAR EVENTS, KIDNEY DISEASE PROGRESSION, PROTEIN ENERGY WASTING AND DIMINISHED MOTOR FUNCTION, COGNITIVE IMPAIRMENT, AS WELL AS OTHER ADVERSE CONSEQUENCES INCLUDING CKD-MINERAL AND BONE DISORDER, ANEMIA, AND INSULIN RESISTANCE. STRATEGIES THAT HAVE BEEN SHOWN TO REDUCE CHRONIC SYSTEMIC INFLAMMATION IN CKD AND CHRONIC DIALYSIS PATIENTS INCLUDE BOTH PHARMACOLOGICAL AND NONPHARMACOLOGICAL INTERVENTIONS. HOWEVER, DESPITE EVIDENCE THAT SYSTEMIC INFLAMMATORY MARKERS CAN BE LOWERED IN KIDNEY DISEASE PATIENTS TREATED WITH VARIOUS STRATEGIES, EVIDENCE THAT THIS IMPROVES CLINICAL OUTCOMES IS LARGELY UNAVAILABLE AND REPRESENTS AN IMPORTANT FUTURE RESEARCH DIRECTION. OVERALL, THERE IS STRONG OBSERVATIONAL EVIDENCE THAT INFLAMMATION IS HIGH IN CHRONIC DIALYSIS PATIENTS AND THAT THIS IS INDEPENDENTLY ASSOCIATED WITH NUMEROUS ADVERSE CLINICAL OUTCOMES. TARGETING INFLAMMATION REPRESENTS A POTENTIALLY NOVEL AND ATTRACTIVE STRATEGY IF IT CAN INDEED IMPROVE ADVERSE OUTCOMES COMMON IN THIS POPULATION. 2018 9 2972 26 GENETIC AND EPIGENETIC STUDIES IN DIABETIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE IS A WORLDWIDE HEALTH CRISIS, WHILE DIABETIC KIDNEY DISEASE (DKD) HAS BECOME THE LEADING CAUSE OF END-STAGE RENAL DISEASE (ESRD). DKD IS A MICROVASCULAR COMPLICATION AND OCCURS IN 30-40% OF DIABETES PATIENTS. EPIDEMIOLOGICAL INVESTIGATIONS AND CLINICAL OBSERVATIONS ON THE FAMILIAL CLUSTERING AND HERITABILITY IN DKD HAVE HIGHLIGHTED AN UNDERLYING GENETIC SUSCEPTIBILITY. FURTHERMORE, DKD IS A PROGRESSIVE AND LONG-TERM DIABETIC COMPLICATION, IN WHICH EPIGENETIC EFFECTS AND ENVIRONMENTAL FACTORS INTERACT WITH AN INDIVIDUAL'S GENETIC BACKGROUND. IN RECENT YEARS, RESEARCHERS HAVE UNDERTAKEN GENETIC AND EPIGENETIC STUDIES OF DKD IN ORDER TO BETTER UNDERSTAND ITS MOLECULAR MECHANISMS. IN THIS REVIEW, CLINICAL MATERIAL, RESEARCH APPROACHES AND EXPERIMENTAL DESIGNS THAT HAVE BEEN USED FOR GENETIC AND EPIGENETIC STUDIES OF DKD ARE DESCRIBED. CURRENT INFORMATION FROM GENETIC AND EPIGENETIC STUDIES OF DKD AND ESRD IN PATIENTS WITH DIABETES, INCLUDING THE APPROACHES OF GENOME-WIDE ASSOCIATION STUDY (GWAS) OR EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) AND CANDIDATE GENE ASSOCIATION ANALYSES, ARE SUMMARIZED. FURTHER INVESTIGATION OF MOLECULAR DEFECTS IN DKD WITH NEW APPROACHES SUCH AS NEXT GENERATION SEQUENCING ANALYSIS AND PHENOME-WIDE ASSOCIATION STUDY (PHEWAS) IS ALSO DISCUSSED. 2019 10 2795 23 FATTY LIVER AND CHRONIC KIDNEY DISEASE: NOVEL MECHANISTIC INSIGHTS AND THERAPEUTIC OPPORTUNITIES. CHRONIC KIDNEY DISEASE (CKD) IS A RISK FACTOR FOR END-STAGE RENAL DISEASE (ESRD) AND CARDIOVASCULAR DISEASE (CVD). ESRD OR CVD DEVELOP IN A SUBSTANTIAL PROPORTION OF PATIENTS WITH CKD RECEIVING STANDARD-OF-CARE THERAPY, AND MORTALITY IN CKD REMAINS UNCHANGED. THESE DATA SUGGEST THAT KEY PATHOGENETIC MECHANISMS UNDERLYING CKD PROGRESSION GO UNAFFECTED BY CURRENT TREATMENTS. GROWING EVIDENCE SUGGESTS THAT NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) AND CKD SHARE COMMON PATHOGENETIC MECHANISMS AND POTENTIAL THERAPEUTIC TARGETS. COMMON NUTRITIONAL CONDITIONS PREDISPOSING TO BOTH NAFLD AND CKD INCLUDE EXCESSIVE FRUCTOSE INTAKE AND VITAMIN D DEFICIENCY. MODULATION OF NUCLEAR TRANSCRIPTION FACTORS REGULATING KEY PATHWAYS OF LIPID METABOLISM, INFLAMMATION, AND FIBROSIS, INCLUDING PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS AND FARNESOID X RECEPTOR, IS ADVANCING TO STAGE III CLINICAL DEVELOPMENT. THE RELEVANCE OF EPIGENETIC REGULATION IN THE PATHOGENESIS OF NAFLD AND CKD IS ALSO EMERGING, AND MODULATION OF MICRORNA21 IS A PROMISING THERAPEUTIC TARGET. ALTHOUGH SINGLE ANTIOXIDANT SUPPLEMENTATION HAS YIELDED VARIABLE RESULTS, MODULATION OF KEY EFFECTORS OF REDOX REGULATION AND MOLECULAR SENSORS OF INTRACELLULAR ENERGY, NUTRIENT, OR OXYGEN STATUS SHOW PROMISING PRECLINICAL RESULTS. OTHER EMERGING THERAPEUTIC APPROACHES TARGET KEY MEDIATORS OF INFLAMMATION, SUCH AS CHEMOKINES; FIBROGENESIS, SUCH AS GALECTIN-3; OR GUT DYSFUNCTION THROUGH GUT MICROBIOTA MANIPULATION AND INCRETIN-BASED THERAPIES. FURTHERMORE, NAFLD PER SE AFFECTS CKD THROUGH LIPOPROTEIN METABOLISM AND HEPATOKINE SECRETION, AND CONVERSELY, TARGETING THE RENAL TUBULE BY SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS CAN IMPROVE BOTH CKD AND NAFLD. IMPLICATIONS FOR THE TREATMENT OF NAFLD AND CKD ARE DISCUSSED IN LIGHT OF THIS NEW THERAPEUTIC ARMAMENTARIUM. 2016 11 307 25 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 12 3035 20 GENETICS/GENOMICS IN CHRONIC KIDNEY DISEASE--TOWARDS PERSONALIZED MEDICINE? THE PROGRESSION RATE OF CHRONIC KIDNEY DISEASE (CKD) TO ITS TERMINAL STAGE, END-STAGE RENAL DISEASE (ESRD), AND THE DEVELOPMENT AND SEVERITY OF VARIOUS COMPLICATIONS, ARE AT LEAST INDIRECTLY INFLUENCED BY GENETIC--AND EPIGENETIC--FACTORS. FOR YEARS, SCIENTISTS HAVE HELD OUT HOPE THAT THE RAPIDLY EVOLVING FIELD OF GENETICS COULD TRANSFORM MEDICAL DIAGNOSIS AND TREATMENT, MOVING BEYOND A TRIAL-AND-ERROR APPROACH TOWARDS "PERSONALIZED MEDICINE." INDEED, THERE ARE NOW SIGNS THAT THE ROLE OF GENETICS AND THE PURSUIT OF "PERSONALIZED MEDICINE" IN MEDICAL CARE WILL BE A PRIORITY FOR GOVERNMENTS DURING YEARS TO COME. BUT THE VISION OF INDIVIDUALIZED TREATMENT BASED ON A PATIENT'S GENETIC MAKEUP AND OTHER BIOLOGICAL MARKERS HAS YET TO MATERIALIZE IN THE FIELD OF CKD AND ESRD. AS THE TOXIC UREMIC ENVIRONMENT MAY RENDER CKD PATIENTS MORE SENSITIVE TO THE EFFECTS OF GENETIC VARIANTS, IT IS LIKELY THAT GENETIC FACTORS COULD BE OF SPECIAL IMPORTANCE IN THIS HIGH-RISK POPULATION. THEREFORE, OUTCOME IN THE CKD POPULATION MAY BE IMPROVED BY ESTABLISHING INDIVIDUAL GENETIC/EPIGENETIC PROFILES, THUS ENABLING PHYSICIANS TO DESIGN AN INDIVIDUALIZED THERAPEUTIC STRATEGY. PERSONALIZED MEDICINE BASED ON A MORE INDIVIDUALIZED THERAPY COULD BE APPLIED IN, FOR EXAMPLE, PHARMACOTHERAPY (CYP GENES), DIALYSIS THERAPY, AND NUTRITIONAL AND LIFESTYLE MODIFICATIONS. 2009 13 6575 29 TREATMENT OF DIABETIC KIDNEY DISEASE: CURRENT AND FUTURE. DIABETIC KIDNEY DISEASE (DKD) IS THE MAJOR CAUSE OF END-STAGE KIDNEY DISEASE. HOWEVER, ONLY RENIN-ANGIOTENSIN SYSTEM INHIBITOR WITH MULTIDISCIPLINARY TREATMENTS IS EFFECTIVE FOR DKD. IN 2019, SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITOR SHOWED EFFICACY AGAINST DKD IN CANAGLIFLOZIN AND RENAL EVENTS IN DIABETES WITH ESTABLISHED NEPHROPATHY CLINICAL EVALUATION (CREDENCE) TRIAL, ADDING A NEW TREATMENT OPTION. HOWEVER, THE PROGRESSION OF DKD HAS NOT BEEN COMPLETELY CONTROLLED. THE PATIENTS WITH TRANSIENT EXPOSURE TO HYPERGLYCEMIA DEVELOP DIABETIC COMPLICATIONS, INCLUDING DKD, EVEN AFTER NORMALIZATION OF THEIR BLOOD GLUCOSE. TEMPORARY HYPERGLYCEMIA CAUSES ADVANCED GLYCATION END PRODUCT (AGE) ACCUMULATIONS AND EPIGENETIC CHANGES AS METABOLIC MEMORY. THE DRUGS THAT IMPROVE METABOLIC MEMORY ARE AWAITED, AND AGE INHIBITORS AND HISTONE MODIFICATION INHIBITORS ARE THE FOCUS OF CLINICAL AND BASIC RESEARCH. IN ADDITION, INCRETIN-RELATED DRUGS SHOWED A RENOPROTECTIVE ABILITY IN MANY CLINICAL TRIALS, AND THESE TRIALS WITH RENAL OUTCOME AS THEIR PRIMARY ENDPOINT ARE CURRENTLY ONGOING. HYPOXIA-INDUCIBLE FACTOR PROLYL HYDROXYLASE INHIBITORS RECENTLY APPROVED FOR RENAL ANEMIA MAY BE RENOPROTECTIVE SINCE THEY IMPROVE TUBULOINTERSTITIAL HYPOXIA. FURTHERMORE, NF-E2-RELATED FACTOR 2 ACTIVATORS IMPROVED THE GLOMERULAR FILTRATION RATE OF DKD PATIENTS IN BARDOXOLONE METHYL TREATMENT: RENAL FUNCTION IN CHRONIC KIDNEY DISEASE/TYPE 2 DIABETES (BEAM) TRIAL AND PHASE II STUDY OF BARDOXOLONE METHYL IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND TYPE 2 DIABETES (TSUBAKI) TRIAL. THUS, FOLLOWING SGLT2 INHIBITOR, NUMEROUS NOVEL DRUGS COULD BE UTILIZED IN TREATING DKD. FUTURE STUDIES ARE EXPECTED TO PROVIDE NEW INSIGHTS. 2021 14 5370 22 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 15 3095 27 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 16 933 27 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 17 1585 20 DNA METHYLATION PROFILING IDENTIFIES EPIGENETIC DIFFERENCES BETWEEN DIABETES PATIENTS WITH ESRD AND DIABETES PATIENTS WITHOUT NEPHROPATHY. WE IDENTIFIED POTENTIAL EPIGENETIC BIOMARKERS FOR CHRONIC KIDNEY DISEASE PROGRESSION BY COMPARING SITE-SPECIFIC DNA METHYLATION LEVELS IN MORE THAN 14,000 GENES BETWEEN AFRICAN AMERICAN AND HISPANIC DIABETES PATIENTS WITH END STAGE RENAL DISEASE (ESRD) AND DIABETES PATIENTS WITHOUT NEPHROPATHY. WE IDENTIFIED 187 GENES THAT ARE DIFFERENTIALLY METHYLATED BETWEEN THE TWO GROUPS ON AT LEAST TWO CPG SITES IN EACH GENE IN DNA EXTRACTED FROM SALIVA. OF THE 187 GENES WHOSE MEAN METHYLATION LEVELS DIFFERED BETWEEN THE TWO GROUPS, 39 GENES, OR CLOSELY RELATED GENE FAMILY MEMBERS, HAVE BEEN REPORTED TO BE INVOLVED IN KIDNEY DEVELOPMENT OR DIABETIC NEPHROPATHY, PER SE, OR HAVE BEEN ASSOCIATED WITH DIALYSIS-INDUCED CHANGES IN GENE EXPRESSION IN PERIPHERAL BLOOD CELLS. THE FACT THAT SUCH A SUBSTANTIAL FRACTION (21%) OF THE 187 CANDIDATE GENES HAVE BEEN IMPLICATED PREVIOUSLY THROUGH GENOME ASSOCIATION OR TRANSCRIPTION PROFILING STUDIES SUGGESTS STRONGLY THAT THE DNA METHYLATION DIFFERENCES WE OBSERVE ARE ASSOCIATED WITH DISEASE PREDISPOSITION AND/OR TREATMENT. THE FACT THAT THESE NEPHROPATHY AND/OR DIALYSIS-ASSOCIATED DIFFERENCES BETWEEN PATIENTS WERE IDENTIFIED IN DNA EXTRACTED FROM SALIVA OFFERS PROOF-OF-PRINCIPLE THAT INTER-INDIVIDUAL EPIGENETIC DIFFERENCES MAY PROVE USEFUL AS PREDICTIVE BIOMARKERS OF DISEASE SUSCEPTIBILITY. 2011 18 6409 27 THE SIGNALING OF CELLULAR SENESCENCE IN DIABETIC NEPHROPATHY. DIABETIC NEPHROPATHY IS THE LEADING CAUSE OF CHRONIC KIDNEY DISEASE (CKD) IN WESTERN COUNTRIES. NOTABLY, IT HAS A RAPIDLY RISING PREVALENCE IN CHINA. THE PATIENTS, COMMONLY COMPLICATED WITH CARDIOVASCULAR DISEASES AND NEUROLOGIC DISORDERS, ARE AT HIGH RISK TO PROGRESS INTO END-STAGE RENAL DISEASE (ESRD) AND DEATH. HOWEVER, THE PATHOGENIC MECHANISMS OF DIABETIC NEPHROPATHY HAVE NOT BEEN DETERMINED. CELLULAR SENESCENCE, WHICH RECENTLY HAS GAINED BROAD ATTENTION, IS THOUGHT TO BE AN IMPORTANT PLAYER IN THE ONSET AND DEVELOPMENT OF DIABETIC NEPHROPATHY. IN THIS ISSUE, WE GENERALLY REVIEW THE MECHANISMS OF CELLULAR SENESCENCE IN DIABETIC NEPHROPATHY, WHICH INVOLVE TELOMERE ATTRITION, DNA DAMAGE, EPIGENETIC ALTERATIONS, MITOCHONDRIAL DYSFUNCTION, LOSS OF KLOTHO, WNT/BETA-CATENIN SIGNALING ACTIVATION, PERSISTENT INFLAMMATION, AND ACCUMULATION OF UREMIC TOXINS. MOREOVER, WE HIGHLIGHT THE POTENTIAL THERAPEUTIC TARGETS OF CELLULAR SENESCENCE IN DIABETIC NEPHROPATHY AND PROVIDE IMPORTANT CLUES FOR CLINICAL STRATEGIES. 2019 19 1832 29 EFFECTS OF METABOLIC MEMORY ON INFLAMMATION AND FIBROSIS ASSOCIATED WITH DIABETIC KIDNEY DISEASE: AN EPIGENETIC PERSPECTIVE. DIABETIC KIDNEY DISEASE (DKD) IS ONE OF THE MOST COMMON MICROVASCULAR COMPLICATION OF BOTH TYPE 1 (T1DM) AND TYPE 2 DIABETES MELLITUS (T2DM), AND THE LEADING CAUSE OF END-STAGE RENAL DISEASE (ESRD) WORLDWIDE. PERSISTENT INFLAMMATION AND SUBSEQUENT CHRONIC FIBROSIS ARE MAJOR CAUSES OF LOSS OF RENAL FUNCTION, WHICH IS ASSOCIATED WITH THE PROGRESSION OF DKD TO ESRD. IN FACT, DKD PROGRESSION IS AFFECTED BY A COMBINATION OF GENETIC AND ENVIRONMENTAL FACTORS. APPROXIMATELY, ONE-THIRD OF DIABETIC PATIENTS PROGRESS TO DEVELOP DKD DESPITE INTENSIVE GLYCEMIC CONTROL, WHICH PROPOSE AN ESSENTIAL CONCEPT "METABOLIC MEMORY." EPIGENETIC MODIFICATIONS, AN EXTENSIVELY STUDIED MECHANISM OF METABOLIC MEMORY, HAVE BEEN SHOWN TO CONTRIBUTE TO THE SUSCEPTIBILITY TO DEVELOP DKD. EPIGENETIC MODIFICATIONS ALSO PLAY A REGULATORY ROLE IN THE INTERACTIONS BETWEEN THE GENES AND THE ENVIRONMENTAL FACTORS. THE EPIGENETIC CONTRIBUTIONS TO THE PROCESSES OF INFLAMMATION AND FIBROGENESIS INVOLVED IN DKD OCCUR AT DIFFERENT REGULATORY LEVELS, INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND NON-CODING RNA MODULATION. COMPARED WITH GENETIC FACTORS, EPIGENETICS REPRESENTS A NEW THERAPEUTIC FRONTIER IN UNDERSTANDING THE DEVELOPMENT DKD AND MAY LEAD TO THERAPEUTIC BREAKTHROUGHS DUE TO THE POSSIBILITY TO REVERSE THESE MODIFICATIONS THERAPEUTICALLY. EARLY RECOGNITION OF EPIGENETIC EVENTS AND BIOMARKERS IS CRUCIAL FOR TIMELY DIAGNOSIS AND INTERVENTION OF DKD, AND FOR THE PREVENTION OF THE PROGRESSION OF DKD TO ESRD. HEREIN, WE WILL REVIEW THE LATEST EPIGENETIC MECHANISMS INVOLVED IN THE RENAL PATHOLOGY OF BOTH TYPE 1 (T1DN) AND TYPE 2 DIABETIC NEPHROPATHY (T2DN) AND HIGHLIGHT THE EMERGING ROLE AND POSSIBLE THERAPEUTIC STRATEGIES BASED ON THE UNDERSTANDING OF THE ROLE OF EPIGENETICS IN DKD-ASSOCIATED INFLAMMATION AND FIBROGENESIS. 2021 20 5988 26 TGF-BETA/SMAD AND RENAL FIBROSIS. RENAL FIBROSIS IS CHARACTERIZED BY EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX (ECM) THAT DISRUPTS AND REPLACES FUNCTIONAL PARENCHYMA, WHICH LEADS TO ORGAN FAILURE. IT IS KNOWN AS THE MAJOR PATHOLOGICAL MECHANISM OF CHRONIC KIDNEY DISEASE (CKD). ALTHOUGH CKD HAS AN IMPACT ON NO LESS THAN 10% OF THE WORLD POPULATION, THERAPEUTIC OPTIONS ARE STILL LIMITED. REGARDLESS OF ETIOLOGY, ELEVATED TGF-BETA LEVELS ARE HIGHLY CORRELATED WITH THE ACTIVATED PRO-FIBROTIC PATHWAYS AND DISEASE PROGRESSION. TGF-BETA, THE KEY DRIVER OF RENAL FIBROSIS, IS INVOLVED IN A DYNAMIC PATHOPHYSIOLOGICAL PROCESS THAT LEADS TO CKD AND END-STAGE RENAL DISEASE (ESRD). IT IS BECOMING CLEAR THAT EPIGENETICS REGULATES RENAL PROGRAMMING, AND THEREFORE, THE DEVELOPMENT AND PROGRESSION OF RENAL DISEASE. INDEED, RECENT EVIDENCE SHOWS TGF-BETA1/SMAD SIGNALING REGULATES RENAL FIBROSIS VIA EPIGENETIC-CORRELATED MECHANISMS. THIS REVIEW FOCUSES ON THE FUNCTION OF TGF-BETA/SMADS IN RENAL FIBROGENESIS, AND THE ROLE OF EPIGENETICS AS A REGULATOR OF PRO-FIBROTIC GENE EXPRESSION. 2019