1 933 212 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 2 3095 46 GENOMIC APPROACHES IN THE SEARCH FOR MOLECULAR BIOMARKERS IN CHRONIC KIDNEY DISEASE. BACKGROUND: CHRONIC KIDNEY DISEASE (CKD) IS RECOGNISED AS A GLOBAL PUBLIC HEALTH PROBLEM, MORE PREVALENT IN OLDER PERSONS AND ASSOCIATED WITH MULTIPLE CO-MORBIDITIES. DIABETES MELLITUS AND HYPERTENSION ARE COMMON AETIOLOGIES FOR CKD, BUT IGA GLOMERULONEPHRITIS, MEMBRANOUS GLOMERULONEPHRITIS, LUPUS NEPHRITIS AND AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE ARE ALSO COMMON CAUSES OF CKD. MAIN BODY: CONVENTIONAL BIOMARKERS FOR CKD INVOLVING THE USE OF ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) DERIVED FROM FOUR VARIABLES (SERUM CREATININE, AGE, GENDER AND ETHNICITY) ARE RECOMMENDED BY CLINICAL GUIDELINES FOR THE EVALUATION, CLASSIFICATION, AND STRATIFICATION OF CKD. HOWEVER, THESE CLINICAL BIOMARKERS PRESENT SOME LIMITATIONS, ESPECIALLY FOR EARLY STAGES OF CKD, ELDERLY INDIVIDUALS, EXTREME BODY MASS INDEX VALUES (SERUM CREATININE), OR ARE INFLUENCED BY INFLAMMATION, STEROID TREATMENT AND THYROID DYSFUNCTION (SERUM CYSTATIN C). THERE IS THEREFORE A NEED TO IDENTIFY ADDITIONAL NON-INVASIVE BIOMARKERS THAT ARE USEFUL IN CLINICAL PRACTICE TO HELP IMPROVE CKD DIAGNOSIS, INFORM PROGNOSIS AND GUIDE THERAPEUTIC MANAGEMENT. CONCLUSION: CKD IS A MULTIFACTORIAL DISEASE WITH ASSOCIATED GENETIC AND ENVIRONMENTAL RISK FACTORS. HENCE, MANY STUDIES HAVE EMPLOYED GENETIC, EPIGENETIC AND TRANSCRIPTOMIC APPROACHES TO IDENTIFY BIOMARKERS FOR KIDNEY DISEASE. IN THIS REVIEW, WE HAVE SUMMARISED THE MOST IMPORTANT STUDIES IN HUMANS INVESTIGATING GENOMIC BIOMARKERS FOR CKD IN THE LAST DECADE. SEVERAL GENES, INCLUDING UMOD, SHROOM3 AND ELMO1 HAVE BEEN STRONGLY ASSOCIATED WITH RENAL DISEASES, AND SOME OF THEIR TRAITS, SUCH AS EGFR AND SERUM CREATININE. THE ROLE OF EPIGENETIC AND TRANSCRIPTOMIC BIOMARKERS IN CKD AND RELATED DISEASES IS STILL UNCLEAR. THE COMBINATION OF MULTIPLE BIOMARKERS INTO CLASSIFIERS, INCLUDING GENOMIC, AND/OR EPIGENOMIC, MAY GIVE A MORE COMPLETE PICTURE OF KIDNEY DISEASES. 2018 3 3884 97 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 1388 34 DIABETIC PATIENTS WITH CHRONIC KIDNEY DISEASE: NON-INVASIVE ASSESSMENT OF CARDIOVASCULAR RISK. THE PREVALENCE AND BURDEN OF DIABETES MELLITUS AND CHRONIC KIDNEY DISEASE ON GLOBAL HEALTH AND SOCIOECONOMIC DEVELOPMENT IS ALREADY HEAVY AND STILL RISING. DIABETES MELLITUS BY ITSELF IS LINKED TO ADVERSE CARDIOVASCULAR EVENTS, AND THE PRESENCE OF CONCOMITANT CHRONIC KIDNEY DISEASE FURTHER AMPLIFIES CARDIOVASCULAR RISK. THE CULMINATION OF TRADITIONAL (MALE GENDER, SMOKING, ADVANCED AGE, OBESITY, ARTERIAL HYPERTENSION AND DYSLIPIDEMIA) AND NON-TRADITIONAL RISK FACTORS (ANEMIA, INFLAMMATION, PROTEINURIA, VOLUME OVERLOAD, MINERAL METABOLISM ABNORMALITIES, OXIDATIVE STRESS, ETC.) CONTRIBUTES TO ADVANCED ATHEROSCLEROSIS AND INCREASED CARDIOVASCULAR RISK. TO DECREASE THE MORBIDITY AND MORTALITY OF THESE PATIENTS DUE TO CARDIOVASCULAR CAUSES, TIMELY AND EFFICIENT CARDIOVASCULAR RISK ASSESSMENT IS OF HUGE IMPORTANCE. CARDIOVASCULAR RISK ASSESSMENT CAN BE BASED ON LABORATORY PARAMETERS, IMAGING TECHNIQUES, ARTERIAL STIFFNESS PARAMETERS, ANKLE-BRACHIAL INDEX AND 24 H BLOOD PRESSURE MEASUREMENTS. NEWER METHODS INCLUDE EPIGENETIC MARKERS, SOLUBLE ADHESION MOLECULES, CYTOKINES AND MARKERS OF OXIDATIVE STRESS. IN THIS REVIEW, THE AUTHORS PRESENT SEVERAL NON-INVASIVE METHODS OF CARDIOVASCULAR RISK ASSESSMENT IN PATIENTS WITH DIABETES MELLITUS AND CHRONIC KIDNEY DISEASE. 2021 5 5204 31 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 1883 46 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 7 6652 39 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 8 307 54 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 9 3502 55 IDENTIFICATION OF POTENTIAL BIOMARKERS OF CHRONIC KIDNEY DISEASE IN INDIVIDUALS WITH DIABETES: PROTOCOL FOR A CROSS-SECTIONAL OBSERVATIONAL STUDY. BACKGROUND: THE IMPORTANCE OF IDENTIFYING PEOPLE WITH DIABETES AND PROGRESSIVE KIDNEY DYSFUNCTION RELATES TO THE EXCESS MORBIDITY AND MORTALITY OF THIS GROUP. RATES OF CARDIOVASCULAR DISEASE ARE MUCH HIGHER IN PEOPLE WITH BOTH DIABETES AND KIDNEY DYSFUNCTION THAN IN THOSE WITH ONLY ONE OF THESE CONDITIONS. BY THE TIME THESE PEOPLE ARE IDENTIFIED IN CURRENT CLINICAL PRACTICE, PROTEINURIA AND RENAL DYSFUNCTION ARE ALREADY ESTABLISHED, LIMITING THE EFFECTIVENESS OF THERAPEUTIC INTERVENTIONS. THE IDENTIFICATION OF AN EPIGENETIC OR BLOOD METABOLITE SIGNATURE OR GUT MICROBIOME PROFILE MAY IDENTIFY THOSE WITH DIABETES AT RISK OF PROGRESSIVE CHRONIC KIDNEY DISEASE, IN TURN PROVIDING TARGETED INTERVENTION TO IMPROVE PATIENT OUTCOMES. OBJECTIVE: THIS STUDY AIMS TO IDENTIFY POTENTIAL BIOMARKERS IN PEOPLE WITH DIABETES AND CHRONIC KIDNEY DISEASE (CKD) ASSOCIATED WITH PROGRESSIVE RENAL INJURY AND TO DISTINGUISH BETWEEN STAGES OF CHRONIC KIDNEY DISEASE. THREE SOURCES OF BIOMARKERS WILL BE EXPLORED, INCLUDING DNA METHYLATION PROFILES IN BLOOD LYMPHOCYTES, THE METABOLOMIC PROFILE OF BLOOD-DERIVED PLASMA AND URINE, AND THE GUT MICROBIOME. METHODS: THE CROSS-SECTIONAL STUDY RECRUITED 121 PEOPLE WITH DIABETES AND VARYING STAGES (STAGES 1-5) OF CHRONIC KIDNEY DISEASE. SINGLE-POINT DATA COLLECTION INCLUDED BLOOD, URINE, AND FECAL SAMPLES IN ADDITION TO CLINICAL DATA SUCH AS ANTHROPOMETRIC MEASUREMENTS AND BIOCHEMICAL PARAMETERS. ADDITIONAL INFORMATION OBTAINED FROM MEDICAL RECORDS INCLUDED PATIENT DEMOGRAPHICS, MEDICAL COMORBIDITIES, AND MEDICATIONS. RESULTS: DATA COLLECTION COMMENCED IN JANUARY 2018 AND WAS COMPLETED IN JUNE 2018. AT THE TIME OF SUBMISSION, 121 PATIENTS HAD BEEN RECRUITED, AND 119 SAMPLES REMAINED AFTER QUALITY CONTROL. THERE WERE 83 PARTICIPANTS IN THE EARLY DIABETES-ASSOCIATED CKD GROUP WITH A MEAN ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) OF 61.2 ML/MIN/1.73 M2 (EARLY CKD GROUP CONSISTING OF STAGE 1, 2, AND 3A CKD), AND 36 PARTICIPANTS IN THE LATE DIABETIC CKD GROUP WITH A MEAN EGFR OF 23.9 ML/MIN/1.73 M2 (LATE CKD GROUP, CONSISTING OF STAGE 3B, 4, AND 5), P<.001. WE HAVE SUCCESSFULLY OBTAINED DNA FOR METHYLATION AND MICROBIOME ANALYSES USING THE BIOSPECIMENS COLLECTED VIA THIS PROTOCOL AND ARE CURRENTLY ANALYZING THESE RESULTS TOGETHER WITH THE METABOLOME OF THIS COHORT OF INDIVIDUALS WITH DIABETIC CKD. CONCLUSIONS: RECENT ADVANCES HAVE IMPROVED OUR UNDERSTANDING OF THE EPIGENOME, METABOLOMICS, AND THE INFLUENCE OF THE GUT MICROBIOME ON THE INCIDENCE OF DISEASES SUCH AS CANCERS, PARTICULARLY THOSE RELATED TO ENVIRONMENTAL EXPOSURES. HOWEVER, THERE IS A PAUCITY OF LITERATURE SURROUNDING THESE INFLUENCERS IN RENAL DISEASE. THIS STUDY WILL PROVIDE INSIGHT INTO THE FUNDAMENTAL UNDERSTANDING OF THE PATHOPHYSIOLOGY OF CKD IN INDIVIDUALS WITH DIABETES, ESPECIALLY IN NOVEL AREAS SUCH AS EPIGENETICS, METABOLOMICS, AND THE KIDNEY-GUT AXIS. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/16277. 2020 10 5846 36 STUDY PROTOCOL: RATIONALE AND DESIGN OF THE COMMUNITY-BASED PROSPECTIVE COHORT STUDY OF KIDNEY FUNCTION AND DIABETES IN RURAL NEW MEXICO, THE COMPASS STUDY. BACKGROUND: RURAL AREAS IN THE STATE OF NEW MEXICO HAVE BEEN THE "GROUND-ZERO" FOR THE EPIDEMIC OF DIABETIC CHRONIC KIDNEY DISEASE (CKD) IN THE UNITED STATES. HOWEVER, THERE IS LIMITED RESEARCH ABOUT RISK FACTORS OF DIABETIC CKD IN THIS AREA AND SCARCE DATA REGARDING THE PERFORMANCE OF EMERGING MARKERS OF RENAL FILTRATION AND EPIGENETIC BIOMARKERS OF RENAL FUNCTION AND DIABETES IN THIS AREA WITH ITS UNIQUE ETHNIC/RACIAL POPULATION. WE DESIGNED THE COMPASS STUDY AS A COMMUNITY-BASED PROGRAM IN RURAL NEW MEXICO AIMING TO SCREEN FOR CKD AND TO DISCOVER CKD-RELATED TRANSLATIONAL BIOMARKERS. METHODS/DESIGN: THE STUDY INVOLVES A PROSPECTIVE, LONGITUDINAL COHORT DESIGN INVOLVING INDIVIDUALS LIVING IN RURAL NEW MEXICO. PARTICIPANTS UNDERGO A SCREENING FOR KIDNEY DISEASE USING MARKERS OF ABNORMAL RENAL FILTRATION (IMPAIRED GLOMERULAR FILTRATION RATE) OR DAMAGE (ALBUMINURIA). THOSE FOUND TO HAVE CKD ON THE BASIS OF THESE TESTS OR THOSE AT RISK FOR CKD ARE ENROLLED IN A PROSPECTIVE LONGITUDINAL COHORT. WE MEASURE MARKERS OF RENAL FUNCTION, INSULIN RESISTANCE AND EPIGENETICS (MICRORNAS) ON PATIENTS. INDIVIDUALS ARE INVITED TO PARTICIPATE IN INTERVIEWS AND FOCUS GROUPS IN ORDER TO CHARACTERIZE THEIR ATTITUDES TOWARDS RESEARCH AND BARRIERS OR FACILITATORS TO PARTICIPATION IN FUTURE RESEARCH STUDIES ABOUT KIDNEY DISEASE. DISCUSSION: THIS STUDY WILL PROVIDE IMPORTANT DATA ABOUT THE LOCAL EPIDEMIOLOGY OF KIDNEY DISEASE IN A HIGH-RISK RURAL SETTING AND THE UTILITY OF EMERGING RENAL FILTRATION MARKERS (BETA 2 MICROGLOBULIN AND CYSTATIN C), WHILE GENERATING DATA AND METHODS FOR THE ANALYSES OF MICRORNA BIOMARKERS. THE QUALITATIVE RESEARCH SUBPROJECT WILL IDENTIFY FACTORS ASSOCIATED WITH INCREASED WILLINGNESS TO PARTICIPATE IN FUTURE TRANSLATIONAL RESEARCH PROJECTS. WITH ITS GEOGRAPHICAL FOCUS, THIS STUDY WILL ADDRESS A CRITICAL DISPARITY IN KIDNEY DISEASE RESEARCH, WHILE GENERATING NOVEL EPIGENETIC DATA THAT ARE RELEVANT FOR FUTURE STUDIES IN THE GENERAL POPULATION. 2018 11 2982 34 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 12 2955 39 GENETIC AND EPIGENETIC FACTORS INFLUENCING CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) HAS BECOME A SERIOUS PUBLIC HEALTH PROBLEM BECAUSE OF ITS ASSOCIATED MORBIDITY, PREMATURE MORTALITY, AND ATTENDANT HEALTHCARE COSTS. THE RISING NUMBER OF PERSONS WITH CKD IS LINKED WITH THE AGING POPULATION STRUCTURE AND AN INCREASED PREVALENCE OF DIABETES, HYPERTENSION, AND OBESITY. THERE IS AN INHERITED RISK ASSOCIATED WITH DEVELOPING CKD, AS EVIDENCED BY FAMILIAL CLUSTERING AND DIFFERING PREVALENCE RATES ACROSS ETHNIC GROUPS. PREVIOUS STUDIES TO DETERMINE THE INHERITED RISK FACTORS FOR CKD RARELY IDENTIFIED GENETIC VARIANTS THAT WERE ROBUSTLY REPLICATED. HOWEVER, IMPROVEMENTS IN GENOTYPING TECHNOLOGIES AND ANALYTIC METHODS ARE NOW HELPING TO IDENTIFY PROMISING GENETIC LOCI AIDED BY INTERNATIONAL COLLABORATION AND MULTICONSORTIA EFFORTS. MORE RECENTLY, EPIGENETIC MODIFICATIONS HAVE BEEN PROPOSED TO PLAY A ROLE IN BOTH THE INHERITED SUSCEPTIBILITY TO CKD AND, IMPORTANTLY, TO EXPLAIN HOW THE ENVIRONMENT DYNAMICALLY INTERACTS WITH THE GENOME TO ALTER AN INDIVIDUAL'S DISEASE RISK. GENOME-WIDE, EPIGENOME-WIDE, AND WHOLE TRANSCRIPTOME STUDIES HAVE BEEN PERFORMED, AND OPTIMAL APPROACHES FOR INTEGRATIVE ANALYSIS ARE BEING DEVELOPED. THIS REVIEW SUMMARIZES RECENT RESEARCH AND THE CURRENT STATUS OF GENETIC AND EPIGENETIC RISK FACTORS INFLUENCING CKD USING POPULATION-BASED INFORMATION. 2014 13 6446 46 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 14 932 47 CHRONIC KIDNEY DISEASE WITH UNKNOWN CAUSE ACROSS THE GLOBAL SPECTRUM. PURPOSE OF REVIEW: IN THE 1990S, A TYPE OF CHRONIC KIDNEY DISEASE WITH UNKNOWN CAUSE (CKDU) WAS IDENTIFIED IN CENTRAL AMERICA AND SRI LANKA. PATIENTS LACKED HYPERTENSION, DIABETES, GLOMERULONEPHRITIS, OR OTHER USUAL CAUSES OF KIDNEY FAILURE. AFFECTED PATIENTS ARE PREDOMINANTLY MALE AGRICULTURAL WORKERS AGED 20-60 YEARS, LIVING IN ECONOMICALLY DISADVANTAGED AREAS WITH POOR ACCESS TO MEDICAL CARE. PATIENTS TYPICALLY PRESENT LATE AND PROGRESS TO END-STAGE KIDNEY DISEASE WITHIN 5 YEARS, RESULTING IN SOCIAL AND ECONOMIC HARDSHIP FOR FAMILIES, REGIONS, AND COUNTRIES. THIS REVIEW COVERS THE CURRENT STATE OF KNOWLEDGE FOR THIS DISEASE. RECENT FINDINGS: THE PREVALENCE OF CKDU IS INCREASING IN KNOWN ENDEMIC REGIONS AND ACROSS THE GLOBE, REACHING EPIDEMIC PROPORTIONS. THERE IS PRIMARY TUBULOINTERSTITIAL INJURY WITH SECONDARY GLOMERULAR AND VASCULAR SCLEROSIS. NO DEFINITIVE ETIOLOGIC FACTORS HAVE BEEN IDENTIFIED, AND THESE MAY VARY OR OVERLAP IN DIFFERENT GEOGRAPHIC LOCATIONS. THE LEADING HYPOTHESES INCLUDE EXPOSURE TO AGROCHEMICALS, HEAVY METALS AND TRACE ELEMENTS, AND KIDNEY INJURY FROM DEHYDRATION/HEAT STRESS. INFECTIONS AND LIFESTYLE FACTORS MAY PLAY A ROLE, BUT ARE LIKELY NOT KEY. GENETIC AND EPIGENETIC FACTORS ARE BEGINNING TO BE EXPLORED. SUMMARY: CKDU IS A LEADING CAUSE OF PREMATURE DEATH IN YOUNG-TO-MIDDLE-AGED ADULTS IN ENDEMIC REGIONS AND HAS BECOME A PUBLIC HEALTH CRISIS. STUDIES ARE UNDERWAY TO INVESTIGATE CLINICAL, EXPOSOME, AND OMICS FACTORS, AND HOPEFULLY WILL PROVIDE INSIGHTS INTO PATHOGENETIC MECHANISMS RESULTING IN BIOMARKER DISCOVERY, PREVENTIVE MEASURES, AND THERAPEUTICS. 2023 15 3140 46 GLOBAL EPIGENETIC SCREENING TECHNOLOGIES: A NOVEL TOOL TO ADDRESS CANCER HEALTH DISPARITIES IN HIGH-RISK POPULATION GROUPS. RACIAL, ETHNIC AND CLASS DISPARITIES IN CANCER INCIDENCE AND MORTALITY HAVE BEEN WELL DOCUMENTED. DISPARITIES IN THE UTILIZATION OF PREVENTIVE, CURATIVE AND TREATMENT SERVICES AMONG ETHNIC MINORITIES HAVE BEEN REPORTED. SCREENING CAN BE EFFECTIVE AT DETECTING CANCER AT TREATABLE STAGES, BUT A LARGE PROPORTION OF PEOPLE AT RISK HAVE NOT BEEN SCREENED OR ARE NOT REGULARLY SCREENED, AS RECOMMENDED BY THE AMERICAN CANCER SOCIETY'S NATIONAL GUIDELINES. EARLY DETECTION TECHNOLOGIES HAVE THE POTENTIAL OF BOTH INFLUENCING MORTALITY FROM CANCER, AS WELL AS ENHANCING PRIMARY PREVENTION THROUGH DETECTION AND REMOVAL OF LESIONS THAT COULD POTENTIALLY DEVELOP INTO CANCER. CANCER IS AN EPIGENETIC DISEASE CHARACTERIZED BY THE BREAKDOWN OF DNA METHYLATION AND HISTONES MODIFICATION PATTERNS. EPIGENETIC APPROACHES MAY CONTRIBUTE TO A REDUCTION IN CANCER HEALTH DISPARITIES IMPACTING EARLY DETECTION AND INCREASING CANCER TREATMENT OPTIONS. EPIGENETIC EVENTS REPRESENT IMPORTANT MECHANISM(S) BY WHICH GENE FUNCTION IS SELECTIVELY ACTIVATED OR INACTIVATED, THROUGH GENETIC AND NON-GENETIC MANIFESTATIONS. EMERGING EVIDENCE INDICATES THAT VARIOUS EPIGENETIC ALTERATIONS, SUCH AS GLOBAL HISTONES MODIFICATIONS AND DNA HYPOMETHYLATION, COMMON TO MOST TYPES OF CANCER, ARE MODIFIED BY ENVIRONMENTAL EXPOSURES THROUGHOUT THE LIFE COURSE. A SIMPLE, EASILY EXPLAINED AND EASY TO UNDERSTAND NON-INVASIVE TEST, SUCH AS THE DNA METHYLATION INDEX, THAT MAY SCREEN FOR SEVERAL CANCER SITES AT ONCE, MAY REMOVE SOME OF THE EXISTING BARRIERS TO CANCER SCREENING UTILIZATION, AND CONTRIBUTE TO THE REDUCTION OF CANCER DISPARITIES. EPIGENETIC APPROACHES MAY ALSO PROVE TO BE USEFUL IN IDENTIFYING ENVIRONMENTAL AND LIFESTYLE FACTORS THAT CONTRIBUTE TO THE PREVALENCE OF OTHER CHRONIC CONDITIONS IN HIGH RISK POPULATIONS, SUCH AS PUERTO RICAN POPULATIONS IN THE UNITED STATES AND PUERTO RICO. 2008 16 1170 50 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 17 931 32 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 18 5439 43 RENAL CONSEQUENCES OF PRETERM BIRTH. BACKGROUND: THE DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASE CONCEPT IDENTIFIES THE BRAIN, CARDIOVASCULAR, LIVER, AND KIDNEY SYSTEMS AS TARGETS OF FETAL ADVERSE PROGRAMMING WITH ADULT CONSEQUENCES. AS THE LIMITS OF VIABILITY IN PREMATURE INFANTS HAVE BEEN PUSHED TO LOWER GESTATIONAL AGES, THE LONG-TERM IMPACT OF PREMATURITY ON KIDNEYS STILL REMAINS A SIGNIFICANT BURDEN DURING HOSPITAL STAY AND BEYOND. OBJECTIVES: THE PURPOSE OF THIS STUDY IS TO SUMMARIZE AVAILABLE EVIDENCE, MECHANISMS, AND SHORT- AND LONG-TERM RENAL CONSEQUENCES OF PREMATURITY AND IDENTIFY NEPHROPROTECTIVE STRATEGIES AND AREAS OF UNCERTAINTY. RESULTS: KIDNEY SIZE AND NEPHRON NUMBER ARE KNOWN TO BE REDUCED IN SURVIVING PREMATURE INFANTS DUE TO DISRUPTION OF ORGANOGENESIS AT A CRUCIAL DEVELOPMENTAL TIME POINT. INFLAMMATION, HYPEROXIA, AND ANTIANGIOGENIC FACTORS PLAY A ROLE IN EPIGENETIC CONDITIONING WITH POTENTIAL LIFE-LONG CONSEQUENCES. ADDITIONAL KIDNEY INJURY FROM HYPOPERFUSION AND NEPHROTOXICITY RESULTS IN STRUCTURAL AND FUNCTIONAL CHANGES OVER TIME WHICH ARE OFTEN UNNOTICED. NEPHROPATHY OF PREMATURITY AND ACUTE KIDNEY INJURY CONFOUND GLOMERULAR AND TUBULAR MATURATION OF PRETERM KIDNEYS. KIDNEY PROTECTIVE STRATEGIES MAY AMELIORATE GROWTH FAILURE AND SUBOPTIMAL NEURODEVELOPMENTAL OUTCOMES IN THE SHORT TERM. IN LATER LIFE, SUBCLINICAL CHRONIC RENAL DISEASE MAY PROGRESS, EVEN IN ASYMPTOMATIC SURVIVORS. CONCLUSION: AWARENESS OF RENAL IMPLICATIONS OF THERAPEUTIC INTERVENTIONS AND RENAL CONSERVATION EFFORTS MAY LEAD TO A VARIETY OF SHORT AND LONG-TERM BENEFITS. ADEQUATE MONITORING AND SUPPLEMENTATION OF MICROELEMENT LOSSES, GATHERING IMPROVED DATA ON RENAL HANDLING, AND EXPLORATION OF NEW AVENUES SUCH AS RELIABLE MARKERS OF INJURY AND NEW THERAPEUTIC STRATEGIES IN CONTEMPORARY POPULATIONS, AS WELL AS LONG-TERM FOLLOW-UP OF RENAL FUNCTION, IS WARRANTED. 2017 19 5183 44 PREMATURE AGING IN CHILDHOOD CANCER SURVIVORS. PROGRESS IN MEDICINE HAS INCREASED THE SURVIVAL TIME OF CHILDREN SUFFERING FROM CANCER; >80% OF PATIENTS SURVIVE FOR AT LEAST 5 YEARS FROM THE END OF TREATMENT. HOWEVER, THERE ARE LATE EFFECTS OF ANTICANCER THERAPY, WHICH ACCOMPANY THIS SUCCESS. TWO-THIRDS OF CHILDHOOD CANCER SURVIVORS (CCSS) HAVE AT LEAST ONE LATE EFFECT (ANY SIDE EFFECTS OR COMPLICATIONS OF ANTICANCER TREATMENT THAT APPEAR MONTHS TO YEARS AFTER THE COMPLETION OF TREATMENT), E.G. ENDOCRINOPATHIES, CARDIOVASCULAR DISEASES OR SUBSEQUENT CANCERS, AND HALF OF THESE LATE EFFECTS ARE SERIOUS OR LIFE THREATENING. THESE LATE CONSEQUENCES OF CHILDHOOD CANCER TREATMENT POSE A SERIOUS HEALTH, SOCIAL AND ECONOMIC PROBLEM. A COMMON MECHANISM FOR DEVELOPING A NUMBER OF LATE EFFECTS IS THE ONSET OF PREMATURE BIOLOGICAL AGING, WHICH IS ASSOCIATED WITH THE EARLY ONSET OF CHRONIC DISEASES AND DEATH. CELLULAR SENESCENCE IN CANCER SURVIVORS IS CAUSED BY THERAPY THAT CAN INDUCE CHROMOSOMAL ABERRATIONS, MUTATIONS, TELOMERE SHORTENING, EPIGENETIC ALTERATIONS AND MITOCHONDRIAL DYSFUNCTIONS. THE MECHANISMS OF ACCELERATED AGING IN CANCER SURVIVORS HAVE NOT YET BEEN FULLY CLARIFIED. THE MEASUREMENT OF BIOLOGICAL AGE IN SURVIVORS CAN HELP IMPROVE THE UNDERSTANDING OF AGING MECHANISMS AND IDENTIFY RISK FACTORS FOR PREMATURE AGING. HOWEVER, TO THE BEST OF OUR KNOWLEDGE, NO SINGLE MARKER FOR THE EVALUATION OF BIOLOGICAL OR FUNCTIONAL AGE IS KNOWN, SO IT IS THEREFORE NECESSARY TO MEASURE THE CONSEQUENCES OF ANTICANCER TREATMENT USING COMPLEX ASSESSMENTS. THE PRESENT REVIEW PRESENTS AN OVERVIEW OF PREMATURE AGING IN CCSS AND OF THE MECHANISMS INVOLVED IN ITS DEVELOPMENT, FOCUSING ON THE ASSOCIATION OF SENESCENCE AND LATE EFFECTS. 2023 20 3676 42 INFLAMMATION AND NEUTROPHIL IMMUNOSENESCENCE IN HEALTH AND DISEASE: TARGETED TREATMENTS TO IMPROVE CLINICAL OUTCOMES IN THE ELDERLY. DESPITE INCREASING LONGEVITY, MANY OLD PEOPLE ARE NOT IN GOOD HEALTH. THERE HAS BEEN AN INCREASE IN THE PREVALENCE OF AGE-ASSOCIATED MULTI-MORBIDITY (TWO OR MORE CHRONIC CONDITIONS IN THE SAME PERSON). ALSO, SEVERE INFECTIONS, SUCH AS PNEUMONIA, REMAIN SIGNIFICANT CAUSES OF MORTALITY AND MORBIDITY IN THIS AGING GROUP. MANY CHRONIC HEALTH CONDITIONS SHARE RISK FACTORS SUCH AS INCREASING AGE, SMOKING, A SEDENTARY LIFE STYLE AND BEING PART OF A LOWER SOCIOECONOMIC GROUP. HOWEVER, DESPITE THIS, MULTI-MORBIDITIES OFTEN CO-OCCUR MORE COMMONLY THAN WOULD BE PREDICTED. THIS HAS LED TO THE HYPOTHESIS THAT THEY SHARE COMMON UNDERLYING MECHANISMS. THIS IS AN IMPORTANT CONCEPT, FOR IF IT WERE TRUE, TREATMENTS COULD BE DEVISED WHICH TARGET THESE COMMON PATHWAYS AND IMPROVE A NUMBER OF AGE-ASSOCIATED HEALTH CONDITIONS. MANY CHRONIC ILLNESSES ASSOCIATED WITH MULTI-MORBIDITY AND SEVERE INFECTIONS ARE CHARACTERIZED BY AN ABNORMAL AND SUSTAINED INFLAMMATORY RESPONSE, WITH NEUTROPHILS BEING KEY EFFECTOR CELLS IN THE PATHOLOGICAL PROCESS. STUDIES HAVE DESCRIBED ABERRANT NEUTROPHIL FUNCTIONS ACROSS THESE CONDITIONS, AND SOME HAVE HIGHLIGHTED POTENTIAL MECHANISMS FOR ALTERED CELL BEHAVIOURS WHICH APPEAR SHARED ACROSS DISEASE STATES. IT HAS BEEN SUGGESTED THAT ALTERED FUNCTIONS MAY REPRESENT NEUTROPHIL "SENESCENCE". THIS REVIEW CONSIDERS HOW AND WHY NEUTROPHIL FUNCTIONS CHANGE AS THE CELL AGES, AND HOW AND WHY NEUTROPHIL FUNCTIONS CHANGE AS THE HOST AGES IN HEALTH AND DISEASE AND DISCUSSES WHETHER NEUTROPHIL FUNCTIONS COULD BE TARGETED TO IMPROVE HEALTH OUTCOMES IN OLDER ADULTS. 2018