2025
Adding insult to injury: the spectrum of tubulointerstitial responses in acute kidney injury
Baker M, Cantley L. Adding insult to injury: the spectrum of tubulointerstitial responses in acute kidney injury. Journal Of Clinical Investigation 2025, 135: e188358. PMID: 40091836, PMCID: PMC11910233, DOI: 10.1172/jci188358.Peer-Reviewed Original ResearchConceptsAcute kidney injuryTubular epithelial cellsKidney injuryTubular cellsCases of acute kidney injuryImmune-mediated processPersistence of inflammationBiphasic immune responseChronic kidney diseaseCell deathTubular cell injuryLymphocyte subsetsTubular repairCell cycle arrestOutflow obstructionTEC differentiationPreclinical findingsLymphocytic infiltrationProinflammatory macrophagesKidney diseaseModulate inflammationImmune responseActivated macrophagesMetabolic reprogrammingTubular casts
2024
Plasma proteomics of acute tubular injury
Schmidt I, Surapaneni A, Zhao R, Upadhyay D, Yeo W, Schlosser P, Huynh C, Srivastava A, Palsson R, Kim T, Stillman I, Barwinska D, Barasch J, Eadon M, El-Achkar T, Henderson J, Moledina D, Rosas S, Claudel S, Verma A, Wen Y, Lindenmayer M, Huber T, Parikh S, Shapiro J, Rovin B, Stanaway I, Sathe N, Bhatraju P, Coresh J, Rhee E, Grams M, Waikar S. Plasma proteomics of acute tubular injury. Nature Communications 2024, 15: 7368. PMID: 39191768, PMCID: PMC11349760, DOI: 10.1038/s41467-024-51304-x.Peer-Reviewed Original ResearchConceptsAcute tubular injuryAcute kidney injuryPathway analysisOrganelle stress responsesSingle-cell RNA sequencingKidney Precision Medicine ProjectKidney diseaseSOMAscan proteomics platformProgression to kidney failureRNA sequencingBiological pathwaysGene expressionStress responseNon-invasive biomarkersProteomics platformMannose receptor 1Kidney injuryTubular injuryImmune regulationReceptor 1Macrophage mannose receptor 1Host responseBiomarker proteinsPrecision Medicine ProjectKidney failure
2023
Urinary Biomarkers of Kidney Tubule Health and Mortality in Persons with CKD and Diabetes Mellitus
Vasquez-Rios G, Katz R, Levitan E, Cushman M, Parikh C, Kimmel P, Bonventre J, Waikar S, Schrauben S, Greenberg J, Sarnak M, Ix J, Shlipak M, Gutierrez O. Urinary Biomarkers of Kidney Tubule Health and Mortality in Persons with CKD and Diabetes Mellitus. Kidney360 2023, 4: e1257-e1264. PMID: 37533144, PMCID: PMC10547219, DOI: 10.34067/kid.0000000000000226.Peer-Reviewed Original ResearchConceptsKidney injury molecule-1Monocyte chemoattractant protein-1Kidney tubule healthCause-specific mortalityUrine biomarkersYKL-40Risk factorsCardiovascular deathCause mortalityHigh riskChitinase-3-like protein 1Greater riskHigher MCP-1Higher urine levelsUrine KIM-1Injury molecule-1Cause-specific deathMortality risk factorsProportional hazards regressionRisk of deathAdditional risk factorsProtein 1Cancer-related deathChemoattractant protein-1Alpha-1-microglobulinAssociations of Biomarkers of Kidney Tubule Health, Injury, and Inflammation with Left Ventricular Hypertrophy in Children with CKD
Jiang K, Greenberg J, Abraham A, Xu Y, Schelling J, Feldman H, Schrauben S, Waikar S, Shlipak M, Wettersten N, Coca S, Vasan R, Gutierrez O, Ix J, Warady B, Kimmel P, Bonventre J, Parikh C, Mitsnefes M, Denburg M, Furth S, Ramachandran V, Schelling J, Denburg M, Furth S, Warady B, Bonventre J, Waikar S, Sabbisetti V, Coresh J, Grams M, Rebholz C, Abraham A, Parikh C, Coca S, Rhee E, Kimmel P, Kusek J, Rovin B, Shlipak M, Sarnak M, Gutiérrez O, Ix J, Dubin R, Hostetter T, Deo R, Feldman H, Xie D, Shou H, Ballard S, Whitehead K, Collins H, Greenberg J, Ganz P. Associations of Biomarkers of Kidney Tubule Health, Injury, and Inflammation with Left Ventricular Hypertrophy in Children with CKD. Kidney360 2023, 4: 1039-1047. PMID: 37303083, PMCID: PMC10476681, DOI: 10.34067/kid.0000000000000183.Peer-Reviewed Original ResearchMeSH KeywordsBiomarkersChildHumansHypertrophy, Left VentricularInflammationKidney TubulesRenal Insufficiency, ChronicConceptsKidney injury molecule-1Left ventricular hypertrophyUrine KIM-1Injury molecule-1Chemoattractant protein-1Ventricular hypertrophyAlpha-1-microglobulinHigher plasmaLVH prevalenceHigh prevalenceMolecule-1Urine kidney injury molecule-1Urine monocyte chemoattractant protein-1Soluble urokinase-type plasminogen activator receptorTumor necrosis factor receptor 2Monocyte chemoattractant protein-1Kidney tubule healthNecrosis factor receptor 2Pathophysiology of LVHUrine MCP-1Multivariable-adjusted modelsMCP-1 concentrationsBody mass indexProtein 1Child Cohort StudyAssociation of Kidney Tubule Biomarkers With Cardiac Structure and Function in the Multiethnic Study of Atherosclerosis
Wettersten N, Katz R, Greenberg J, Gutierrez O, Lima J, Sarnak M, Schrauben S, Deo R, Bonventre J, Vasan R, Kimmel P, Shlipak M, Ix J. Association of Kidney Tubule Biomarkers With Cardiac Structure and Function in the Multiethnic Study of Atherosclerosis. The American Journal Of Cardiology 2023, 196: 11-18. PMID: 37086700, PMCID: PMC10204591, DOI: 10.1016/j.amjcard.2023.02.031.Peer-Reviewed Original ResearchConceptsPlasma soluble urokinase plasminogen activator receptorSoluble urokinase plasminogen activator receptorKidney tubule injuryCardiac structural abnormalitiesUrokinase plasminogen activator receptorCardiovascular diseasePlasminogen activator receptorLower LVEFTubule injurySystemic inflammationVentricular mass/volume ratioStructural abnormalitiesChitinase-3-like protein 1Activator receptorTwofold greater concentrationCardiac magnetic resonance imagingKidney tubule healthChronic kidney diseaseIncident cardiovascular diseaseGlomerular filtration rateVentricular ejection fractionProtein 1Chemoattractant protein-1Multi-Ethnic StudyAlpha-1-microglobulin
2022
Immune-mediated tubule atrophy promotes acute kidney injury to chronic kidney disease transition
Xu L, Guo J, Moledina DG, Cantley LG. Immune-mediated tubule atrophy promotes acute kidney injury to chronic kidney disease transition. Nature Communications 2022, 13: 4892. PMID: 35986026, PMCID: PMC9391331, DOI: 10.1038/s41467-022-32634-0.Peer-Reviewed Original ResearchMeSH KeywordsAcute Kidney InjuryAnimalsAtrophyKidneyKidney TubulesMiceRenal Insufficiency, ChronicReperfusion InjuryConceptsAcute kidney injuryKidney injuryT cellsChronic kidney disease transitionIschemia-reperfusion kidney injuryKidney disease transitionChronic kidney diseaseDepletion of neutrophilsGlomerular filtration rateT cell recruitmentTubular cell lossMacrophage persistenceProinflammatory neutrophilsTubule damageKidney atrophyContralateral kidneyNeutrophil numbersContralateral nephrectomyKidney diseaseTubule atrophyFiltration rateCell recruitmentMore macrophagesDay 14Day 5Characterization of temporospatial distribution of renal tubular casts by nephron tracking after ischemia-reperfusion injury
Shin NS, Marlier A, Xu L, Lam T, Cantley LG, Guo JK. Characterization of temporospatial distribution of renal tubular casts by nephron tracking after ischemia-reperfusion injury. American Journal Of Physiology. Renal Physiology 2022, 322: f322-f334. PMID: 35100823, PMCID: PMC8897010, DOI: 10.1152/ajprenal.00284.2021.Peer-Reviewed Original ResearchConceptsIschemia-reperfusion injuryCast formationGlomerular filtration rateTubular cast formationUrine 24 hDetached epithelial cellsDead cell debrisRenal recoveryRenal functionFiltration rateS3 tubulesTubular castsTubular cellsTubular nucleiKidney sectionsOuter medullaTrypsin levelsEntire nephronRenal tubular castsFuture interventionsInjurySelective lossTubule segmentsEpithelial cellsKidney
2021
Urine Biomarkers of Kidney Tubule Health, Injury, and Inflammation are Associated with Progression of CKD in Children
Greenberg JH, Abraham AG, Xu Y, Schelling JR, Feldman HI, Sabbisetti VS, Ix JH, Jogalekar MP, Coca S, Waikar SS, Shlipak MG, Warady BA, Vasan RS, Kimmel PL, Bonventre JV, Denburg M, Parikh CR, Furth S, Consortium O. Urine Biomarkers of Kidney Tubule Health, Injury, and Inflammation are Associated with Progression of CKD in Children. Journal Of The American Society Of Nephrology 2021, 32: 2664-2677. PMID: 34544821, PMCID: PMC8722795, DOI: 10.1681/asn.2021010094.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAlbuminuriaAlpha-GlobulinsBiomarkersChemokine CCL2ChildChitinase-3-Like Protein 1CreatinineDisease ProgressionEpidermal Growth FactorFemaleFollow-Up StudiesGlomerular Filtration RateHepatitis A Virus Cellular Receptor 1HumansKidney TubulesMaleNephritisProspective StudiesRenal Insufficiency, ChronicConceptsUrine KIM-1CKD progressionUrine biomarkersMicroglobulin concentrationsHighest quartileKIM-1MCP-1High riskRapid kidney function declineBiomarker concentrationsEGF concentrationsKidney tubule healthNovel urine biomarkersUrine biomarker concentrationsKidney function declineProgression of CKDUrine creatinine concentrationIdentification of childrenTubular healthMultivariable adjustmentComposite outcomeTubular injuryPrimary outcomeFunction declineStudy enrollmentA polycystin-2 protein with modified channel properties leads to an increased diameter of renal tubules and to renal cysts
Grosch M, Brunner K, Ilyaskin AV, Schober M, Staudner T, Schmied D, Stumpp T, Schmidt KN, Madej MG, Pessoa TD, Othmen H, Kubitza M, Osten L, de Vries U, Mair MM, Somlo S, Moser M, Kunzelmann K, Ziegler C, Haerteis S, Korbmacher C, Witzgall R. A polycystin-2 protein with modified channel properties leads to an increased diameter of renal tubules and to renal cysts. Journal Of Cell Science 2021, 134: jcs259013. PMID: 34345895, PMCID: PMC8435292, DOI: 10.1242/jcs.259013.Peer-Reviewed Original ResearchLoss of endothelial glucocorticoid receptor accelerates diabetic nephropathy
Srivastava SP, Zhou H, Setia O, Liu B, Kanasaki K, Koya D, Dardik A, Fernandez-Hernando C, Goodwin J. Loss of endothelial glucocorticoid receptor accelerates diabetic nephropathy. Nature Communications 2021, 12: 2368. PMID: 33888696, PMCID: PMC8062600, DOI: 10.1038/s41467-021-22617-y.Peer-Reviewed Original ResearchMeSH KeywordsAdrenalectomyAnimalsDiabetes Mellitus, ExperimentalDiabetic NephropathiesEndothelial CellsEndotheliumEpithelial-Mesenchymal TransitionFatty AcidsFibrosisGlucocorticoidsHumansHypercholesterolemiaInterleukin-6Kidney TubulesMaleMiceMice, Knockout, ApoEOxidation-ReductionReceptors, GlucocorticoidStreptozocinWnt Signaling PathwayConceptsEndothelial glucocorticoid receptorGlucocorticoid receptorEndothelial cell homeostasisDiabetic miceRenal fibrosisEndothelial cellsMesenchymal transitionSevere renal fibrosisTubular epithelial cellsCell homeostasisFatty acid oxidationDiabetic controlDiabetic nephropathyAntifibrotic moleculesIL-6Kidney fibrosisMesenchymal activationRegulation of diseaseOrgan fibrosisAberrant cytokineFibrogenic phenotypeFibrosisMiceEpithelial cellsDefective regulation
2020
Pathophysiology of Diuretic Resistance and Its Implications for the Management of Chronic Heart Failure
Wilcox CS, Testani JM, Pitt B. Pathophysiology of Diuretic Resistance and Its Implications for the Management of Chronic Heart Failure. Hypertension 2020, 76: 1045-1054. PMID: 32829662, PMCID: PMC10683075, DOI: 10.1161/hypertensionaha.120.15205.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsChronic heart failureDiuretic resistanceHeart failureHigh daily salt intakeDiuretic-resistant patientsSequential nephron blockadeDaily salt intakeHypochloremic metabolic alkalosisLoop of HenleMultiple diureticsRenal nervesReflex activationLoop diureticsSalt intakeRecurrent hospitalizationsVolume overloadPathophysiological mechanismsSingle doseSodium outputMetabolic alkalosisPharmacokinetic mechanismsDistal tubulesDiureticsProximal tubulesRenal tubulesSignaling through tumor necrosis receptor 2 induces stem cell marker in CD133+ regenerating tubular epithelial cells in acute cell-mediated rejection of human renal allografts
Bradley JR, Wang J, Bardsley V, Broecker V, Thiru S, Pober JS, Al-Lamki R. Signaling through tumor necrosis receptor 2 induces stem cell marker in CD133+ regenerating tubular epithelial cells in acute cell-mediated rejection of human renal allografts. American Journal Of Transplantation 2020, 20: 2380-2391. PMID: 32167668, DOI: 10.1111/ajt.15846.Peer-Reviewed Original ResearchMeSH KeywordsAllograftsEpithelial CellsGraft RejectionHumansKidneyKidney TransplantationKidney TubulesNecrosisNeoplasmsStem Cells
2019
Tubular GM-CSF Promotes Late MCP-1/CCR2-Mediated Fibrosis and Inflammation after Ischemia/Reperfusion Injury
Xu L, Sharkey D, Cantley LG. Tubular GM-CSF Promotes Late MCP-1/CCR2-Mediated Fibrosis and Inflammation after Ischemia/Reperfusion Injury. Journal Of The American Society Of Nephrology 2019, 30: 1825-1840. PMID: 31315923, PMCID: PMC6779361, DOI: 10.1681/asn.2019010068.Peer-Reviewed Original ResearchConceptsIschemia/reperfusion injuryWild-type miceTubular cellsTubular injuryReperfusion injuryImmune cellsKidney ischemia/reperfusion injuryUnilateral ischemia/reperfusion injuryMCP-1/CCR2Monocyte chemoattractant protein-1Initial kidney damageInjured tubular cellsKidney 14 daysKidney injury markersProgressive interstitial fibrosisProfibrotic growth factorsChemoattractant protein-1MCP-1 receptorGranulocyte-macrophage colony-stimulating factorRenal tubular cellsNumber of macrophagesTime of repairColony-stimulating factorCoculture of macrophagesMacrophages persistEndocrine regulation of MFS2 by branchless controls phosphate excretion and stone formation in Drosophila renal tubules
Rose E, Lee D, Xiao E, Zhao W, Wee M, Cohen J, Bergwitz C. Endocrine regulation of MFS2 by branchless controls phosphate excretion and stone formation in Drosophila renal tubules. Scientific Reports 2019, 9: 8798. PMID: 31217461, PMCID: PMC6584732, DOI: 10.1038/s41598-019-45269-x.Peer-Reviewed Original ResearchConceptsDrosophila renal tubulesFly life spanGenetic ablationRNAi-mediated knockdownInorganic phosphate (Pi) homeostasisHigh-Pi mediumPi transportersAdult fliesControl of FGF signalingHigher speciesPi mediumInduces expressionMFS2FGF signalingExcretion of PiPhosphate homeostasisDrosophilaFly longevityEndocrine regulationHormone fibroblast growth factor 23Renal tubulesHormonal controlPi transportFibroblast growth factor 23Genetic overexpressionDifferentiating Acute Interstitial Nephritis from Acute Tubular Injury: A Challenge for Clinicians
Moledina DG, Parikh CR. Differentiating Acute Interstitial Nephritis from Acute Tubular Injury: A Challenge for Clinicians. Nephron 2019, 143: 211-216. PMID: 31203275, PMCID: PMC6821567, DOI: 10.1159/000501207.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsAcute interstitial nephritisAcute tubular injuryAcute kidney injuryUrine TNFTubular injuryInterstitial nephritisClinical featuresHistological diagnosisInterleukin-9Novel biomarkersClinical practiceChronic kidney diseaseProspective cohort studyHigh-risk populationDisease-specific therapiesCourse of careImmunosuppressive therapyKidney injuryCohort studyKidney biopsyKidney diseasePlasma levelsKidney fibrosisInter-rater variabilityLaboratory assessment
2018
Mcp1 Promotes Macrophage-Dependent Cyst Expansion in Autosomal Dominant Polycystic Kidney Disease
Cassini MF, Kakade VR, Kurtz E, Sulkowski P, Glazer P, Torres R, Somlo S, Cantley LG. Mcp1 Promotes Macrophage-Dependent Cyst Expansion in Autosomal Dominant Polycystic Kidney Disease. Journal Of The American Society Of Nephrology 2018, 29: 2471-2481. PMID: 30209078, PMCID: PMC6171277, DOI: 10.1681/asn.2018050518.Peer-Reviewed Original ResearchConceptsAutosomal dominant polycystic kidney diseaseSingle knockout miceTubular cell injuryDominant polycystic kidney diseaseCyst growthPolycystic kidney diseaseKidney diseaseCell injuryMonocyte chemoattractant protein-1Alternative activation phenotypeChemoattractant protein-1Double knockout miceOrthologous mouse modelCell proliferative rateRenal functionMacrophage accumulationMacrophage infiltrationReceptor CCR2Cystic dilationMacrophage numbersFunctional improvementOxidative DNA damageMouse modelActivation phenotypeCyst expansionBurosumab Therapy in Children with X-Linked Hypophosphatemia
Carpenter TO, Whyte MP, Imel EA, Boot AM, Högler W, Linglart A, Padidela R, Van't Hoff W, Mao M, Chen CY, Skrinar A, Kakkis E, San Martin J, Portale AA. Burosumab Therapy in Children with X-Linked Hypophosphatemia. New England Journal Of Medicine 2018, 378: 1987-1998. PMID: 29791829, DOI: 10.1056/nejmoa1714641.Peer-Reviewed Original ResearchMeSH KeywordsAlkaline PhosphataseAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedChildChild, PreschoolFamilial Hypophosphatemic RicketsFemaleFibroblast Growth Factor-23Fibroblast Growth FactorsGenetic Diseases, X-LinkedGrowthHumansKidney TubulesKnee JointMalePain ManagementPhosphorusRadiographySeverity of Illness IndexConceptsSerum phosphorus levelsRenal tubular phosphate reabsorptionTubular phosphate reabsorptionWeek 40Week 64Adverse eventsPhosphate reabsorptionNormal rangeMean serum phosphorus levelFibroblast growth factor 23End pointMean serum alkaline phosphatase levelSerum alkaline phosphatase levelsTotal scorePrimary end pointPhase 2 trialGrowth factor 23Additional end pointsPatient-reported outcomesAlkaline phosphatase levelsRadiographic Global ImpressionPhosphorus levelsOverall mean increaseBurosumab therapySubcutaneous burosumabPhenotyping of Acute Kidney Injury: Beyond Serum Creatinine
Moledina DG, Parikh CR. Phenotyping of Acute Kidney Injury: Beyond Serum Creatinine. Seminars In Nephrology 2018, 38: 3-11. PMID: 29291759, PMCID: PMC5753429, DOI: 10.1016/j.semnephrol.2017.09.002.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMeSH KeywordsAcute Kidney InjuryBiomarkersCreatinineGlomerular Filtration RateHemodynamicsHumansKidney TubulesPhenotypePrognosisConceptsAcute kidney injuryKidney injuryAKI definitionSerum creatinineStructural kidney injuryGlomerular filtration rateLong-term outcomesAKI phenotypesCommon complicationHospitalized patientsFiltration rateDifferent therapiesConsensus definitionInjuryLack sensitivityMolecular pathwaysCreatinineDistinct phenotypesHeterogeneous conditionPhenotypeComplicationsPatientsPrognosisTherapyEtiologyPathologic Perspectives on Acute Tubular Injury Assessment in the Kidney Biopsy
Moeckel GW. Pathologic Perspectives on Acute Tubular Injury Assessment in the Kidney Biopsy. Seminars In Nephrology 2018, 38: 21-30. PMID: 29291758, DOI: 10.1016/j.semnephrol.2017.09.003.Peer-Reviewed Original ResearchMeSH KeywordsAcute Kidney InjuryApoptosisBiopsyEndoplasmic Reticulum StressHumansKidneyKidney TubulesOrganellesConceptsAcute tubular injuryKidney biopsy analysisRenal pathology laboratoryTissue injury markersClinical time courseCell injury pathwaysTime courseNephrologists' managementInjury markersTubular injuryTubular lesionsKidney biopsyPathophysiological mechanismsTreatment modalitiesPatient managementDrug choiceEtiologic mechanismsInjury pathwaysToxic injuryPathologic perspectiveToxic etiologyBiopsy samplesClinical practiceBiopsy analysisPathology practice
2017
Performance of Serum Creatinine and Kidney Injury Biomarkers for Diagnosing Histologic Acute Tubular Injury
Moledina DG, Hall IE, Thiessen-Philbrook H, Reese PP, Weng FL, Schröppel B, Doshi MD, Wilson FP, Coca SG, Parikh CR. Performance of Serum Creatinine and Kidney Injury Biomarkers for Diagnosing Histologic Acute Tubular Injury. American Journal Of Kidney Diseases 2017, 70: 807-816. PMID: 28844586, PMCID: PMC5701867, DOI: 10.1053/j.ajkd.2017.06.031.Peer-Reviewed Original ResearchMeSH KeywordsAcute Kidney InjuryAdultArea Under CurveBiomarkersCohort StudiesCreatinineCross-Sectional StudiesFatty Acid-Binding ProteinsFemaleHepatitis A Virus Cellular Receptor 1HumansInterleukin-18Kidney TransplantationKidney TubulesLipocalin-2MaleMiddle AgedProspective StudiesROC CurveSeverity of Illness IndexTissue DonorsConceptsSevere acute tubular injuryAcute kidney injuryAcute tubular injuryTubular injurySCr concentrationNGAL concentrationsUrinary biomarkersDeceased donorsOrgan procurementMulticenter prospective cohortUrinary L-FABPUrinary NGAL concentrationsDeceased kidney donorsKidney injury biomarkersSerum creatinine concentrationPoor diagnostic performanceAKI casesAKI causesDonor hospitalizationKidney injuryProspective cohortSerum creatinineInjury biomarkersKidney biopsyIL-18
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