2017
Randomized, Controlled Trial of TRC101 to Increase Serum Bicarbonate in Patients with CKD
Bushinsky DA, Hostetter T, Klaerner G, Stasiv Y, Lockey C, McNulty S, Lee A, Parsell D, Mathur V, Li E, Buysse J, Alpern R. Randomized, Controlled Trial of TRC101 to Increase Serum Bicarbonate in Patients with CKD. Clinical Journal Of The American Society Of Nephrology 2017, 13: 26-35. PMID: 29102959, PMCID: PMC5753317, DOI: 10.2215/cjn.07300717.Peer-Reviewed Original ResearchConceptsSerum bicarbonateEnd of treatmentMetabolic acidosisTreatment groupsBaseline serum bicarbonateMean baseline eGFRMEq/LSignificant adverse effectsBaseline eGFRGastrointestinal eventsAdverse eventsFirst doseControlled TrialsHeart failurePatientsCKDBaseline levelsMean increaseAbstractTextUnit studiesAcidosisAdverse effectsPlaceboTreatmentDays
2013
Chapter 59 Clinical Syndromes of Metabolic Acidosis
Krapf R, Seldin D, Alpern R. Chapter 59 Clinical Syndromes of Metabolic Acidosis. 2013, 2049-2111. DOI: 10.1016/b978-0-12-381462-3.00059-8.Peer-Reviewed Original ResearchMetabolic acidosisDivalent ion metabolismMaladaptive renal responseUrine anion gapAcute metabolic acidosisNegative nitrogen balanceAcid-base disturbancesBlood buffer capacitySecondary hypocapniaClinical sequelaeRenal responseChronic settingClinical syndromeVentilatory responseBone metabolismBone massAnion gapPrimary decreaseSevere formDiagnostic criteriaBone qualitySecondary decreaseAcidosisElectrolyte changesClinical setting
2004
An autocrine role for endothelin-1 in the regulation of proximal tubule NHE3
Licht C, Laghmani K, Yanagisawa M, Preisig PA, Alpern RJ. An autocrine role for endothelin-1 in the regulation of proximal tubule NHE3. Kidney International 2004, 65: 1320-1326. PMID: 15086471, DOI: 10.1111/j.1523-1755.2004.00506.x.Peer-Reviewed Original ResearchConceptsChronic metabolic acidosisMetabolic acidosisReverse transcription-polymerase chain reactionProximal tubulesKidney cortexCompetitive reverse transcription-polymerase chain reactionProximal tubule NHE3NHE3 activityPreproET-1 expressionEndothelin B receptorEndothelin-1 expressionET-1 expressionPreproET-1 mRNA abundancePreproET-1 mRNA expressionTranscription-polymerase chain reactionProximal tubule cellsRenal proximal tubulesMRNA abundanceEndothelin-1Control ratsAbdominal aortaAutocrine roleAcidosisTubule cellsAutocrine regulation
2002
Role of c-SRC and ERK in acid-induced activation of NHE3
Tsuganezawa H, Sato S, Yamaji Y, Preisig PA, Moe OW, Alpern RJ. Role of c-SRC and ERK in acid-induced activation of NHE3. Kidney International 2002, 62: 41-50. PMID: 12081562, DOI: 10.1046/j.1523-1755.2002.00418.x.Peer-Reviewed Original ResearchMeSH KeywordsAcidosisAmmonium ChlorideAnimalsCells, CulturedCSK Tyrosine-Protein KinaseEnzyme ActivationJNK Mitogen-Activated Protein KinasesMaleMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Mitogen-Activated Protein KinasesPhosphorylationProtein Serine-Threonine KinasesProtein-Tyrosine KinasesProto-Oncogene Proteins c-fosRatsRats, Sprague-DawleySodium-Hydrogen Exchanger 3Sodium-Hydrogen ExchangersSrc-Family KinasesConceptsOKP cellsAcid-induced activationNHE3 activityERK/c-fosC-fos expressionC-Fos activationCytoplasmic pH (pHi) recoveryC-SrcRenal proximal tubulesAcid incubationActivation of NHE3Renal epithelial cellsCultured renal epithelial cellsProximal tubulesChronic acidosisInhibition of MEKNHE3 activationInhibited activationNormal levelsAcid loadImmune complex kinase assayERK kinaseAcidosisPH recoveryEpithelial cellsThe role of endothelin in proximal tubule proton secretion and the adaptation to a chronic metabolic acidosis.
Laghmani K, Preisig PA, Alpern RJ. The role of endothelin in proximal tubule proton secretion and the adaptation to a chronic metabolic acidosis. Journal Of Nephrology 2002, 15 Suppl 5: s75-87. PMID: 12027224.Peer-Reviewed Original ResearchConceptsProximal tubulesMetabolic acidosisEndothelin-1NHE3 activityRole of endothelinImmediate early gene c-fosEndothelin B receptorEarly gene c-fosChronic metabolic acidosisGene c-fosKidney functionActivation of Pyk2Endothelin effectsApical membrane NHE3NHE3 abundanceB receptorEndothelinApical membraneAcidosisSecretionEffector agentsC-fosTubulesProton secretionC-Jun
2000
Chronic metabolic acidosis increases NaDC-1 mRNA and protein abundance in rat kidney
Aruga S, Wehrli S, Kaissling B, Moe O, Preisig P, Pajor A, Alpern R. Chronic metabolic acidosis increases NaDC-1 mRNA and protein abundance in rat kidney. Kidney International 2000, 58: 206-215. PMID: 10886565, DOI: 10.1046/j.1523-1755.2000.00155.x.Peer-Reviewed Original ResearchMeSH KeywordsAcidosisAcidsAcute DiseaseAlkaliesAmmonium ChlorideAnimalsCarrier ProteinsChronic DiseaseCitratesDicarboxylic Acid TransportersGene ExpressionKidney CortexKidney Tubules, ProximalMaleMembrane ProteinsOrganic Anion Transporters, Sodium-DependentRatsRats, Sprague-DawleyRNA, MessengerSodium BicarbonateSymporters
1998
Converting enzyme inhibition causes hypocitraturia independent of acidosis or hypokalemia
Melnick J, Preisig P, Haynes S, Pak C, Sakhaee K, Alpern R. Converting enzyme inhibition causes hypocitraturia independent of acidosis or hypokalemia. Kidney International 1998, 54: 1670-1674. PMID: 9844143, DOI: 10.1046/j.1523-1755.1998.00150.x.Peer-Reviewed Original ResearchConceptsUrinary citrate excretionCitrate excretionUrinary citrateMetabolic acidosisATP-citrate lyaseEffects of enalaprilRenal citrate metabolismUrine citrate concentrationRenal cortical tissueChronic metabolic acidosisProximal tubular cellsPlasma pHNa/H antiporterAngiotensin IIIntracellular acidosisEnalaprilTubular cellsCitrate lyaseHypokalemiaEnzyme inhibitorsATP citrate lyase activityAcidosisCortical tissueRatsCitrate metabolismDominant negative c-Src inhibits angiotensin II induced activation of NHE3 in OKP cells
Tsuganezawa H, Preisig P, Alpern R. Dominant negative c-Src inhibits angiotensin II induced activation of NHE3 in OKP cells. Kidney International 1998, 54: 394-398. PMID: 9690205, DOI: 10.1046/j.1523-1755.1998.00029.x.Peer-Reviewed Original ResearchConceptsNa/H antiporter activityAngiotensin IIOKP cellsInhibits angiotensin IIVascular smooth muscleTyrosine kinase inhibitorsC-SrcHerbimycin AAntiporter activityNa/H antiporterActivation of NHE3Smooth muscleProximal tubulesPotent stimulatorNHE3 activationRegulation of NHE3Key mediatorKinase inhibitorsClonal cell linesNHE3 activityAntiporter activationCyclic AMPCell linesNHE3AcidosisRenal cortical mitochondrial aconitase is regulated in hypo- and hypercitraturia
Melnick J, Preisig P, Moe O, Srere P, Alpern R. Renal cortical mitochondrial aconitase is regulated in hypo- and hypercitraturia. Kidney International 1998, 54: 160-165. PMID: 9648074, DOI: 10.1046/j.1523-1755.1998.00974.x.Peer-Reviewed Original Research
1997
Media acidification inhibits TGF beta-mediated growth suppression in cultured rabbit proximal tubule cells.
Tovbin D, Franch HA, Alpern RJ, Preisig PA. Media acidification inhibits TGF beta-mediated growth suppression in cultured rabbit proximal tubule cells. Proceedings Of The Association Of American Physicians 1997, 109: 572-9. PMID: 9394419.Peer-Reviewed Original ResearchConceptsDirect antiproliferative effectRabbit proximal tubule cellsProximal tubule cellsAntiproliferative effectsGrowth-suppressive effectsMetabolic acidosisCultured rabbit proximal tubule cellsTubule cellsChronic metabolic acidosisInhibits cell cycle progressionRenal functionRenal growthMitogen-stimulated cellsRenal epithelial cellsProgressive lossHyperplasiaHypertrophyCell cycle progressionEpithelial cellsPrimary culturesPRB phosphorylationAcidosisEGF-induced phosphorylationGrowth suppressionCycle progressionAdaptation to low-K+ media increases H(+)-K(+)-ATPase but not H(+)-ATPase-mediated pHi recovery in OMCD1 cells
Guntupalli J, Onuigbo M, Wall S, Alpern RJ, DuBose TD. Adaptation to low-K+ media increases H(+)-K(+)-ATPase but not H(+)-ATPase-mediated pHi recovery in OMCD1 cells. American Journal Of Physiology 1997, 273: c558-c571. PMID: 9277353, DOI: 10.1152/ajpcell.1997.273.2.c558.Peer-Reviewed Original ResearchThe clinical spectrum of chronic metabolic acidosis: Homeostatic mechanisms produce significant morbidity
Alpern R, Sakhaee K. The clinical spectrum of chronic metabolic acidosis: Homeostatic mechanisms produce significant morbidity. American Journal Of Kidney Diseases 1997, 29: 291-302. PMID: 9016905, DOI: 10.1016/s0272-6386(97)90045-7.Peer-Reviewed Original ResearchConceptsChronic metabolic acidosisMetabolic acidosisHomeostatic responseSerum HCO3Acid loadBody's homeostatic responseHomeostatic mechanismsMuscle protein breakdownNormal homeostatic mechanismsSignificant morbidityClinical spectrumMeat ingestionBone demineralizationRenal growthClinical conditionsPathologic processesPathologic consequencesAcidosisProtein breakdownBloodResponseMorbidityPatientsNephrolithiasisIngestion
1996
Adenosine triphosphate citrate lyase mediates hypocitraturia in rats.
Melnick JZ, Srere PA, Elshourbagy NA, Moe OW, Preisig PA, Alpern RJ. Adenosine triphosphate citrate lyase mediates hypocitraturia in rats. Journal Of Clinical Investigation 1996, 98: 2381-2387. PMID: 8941657, PMCID: PMC507690, DOI: 10.1172/jci119051.Peer-Reviewed Original ResearchConceptsChronic metabolic acidosisMetabolic acidosisATP citrate lyase activityATP-citrate lyaseCitrate lyase activityCitrate lyaseHypocitraturiaAcid dietAcidosisCitrate metabolismProtein abundanceRatsMRNA abundanceLyase activityMetabolismPresent studySignificant changesCitrate uptakeInhibitionHypercitraturiaHypokalemiaCytosolic enzymeCompetitive inhibitorActivityImportant roleChronic metabolic acidosis increases NHE3 protein abundance in rat kidney
Ambuhl P, Amemiya M, Danczkay M, Lotscher M, Kaissling B, Moe OW, Preisig PA, Alpern RJ. Chronic metabolic acidosis increases NHE3 protein abundance in rat kidney. American Journal Of Physiology 1996, 271: f917-f925. PMID: 8898023, DOI: 10.1152/ajprenal.1996.271.4.f917.Peer-Reviewed Original ResearchConceptsNHE3 protein abundanceChronic metabolic acidosisNHE3 mRNA abundanceMetabolic acidosisThick ascending limbProximal tubulesAscending limbNa/H antiporter activityAcidosis-induced increaseMRNA abundanceNa/H antiporterNHE3 abundanceProtein abundanceAcidosisRat kidneyWestern blotS2 segmentsH antiporterRatsNHE3 isoformPresent studyLimbTubules
1991
Chronic adaptations in proximal tubular H/HCO3 transporters.
Alpern RJ, Horie S, Moe O, Tejedor A, Miller RT, Preisig PA. Chronic adaptations in proximal tubular H/HCO3 transporters. Kidney International Supplement 1991, 33: s29-32. PMID: 1653870.Peer-Reviewed Original ResearchConceptsCultured proximal tubule cellsChronic hyperfiltrationNa/H antiporterProximal tubule cellsChronic acidosisTubule cellsNa/H antiporter activityH antiporterK deficiencyEffect of acidosisExtracellular fluid pHChronic adaptationsAcidosisHyperfiltrationCotransporter activityAbundance of mRNAParallel increaseHCO3- transportersAcid preincubationDeficiencyFluid pHCellsAntiporter activityProtein synthesisExtracellular signals
1990
Preincubation in acid medium increases Na/H antiporter activity in cultured renal proximal tubule cells.
Horie S, Moe O, Tejedor A, Alpern RJ. Preincubation in acid medium increases Na/H antiporter activity in cultured renal proximal tubule cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 1990, 87: 4742-4745. PMID: 2162055, PMCID: PMC54193, DOI: 10.1073/pnas.87.12.4742.Peer-Reviewed Original ResearchConceptsNa/H antiporter activityProximal tubule cellsTubule cellsCultured renal proximal tubule cellsCultured proximal tubule cellsRenal proximal tubule cellsPreincubation of fibroblastsExtracellular fluidAntiporter activityChronic acidosisAcidotic environmentCO2/HCO3Small inhibitionPreincubationPreincubation mediumAddition of cycloheximideCell acidificationAcid preincubationPresent studyProtein synthesisCellsAcidosisActivityEpithelium
1989
Basolateral membrane H-OH-HCO3 transport in the proximal tubule
Preisig P, Alpern R. Basolateral membrane H-OH-HCO3 transport in the proximal tubule. American Journal Of Physiology 1989, 256: f751-f765. PMID: 2541627, DOI: 10.1152/ajprenal.1989.256.5.f751.Peer-Reviewed Original ResearchConceptsProximal tubulesS3 proximal tubuleChronic respiratory acidosisChronic metabolic acidosisRabbit proximal tubuleChronic hyperfiltrationMetabolic acidosisNa-H antiporterRespiratory acidosisCl-HCO3 exchangerCl absorptionGreater transport capacityAlkalosisAcidosisTubulesTransporter activityMembrane mechanismsBasolateral membraneCotransporterHyperfiltrationRatsEpithelium
1988
Chronic metabolic acidosis causes an adaptation in the apical membrane Na/H antiporter and basolateral membrane Na(HCO3)3 symporter in the rat proximal convoluted tubule.
Preisig PA, Alpern RJ. Chronic metabolic acidosis causes an adaptation in the apical membrane Na/H antiporter and basolateral membrane Na(HCO3)3 symporter in the rat proximal convoluted tubule. Journal Of Clinical Investigation 1988, 82: 1445-1453. PMID: 2844858, PMCID: PMC442703, DOI: 10.1172/jci113750.Peer-Reviewed Original ResearchConceptsChronic metabolic acidosisNa/H antiporterMetabolic acidosisAcidotic animalsH antiporterVivo microperfused rat proximal tubuleDpHi/dtRat proximal tubuleBasolateral membraneTransporter activityDietary acidPeritubular capillariesProximal tubulesNa/HPH-sensitive fluorescent dyeAcidosisTubulesSubsequent studiesAnimalsCarboxy-fluoresceinAbsence of contactCells
1984
Increased Vmax for Na+/H+ antiporter activity in proximal tubule brush border vesicles from rabbits with metabolic acidosis
Tsai CJ, Ives HE, Alpern RJ, Yee VJ, Warnock DG, Rector FC. Increased Vmax for Na+/H+ antiporter activity in proximal tubule brush border vesicles from rabbits with metabolic acidosis. American Journal Of Physiology 1984, 247: f339-f343. PMID: 6087681, DOI: 10.1152/ajprenal.1984.247.2.f339.Peer-Reviewed Original Research