The aging kidney

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NEPHROLOGY NEPHROLOGYFORUM FORUM

The Theaging The agingkidney kidney Principal Principaldiscussant: discussant:DIEGO DIEGORODRiGUEZPUYOL RODRiGUEZPUYOL University UniversityHospital Hospital "Prmncipe "PrIncipede de.-lsturias' Asturias"and andUniversity UniversityofofAlcalá, Alcald.Madrid, Madrü& Madrid,Spain Spain Spain

2+2+for forfor protein protein protein and and and contained contained contained SS red 5red red cells cells cells and and andsome some somegranular granularcasts/highcasts/high-

Editors Editors JORDAN JORDAN J. J. COHEN COHEN JOHN JOHNT.T.HARRINGTON HARRINGTON

Nicoios NlcoI.AosE.E.MADIAS MADIAS Editor Managing Editor Managing J. CHERYL CHERYL CHERYL J. J.ZUSM/d4 ZtJSMAN Univeiciry Tufts TuftsUniveiciry UniversitySchool SchoolofofMedicine Medicine

CASE CASEPRESENTATION PRESENTATION woman admitted toto the Patient 87-year-old 87-year-old woman was was admitted admitted to the the emergency emergencyroom room Patient 1.1. AnAn 87-year-old emergency room

ofofthe the theAIcalá Alcalá AIcaIá de dede Henares Henares Henares Hospital Hospital Hospital after after after aafall afall fall atathome. athome. home. She She She had had had aaa

power powerfield. field. Fractional Fractional excretion excretion ofof sodium sodium was was2.7%. 2.7%.No No Nocosinophils eosinophilswere were were detected detected detectedin inin the the theurine. urine. urine.An An Anultrasound ultrasound ultrasoundexamination examination examinationof ofof the the theabdomen abdomen abdomenfailed failed failedto toto reveal revealobstruction obstructionof ofof the the theurinary urinary urinary tract. tract. tract. Acute Acute Acute tubular tubular tubular necrosis necrosis necrosis was was was diagnosed diagnosed diagnosed and andprobably probably probably was was was due due due toto the the use use ofof aminoglycosides. aminoglycosides. aminoglycosides. She Sherequircd requiredsixsix hemodialysis hemodialysis hemodialysis sessions. sessions. sessions.Urine Urine Urineflow flow flow progressively progressively increased increasedand and andshe she shewas was wasdischargcd dischargcd dischargedwith with withaaserum aserum serumcreatinine creatinine creatinineof ofof 2.9 2.9mg/dL mg/dl.Subsequently Subsequently Subsequentlythe the theserum serum serumcrcatinine crcatinine crcatininefell fell fellto toto1.2 1.2 1.2mgId, mgId, mgldl, with with with aa creatinjne clearance ofof 4141mI/mm. mI/mm. creatinineclearance clearanceof mI/mm. Patient Patient2.2.An An 80-ycar-old 80-ycar-old 80-year-old woman woman woman was was was admitted admitted toto the theemergency emergency emergencyroom room room ofofthe Alcali de dede Henares Henares Hospital Hospital bccausc bccausc of ofasthenia asthenia and and muscle muscle theAlcali Alcalá Henares Hospital because of asthenia and muscle weakness. weakness. She had had hypertension for long blood weakness.She Shehad hadhad hadhypertension hypertensionfor foraa along longtime, time,but buther herblood blood pressure pressure pressurewas was waswell well wellcontrolled controlled controlledwith with withhydruhorothiazide, hydruchlorothiazide, amiloride, amiloride,and and captopril. captopril. capropril. The The The patient patient patient had had hadnonosigns signsof ofofrcna rcna renal disease, disease, disease, and and andin inin aa recent arecent recent examination, examination, examination, thc thc the serum serum serumcreatinine creatinine was was 1.3 1.3 1.3 mg/dI; mg/dI; mgldl; urea, urea, urea, 68 6868 mgldl; mg(dl; mgldl; sodium, sodium, 137 137mmollhtcr; mmollhtcr; mmollliter; and and potassium, potassium, potassium, 5.0 5.0 5.0 mmotlliter. mmotlliter. mmol/Iiter. with with a normal a normal urinalysis. urinalysis. Because Because Becauseof ofofgeneralized generalizedarticular articularpain, pain, a general a generalpractitioner practitioner practitioner prescribed prescribed prescribed tenoxicam, tenoxicam, a nonsterojdal a nonsteroidalantiinflammatory antiinflammatory antiinflammatory agent. agent. agent. 10 1010 days days days before before before admisadmisadmission. sion. Evaluation Evaluation Evaluation jtjt the at thethe emergency emergency emergency room room room showed showed showeda amildly mildly mildly obese obese obesewoman woman womanwho who who appeared appeared appearedill, ill,ill, with with with significant significant significant muscle muscle muscle weakness weakness weaknessand and andminimal minimal minimaldryness dryness drynessof ofof the the the mouth. mouth.The Theheniatocrit heniatocrit hematocritwas was was30.9%; 30.9%; 30.9%;hemoglobin, hemoglobin, hemoglobin,lO.2fdl; lO.2fdl; l0.2fdl;white whiteblood bloodcell cell urea urea was9292 and platelet count, 164,000/mm The Theurea was count, count,5900/mm3; 5900/mm3;and andplatelet plateletcount, count,164,000/mm 164,000/mm.. .The 8.5 mgldl; serum creatinine, creatinine, 2,5 2.5 mg/cu; mg/dI; sodium, sodium, 143 143 mmol/liter; mmol/liter; potassium, potassium, 8.5 8.5 mg/dl; serum creatinine, 2,5 mg/cu; sodium, 143 mmol/liter; potassium, mmollliter: chloride. 118 mmol/liter; arterial blood pH, 7.24;and andbicarbicarmmollliter: mmollliter: chloridc, chloridc, 118 118 mmol/Iiter; mmol/Iiter; arterial arterial blood blood pH, pH, 7.24; 7.24; bonate mmol/liter. The The urine was was normal. was was an anan ultrasound ultrasound bonate14.6 14.6mmol/liter. mmol/liter. Theurine urine wasnormal. normal,aaas was ultrasound e.aminatIon examination ofof thethe abdomen. abdomen. abdomen. An An An clectrocardiograni clectrocardiograni electrocardiogramrevealed revealed revealedwidening widening wideningof ofof the theQRS QRScomplex complex complexwith with peaked peaked peakedT-waves. T-waves. T-waves. Thc Thepatient's patient'sitlncss illnesswas wasattributed attributedtotothc thecombined combinedtreatment treatment treatmentwith with with nonsteroidal nonsteroidal nonsteroidalantiinflammatoiy antiinflammatoiy antiinflarnmatory drugs, drugs, angiotensin-Il angiotensin-Il converting-enzyme converting-enzyme convening-enzyme inhibitors, inhibitors, inhibitors, and and andamiloridc, amiloridc, amitoride, with with with the the the subsequent subsequent subsequent hyperkalemia. hyperkalemia. hyperkalemia. She She She was was treated treated with calcium, glucose, glucose, and cation-extreatedwith withintravenous intravenouscalcium, calcium, glucose,bicarbonate, bicarbonate,and andcation-excation-exchangt change resins. resins. resins. All AllAll drugs drugs drugs were were were stopped. stopped. 11cr 11cr hlord hlord blood pressure pressure pressure was was was controUed controUed controlled with with with calcium calcium calcium antagonists, antagonists, antagonists, and andthe thearticular articularpain painwas wastreated treated treatedwith with withacetacetaminophen. The potassium level decrcased quickly and the glomeraminophen. iheserum serumpotassium potassiululevel leveldecrcased decreasedquickly quicklyand andthe theglomerglomerular ularfiltration filtration filtration rate rate rate improvcd. improvcd. improved. She She She was was was dischargcd dischargcd discharged with with with aa scrum a serum creatinine creatinine ofof and 5.8 2 mg/dl 2mg/dl mgldl and and a potassium apotassium potassiumof ofof 5.8 5.8mmol/liter. mmol/litcr. One One One month month month later, later, later, the the theserum serum serum mmol/liter. creatinine creatinine was was 1.5Iimg/dl mgldland andpotassium potassium4.3 4.3mmot/Iitcr. mmot/Iitcr. mmol/litcr.

long-standing long-standinghistory historyofofhypertension, hypertension, hypertension,which which whichwas was waswell well wellcontrolled controlled controlledwith with with nifedipine nifedipine and and indapamide. indapamide. AAhysterectomy had had been been performed performed 30 3030 years years nifedipine and indapamide. Ahysterectomy hysterectomy had been performed years ago. ago.Evaluation Evaluationatatthe theemergency emergency emergencyroom room roomrevealed revealed revealedaaafemoral femoral femoralneck neck neckfracture, fracture, fracture, and andshe she shewas was wasprepared prepared preparedfor for foran an aninternal internal internalfixation fixation fixation under under under epidural epidural epidural ancsthesia. ancsthesia. ancsthesia. Pre-operatoiy Pre-operatoiyevaluation evaluationdisclosed disclosednonosignificant significant significant metabotic metabotic metabolic alterations, alterations, alterations, the theplasma plasma plasma creatinine creatinine creatinine concentration concentration concentration was was was 1.0 1.0 1.0 mgidl mg/dI mgidl with with with aanormal normal a normal urinalurinalurinalysis, ysis,and andnonosignificant significant significant cardiologic cardiologic cardiotogic problems problems problems were were were detected. detected. detected. 1'he The surgical surgical procedure proceduretook tookplacc placewithout without without complications, complications, complications, and and and the the the patient patient patient was was was treated treated treated with with with intravenous intravenous intravenous fluids, fluids, fluids, analgesics, analgesics, analgesics, gentamicin, gentamicin, gentamicin, and and and cefazolin cefazolin cefazolin at atat standard standard standard doses. doses. doses.Six Six Sixdays days daysafter after afterthe the thesurgical surgical surgical procedure, procedure, procedure, aaprogressive aprogressive progressive decrease decrease decrease ininin the ththe urine urine volume volume volume was was was detected, detected,and and andaa nephrology anephrology nephrologyconsultant consultant consultantwas was wascontacted. contacted. contacted. AA A careful careful careful analysis analysis analysis of ofof the thethe evolution evolution evolution of ofof the thethe patient's patient's patient's course coursewas was wasunable unable unableto toto deeci s*gnificant s*gnificant hemodynamic hemodynamic changes changes after after the the surgica' surgica' procedure, procedure, and and detect significant hemodynamic changes after the surgical procedure, and moderate moderatefever feverwas wasdetected detected detectedonly only onon days days2 2and and3.3.On Onphysical physical physical examinaexaminaexamination, tion, she she appeared well, without dyspnea, dyspnea, clirncal signs signs of ofof tion, sheappeared appearedwell, well,without without dyspnea,edcma, edema,ororclirncal clinical signs volume volumedepletion. depletion.AAgrade grade grade Il/VI Il/VI I1(V1systolic systolic systolicejecflon ejecflon ejectionmurmur murmur murmur as was as audible; audible;no no pericardial pericardialfriction friction friction rub rub rub was was was heard. heard. heard. The The The surgical surgical surgical area area areaappearcd appearcd appearedwell, well, well, DISCUSSiON without without without infection. infection. infection. Neurologic Neurologic Neurologic examination examination examination was was was negative; negative; negative;flapping flapping was wasnot not DISCUSSiON detected. detected. detected.The Thercst restofofthe thephysical physical examination examination examination was was was unremarkable. unremarkable. unremarkable. DIEGO RODR1GUEZ-PUYOL (Chief DR. DR.DIEGO DtEGO RODR1GUEZ-PUYOL RODR1GUEZ-PUYO!. (Chief (Chief Nephro1o Nephrolo Section, Section, Nephro1o Section, The was 28%; hemoglobin. .2 g/dl; g/dl; white blood blood cell count, count, Thehematocrit hematocritwas was28%; 28%;hemoglobin. hemoglobin,.2 9.2 g/dl; white bloodcell cell count, University Hospital "PrIncipe de Asturias, "Alcalá de Henares, University Hospital "PrIncipe de A.sturias, "A/ca/a de Henares, 10,900/mm3. 10,900/mm3.The Theurea ureawas was143 143 143mg/d; mg/d; mg/dl; creatinine, creatinine, 6363rng/dl; rng/dl; rng/dl; sodium, sodium, sodium, 130 130 130 mmol/iitcr mmol/iitcr mmol/liter potassium, potassium, potassium,4.3 4.3 4.3mmol/titer; mmol/titer; mmol/liter;chloride, chloride,107 107 107mmol/Iiter; mmol/Iiter; mrnol/liter;calcium, calcium, and andAssLstant Assistant Assi.ttantProfessor Professor Professorof ofofMedicine, Medicine, Medicine,University University Universityof ofofAlcald, Alcald, Alcald, 8.7 8.7ing/dI; ing/dI; phosphorus, phosphorus, phosphorus,5.4 5.4 5.4mgldl; mgldl; mgldl;albumin, albumin,2.3 2.3 2.3g/d!; g/d!; g/dl;glucose, glucose, glucose,lt)7 lt)7 lt)7mg/dI; mg/dI; mgfdl; Madrid, Madrid, Spain): Spain): These These patients patients iliustrate illustrate some some of of the the clinclinand arterial arterial blood blood pH, pH, 7.33; 7.33; and and bicarbonate, bicarbonate, bicarbonate. 19.2 19.2 19.2mmol/titer. mmol/titer. mmol/liter. The The The urine urine urine was was was blood pH, 7.33;

ical icalproblems problemsthat thatchallenge challengenephrologists nephro[ogistsattending attendingelderly elderly individuals individuals(defined (definedfor forthe thepurpose purposeofofthis thisForum Forumasasolder older purpose than first case, hip than7070years). years).InInthe thefirst firstcase, case,ananeldcriy elderlywoman womanwith withaa ahip hip Key Key words words renal renal parcnchyma. parcnchyma. reactive reactive oxygen oxygen intermediates, intermediates, advanced advanced Key words renal parenchyma, reactive oxygen intermediates, advanced fracture necessifracturedeveloped developedsevere, severe,acute acuterenal renal renalfailure failure failurethat that thatnecessinecessiacute glycosylation glycosylation glycosylation end end end products, products,tubular tubulardysfunction, dysfunction, lenin lenin lenin sytithesis. sytithesis. synthesis. tated tatedtemporary temporary temporaryhemodialysis. hemodialysis. hemodialysis.She She Shehad had hadbeen been beenwell well wellpreviously previously previously

Presentation Presentation ofofthis made possible by grants from Merck && Presentationof thisForum Forumisismade madepossible possibleby bygrants grantsfrom fromMerck Merck& andhad hadnonoevidence evidenceofofrenal renaldisease; disease;the thepharmacologic pharmacologic Company, Company,Incorporated; Incorporated;Astra AstraPharmaceuticals; Pharmaceuticals; Pharmaceuticals;Hoechst Hoechst HoechstMarion Marion MarionRousRousRous- and sd, Incorporated; Incorporated; Dialysis Dialysis Clinic, Clinic, incorporated; incorporated; and and RR & && DDLahorato,-ies, sel, Incorporated; Dialysis Clinic, Incorporated: and DLaboratories, Laboratories, treatment, treatment,including includingdosage, dosage,was wasapparentiy apparentlyappropriate; appropriate; Incorporated. Incorporated. and andnonomajor majorvolume volumedepletion depletionwas wasevident. evident.InInthis thissetting, setting, 1998 0 01998 1998by bythe theInternational InternationalSociety SocietyofofNcphrology Nephrology thecombination combinationofofdifferent differentnoxious noxiousstimuli, stimuli,including including the by

0

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Nephroiog Nephroiogr Forum: Forum: The The aging aging Aidney Aidney

aging phenotype phenotype in humans, in humans, is homologous is homologous to atofamily a family of of minimal minimal degrees degrees of renal of renal hypoperfusion hypoperfusion andand aminoglycoaminoglyco-aging DNA DNA helicases helicases of Escherichia of Escherichia coli coli [2). [2). Aging Aging thus thus mighi might be be sideside exposure exposure induced induced parenchymal parenchymal damage damage thitthat practically practically a cellular autonomous autonomous process. process. ButBut wewe must must remember remember abolished abolished thethe glomerular glomerular filtration filtration rate. rate. TheThe second second pa-pa-a cellular in addition to containing individual cells, organisms that, in addition to containing individual cells, organisms tient, a stable hypertensive woman receiving pharmacologic tient, a stable hypertensive woman receiving pharmacologicthat, exhibit exhibit a complex a complex system system of cell-to-cell of cell-to-cell re'ationships, relationships, treatment, entered thethe emergency room with severe hypertreatment, entered emergency room with severe hyper-alsoalso

derangements derangements in these in these relationships relationships alsoalso could could be be kalemia kalemia after after receiving receiving nonsteroidal nonsteroidal antiinflammatory antiinflammatoryandand in aging. involved in aging. drugs drugs because because of articular of articular pain. pain. HerHer plasma plasma creatinine creatinine 'evel levelinvolved Independently of these of these considerations, considerations, twotwo main main theories theories hadhad been been in the in the normal normal range, range, andand sheshe hadhad tolerated tolerated well well Independently have been proposed to explain aging. The first hypothesis. have been proposed to explain aging. The first hypothesis. therapy therapy with with hydrochlorothiazide, hydrochlorothiazide, amiloride, amiloride, andand captopril. captopril.

environmental environmental one, one, suggests suggests thatthat aging aging is the is the conseconseSheShe hadhad a normal blood pressure andand no no electrolyte a normal blood pressure electrolytean an of the repetitive action of exogenous factors in ain a quence of the repetitive action of exogenous factors disturbances. By By blocking prostaglandin synthesis, the the nondisturbances. blocking prostaglandin synthesis, non-quence organism, resulting in an damage thatthat normal organism, resulting in accumulated an accumulated damage steroidal steroidal antiinflanimatory antiinflammatory drug drug blunted blunted thethe critical critical equiequi-normal outstrips thethe normal normal repair repair processes. processes. TheThe second, second, or or libnum librium in the in the rcnin-angiotensin-aldosterone rcnin-angiotensin-aldosterone rcnin-angiotensin-aldosterone system system system of of the the of theoutstrips theory genetic, genetic, theoiy theory proposes proposes that that aging aging occurs occurs because because of aof a patient, patient, producing producing thethe dangerous dangerous hyperkalemia. hyperkalemia. In aged In aged individuals, individuals, thisthis special special sensitivity sensitivity of the of the kidney kidneygenetic genetic program program thatthat determines determines thethe progressive progressive appearappear-

ance of the of the different different aging-related aging-related phenotypic phenotypic changes. changes. to atovariety a variety of adverse of adverse situations situations is reminiscent is reminiscent of the of theance

These twotwo ideas ideas arcarc notnot mutually mutually exclusivc, exclusive, andand thethe accuaccubiologic biologic responses responses of patients of patients with with chronic chronic renal renal failure. failure.These mulated damage damage could could reflect reflect an an environment-dependent environment-dependent Although thethe changes in renal structure andand function thatthatmtiiated Although changes in renal structure function injury thatthat triggers a genetic program of aging 12. 3]. develop develop with with aging aging usually usually areare considered considered "physiologic," "physiologic,"repetitive repetitive injury triggers a genetic program of aging 12.3]. must obtain nutrients and, in the case of of must obtain nutrients and, in the case clinicians clinicians must must be aware be aware thatthat thethe renal renal parenchyma parenchyma of the of the Organisms Organisms organisms, oxygen from thethe external media or or aerobic organisms, oxygen from external media elderly elderly shares shares some some of the of the characteristics characteristics of the of the chronically chronicallyaerobic environment, environment, to maintain to maintain cellular cellular function function and and homeosta homeostadamaged damaged kidney, kidney, making making necessary necessary a careful a careful analysis analysis andand During the the cellular metabolism of nutrients andand oxygen, During cellular metabolism of nutrients oxygen, management of clinical situations as well as judicious management of clinical situations as well as judicioussis.sis. different toxic intermediate molecules arise, cells have toxic intermediate molecules arise, buthut cells have administration administration of drugs. of drugs. In this In this Forum, Forum, I will I will describe describe in indifferent defense systems systems ableable to clear to clear these these molecules. molecules. Sometimes, Sometimes, detail thethe aging-related morphologic andand functional renal detail aging-related morphologic functional renaldefense however, production production of toxic of toxic molecules molecules overrides overrides thethe pro-prochanges to provide a better understanding of the basal changes to provide a better understanding of the basalhowever, mechanisms; thethe resultant damage characterizes tective mechanisms; resultant damage characterizes renal renal situation situation of elderly of elderly individuals. individuals. In addition, In addition, I will I willtective analyze thethe possible mechanisms involved in the developanalyze possible mechanisms involved in the develop-progressive progressive aging. aging. TheThe most most important important evidence evidence supporting supporting hypothesis hypothesis is that is that dietary dietary restriction—that restriction—that is, caloric is, caloric ment ment of the of the renal renal parenchymal parenchymal alterations alterations in these in these individindivid-thisthis without compromising essential nutrients—is restriction without compromising essential nutrients—is uals. uals. Before Before starting starting thisthis analysis, analysis, however, however, let let meme review reviewrestriction briefly thethe available information about thethe biology of the briefly available information about biology of thethethe most most reproducible reproducible wayway of slowing of slowing aging aging [4J.[4]. aging aging process process in general. in general.

main groups of toxic molecules likely areare involved in in Two Two main groups of toxic molecules likely involved

thethe aging aging process. process. Reactive Reactive oxygen oxygen intermediates intermediates (ROl) (ROl) General General mechanisms mechanisms of aging of aging probably probably have have been been thethe most most widely widely studied. studied. These These molemoleA careful A careful analysis analysis of the of the multiple multiple theories theories proposed proposed to tocules, cules, including including superoxide superoxide anion, anion, hydrogen hydrogen peroxide, peroxide, andand hydroxyl radicaL, radical, among among others, others, areare formed formed during during thethe explain thethe aging phenomenon is beyond thethe scope of this explain aging phenomenon is beyond scope of thishydroxyl reduction of molecular oxygen to form water progressive reduction of molecular oxygen to form water discussion. discussion. However, However, some some understanding understanding of the of the general generalprogressive within thethe cell, cell, butbut alsoalso as aasconsequence a consequence of of thethe action action of of mechanisms mechanisms of aging of aging cancan help help us better us better understand understand thethewithin Reactive Reactive Reactive oxygen oxygen intermediintermedidifferent different cellular cellular enzymes enzymes [51[51 relationship between aging andand renal dysfunction. relationship between aging renal dysfunction. cancan induce induce chemical chemical changes changes in many in many substances substances Theories Theories on on aging aging have have evolved evolved according according to the to the develdevel-atesates essential for for normal normal cellcell function, function, including including nucleic nucleic acids. acids. opment opment of our of our understanding understanding of biology. of biology. General General theories theoriesessential proteins, andand lipids, lipids, with with subsequent subsequent subsequent structural structura' structural andand funcfuncfuncthatthat considered aging a global system-wide process have considered aging a global system-wide process haveproteins, tional cellcell damage. damage. Moreover, Moreover, thethe levels levels of macromolecules of macromolecules been been replaced replaced by by thethe ideaidea thatthat thethe aging aging of aofparticular a particulartional oxidative damage increase in certain tissues of of exhibiting oxidative damage increase in certain tissues organism organism results results from from the the sumsum of the of the aging aging of its of individual its individualexhibiting cells. cells, This approach to the understanding of aging is isaged cells, This approach to the understanding of aging organisms [61.[6]. Two recent studies clearly support the the aged organisms Two recent studies clearly support of ROl of ROI in aging. in aging. First, First, drosophila drosophila strains strains bearing bearing extra extra supported supported by much by much experimental experimental evidence. evidence. Thus, Thus, in human in humanrolerole of genes encoding both superoxide dismutase andand copies of genes encoding both superoxide dismutase beings, beings, the the aging-related aging-related dysfunction dysfunction of organs of organs andand tissues, tissues,copies catalase, the the main main enzymes enzymes involved involved in ROI in ROl removal, removal, havehave such such as the as the brain brain or subcutaneous or subcutaneous fat,fat, is closely is closely related related to tocatalase, longer lifelife spans spans thanthan do do drosophila drosophila without without thethe extra extra genes genes a reduction a reduction in the in the number number of cells. of cells. Moreover, Moreover, thethe replicareplica-longer age-i mutant elegaris, characterized Second, thethe age-i mutant of of C. C. elegaris, characterized tivetive capacity capacity of cells of cells explanted explanted from from a variety a variety of mammals of mammals[7).[71• Second, an an increased increased lifelife span, span, alsoalso displays displays higher higher levels levels of of is roughly is roughly proportional proportional to the to the lifelife span span of the of the animals animals El];El];by by thisthis finding suggests a relationship between cellular aging finding suggests a relationship between cellular agingsuperoxide superoxide dismutase dismutase [81.[8]. andand whole-animal whole-animal aging. aging. In addition, In addition, thethe WRN WRN gene, gene, a a Advanced Advanced glycosylation products (AGEs) comprise glycosylation endend products (AGEs) comprise other group of molecules (formed as aasconsequence of of other group of molecules (formed a consequence gene gene involved involved in the in the development development development of of Werner's Werners of Werner's syndrome, syndrome, a athethe the the basic basic living living process) process) that that seems seems to play to play a pathogenetic a pathogenetic disease disease characterized characterized by by thethe appearance appearance of aofprecocious a precocious

Nephro1oy NephrologyForum: Forum:The Theaging agingkidney kidney

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Organism Orgarsm ]]

Fig. Schematicrepresentation representationof ofthe theaging aging Fig.1.1.Schematic process, process,considering consideringthe theorganism organismasasthe thesum sum ofofIts Itsdifferent differentcells. cells.Abbreviations Abbreviationsare: are:Rot, Rot, reactive reactiveoxygen oxygenintermediates; intermediates;AGE, AGE,advanced advanced glycosylation glycosylationend endproducts; products;ruedialors, mediators,other other possible possiblemediators. mediators.

role rolein inaging agingdevelopment development[9]. [9].Formed Formedby bythe thelong-term long-term interaction interactionof ofreducing reducingsugars, sugars,such suchas asgiucose glucoseor orfructose, fructose, with withthe theamino aminogroups groupsof ofintracellular intracellularor orextracellular extracellular proteins proteins[9], [9],AGEs AGEsare areincreased increasedin inseveral severalpathologic pathologic situations, situations,particularly particularlydiabetes, diabetes,and andin inaged agedorganisms. organisms. Protein Proteinglycosylation glycosylationor orthe theinteraction interactionof ofAGEs AGEswith with specific specificcell cellreceptors receptorsisisassociated associatedwith withthe thedevelopment developmentof of functional functionaland andstructural structuralchanges changessimilar similarto tothose thosecharaccharacterizing terizingaging aging[9]. [9].AAclose closerelationship relationshipexists existsbetween betweenAGE AGE

and andRO!, RO!,as asititseems seemsthat thatROl ROlare aregenerated generatedin incells cellsafter after Morethe the interaction interaction of of AGEs AGEs with their receptors 10J. [10].Moreover, over,glycated glycatedproteins proteinscan canundergo undergooxidative oxidativedamage, damage,with with

the thesubsequent subsequentaccumulation accumulationof ofglycoxidation glycoxidationproducts products such suchas asN-epsilon N-epsilon (carboxymethyl) (carboxymethyl) lysine, which are are concon sideredgood goodmarkers markersofofaging-related aging-relatedtissue tissuedamage damage[1[11]. sidered 1]. The Thegenetic genetictheory theoryof ofaging agingproposes proposesthat thatthe thelife lifespan spanof of aaparticular particularorganism organismisisdetermined determinedby byaaspecific specificgenetic genetic program,which whichculls cullsolder olderindividuals individualsfrom fromthe thegeneral general program, population. population.One Oneinteresting interestingpiece pieceof ofevidence evidencesupporting supporting thistheory theoryisisthe theobservation observationthat thatPacific Pacificsalmon salmonundergo undergo this rapid rapidsenescence senescenceafter afterspawning spawning[2]. [2].Moreover, Moreover,aalimited limited

number numberof ofgenes, genes,including includingage-i, age-i,daf-2, daf-2,and andclk elkin inC. C. elegansand andWRN WRNininhuman humanbeings, beings,have havebeen beenrelated relatedtoto elegans the thedevelopment developmentof ofaging-related aging-relatedphenotypic phenotypicchanges changes[2,81. [2,81.

The Theexact exactmechanism mechanismof ofthis thisprogrammed programmedcell celldeath deathhas has

not notbeen beenadequately adequatelydefined; defined;several severalpossibilities possibilitieshave havebeen been proposed proposed[2,3]. [2,3].The The"telomere "telomereshortening shorteningtheory" theory"proposes proposes

the theactivation activationor orinactivation inactivationof ofparticular particulargenes genesafter afteraa certain certainnumber numberof ofcell celldivisions. divisions.Other Otherhypotheses hypothesesenvision envision aging agingas asthe theresult resultof ofminimal minimalbut butrepetitive repetitiveDNA DNAinjuries, injuries, or orprogressive progressivetoss loss lossof ofcopies copiesof ofimportant importantgenes. genes.NevertheNevertheless, less,these thesetheories theoriesonly onlypartially partiallyexplain explainthe theaging agingphenomphenomenon, enon,particularly particularlyatataacellular cellularlevel, level,and andaauniversal universalmechmechanism anismof ofcell cellaging aginghas hasnot notyet yetbeen beendetermined. determined. Figure Figure11summarizes summarizesthe theaging agingprocess. process.Living Livingorganisms organisms are areprovided providedwith withaagenetic geneticprogram, program,including includingperhaps perhapsaa specific specificaging agingprogram, program,which whichcontrols controlstheir theirdifferent differentfuncfunctions.To Tomaintain maintainthese thesefunctions, functions,organisms organismsmust mustobtain obtain tions. nutrients nutrientsand andoxygen oxygenfrom fromthe theexternal externalmedium mediumand, and,ininthe the

processing processingof ofthese thesemetabolites, metabolites,toxic toxicmolecules moleculesare are formed. formed.Although Althoughorganisms organismscan candisarm disarmmost mostof ofthese these molecules, molecules,aasmall smallnumber numberof ofthem themcan caninterfere interferewith with normal normalbasic basicfunctions, functions,or oreven evenwith withthe thegenetic geneticprogram, program, thus thusdetermining determiningaaparticular particularrate rateof ofaging. aging.Other Otherexternal external stimuli stimulialso alsomight mightinfluence influencethe theaging agingprocess. process.

Aging-related Aging-relatedrenal renalchanges changes Morphologic Morphologicchanges. changes.Although Althoughasscssment assessmentof ofspecific specific aging-related aging-relatedmorphologic morphologicrenal renalchanges changesin inthe theelderly elderlyisis not noteasy easybecause becauseof ofthe thehigh highprevalence prevalenceof ofsuperimposed superimposed vascular vascularor orinflammatory inflammatorydiseases, diseases,studies studiesin inapparently apparently disease-free disease-freeindividuals individualshave haveprovided providedvaluable valuableinformainformation tion(Table (Table1) 1)[12, [12,13J. 13].Renal Renalmass massincreases increasesprogressively progressively from from about about 50 50 gg at at birth birth to to over over 400 400ggatatthe thefourth fourthdecade, decade, and and then then declines declines to to under under 300 300 ggby bythe theninth ninthdecade. decade.The The loss of ofrenal renalmass massmainly mainlydepends dependson onprogressive progressiveatrophy atrophyofof loss

that thatcells cellsdo donot notcompletely completelyrep'icate replicatetheir theirchromosomes chromosomes during duringaacell celldivision divisioncycle, cycle,so sothat thatvery verylate latereplicating replicating renalcortex, cortex,with withrelative relativesparing sparingof ofthe themedulla. medulla.The The DNA DNAsequences sequencesare arelost. lost.IfIfcertain certainnonessentiat nonessentialrepetitive repetitive renal corticalatrophy atrophyroughly roughlyreflects reflectsaadecreased decreasednumber numberof of DNA DNAsequences sequenceswere wereatatthe theends endsof ofreplicative repticativeunits, units, cortical essential essentialgenes geneswould wouldnot notbe belost lostuntil untilaanumber numberof ofdivisions divisions functioning functioningnephrons. nephrons.Under Underage age40, 40,few fewglomeruli glomeruliappear appear were wereachieved. achieved.The Thetheory theoryof of"terminal "terminaldifferentiation" differentiation" sclerosed; sclerosed;inincontrast, contrast,by bythe theeighth eighthdecade, decade,between between1O l0' and30% 30%of ofthe theglomeruli glomeruliare arecompletely completelysclerosed, sclerosed,the the posits positsprogrammed programmedcell cellsenescence senescenceas asthe theconsequence consequenceof of and

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Nephrology Nephrology Forum: Forum: TheThe aging aging kidney kidney

Table 1. Morphologic Table 1. Morphologic changes in the kidneys of cidcrv individuals changes in the kidneys of cldcrtv individuals Macroscopic Macroscopic changes changes Vascular Vascular changes changes Ghrneru1ar Glonierular Ghrneru1ar changes changes changes

Tubular Tubular changes changes

Interstitial Interstitial changcs changes

flattening flattening andand atrophy atrophy of the of the tubular tubular epithelia. epithelia. Interstitial Interstitial

fibrosis, fibrosis, a constant a constant characteristic characteristic of these of these animals animals [15], [15], hashas Reduced Reduced sizesize andand weight weight Relative cortical Relative cortical atrophy been been detected detected as early as early as after as after 8 months 8 months in Lewis in Lewis rats rats [18]. [18]. alrophv 1-Jyalinosis 1-Jyalinosis 1-Jyalinosis ofarterial arterial of arterial walls of walls In fact, some authors believe that the interstitial changes In fact, some authors believe that the interstitial changes Increased Increased number number of scierosed of scierosed glomeruJi glomeruli Hypertrephy of the glomerui? Hvpertrophy of remnant the remnant glomeruli precede precede gloinerular glornerular sclerosis sclerosis in the in the renal renal aging aging process process [191. [19]. Increased Increased thickness thickness ol basal of basal membrane membrane Recently, group performed morphologic studies Recently, ourour group hashas performed morphologic studies MeangiaJ Mesangial nlalrix matrix expansion expansion in 24-month-old Wistar rats. TheThe morphologic changes in 24-month-old Wistar rats. morphologic changes 1rrtguIar Irregular fusion fusion of fooi of foot processes processes observed observed were were similar similar to those to those previousiy previously described described (Fig. (Fig. Reduction Reduction in the in the number number of tubuks of tubules Atrophy Atrophy of the of the tubular tubular epithelium epithelium After staining with Syrius used a computer2).2). After staining with Syrius red,red, wewe used a computerTubular Tubular di'ation dilation assisted planimetric planimetric procedure procedure deve'oped developed at the at the Pathology Pathology Increased Increased thickness thickness of basal of basal mcmhranc membrane assisted Interstitial fibrosis Iiiterstitiaj fibrosis Department of the University of Granada, which allowed Department of the University of Granada, which allowed

Well Well documented documented in rats, mis. in rats, but but controversy controversy exists exists in in humans. in humans. humans.

us us to accurately measure mesangial matrix expansion andand to accurately measure mesangial matrix expansion interstitial fibrosis. Mean increases of 273% andand 181% were interstitial fibrosis. Mean increases of 273% 181% were

detected, respectively, forfor these twotwo parameters, when detected, respectively, these parameters, when

glomeruli of the of the outer outer cortex cortex being being especially especially affected. affected. TheThecompared glomeruli compared to 3-month-old to 3-month-old animals animals [20]. [20].

remaining remaining functioning functioning glorneruli glomeruli appear appear to increase to increase in size. in size. ToTo complete analysis of aging-related morphologic complete thethe analysis of aging-related morphologic although recent measurements performed computer-changes, although recent measurements performed by by computerchanges, let let meme comment comment on on thethe biochemical biochemical nature nature of the of the assisted image analysis suggest thatthat after thethe fourth decade assisted image analysis suggest after fourth decadeextracellular extracellular matrix matrix accumulation accumulation in the in the aging aging kidney. kidney.

glomerular glomerular size size declines declines slightly slightly [14]. [.14]. TheThe glomerular glomerularStudies performed both in human beings andand in rats have Studies performed both in human beings in rats have

changes changes thatthat determine determine thethe development development of sclerosis of sclerosis have haveconfirmed confirmed thatthat thethe chemical chemical composition composition of the of the glomerular glomerular

been studied previously [12, 13]. Mesangial matrix in-in-basement been studied previously [12, 13]. Mesangial matrix basement membrane membrane differs differs between between young young andand oldold indiindicreases progressively, andand glomerular basement membrane creases progressively, glomerular basement membraneviduals. viduals. Several Several changes changes have have been been detected detected in the in the latter, latter, undergoes undergoes progressive progressive thickening; thickening; freefree intraglomerular intraglomerularincluding including increased increased non-enzymatic non-enzymatic glycosylation glycosylation of proteins of proteins anastomoses appear andand functioning capillary loops areareandand anastomoses appear functioning capillary loops changes changes in the in the degree degree of sulfation of sulfation of glycosaminoglyof glycosaniinoglyreduced (so-called "glornerular simplification"). Eventu - cans, reduced (so-called "glomerular simplification"). Eventucans, butbut thethe most most widely widely found found biochemical biochemical change change is is ally, thethe increased increased extracellular extracellular matrix matrix condenses condenses into intoincreased ally, collagen content [14]. However, Abrass et al increased collagen content [14]. However, Abrass et al hyaline material andand collapses thethe glornerular tuft,tuft, finally hyaline material collapses glonierular finally recently recently questioned questioned thethe hypothesis hypothesis of collagen of collagen accumulaaccumulainducing complete glomerular sclerosis. Degeneration of oftiontion inducing complete glomerular sclerosis. Degeneration by by performing performing immunofluorescence immunofluorescence studies studies in Fisher in Fisher glomeruli glomeruli in the in the renal renal cortex cortex in turn in turn results results in atrophy in atrophy of of 344344 ratsrats with with a wide a wide panel panel of antibodies of antibodies [19]. [19]. These These authors authors thethe afferent afferent andand efferent efferent arterioles; arterioles; in the in the juxtamedullary juxtamedullary demonstrated demonstrated a moderate a moderate increase increase of of collagens collagens I and I and IllIII area, area, glomerulosclerosis glomeruloscierosis seems seems to cause to cause thethe formation formation of aof a only in areas with interstitial fibrosis, but detected no only in areas with interstitial fibrosis, but detected no arterioles. arterioles. These chandirect direct channel channel between between these these twotwo arterioles. These chan-

in collagens 1, III, andand IVIV at at thethe glomerular level. changes in collagens I, III, glomerular level. nels nels could could contribute contribute to to thethe maintenance maintenance of of medullary medullarychanges The changes observed in the glomerular tuft, particularly in in The changes observed in the glomerular tuft, particularly blood blood flow flow as cortical as cortical perfusion perfusion declines. declines. Tubular Tubular strucstructhe the glomerular glomerular basement basement membrane, membrane, were were related related to an to an tures tures also also decrease decrease with with aging. aging. Although Although some some studies studies increased content of various laminin isoforms, whereas in increased content of various laminin isoforms, whereas in suggested suggested a dissociation a dissociation between between glomerular glomerular andand tubular tubular the the interstitial interstitial compartment, compartment, they they observed observed a generalized a generalized atrophy, hypothesis been confirmed, atrophy, thisthis hypothesis hashas notnot been confirmed, andand a a immunostaining forfor fibronectin fibronectin andand thrombospondin. thrombospondin. TheThe close relationship appears to exist between degenerative close relationship appears to exist between degenerativeimmunostaining relationship relationship between between interstitial interstitial fibrosis fibrosis and and collagen collagen I I changes in glomeruli those in tubules Interchanges in glomeruli andand those in tubules [12,[12, 13].13]. Interaccumulation accumulation also also seems seems to be to be supported supported by by the the demondemonstitial stitial changes, changes, with with increased increased fibrosis, fibrosis, alsoalso frequently frequently occur occur

stration stration of increased of increased levels levels of type-I of type-I collagen collagen mRNA mRNA in the in the in the in the aging aging kidney kidney (12,(12, 13].13]. cortex cortex of of old old rats rats [21]. [21]. In In contrast contrast to to the the results results from from Studies of aging-related renal reual changes in experimental Studies of aging-related renal changes in experimental Abrass, Abrass, preliminary preliminary results results from from our our laboratory laboratory demondemonmodels, models, performed performed mostly mostly in albino in albino rats, rats, areare consistent consistent with with strate anan increased increased collagen collagen type-IV type-IV mRNA mRNA (alpha-i (alpha-i thethe pathologic pathologic findings findings in humans in humans [15]. [15]. Two Two strains strains of rats, of rats,strate in the renal cortex of 24-month-old Wistar ratsrats (Fig. chain) in the renal cortex of 24-month-old Wistar (Fig. Fisher 344344 andand Sprague-Dawley, areare especially prone to the Fisher Sprague-Dawley, especially prone to thechain) This This finding finding suggests suggests thatthat accumulation accumulation of this of this collagen collagen development development of of age-related age-related nephropathy, nephropathy, butbut other other albino albino3). 3). plays a role a role in the in the genesis genesis of the of the morphologic morphologic renal renal changes changes strains strains alsoalso develop develop variable variable degrees degrees of renal of renal damage damage with withplays observed observed in aged in aged rats. rats. Differences Differences in rat in rat strain, strain, age age of the of the In In these animals, glomerular sclerosis is readily aging [15). In these animals, glomerular sclerosis is readily aging [15). at the at the time time of the of the study, study, or sensitivity or sensitivity of the of the techniques techniques demonstrated demonstrated after after 24 24 months, months, butbut increased increased glomerular glomerularrat rat account forfor thethe apparent discrepancies detected in in might account apparent discrepancies detected basement basement membrane membrane thickness thickness andand progressive progressive expansion expansionmight the different studies. the different studies. of mesangial of mesangial matrix matrix arcarc detected detected as early as early as 3asmonths 3 months (15}. (15]. Giomerular Giomerular sizesize of the of the intact intact glomeruli glomeruli increases increases with with ageage Functional Functional changes. changes. kidneys kidneys manifest manifest significant significant Elderly Elderly

as well as morphologic, changes (Table 2). 2). In In functional as well as morphologic, changes ('Table [14, 16]. It isIt interesting thatthat Hayashida et al an anfunctional [14, 16]. is interesting Hayashida et noted al noted human beings, beings, rena' renal blood blood flow flow (RBF) (RBF) decreases decreases about about increase increase in the in the number number of mesangial of mesangial cells cells with with ageage [17].human 10% perper decade decade after after thethe maximum maximum reached reached in young in young Intratubular Intratubular casts casts occur occur more more frequently frequently in old in oki rats, rats, with with10%

Nephrology Fonni. The aging kidney

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Fig. 2. Morphologic changes in the renal

cortex of 24-month-old Wistar rats. (1) Diffuse gtomerular and tubular changes, with cystic appearance and atrophy of the glomerular tuft of some glomeruli, gIomeruIoscIeross, tubular dilation, and intratubuar casts (PAS X 100). (2) Tubular atrophy, teduplication of basal membranes, and interstitial expansion (PAS X 400). (3) Magnification of a scleroscd glornerulus. near another gtomerulus with cyst(c appearance. in an area with interstitial ecpansion (PAS X 400). (4) Arterolar hyalinosis (PAS x 600).

3

2

1

4

Table 2. Functional changes in the kidneys of elderly ndividuaIs Renal blood flow

Decreased

Relative increasc of medullary blood flow Decreased glomerufar filtration rat& Increased filtration fraction Increased permeability to macromoleculesb Tubule Impaired ability (or sodium handling Deranged tubular transport Impaired concentration and dilution Impaired acidification Other Decreased synthesis ol renin Decreased 1-aipha-hydroxylase activity GeneraUy accepted in humans but not in rats. b Increased prevalence of mcroaIbuminuria in humans. Over proteinuria in rats. Glomerutus

COL (V

1

2

3

4

28S mRNA (a-i chain in the renal Fig. 3. Expression of the collagen type4V cortex ri-om J-month.old (lanes 1 and 2) and 24-month-old (lanes 3 and 4) rats.

blood perfusion per unit of renal tissue mass (22]. Neither can changes in cardiac function account for the reduction in this parameter, as the minimal reduction in the percentage of cardiac output directed to the kidney (that occurs in the elderly) does not explain the observed decline in RBF [23]. Studies utilizing the xenon washout technique have dem-

adulthood. Thus, renal plasma flow (RPF) of approximately 600 ml/min/I.73 m2 during the third decade de- onstrated that the reduction in RBF is not uniform creases to about 300 rnl/minJl.73 m2, a 50% reduction, in the ninth decade 112, 13]. The decrease in RBF is associ-

throughout the kidney. In fact, and according to the

anatomic descriptions, cortical blood flow is preferentially ated with significant increases in afferent and efferent decreased in the elderly, with a relative sparing of the blood arteriolar resistances [12, 13J. The decline in RBF cannot flow in juxtamedullary glorneruli [22]. As these glomerular he exp'ained as a secondary phenomenon associated with structures have a higher filtration fraction than do the the previously described renal mass reduction, as specific cortical glorneruli, the observation that filtration fraction studies designed to answer this question demonstrated that increases with advancing age could be ecplained by this the decreased RBF was accompanied by a real decline in observation.

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Nephrology Forum: Nephrology Forum: The The aging kidney aging kidney

Changes in in RBF in in experimental anirnas differ from Changes RBF experimental animals differ fromteinuria teinuria is aisconstant a constant manifestation manifestation of renal of renal dysfunction dysfunction in in those those obsei'ed observed in human in human beings: beings: the the absolute absolute values values of ofoldold ratsrats in strains thatthat develop glomerulosclerosis [15,[15, 31].31]. in strains develop glomerulosclerosis RBF remain stable between 3 and to 24 months Although thethe exact exact nature nature of this of this selcctivity selectivity defect defect hashas notnot RBF remain stable between 3 and 20 20 to 24 months [16,[16, 24,24,Although 25j,25], andand even even slight slight increases increases in this in this parameter parameter have have been beenbeen been elucidated, elucidated, some some evidence evidence points points to to a combined a combined observed observed in 15in 15to 18-month-old to 18-month-old Sprague-Dawley Sprague-Dawley ratsrats [24,[24,charge charge andand sizesize defect defect as responsible as responsible forfor thethe aging-related aging-related 26].26]. When When RBF RBF waswas factored factored by kidney by kidney weight, weight, however, however, it itincreased increased proteinuria proteinuria [32]. [32]. significanttv significantly decreased decreased with with aging aging [16,[16, 24J; 24]; these these data data have have Tubular Tubular absorption absorption of sodium of sodium scems seems to be to be impaired impaired as aas a been been sometimes sometinles interpreted interpreted as as indicative indicative of of an an agingaging-consequence of aging. When oldold individuals areare sodiumconsequence of aging. When individuals sodiumrelated related significant significant derangement derangement of of RBF. RBF. TheThe analysis analysis of ofdeprived, sodium excretion progressively declines, butbut it it deprived, sodium excretion progressively declines, takes longer longer to to achieve to achieve achieve equilibrium equilibrium than than when when younger younger preglomerular preglomerular andand postglonierular postglonierular resistances resistances byby mi-mi-takes longer cropuncture hashas vicided different results, depending on on thethepeople cropuncture vie Ided different results, depending people undergo undergo thethe same same deprivation. deprivation. TheThe mean mean half-time half-time ratrat strain. Thus, these resistances were increased in old strain. Thus. these resistances were increased in oldforfor reduction of sodium excretion is 17 hours in individuals reduction of sodium excretion is 17 hours in individuals but were Munich-Wistai Munich-Wistar rats rats 1161, 1161, but but were decreased decreased in Spraguein Sprague-less less thatthat 3030 years years old, old, buthut is prolonged is prolonged to to 3131 hours hours in in subjects more than years Nevertheless, elderly subjects more than 60 60 years old.old. Nevertheless, the the elderly Dawley Dawlev animals animals (25(25 27}.27]. Glorneruar Glomerular filtration filtration raterate (GFR) (GFR) hashas been been studied studied ex-ex-cancan achieve achieve a sodium a sodium equilibrium equilibrium even even when when given given diets diets tensively in the elderly. Cross-sectional studies have dem-with tensively in the elderly. Cross-sectional studies have demwith a very a very lowlow sodium sodium content content [33]. [33]. OldOld subjects subjects alsoalso have have onstrated onstrated thatthat GFR GFR decreases decreases progressively progressively after after ageage 30 30 to toproblems problems with with sodium sodium overloads, overloads, andand edema edema andand hypertenhyperten4040 years years [12. [12. 13]. 13]. This This decreased decreased GFR GFR was was notnot only onlysion frequently occur in this population. Short-term sodision frequently occur in this population. Short-term sodidetected detected in cross-sectional in cross-sectional studies studies butbut alsoalso in longitudinal in longitudinalum-loading um-loading studies studies show show distinct distinct age-related age-related sodium sodium sodium excreexcreexcrestudies. TheThe Bajtiniore Longitudinal Study of of Aging a'so studies. Baltimore Longitudinal Study Aging alsotion tion patterns: patterns: after after a 2-liter a 2-liter normal normal saline saline load, load, individuais individuals found a progressive decline of glomerular filtration witholder found a progressive decline of glomerular filtration with than 40 40 years show a lower 24-hour sodium excretion older than years show a lower 24-hour sodium excretion aging. aging. TheThe raterate of decline of decline waswas 0.80.8 ml/minll.73 ml/minll.73 m2/year, m2/ycar, a a(with (with a significantly a significantly greater greater portion portion of the of the sodium sodium excreted excreted raterate similar similar to that to that previously previously reported reported in cross-sectional in cross-sectionalat night) at night) than than do do their their younger younger counterparts counterparts [34]. [34]. studies [281. Interestingly, GFR diddid notnot change in approxstudies [281. Interestingly, GFR change in approx- Perhaps Perhaps oneone of of thethe best-known best-known aspects aspects of of tubular tubular dysdysimately imately one-third one-third of the of the patients patients included included in this in this longitudilongitudi-function in the elderly is their relative inability to adefunction in the elderly is their relative inability to adequately quately concentrate concentrate andand dilute dilute thethe urine. urine. Studies Studies comparcornparnalnal study study [28]. [28]. In contrast In contrast to the to the decline decline in GFR, in GFR, plasma plasma creatinine creatinine does doesmgmg thethe maximal maximal urinary urinary density density or osmolarity or osmolarity after after water water in in young andand oldold individuals have clearly deprivation young individuals have clearly notnot change with increasing age.age. As As it happens, muscle mass, change with increasing it happens, muscle mass,deprivation from from which which creatiiiiiie creatinine is derived, is derived, decreases decreases with with ageage at atdemonstrated demonstrated thatthat kidneys kidneys from from oldold subjects subjects do do notnot form form approximately approximately thethe same same raterate as does as does GFR. GFR. In consequence, In consequence,urine as concentrated as that of young people [35]. Renal urine as concentrated as that of young people [35]. Renal thethe age-related lossloss of GFR is not reflected by an age-related of GFR is not reflected by increased an increaseddiluting ability also is impaired in elderly individuals. diluting ability also is impaired in elderly individuals. concentration of plasma creatinine. Thus, parameterDuring concentration of plasma creatinine. Thus, thisthis parameter During water water diuresis, diuresis, urine urine osmolarity osmolarity in old in old subjects subjects is is must must be be used used with with caution caution iii aged in aged populations populations to assess to assesssignificantly significantly higher higher than than thatthat in in young young subjects, subjects, andand solute. soluteGFR, as as it underestimates renal function; thethe commonly GFR, it underestimates renal function; commonlyfree water clearance is lower 133]. The same defects in in free water clearance is lower [33]. The same defects

used used formulas formulas forfor estimating estimating creatinine creatiriine clearance clearance from fromurinary urinary concentration concentration andand dilution dilution also also have have been been de-deplasma plasma creatinine creatinine values values always always take take intointo account account the thethe age ageagescribed scribed in laboratory in laboratory ratsrats (t5j. of of thethe patients. patients. Other disorders of tubular transport widely studied areare Other disorders of tubular transport widely studied Another aspect of of glomerular function thatthat hashas been Another aspect glomerular function beendecreases in in sodium-hydrogen exchange andand in in sodiumdecreases sodium-hydrogen exchange sodiumextensively extensively studied studied is the is the permselectivity permselectivity of the of the filtration filtrationcoupled coupled phosphorus phosphorus reabsorption. reabsorption. TheThe latter latter defect defect also also barrier. barrier. Although Although some some reports reports describe describe an an increased increased prevprev-hashas been been demonstrated demonstrated in laboratory in laboratory animals animals andand even even in in alence alence of of proteinuria proteinuria in ainpopulation a population of of persons persons over over 65 65preparations preparations of of brush-border brush-border vesicles vesicles [15, [15, 36]. 36]. This This age. ageyears [29J, only a minority of disease-free patients over years [29J, only a minority of disease-free patients over 80 80related related decline decline in sodium-dependent in sodium-dependent phosphate phosphate transport transport thethe effect of age on on sodium-hydrogen exchange in in years years show show clinical clinical proteinuria proteinuria [13]. [13]. Moreover, Moreover, when when thetheprecedes precedes effect of age sodium-hydrogen exchange glomerular glomerular permeability permeability to macromolecules to macromolecules hashas been been studstud-brush-border brush-border membrane membrane vesicles vesicles [37). [37]. These These datadata suggest suggest ied,ied, no no differences differences were were detected detected between between young young andand oldoldthatthat all all membrane membrane transport transport functions functions at the at the proximal proximal individuals individuals [30]. [30]. Thus, Thus, it seems it seems thatthat thethe permselectivity permselectivity of oftubule tubule areare notnot similarly similarly affected affected during during thethe aging aging process. process. thethe glomerular glomerular filtration filtration barrier barrier in human in human beings beings is only is onlyAsAs in the in the case case of the of the other other tubular tubular functions, functions, under under normal normal minimally altered in the elderly. minimally altered in the elderly. physiologic physiologic conditions conditions older older individuals individuals maintain maintain normal normal Again, Again, glomerular gomerular glomerular function function function in in old old in old rats ratsrats differs differs differs from from from thatthat in inacid-base acid-base excretion. excretion. However, However, thethe elderly elderly do do have have a dea deolder humans. Assessing different reports onon GFR is iscreased older humans. Assessing different reports GFR time-referred acidacid excretion (when compared withwith creased time-referred excretion (when compared difficult difficult because because data data arcare frequently frequently expressed expressed corrected correctedyoung controls) when challenged with an an acid load; in in young controls) when challenged with acid load; forfor thethe body body andand kidney kidney weight, weight, andand these these twotwo variables variablesaddition, addition, young young subjects subjects excrete excrete a significantly a significantly higher higher proproincrease increase in old in old anima's. animals, buthut it does it does seem seem thatthat GFR GFR remains remainsportion portion of the of the acid acid load load as ammonium as amnionium [38J. [38]. stable stable in albino in albino ratsrats until until 1818 to to 2424 months months of of ageage f16, f 16, 24]24] The The renal renal renal aging aging aging process process process is is also also is also characterized characterized by by de-deandand then then declines declines progressively. progressivelY. OnOn thethe other other hand, hand. propro-creased renin syffihesis. synthesis. Studies in humans andand in rats have creased renin synthesis. Studies in humans in rats have

Nephmlogy Nephmlogy !on,n: Jonan: The 1/ic avig aging kiclnc kiclnc LicInc Nephmlogy !on,n: The avig

demonstrated decreased concentrations andand activities of of demonstrated decreased concentrations activities plasma plasma renin renin despite despite normal normal plasma plasma concentration concentration of of renin renin

2253 2253 2253

Table 3. Mechanisms tndand Table 3. Mechanisms factors factors involved involved expansion in in thethe expansion of of matrix and changc in cel' extrtceUuIur extraceflular matrix matrix and and changc changes in cel' in numbers cell numbers in numbers in in

renal renal diseases diseases progressive progressive

substrate, substrate, as as weU wefl weU as as a decreased a decreased reial renal renin renin content content Iii in

General median isms mechanisms individuals, in these these subjects. maneuvers elderly individuals, individuals, in in these subjects. subjects. maneuvers maneuvers designed designedGeneral edcrly raterate of resident Changes in the proliferation of resident or infiltrating or infiltrating cells resident cells Changes in the proliferation

infiltrating cells to to stimuatc stimulate rcnin rcnin secretion secretion amplified amplified thethe differences differences in in Changes raterate in the apoptosis rate of ofresident ororinfiltrating cells Changes in the apoptosis resident of resident or infiltrating cells infiltrating cells plasma renin levels with respect young population increased plasma renin levels with respect to to thethe young popu'ation Increased synthesis synthesis synthesis of of normal normal f normal or abnormal or abnormal extracellular extracellular matrix matrix components [39]. [39]. Jung Jung et et at at demonstrated demonstrated decreased decreased rcnin rcnin rnRNA mRNA components degradation of norma' or ibnormal extracellular matrix Decreased degradation of normal or abnormal extracellular matrix renal content content in in renal renal tissue tissue tissue ininin 12-month-old 12-month-old 12-month-old Spraguc-Dawlcy Sprague-Dawley Decceased components components rats, rats, even even in in thethe absence absence of of significant significant changes changes in in ren& renalFactors Factors involved in the regulation of these mechanisms involved in the regulation of these mechanisms

1GF-1 Growth factors: factors: PDGF, PDGF, EGF, EGF, TGFP, TGFP, lGF-1 FGF,FGF, In In contrast, contrast, Corman Corman et al et detected at detected a significantly a significantly Growth renin renin [401. [401.

Cytokines Il-i,lI-I, fl-13, 11-13, TNFTNF decreased decreased rcnin renin content content in in 30-month-old 30-month-old female female WAG/nj WAG/nj Cytokiiies ANP Vasoactive Vasoactive peptides: peptides: All,Alt, ET,ET, ANP rats, rats, without without changes changes in in renin renin mRNA mRNA expression expression [41]. [41]. A A Lipid PAF PAF mediators: mediators: POE2, POE2, P012, P012, TxA,, TxA,, PAF mediators: PGE2, PGI, TxA2, Lipid Others: NO,NO, ROtROt deficit deficit in 1-alpha-hydroxylase in 1-alpha-hydroxylase activity activity is another is another charactercharacter- Others:

istic istic of of aged aged subjects. subjects. AsAs a consequence a consequence of of thisthis defect, defect,

Abbreviations: Abbreviations: PDGF, PDGF, platelet-derived platelet-derived growth growth factor; factor; EGF, EGF, epidermal epidermal

factor: TGFP, transforming growth factor j3; j3; FOF, fibroblastic growth factor; TGF, transforming growth factor FGF, fibroblastic plasma plasma levels levels levels of of Iof 1,25-dihydroxycholecalciferol ,25-d 1,25-dihydroxycholecalciferol i hydroxycholecalciferol decrease decrease in in ingrowth growth growth factor; factor; IGF-1, IGF.1, insulin-like insulin-like growth growth factor factor 1; 11-1, 1; 11-1, interleukin-I; interleukin-1; 11-13, 11-13, thisthis population, population, with with a subsequent a subsequent derangement derangement in calcium in calciuminterleukin-13; TNF. TNF. tumor necrosis All, All, angiotensin interleukin-13; TNF. tumor tumor necrosis necrosis factor; factor; All, angiotensin angiotensin 11; ET, 11;IL; ET,ET. endothelin; endothelin; ASP, atrial natriuretic peptide; POE-,, prostagandin ASP, atrial natriuretic peptide; POE-., prostagandin E2; E2;E2; endothelin; ANP, atrial natriuretic peptide; PGE2, prostaglandin homeostasis homeostasis [421. [42]. thromboxane fac-facpGr,, PGI,, A,;A2; pGr,, prostacyctin; TxA2, thromboxane A,; PAF, platelet-activating facPAF, PAF, platelet-activating prostacyctin; prostacyclin; TxA2, TxA2, thromnboxane platelet-activating

intermediatcs. nitric NO, NO, nitric oxide; ROl, reactive oxygen intermediatcs. NO, nitric oxide; ROt, reactive oxygen intermediates. ROl, reactive oxygen Mechanisms Mechanisms responsible responsible forfor renal renal changes changes during during aging aging tor;tor; Analysis Analysis of of thethe mechanisms mechanisms involved involved in the in the dev&opmcnt development aging-related renal changes been performed at twobetween of of aging-related renal changes hashas been performed at two between matrix matrix synthesis synthesis andand degradation degradation are,are, perhaps, perhaps, thethe levels. levels. Most Most studies studies have have looked looked forfor thethe immediate immediate reasons reasonsmain main critical point fibrosis development. Fourth, from critical point in in fibrosis development. Fourth, from a a that that explain explain thethe changes changes detected detected in in renal renal structure structure andandfunctional functional point point of of view, view, a wide a wide overlap overlap exists exists between between thethe function function in in oldold human human beings beings or or animals. animals. However, However, these thesedassical classical growth growth factors factors andand different different vasoactive vasoactive factors, factors, as as studies studies have have notnot established established a re1ationshp a relationship between between thethethethe former former may may induce induce significant significant hemodynamic hemodynamic effects, effects, specific specific mechanisms mechanisms studied studied andand thethe aging aging process. process. In Inwhereas whereas thethe latter latter may may modif' modif' thethe raterate of of proliferation proliferation andand consequence, consequence, a second a second setset of of studies studies or or hypotheses hypotheses have have protein protein synthesis synthesis in different in different cells. cells. tried tried to to estahish establish a casual a casual linklink between between thethe aging aging process process These These mechanisms mechanisms have have been been scarcely scarcely explored explored in aging. in aging. itself itself andand thethe possible possible mechanisms mechanisms involved involved in the in the genesis genesisThe number of of niesangial mesangial cells increases in the early stages The number niesangial cells increases in the early stages of of thethe renal renal changes. changes. In In thisthis second second part part of of thisthis discussion, discussion,of aging of aging in rats in rats [171, [171, butbut no no additional additional studies studies have have conconI wilt I will focus focus onon mechanisms mechanisms responsib'e responsible forfor aging-related aging-relatedfirmed firmed thisthis finding. finding. It would It would be be very very important important to assess to assess thethe morphologic andand functional renal changes, andand links be-be-rates rates of of proliferation proliferation andand apoptosis apoptosis of of thethe different different renal renal morphologic functional renal changes, links cells cells as as a function a function of of ageage to to ascertain ascertain thcthe importance importance of of tween aging phenomenon these mechanisms. tween thethe aging phenomenon andand these mechanisms. these these phenomena phenomena in the in the genesis genesis of of the the progressive progressive replacereplaceMorphologic. Aging-related Aging-related Aging-related morpho'ogic morpho'ogic morphologic renal renal changes changes Morphologic. Morphologic. ment of of cells cells byby extracellular extracellular matrix. matrix. In In addition, addition, glomerglomerareare similar similar to to those those detected detected in in renal renal disease disease andand experiexperi-ment ular hypertrophy hypertrophy frequently frequently occurs occurs in in elderly elderly individuals individuals mental mental models models characterized characterized characterized by byby progressive progressive progressive chronic chronic chronic renal renal renalular oldold ratsrats [12—141. [12—14]. Although Although this this hypertrophy hypertrophy hashas been been failure, failure, includkig including glomerulonephritis, glomerulonephritis, diabetes, diabetes, andand surgical surgicalandand frequently considered considered thethe consequence consequence of of intrarenal intrarenal hemohemoreduction reduction of of renal renal mass mass [43J. [43J. Although Although thethe exact exact biochembiochem-frequently some authors authors believe believe thatthat thethe hyperhypericalical composition composition of of thethe expanded expanded cxtracellular cxtracellular matrix matrix in indynamic dynamic changes changes some trophy dcpends depends depends on on thethe release release release of of local of local local mediators, mediators, mediators, including including including aging aging kidneys kidneys is not is not fully fully comparable comparable to that to that in any in any of of those thosetrophy growth factors factors [50J, [50], andand thatthat it could it could be be an an indirect indirect marker marker pathologic pathologic situations situations [19], [19], oneone could could hypothesize hypothesize thatthat aging aginggrowth thethe increased increased local local production production of of growth-promoting growth-promoting shares shares some some of of thethe pathogenetic pathogenetic mechanisms mechanisms proposed proposed forforof of metabolites. Only Only oneone recent recent report report hashas analyzcd analyzed thethe levek levels these these discases. diseases. Table Table 3 lists 3 lists thethe most most widely widely accepted acceptedmetabolites. oneone of of these growth factors in elderly individuals. Chou these growth factors in elderly individuals. Chou mechanisms of of extracellular matrix expansion andand changes mechanisms extracellular matrix expansion changesof of et demo demonstratcd al demonstrated nstratcd an anan inverse inverse inverse relationship relationship relationship between between urinary urinary in cefi numbers in in thethe kidney in in progressive renal diseases. in cell numbers kidney progressive renal diseases.et al Some Some of of these these mechanisms mechanisms have have been beenwidely widelyexplored exploredn in epidermal epidermal growth growth factor factor cxcretion excretion andand age, age, andand suggested suggested a reduced a reduced production production of of thisthis growth growth factor factor retards retards thcthe experimental experimental models models of of glomerulonephritis glomerulonephritis or or diabetes, diabetes, as asthatthat wefi well as as in rats in rats with with surgical surgical renal renal mass mass reduction reduction [43—481. [43—48].repair repair process process at the at the kidney kidney level level [51. [51. In In contrast, contrast, different different Four main aspects table must stressed. First, vasoactive autacoids autacoids have have been been studied studied as as possiblc possible mediamediaFour main aspects of of thethe tab'e must be he stressed. First, thethevasoactive of of thethe functional functional changes changes of of thethe aging aging kidney, kidney, andand it isit is number of of cells at aatparticular time in disease progression number cells a particular time in disease progressiontorstors now a well-recognized a well-recognized fact fact that that autacoids autacoids regu'ate regulate cellcell is regulated is regulated by by thethe balance balance between between cellcell proUferation proliferation andand now proliferation and/or and/or extracellular extracettular matrix matrix synthesis. synthesis. Thus, Thus, apoptosis apoptosis (programmed (programmed cellcell death). death). Second, Second, increased increased cellcellproliferation angiotensin angiotensin IL IL and and endothelin endothelin have have well-defined well-defined effects effects on on and interstitial numbers cancan precede glomerulosclerosis numbers precede glomerulosclerosis and interstitial precede glomerulosclerosis cell proliferation, proliferation, whereas whereas nitric nitric oxide oxide (NO) (NO) andand atrial atrial fibrosis, fibrosis, even even in situations in situations in which in which cellcell proliferation proliferation is not is notcell natniuretic peptidc (ANP) possibly inhibit growth peptide peptidc (ANP) possibly inhibit cellcell growth andand readUy detected. Third, changes in in thethe complex equilibrium readily detected. Third, changes complex equilibrium natriuretk

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extracellutar matrix synthesis [441. Changes in these vasoactive, growth-promoting metabolites could be involved in the development of the aging-related morphologic changes.

I will return to this topic. Finally, data about the possible importance of the extracellular matrix degradation in the genesis of the structural changes related to agthg have been provided by Schaefer et al [52] and Reckeihoff et al [53], who found that glomerular and tubular proteinase activities decreased in aging rat kidneys. According to the previously discussed criteria, the possible consequences of this decreased proteinase activity would be increased extracellular matrix and subsequent morphologic changes in the kidney.

FIg. 4. Expression of the TGF- mRNA in the renal cortex from 3-month-old, 18-month-old, 24-month-old, and 30-month-old rats. Upper panel, the simultaneous amplification of the TGF-1 and GAPDH (housekeeping gene) mRNAs by using RT-PCR, in samples from rats of different ages. Lotver panel, the ratio between the two amplification products (TGF131/GAPDH) were calculated and the mean SEM of 6 different rats are given. P < 0.05 versus 3-month-old rats. (Published with permission of! Am Soc Nephrol.)

renal dysfunction in male rats without modifying the pattern of renal damage in female rats [161. Studies from our laboratory suggest that TGFf3 is involved in the development of aging-related morphologic changes, particularly interstitial fibrosis [20]. Using semiquantitative reverse transcriptase-polymerase chain reaction techniques, we demonstrated that exprcssion of TGFf3 mRNA in renal cortex of Wistar rats increased progressively with aging (Fig. 4). The blockade of TGFf3 expression

by long-term treatment with captopril partially prevented the development of interstitial fibrosis but not of glomerulosclerosis. One of the growth factors most widely studied Some of these mechanisms are likely influenced by for its role in the structural changes in different pathologic gender, an important determinant of the rate at which the conditions, TGFf3 modulates the proliferation rate of difkidney is damaged with age. Morphologic alterations are ferent renal cell types, as well as matrix synthesis and less severe in old women than in old men [12, 13), and male degradation. Thus, the progressive glomerulosclcrosis asrats have a higher mortality rate due to renal failure [16]. sociated with experimental glorneruloncphritis, diabetes, or These gender differences seem to depend on the presence renal mass reduction could depend on TGFf3 niRNA

of androgcns rather than on the absence of estrogens; overexpression [48]. We expected to find significant

castration of older animals prevented the development of changes in this growth factor in our experiments in old rats.

Wephi1ot Wephi1ort Fonan: Fonan: TheThe aging aging kidney kidney

2255 2255

Although we demonstrated Although we demonstrated a direct temporal relationshipsystem a direct temporal relationship system might might be be involved involved in the in the impaired impaired renal renal vascular vascular and between aging response observed in old Three vasodilatory response observed in individuaLs. old individuals. Three between aging and TGFI3 mRNA expression (201, onlyvasodilator TGFI3 mRNA expression 2O1, only

interstitial interstitial fibrosis fibrosis seemed seemed to depend to depend on on thisthis overexpresoverexpres-mechanisms mechanisms could could account account forfor thisthis possible possible defective defective re- resion, sion, in contrast in contrast with with previous previous results results in other in other pathologic pathologicsponse: sponse: reduced reduced production production of NO of NO in response in response to different to different situations. situations. Perhaps, Perhaps, as suggested as suggested by by Abrass Abrass et al et [19), al [19), thethestimuli, stimuli, increased increased degradation degradation of the of the NONO released, released, or or nature nature andand pathogenesis pathogenesis of aging-related of aging-related renal renal dysfunction dysfunctionincreased increased synthesis synthesis of this of this metabolite metabolite with with a decreased a decreased areare notnot fully fully comparable comparable to those to those of glomerulonephritis, of glomerulonephritts,response response of of thethe target target cells. cells. TheThe first first of of these these three three diabetes, diabetes, or renal or renal mass mass reduction. reduction. hypotheses is supported by by thethe factfact thatthat thethe 24-hour urinaly hypotheses is supported 24-hour urinaly of nitrites plusplus nitrates (considered an an indirect excretion of nitrites nitrates (considered indirect Functional. Functional. Aging-related Aging-related functional functional changes changes areare closely closelyexcretion related related to the to the morphologic morphologic alteFations alterations previously previously described. described.index index of NO of NO synthesis synthesis in the in the kidney kidney [57]) [57]) as well as well as the as the However, However, they they areare notnot only only thethe consequence consequence of structural of structuralglomerular synthesis of nitrites [58][58] are are decreased in older glomerutar synthesis of nitrites decreased in older changes, changes, as aasderanged a deranged regulation regulation of different of different aspects aspects of ofrats.rats. However, in studies of aged with synthesis However, in studies of aged Fatsrats with NONO synthesis normal renal function seems to be involved in theblockade, normal renal function alsoalso seems to be involved in the blockade, Reckeihoff Reckelhoff andand Manning Manning demonstrated demonstrated thatthat thethe genesis genesis of these of these changes. changes. Moreover, Moreover, a complex a complex network network of ofdependence dependence of renal of renal blood blood flow flow on nitric on nitric oxide oxide is greater is greater in in functional relationships between thethe different renal strucfunctional relationships between different renal struc-oldold than in young individuals. They suggested thatthat in- inthan in young individuals. They suggested tures exists, andand changes in the function of aofparticular tures exists, changes in the function a particularcreased synthesis of this compound is necessary to maintain creased synthesis of this compound is necessary to maintain structure structure cancan depend depend on on thethe dysfunction dysfunction of others. of others. renal perfusion [251. As As a conscquence of the increased andand renal perfusion [25). a consequence of the increased Renal vessels in healthy elderly humans or rats do do notnotmaintained Renal vessels in healthy elderly humans or rats maintained basal basal NONO synthesis, synthesis, the the response response to stimuli to stimuli such such as acetyicholine or amino or amino acids acids would would decrease. decrease. UnfortuUnfortushow show structural structural changes changes significant significant enough enough to completely to completelyas acetylcholine explain explain thethe reduction reduction in RBF, in RBF, except except when when other other pathopatho-nately, neither direct measurements of local NONO synthesis nately, neither direct measurements of local synthesis logic situations such as arteriosclerosis areare superimposed logic situations such as arteriosclerosis superimposedin renal in renal vessels vessels nornor a detailed a detailed analysis analysis of the of the expression expression andand on on thethe basic basic aging aging process. process. In consequence, In consequence, authors authors have haveactivity activity of NO of NO synthases synthases in renal in renal cortex cortex is available is available at at looked forfor thethe intrinsic causes of the decreased renal looked intrinsic causes of the decreased renalpresent. present. However, However, a report a report from from Hwang Hwang et aletdemonstrated at demonstrated plasma plasma flow flow in the in the disease-free disease-free elderly elderly individual. individual. It isIt isthatthat cultured cultured proximal proximal tubule tubule epithelial epithelial cells cells from from kidneys kidneys generally generally accepted accepted thatthat thethe basic basic defect defect in the in the vessels vessels of ofof old donors express significantly significantly higher higher amounts amounts of of of of old donors express significantly higher amounts these individuals is an impaired ability to relax in the these individuals is an impaired ability to relax in theconstitutive constitutive NONO synthase synthase [59]; [591; thisthis report report opens opens newnew per-perpresence presence of some of some well-defined well-defined vasorelaxant vasorelaxant stimuli. stimuli. From Fromspectives spectives in the in the study study of this of this problem. problem. TheThe reasons reasons forfor a a thethe initial initial description description of decreased of decreased renal renal vasodilation vasodilation after afterpossible possible increase increase of basal of basal NONO synthesis synthesis in renal in renal cortex cortex of of pyrogen pyrogen injection injection in human in human beings beings 4 decades 4 decades ago, ago, authors authorsthethe aging aging kidney kidney areare unclear. unclear. Nitric Nitric oxide oxide could could actact as aas a have have demonstrated, demonstrated, in human in human beings beings or in or animals, in animals, thatthat thethecounteracting counteracting mechanism mechanism of some of some vasoconstrictor vasoconstrictor mediamediathatthat might might be be increased increased in aging. in aging. High High circulating circulating normal normal vasodilatory vasodilatory responses responses induced induced by by acetylcholine, acetylcholine,torstors amino amino acids, acids, glycine, glycine, or after or after food food ingestion ingestion areare blunted blunted in inendothelin endothelin levels levels have have been been described described in plasma in plasma of aging of aging [60], endothelin mRNA expression is increased in in men [60], endothelin mRNA expression is increased thethe elderly [22,[22, 24, 24, 54].54]. However, some discrepancies existexistmen elderly However, some discrepancies in this in this area. area. HillHill andand coworkers coworkers described described a normal, a normal,cultured cultured vascular endothelial cells from compared with vascular endothelial endothelial cells cells from from old oldold compared compared with with unblunted unblunted renal renal vasodilatory vasodilatory response response to acetylcholine to acetylcholine andandyoung young individuals individuals [61], [61], andand increased increased endothelin-1 endothelin-l secresecrewaswas detected in aged cultured human umbilical vein L-arginine L-arginine infusion infusion in older in older ratsrats [55]. [55]. OnOn thethe other other hand, hand,tiontion detected in aged cultured human umbilical vein thethe agonistinduced agonist.induced renal renal vasocontrictive vasocontrictive response response in the in theendothelial endothelial cells cells [62]. [62]. Endotlielin, Endothelin, Endothelin, viavia its ET-B its ET-B ET-B receptor, receptor, receptor, aging kidney might notnot he the same in human beings andandmight aging kidney might be the same in human beings increase NONO synthesis. OurOur group, in collaboration collaboration might increase synthesis. group, in collaboration

rats. rats. Hollenberg Hollenberg andand colleagues colleagues demonstrated demonstrated thatthat the thewith with thethe Department Department of Pathology of Pathology of the of the University University of of angiotensin angiotensin Il-induced II- induced reduction reduction of RBF of RBF in elderly in elderly humans humansGranada, Granada, hashas found found thatthat mRNA mRNA expression expression of preproenof preproenwaswas itidependcnt independent of the of the ageage of the of the subjects subjects (221, (221, andand the thedothelins dothelins I and 3 increases in old (unpublished data) I and 3 increases in old ratsrats (unpublished data) (Fig. 5); 5); thisthis work work thus thus supports supports a possible a possible rolerole forfor thisthis renal renal vasodilatory vasodilatory response response to acute to acute angiotensin angiotensin converting converting(Fig. enzyme enzyme inhibition inhibition persisted persisted even even in old in old people people [561. [561. In Inpeptide peptide in the in the vascular vascular renal renal changes changes thatthat characterize characterize

contrast, contrast, Tank Tank et al et found a! found thatthat kidneys kidneys of aged of aged ratsratsaging. aging.

exhibited exhibited an exaggcrated an exaggerated response response to systemic to systemic vasoconstricvasoconstric- Nitric Nitric oxide oxide andand endothelin endothelin are are notnot the the onlyonly vasoactive vasoactive tor tor stimuli stimuli [261. [261. Taken Taken together, together, these these datadata suggest suggest thatthat thethesystems systems thatthat have have been been studied studied as possible as possible mediators mediators of of combination combination of defective of defective vasodilatjon vasodilation vasodilation with with normal normal or inor in-aging-related functional changes. Impaired arterial haroreaging-related functional changes. Impaired arterial barorecreased creased vasoconstriction vasoconstriction accounts accounts forfor thethe reduced reduced RBF RBFflex,flex, with with a subsequent a subsequent increased increased renal renal sympathetic sympathetic activity, activity, thatthat characterizes characterizes aging. aging. hashas been been proposed proposed as aaspossible a possible mechanism mechanism for for increased increased

TheThe basis basis forfor these these altered altered vascular vascular responses responses in the in therenal renal vascular vascular resistance resistance [54]. [54]. TheThe previously previously mentioned mentioned data concerning renin synthesis in elderly human beings concerning renin synthesis in elderly human beings aging kidney is not understood. Pyrogen injection, acetyt-data aging kidney is not understood. Pyrogen injection, acetylacetytcholine, andand amino acidacid infusion share a common mecharatsrats [39—41] [39—4would 1] would leadlead us to usexpect to expect thatthat angiotensin angiotensin II 11 choline, amino infusion share a common mecha-andand with aging, andand some studies support thisthis connism of inducing renal vessel relaxation, thatthat is, the local nism of inducing renal vessel relaxation, is, the localdecreases decreases with aging, some studies support conretease release of NO, of NO, oneone of the of the most most important important vasodilator vasodilatortention one recent report proposing thatthat tention [41]. [411. However, However, oneone recent recent report report proposing [41]. However, mechanisms. mechanisms. Defective Defective synthesis synthesis or activity or activity of the of the NONOthisthis peptide actually increases with [63], peptide actually increases with ageage [63], andand thethe

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The aging kidney

24 months

Prepro ET

GAPDH

Fig. 5. Northern blot analysis of the expression of the preproendothelin-1 and GAPDH (housekeeping gene) mRNAs in 3-month-old and 24-month-old

rats.

significant renal vasodilalion with increases in renal plasma

Changes in GFR in the elderly are generally attributed to

flow observed in older rats in response to the acute progressive glomerular sclerosis and decreased renal angiotensin II blockade [64], suggest that intrarenal anglo- plasma flow. However, formation of the glomerular ultratensin 11 is activated in senescent rats. Synthesis of platelet filtrate is a finely regulated phenomenon, and the reduction activating factor (PAF), a lipid mediator with well-recog- in GFR occurs more slowly than does the fall in RPF, the

nized vasoconstrictor ability, seems to be increased in isolated glomeruli of aged rats [31J; this finding suggests a pathogenetic role for this autacoid in aging-induced altered vascular responses. The equilibrium between prostacyclin and thromboxane also is deranged with aging, and the ratio

result being an increased filtration fraction. Two mechanisms might account for the relative GFR maintenance,

even in the presence of significant hemodynamic and

structural changes. First, as I said before, the aging process produces a non-homogeneous derangement of renal blood of prostaglandin 12 to thromboxane A2 decreases in the flow, with a preferentially decreased cortical flow [22j. As urine of older humans, as well as in the glomeruli and inner the filtration fraction of the juxtamedullary glomeruli and outer medulla of older rat kidneys 162, 65]. Finally, seems to be higher than that of the cortical glomeruli, the impaired ANP-induced relaxation of renal arteries in rats GFR would diminish less than in the case of a homogeand monkeys 166] provides yet another way of impairing neous reduction in renal perfusion. Second, it is well known renal vasodilation. that the remaining glomeruli undergo hemodynamic

Another possible explanation for the impaired renal changes to compensate for the lack of function of the sclerosed glomeruli [49]. This phenomenon, known as secondary hyperfiltration, could maintain adequate GFR

vasodilatory response is defective activation of intracellular second messengers that mediate vascular smooth cell relaxation. A blunted cAMP response to 3-adrenergic agonists has been described in blood vessels with aging, and Lakatta has proposed that this alteration modifies vascular responses to stress and exercise [67J. Further study reveals

to clarify the importance of these mechanisms in the

even in the presence of a significant reduction of functioning nephrons. The mechanisms involved in the development of hyperfiltration have been extensively studied in different experimental models. In most cases, hyperfiltration seems to depend on increased glornerular plasma flow and increased hydrostatic pressure in the glomerular capillary network as a consequence of selective vasodilation of the afferent arteriole [491. Micropuncture studies in aged rats have analyzed the determinants of glomerular ultrafiltration. Most of these studies demonstrate decreased resistance of the glomerular afferent arteriole with an increased glomerular plasma flow [25—27]. Controversy exists, however, with respect to changes in the glomerular capillary pressure in these old rats, because normal [16, 25, 27] or increased values [701 have been detected. Moreover, an

development of aging-related decreased renal plasma flow.

increased age-related ultrafiltration coefficient also has

that this response could depend on impaired guanine nucleotide regulatory protein (0 protein) function [68]. However, it was not possible to detect changes in the amount of these G proteins in aged rats, particularly Gs and Gi, at the renal level [69]. On the other hand, the defective response to ANP in blood vessels from elderly individuals might be due to accelerated degradation of cGMP by phosphodiesterases [661. Additional studies arc needed, including evaluations of the different intracellular systems involved in vascular smooth muscle cell relaxation,

Nephro1oey Fonwi, TheThe aging kü!nev NephioIoey Nephro1oey Fonwi, Fonwi, The aging kü!ney kühiey

2257 2257

been described [75]. Moreover, Moreover, non-osmotic non-osmotic AVP AVPrelease release also also might might bebe been described A recent A recent micropuncture micropuncture study study by by[75]. [25,[25, 27].27]. by Baylis, performed in in Munich-Wistar Munich-Wistar rats, rats, failed failed to to demondemon-deranged Baylis, performed deranged in the in the elderly elderly [74.[74, 75}. 75]. In In any any case, case, it isit generafly is generally strate strate thethe previously previously described described changes changes in old in old rats, rats, as asaccepted accepted thatthat thethe most most important important mechanism mechanism involved involved in in glomeruktr glomerular plasma plasma flow flow decreased decreased andand afferent afferent arteriole arteriolethethe elderly's elderly's renal renal concentrating concentrating defect defect is an is an inadequate inadequate resistance increased, whereas increased, whereas the ultrafiltration ultrafiltration coefficient resistance increased, whereas the the ultrafiltration coefficient coefficientrenal renal response response to endogenous to endogenous AVP. AVP. In humans. In humans. thisthis lacklack of of This change [16]. This study points to a possible inter-response diddid notnot change [161. study points to a possible interresponse hashas been been attributed attributed to aging-related to aging-related tubulointertuhulointerstrain variability in in thethe mechanisms involved in in thethe develstrain variability mechanisms involved devel-stitial stitial structural structural changes changes as as well well asas to to a derangement a derangement in the in the intrarenal mechanisms mechanisms responsible responsible forfor thethe maintenance maintenance of of opment opment of of aging-induced aging-induced GFR GFR changes. changes. In In any any case, case, weweintrarenal must remember that these studies were performed in in rats must remember that these studies were performed rats medullary medullary hypertonicity, hypertonicity,induding including solute solute transport transport byby thethe as as oldold as as 2 years, 2 years, when when glomeruloscierosis glomerulosclerosis glomerulosclerosis andand proteinuria proteinuriathick thick ascending ascending limb limb of the of the loop loop loop of of 1-lenle Henle of Henle and and and relatively relatively relatively areare readily detected [15] butbut when absolute values of GFR readily detected [15] when absolute values of GFRslow medullary blood flow [22, slow medullary blood flow [22, 33]. Studies Studies in in rats rats also also 33]. areare maintained [16,[16, 24].24]. maintained suggest suggest thatthat impaired impaired responsiveness responsiveness of the of the collecting collecting duct duct AsAs in in thethe case case of RBF, of RBF, changes changes in GFR in GFR in the in the elderly elderlycells to AVP is is involved in in thethe concentrating defect ii old cells to AVP involved concentrating defect in old might might bebe due, due, at at least least partially, partially, to to anan imbalance imbalance among among thetheanimals. The basis ofof this decreascd animals. The basis thisdefect defectcou'd couldbehea a decreased number receptors, a recent report failed of of V2V2receptors, huthut a recent report failed to to autacoids autacoids thatthat regulate regulate intraglomerular intraglomerular hemodynamics. hemodynamics. number However, nono studies have analyzed independently these However, studies have analyzed independently thesedemonstrate demonstrate such such a decrcase. a decrease. In consequence, In consequence, defective defective possible possible local local mediators. mediators. As As regulation regulation of of intraglomerular intraglomerularcoupling ofof this receptor totothethe adenylate cyclase system coupling this receptor adenylate cyclase system hemodynamics depends on on thethe regulation of the afferent hemodynamics depends regulation of the afferentlikely explains thethe lack of of response to AVP in older ratsrats [76.[76, likely explains lack response to AVP in older andand efferent arterioles, thethe autacoids Involved could bebe thethe 77]. efferent arterioles, autacoids involved could 77]. The The intrinsic intrinsic mechanisms mechanisms of of thethe rena' renal diluting diluting defect defect in in same same in both in both processes. processes. ButBut additional additional studies studies areare needed needed thethe elderly elderly have have been been lessless studied, studied, huthut they they might might relate relate to to to to clarify specific that lead to to thethe renoclarifythe the specificmediators mediators that lead reno-thethe aging-related aging-related decrease decrease in GFR in GFR and and decreased decreased solute solute transport in the thick ascending limb loop Henle. transport in the thick ascending limb ofof thethe 'oop of of Hene. vascular vascular and and gomerular glomerular changes changes of of aging. aging. What What accounts accounts for for the the relative relative inability inability of elderly of elderly indiindi- Other Other aging-related tubular defects, including defective aging.reiated tubular defects, including defective viduals viduals to to reabsorb reabsorb sodium sodium normally? normally? First, First, aging-associaging-associ-renal renal acidification acidification and and phosphate phosphate phosphate management, management, management, have have have been been been ated ated structural structural renal renal alterations, alterations, such such as interstitial as interstitial fibrosis fibrosisanalyzed analyzed lessless extensively. extensively. Impaired Impaired acidification acidification seems seems to to or or a decreased number of tubules, might play a part in the a decreased number of tubules, might play a part in thebe be a consequence a consequence of reduced of reduced renal renal mass mass [38], [38], although although homeostasis. homeostasis. Second, Second, decreased decreased GFR GFR andand its its attendant attendantsome some studies studies suggest suggest an intrinsic an intrinsic acidification acidification defect, defect, pospossibly associated associated with with impaircd impaired ammoniuni ammonium excretion excretion [78]. [78]. hyperfiltrating glomeruli of of sibly hyperfiltrating glomerulialso alsomight mightexplain explainsome someaspects aspects thethe deranged deranged sodium sodium homeostasis. homeostasis. Thus, Thus, a decreased a decreased GFR GFR Defective Defective phosphate reabsorption proximal tubule phosphate reabsorption by by thethe proximal tubuk could produce, on on a short-term basis, a relative inability to to partially could produce, a short-term basis, a relative inability partially depends increased PTH concentration depends onon thethe increased PTH concentration excrete a sodium load. OnOn thethe other hand, the the hyperfilterexcrete a sodium load. other hand, hyperfilter-associated associated with with decreased decreased GFR GFR [361. [361. ButBut parathyroidecparathyroidecinging nephrons nephrons excrete excrete a solute a solute loadload significantly significantly higher higher than thantomy only partially this soso alternative tomy only partiallyprevents prevents thisdefect, defect, alternative dodo normal normal nephrons, nephrons, with with a subsequent a subsequent osmotic osmotic diuresis diuresismechanisms mechanisms of deranged deranged phosphate hehe mechanisms of deranged phosphate reabsorption must of phosphate reabsorption must andand natriuresis; natriuresis; these these hyperfiltering hyperfiltering nephrons nephrons areare unable unable to toat play. at play. Phosphate Phosphate transport transport is decreased is decreased in cultured in cultured renal renal readily readily reabsorb reabsorb sodium. sodium. Third, Third, hormonal hormonalchanges changes also also tubular tubular cells cells [79j, [79], and and Levi Levieteta!a!have have suggested suggested that that this this might might account account forfor changes changes in sodium in sodium homeostasis. homeostasis. When Whendecreased decreased transport transport results results from from changes changes n the in the chemicat chemical plasma aldosterone waswas measured in elderly individuals, plasma aldosterone measured in elderly individuals,composition composition of of cefl cell membranes membranes [801. [801. Moreover, Moreover, thethe exprcsexpresvalues values were were significantly significantly lower lower than than those those in in young young people peoplesion sion of of thethe type-LI type-LI Na-Pi Na-Picotransporter cotransporter decreases decreases with with ageage [71]. [71]. This This decreased decreased adosterone aldosterone synthesis synthesis could could contribute contribute in tubular cells [81]. in tubular cells [81]. to to thethe relative relative inability inability ofofthe the aging aging kidney kidney totoconserve conserve and activation mechanisms involved and activation ofof thethe mechanisms involved in in thethe Aging sodium. sodium. The The hormone hormone proposed proposed to account to account forfor thisthis de-de-Aging renal renal changes changes in in the the elderly elderly ranged ranged sodium sodium excretion excretion is ANP; is ANP; plasma plasma levels levels of this of this I stated I stated before, before, most most studies studies deafiug dealing with with thethe mechmechhormone hormone significantly significantly increase increase in in elderly elderly subjects subjects [72]. [72]. AsAs However, thethe natriuretic response after thethe infusion of ofanisms However, natriuretic response after infusion anisms involved involved in in thethe development development of aging-related of aging-related mormorexogenous exogenous ANP ANP seems seems to be to be decreased decreased in healthy in healthy elderly elderlyphologic phologic and and functIonal functionalrenal renalchanges changes have have focused focused onon a a men men [73. [73]. These These data data have have been been interpreted interpreted as as a relative a relative particular deranged aspect of renal structure or function. particular deranged aspect of renal structure or function. decreased decreased responsiveness responsiveness of the of the aging aging kidney kidney to ANP. to ANP. However, these studies have provided enough clues However, these studies have notnot provided enough clues how aging determines thethe activation of of these mechDecreased Decreased concentrating concentrating ability ability in in thethe elderly elderly hashas been beenabout about how aging determines activation these mechattributed to to changes in the functional status of the hypoattributed changes in the functional status of the hypo-anisms. anisms. ForFor instance, instance, some some authors authors have have proposed proposed thatthat thalamic-pituitary thalamic-pituitary axis. axis. However, However, when when thethe release release of of argiargi-reduced reduced RBF RBF in elderly in elderly individuals individualsdepends depends onon changes changes in in local synthesis of NO [25,[25, but we still do not know local synthesis of NO 75]. but we still do not know nine vasopressin (AVP) was analyzed under different physnine vasopressin (AVP) was analyzed under different phys- thethe 75]. how aging aging induces induces these these changes. changes. OurOur knowledge knowledge of of thethe iologic iologic stimuli, stimuli, elderly elderly subjects subjects exhibited exhibited increased increased AVP AVPhow release release with with respect respect to young to young individuals individuals [741. [74]. NotNot allallgeneral general mechanisms mechanisms of aging of aging andand of the of the direct direct mediators mediators of of studies studies have have hadhad similar similar results, results, however, however, and and decreased decreasedrenal renal dysfunction dysfunction may may help help usus to to better better understand understand thethe aging-related aging-related AVP AVP release release also also hashas been been demonstrated demonstratedaging aging process process at the at the renal renal 'eveL level.

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Nephro1o' Forum: liie aging kidney C

4

8

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Prepro ET (2.3 Kb)

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Fig. 6 Northern blot analysis of the changes in the preproendothclin.I niRNA expression In cultured boine aortic endotheflni ceH incubated with hydrogen peroxide (100 ELM) for

different times (4 to 24 hours).

Alterations in the genetic program, induced by turning on the cell death program (apoptosis) or by exogenous damage to DNA may explain the activation of particular pathogenetic mechanisms in the aging kidney. Thus.

in female Munich-Wistar rats, which do not develop gb-

nieruloscierosis, did not differ from values in intact male rats [16]. Other rat strains that develop glomerulosclerosis earlier, for example, Sprague-Dawley, show small increases

changes in the synthesis of certain growth factors, vasoac- of intragbonierular pressure at 13 to 18 months but not at 20 live mediators. or cell transporters might be associated with to 22 months of age [25]. All these data suggest that the genetic changes that induce aging Unfortunately, a intragloinerutar hypertension is a relevant, but not the sole, detailed analysis of the genetic changes in senescent kidncy factor in aging-related renal damage. Nor is it likely the cells, unlike in senescent fibroblasts [1], has not been initial mechanism that triggers progressive renal dysfunction in the elderly. performed. Reactive oxygen intermediates also might be a link One attractive hypothesis might explain how the kidney ages. Anderson and Brenner suggest that aging-related. between aging and renal damage. The first argument progressive renal damage is the consequence of a continu- supporting a role for ROl in the progressive renal damage ous exogenous stimu)us, the diet, on renal structure and of aging comes from the observation that these metabolites function [49]. This hypothesis supports the general niech- likety are involved in the pathogenesis of other renal anisms of aging that I atready discussed. Long-term low- diseases characterized by progressive extracellular matrix protein feeding and chronic angiotensin II converting- expansion and decreased GFR, such as experimental renal enzyme inhibition have a protective effect on the mass reduction or glomerulonephritis [84]. Moreover, the glomerulus in the aging rat [15, 49, 7O1 Because these two cellular biology of resident glomerular cells is clearly maneuvers lower intraglomerular pressure in other exper- influenced by ROl. Although high concentrations of these imental models of renal disease, these data have been metabolites usually induce cell necrosis, under particular interpreted as indicating that glomeruar hypertension, experimental conditions, they induce proliferation of mesinduced by a high-protein diet, causes age-induced ne- angial cells [851. This fact could be related to tyrosine phropathy. The mechanisms connecting intraglomcrular phosphorylation of the platelet-derived growth factor rehypertension with progressive damage of glomerular struc- ceptor and the pp6Oc-src protein [86]. Further, ROl protures are currently being investigated, and it seems that mote changes resembling apoptosis in tubular cells [87]. By changes in the mechanical forces acting on the cells might promoting cell proliferation or apoptosis, ROl might play induce significant phenotypic changes in resident glomeru- different pathogenetic roles during different stages of lar cells, thereby modulating the release of local mediators aging. In early stages, increased cell proliferation associated with increased synthesis of extracellular matrix might [82, 83]. The critical point for validating this theory would be the induce matrix expansion. in more advanced stages, apoptodirect demonstration of increased iniraglomerular pressure sis could reduce the number of cells in different parts of the in elderly experimental animals. Anderson et al reported nepliron as well as in the interstitium. Reactive oxygen intermediates also might modulate synincreased intraglomerular pressure in 24-month-old Munich-Wistar rats [70]. However, Baylis did not find signifi- thesis of the vasoactive factors involved in the dysfunction

cant changes in glomerular pressure in males up to 20 of the aging kidney. Reactive oxygen intermediates inmonths of age of the same rat strain, even though the crease prostanoid synthesis in varying renal structures [84]. animals had significant glornerular structura' damage [16]. Moreover, PAF synthesis by inesangial cells also might be Moreover, intraglomcrular pressures in castrated male and increased in the presence of ROl [88]. In addition, ROt

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that of of ROT in in thethe pathogenesis of the changes that importance importance ROT pathogenesis pathogenesis ofof thethe changes changes characterize characterize thethe aging aging kidney. kidney. in in thethe first first ofof these these studies. studies. characterize wewe demonstrated demonstrated increased increased ROt ROt synthesis synthesis byby isolated isolated gbgbwell as meruli meruli and and cultured cultured mesangial mesangial cells cells from from oldold rats, rats, asas well well asas

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increased increased oxidative oxidative damage damage inin thethe renal renal cortex cortex ofof these these 250 250

animals animals [31]. [31]. InIn thethe second, second, probucol, probucol, a drug a drug with with antioxiantioxidant properties used hypercholesterolcm ia, prevented dant properties used forforhypercholesterolemia, prevented protein protein accumulation accumulation in in thethe glomeruli glomeruli ofof aged aged rats rats without without modifying modifying cholesterol cholesterol levels levels [96]. [96]. These These data data indicate indicate that that increased increased age-related age-related ROl ROI ROT synthesis synthesis induces induces well-defined well-defined effects effects in in different different renal renal structures, structures, and and triggers triggers thethe funcfunctiona tional andand morphotogic morphologic changes changes that that characterize characterize aging. aging. The The role role ofof AGEs AGEs in in thethe development development ofof diabetic diabetic comcomin in Increased plications plications has has been been studied studied extensive'y extensively [91. [91.Increased might induce some of the elderly individuals [9], AGEs AGEs might induce some of the elderly individuals 191,

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changes changesinvolved involved inin thethe development development ofof aging-induced aging-induced rena( renaldysfunction. dysfunction.Receptors ReceptorsforforAGEs AGEshave havebeen beendedeThese cells, scribed in in macrophages and monocytes [97j. cells, scribed macrophages and monocytes [97]. These cells, which transient(y infiltrate thethe renal parenchyma, might which transiently infiltrate renal parenchyma, might

synthesize synthesize interleukin-1, interleukin-1, insulin-like insulin-like growth growth factor factor 1, tumor I, tumor necrosis necrosis factor, factor, and and granulocyte-macrophage granulocyte-macrophage colony colony stim stimNorthern blotblot analysis of the changes in the endothellal constiFig. Northern analysis of the changes in the endothelial consti. Fig. 7. 7. X-XO X-XO (0.1 (0.1 M—1 M—i mU/mi) mU/mi)

nRNA nitric nitric oxide synthase (NOS-3) nRNA tutive tutive nitric oxide oxide synthase synthase (NOS-3) (NOS-3) nRNA expression expression (upper (upper panel) panel) andand expression of of arginine to to enzyme, enzyme, measured measured as as conversion conversion arginine in activity of enzyme, measured as thethe conversion of arginine to of thethe activity ofthis thisthis in the in activity In cultured bovine aortic endothelial cells incucultured bovine aortic endothelial cells incubovine aortic endotheilal cells incucitrulilne citrulilne panel), in cultured citrulilne (lower (lower (lower panel), panel), 1 mU/mi) xanthlne oxidase (XO, bated wIth with xanthlne (X,(X, 0.10.1 M) M) plus xanthlne oxidase (XO, 1 mU/tnt) mU/mI) for for bated with xanthlne plus different times (4 24 to 24 hours). different tImes times (4 to hours). different

ulating ulating factor factor inin response response toto receptor receptor binding binding byby AGEs AGEs [98]. [98]. InIn addition, addition, AGE AGE receptors receptors have have been been identified identified onon

glornerular glornerular mesangial mesangial cells, cells, where where they they seem seem to to play play a role a role in in thethe modulation ofofPDGF-induced modulation PDGF-inducedextracellular extracellutarniattix matrix synthesis synthesis [99]. [99]. Prolonged Prolonged administration administration ofof AGEs AGEs to to nornormal rats induced glomerular hypertrophy and extracellular extracellular mal rats induced glomerular hypertrophy and extracellular stimulate endothelin endothelin production production in in cultured cultured human human mesanmesanstimulate this finding underscores the impormatrix expansion [100]; this finding underscores impormatrix expansion [100]; this finding underscores thethe imporexpansion [100]; gial cells [89]. InIn our own laboratory, expression ofof pregial cells [89]. our own laboratory, expression pre- tance ofof these metabolites in in thethe development ofof glomertance these metabotites development glomerproendothelin-1 mRNA increased in in cultured bovine aortic proendotheiin-1 mRNA increased cultured bovine aortic uloscierosis. uloscierosis. Finally, Finally, thethe functional functional properties properties ofof several several endothelial endothelial cells cells incubated incubated with with hydrogen hydrogen peroxide peroxide (Fig. (Fig. 6) 6) important important matrix matrix components components areare a'tered altered byby AGE AGE forniaforma[90]. [90]. The The relationships relationships between between NO NO and and ROt ROt areare less less well welltion, tion, disrupting disrupting thethe normal normal matrix-to-matrix matrix-to-matrix and and cell-tocell-todocumented. Superoxide anion may inactivate NO, thereby documented. Superoxide anion may inactivate NO, therebymatrix interactions [101, 102j, thus favoring thethe progressive matrix interactions [101, 102], thus favoring progressive inhibiting inhibiting this this vasodilatory vasodilatory system system [91]. [91]. However, However, recent recent matrix matrix expansion expansion of of aging aging kidneys. kidneys. results from ourour laboratory point to to alternative possibilities results from laboratory point alternative possibilities Before Before I finish I finish this this discussion, discussion, I would I would like like to to mention mention a a [92]; [92]; messenger messenger RNA RNA expression expression ofof one one ofof thethe enzymes enzymes particular particular point point ofof view view regarding regarding thethe pathogenesis pathogenesis ofof renal renal involved in in NO synthesis, thcthe endothelial constitutive nitric involved NO synthesis, endothelial constitutive nitric dysfunction aging kidney. The finding that about dysfunction inin thethe aging kidney. The finding that about oxide oxide synthase, synthase, as as well well as as itsits activity, activity, might might bebe increased increased in in one-third one-third ofof thethe subjects subjects included included in in thethe Baltimore Baltimore LongiLongi-

cultured cultured bovine bovine aortic aortic endothelial endothelial cells cells incubated incubated with with aa the tudinal Study Study ofof Aging Aging diddid notnot show show any any change change inin the the RU! generating system such xanthine-xanthine oxidasetudinal RU! generating system such asas xanthine-xanthine oxidase glomerular glomerular filtration filtration rate rate [281, [281, and and thethe existence existence ofof ratrat (Fig. (Fig. 7).7). The The relationship relationship between between these these in-vitro in-vitro findings findings strains that develop any aging-related renal damage that dodo notnot develop any aging-related renal damage and thethe in-vivo results in in aged individuals must bebe evaluand in-vivo results aged individuals must evalu- strains [1031, suggest that the renal dysfunction of thc elderly is is [1031, suggest that the renal dysfunction of the elderly ateci atedcarefully carefullyininthethe future. future. due to an accumulation of damage induced by minimal, due to an accumulation of damage induced by minimal, Data concerning ability ROl modulate cytokine Data concerning thethe ability of of ROl to to modulate cytokine clinically undetected, renal disease, and is is notnot thethe conseclinically undetected, renal disease, and consesynthesis byby different glomerular cells areare scarce. Synthesis synthesis different glomerular cells scarce. Synthesis quence quence of of the the aging aging process process itself. itself. Although Although it is it is a wella wellofof tumor necrosis factor seems toto bebe stimulated byby ROl tumor necrosis factor seems stimulated ROl recognized fact that aged patients with superimposed disrecognized fact that aged patients with superimposed dis[93], and anan iron chelator with well-defined [93J, and deferoxamine, iron chelator with well-defined deferoxamine, [93], and eases, eases, such such as as hypertension hypertension or or diabetes, diabetes, show show a more a more rapid rapid antioxidant properties, might regulate tumor necrosis facantioxidant properties, might regulate tumor necrosis facdecrease ofof renal renal function, function, healthy healthy human human beings beings and and tortor release release in in mesangial mesangial cells cells [94]. [94]. OnOn thethe other other hand, hand, ROl ROI ROl decrease rats with well-controlled disease develop these laboratory rats with well-controlled disease develop these might might bebe anan intermediate intermediate metabolite metabolite inin thethe release release ofof laboratory renal changes changes in in thethe absence absence ofof any any detected detected renal renal disease. disease. nionocyte monocyte chernoattractant chemoattractant protein protein and and monocyte monocyte colonycolony-renal is is likely that a complex relationship between external likely that a complex relationship between external stimulating stimulating factor factor induced induced byby tumor tumor necrosis necrosis factor factor [95]. [95]. It It influences, including including diet, diet, and and thethe genetic genetic program program ofof aa Thepossible possible role these cytokines aging kidney role ofof these cytokines in in thethe aging kidney hashas influences, The particular particular individual individual determines determines thethe variability variability observed observed in in notnot been been studied. studied. aging humans. humans. Two Two recent recent reports reports from from our our laboratory laboratory stressed stressed thethe aging

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NtphrIogy Ntph;'Iogv Forum: 77w77w aging kidney Ntphrlogy Forum: aging kidney

II inIIthe in the aging-re'ated aging-related reduction reduction in renal in renal blood blood flowflow reducreductiontion is not known. Different experimental approaches, such is not known. Different experimental approaches, such JOHN T. HARRJNJTON T. HARRJNGTON JOHN DR.DR. as measuring the the circulating circulating levels levels of renin of renin or angiotensin or angiotensin Tufts Tufts University University School Schoolas measuring (Dean. (Dean. or measuring the the angiotensin angiotensin 11 turnover, II turnover, have have provided provided of Medicine, of Medicine, Boston, Boston, Massachusetts, Massachusetts, USA): USA): Thank Thank you,you,U orUmeasuring Diego, for for a wonderful summary andand synthesis of aofgreat Diego, a wonderful summary synthesis a greatconflicting conflicting results results r39—41, [39—41, 63 63, 64].64]. TheThe conflicting conflicting results results dealdeal of data of data regarding regarding aging aging of the of the kidney. kidney. MyMy question question is. is.are is, arc arc not not too too surprising, surprising, as the as the critical critical question—the question—the degree degree are are ratsrats a good model for for these studies? AreAre there compaa good model these studies? there compa-of activation of activation of the local renin-angiotensin system— cannot of the local renin-angiotensin renin-angiotensin system—cannot system—crnnot rable rable studies studies in mice, in mice, hamsters, hamsters, or dogs? or dogs? be directly be directly explored. explored. When When ACE ACE inhibitors inhibitors areare used used to to DR.DR. RODR1GUEZ-PUYOL: Most information informationhashas been been ob-ob-block RODR1GUEZ-PUYOL: Most block the the synthesis synthesis of angiotensin of angiotensin II, renal II, renal plasma plasma flowflow in in QUESTIONS AND ANSWERS QUESTIONS AND ANSWERS

tained tained in rats in rats andand mice, mice, perhaps perhaps because because of the of the wide wideolder older ratsrats increases increases [64], [64], thusthus suggesting suggesting that, that, at 'east at least availability availability of these of these animals. animals. ButBut discrepancies discrepancies do exist do exist withwithpartially. partially, renal renal vasoconstriction vasoconstriction maymay depend depend on increased on increased respect respect to the to the adequacy adequacy of the of the model. model. In contrast In contrast to human to humanlocal synthesis of angiotensin I! inI! rats. Young andand oldold local synthesis of angiotensin in rats. Young beings, beings, ratsrats are are characterized characterized by the by the early early appearance appearance of ofhuman human beings beings show show a comparable a comparable hemodynamic hemodynamic response response proteinuria proteinuria andand thethe maintenance maintenance of aofnormal a normal GFR GFR until untilto angiotensin to angiotensin 11 blockade II blockade [54,[54, 64].64]. veryvery advanced advanced ages. ages. In some In some rat strains, rat strains, almost almost no changes no changes DR.DR. MANUEL MANUEL ARIAs ARIAS (Head, (Head, Naphro1o' Nephrology Department, Department, Uni-Uniare are detected in the kidney eveneven in very old old animals [103]. In Inve,ity detected in the kidney in very animals [103]. ve,:sity Hospital Hospital "Marques "MarquEs de Valdecilla": de Valdecilla": We have We have some some datadata

consequence, consequence, some some authors authors authors be'ieve beicve believe thatthat rodents, rodents, particuparticu-in patients withwith advanced chronic renal failure showing a a in patients advanced chronic renal failure showing larly larly rats,rats, are are notnot the the most most suitable suitable model model for for studics studies studies of ofpredominance predominance of FAS of FAS andand a decrement a decrement of bcl-2, of bcl-2, a pattern a pattern aging. aging. TheThe available available information information about about the the aging aging phenoniphenom-of increased of increased programmed programmed cellcell death. death. DoDo youyou have have anyany enon in other animal models is scarce, no definite experience in the in the analysis analysis of renal of renal tissue tissue for for the the apoptosis apoptosis enon in other animal models is scarce, andand no definite datadataexperience point point to atoparticular a particular species species as the as the bestbest model model for for these thesegenes? genes? Do Do youyou think think thatthat apoptosis apoptosis might might be responsible be responsible aging of the kidney? studies. studies. In fact, In fact, efforts efforts are are underway underway to develop to develop rat strains rat strainsfor for aging of the kidney? DR.DR. RODR1GUEZ-PUYOL: RODR1GUEZ-PUYOL: RODRIGUEz-PuYoL: ThatThat That aisvery a very interesting interesting quesquesthatthat could constitute better models for for analyzing aging could constitute better models analyzing aging DR. is aisvcry interesting question. tion. We We havc have have considered considered the the hypothesis hypothesis that that a change a change in in [104]. [104]. the the apoptosis apoptosis rate rate is a is pathogenetic a pathogenetic mechanism mechanism in the in the aging aging second question is more specific. DR. DR. HARRINGTON: HARRINGTON: My second question is more specific. My kidney. Using Using Northern Northern blotblot analysis, analysis, we we were were unable unable to to CanCan youyou block block the the production production of mesangial of mesangial matrix, matrix, specifspecif-kidney. detect detect changes changes in the in the mRNA mRNA expression expression of bcl-2, of bcl-2, whereas whereas ically ically taminin? laminin? slightly slightly buthut significantly significantly decreased decreased in the in the renal renal cortex cortex for blocking mcsanmesanDR. DR. RODR1GUEZ-PUYOL: R0DRIGUEz-PuYoL: Strategies for blocking mesan-baxbax Strategies from oldold rats. rats. However, However, these these results results areare preliminary preliminary andand gialgial matrix matrix synthesis synthesis havc have have been been directed directed to the to the blockade blockade of offrom incomplete, as bcl-2fbax as hcl-2/bax are are notnot the the onlyonly the the genes genes involved involved TGFp, asas this growth factor is likely responsible for for the theincomplcte, TGF, this growth factor is likely responsible regulation of of apoptosis. Additional studies areare thethe regulation apoptosis. Additional studies increased increased extracellular extracellular matrix matrix observed observed in ainvariety a variety of ofin in needed to adequately to adequately answer answer your your question. question. pathophysiologic conditions. ACE inhibitors, anti-TGFp pathophysiologic conditions. ACE inhibitors, anti-TGFf3needed èssorèssor MARIA MORALES of MediJose JosÉ MARIA MORALES Assistant of Mediantibodies. antibodies, andand decorin decorin have have been been the the most most widely widely used used DR.DR. Assistane ProfProf you havehave cine, Hospital "12 de Octubre, de Octubre, "Madrid, "Madrid, "Madrid, Spain): Spain): Spain): Do Do Do you tools for blocking blocking TGFI3. TGFp. To To my my knowledge, no studies cine, Hospital "12 de Octubre, tools for blocking TGFf3. To my knowledge, no studies have have been been designed designed thatthat specifically specifically block block larninin laminin synthesis synthesisinformation information regarding regarding cyclosporine's cyclosporine's nephrotoxicity nephrotoxicity in agin ag-

in experimental in experimental models models of renal of renal disease, disease, hccause because thisthising ing kidneys? kidneys? R0DRIGuEz-PuYoL: As I As saidI said earlier, our our group RODR1GUEZ-PUYOL: earlier, group matrix protein hashas not not been considered as pathophysiologimatrix protein been considered as pathophysiologi- Dg.Dg. believes reactive oxygen species seem to involved be involved thatthat rcactive reactive oxygen species seem to be in in cally relevant as collagens or uibronectin. TheThe interesting cally relevant as collagens or fibronectin. interestingbelieves pathogeiiesis pathogenesis pathogenesis of aging-related of aging-related renal renal changes. changes. Moreover, Moreover, observations observations from from Abrass Abrass andand colleagues colleagues demonstrating demonstratingthe the have recently demonstrated thatthat cyclosporine A inhave recently demonstrated cyclosporine A inthe the accumulation of laminin in the glomerular basement basement accumulation of laminin in the glomerular basementwe we creascs creases the the synthesis synthesis of ROS of ROS by cultured by cultured human human mesangial mesangial membrane of old ratsrats suggest thatthat thisthis extracellular protein membrane of old suggest extraceflular proteincreases [105]. [105]. In consequence, In consequence, it isitpossible is possible thatthat cyclosporine cyclosporine plays a role in the genesis of the aging-related renal plays a role in the genesis of the aging-related renalcellscells A is A more is more nephrotoxic nephrotoxic in the in the elderly. elderly. The The influence influence of age of age changes [19]. In consequence, experiments directed changes [19]. In consequence, experiments directed at at in cyclosporine in cyclosporine A-induced A-induced nephrotoxicity nephrotoxicity has has been been studied studied specifically specifically blocking blocking particular particular laminin laminin isofonns isoforms could could pro-pro[106], butbut ratsrats are are notnot a good model for for analyzing in rats [106], a good model analyzing interesting information regarding mechanismsin rats 'ide'ide intcresting interesting information regarding thethe mechanisms cyclosporine-induced cyclosporine-induced damage damage because because the the dose dose thatthat must must involved involved in the in the aging aging process. process. be used to induce to induce renal renal damage damage is much is much higher higher thanthan thethe FRANCISCO DR.DR. ANGEL ANGEL DE DE FRANCISCO (Professor of Nep/wolo, Nephrolo, of Nephrolo.', Uni-Uni-be used (Professor usual doses doses in human in human beings beings (50(50 mg/kg/day). mg/kg/day). In patients In patients "MarquEs tie Santander, Spain): versity Hospital "MarquEs tie Valdecilla," Valdecilla," Santander, versity Hospital "MarquEs tie Valdecilla," Santander, Spain):usual versity Hospital receiving a renal a renal graft, graft, cyclosporine cyclosporine A nephrotoxity A nephrotoxity does does I have I have a question a question concerning concerning the the hemodynamic hemodynamic actions actions of ofreceiving seem to be withwith increasing donor ageage [107]. seem to increased be increased increasing donor [107]. ACE ACE inhibitors inhibitors in aging. in aging. Aging Aging is accompanied is accompanied by renal by renalnotnot my my knowledge, knowledge, however, however, no clinical no clinical studies studies have have been been vasoconstriction. vasoconstriction. Taking Taking intointo account account the the importance importance of ofTo To designed to answer to answer thisthis question question specifically. specifically. These These studies studies angiotensin angiotensin 11 in II the in the regulation regulation of renal of renal blood blood flow, flow, do do youyoudesigned should be performed be performed in patients in patients with with heart, heart, liver, liver, or lung or lung believe believe thatthat ACE ACE inhibitors inhibitors could could be useful be useful in preventing in preventingshould transplants. transplants. or in orpatients in patients receiving receiving cyclosporine cyclosporine because because of of thethe aging-related aging-related reduction reduction reduction in in rena' rcna in renal blood blood flow? flow? extrarenal diseases. diseases. The The DR. DR. RODRJGUEZ-PUYOL: RoDRIGuEz-Pu\oL: importance of angiotensinextrarenat importance of angiotensin

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DR. JAVTER DIEZ DR. JAVTER JAVTER DIEZ DIEZ (Professor intrinsic renal is difficult difficult to separate to separate separate intrinsic intrinsic renal damage damage from from of Medicine, Medicine, Head, Head, Vascularis difficult (Professor ofof Medicine, Vascular damage from thethe to (Professor Path Navarra, vascular vascular process patients with severe vascular disease, process in in patients with severe vascular disease, Pathophysiology ophysiologv Unit, Unit, University University Navarra,Pa,nplona, Pa,nplona, vascular of of Spain): Frohlich and colleagues have shown that blockade Spain): Frohlich and colleagues have shown that blockade renal renal dysfunction cannot solely explained structural renal dysfunction cannot bebe solely explained byby structural of of thethe endothelial endothelial constitutive constitutive nitric nitric oxide oxide synthase synthase in in arterial arterial changes changes in in older older healthy healthy humans. humans. Several Several investiinvesti-

young young SHR SHR rats rats causes causes morphologic morphologic and and functional functional renal renalgations gations have have demonstrated demonstrated that that thethe renal renal circulation circulation in in changes similar to to those present in in untreated, oldold SHR ratsrats older changes similar those present untreated, SHR older individuals individuals hashas characteristic characteristic patterns patterns of of response response to to This This group also demonstrated that ACE inhibitors group also demonstrated that ACE inhibitors thethe administration administration of of different different drugs. drugs. These These responses responses were were [108). [108). cancan prevent these renal changes. Can hypertension accelprevent these renal changes. Can hypertension accel- defective when compared to those in young subjects, andand I I defective when compared to those in young subjects, erate erate thethe aging aging process process byby amplifying amplifying thethe alterations alterations duedue to tododo notnot believe believe that that thethe differences differences can can hehe explained explained byby diminished nitric oxide availability? Is Is there a role forfor ACE diminished nitric oxide availability? there a role ACEarteriosclerotic arteriosclerotic damage damage [22, [22, 24,24, 54]. 54]. ARMANDO ARMANDO TORRES TORRES (Professor (Professor of Nephrology, Nephrology, UniverUniverinhibitors inhibitors in in preventing preventing renal renal aging aging in in hypertensive hypertensive pa-pa- DR.DR. ARMANDO TORRES (Professor of of Nephrology, Univertients? tients? sitysity Hospital, Hospital,Tenerife, Tenerife, Spain): Spain): Insertion-deletion Insertion-deletion polymorpolymorDR. RODR1GUEZ-PUYOL: RODR1GUEZ-PUYOL: I have I have tried to to communicate communicate my mymyphism DR. RODR1GUEZ-PUYOL: I tried have tried to communicate phism ofof thethe ACE ACE might might contribute contribute to to progression progression ofof particular point of of view, which is that aging is an evolutionparticular point view, which is that aging is an evolution- chronic chronic renal renal failure. failure. AsAs you you mentioned, mentioned, about about 30% 30% ofof aryary process in in which thethe equilibrium between thethe deleteriprocess which equilibrium between deleteri- older older individuals have age-related decrease individuals dodo notnot have anan age-related decrease in in ous vasoconstrictor/profibrotic local mediators and thethe GFR. ous vasoconstrictor/profibrotic local mediators and GFR. Has Has any any evidence evidence disclosed disclosed anan association association between between beneficial beneficial vasodilator/antifibrotic vasodilator/antifibrotic autacoids autacoids is progressively is progressively ACE ACE polymorphism and age-related decrease GFR? polymorphism and anan age-related decrease in in GFR? displaced displaced towards towards thethe former. former. ForFor instance, instance, nitric nitric oxide oxide DR. DR. R0DRIGUEz-PuyoL: The RODR1GUEZ-PUYOL: The lack of in in of renal renaldysfunction dysfunction could could counterbalance counterbalance thethe effects effects of of angiotensin angiotensin II for II for long long a substantial a substantial minority minority of of thethe aged aged population population hashas been been periods, periods, until until thethe nitric nitric oxide oxide system system fails fails and and renal renal dysdys- explained explained byby different different mechanisms. mechanisms. It has It has been been attributed attributed function function develops. develops. If this If this hypothesis hypothesis were were right, right, thethe answers answersto to environmental environmental differences differences and and to to thethe absence absence of of any any overt renal renal disease. disease. Obviously, Obviously, genetic genetic factors factors would would bebe to to your your two two questions questions would would bebe yes. yes. Hypertension, Hypertension, bybyovert inducing endothelial dysfunction, could decrease thethe activinducing endothelial dysfunction, could decrease activ- important; in in this sense, ACE polymorphism could bebe important; this sense, ACE polymorphism could ityity of of NOS-3, NOS-3, and and subsequently subsequently accelerate accelerate renal renal aging. aging. OnOn involved. Unfortunately, thisthis hypothesis hashas notnot been tested involved. Unfortunately, hypothesis been tested thethe other other hand, hand, thethe decreased decreased local local concentration concentration of of angioangio-yet.yet. tensin tensin II II that that occurs occurs after after ACE ACE inhibitor inhibitor treatment treatment could could DR.DR. NELIDA ELENO (Associate NELIDA ELENO 4ssociate Professor, NELIDA ELENO 4ssociate Professor, Department Professor, Department of of slow slow thethe aging aging process. process. ButBut as as I said, I said, neither neither thethe exact exact role role Physiology', Physiology, University University of of Saiwnanca, Salwi,anca, Salanianca, Spain): Spain): Did Did you you trytry to to of of angiotensin angiotensin II nor II nor thethe nature nature of of thethe changes changes in in thethe nitric nitric give give antioxidant antioxidanttreatment treatmenttotothose thoseodold rats rats that that you you oxide oxide system system hashas been been adequately adequately clarified clarified inin thethe pathogen. pathogen- presented presented in in your your talk? talk? esis of of aging in in thethe kidneys. More studies areare needed. esis aging kidneys. More studies needed. DR. DR. DR. RODR1GUEZ-PUYOL: RODR1GUEZ-PUYOL: RODR1GUEZ-PUYOL: WeWe We tried tried to determine determine whether whether tried to to determine whether DR. DR. M.ruEL. Muuei.PiG PRAG PiG(Assistant vitamin E could E could block block thethe expression expression of the of the TGFp TGF mRNA mRNA DR. M.ruEL. Professor of (Assistant (Assistant Professor Professor of Medicine, of Medicine, Medicine, vitamin Hospital Hospital "12"12 dede Octubre"): Octubre"): AsAs you you know, know, several several studies studies in in thethe renal renal cortex cortex ofof older older rats, rats, butbut wewe diddid notnot obtain obtain have have shown shown that that ACE ACE inhibitors inhibitors can can slow slow thethe progression progression of ofconclusive conclusive results. results. WeWe areare now now working working with with taurine, taurine, anan renal disease different clinical settings [109]. However, amino renal disease in in different clinical settings [109]. However, acid with antioxidant properties. It It seems that amino acid with antioxidant properties. seems that patients patients over over 65-70 65-70 years years oldold generally generally have have been been excluded excluded taurine taurine could could block block thethe mRNA mRNA expression expression of of some some collagen collagen from from these these studies. studies. DoDo youyou think think thatthat ACE ACE inhibitors inhibitors alsoalsotypes in in thethe renal cortex. However, these results areare very types renal cortex. However, these results very could could slow slow thethe progression progression of of thethe age-related age-related decline decline in inpreliminary. preliminary. renal function? renal function? DR. DR. MANUEL MANUEL MART1NEZ-MALDONADO MART1NEZ-MALDONADO (Professor of MediMART1NEZ-MALDONADO (Professor of of MediMedi(Professor DR. DR. R0DR1GuEz-PUY0L: R0DRIGuEz-PUY0L: WeWe believe believe that that ACE ACE inhibitors inhibitors cine, cine, Emoiy Emoiy University, University, Atlanta, Atlanta, Georgia, Georgia, USA): USA): Data Data sugsugcancan slow slow thethe progressive progressive decline decline of of renal renal function function in in thethegest a beneficial effect of of ACE inhibitors in reducing thethe gest a beneficial effect ACE inhibitors in reducing elderly. elderly. Our Our own own results results in in rats, rats, which which have have been been presented presentedaging-related aging-related morphologic morphologic and and functional functional renal renal alterations alterations rats rats [1101. [1101. Are Are there there studies studies of of a similar a similar nature, nature, or or previously previously [201, [20], support support this this contention. contention. However, However, nono studstud- in in iesies in in elderly human beings (older than 65—70 years) have elderly human beings (older than 65—70 years) have studies studies examining examining other other functional functional aspects, aspects, such such as as urine urine been performed. It would very interesting analyze, been performed. It would bebe very interesting to to analyze, ononconcentration concentration and and dilution, dilution, in in humans? humans? What What is the is the effect effect a long-term basis, thethe role ofof ACE inhibitors onon thetheof of a long-term basis, role ACE inhibitors nutrients onon renal function as as aging proceeds? Could thisthis nutrients renal function aging proceeds? Could bebe thethe reason patients were separated into three groups in in reason patients were separated into three groups progression progression of of aging-related aging-related renal renal changes. changes. Di. CARLOS Clinical CARLOS QUEREDA Di.Di. CARLOS QUEREDA (Chief, Clinical Section of NephrolQUEREDA (Chief; (Chief Clinical Section of NephrolSection of Nephrolthethe Baltimore Baltimore aging agingstudy study281? [281? R0DRIGUEz-PuyoL: RODR1GUEZ-PUYOL: R0DRIGuEz-PUY0L: Unfortunately, there there areare nono defdefogy, ogy, University University Hospital Hospital "Ramôn "RamOn y Cajal," y Cajal," Madrid): Madrid): AsAs thethe DR.DR. Unfortunately, kidneys kidneys areare mainly mainly vascular vascular organs, organs, to to what what extent extent dodo you you inite inite answers answers forfor your your questions. questions. The The ability ability ofof ACE ACE think think that that aging-related aging-related functional functional changes changes depend depend onon inhibitors to to prevent thethe aging-related morphologic and inhibitors prevent aging-related morphologic and structural vascular damage? other words, you believefunctional structural vascular damage? In In other words, dodo you believe renal changes hashas notnot been tested in in long-term functional renal changes been tested long-term

that that most most of of thethe renal renal dysfunction dysfunction is is a consequence a consequence of ofstudies studies in in humans. humans. With With respect respect to to thethe ability ability ofof ACE ACE arteriosclerosis? arteriosclerosis? inhibitors inhibitors to to modify modify thethe non-hemodynamic, non-hemodynamic, non-glomerunon-glomeruDR. D.R0DR1GuEz-PuyoL: RoDRIGuEz-PuYoL:That RODR1GUEZ-PUYOL: That alterations alterations that that characterize characterize renal renal aging aging in in men, men, nono data data DR. That very interesting question very very interesting interesting question question larlar available. available. ACE ACE inhibitors inhibitors might might prevent prevent interstitia' interstitial was was specifically specifically addressed addressed some some years years agoago [221. [221. Although Although it it areare

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Forum: Forum: Theaging The agingaging Nephroiogy Forum: The kidney kidney kidney Nephroiogy Nephroiogy

kines kines could could bebeinvolved involved ininthe the genesis ofofthe the renal changes changes kines could be involved ingenesis the genesis ofrenal the renal changes fibrosis fibrosis fibrosis ininaging aging in aging rats. rats.rats. Likewise, Likewise, Likewise, these these these agents agents agents might might might improve improve improve

that thatcharacterize that characterize characterize aging. aging. aging. You YouYou also alsoalso reviewed reviewed reviewed the therole the rolerole ofof of tubular tubular tubular function function function ininhumans, humans, in humans, but butthe hut thefunctional the functional functional improveimproveimproveendothelial endothelial endothelial constitutive constitutive constitutive NOS NOS NOS and andendothelin. and endothelin. endothelin. Did Didyou Did youtest you test test ment ment ment would would would bebevery very he very difficult difficult difficult totodistinguish distinguish to distinguish from from from the thehemothe hemohemoiNOS iNOS iNOS expression? expression? expression? dynamic dynamic modifications. modifications. Finally, Finally, one oneof ofthe the possible explaexpladynamic modifications. Finally, one ofpossible the possible explaDR.R0DRIGuEz-PUY0L: R0DRIGuEz-PuY0L: No, we wewe have have have not notnot tested tested tested iNOS iNOS iNOS DR. R0DRIGUEz-PUY0L:No, nations nations for forthe theexistence existence ofofthree three different different groups groups ininthe the nations for the existence of three different groups in theDR. No, expression expression ininaging aging kidneys. kidneys. However, However, we webelieve believe that thatthis thisthis expression in aging kidneys. However, we believe that Baltimore Baltimore Baltimore study study study could could could bebediet, diet, be diet, but butother other hut other afternatives afternatives alternatives exist, exist, exist, NOS NOS NOS isoform isoform isoform must mustmust bebeinvolved involved be involved ininthe the inaging aging the aging process, process, process, atatleast least at least asasI Isaid as said I before. said before. before. inthe the development ofofthe the functional changes, changes, aUhough aUhough we we we indevelopment the development offunctional the functional changes, although Dj. Dj.FRANCISCO FRANCISCO Dj. FRANCISCO ORTEGA (Head, Health-Related Quality ORTEGA ORTEGA (Head, (Head,Health-Related Health-Related Quality Quality ofof inof are arenot are notsure not suresure about about about the therelationships the relationships relationships between between between iNOS iNOS iNOS and andand Life LifeLife Unit, Unit, Unit, Hospital Hospital Hospital central central Central dedeAsturias, Asturias, de Asturias, and andNephrotogy Nephrotogy and Nephrolo' aging. aging. One OneOne ofofthe the firstfirst demonstrations demonstrations ofofaging-related aging-related Spain): Spain): InInour our aging. offirst the demonstrations of aging-related Research Research Research Instiri.ae Instiri.ae Institute "Reina "Reina "Reina Sofia, Sofia, Sofia," ' 'Oviedo, Oviedo, Spain): In our Oviedo, impaired impaired renal renal vasodilatlon vasodilatlon was wasperformed performed ininrats rats treated impaired renal vasodilation was performed in treated rats treated studies, studies, patients patients over overover 65 65years years undergoing undergoing chronic chronic hemodihemodistudies, patients 65 years undergoing chronic hemodiand and it it is is now it now is now a a welt-recognized welt-recognized a well-recognized fact fact that fact that that and alysis alysis alysis had hadahad aworse worse a worse quality quality quality ofoflife life ofthan life thanthan did didthose did those those ininthe the in the with withpyrogen with pyrogen pyrogen [1313 [1313 [131, some some of of the the components components of of pyrogen pyrogen induce induce iNOS iNOS expresexpressome of the components of pyrogen induce iNOS expresnormal normal normal population population population randorny randorny randomly selected, selected, selected, but butelderly but elderly elderly patients patients patients sion. sion.sion. with withwith a afunctioning functioning a functioning kidney kidney kidney graft graft graft had hadahad asimilar similar a similar quality quality quality ofof'ife, 'ife, of life, DR.DR. DIEz: DIEz: Diego, Diego, atatthe the vascular level, level, one oneof ofthe the most DIEz: Diego, atvascular the vascular level, one ofmost the most even eveneven better better better ininsome some in some dimensions, dimensions, dimensions, than thanthan this thisnormal this normal normal populapopulapopula-DR. important important sources sources ofofROl ROl isisthe the NADP-NADPH oxidase oxidase important sources of ROl isNADP-NADPH the NADP-NADPH oxidase non tion[Ill]. tion [Ill]. [111]. Do Doyou you Dothink think you think that thatathat afunctioning functioning a functioning kidney kidney kidney transtranstranssystem. system. An Anoverproduction overproduction ofofROl ROl has hasbeen beenbeen reported reported ininthe the system. An overproduction of ROl has reported in the plant plant plant caji cajidelay can delay delay the theconsequences the consequences consequences ofofgeneral general of general aging aging aging on on on quality quality quality ofoflife? life? of life? aorta aorta aorta from fromfrom spontaneously spontaneously spontaneously hypertensive hypertensive hypertensive rats rats[1121. rats [1121. [1121. Havc Havc Have you youyou any information concerning possible alterations in the I Iam notfamiliar not familiar familiar with your data datadata any anyinformation information concerning concerning possible possible alterations alterations ininthe the amInot am Dg. Dg.R0DRiGUEz-PuvoL: D. R0DRiGUEz-PuY0L: RoDRIGuEz-PuvoL: withwith youryour expression expression ofofthis this enzyme ininthe the kidneys from from old oldnormonormoexpression of enzyme this enzyme inkidneys the kidneys from old normoon onquality quality ofoflife, life, butIhut Ido donot believe that thatrenal renal transplantransplanon quality of but life, I not dobelieve not believe that renal transplantensive rats? rats?rats? tation tation tation specifically specifically specifically de'ays de'ays delays the theconsequences the consequences consequences ofofaging. aging. of aging. I I tensive I tensive DR.R0DRIGuEz-PuYo1.: R0DRIGuEz-PuYol.: We Wehave have notperformed performed this thiskind kind DR. RODR1GUEZ-PuY0L: Wenot have not performed this kind believe believe believe that thatathat arenal renal a renal graft graft graft improves improves improves the thequality the quality quality ofoflife life of in life in in DR. ofofanalysis analysis of analysis and, and,and, totomy my toknowledge, my knowledge, knowledge, this thisspecific this specific specific information information information every every patient, patient, including including the theelderly, elderly, ininsuch such a asignificant significant way wayway every patient, including the elderly, in such a significant has hasnot notbeen beenbeen published. published. But ButitBut itwould would bebevery very interesting interesting toto to has not published. it would be very interesting that thatusual that usual usual quality-of-life quality-of-life quality-of-life tests teststests cannot cannot cannot detect detect detect significant significant significant analyze analyze the theNADP-NADPH the NADP-NADPH NADP-NADPH oxidase oxidase oxidase system system system ininaging, aging, in aging, asas as differences differences differences between between between the thegrafted the grafted grafted and andnormal and normal normal populations. populations. populations.analyze DiviDivi-Divisome some some vasoactive vasoactive vasoactive factors, factors, factors, particularly particularly particularly angiotensin angiotensin angiotensin II,II,stimustimuII, stimuDR. DR.ALBERTO DR. ALBERTO ALBERTO MARTINEZ-CASTELAO MARTINEZ-CASTELAO MARTINEZ-CASTELAO (Chief, (Chief, (Chief Dialysis Dialysis Dialysis late lateROl late ROlROl synthesis synthesis synthesis by byactivating activating by activating this thissystem. this system. system. The TheNADPThe NADPNADPsion, Bellvi:ge CS. (lB., Barcelona,Spain): Spain):In In our experision, sion, Bellvi:ge Bellvi:ge c.S. c.S. U.B., U.B., Barcelona, Barcelona, Spain): Inour ourexperiexperiNADPH NADPH oxidase oxidase system system could could constitute constitute the thelink linkbetween between NADPH oxidase system could constitute the link between eiice. ence. ence. more more more than thanthan 50% 50%50% ofofpatients patients of patients with withwith nonsteroidal nonsteroidal nonsteroidal antiinantiinantiinananincreased increased synthesis synthesis ofoflocal local mediators mediators and andROl ROlROl overprooverproan increased synthesis of local mediators and overproflammatory flammatory fiammatory drug drugdrug nephrotoxicity nephrotoxicity nephrotoxicity are arediagnosed are diagnosed diagnosed after afterafter age age65. age 65. 65. duction. duction. duction. Do Doyou Do youhave you havehave any anyevidence any evidence evidence that thatrelates that relates relates ROl ROloverproduction ROl overproduction overproduction with withwith this thisincreased this increased increased sensitivity? sensitivity? sensitivity? DR. DR.DR. Juuo Juuo Juuo PAScUAL PAscui PAscuAI (Division (Division (Division of of Nephro!og Nephro!og of Nephro!og Hospital Hospital Hospital DR. DR.RODR1GUEZ-PUYOL: DR. RODR1GUEZ-PUYOL: R0DRIGUEZ-PUYOL: To my knowledge, nonsteroidal "Ramón "Ramón yyCajal," Cajal," Madrid): Madrid): Looking Looking atataging aging asasaaas slowly slowly To Tomy myknowledge, knowledge, nonsteroidal nonsteroidal "Ramón y ('ajal," Madrid): Looking at aging a slowly progressive progressive progressive death death death process, process, process, do doyou you do think you think think that thatROl that ROlROl play playplay aa a antiinflammatory antiinflammatory antiinfiammatoiy drugs drugs drugs do donot not doinduce not induce induce ROl ROlROl overproduction. overproduction. overproduction. relevant relevant relevant role role in role in high high in high morbidity-mortality morbidity-mortality morbidity-mortality conditions conditions conditions such such such as as as En Enfact, fact, En fact, cyclo-oxygenase cyclo-oxygenase cyclo-oxygenase and andlipoxygenase and lipoxygenase lipoxygenase activation activation activation might might might acute acute acute renal renal renal failure failure failure with withwith multiorgan multiorgan multiorgan failure, failure, failure, ororeven even or even chronic chronic chronic bebelinked linked be linked totoROl ROl to ROl synthesis. synthesis. synthesis. The Thedeleterious The deleterious deleterious effect effect effect ofofthese these of these agents agents ininelderly elderly individuals individuals must must bebedue, due, asasininas other other renal renal agents in elderly individuals must be due, in other renal dialysis dialysis dialysis ininelderly elderly in elderly patients? patients? patients? DR.RODRIGUEZ-PUYOL: DR. RODRIGUEZ-PUYOL: RODR1GUEZ-PUYOL: From From From a atheoretical theoretical a theoretical point point point ofofview, view, of view, diseases, diseases, totothe the importance ofofarachidonic arachidonic acid acidacid derivatives derivatives diseases, toimportance the importance of arachidonic derivativesDR. the theanswer the answer answer isisyes. yes. is Reactive yes. Reactive Reactive oxygen oxygen oxygen intermediates intermediates intermediates might might might bebe be ininthe the inmaintenance the maintenance maintenance ofofrenal renal of renal function. function. function.

increased increased increased ininthe the inpatients the patients patients that thatyou that youhave you have have mentioned, mentioned, mentioned, and andand DR. DR.FERNANDO FERNANDO VALDERRABANO VALDERRABANO (Professor (Professor ofofMedicine, Medicine, DR. FERNANDO VALDERRABANO (Professor of Medicine, aging aging could could increase increase local local synthesis synthesis ofofthese these mediators. mediators. aging could increase local synthesis of these mediators. University University University Hospital Hospital Hospital "Gregorio "Gregorio "Gregorio Marañón," Marañón," Marañón," Madrid): Madrid): Madrid): Diego, Diego, Diego, However, However, the theMadrid Madrid Acute Acute Renal Renal Failure Failure Study Study Group Group However, the Madrid Acute Renal Failure Study Group congratulations congratulations congratulations for foryour for youryour excellent excellent excellent review. review. review. Nowadays, Nowadays, Nowadays, we we we the theprognosis prognosis ofofacute acute renal renal failure failure ininolder older determined the prognosis of acute renal failure in older frequently frequently frequently transplant transplant transplant organs organs organs from from from donors donors donors older older older than thanthan 65 65toto 65 determined todetermined patients totobe be tosimilar similar be similar totothat that to that ininyounger younger in younger patients patients patients [1131; [1131; [1131; young young patients. patients. IsIsthere there any anyevidence evidence regarding regarding changes changes inin patients young patients. Is there any evidence regarding changes inpatients these these data data suggest suggest that that age age is is not not a a particularly particularly poor poor these data suggest that age is not a particularly poor the theprocess the process process ofofaging aging of aging ininthese these in these cases? cases? cases? DR. DR.RODRIGUEZ-PUYOL: RODRIGUEZ-PUYOL: Transplantation Transplantation ofofold old kidneys DR. RODRIGUEZ-PUYOL: Transplantation ofkidneys old kidneys prognostic prognostic prognostic sign. sign.sign. ask TheThe HARRINGTON: HARRINGTON: LetLetme me Let ask methe the asklast last thequestion. question. last question. The DR. DR. HARRINGTON: into intoyoung into young young patients patients patients could could could bebeaabe very very a very interesting interesting interesting model model model for for forDR. analyzing analyzing the therelative relative importance importance ofofgenetic genetic and andambient ambient analyzing the relative importance of genetic and ambient patients you presented had iatrogenic renal problems. patients patients you youpresented presented both bothboth had hadiatrogenic iatrogenic renal renal problems. problems. How How How should should should we wedeal we dealdeal with withwith our ourincreasing our increasing increasing aging aging aging population population population factors factors factors ininthe the indevelopment the development development ofofaging-related aging-related of aging-related renal renal renal changes. changes. changes. This ThisThis question question has hasnot notbeen beenbeen systematically systematically considered, considered, and andI and I toto prevent to prevent the thetype the typetype ofofproblems problems of problems seen seenseen ininyour your in your patients? patients? patients? question has not systematically considered, Iprevent DR.R0DRIGuEz-PuYoL: DR. RODRIGuEz-PuYOL: R0DRIGUEz-PuY0L: If Ifyou you Ifconsider you consider consider the thetwo the twopatients two patients patients beHeve beHeve that thatthat taking taking into intointo account account the thecomplex complex situation situation ofof of DR. believe taking account the complex situation

whom whom whom I Ipresented, presented, I presented, the theproblems the problems problems began began began inintwo two in different two different different the thetransplant the transplant transplant recipient. recipient. recipient, ititwill will it will bebevery very he very difficult difficult difficult totoreach reach to reach significant significant conclusions conclusions from from these these kind kind of of grafts. grafts. significant conclusions from these kind of grafts. settings. settings. settings. InInthe the Insecond the second second case, case, case, nephrotoxic nephrotoxic ncphrotoxic drugs drugs drugs were were were prepre-prescribed scribed scribed by bygenera' genera' by general physicians physicians physicians on onanan onoutpatient outpatient an outpatient basis. basis. basis. GenGenGenDR. DR.SANTOS DR. SANTOS SANTOS CAsADO CAsADO (Head. (Head.(Head. CASADO Nephrok Nephrok Nephrolo Department, Department, Department, FunFun-Funeral eraleral physicians physicians must must be beextensively extensively and andrepeatedly repeatedly inin- inphysicians must be extensively and repeatedly dación dación dación Jirnénez Jirnénez Jinienez DIaz. DIaz. DIaz. Mad,id): Mad,id): Madrid): Dr. Dr.RodrIguez-Puyol, Dr. RodrIguez-Puyol, RodrIguez-Puyol, ininyour your in your formed formed formed about about about the thepotential the potential potential nephrotoxicity nephrotoxicity nephrotoxicity ofofthree three of three kinds kinds kinds ofof of presentation. presentation. you youmentioned mentioned that thatROl ROlROl and anddifferent different cvtocvtOpresentation. you mentioned that and different cyto-

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Ne'phro1o !ve'phroloKc Forum: Forum: The aging The aging kidney kidney

RL.tz-ToREs RL.iz-ToREs NIP.NIP. RLIZ-TORRES RI OV.\t.LE BOSCH BOSCH RI OV.i.LE RJ. 0VALLt1 F.F. G.ck F.GARCk GARCIA DEL DEL MORAL DEL R. MORAL MORAL R. R. drugs. nonsteroidal antiinflammatorv drugs. ACE inhibi- 20. 20. drugs. nonsteroida nonsteroida antiinflammatorv antiinflammator drugs. drugs, ACE ACE inhibiinhibiRAMIREZ C. C.MASSEROL1 MASSEROL1 C. MASSEROL1 IGLESLS M, PREZ-CABALLERo PREZ-CAB.LERO C,C,IGLESLS MC, M, PREZ-CAB.LERO C, IGLEStAS MC, MC, tors, tors, andand diuretics. diuretics. diuretics. particularly particularly they if they areare prescribed prescribed to-to- RAMIREz ifif they are prescribed toRODRiGI,Ez.PuvoL D: Age.rdated RDRiGLEZ-PLVOL NI,RoDRk;uczPu\ RoDRk;uczPu\ RooRic,ucz-Pu\ot. OL D: Age-rciated increased increased increased RDRiGLEZ-PLVOL NI. NI, Age-related gether. gether. Within Within thethe hospital, hospital, as was as was thethe case case with with thethe first first thekidney. rat kidney. otTGFp1 in Relationship Relationship to morphologic morphologic to morphologic expression otTGFp1 in he heinrat rat kidney. Relationship to expression ofTGF-p1 expression So Sot Nephml. in press changes. changes. J Am J Ant M'phrol. in patient. patient. thethe probkm problem is more is more comp'ex. complex. TheThe situation situation of of thethe in press press PELE(; 1,1,GREENFELD GREENFELD Z.Z. COOPERMAN CoorER1AN SHosu; 21. PELEC; I, GREENFELD Z. COOPERMAN H,H,SHosu; H, SHosu. S:S:Type S: Type IIand type type Type andland type patient is more critical, more potentially nephrotoxic drugs patient is more critical, more potentially nephrotoxic drugs 2L P)LE(; ITt coIIgen III collagen rnRNA mRNA levels levels in kidney in kidney regions regions of ld of and old and young young rats.rats. and used, and and intravenous intravenous fluid fluid therapy therapy frequently frequently areare used, intravenous fluid therapy frequently is is Thtri Thtrit 13:28—287. 13:281—287. 19931993

UOLLENBERG UOLLEr8ERG UOLLEr8ERG NK. NK.NK. AnAMS AnAMS AnAsts DF. DF.SOLOMON DF, SoLoIoN SOLOMON HS, HS,RA5HID RA5HID HS, R\SHID A. A. ARRAMS ARRAMS A. ARRAMS needed. needed. In In addition addition to adequate to adequate monitoring monitoring of of thethe extraextra- 22. 22.

I-IL.HL. MIiRRILL MERRILL JP: Senescence JP: Senescence andand thethe renal vasculature in normal renal vasculature in normal cellular cellular volume volume status status andand biochemical biochemical parameters, parameters, as well as well man. CircCirc man. RcsRes Res 34:309—31974 16.1974 34:309—316. as to as judicious to judicious useuse of drugs of drugs andand fluids, fluids, early early contact contact with with thethe 23. 23. NAEIJE NAEtJ NAEU R. Fr.ssE FrsSE R. FrssSE A. A. CAILIER E. OPsoNIER CARLIER A. CARI.IER OPsoNIER E. OPsoNtER M, M, LEEMAN M, LEEMAN LEEMAN M: M: Systemic Systemic M: Systemic effects renal hemodynamic andand renal hemodynamic effects of angiotensin converting enzyme of angiotensin converting enzyme nephrology nephrology team team may may avoid avoid unnecessary unnecessary complications. complications.

inhibition by zahicipril in young andand n old in normal old normal men.men. EurJEu,cmI ClOt inhibition by zahicipril in young P/ia,maco! P/,a,maco! P/ia,maco! 44:35—39. 44:35—39. 19931993 Reprint Reprint requests nqucxts requests to to Di Di toB. B. Di:Rodriguez-Puyo!. Rodriguez-Puyo!. D. Rodriguez-Puyol. chief chief chief Vephro!ogv Vephro!ogv Nephrologv Section, Section, Section, 24. BAYL!S BAYLLS FREDERICKS 24. BAYC, LIS C, FREDERIcKs M, WiLsoN C. MUNGER MUNGER C, MONGER K,K,COWNs K, COwNs COWNS R: R:Rena' R: Rena' Renal C, FREDERICKS M, WILSoN M, Hospücd Hospital 'PrIncipe "PrIsu'ipe deAsrurias, Asrurias, de Asrurias, Alcalá "Alcald de Henares, Henares. de Henares, 2&'O5 28805 !4adr4 !!adr4 !4adrid, Spain Spain Hospücd 'PrIncipc de " Alcalá to aging rat kidney. kidney. vasodilatorv response to intravenous glycine in the aging rat vasodilatory response to intravenous glycine in the aging rat kidney. vasodilatorv response

AmlKidnevDis AmlKidnevDis 19901990 15:244—251, 15:244—251, 25.25. RCKELHO RcKELHo iF, MAxING RD: of endotheliurn-derived RECKELHOFE M.ING iF, MANNING RD: Role Role RD: Role of endotheliurn-derived of endothelium-derived nitric nitric oxide in control oxide in control of renal of of renal microvasculature in aging in aging male male rats. Am J 3 microvasculature AmAm rats. TheThe from studies studies inciuded included in in this this in this discussion discussion discussion were were supported supported by grants by grants from from 19931993 Physio! Ph'siol 265:R1126—R1131, 265:R1126—R113l, the andand F1SS F1SS the the CICYT CICYT (SAF-93.0713, (SAF.93-0713, Prin PrinCICYT (95/0027). (95/0027). TheThe SAF-98.0054) SAF-98-0054)

ACKNOWLEDGMENTS ACKNOWLEDGMENTS

iLII.V0RA VORA LEOUGHTON 2.6. T.K T.KH. V0RAJP, JP,LEOuGHTON ll000FcroNDC, DC, ANDERSON ANDERSON 5: Altered 5: S: Altered renal renal cipal would like to cipal Discussant would to thank R. Garcia Moral, Lopez 2.6. dpal Discussant would likelike to thank thank R. R. Garcia Garcia del del del Moral, Moral, i.M.J.M. Lopez vascu'ar vascu'ar vascular responses responses the in aging the aging aging rat kidney. rat kidney. Am AmAm J Physio! I Physiol 266:F942— 26:F942.responses inin the Novoa, Novoa, F.i. F.J. Lucin. Lucio. M. M.Rodriguez-Puyol, M. RodrIguez-PuyoL, and andand S. S.Lamas Lamas S. Lamas for fortheir their valuable valuable for their valuable Rodriguez-Puyol, F948, F948, 1994 1994 helphelp in the preparation of ofthis this manuscript. in the preparation of this manuscript. preparation manuscript. 27. 27. C: The RECELHOFF RECIc.ELHOFF RECKELHOFF iF,iF,SAMSLL iF, SAMSLL SAMSELL L, DY L, DEY R, RAcUSEN L,BAYLIS BAYLIS L, BAYLIS C: The R, R, RACUSEN RACUSEN L, L, of effect effect of 1ging of aging on glomerular glomerular on glomerular hemodynarnics hemodynarnics hemodynamics in the in the rat. rat. AmAm J Kidney J Kidney on 1ging REFERENCES REFERENCES

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Gurn L:

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SAYERS SAYERS HG, HG, ORLOFI ORLOFI Mi:MJ: Quantitative Quantitative morphological morphological Ageing Dcv 84:1—13. studies studies uf agilg of aging changes changes in inkidney the kidney of ofLewis the Lewis rat. rat.Rena! rat. Rena! Renal Phvsio! Phvsiol 1995 1995 1995 changes in the the kidney of the the Lewis Effect ofage 42. 42. ARMBRECHT ARMBRECHT Hi. FORTE Hi. FORTE LR, LR, HALLORAN HALLORAN Effect of age dietary BP: BP: Effect of 7:176.-L84. 1984 1984 and dictary 7:176—184, LR,HALLORAN age andand dictary calcium on on rcnal rcnal 25(OH)D metabolism, serum 19. 19. ABRASS ABRSS ABRASS CK. CK. CK. ADcox ADcox Aocox Mi, Mi,RAUGI RAUGI Gi: Gi:Aging-associated Aging-associated changes changes inin in calcium calcium on renal 25(OH)D 25(OH)D metabolism, metabolism, serum serum 1,25(OH)_D, l,25(O1-t)D, and and Mi, RuGI Gi: 1,25(OH)_D, and changes Aging-associated Am J Phvio! renal extraceltular matrix. A,n Am JJ Patho! Patho! 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43. 43.STRIKER STRIKER 43. STRIKER GE, PETEN GE, PETEN PETEN EP.YANG EP, YANG YANG CW, STRIKER STRIKER STRIKER U: U:Glomeruloscierosis: U: Glomeruloscierosis: EP. Glomeruloscierosis: ness nessof ofvascular smooth ness vascular of vascular smooth smooth muscle muscle muscle with withincreasing with increasing increasing J Phonnacol J P/wrmacol P/wrmacol E'cpE'cp GE, CW,CW, age. age.Jage. E'cp Studies of its pathogcncsis in humans and animals. Contrib Nephrol Studies Studies ofofitsits pathogencsis pathogencsis ininhumans humans and andanimals. animals. Con Conn-lb Ther249:R12— 249:R12— Ther Ther 249:812—819, 819, 19891989 n-lbNephrol Nephrol 819,1989 1994 19941994 107:124—131, 69.CHIN 107:124—13L 107:124—13L 69. 69. CHIN CHIN iH, iH,HREMATH JH. HREMATH HIREMATH AN, AN,HOFFMAN HOFFMAN AN, HOFFMAN BB: BB: cAMP BB: cAMP signa'ing signa'ing signaling mechamechamecha-

44. 44.Ecno 44. Ecno Eoino J:J:Nephrolo Nephrology J: Nephrolo' Forum: Forum: Forum: Vasoactive Vasoactive Vasoactive hormones hormones hormones and and renal and renalsclerenal scle-scle-

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Physiol I Physiol 267:F35—F43, 267:F35—F43, 1994 AmI Am I Physiol 267:F35—F43, 19941994 46. 46. BROWN BROWN i:i: Regulation 46. BROWN RoBsoN Z, RoBsoN WESTWWK RL, WEST1CK J: Regulation and expression RL, and ofof of71. 71.HEGST,D HEGST,D R,R, BROWN BROWN Z,Z,RonsoN N, N, KAO KAO P.P.WENs11Iu3ouM WENSHIU3OUM RM, RL,WESTWWK 71. HEOSTAD R, BROWN R, JIANG N, K.AO P. WEINSIIIu3OUM Regulation andexpression expression Jur'o R,R,Jur'o RM,RM, cheniokines: Potential role rolein ing)omeruionephritis. g)omeruionephritis. Leukoc BiolBiol STRONG cheniokines: Potential cheruokines: Potential role in glomerulonephritis. I ILeukoc J Leukoc Biol and STRONG STRONG WISGERHOF C, WI5GERHOF M: Aging and aldosterone J Med C, WISGERHOF Aging and a)dosterone .AniAm JJMed .Ani Med M:M:Aging 59:75—80, 59:75—80, 59:75—80, 1996 19961996 19831983 74:442—448, 1983 74:442—448, 74:442—448, MOONEY it What 47. 47.S.WTLL S.WTLL 47. SWILL HUGHES it What role does apoptosis playin in in72. A, HUGHES J: role What does role apoptosis does apoptosis play play A.A.HUGHES 72.OHASHI 72. OH ASH! M, Fuilo N, NAWATA K, OHASHI Fwio N,NAWATA NAWATA H,KATO KATO K,1R.vASjIL 1R.vASjIL K, lR,\YAsItt KANGA\*A H, K.ANGA\A K. K. K. i,i,MOONEY I, MooNey N, H,H,KANGA\*A M,M,Fuiio H, H, KATO progression progression progression ofofrenal renal of renal iiseasc? iiseasc? disease? Curr CurrCurr H:H:High MAISUO MAISUO H: plasma High plasma concentration of human alrial natriuretic High plasma concentration concentration ofofhuman human airial airial natriuretic natriuretic Opin OpinOpin Nephrol Nephrol Nephrol Hyperiens Hyperiens Hyperiens 5:369— 5:369— 5:369— MAISUO 374. 374. 374.1996 19961996 J JClin peptide peplide aged in aged man. man. Clin I Clin Endocnnol EndocrinolMetob 64:81—85, 1987 1987 Endocnnol Metob Metob 64:81—85, 64:81—85, 1987 peptide ininaged man. 48.BORDER 48. 48. BoRDER BORDER WA. WA,WA. NonLr NonLr NOBLE NA: NA:TGF-heta TGF-heta NA: TGF-heta inin kidney kidney in kidney fibrosis: fibrosis: fibrosis: AA target target A for target for for73. 73.OR OR K, RICHARDS ESPINER EA,YANDLE YANDLE GLCHRIST 73.K, ORRICHARDS K, RICHARDS A, ESPINER EA, EA, YANDu T:T:GftCHRIST T, GILCHRIST N, SAINSSAINSA,A,ESPINER N,N,SAINS Kidney Ing 1997 BURY BURY genegene therapy. therapy. Kidney Kidney mt 51:1388—1396, 51:1388—1396, mt 51:1388—1396, 19971997 BURY R:R:Effect Effect R: Effect ofoflow low of dose dose lowinfusions dose infusions infusions ofofatrial atrjal of natriuretic atrial natriuretic natriuretic peptide peptide peptide in in in gene therapy. BM: 49.ANDERSON ANDERSON 49. BiiR 49. 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SCHAEFER L,L,TESCUNER TESCUNER L, TESC}INER M, M,LING LING M, LING H,H,OLD,KowsxA OLD,KowsxA H, OLD..KowsxA U,U, HEIDLAND HFJDLAND U, HEIDLAND A,A, A, there there there a ade&iency de&iency a de&iency ofofvasopressin? vasopressin? of vasopressin? Age AgeAgeing Age Ageing Ageing 22:114—120, 22:114—120, 22:114—120, 1993 1993 1993 SCHAEFER SCHAEFER SCHAEFER RM: RM:The RM: Therat aging rat kidney displays low glomerular DAVIDSON YS, YS,FOTHERINGIAM FOTHERINGIAM 76. DAVIDSON YS, FOTHERINGIAM DAVIES AP, DAVIES MORRIS 1, MoRRIS iA:iA:AgeAgeIA: AgeThe aging aging ratkidney kidney displays displays low lowg1omeruar g1omeruar and and and76.76.DAVIDSON AP, AP,DAVIES 1,1,Moiuus J JKidney tubular tubular tubular proteinase proteinase activities. activities. activities. Am AmAm J Kidney Dis DisDis 24:499—504, 24:499—504, 1994 1994 1994 related related postreceptor postreceptor mechanisms. mechanisms. Changes Changes n naden aden late.cclase late.cclasebut but but related postreceptor mechanisms. 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101. 101. TstLtn.s.Ry KoLIKos 00, 00, CHAISONIS AS, AS. VOGEL AM, AM, REcER REGER 101.TsiLIOARY TSILIa&RYEC, EC, KoLIKos KOLIAKOS CHAISONIS AS, VOGEL AM, REGER LA. FURCHT LA. FURCHT LT: LT: The The effect effectof nonenzymaticglucosylation glucosvlationon onthe the LA. FURCHT LT: The effect ofofnonenzymatic nonenzymatic glucosylation on the

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