TUBULAR AND INTERSTITIAL DISEASES

8/7/2019 TUBULAR AND INTERSTITIAL DISEASES

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sublethal endothelial injury:leading to increasedrelease ofthe vasoconstrictorendothelin anddecreasedproduction ofthe vasodilators nitricoxideandprostacyclin (prostaglandin I2).

y direct effectof ischemiaortoxinson the glomerulus reduced glomerularultrafiltration coefficient,possiblyduetomesangialcontraction

y The patchinessoftubularnecrosisandmaintenance oftheintegrityofthe basementmembrane along manysegmentsallow readyrepairofthe necrotic foci andrecoveryof function ifthe precipitating cause isremoved

y repairisdependenton the capacityofreversibly injuredepithelialcellstoproliferate anddifferentiate

y Re-epithelialization- mediatedbya varietyof growth factorsandcytokinesproducedlocallybythe tubularcellsthemselves(autocrine stimulation) orby inflammatorycells in the vicinityofnecrotic foci (paracrine stimulation)

y important in renaltubularrepair:oepidermal growth factor,oTGF-,o insulin-like growth factortype 1ohepatocyte growth factor

y Growth factorsare being exploredaspossible therapeuticagentsto enhance re-epithelialization in AKI

Morphologyy Ischemic AKI ischaracterizedbyo focaltubularepithelial necrosisatmultiple pointsalong the

nephron

owithlarge skipareas in betweenooften accompaniedbyrupture ofbasementmembranes(tubulorrhexis) andocclusion oftubularlumensbycasts

y The straightportion ofthe proximaltubule andthe ascendingthick limb in the renalmedulla vulnerable

y focallesionsmayalsooccurin the distaltubule,often inconjunction withcasts

y the clinicalsyndrome of AKI isoften associated withlesserdegreesoftubular injury. Includes:oattenuation orlossofproximaltubule brushbordersosimplification ofcellstructure

ocellswelling and vacuolizationosloughing of non-necrotictubularcells intothe tubular

luminay The severityofthe morphologic findingsoften does not

correlate well withthe severityofthe clinicalmanifestations.y Eosinophilichyaline casts,as wellaspigmented granular

casts,are common,particularly in distaltubulesandcollecting

ductsy these castsconsistprincipallyof Tamm-Horsfallprotein(a

urinary glycoprotein normallysecretedbythe cellsofascending thick limbanddistaltubules) in conjunction withotherplasmaproteins.

y Otherfindings in ischemic AKI:o interstitial edemaoaccumulationsofleukocytes within dilated vasarecta

y There isalso evidence of epithelialregenerationo flattened epithelialcells withhyperchromatic nucleiomitotic figuresare often present

* In the course oftime thisregeneration repopulatesthe tubulessothat, noresidual evidence ofdamage isseen.y Toxic AKI ismanifestedbyacute tubularinjury,mostobvious in

the proximalconvolutedtubulesy On histologic examination the tubularnecrosismaybe entirely

nonspecific,but it issomewhatdistinctive in poisoning withcertain agentsomercuricchloride severely injuredcellsmaycontain large acidophilic

inclusions Later,these cellsbecome totally necrotic,are

desquamated intothe lumen,andmayundergocalcification

oCarbon tetrachloride poisoning characterizedbythe accumulation of neutrallipids in

injuredcells fattychange is followedby necrosis

oEthylene glycol producesmarkedballooning andhydropicorvacuolar

degeneration ofproximalconvolutedtubules Calciumoxalate crystalsare often found in the tubular

lumens in suchpoisoning

Clinical Coursey highly variabley classiccase maybe divided into:o initiation phase lasts forabout 36 hours dominatedbythe inciting medical,surgical,orobstetric

event in the ischemic formof AKI. The only indication ofrenal involvement isaslightdecline

in urine output witharise in BUN oliguriacouldbe explainedon the basisofatransient

decrease in blood flow anddeclining GFRomaintenance phase characterizedby: sustaineddecreases in urine outputtobetween 40 and

400 mL/day (oliguria) saltand wateroverload rising BUN concentrationshyperkalemiametabolicacidosisothermanifestationsofuremia


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Withappropriate attention tothe balance of waterandblood electrolytes, including dialysis,the patientcan besupportedthroughthisoliguriccrisis

o recoveryphase ushered in byasteady increase in urine volume thatmay

reachupto 3 L/day tubulesare stilldamaged,solarge amountsof water,

sodium,andpotassiumare lost in the floodofurine Hypokalemia,ratherthan hyperkalemia,becomesaclinicalproblem

There isapeculiarincreased vulnerabilityto infection atthisstage

Eventually,renaltubularfunction isrestoredandconcentrating ability improves

BUN andcreatinine levelsbegin toreturn to normal Subtle tubular functional impairmentmaypersist for

months,butmostpatients whoreachthisphaseeventuallyrecovercompletely.

y The prognosisof AKI dependson the clinicalsetting.y Recovery is expected with nephrotoxic AKI when the toxin has

notcausedseriousdamage tootherorgans,suchasthe liverorheart.

y 95% recovery in shock relatedtosepsis, extensive burns,orothercausesof

multi-organ failure - mortalityrate: > 50%.y 50% ofpatients with AKI do nothave oliguriabuthave

increasedurine volumes =nonoliguric AKIooccursparticularlyoften with nephrotoxinsogenerallytendsto follow amore benign clinicalcourse.

TUBULOINTERSTITIAL NEPHRITISy This groupofrenaldiseases ischaracterizedbyhistologicand

functionalalterationsthat involve predominantlythe tubulesand interstitium.

y chronictubulointerstitial injurymayoccurin diseasesthatprimarilyaffectthe glomerulus - an importantcause ofprogression in tubulointerstitial nephritis

y Secondarytubulointerstitial nephritis ispresent in a varietyofvascular,cystic (polycystic kidneydisease),andmetabolic(diabetes) renaldisorders, in which itmayalsocontribute toprogressive damage

y Glomerularand vascularabnormalitiesmayalsobe presentbut eitherare mildoroccuronly in advancedstagesofthesediseases.

Causesof Tubulointerstitial Nephritis

INFECTIONS

Acute bacterialpyelonephritisChronicpyelonephritis (includingreflux nephropathy)Otherinfections (e.g., viruses,parasites)

TOXINS

DrugsAcute-hypersensitivity interstitial nephritisAnalgesicsHeavymetalsLead,cadmium

METABOLIC DISEASES

Urate nephropathyNephrocalcinosis (hypercalcemic nephropathy)

Acute phosphate nephropathyHypokalemic nephropathy

Oxalate nephropathyPHYSICAL FACTORS

Chronicurinarytractobstruction

NEOPLASMS

Multiple myeloma (light-chain cast nephropathy)IMMUNOLOGIC REACTIONS

Transplantrejection

Sjgren syndromeSarcoidosis

VASCULAR DISEASESMISCELLANEOUS

Balkan nephropathyNephronophthisismedullarycysticdisease complex

Idiopathic interstitial nephritis

y Tubulointerstitial nephritiscan be:oAcute hasarapidclinicalonset characterizedhistologicallyby interstitial edema often accompaniedbyleukocytic infiltration ofthe

interstitiumandtubules,and focaltubularnecrosisochronic there is infiltration withpredominantlymononuclear

leukocytes,prominent interstitial fibrosis,and widespreadtubularatrophy.

Morphologic featureshelpful in separating acute fromchronictubulointerstitial nephritis: Edema, eosinophilsand neutrophils = acute form fibrosisandtubularatrophy = chronic form

y distinguishedclinically fromthe glomerulardiseasesbytheoabsence, in earlystages,ofsuchhallmarksof glomerular

injuryas nephriticornephroticsyndromeopresence ofdefects in tubularfunction maybe subtle include: impairedabilitytoconcentrate urine, evidenced

clinicallybypolyuriaornocturia salt wastingdiminishedabilityto excrete acids (metabolicacidosis) isolateddefects in tubularreabsorption orsecretion.

advanced forms - difficulttodistinguishclinically fromothercausesofrenal insufficiency

PYELONEPHRITIS AND URINARY TRACT INFECTIONy Pyelonephritis isarenaldisorderaffecting the tubules,

interstitium,andrenalpelvisy one ofthe mostcommon diseasesofthe kidneyy two formsoAcute pyelonephritis causedbybacterial infection renallesion associated withurinarytract infection

oChronicpyelonephritis isamore complexdisorder bacterial infection playsadominantrole otherfactors (vesicoureteralreflux,obstruction) are

involved in itspathogenesisy aseriouscomplication ofurinarytract infectionsthataffectthe:obladder(cystitis)o the kidneysandtheircollecting systems (pyelonephritis)oorboth


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y Bacterial infection ofthe lowerurinarytractmaybe completelyasymptomatic (asymptomaticbacteriuria) andmostoftenremainslocalizedtothe bladderwithoutthe developmentofrenal infection

y lowerurinarytract infection alwayscarriesthe potentialofspreadtothe kidney

Etiologyand Pathogenesis.y The dominant etiologicagents (>85% of UTI):ogram-negative bacilli - normal inhabitantsofthe intestinal

tract Escherichiacoli mostcommon Proteus Klebsiella Enterobacter

oStreptococcus faecalis,alsoof entericoriginoStaphylococci

y virtually everyotherbacterialand fungalagentcan alsocauselowerurinarytractandrenal infection

y In immunocompromisedpersons (eg. those withtransplantedorgans) - virusescan be acause ofrenal infection:oPolyomavirusoCytomegalovirusoadenovirus

y mostpatients with UTI - infecting organismsare fromthepatient'sown fecal flora = endogenous infection

y tworoutesby whichbacteriacan reachthe kidneys:o throughthe bloodstream (hematogenous infection) lesscommon results fromseeding ofthe kidneysbybacteria from

distant foci in the course ofsepticemiaorinfectiveendocarditis

more likelytooccurin the presence ofureteralobstruction in debilitatedpatients in patientsreceiving immunosuppressive therapy with nonentericorganisms (e.g. staphylococci andcertain fungi and viruses)

o fromthe lowerurinarytract (ascending infection). mostcommon cause ofclinicalpyelonephritis

* Normalhuman bladderandbladderurine are sterile;therefore,a numberofstepsmustoccurforrenalinfection tooccur: 1ststep:colonization ofthe distalurethraand introitus

(in the female) bycoliformbacteriay colonization is influencedbythe abilityofbacteriato

adhere tourethralmucosal epithelialcellsy bacterialadherenceinvolvesadhesive molecules

(adhesins) on the P-fimbriae (pili) ofbacteriathatinteract withreceptorson the surface ofuroepithelialcells

y Specificadhesins (e.g.,that encodedbythepyelonephritis-associatedpili [pap] gene) areassociated with infection

y certain typesof fimbriae promote renaltropism,persistence of infection,oran enhancedinflammatoryresponse

Fromthe urethratothe bladder,organisms gainentrance during urethralcatheterization orotherinstrumentationy Long-termcatheterization risk of infection

y urinary infectionsare muchmore common infemalesin the absence of instrumentationodue toshorterurethra in femalesoabsence ofantibacterialpropertiessuchasare

found in prostatic fluidohormonalchangesaffecting adherence of

bacteriatothe mucosa

ourethraltraumaduring sexual intercourseocombination ofthese factors. Urinarytractobstruction andstasisofuriney Normal:organisms introduced intobladder

clearedbycontinual flushing of voiding +antibacterialmechanisms

y outflow obstruction orbladderdysfunction inincomplete emptying and increasedresidual volumeofurine

y In stasis:bacteria introduced intobladdercanmultiplyunhindered withoutbeing flushedoutordestroyed

y UTI isparticularly frequentamong patients withlowerurinarytractobstruction:o benign prostatichypertrophyo tumorso calculio neurogenicbladderdysfunction causedby

diabetesorspinalcord injury. Vesicoureteralreflux.y incompetence ofthe vesicoureteral valve - allows

bacteriatoascendthe ureterintothe renalpelvis.y normalureteral insertion:competentone-way valve

- preventsretrograde flow ofurine (duringmicturition) when the intravesicalpressure rises

yAn incompetent vesicoureteralorifice allowstherefluxofbladderurine intothe ureters(vesicoureteralreflux)

y Reflux ismostoften due toacongenitalabsence orshortening ofthe intravesicalportion ofthe ureter ureteris notcompressedduring micturition

y bladderinfection itselfcan cause oraccentuatevesicoureteralrefluxoasaresultofthe action ofbacterialor

inflammatoryproductson ureteralcontractility,,particularly in children

y affect 1% to 2% ofotherwise normalchildrenyAcquired vesicoureteralreflux in adults

persistentbladderatonycausedbyspinalcordinjury

y effectof vesicoureteralreflux issimilartothatofanobstruction - residualurine in the urinarytractaftervoiding favorsbacterial growth.

Intrarenalreflux.y Vesicoureteralreflux infectedbladderurine

forceduptothe renalpelvis deep intothe renalparenchymathroughopen ductsatthe tipsofthepapillae (intrarenalreflux)

y mostcommon in the upperandlowerpolesofthekidney

y where papillae tendtohave flattenedorconcavetips vs. convexpointedtype in the midzonesofthekidney


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y Refluxcan be demonstratedradiographicallybyavoiding cystourethrogram:obladderis filled witharadiopaque dye films

are taken during micturition

y In the absence of vesicoureteralreflux, infection usuallyremainslocalized in the bladder.

y majorityof individuals withrepeatedorpersistentbacterialcolonization ofthe urinarytractsufferfromcystitisandurethritis(lowerurinarytract infection) ratherthan pyelonephritis.

Acute Pyelonephritisy acute suppurative inflammation ofthe kidneycausedby

bacterialandsometimes viral (e.g.,polyomavirus) infectiony maybehematogenousand inducedbysepticemicspreador

ascending andassociated with vesicoureteralreflux

Morphologyy hallmarks:opatchy interstitialsuppurative inflammationo intratubularaggregatesof neutrophilso tubularnecrosis

y suppuration mayoccurasdiscrete focalabscesses involvingone orboth kidneys, whichcan extendtolarge wedge-shapedareasofsuppuration

y distribution oflesions:unpredictable andhaphazardy in pyelonephritisassociated withreflux:damage iscommon in

the lowerandupperpolesy earlystagesoneutrophilic infiltration islimitedtothe interstitialtissueoSoon,the reaction involvestubules producesacharacteristicabscess withthe destruction of

the engulfedtubules

o tubularlumens - readypathway forthe extension oftheinfection large massesof intraluminal neutrophils frequently extend

along the involved nephron intothe collecting tubules.oglomeruli is relativelyresistantto infection Large areasofsevere necrosis destroythe glomeruli fungalpyelonephritis (e.g., Candida) often affects

glomeruliy Three complications (encountered in specialcircumstances)oPapillary necrosis seen mainly in diabeticsand in those withurinarytract

obstruction usuallybilateralbutmaybe unilateral One orallofthe pyramidsofthe affected kidneymaybe

involved cutsection:the tipsordistaltwothirdsofthe pyramids

have areasof gray-white toyellow necrosis microscopic examination: coagulative necrosis, withpreservation ofoutlinesof

tubules leukocyticresponse:limitedtothe junctionsbetween

preservedanddestroyedtissue.

oPyonephrosis totaloralmostcomplete obstruction,particularly when it

ishigh in the urinarytract suppurative exudateunable todrain fillsthe renalpelvis,calyces,andureterwithpus.

oPerinephricabscess extension ofsuppurative inflammation throughthe renal

capsule intothe perinephrictissueyAfterthe acute phase ofpyelonephritis,healing occursoneutrophilic infiltrate replacedbyone that is

predominantlycomposedofmacrophages,plasmacells,and (later) lymphocytes

o inflammatory foci replacedby irregularscars - seen onthe corticalsurface as fibrousdepressions characterizedmicroscopicallyby: tubularatrophy interstitial fibrosis lymphocytic infiltrate* in acharacteristicpatchy, jigsaw pattern withintervening preservedparenchyma

pyelonephriticscar:associated with inflammation,fibrosis,anddeformation ofthe underlying calyxandpelvis reflectsthe role ofascending infection and

vesicoureteralreflux in the pathogenesisofthedisease.

Clinical Features

y often associated withpredisposing conditions:oUrinarytractobstruction, eithercongenitaloracquiredo Instrumentation ofthe urinarytract,mostcommonly

catheterizationoVesicoureteralrefluxoPregnancy 4% - 6%:developbacteriuriasometime during pregnancy 20% - 40% ofthese eventuallydevelopsymptomatic

urinary infection if nottreatedoGenderandage


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y Overtrenal insufficiencyoccurs in halfofthose withmultiplemyelomaandrelatedlymphoplasmacyticdisorders.

y Several factorscontribute torenaldamage:oBence Jonesproteinuriaandcast nephropathy. main cause ofrenaldysfunction isrelatedto Bence Jones

(light-chain) proteinuria Renal failure correlates well withthe presence and

amountofsuchproteinuriaand isuncommon in itsabsence.

Twomechanismsaccount forthe renaltoxicityof BenceJonesproteins. First,some lightchainsare directlytoxicto epithelial

cells,apparentlybecause oftheirintrinsicphysicochemicalproperties.

Second, Bence Jonesproteinscombine withtheurinary glycoprotein (Tamm-Horsfallprotein) underacidicconditions formlarge,histologicallydistincttubularcaststhatobstructthe tubularlumensandinduce acharacteristic inflammatoryreaction aroundthe casts (light-chain cast nephropathy).

oAmyloidosis,of AL type formed from free lightchains(usuallyof type), whichoccurs in 6% to 24% of individuals

withmyeloma.oLight-chain deposition disease lightchains ( type) deposit in: GBMsandmesangium in nonfibrillarforms

causing a glomerulopathy tubularbasementmembranes cause

tubulointerstitial nephritisoHypercalcemiaandhyperuricemiaare often present in these

patients.

Morphology.y tubulointerstitialchanges in light-chain cast nephropathyare

fairlycharacteristic.y The Bence Jonestubularcastso

appearaspink toblue amorphousmassesosometimesconcentricallylaminatedandoften fractured,

which fillanddistendthe tubularlumensy Some ofthe castsare surroundedbymultinucleate giantcells

thatare derived frommononuclearphagocytesy The adjacent interstitialtissue usuallyshowsa nonspecific

inflammatoryresponse and fibrosis.y the casts erode theirway fromthe tubules intothe

interstitium evoke a granulomatous inflammatoryreaction.yAmyloidosis,light-chain deposition disease, nephrocalcinosis,

and infection mayalsobe present.

Clinical Featuresy chronicrenal failure develops insidiouslyandusually

progressesslowlyduring aperiodofseveralmonthstoyears.yAnotherformoccurssuddenlyand ismanifestedbyacute renal

failure witholiguria.oPrecipitating factors include: Dehydration Hypercalcemia acute infection treatment with nephrotoxicantibiotics

y Bence Jonesproteinuriaoccurs in 70% of individuals withmultiple myeloma

y presence ofsignificant nonlight-chain proteinuria (e.g.,albuminuria) suggests AL amyloidosisorlight-chain depositiondisease.

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TUBULAR AND INTERSTITIAL DISEASES