Acute kidney injury chronic kidney disease

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Gross structure and location

Kidney anatomy

Nephron

Nephron

Ultrastructure

µ-structure – the renal corpuscle

µ-structure – tubular segments

µ-structure – tubular segments

Glomerulus

Ultrastructure

2D 3D

Vasculature

Kidney functions

•  Excretion(bloodfiltration,reabsorption,secretion)• Homeostasis=minerals,water,pH• Osmolality•  Endocrinefunctions

Urine formation

Filtration

Reabsorption,secretion

Useful terms

• Creatinine• Urea/Bloodureanitrogen• Glomerularfiltrationrate• Renalclearance

Creatinine

• Breakdownproductofcreatinephosphate(energyreservoir)• Usuallyproducedatconstantrate(dependingonmusclemass)•  Excretedunchangedbythekidneys:•  glomerularfiltration-mostly•  proximaltubularsecretion–minor

•  Littletonotubularreabsorption•  45-90μmol/L(0.5-1.0mg/dL)forwomen;60-110μmol/L(0.7-1.2mg/dL)formen

Urea / Blood urea nitrogen

• Urea–producedintheliverasawasteproductofproteindigestion• BUN–themassofnitrogenwithinurea/volume• Normalrange1.8-7.1mmol/Lurea(6–20mg/dLBUN)•  Increasedurea/BUN–decreasedkidneyfunction•  Highproteindiet•  Hypovolemia•  Hemorrhage•  Fever•  Increasedcatabolism

BUN-to-creatinine ratio

•  Todeterminethecauseofacutekidneyinjuryordehydration• Principle:•  Bothureaandcreatininearefreelyfilteredthroughglomeruli

•  Reabsorptionofurea(notcreatinine)canberegulated(upordown)

BUN:Cr Urea:Cr Location Mechanism

>20:1 >100:1 Prerenal(beforethekidney)

BUNreabsorptionisincreased.BUNisdisproportionatelyelevatedrelativetocreatinineinserum.Dehydrationorhypoperfusionissuspected.

10-20:1 40-100:1NormalorPostrenal(afterthekidney)

Normalrange.Canalsobepostrenaldisease.BUNreabsorptioniswithinnormallimits.

<10:1 <40:1 Intrarenal(withinkidney)

RenaldamagecausesreducedreabsorptionofBUN,thereforeloweringtheBUN:Crratio.

But...

• BUNandcreatininewillnotberaisedabovethenormalrangeuntil60%oftotalkidneyfunctionislost•  Therefore,moreaccuratemethodsareuseful

Glomerular filtration rate

• Volumeofbloodfilteredperminute• ml/min/1.73m2•  Flowrateoffilteredfluidthroughthekidneys

•  EstimatedGFR(eGFR)–serumcreatinine•  Sex,age,weight,height,race

Creatinine clearance

• ApproximationofGFR• Volumeofbloodplasmathatisclearedofcreatinineperunitoftime

Estimated clearance

• Basedonserumcreatinineconcentration

Acute kidney injury

•  Lossofkidneyfunctionthatdevelopswithin7days• Previously:acuterenalfailure• Widespectrumofinjuries,notjustfailure• Commonincriticallyillpatients•  13-18%ofallpeopleadmittedtohospital

History

•  1802ischuriarenalis•  1909Bright’sdisease–aconsequenceoftoxicagents,pregnancy,burn,traumaoroperations•  FirstWW–warnephritis•  SecondWW–acutetubularnecrosis•  1951–acuterenalfailure•  2004–acutekidneyinjury

Classification

• RIFLE–risk,injury,failure,loss,end-stagekidneydisease• AKIN–AcuteKidneyInjuryNetworkgroup

Classification

• KDIGO–KidneyDisease:ImprovingGlobalOutcomes

Biomarkers of AKI

Additional diagnosis

•  Urinedipstick•  Blood•  Protein•  Leukocytes•  Nitrites•  Glucose

•  Urinemicroscopy•  Redcellcasts•  Dysmorphicredcells•  Tubularepithelialcells

•  Ultrasound•  Auto-immuneprofile•  Biopsy

Urine microscopy

Urine microscopy

Etiology

• Prerenal(55%)•  Intrinsic(40%)• Postrenal(5%)

Etiology

• Mostcommoncauses:•  Ischemia•  Sepsis•  Hypovolemia•  Drugs

Precipitating factors for AKI

Ischemic AKI

•  Themostcommon• Highsusceptibilityofkidneytoischemicinjury•  Structuralassociationsbetweenrenaltubulesandbloodvesselsinoutermedulla•  vasoconstriction•  epithelialinjury(lowATP)–necrosisorapoptosis•  activationofinflammatoryprocesses

• Allsegmentsofnephroncanbeaffected,butproximaltubularcellsaremostcommonlyinjured

Consequences of AKI

• Accumulationof•  wasteproducts–azotemia(accumulationofnitrogenouscompounds)

•  electrolytes–disruptedhomeostasisofwater,mineralsandacid-basebalance

•  fluids• Reducedimmunity• Dysfunctionofnon-renalorgans(organcross-talk)

Consequences of AKI

Distal organ injury

Kidney-lung interactions

Cardiorenal syndrome

Hepatorenal syndrome

• Rapiddecreaseinkidneyfunctioninindividualswithcirrhosisorfulminantliverfailure•  1.Alteredliverfunction•  2.Abnormalitiesincirculation–constrictionofvesselsinkidneysanddilationinsplanchniccirculation(intestines)•  3.Kidneyfailure

Therapy

•  Fluids–expansionofintravascularvolume•  Isotoniccrystalloidsratherthancolloids

• Vasopressors•  Norepinephrine,vasopressin

• Hemodynamicmanagement

• Glycemiccontrolandnutritionalsupport• RenalReplacementTherapy•  Considerbroaderclinicalcontext,trendsoflaboratorytests

Outcomes after AKI episode

•  1.Fullrecoveryandreturnofrenalfunctiontobaseline•  2.IncompleterecoveryofrenalfunctionresultinginCKD•  3.Exacerbationofpre-existingCKDacceleratingprogressiontoESKD•  4.Non-recoveryofrenalfunctionleadingtoESKD

Animal models of AKI

• Bilateralnephrectomy

• Bilateralischemiareperfusioninjury

• Bilateralureteralligation

•  cisplatin,adriamycin,rapamycin,glycerol,folicacid…

Chronic kidney disease

• Progressivelossofkidneyfunctionoveraperiodofmonthsoryears• Previously:chronicrenalfailure• Definition:•  Decreasedkidneyfunction-lessthan60ml/min/1,73m2OR

•  MarkersofkidneydamageOR•  Both•  Atleast3monthsduration•  Regardlessofcause

Markers od kidney damage

• Albuminuria(albumin:creatinineratio≥30mg/g)• Urinarysedimentabnormality•  Electrolyteabnormality• Histologicalabnormality•  Structuralabnormalitydetectedbyimaging• Historyofkidneytransplantation

Risk factors

Mortality attributed to CKD

Prevalence of CKD

Clinical manifestation

• Accumulationofnitrogenouswastes(uremia)•  neurologicaldisorders(uremicencephalopathy)•  uremicfrost

• Mineralbonedisease–disturbedvitaminD,calciumandphosphatemetabolism• Renalhypertension• Anemia• ReducedRBCsurvivalandirondeficiency• Alterationsinwater,acid-baseandelectrolytebalance

Etiology

• Diabetes(30-50%offallcases)• Hypertension

• Glomerulonephritis• Polycystickidneydisease• Chronicpyelonephritis

Diabetic nephropathy

• Majorcomplicationofdiabetes

• Highglucose• Hyperfiltration•  Thickeningofbasementmembrane–sclerosis• Mesangioproliferativechanges• Microalbuminuria(30-300mgprotein/day)• Proteinuria

Hypertension

• Causeandconsequenceofkidneydisease

• Changesinglomerularstructures• Damagetobloodvessels• Decreasingfiltrationrate•  Increasingbloodvolume

Glomerular vessels

GFR Renalperfusion

AfferentarterioleVasoconstriction

↓

↓

AfferentarterioleVasodilation

↑

↑

EfferentarterioleVasoconstriction

↑

↓

EfferentarterioleVasodilatation

↓ ↑

Diagnosis

• Asymptomaticornon-specificsymptoms:•  Lethargy•  Itch•  Lossofappetite

• Oftenbychancefindings•  Screeningtests•  Severesymptoms

Complications

• Renalfibrosisasaresponsetoinjury• Replacementoffunctionaltissuebyfibrotictissue

Therapy

• Conservative•  dietaryrestriction•  BPmanagement

• Renalreplacementtherapy•  Hemodialysis(diffusion)•  Peritonealdialysis•  Hemofiltration(convection–increasedhydrostaticpressure)

•  Hemodiafiltration•  Kidneytransplantation

Management

• AnnualfrequencyofeGFRtestinginCKDpatients

• BloodpressuretargetinCKDpatients

Animal models of CKD

•  5/6nephrectomy•  Unilateralureteralobstruction•  Ischemiareperfusioninjury•  Alportmice

AKI vs. CKD

• Noindependententities

• AKIisariskfactorforCKD• CKDisariskfactorforAKI• Bothareriskfactorsforcardiovasculardisease

Acute-on-chronic kidney disease

• AKIoccursonthebackgroundofpre-existingCKD• CKDasriskfactorforAKI• Mostcommoncauses:•  Systemicinfection•  Drugs–diuretics,ACE-inhibitors•  Dehydration•  Urinarytractobstruction

Questions

•  DiagnosisofAKIbasedon•  sCrlevelsORurinevolume

• MostcommoncausesofAKIinclude•  Ischemia,sepsis,hypovolemia,drugs

•  DiagnosisofCKDbasedon•  Decreasedkidneyfunction-lessthan60ml/min/1,73m2OR•  MarkersofkidneydamageOR•  Both•  Atleast3monthsduration

•  PrognosisofCKDbasedon•  eGFRandproteinuria

•  TwomajorcausesofCKDare•  Diabetesandhypertension

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