AcuteKidneyInjury(AKI)

MathewThambi,PharmD,MPH

Outline
AKIdefinition,background,&prevention
TypesofAKI:
1. PrerenalAKI
Assessment&Treatment

2. Intrinsic
AcuteTubularNecrosis(ATN)
AcuteInterstitialnephritis(AIN)
AcuteGlomerulonephropathies (GN)

3. Postrenal
KidneyStones

Objectives

DefineAcuteKidneyInjury(AKI)
UnderstandstagingofAKI
UnderstandassessmentofAKI
DiscussthethreetypesofAKIandcomparewithrespectto
pathophysiology,clinicalcharacteristics,diagnosticcriteria,and
treatmentapproach

AKI Definition
Acutedeclineinkidneyfunction
InitsmostsevereformAKIiscalledacuterenalfailure(ARF)

Modified RIFLE Criteria

SerumCreatinine

UrineOutputCriteria

Stage 1
(Risk)

Baseline SCr x1.5 1.9 UO<0.5mL/kg/hx6 12h

or ofSCr by> 0.3mg/dl

Stage2
(Injury)

Baseline SCr x2 2.9

UO<0.5mL/kg/hx> 12h

Stage3
(Failure)

Baseline SCr x> 3or

SCr to> 4.0mg/dL or
InitiationofDialysis

UO<0.3mL/kg/hx> 24hor
Anuriax> 12h

Loss

PersistentARF=completelossofkidneyfunction x4weeks

ESKD

ESKD=completelossofkidneyfunction >3months
ForYourReference DoNotNeedtoMemorize

Risk Factors for AKI

NotPreventable

Preventable

Nephrotoxins

CKD
Age>75y
PeripheralVascularDz
HeartFailure
LiverDisease
Diabetes

NSAIDs
Aminoglycosides
Moretocome

Hypotension
Hypovolemia
Cardiacdisease

Sepsis

Signs & Symptoms of Acute Renal Failure

Retentionof:
Naandwater
Edema(peripheral,pulmonary,ascites,)

Potassium,Magnesium,Phosphate
Acid
Nitrogeneous waste
IncreasedBUN
Uremia(nausea,vomiting,drowsiness,confusion,bleeding,
pericarditis) notcommoninacute kidneyinjury

Types of AKI based on cause of AKI

INTRINSIC
PRERENAL

POST
RENAL

Canhavemorethantypeoneatatime

Prerenal AKI
Duetoasuddenreductioninbloodflowtothekidneys
Resultsindecreasedfiltration>increasedSCr
Severeand/orsustainedreductioninrenalbloodflow>
IntrinsicAKI

PRE-RENAL AKI - Causes

ReducedCardiac
Output

Intravascular
Volume
Depletion

Vascular
Obstruction

DecreasedRenal
BloodFlow

SCr

Prerenal AKI: Causes

1. IntravascularVolumeDepletion
dueto:
Hypovolemia(ordehydration)
Hemorrhage
GIlosses(diarrhea,vomiting)
Urinarylosses(diuretics,saltwastingsyndrome)
Decreasedeffectivevolume(cirrhosis,CHF)
Peripheralvasodilation(sepsis,vasodilators)

2. ReducedCardiacOutput

Hypotension
HF
MI
Drugs(CCBs)

3. VascularObstruction
Bilateralrenalarterystenosis
RenalAfferentArterioleVasoconstriction
NSAIDs
Vasopressors(Epinephrine,Norepinephrine)
Tacrolimus,Cyclosporine

Prerenal AKI: Diagnosis & Evaluation

History
Dehydration,diarrhea,diuresis

Physicalexam
Orthostatichypotensionwithtachycardia

Labsandurinetests:
BUN:SCr >20
UrineSpecificGravity>1.015
UrineOsmolality(mOsm/L)>500
UrineNaconc (mEq/L)<20,usually<10
FENa <1%

Prerenal AKI
Decreased
BloodFlow

Na
Excretion

ADH

Activationof
RAAS

H2O
Excretion

Aldosterone

Highly
concentrated
urinewithlowNa

Na
Excretion

Case
A62 yearoldmanwithahistoryofHTN
recentlytreatedforCAPisadmittedforN&V,
diarrheaforfourdays
Afteradmission,hewasnotedtohavea
serumcreatinineof1.5mg/dL (froma
baselineof0.7mg/dL).

http://www.clinicalcorrelations.org/?p=5795

Diagnostic Challenge
IstheAKIPreRenalorIntrinsic?
PostRenalAKIisnotlikelywithoutcomplaintsofurinary
frequencyorbladderfullness.

The Easy Way

History&PhysicalExam
Isthepatienthypovolemic(dry)?
LowBP,highHR
Dryoralmucosa
Poorskinturgor

Ifso,AKIisprobablyPreRenalandpatient
needsfluid

 Ifoverthypovolemia,canattemptafluidchallenge:
Givefluidbolusand/orstartmaintenanceIVfluids
IfSCr significantlyimproves,AKIisprerenal.
Ifitdoesnot,AKIisIntrinsic.

The Hard Way

Ifthepatientisnotovertlyvolumedepleted
ormaynottolerateafluidbolus:
Labsandurinetests:

BUN:SCr >20
UrineSpecificGravity>1.015
UrineOsmolality(mOsm/L)>500
UrineNaconc (mEq/L)<20,usually<10
FENa <1%

FENa
FractionalExcretionofSodium
Measuresthepercentoffilteredsodiumthatisexcretedinthe
urine
UsedtodifferentiatebetweenPrerenalAKIandIntrinsicAKI

FENa

ExcretedNa
FilteredNa

FENa
Reducedbloodflowtokidneys
Kidneysthinkthebodyislowonvolume
TrytoholdontoNaandminimizeitsexcretion
LoweringFENa to<1%

UNaxSCr
FENa,percent= x100
SNaxUCr
<1:suggestsprerenaldisease
1 2:maybeeitherprerenal orintrinsic
>2:suggestsintrinsicrenaldisease

Limitations of FENa
OnlyaccurateinoliguricAKI
Shouldnotbeusedinpatientstakingdiuretics
>useFEUrea

Oliguric =UrineOutput<400 500mL/d

FEUrea
FENa willbefalselyelevatedinpatientstakingdiuretics
CanuseFEUrea:
UrineUrea xSCr
FEUrea,percent= x100
SNaxBUN
<35%:PreRenaldisease
50 65%:Intrinsicrenaldisease

Case
86yo Fwithc/oSOB,WBC,HR.AlsohasLEedemaand
pleuraleffusions
MaxillarySCCPOD#10s/pmaxillectomy,tracheostomy,andL
scapularfreeflapreconstructionwithSTSG
PMHofHLD,hypothyroid,osteoporosis
MedsPTA:levothyroxine50mcgQday
TreatedwithVancomycin andZosyn

Diagnostic Dilemma: Pre-Renal vs Intrinsic

AKI
Patienthaslowerextremityedemaandpleuraleffusions
Cannotgivefluidchallenge(theeasyway)

Thehardway:
BUN:SCr =9/1.58=6(>20)
UrineSpecificGravity=1.020(>1.015)
UrineOsmolality(mOsm/L)>500> notdone
UrineNaconc (mEq/L)=111(<20)
FENa =111X1.58/(138X35)X100=3.6%

Case: Management
Discontinueallpossiblenephrotoxins:Vancomycin
WilldiscussmorewithIntrinsicAKI

General Management of Pre-Renal AKI

Reversethecauseifpossible
Ifcauseisassociatedwithhypovolemia:
Hydrationwithfluidbolusof500 1000mLand/ormaintenanceIV
fluidsat35ml/kg/day
Use0.9%NaCl (normalsaline,NS)orLactatedRingers(LR)
Dextrose5%(D5)doesnotstayintheintravascularcompartmentasmuch
andshouldnotbeusedforPreRenalAKIorHypovolemia

Types of AKI
1. Prerenal AKI
2. Intrinsic AKI
3. Postrenal AKI

Intrinsic Renal Disease

ProlongedPrerenalAKI
ProlongedPostrenalAKI
AcuteTubularNecrosis(ATN)
AcuteInterstitialnephritis(AIN)
AcuteGlomerulonephropathies
Malignanthypertension
Pyelonephritis
Others

ATN versus AIN

AcuteTubularNecrosis
DuetoprolongedorseverePreRenalAKI>ischemia
Resultsinnecrosisofthetubules>granularcasts

AcuteInterstitialNephritis

Autoimmunemediated
Causedbydrugallergy(75%)orautoimmunediseases(SLE,sarcoidosis)
Maypresentwithothersignsofallergy:rash,fever,and/oreosinophilia
Maypresentwithsterilepyuria

Urine Casts

Drug Induced AIN

NSAIDs
Penicillins andcephalosporins
Vancomycin
Rifampin
Antimicrobialsulfonamides(eg,Bactrim)
Allopurinol
PPIs
Indinavir
Mesalamine
NotonExam
Others

Intrinsic Renal Disease

ProlongedPrerenalAKI
ProlongedPostrenalAKI
AcuteTubularNecrosis(ATN)
AcuteInterstitialnephritis(AIN)
AcuteGlomerulonephropathies
Malignanthypertension
Pyelonephritis
Others

Glomerulonephropathies (GNs)
Damagetotheglomerulusgenerallyduetoautoimmune
disease
CharacteristicfindingisProteinuria

Bowmans
capsule
Mesangium

Proximal
Tubule
Podocytes
38

Electronmicrogramofpodocytecellsina
glomerulus

Fennestrated
Endothelium
Basement
Membrane

40

Nephrotic Range Proteinuria

Whenurineproteinis>3.5gm/d(bydefinition)
Normalis<80mg/dfora24hoururinesample

41

General Course of the Proteinuria in GN

Selectiveproteinuria(albuminuria) <3.5gm/d
Nonselectiveproteinuria<3.5gm/d
Nephrotic rangeproteinuria>3.5gm/d
Inflammation/Hematuria=NephriticSyndrome
42

Assessment
CrCl mayoverestimatetrueGFR innephrotic syndromeby>
50%
Useyourjudgement whenadjustingmedicationsbasedonCrCl in
patientswithnephrotic syndrome

Proteinuria
Initiallyfoundonurinalysis
Quantificationofproteinlossdonewith:
24hoururinecollection goldstandard
Random(spot)albumintocreatinine ratio
43

Albumin to Creatinine Ratio

MoresensitivethanProteintoCreatinine Ratio
Resultcorrelatesto24hoururinecollection:
E.g.,SpotalbumintoCreatinine Ratioof3.5gm/gm correlatesto3.5
gm/dayofAlbuminexcretion
SensitivebutnotSpecific
Usedtoruleoutproteinuria
Significantproteinuriashouldbeconfirmedwith24hoururinecollection

44

Nephrotic Syndrome
Notadiseasebutagroupofsigns&sxs seeninpatientswith
nephrotic rangeproteinuria:
Edema Hallmarkfeature
Frothyurine duetoproteininurine
LossofAntithrombin whichbindstoandinactivatesseveralclotting
factors highriskofvenousclots:DVTs &PEs(VTEs)
LossofLMWcomplementsandAbs increasedriskofinfection
IncreasedCholesterol,LDLandVLDLhepaticproduction;increased
TGs
45

Clinical Presentation
Edema usuallypresentwhenproteinlossesaresohigh(>3.5
g/d)
IncreasedSCr notedonclin chem
Increasedproteinuriaonurinalysis

46

47

48

Nephritic Syndrome
Characterizedbyintraglomerular inflammation
Allofthes/ssofNephrotic Syndromeplus:

Hematuriawithdysmorphic RBCsand/orRBCcasts Hallmarkfeature

Oliguria
DecreasedCrCl
Hypertension

Proteinuriacanbelessthanwithnephrotic syndromeasnephrons
becomecompletelydysfunctionalandnotabletoexcreteproteins
49

Types of GN (Determined by Biopsy):

Minimalchangedisease
Focalsegmentalglomerulosclerosis
Membranoproliferative glomerulonephritis
PostStrepGlomerulonephritis
ImmunoglobulinAnephropathy
HenochSchonlein purpura nephritis
Lupusnephritis
Pauciimmunefocalandsegmentalnecrotizingglomerulonephritis
Antiglomerularbasementmembraneantibodyglomerulonephritis
Donotneedtomemorize

50

General Approach to Treatment of GNs

ImmunosuppressiveTherapy
Beyondthescopeofthislecture

SupportiveTherapyfor:
Proteinuria
Hyperlipidemia
Hypertension
Clots(VTEs)
Edema
51

Proteinuria
Ensureadequatedietaryintaketomakeupforlosses:0.8 1
gm protein/d
Goalistoreduceproteinurialevelsto<0.5g/d
Innephrotic syndrome,reducingproteinuriacan:
Increaseserumalbumin
Reduceedema
ImproveQOL

52

Proteinuria (cont.)
Treatment
ACEIsorARBs

Mayreduceproteinuriabyupto40 50%
Causesefferentarteriolarvasodilation
Effectmaybeimprovedwithsaltrestriction
A10 20%riseinSCr isexpectedandshouldnotcausecessationoftx

53

ACEI/ARB InducedEfferentVasodilation
SCr
GFR

EfferentArteriolar
Vasodilation

Arteriolar
Pressure

54

Hyperlipidemia
Followcurrentlipidguidelines
Lifestylemodification

55

Hypertension
GenerallyassociatedwithGNs
JNC8recommendsgoalBPof<140/90
ACEIsorARBsarefirstline

56

Anticoagulation
Riskofclotsismainlyvenous(VTE):
Renalveinthrombosis,PE,DVT

AssureVTEprophylaxiswhileinthehospital:
HeparinSCQ8 12h

PatientswithVTEshouldbeanticoagulateduntilremissionof
nephroticsyndromeorVTEistreated(whicheverislonger)
Warfarin,LMWHs
Dabigatran, Rivaroxaban,Apixiban shouldprobablybeavoideddue
torenalclearance
57

OverviewofManagementofIntrinsicRenalAKI

Treatment
Goal:TopreventprogressionofAKIandneedforRenal
ReplacementTherapy
Management:
Removalofthecauseifpossible/known
PreventHypotensionandHypovolemia
AvoidNephrotoxins

Edema
Mildsodiumrestrictiontopreventedema:<2
gm/d
AssureIns=Outs,andlimitedweightgain
Ifsignificantedema(pulmonaryedema):
Sodiumrestrictto 1 1.5gm/d
Loopdiuretics

Indications for Dialysis

A
E
I
O
U

MetabolicAcidosis(pH<7.1)
Electolytes:K>6.5orrapidlyrisingK
Intoxication
RefractoryfluidOverload
Uremia confusion

StartingdialysisearlierinthecourseofrenalfailuredoesNOT
improveoutcomes.
(ARCTofEarlyversusLateInitiationofDialysis.NEngl JMed2010;363:60919.)

Types of Dialysis
Intermittentdialysis
Intheacutesetting:hemodialysis(HD)
Inthechronicsetting:hemodialysisorperitoneal
dialysis

Continuousrenalreplacementtherapies
(CRRT)
ContinuousVenoVenousHemofiltration(CVVH)
ForICUpatientswhocannottoleratelargemounts
offluidremovalduringshortdialysissession

Types of AKI
1. Prerenal AKI
2. IntrinsicAKI
3. Postrenal AKI

Pathogenesis of AKI from Post-Renal

Obstruction
Obstruction ofureters/urethra
Backupofurineintokidneys(hydronephrosis)
Increasedpressureandstagnanturinein
nephrons
Interstitialdamagetokidneys
IncreasedriskofUTIsandpyelonephritis

Post-Renal Kidney Disease

Congenitalabnormalities children
Calculi(stones) youngadults
BPH,ProstateCancer oldermen

Kidney Stones

Definitions
Urolithiasis stonesthatformintheurinarysystem;2sub
types:
Nephrolithiasis stonesinthekidneys
Ureterolithiasis stonesintheureters

1in11peoplewillgetkidneystones
Prevalenceisincreasing
Recurrenceratesarehigh:50%within10years
Acommontopicthatpatientshavequestionsaboutfor
pharmacists
ALOTofmisinformationexistsintheinternet

Pathophysiology
Notwillunderstood
Occurswhennormallysolublesaltsprecipitateintocrystals/
stones

Pathogenesis of Stone Formation

Supersaturationofsalt
(e.g.,calciumandoxalate)
Crystalformation(e.g.,calciumoxalate)
Damageepitheliallumenofureters
Allowscrystalstoanchorthereandgrow
Recurrence

Stone composition
80%of
allstones

Calcium
usuallycalciumoxalate;alsocalciumphosphate
RiskFactors:increasedurinaryCalcium,oxalate,phosphate,or
uricacid;decreasedurinarycitrate;decreasedurinevolume

UricAcid
Riskfactor:acidicurine

20%of
all
stones

Struvite(magnesiumammoniumphosphate)
Knownasinfectionstones;occurwithchronicUTIs
Formedbyureaseproducingbacteria(Pseuodomonas,
Klebsiella,Proteus)oryeast

Cystine
Seeninpatientswithcystinuria,ageneticdisorder

RiskFactorsforCalciumStones
Diseases

Diabetes
Obesity
Gout
Hypertension
H/opreviouskidneystone
50%recurrencewithin10years

PrimaryHyperparathyroidism
Familyh/oofkidneystones
Bariatricsurgery

DietaryRiskFactors
Lowfluidintake
Highdietarysodiumintake
Highmeatconsumption
Highsugarconsumption
Highcolaconsumption
(phosphoricacid)
Medications

VitaminC
Increasedriskinmen(AJKD67(3),2016)
The Role of the Pharmacist in the Management of
Kidney Stone Disease.
http://www.powerpak.com/course/print/110665

Drugs associated with Kidney Stones

Clinical Manifestations
Asymptomatic
Classicpresentation:Flank
pain(renalcolic),N/V,&
hematuria
Pain
Duetodistensionofrenal
capsuleorureteralspasms
Canvaryfrombarelynoticeable
achetothatwhichrequires
parenteralanalgesics
Typicallywaxesandwanes

Diagnosis
Imagingstudiesshouldbedonetodeterminesizeand
composition
Stones>10mmareunlikelytopassspontaneously
Stones<5mmarelikelytopassspontaneously
Proximalureteralstonesarealsolesslikelytopassspontaneously

Treatment
Conservativemanagement allowstonetopassifsmall
HydratewithPOorIVfluids
Paincontrolwithopiates
NSAIDscanbeusedifSCr isnormal

Patientsmaystraintheirurinetocatchthestone(s)for
analysis:
Composition
Size

 Facilitatingpassageofstone:
PreviouslyusedNifedipine orTamsulosin butbenefitsweredisproven
intheSUSPENDtrial(Lancet2015)
Somehavemajorcriticismsofthetrialandmaystilluse

InterventionbyaUrologistisrequiredif:
AKI,largerstones,orstonesthatwillnotpass

Interventions:shockwavelithotripsy(SWL),ureteroscopic
lithotripsywithelectrohydraulicorlaserprobes,percutaneous
nephrolithotomy,laparoscopicstoneremoval

Prevention of Calcium Stones: Diet

Strength
of
Evidence

Increasefluidintaketopreventsupersaturation
Targeturinevolumeof2 2.5L/d

Avoiddarkcolas(containphosphoricacid)
Sodiumrestriction(decreasescalciumandoxalateexcretion)
Lowproteindiet(<52gm/d) proteinintakeincreasesoxalate
production
Studiesareconflictingforefficacy

Reduceconsumptionofoxalaterichfoods
Spinach,rhubarb,wheatbran,chocolate,beets,miso,tahini,nuts

Prevention of Calcium Stones: Meds

Thiazidediuretic lowerscalciumconcentrationintheurine
ed stoneformationby>50%over3yinRCT

PotassiumCitrate
CitricacidbindstoCalciumbutismuchmoresolublethanCalcium
OxalateandCalciumPhosphate
30 60mEq/dtoaurinepHof6.5(6.0isnormal)
SEs:GIupset,hyperkalemia
Trialsarelacking

Do NOT:
TakeVitaminCsupplements mayincreaseoxalateproduction
RestrictCalciumintake>thisreducesbindingofoxalateinthe
gutandenhancesoxalateabsorption>Calciumrestrictionis
associatedwithincreasedcalciumoxalatekidneystones
TakeCalciumsupplements>increasesriskofkidneystones

Prevention of Uric Acid Stones

UricAcidStones
LowurinarypHisthemaincauseasopposedtohyperuricosuria
PreventionwithPotassiumCitrate

StruviteStones
Limiturinarytractinfections

Cystine Stones
Urinaryalkalinization,increasedfluidintake,sodiumandprotein
restriction
Cysteinebindingagents:dPenicillamine,Tiopronin

Outline
AKIdefinition,background,&prevention
TypesofAKI:
1. PrerenalAKI
Assessment

2. Intrinsic
AcuteTubularNecrosis(ATN)
AcuteInterstitialnephritis(AIN)
AcuteGlomerulonephropathies (GN)

3. Postrenal
KidneyStones

AKI

Questions?