WorkupandManagementofAcuteKidneyInjury

MatthewRivara,MD,FASNAssistantProfessorofMedicine

DivisionofNephrologyUniversityofWashington

Disclosures•  Ihavenothingtodisclose

Objectives

1.  Reviewcommon(anduncommon)causesofacutekidneyinjury(AKI)inhospitalizedpatients

2.  DiscusspracticaldiagnosticevaluationforthehospitalizedpatientwithAKI

3.  DiscusspreventionandmanagementofselectAKIetiologies

Case1

HPI:•  43y/owomanwithahistoryofchronicHCV,presentstoEDwithabdominalpain,vomitingx3days•  Temp38,BP95/60,HR100•  Examshowsabdominaltenderness,1+LEedema▫  Receives1literLR,vancomycinandcefepimex1▫  F/uBP105/70àadmittedtomedicine

PMH:•  H/owristfracture1yearago,creatinine0.7mg/dL

Laboratory/imagingevaluation

Urinalysis: 1+ RBCs, 1+ protein Urine protein/creat: 0.5 g/g 134

4.2 102

21

20

1.2 94

HCVviralload:800,000IU/LC3,C4bothlowINR:1.4Totalbilirubin:6.0mg/dL

Case1,continued

0

0.5

1

1.5

2

2.5

3

0 2 4 6 8 10 12

SERU

MCRE

ATININE(M

G/DL

)

HOSPITALDAY

Trendinserumcreatinine

Vanco level 40

Vanco/cefepime

Whatiscausingthispatient’sAKI?

AcuteKidneyInjury

Pre-renal(lowEABV)

Acutetubularinjury/necrosis

Hepatorenalsyndrome

Acuteinterstitialnephritis

Vancomycinnephrotoxicity

GN/MPGNrelatedtoHepatitisC

“AcuteKidneyInjury"isaclinicalsyndrome

ElevatedCreatinine/DecreasedeGFR Lowurineoutput

KDIGO AKI Guidelines, 2012

•  AKIisnotasinglediseaseentity–itisaheterogeneousgroupofconditionswithdifferentcausesandpathophysiologicmechanisms

•  Therearenopharmacologicagentsavailableforthepreventionortreatmentofacutekidneyinjury

•  Thus,treatmentisalways▫  Identificationandmanagementofunderlyingdisorder▫ Managementofvolumeandmetaboliccomplications

TREATMENT OF AKI

AKIiscommoninhospitalizedpatients!

Zeng et al, CJASN, 2014

UrinarybiomarkersforAKI–NOTYET!

Ostermann M, et al.. Crit Care. 2016.

Tubularfunctionasastresstest

77 patients with AKI who received FST à followed for development of stage 3 AKI, RRT, death FUROSEMIDE OUTPERFORMED URINARY BIOMARKERS FOR ALL OUTCOMES

Koyner et al, JASN, 2015

CausesofAKI

Pre-renal Post-renalIntra-renal

•  Volume depletion •  Cardiorenal syndrome •  Hepatorenal syndrome •  Abdominal compartment

syndrome •  Renal artery occlusion/ •  Dissection •  Renal vein thrombosis

•  Acute tubular necrosis •  Glomerular disorders •  Microvascular disorders •  Tubulointerstitial Disorders

•  Ureteral obstruction •  Bladder outlet

obstruction

DecreasedEABV/Renal

veincongestion

Jefferson, Haseley. Comprehensive Clinical Nephrology. Chapter 66, Sixth edition.

CausesofAKI–AnAnatomicApproach

Case2•  20y/omanhospitalizedforvolumedepletionafterreturningfromMexico•  Reports5daysof6-10loosestools/day,nausea,poorPOintake•  BPis80/50,dizzywithstanding•  Creatinine1yearago0.9.

126 4.5

90

16

75

3.5 90

Urine: UNa 8 mEq/L Ucreat: 35 mg/dL Uosm: 560 mOsm/kg Fe Na 0.6% Urine sediment: Bland

CausesofAKIinhospitalizedpatients

Nash et al., AJKD, 2002

55

39

2 4 30

10

20

30

40

50

60

ATN Decrease EABV Obstruction Parenchymal diseases not

ATN

Not classified

%

> 90% of all AKI!

“Pre-renal” ATNUOP/creatininerespondquicklytofluids(ifgivenenough)

UOP/creatininedonotrespondtofluids

BUNoutofproportiontoCr BUN/Cr<20:1

UOP<15ml/hrbutnotanuric Canbeanuric

Courseimprovedwithintervention Courseunaffectedbyinterventionprovidedfurtherinsultavoided

Urinesodiumlow(<10meq/L),FeNalow(<1%)

UrinesodiumNOTlow(>20meq/L),FeNanotlow(>2%)

Somecaseshaveconsiderableoverlap

If volume status unclear: 1. Early therapeutic trial of withholding diuretics, give 500cc-1000cc isotonic fluid over 1-4 hours 2. Watch for UOP and serum creatinine over next 12-24 hours

FENa

65%

20-25%

5-7%

2-5%

= Excreted Na Filtered Na = Urine Na x Serum Cr x 100 Serum Na x Urine Cr •  FENa <1% prerenal azotemia

•  Sensitivity: 90% Specificity: 93%

•  FENa > 1% ATN •  Sensitivity: 93%

Specificity: 90%

Espinel. JAMA. 1976:236(579-581) Miller et al. Ann Int Med. 1978;89(47-50)

Na

ON DIURETICS? ✔FEUrea

65%

20-25%

5-7%

2-5%

= Excreted Urea Filtered Urea = Urine Urea x Serum Cr x 100 Serum Urea x Urine Cr •  Normal FE Urea 50-65 %

•  Prerenal Azotemia < 35%

Urea

Urea

What’swrongwithfractionalexcretionmeasures?

Perazella et al. CJASN 2012

•  Restorerenalperfusion/treatunderlyingcondition

MANAGEMENT OF PRERENAL AKI

DecreasedEABVAKI–morethan“pre-renal”

Intravascularvolumedepletion

Hemorrhage

GIorrenallosses

Reducedcardiacoutput

CHF/cardiogenicshock

Pericardialdiseases

Systemicvasodilation

Sepsis

Cirrhosis

Anaphylaxis

RenalVasoconstriction

Hepatorenalsyndrome

Acutehypercalcemia

Drugs–ACEI,NSAIDS,calcineurininhibitors

Othercommonlow-EABVAKIconditions

Type1cardiorenalsyndrome

Hepatorenalsyndrome(HRS)

MechanismsofCRS

Soni Clinical Queries: Nephrology 2014

Clinicalconundrumwithacutecardiorenalsyndrome,type1

Heartfailureexacerbation

Fluidoverload

Venouscongestion

LowBP

Gentlediuresis?

Aggressivediuresis?

Mechanicalultrafiltration?

Worsevs.improvedkidney

function?

Diureticdosing•  DOSE trial •  308 patients with acute decompensated heart failure •  Randomized to furosemide IV bolus q12 hours vs. infusion and at

either low dose (equivalent to home oral dose) vs. high dose (2.5x home oral dose)

Felker NEJM 2011

Take home message: diuretic dosing is flexible

Ultrafiltration•  CARRESS-HF trial •  188 patients with acute decompensated heart failure, AKI and persistent

congestion •  Stepped pharmacologic therapy (IV diuretics) vs. ultrafiltration •  No difference in weight loss between groups •  Higher rate of adverse events and greater increase in Cr in UF group

Bart NEJM 2012

Take home message: diuresis is likely a safer strategy (vs. UF)

HEPATORENAL SYNDROME (HRS)

Reversiblefunctionalrenalimpairmentthatoccursinpatientswithadvancedliverdisease.

LowGFR

Absenceofshock,currentinfection,fluidlosses,nephrotoxic

drugs

Noimprovementinrenalfunctionafter

diureticwithdrawalandexpansionofvolume

Proteinuria<500mg/d

Noobstruction

Nointrinsicrenaldisease(noATN,no

GN)

Typically IV albumin 1g/kg of body weight x 2 days

PrecipitatingfactorsinHRS

3 interrelated pathways: 1.  Splanchnic

vasodilation decreasing EABV

2.  Renal sympathetic stimulation

3.  Cardiac dysfunction leading to renal hypo-perfusion

Wadei et al, CJASN, 2006

HRSTreatmentIncriticallyillpatients:•  NorepinephrineIVtoraiseMAPby10mmHguntilnoresponseorresolutionofAKI(atleast2days)

Innon-criticallyillpatients:•  Midodrine7.5-15mgTID•  Octreotide100mcg-200mcgTID•  Trialx2days

Innon-responders:•  ConsiderTIPS(controversial)•  Iflivertransplantcandidate,dialysisasbridgetotransplant

Case3•  20y/omanhospitalizedforvolumedepletionafterreturningfromMexico•  Reports5daysof6-10loosestools/day,nausea,poorPOintake•  BPis80/50,dizzywithstanding•  Creatinine1yearago0.9.

126 4.5

90

16

75

3.5 90

Urine: UNa 30 mEq/L Ucreat: 42 mg/dL Uosm: 300 mOsm/kg Fe Na 2%

Case3:urinesediment

ValueofUrineSediment

Perazella et al. CJASN 2012

NEPHROTOXINS AND ATN

Endogenous Exogenous/Drugs Myoglobin(Rhabdomyolysis)Uricacid(TumorLysisSyndrome)Hemoglobin(Hemolysis)

AmphotericinAminoglycosidesCisplatinIfosfamideAcetaminophenSalicyclatesRadiocontrastagents(?)IntravenousimmunoglobulinZolendronateVancomycin

Isvancomycinnephrotoxic?•  Isitthis?

• Orisitthis?

Vanco levels Serum creatinine

causality

causality Serum creatinine Vanco levels

Notamenabletorandomizedcontrolledtrial!

Vancomycinnephrotoxicity

7 randomized and controlled trials N = 4033 6 – vancomycin vs linezolid 1 – vancomycin vs certaroline 6/7 – vancomycin associated with higher risk of AKI

RR 2.45 (95% confidence interval, 1.69 to 3.55)

Ray et al, CJASN 2016

Vancomycin-associatedcastnephropathy

Vancomycinnephrotoxicityasafunctionoftroughlevel

Troughconcentration(mg/L) Toxicity

5–1010.1–1515.1–2020.1–35>35

5%3%11%23%82%

Horey et al. Ann Pharmacother. 2012;46:1477-83

Whatabout“contrastnephropathy?”

•  6,000,000 hospitalized pts; no AKI on admit, LOS < 10 d

•  Evaluated for hospital-acquired AKI Contrast No Contrast 5.5% 5.6% (unadjusted)

5.6% 5.1% (adjusted)

Conclusions: “…our analyses suggest that the incremental risk of AKI that can be attributed to radiocontrast is modest at worst, and almost certainly overestimated by patients, physicians, surgeons, radiologists, and other decision-makers.”

Preventionofcontrast-nephropathy

Myapproach:•  IfeGFR>45mL/min,nochangeinmanagementwithanyiodinatedcontrastscan•  IfeGFR30-45mL/min,USUALLYnochangeinmanagementàevaluateforriskfactorsforAKI•  IfeGFR<30▫  Ifcantoleratefluid,give1cc/kg/hrisotonicfluid(NSversusLR)for6hourspre-procedure,andfor6hourspost-procedure▫  DonotgiveNAC,donotwithholdACEI/ARB,statins

•  Restorerenalperfusion/treatunderlyingcondition•  Avoidfurtherinsultsifpossible;ifdrug-related,withdrawntheoffendingdrug• Manageaccompanyingvolume/electrolyte/acid-baseabnormalities•  Adjustrenally–excretedmedstocurrentlevelofkidneyfunction• Watchforuremicmanifestations,orotherindicationsforinitiationofdialysis

MANAGEMENT OF ATN

Obstructivenephropathy,anuncommoncauseofAKI

•  Evaluation:▫  Bladderscan,bladdercatheterization▫  Renalu/s

Intrarenalobstruction Ureteralobstruction Bladderoutletobstruction

•  Stones •  Transitional cell

carcinoma •  Clots •  Papillary necrosis

•  Stones •  Transitional cell

carcinoma •  External compression

•  Tumors •  RP fibrosis •  Lymph nodes

•  BPH •  Neurogenic bladder

ShouldyougetarenalultrasoundinallAKI?

No,butyoushouldatleastconsider….•  Largekidneys-amyloid(otherinfiltrativedisease),AIN,HIV,diabetes•  Smallkidneys-likelychronicprocess,unlikelytobenefitfromtreatment•  Polycystickidneydisease•  Singlekidney

Case4•  55y/omanhospitalizedforsepsis,foundtohaveMRSAbacteremia2/2severesofttissueinfection•  TreatedwithIVvancomycin•  Initiallabs:

134 4.5

100

20

20

1.5 90

Urine: UNa 20 mEq/L Fe Na 1% Urine sediment: dysmorphic RBCs

Creatinine subsequently climbed daily: 1.5 à 1.7 à 2.1 à 2.3 à 2.6 à 2.9

C3: low C4: WNL

DYSMORPHIC RBCS

GLOMERULONEPHRITIS/RPGN

SystemicDisease Mechanism Disease

Antibody-mediatedPauci-immuneImmunecomplex

Anti-GBMdiseaseSmallvesselvasculitis(GPA,MPA,Churg-Strauss)LupusnephritisCryoglobulinemia

Laboratory evaluation: Complement levels, ANCA group, anti GBM, ANA with reflexive panel, HCV PCR, cyroglobulinemia titers/cryocrit Definitive diagnosis: Kidney biopsy

PrimaryGlomerularDisease

Mechanism Disease

Immunecomplex

IgAnephropathyMPGN(HCV)Infection-relatedGN

• NearlyalwaysassociatedwithCONCURRENTstaphinfection•  Distinctfrompost-streptococcalGN▫  Post-strepGNoccursAFTERinfection•  Canbeaccompaniedbyvasculitisskinrash•  Serumcomplementslow▫  LowC3morecommonthanlowC4• Noserologictestavailable;definitivediagnosisrequireskidneybiopsy

INFECTION-RELATED GLOMERULONEPHRITIS

Clinicalcluesthatshouldpromptnephrologyconsultation

RenalConsult

Nephroticsyndrome

Concernforpulmonary-

renalsyndromes

ConcernforAIN

AKIinkidneytransplant

PersistentoligoanuriawithAKI

Take-homepoints•  >90%ofAKIinhospitalizedpatientsislowEABV(includingpre-renal,cardiorenal,hepatorenal)orATN

• Urinemicroscopyisasimpleandusefultool▫  Granularcastsàif>6/lpf,likelytobeATN▫  DysmorphicRBCsàalwaysglomerularpathology

•  AKIinthecontemporaryhospitalizedpatientisoftenmultifactorialwithoverlappingcauses

Questions?