Acute Renal FailureAn Update

Jai Radhakrishnan, MD, MS, FASN, FACCAssociate Professor of Clinical Medicine

Columbia University

Objectives

Epidemiology of ARF

Diagnostic workup

Specific syndromes of ARF

Treatment and Prevention

ARF-Definitions Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group Crit Care. 2004 Aug;8(4):R204

Changes in mortality in patients with acute renal failure over 47 years

Ympa YP Am J Med. 2005 Aug;118(8):827-32.

Etiology of ARF

Pre-renal (hemodynamic)

Intra-Renal (parenchymal)

Post-renal (obstructive)

ARF: Pre-renal

Volume DepletionCardiacRedistributionHepatorenalsyndrome

NSAIDSACE-inhibitors

Prostaglandins Angiotensin-II

Hepatorenal Syndrome: Diagnostic Criteria

Hepatology. 1996 Jan;23(1):164-76

MAJOR CRITERIA: Chronic/Acute liver disease with advanced hepatic failure and portal hypertensionLow GFR (Creatinine>1.5mg/dL or CrCl<40ml/min)Absence of shock, bacterial infection, nephrotoxin, GI /renal fluid lossesNo sustained renal improvement after withdrawing diuretics and volume expansion (1.5 L NS)Proteinuria<500mg/d and renal usg without obstruction or parenchymal abnormality

MINOR CRITERIAUrine Volume <500ml/dayUrine Na <10meq/LUrine RBC<50/HPFSerum Na <130meq/L

100100

9090

8080

7070

6060

5050

4040

3030

2020

1010

00--1414 --1313 --1212 --1111 --1010 --99 --88 --77 --66 --55

Agonist (Log M)Agonist (Log M)

Edwards AJP 1989Edwards AJP 1989

AVPAVPNENE

100100

9090

8080

7070

6060

5050

4040

3030

2020

1010

00--1414 --1313 --1212 --1111 --1010 --99 --88 --77 --66 --55

Agonist (Log M)Agonist (Log M)

AVPAVPNENE

% R

educ

tion

in L

umen

Dia

met

er%

Red

uctio

n in

Lum

en D

iam

eter

Efferent and Afferent Arterioles of Rabbit

Efferent Afferent

Terlipressin +/- Albumin In HRS

Hepatology 36 (2002), pp. 941–948

Hepatorenal Syndrome Type I: Vasopressin in One Patient

120120

100100

8080

6060

4040

2020

00

120120

100100

8080

6060

4040

2020

00--66 --44 --22 00 22 44 66 88

SBP SBP (mm Hg)(mm Hg)

Time (hrs)Time (hrs)

AVPAVP

SPASPA

SBP SBP (mm Hg)(mm Hg)

UOUO(cc/h)(cc/h)

UOUO(cc/h)(cc/h)

Diclofenac Residues as the Cause of Vulture population Decline in Pakistan

Nature. 2004 Feb 12;427(6975):

ARF: Post-renal

Consider obstruction in every patient with ARF.Sites of obstruction leading to ARF:

Bladder neck obstructionBilateral ureters

Urine volume variable.Renal USG or Bladder catheterization.

ARF: Intra-Renal

VASCULARVascular occlusionAtheroembolicdiseaseThrombotic microangiopathy

INTERSTITIALInterstitial nephritis

GLOMERULARAcute/Rapidly progressive glomerulonephritis

TUBULARCrystal ATN

Atheroembolic disease

ARF precipitated by angiographyOften eosinophilia and low complementMulti-organ dysfunction, livedo reticularis, blue toesGenerally irreversible

Acute Interstitial Nephritis

Triad of fever, skin rash and eosinophiliaEosinophiluriaDrugs: penicillin, cephalosporins, diuretics, NSAIDS, dilantinUsually completely reversible upon withdrawing drug?Glucocorticoids

Rapidly Progressive Glomerulonephritis

ETIOLOGYImmune complex GN: -post infectious,SLE, IgAN, SBE, cryoglobulinemiaAnti GBM antibody diseaseVasculitis: -Wegener’s, microscopic PAN, idiopathic crescentic GN

DIAGNOSTIC CLUESSystemic findingsSignificant proteinuria, RBC, RBC casts

Crystal-induced ARF

Uric acid (tumor-lysis)Oxalate (ethylene glycol)MethotrexateAcyclovirSulfonamidesIndinavirPhospho Soda

Uric Acid

Oxalate

Indinavir- Urine Crystals

Gagnon RF.. Am J Kidney Dis 2000 Sep;36(3):507-515

Osmotic Nephrosis

SucroseMannitolIntravenous immunoglobulinRadiocontrast agents

DextranHydroxyethyl starch

Ebcioglu Z.. Kidney International (2006) 70, 1873–1876.

J Am Soc Nephrol. 2005 Nov;16(11):3389-96.

Etiology of ATN

IschemicAll pre-renal causes

Exogenous ToxinsAntibioticsContrastChemotherapyOrg. solvents, Heavy metals

Endogenous Toxins

HemoglobinMyoglobinLight chains

Radiocontrast NephropathyClinical Course:

Onset of oliguria within 24 hoursPeak creatinine in 4-5 days followed by recovery in the majorityDifferential diagnosis: atheroembolic disease

Risk factors: AgeChronic kidney disease esp. diabetesPre-renal azotemia (e.g. cirrhosis, CHF)Volume of contrast

Contrast Nephropathy RiskS Creatinine> 0.5 mg/dl or > 25%at 48-72 h

Mehran R.. J Am Coll Cardiol. 2004 Oct 6;44(7):1393-9.

Heme Pigment Induced ATN

Rhabdomyolysis: traumatic or non-traumaticIntravascular hemolysisMechanism uncertain: Vasoconstriction, precipitation/obstruction, toxicity of other breakdown productsConcomitant volume depletion

Aminoglycoside NephrotoxicityNon-oliguric renal failureOnset several days after treatmentRecovery is usually complete within 3 weeks

Mingeot-Leclercq MP… Antimicrob Agents Chemother. 1999 May;43(5):1003-12.

Top 5 Causes of ARF

Am J Kidney Dis. 2002 May;39(5):930-6

Urinary Indices in Oliguric ARF

*UNa / PNa ÷ UCr / PCr

Urinary Index Pre-renal ATN

Osmolality (mOsom/kg)

>500 <400

Sodium (meq/L) <20 >40

Fractional ex of Na <1 % >2%

Urine Microscopy

Red Cell Cast WBC Cast

Muddy (granular) Cast Broad Cast

Workup of Renal Failure

Post-Renal

Glomerular Vascular Interstitial Tubular

Renal Pre-Renal

Acute or Chronic

RENAL FAILURE

History, Physical, Urine analysis, USG

Treatment of ATN-2005

SUPPORTIVE CARE• Acid-base/electrolyte balance• Fluid balance• Nutrition• Review of drugs• Dialysis:

• PD, HD, Continuous modalities

Intensity of Renal Support in Critically Ill Patients with Acute Kidney Injury.

N Engl J Med. 2008 May 20. [Epub ahead of print]

35 ml/kg/h

20 ml/kg/h

Course and Outcome of ATN

Am J Kidney Dis. 2002 May;39(5):930-6

Bruce A. Molitoris & Robert Bacallao

Pathogenesis of ATN

Tubuloglomerular feedback

EndothelinAdenosine

Nitric OxideProstacyclin

Source of ROS:XanthineDehydrogenaseNADH Oxidase

Pathogenesis of ATN: Reactive Oxygen Species

QUESTION: What preventive strategies have been consistently shown to be effective against ATN?

Maintaining euvolemia ?N-acetyl cysteine ?Dopamine ?Iso-osmolar contrast ?

Preventive StrategiesPOSITIVE:

HydrationEQUIVOCAL:

BicarbonateN-Acetyl CysteineTheophyllineIsoosmolar ContrastCRRT/Dialysis

NEGATIVE:Atrial natriuretic peptide Anti-endothelinantagonistFenoldopam

The Data

Effect on Mortality

Effect on need for Renal Replacement Therapy

Friedrich JO; Adhikari N; Herridge MS; Beyene J. Meta-analysis: low-dose dopamine increases urine output but does not prevent renal dysfunction or death.Ann Intern Med 2005 Apr 5;142(7):510-24.

High-dose Furosemide for Established ARF

338 pts with ARF on dialysisFurosemide (25mg/kg IV or 35mg/kg PO, or matched placebo) daily.No difference in :

SurvivalRenal recovery

Shorter time to 2L/day diuresis

Am J Kidney Dis. 2004 Sep;44(3):402-9

Course and Outcome of ATN

Am J Kidney Dis. 2002 May;39(5):930-6

ARF Outcomes after Discharge: Survival979 pts who received CRRT69% in-hospital mortalityPost discharge survival:

6M: 89%5 Y: 50%

Morgera, S. American Journal of Kidney Disease 2002; 40(2):275-279

Morgera, S. American Journal of Kidney Disease 2002; 40(2):275-279

Korkeila, M. Nephrology, Dialysis, and Transplantation 2000

77% assessed health as “Good to excellent”69% resumed working57% self-sustainingMost Common Complaints:

Loss of energyDifficulty with heavy houseworkLimited physical mobility

ARF: Outcomes after DischargeQuality of Life

Future Developments

Biomarkers:Cell-based therapy

Current Status of Biomarkers

Neutrophil Gelatinase-associated Lipocalcin(NGAL)Kidney Injury Molecule-1Interleukin 18

Nickolas T.. Curr Opin Nephrol Hypertens. 2008 Mar;17(2):127-132

1514131211109876543210

25

50

75

100

125

150

175

200

225

2 4 6 8 12 24 36 48 60 72 84 96 108 120

Post CPB Time (hours)

Urin

e N

GAL

(ng/

ml)

No ARF(n=51)

ARF(n=20)

Serum Creat Rise

Urine NGAL is upregulated 15-fold within 2 hours after CPB in patients who later develop ARF

Lancet. 2005Apr;365(9466):1231-8.

2100

100

200

300

400

500

600

ARF(n=20)

No ARF(n=51)

Urin

e N

GAL

(ng/

ml)

2 hr

pos

t CPB

Urinary NGAL at 2 Hours Post CPB

50

The 2-hour urine NGAL was 50 ng/ml or higher in all patients who subsequently developed ARF

Lancet. 2005Apr;365(9466):1231-8.

Sensitivity: 100%Specificity: 98%PPV: 95%NPV: 100%

Ann Intern Med. 2008 Jun 3;148(11):810-9.

ConclusionsARF is common in hospitalized patients & has a high mortalityA significant number of patients recoverThe best (and least expensive) preventive strategy is to maintain euvolumia