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