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Acute Renal Failure
    An Update

Jai Radhakrishnan, MD, MS, FASN, FACC
 Associate 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
02 Radhakrishnan   Acute Renal Failure Update
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 Depletion   Prostaglandins Angiotensin-II
Cardiac
Redistribution
Hepatorenal
syndrome

NSAIDS
ACE-inhibitors
Hepatorenal Syndrome:
Diagnostic Criteria
  MAJOR CRITERIA:
     Chronic/Acute liver disease with advanced hepatic failure and
     portal hypertension
     Low GFR (Creatinine>1.5mg/dL or CrCl<40ml/min)
     Absence of shock, bacterial infection, nephrotoxin, GI /renal fluid
     losses
     No 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 CRITERIA
     Urine Volume <500ml/day
     Urine Na <10meq/L
     Urine RBC<50/HPF
     Serum Na <130meq/L

                                      Hepatology. 1996 Jan;23(1):164-76
02 Radhakrishnan   Acute Renal Failure Update
Efferent and Afferent Arterioles of
                                      Rabbit
                                100                                                      100
                                           AVP                                                       AVP
% Reduction in Lumen Diameter




                                90                                                       90
                                           NE                                                        NE
                                80                                                       80

                                70                                                       70

                                60                                                       60

                                50                                                       50

                                40                                                       40

                                30                                                       30

                                20                                                       20

                                10                                                       10

                                 0                                                        0
                                      -14 -13   -12   -11 -10   -9   -8   -7   -6   -5         -14   -13   -12   -11 -10   -9   -8   -7   -6   -5

                                                      Agonist (Log M)                                             Agonist (Log M)

                                                 Efferent                                                        Afferent
                                                      Edwards AJP 1989
Terlipressin +/- Albumin In HRS




Hepatology 36 (2002), pp. 941–948
Hepatorenal Syndrome Type I: Vasopressin in One
            Patient
                                                             AVP
     SPA
      120                                                    120


  SBP 100                                                    100
                                                                    SBP
(mm Hg)
                                                                  (mm Hg)
       80                                                    80


       60                                                    60



  UO 40                                                      40
                                                                    UO
 (cc/h)                                                            (cc/h)
       20                                                    20


        0                                                    0
                -6   -4    -2      0         2   4   6   8

                                Time (hrs)
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 obstruction
  Bilateral ureters
Urine volume variable.
Renal USG or
Bladder catheterization.
ARF: Intra-Renal
 VASCULAR                   GLOMERULAR
   Vascular occlusion        Acute/Rapidly
                             progressive
   Atheroembolic             glomerulonephritis
   disease
   Thrombotic
   microangiopathy
                            TUBULAR
                             Crystal
 INTERSTITIAL
                             ATN
   Interstitial nephritis
Atheroembolic disease

 ARF precipitated by
 angiography
 Often eosinophilia and
 low complement
 Multi-organ dysfunction,
 livedo reticularis, blue
 toes
 Generally irreversible
Acute Interstitial Nephritis

Triad of fever, skin rash
and eosinophilia
Eosinophiluria
Drugs: penicillin,
cephalosporins, diuretics,
NSAIDS, dilantin
Usually completely
reversible upon
withdrawing drug
?Glucocorticoids
Rapidly Progressive Glomerulonephritis

 ETIOLOGY
    Immune complex GN:
    -post infectious,SLE, IgAN, SBE,
    cryoglobulinemia
    Anti GBM antibody disease
    Vasculitis:
    -Wegener’s, microscopic PAN,
    idiopathic crescentic GN


 DIAGNOSTIC CLUES
    Systemic findings
    Significant proteinuria, RBC,
    RBC casts
Crystal-induced ARF

 Uric acid (tumor-lysis)
 Oxalate (ethylene glycol)
 Methotrexate
 Acyclovir
 Sulfonamides
                              Oxalate
 Indinavir
 Phospho Soda



                             Uric Acid
Indinavir- Urine Crystals




         Gagnon RF.. Am J Kidney Dis 2000 Sep;36(3):507-515
Osmotic Nephrosis
                             Sucrose
                             Mannitol
                             Intravenous
                             immunoglobulin
                              Radiocontrast agents
                             Dextran
                             Hydroxyethyl starch


      Ebcioglu Z.. Kidney International (2006) 70, 1873–1876.
J Am Soc Nephrol. 2005 Nov;16(11):3389-96.
02 Radhakrishnan   Acute Renal Failure Update
02 Radhakrishnan   Acute Renal Failure Update
Etiology of ATN

 Ischemic
    All pre-renal causes



 Endogenous                Exogenous Toxins
 Toxins                      Antibiotics
   Hemoglobin                Contrast
   Myoglobin                 Chemotherapy
   Light chains              Org. solvents,
                             Heavy metals
Radiocontrast Nephropathy
  Clinical Course:
    Onset of oliguria within 24 hours
    Peak creatinine in 4-5 days followed by
    recovery in the majority
    Differential diagnosis: atheroembolic disease
  Risk factors:
    Age
    Chronic kidney disease esp. diabetes
    Pre-renal azotemia (e.g. cirrhosis, CHF)
    Volume of contrast
Contrast Nephropathy Risk
S 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-traumatic
 Intravascular hemolysis
 Mechanism uncertain: Vasoconstriction,
 precipitation/obstruction, toxicity of other
 breakdown products
 Concomitant volume depletion
Aminoglycoside Nephrotoxicity
Non-oliguric renal
failure
Onset several days
after treatment
Recovery 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

Urinary Index           Pre-renal ATN

Osmolality              >500       <400
(mOsom/kg)
Sodium (meq/L)          <20        >40

Fractional ex of Na     <1 %       >2%



                      *UNa / PNa ÷ UCr / PCr
Urine Microscopy




 Red Cell Cast          WBC Cast




Muddy (granular) Cast   Broad Cast
Workup of Renal Failure
             RENAL FAILURE

               Acute or Chronic

      Post-Renal    Renal       Pre-Renal

Glomerular   Vascular   Interstitial   Tubular
   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.




                                                   35 ml/kg/h


                                                   20 ml/kg/h




N Engl J Med. 2008 May 20. [Epub ahead of print]
Course and Outcome of ATN




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




                      Bruce A. Molitoris & Robert Bacallao
Tubuloglomerular feedback




                  Endothelin
                  Adenosine

                  Nitric Oxide
                  Prostacyclin
Pathogenesis of ATN:
  Reactive Oxygen Species
Source of ROS:
  Xanthine
  Dehydrogenase
  NADH Oxidase
QUESTION: What preventive strategies
have been consistently shown to be effective
against ATN?
 Maintaining euvolemia ?
 N-acetyl cysteine ?
 Dopamine ?
 Iso-osmolar contrast ?
Preventive Strategies
 POSITIVE:
     Hydration
 EQUIVOCAL:
     Bicarbonate
     N-Acetyl Cysteine
     Theophylline
     Isoosmolar Contrast
     CRRT/Dialysis
 NEGATIVE:
     Atrial natriuretic peptide
     Anti-endothelin
     antagonist
     Fenoldopam
The Data
Effect on Mortality                          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.




                  Effect on need for Renal
                  Replacement Therapy
High-dose Furosemide for
Established ARF
338 pts with ARF on dialysis
Furosemide (25mg/kg IV or 35mg/kg PO, or
matched placebo) daily.
No difference in :
  Survival
  Renal 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:
 Survival
 979 pts who
 received CRRT
 69% in-hospital
 mortality
 Post discharge
 survival:
     6M: 89%
     5 Y: 50%




Morgera, S. American Journal of Kidney Disease 2002; 40(2):275-279
ARF: Outcomes after Discharge
 Quality of Life

  77% assessed health as “Good to excellent”
  69% resumed working
  57% self-sustaining
  Most Common Complaints:
      Loss of energy
     Difficulty with heavy housework
     Limited physical mobility


    Morgera, S. American Journal of Kidney Disease 2002; 40(2):275-279
    Korkeila, M. Nephrology, Dialysis, and Transplantation 2000
Future Developments
 Biomarkers:
 Cell-based therapy
Current Status of Biomarkers




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


    Nickolas T.. Curr Opin Nephrol Hypertens. 2008 Mar;17(2):127-132
225


                            200
                                                                             Serum Creat Rise
                            175
       Urine NGAL (ng/ml)




                            150


                            125


                            100


                             75
                                                                                                                       ARF
                             50                                                                                       (n=20)

                             25

                                                                                                                      No ARF
                              0   1   2       3       4       5      6   7      8   9   10   11   12   13   14   15



                                                                                                                      (n=51)
                                      2   4       6       8       12 24 36 48 60 72 84 96 108 120

                                                                    Post CPB Time (hours)

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

                                                                   Lancet. 2005Apr;365(9466):1231-8.
Urinary NGAL at 2 Hours Post CPB
                                               600


                                                                             Sensitivity:      100%
                                               500
                                                                             Specificity:      98%
           Urine NGAL (ng/ml) 2 hr post CPB




                                               400
                                                                             PPV:              95%
                                                                             NPV:              100%
                                               300




                                               200




                                               100



                                              50
                                                   0   0       1             2




                                                             ARF           No ARF
                                                            (n=20)         (n=51)

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

                                                           Lancet. 2005Apr;365(9466):1231-8.
Ann Intern Med. 2008 Jun 3;148(11):810-9.
Conclusions
ARF is common in hospitalized patients & has a
high mortality
A significant number of patients recover
The best (and least expensive) preventive
strategy is to maintain euvolumia

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02 Radhakrishnan Acute Renal Failure Update

  • 1. Acute Renal Failure An Update Jai Radhakrishnan, MD, MS, FASN, FACC Associate Professor of Clinical Medicine Columbia University
  • 2. Objectives Epidemiology of ARF Diagnostic workup Specific syndromes of ARF Treatment and Prevention
  • 3. ARF-Definitions Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group Crit Care. 2004 Aug;8(4):R204
  • 5. Changes in mortality in patients with acute renal failure over 47 years Ympa YP Am J Med. 2005 Aug;118(8):827-32.
  • 6. Etiology of ARF Pre-renal (hemodynamic) Intra-Renal (parenchymal) Post-renal (obstructive)
  • 7. ARF: Pre-renal Volume Depletion Prostaglandins Angiotensin-II Cardiac Redistribution Hepatorenal syndrome NSAIDS ACE-inhibitors
  • 8. Hepatorenal Syndrome: Diagnostic Criteria MAJOR CRITERIA: Chronic/Acute liver disease with advanced hepatic failure and portal hypertension Low GFR (Creatinine>1.5mg/dL or CrCl<40ml/min) Absence of shock, bacterial infection, nephrotoxin, GI /renal fluid losses No 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 CRITERIA Urine Volume <500ml/day Urine Na <10meq/L Urine RBC<50/HPF Serum Na <130meq/L Hepatology. 1996 Jan;23(1):164-76
  • 10. Efferent and Afferent Arterioles of Rabbit 100 100 AVP AVP % Reduction in Lumen Diameter 90 90 NE NE 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 -14 -13 -12 -11 -10 -9 -8 -7 -6 -5 -14 -13 -12 -11 -10 -9 -8 -7 -6 -5 Agonist (Log M) Agonist (Log M) Efferent Afferent Edwards AJP 1989
  • 11. Terlipressin +/- Albumin In HRS Hepatology 36 (2002), pp. 941–948
  • 12. Hepatorenal Syndrome Type I: Vasopressin in One Patient AVP SPA 120 120 SBP 100 100 SBP (mm Hg) (mm Hg) 80 80 60 60 UO 40 40 UO (cc/h) (cc/h) 20 20 0 0 -6 -4 -2 0 2 4 6 8 Time (hrs)
  • 13. Diclofenac Residues as the Cause of Vulture population Decline in Pakistan Nature. 2004 Feb 12;427(6975):
  • 14. ARF: Post-renal Consider obstruction in every patient with ARF. Sites of obstruction leading to ARF: Bladder neck obstruction Bilateral ureters Urine volume variable. Renal USG or Bladder catheterization.
  • 15. ARF: Intra-Renal VASCULAR GLOMERULAR Vascular occlusion Acute/Rapidly progressive Atheroembolic glomerulonephritis disease Thrombotic microangiopathy TUBULAR Crystal INTERSTITIAL ATN Interstitial nephritis
  • 16. Atheroembolic disease ARF precipitated by angiography Often eosinophilia and low complement Multi-organ dysfunction, livedo reticularis, blue toes Generally irreversible
  • 17. Acute Interstitial Nephritis Triad of fever, skin rash and eosinophilia Eosinophiluria Drugs: penicillin, cephalosporins, diuretics, NSAIDS, dilantin Usually completely reversible upon withdrawing drug ?Glucocorticoids
  • 18. Rapidly Progressive Glomerulonephritis ETIOLOGY Immune complex GN: -post infectious,SLE, IgAN, SBE, cryoglobulinemia Anti GBM antibody disease Vasculitis: -Wegener’s, microscopic PAN, idiopathic crescentic GN DIAGNOSTIC CLUES Systemic findings Significant proteinuria, RBC, RBC casts
  • 19. Crystal-induced ARF Uric acid (tumor-lysis) Oxalate (ethylene glycol) Methotrexate Acyclovir Sulfonamides Oxalate Indinavir Phospho Soda Uric Acid
  • 20. Indinavir- Urine Crystals Gagnon RF.. Am J Kidney Dis 2000 Sep;36(3):507-515
  • 21. Osmotic Nephrosis Sucrose Mannitol Intravenous immunoglobulin Radiocontrast agents Dextran Hydroxyethyl starch Ebcioglu Z.. Kidney International (2006) 70, 1873–1876.
  • 22. J Am Soc Nephrol. 2005 Nov;16(11):3389-96.
  • 25. Etiology of ATN Ischemic All pre-renal causes Endogenous Exogenous Toxins Toxins Antibiotics Hemoglobin Contrast Myoglobin Chemotherapy Light chains Org. solvents, Heavy metals
  • 26. Radiocontrast Nephropathy Clinical Course: Onset of oliguria within 24 hours Peak creatinine in 4-5 days followed by recovery in the majority Differential diagnosis: atheroembolic disease Risk factors: Age Chronic kidney disease esp. diabetes Pre-renal azotemia (e.g. cirrhosis, CHF) Volume of contrast
  • 27. Contrast Nephropathy Risk S Creatinine> 0.5 mg/dl or > 25%at 48-72 h Mehran R.. J Am Coll Cardiol. 2004 Oct 6;44(7):1393-9.
  • 28. Heme Pigment Induced ATN Rhabdomyolysis: traumatic or non-traumatic Intravascular hemolysis Mechanism uncertain: Vasoconstriction, precipitation/obstruction, toxicity of other breakdown products Concomitant volume depletion
  • 29. Aminoglycoside Nephrotoxicity Non-oliguric renal failure Onset several days after treatment Recovery is usually complete within 3 weeks Mingeot-Leclercq MP… Antimicrob Agents Chemother. 1999 May;43(5):1003-12.
  • 30. Top 5 Causes of ARF Am J Kidney Dis. 2002 May;39(5):930-6
  • 31. Urinary Indices in Oliguric ARF Urinary Index Pre-renal ATN Osmolality >500 <400 (mOsom/kg) Sodium (meq/L) <20 >40 Fractional ex of Na <1 % >2% *UNa / PNa ÷ UCr / PCr
  • 32. Urine Microscopy Red Cell Cast WBC Cast Muddy (granular) Cast Broad Cast
  • 33. Workup of Renal Failure RENAL FAILURE Acute or Chronic Post-Renal Renal Pre-Renal Glomerular Vascular Interstitial Tubular History, Physical, Urine analysis, USG
  • 34. Treatment of ATN-2005 SUPPORTIVE CARE • Acid-base/electrolyte balance • Fluid balance • Nutrition • Review of drugs • Dialysis: • PD, HD, Continuous modalities
  • 35. Intensity of Renal Support in Critically Ill Patients with Acute Kidney Injury. 35 ml/kg/h 20 ml/kg/h N Engl J Med. 2008 May 20. [Epub ahead of print]
  • 36. Course and Outcome of ATN Am J Kidney Dis. 2002 May;39(5):930-6
  • 37. Pathogenesis of ATN Bruce A. Molitoris & Robert Bacallao
  • 38. Tubuloglomerular feedback Endothelin Adenosine Nitric Oxide Prostacyclin
  • 39. Pathogenesis of ATN: Reactive Oxygen Species Source of ROS: Xanthine Dehydrogenase NADH Oxidase
  • 40. QUESTION: What preventive strategies have been consistently shown to be effective against ATN? Maintaining euvolemia ? N-acetyl cysteine ? Dopamine ? Iso-osmolar contrast ?
  • 41. Preventive Strategies POSITIVE: Hydration EQUIVOCAL: Bicarbonate N-Acetyl Cysteine Theophylline Isoosmolar Contrast CRRT/Dialysis NEGATIVE: Atrial natriuretic peptide Anti-endothelin antagonist Fenoldopam
  • 42. The Data Effect on Mortality 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. Effect on need for Renal Replacement Therapy
  • 43. High-dose Furosemide for Established ARF 338 pts with ARF on dialysis Furosemide (25mg/kg IV or 35mg/kg PO, or matched placebo) daily. No difference in : Survival Renal recovery Shorter time to 2L/day diuresis Am J Kidney Dis. 2004 Sep;44(3):402-9
  • 44. Course and Outcome of ATN Am J Kidney Dis. 2002 May;39(5):930-6
  • 45. ARF Outcomes after Discharge: Survival 979 pts who received CRRT 69% in-hospital mortality Post discharge survival: 6M: 89% 5 Y: 50% Morgera, S. American Journal of Kidney Disease 2002; 40(2):275-279
  • 46. ARF: Outcomes after Discharge Quality of Life 77% assessed health as “Good to excellent” 69% resumed working 57% self-sustaining Most Common Complaints: Loss of energy Difficulty with heavy housework Limited physical mobility Morgera, S. American Journal of Kidney Disease 2002; 40(2):275-279 Korkeila, M. Nephrology, Dialysis, and Transplantation 2000
  • 47. Future Developments Biomarkers: Cell-based therapy
  • 48. Current Status of Biomarkers Neutrophil Gelatinase-associated Lipocalcin (NGAL) Kidney Injury Molecule-1 Interleukin 18 Nickolas T.. Curr Opin Nephrol Hypertens. 2008 Mar;17(2):127-132
  • 49. 225 200 Serum Creat Rise 175 Urine NGAL (ng/ml) 150 125 100 75 ARF 50 (n=20) 25 No ARF 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 (n=51) 2 4 6 8 12 24 36 48 60 72 84 96 108 120 Post CPB Time (hours) Urine NGAL is upregulated 15-fold within 2 hours after CPB in patients who later develop ARF Lancet. 2005Apr;365(9466):1231-8.
  • 50. Urinary NGAL at 2 Hours Post CPB 600 Sensitivity: 100% 500 Specificity: 98% Urine NGAL (ng/ml) 2 hr post CPB 400 PPV: 95% NPV: 100% 300 200 100 50 0 0 1 2 ARF No ARF (n=20) (n=51) The 2-hour urine NGAL was 50 ng/ml or higher in all patients who subsequently developed ARF Lancet. 2005Apr;365(9466):1231-8.
  • 51. Ann Intern Med. 2008 Jun 3;148(11):810-9.
  • 52. Conclusions ARF is common in hospitalized patients & has a high mortality A significant number of patients recover The best (and least expensive) preventive strategy is to maintain euvolumia