Acute Renal Failure
    An Update

Jai Radhakrishnan, MD, MS, FASN, FACC
 Associate Professor of Clinical Medicine
       ...
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....
Changes in mortality in patients with
acute renal failure over 47 years




                   Ympa YP Am J Med. 2005 Aug;...
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-i...
Hepatorenal Syndrome:
Diagnostic Criteria
  MAJOR CRITERIA:
     Chronic/Acute liver disease with advanced hepatic failure...
Efferent and Afferent Arterioles of
                                      Rabbit
                                100      ...
Terlipressin +/- Albumin In HRS




Hepatology 36 (2002), pp. 941–948
Hepatorenal Syndrome Type I: Vasopressin in One
            Patient
                                                      ...
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 obstr...
ARF: Intra-Renal
 VASCULAR                   GLOMERULAR
   Vascular occlusion        Acute/Rapidly
                       ...
Atheroembolic disease

 ARF precipitated by
 angiography
 Often eosinophilia and
 low complement
 Multi-organ dysfunction,...
Acute Interstitial Nephritis

Triad of fever, skin rash
and eosinophilia
Eosinophiluria
Drugs: penicillin,
cephalosporins,...
Rapidly Progressive Glomerulonephritis

 ETIOLOGY
    Immune complex GN:
    -post infectious,SLE, IgAN, SBE,
    cryoglob...
Crystal-induced ARF

 Uric acid (tumor-lysis)
 Oxalate (ethylene glycol)
 Methotrexate
 Acyclovir
 Sulfonamides
          ...
Indinavir- Urine Crystals




         Gagnon RF.. Am J Kidney Dis 2000 Sep;36(3):507-515
Osmotic Nephrosis
                             Sucrose
                             Mannitol
                             ...
J Am Soc Nephrol. 2005 Nov;16(11):3389-96.
Etiology of ATN

 Ischemic
    All pre-renal causes



 Endogenous                Exogenous Toxins
 Toxins                ...
Radiocontrast Nephropathy
  Clinical Course:
    Onset of oliguria within 24 hours
    Peak creatinine in 4-5 days followe...
Contrast Nephropathy Risk
S Creatinine> 0.5 mg/dl or > 25%at 48-72 h




            Mehran R.. J Am Coll Cardiol. 2004 Oc...
Heme Pigment Induced ATN
 Rhabdomyolysis: traumatic or non-traumatic
 Intravascular hemolysis
 Mechanism uncertain: Vasoco...
Aminoglycoside Nephrotoxicity
Non-oliguric renal
failure
Onset several days
after treatment
Recovery is usually
complete w...
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)...
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-R...
Treatment of ATN-2005

         SUPPORTIVE CARE
    •   Acid-base/electrolyte balance
    •   Fluid balance
    •   Nutrit...
Intensity of Renal Support in Critically Ill
 Patients with Acute Kidney Injury.




                                     ...
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
   ...
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...
Preventive Strategies
 POSITIVE:
     Hydration
 EQUIVOCAL:
     Bicarbonate
     N-Acetyl Cysteine
     Theophylline
    ...
The Data
Effect on Mortality                          Friedrich JO; Adhikari N; Herridge MS; Beyene J.
                   ...
High-dose Furosemide for
Established ARF
338 pts with ARF on dialysis
Furosemide (25mg/kg IV or 35mg/kg PO, or
matched pla...
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:...
ARF: Outcomes after Discharge
 Quality of Life

  77% assessed health as “Good to excellent”
  69% resumed working
  57% s...
Future Developments
 Biomarkers:
 Cell-based therapy
Current Status of Biomarkers




Neutrophil Gelatinase-associated Lipocalcin
(NGAL)
Kidney Injury Molecule-1
Interleukin 1...
225


                            200
                                                                             Serum C...
Urinary NGAL at 2 Hours Post CPB
                                               600


                                    ...
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 bes...
02 Radhakrishnan   Acute Renal Failure Update
02 Radhakrishnan   Acute Renal Failure Update
02 Radhakrishnan   Acute Renal Failure Update
02 Radhakrishnan   Acute Renal Failure Update
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02 Radhakrishnan Acute Renal Failure Update

  1. 1. Acute Renal Failure An Update Jai Radhakrishnan, MD, MS, FASN, FACC Associate Professor of Clinical Medicine Columbia University
  2. 2. Objectives Epidemiology of ARF Diagnostic workup Specific syndromes of ARF Treatment and Prevention
  3. 3. ARF-Definitions Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group Crit Care. 2004 Aug;8(4):R204
  4. 4. Changes in mortality in patients with acute renal failure over 47 years Ympa YP Am J Med. 2005 Aug;118(8):827-32.
  5. 5. Etiology of ARF Pre-renal (hemodynamic) Intra-Renal (parenchymal) Post-renal (obstructive)
  6. 6. ARF: Pre-renal Volume Depletion Prostaglandins Angiotensin-II Cardiac Redistribution Hepatorenal syndrome NSAIDS ACE-inhibitors
  7. 7. 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
  8. 8. 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
  9. 9. Terlipressin +/- Albumin In HRS Hepatology 36 (2002), pp. 941–948
  10. 10. 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)
  11. 11. Diclofenac Residues as the Cause of Vulture population Decline in Pakistan Nature. 2004 Feb 12;427(6975):
  12. 12. 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.
  13. 13. ARF: Intra-Renal VASCULAR GLOMERULAR Vascular occlusion Acute/Rapidly progressive Atheroembolic glomerulonephritis disease Thrombotic microangiopathy TUBULAR Crystal INTERSTITIAL ATN Interstitial nephritis
  14. 14. Atheroembolic disease ARF precipitated by angiography Often eosinophilia and low complement Multi-organ dysfunction, livedo reticularis, blue toes Generally irreversible
  15. 15. Acute Interstitial Nephritis Triad of fever, skin rash and eosinophilia Eosinophiluria Drugs: penicillin, cephalosporins, diuretics, NSAIDS, dilantin Usually completely reversible upon withdrawing drug ?Glucocorticoids
  16. 16. 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
  17. 17. Crystal-induced ARF Uric acid (tumor-lysis) Oxalate (ethylene glycol) Methotrexate Acyclovir Sulfonamides Oxalate Indinavir Phospho Soda Uric Acid
  18. 18. Indinavir- Urine Crystals Gagnon RF.. Am J Kidney Dis 2000 Sep;36(3):507-515
  19. 19. Osmotic Nephrosis Sucrose Mannitol Intravenous immunoglobulin Radiocontrast agents Dextran Hydroxyethyl starch Ebcioglu Z.. Kidney International (2006) 70, 1873–1876.
  20. 20. J Am Soc Nephrol. 2005 Nov;16(11):3389-96.
  21. 21. Etiology of ATN Ischemic All pre-renal causes Endogenous Exogenous Toxins Toxins Antibiotics Hemoglobin Contrast Myoglobin Chemotherapy Light chains Org. solvents, Heavy metals
  22. 22. 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
  23. 23. 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.
  24. 24. Heme Pigment Induced ATN Rhabdomyolysis: traumatic or non-traumatic Intravascular hemolysis Mechanism uncertain: Vasoconstriction, precipitation/obstruction, toxicity of other breakdown products Concomitant volume depletion
  25. 25. 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.
  26. 26. Top 5 Causes of ARF Am J Kidney Dis. 2002 May;39(5):930-6
  27. 27. 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
  28. 28. Urine Microscopy Red Cell Cast WBC Cast Muddy (granular) Cast Broad Cast
  29. 29. Workup of Renal Failure RENAL FAILURE Acute or Chronic Post-Renal Renal Pre-Renal Glomerular Vascular Interstitial Tubular History, Physical, Urine analysis, USG
  30. 30. Treatment of ATN-2005 SUPPORTIVE CARE • Acid-base/electrolyte balance • Fluid balance • Nutrition • Review of drugs • Dialysis: • PD, HD, Continuous modalities
  31. 31. 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]
  32. 32. Course and Outcome of ATN Am J Kidney Dis. 2002 May;39(5):930-6
  33. 33. Pathogenesis of ATN Bruce A. Molitoris & Robert Bacallao
  34. 34. Tubuloglomerular feedback Endothelin Adenosine Nitric Oxide Prostacyclin
  35. 35. Pathogenesis of ATN: Reactive Oxygen Species Source of ROS: Xanthine Dehydrogenase NADH Oxidase
  36. 36. QUESTION: What preventive strategies have been consistently shown to be effective against ATN? Maintaining euvolemia ? N-acetyl cysteine ? Dopamine ? Iso-osmolar contrast ?
  37. 37. Preventive Strategies POSITIVE: Hydration EQUIVOCAL: Bicarbonate N-Acetyl Cysteine Theophylline Isoosmolar Contrast CRRT/Dialysis NEGATIVE: Atrial natriuretic peptide Anti-endothelin antagonist Fenoldopam
  38. 38. 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
  39. 39. 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
  40. 40. Course and Outcome of ATN Am J Kidney Dis. 2002 May;39(5):930-6
  41. 41. 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
  42. 42. 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
  43. 43. Future Developments Biomarkers: Cell-based therapy
  44. 44. 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
  45. 45. 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.
  46. 46. 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.
  47. 47. Ann Intern Med. 2008 Jun 3;148(11):810-9.
  48. 48. 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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