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uptodate on acute kidney injury

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  • 1. DR. SHERIF ALY Consultant (A) Nephrology Assir central hospital Abha 10/10/10 Acute Renal Failure UPDATE
  • 2. OBJECTIVES :
    • Introduction Concept of AKI
    • Introducing RIFIE and AKIN staging criteria for AKI
    • Describe the need for Biomarkers in AKI
    • Describe the role of Biomarkers in AKI
    • Discuss examples of promising AKI biomarkers
    • Discuss pharmacological treatment of AKI
    • Discuss new anticoagulants
  • 3.  
  • 4. Introduction
    • A. ) AKI Versus ARF
    • AKI reflects the entire spectrum of the disease and recognizes that acute decline in kidney function is often secondary to an injury that causes functional or structural changes in the kidney
    • B.) History
    • - In 2002 , ADQI proposed RIFLE classification system
    • - Categorizes and stratifies a population of patients based on their renal function.
    • - Three severity categories : RISK , INJURY & FAILURE
    • - Two outcome categories : LOSS & END-STAGE DISEASE
    • - In 2004 Acute Kidney Injury Network (AKIN) formed
    • - Prposed a diagnostic criteria for the definition of AKI
    • - In 2004 ADQI , ISN and ASN met and proposed the term of AKI.
  • 5. AKI : A Common Serious Problem
    • AKI is present in 5% of all hospitalized patients , and up to 30% of patients in ICUs.
    • The incidence is increasing at an alarming rate.
    • Mortality rate > 50% in dialyzed ICU patients.
    • 25% of ICU dialysis survivors progress to ESRD within 3 years.
  • 6. The Effect of AKI on Mortality Green bars are unadjusted, blue bars are age and gender adjusted, and gray bars are multivariable adjusted. Multivariable analyses adjusted for age, gender, diagnosis-related group (DRG) weight, CKD status, and ICD-9-CM codes for respiratory, gastrointestinal, malignant, and infectious diseases; n = 1564, 885, 246, and 105 for change in SCr 0.3 to 0.4, 0.5 to 0.9, 1.0 to 1.9, and 2.0 mg/dl. Chertow et al, JASN 2005
  • 7. The Effects of AKI on Hospital Costs Green bars are unadjusted, blue bars are age and gender adjusted, and gray bars are multivariable adjusted. Multivariable analyses adjusted for age, gender, diagnosis-related group (DRG) weight, CKD status, and ICD-9-CM codes for respiratory, GI, malignant, and infectious diseases; n = 1564, 885, 246, and 105 for change in SCr 0.3 to 0.4, 0.5 to 0.9, 1.0 to 1.9, and 2.0 mg/dl. Chertow et al, JASN 2005
  • 8. AKI Definition and Staging AKIN 2007
    • * An abrupt (within 48 hrs) reduction in kidney function defined as an absolute increase in serum creatinine level of ≥ 26.4 Mmol/L (0.3mg1dl) or a percentage increase in serum creatinine level of ≥ 50% (1.5 fold from base line) or a reduction in urine output (documented oligurea of < 0.5 ml/kg/ hr for > 6 hrs.)
  • 9. Acute Kidney Injury Network (AKIN) Staging System for Acute Renal Failure
    • Modifiable RIFLE Criteria
    AKIN Stage Serum Creatinine Criteria UOP
    • Risk
    ↑ S. Creat ≥ 26.4 Mmol/L or 50-100% above base line < 0.5 ml/kg/m 2 for > 6 hours
    • Injury
    Increase of 2-3 folds over base line < 0.5 ml/kg/m 2 for > 12 hours
    • Failure
    Increase of > 3 folds over base line or S. Creat > 354 Mmol/L acute increase of at least 0.5 mg/dl (44 Mmol/L) Need RRT < 0.5 ml/kg/m 2 for > 24 hours
  • 10. Progression of Early Kidney Disease
    • Hosle EAJ , etal Crit care 2006 , 10 : R 73
  • 11. Conceptual Model for AKI Normal Increased risk Damage ↓ GFR Kidney Failure Death
  • 12. Mechanism of Ischemic Acute Kidney Injury
    • Tubular cell metabolism
    • Tubular cell structure
    • Microvasculature and inflammation
  • 13.  
  • 14.  
  • 15. Biomarkers: AMI versus AKI Multiple Therapies 50% ↓ Mortality Supportive Care High Mortality Need early biomarkers of AKI for improved understanding, early treatment and better outcomes Period Acute Myocardial Infarction Acute Kidney Injury 1960s LDH Serum creatinine 1970s CPK, myoglobin Serum creatinine 1980s CK-MB Serum creatinine 1990s Troponin T Serum creatinine 2000s Troponin I Serum creatinine
  • 16. What is wrong with Serum Creatinine?
    • The production of creatinine is highly variable (age, sex, muscle mass)
    • Serum creatinine may not show significant increased until 50% of kidney function is lost.
    • Does not depict real-time changes in GFR that occur with acute reduction in kidney function.
    • Require time to accumulate to prior to being detected.
  • 17. The Ideal Biomaker of AKI
    • Easy, rapid and inexpensive to measure.
    • Precise and reliable
    • Highly sensitive for AKI.
    • It should be able to monitor the injury and predicts the severity.
    • It should be specific.
  • 18. Serum and Urinary Biomakers for AKI SG Coca etal kid. International 2008 73 , 1008 -1016
  • 19. Scoring system for validity used in this systematic review Validity Criterion Explanation Scoring Comments Participant recruitment Was recruitment based on presenting symptoms, results from previous tests, or fact that participants received index tests? Presenting sx=1 Previous tests or index tests=0 Based on presenting symptoms in all 31 studies. Participant sampling Was it study population or a convenience sample or a consecutive series? Consecutive series=1 Convenience sample=0 Based on convenience sample in 5 10, 19, 20, 22, 25, 37 studies. Data collection Was data collection planned before the index test and reference standard were performed prospectively or retrospectively? Prospective=1 Retrospective=0 Planned and performed prospectively in all 31 studies. Reference standard Was the rationale for the reference standard stated? Stated=1 Not stated=0 Not stated for two 12, 18 studies. Materials and methods Were technical specifications of material and methods stated including how and when measurements were taken? Stated=1 Not stated=0 Stated in all but one 19 of the articles. Index test Were the definitions of and rationales for the units, cutoffs, and/or categories of the results of the index tests stated? Stated=1 Not stated=0 Not stated in two 12, 19 of the 31 articles. Blinding Were readers of index test and reference standard blinded? Blinded=1 Not blinded or not stated=0 Stated that the readers of index test and reference standard were blinded in 17 10, 11, 19, 29, 30, 35, 36, 37, 38, 39 articles. Completion Was the number of participants that did not undergo index tests (no. of tests vs sample size) stated? Stated=1 Not stated=0 Stated in all but one 19 of the studies. Time interval Was the time interval from index test to reference standard stated? Stated=1 Not stated=0 The time interval between index test and reference standard (clinical diagnosis of AKI or severity end point such as dialysis or death) was not stated in five 19, 20, 25, 34, 36 articles. Distribution of severity of disease Was there a representative distribution of severity of disease? (mild, moderate, severe AKI; non-oliguric vs oliguric) Yes=1 No=0 A broad distribution of disease severity was found in all but four 12, 25, 27, 37 of the studies.
  • 20. Studies of biomarkers for the early diagnosis of AKI References Biomarker Clinical setting Subjects Sensitivity/specificity Area under ROC Positive LR Quality score Serum   Herget-Rosenthal et al. 9 Cystatin C ICU 85 0.82/0.95 NR 16.4 9   Ahlstrom et al. 24 Cystatin C ICU 202 NR 0.901 N/A 9   Mazul-Sunko et al. 25 Cystatin C ICU 29 0.5/0.5 NR 1.0 6   Mazul-Sunko et al. 25 ProANP(1-98) ICU 29 NR/NR NR N/A 6   Mishra et al. 11 NGAL Cardiac surgery in children 71 0.70/0.94 NR 11.6 10   Rinder et al. 27 Neutrophil CD11b Cardiac surgery 75 NR NR 62.6 † 8 Urine   Mishra et al. 11 NGAL Cardiac surgery in children 71 1.0/0.98 0.998 50.0 10   Wagener et al. 28 NGAL Cardiac surgery 81 0.73/0.78 0.8 3.3 9   Zappitelli et al. 38 NGAL Critically ill children 140 0.77/0.72 0.78 2.75 10   Parikh et al. 29 NGAL Post-transplant 63 0.9/0.83 0.9 5.3 10   Parikh et al. 10 IL-18 ICU 138 0.5/0.85 0.73 3.3 9   Parikh et al. 29 IL-18 Post-transplant 63 NR 0.9 N/A 10   Parikh et al. 30 IL-18 Cardiac surgery 71 0.5/0.94 0.75 8.3 10   Han et al. 40 IL-18 Critically ill children 137 0.25/0.81 0.54 1.3 10   Han et al. 37 KIM-1 Cardiac surgery 40 0.74/0.90 0.83 3.16 8   Han et al. 37 NAG Cardiac surgery 40 1.0/0.3 0.69 1.43 8   Han et al. 37 MMP-9 Cardiac surgery 40 NR 0.50 N/A 8   Eijkenboom et al. 31 GST Cardiac surgery 84 NR NR N/A 9   Westhuyzen et al. 32   -GT ICU 26 1.0/0.9 0.95 10.0 9   Westhuyzen et al. 32   -GST ICU 26 1.0/0.9 0.929 10.0 9   Westhuyzen et al. 32   -GST ICU 26 0.75/0.9 0.893 7.5 9   Westhuyzen et al. 32 AP ICU 26 0.5/0.95 0.863 10.0 9   Westhuyzen et al. 32 NAG ICU 26 1.0/0.81 0.845 5.3 9   Westhuyzen et al. 32 LDH ICU 26 0.5/0.95 0.688 10.0 9
  • 21. Promising Biomakers
    • Urinary Biomakers
    • A.) Inflammatory Biomakers
            • NGAL
            • IL - 18
    • B.) Tubular Proteins
            • KIM - I
  • 22.
    • NGAL
    • (Neutrophil Gelatiaase Associated Lipocalin)
    • - 25 kd protein up regulated in proximal tubule cells in response to Ischemic or nephrotoxic injury.
  • 23.
    • Mouse Ischemia
    • 30 min ischemia
    • S creat ↑ 24 h
    • Kidney NGAL ↑ 3 h
    • Colocalize with PCNA
    • (proliferating cell
    • nuclear antigen)
    Kidney NGAL in Ischemic AKI Mishra et al, JASN 14:2534-43, 2003 Mishra et al, JASN 15:3073-82, 2004
  • 24. Urine NGAL in Ischemic AKI
    • Mouse Ischemia
    • 30 min ischemia
    • S creat ↑ 24 h
    • Urine NAG ↑ 8 h
    • Urine B2M ↑ 8 h
    • Urine NGAL ↑ 2 h
    Mishra et al, JASN 14:2534-43, 2003 Mishra et al, JASN 15:3073-82, 2004
  • 25. * In development. Currently not for sale in US ® * Phase 3 Transition: Plasma NGAL Kit
  • 26.
    • Abbott Diagnostics
    • ARCHITECT: Standardized clinical platform
    Urine NGAL Platform
  • 27. IL - 18
    • Pro inflammatory Cytokine induced and cleared in proximal tubule after AKI.
    • 20 patient developed AKI post CPB
    • AKI defined as > 50% ↑ in serum creatinine
    • 35 control who did not develop AKI
    • Results :
    • Using serum creatinine , AKI was detected only 48 – 72 hrs. after CPB.
    • Urine IL – 18 ↑ at 4 – 6 hrs. after CPB and peaked at 12 hrs.
    • Parlikin CR Kid. Int. 2006 , 70 – 199 - 203
  • 28. Tubular Protein
    • KIM – I (Kidney Injury Molecule – I)
    • Trans membrane protein over expressed in proximal tubule cells I ischemic or nephrotoxic AKI
  • 29. Conclusion
    • Urinary biomakers allow diagnosis of AKI earlier than a rise in serum creatinine.
    • Most of recently discovered biomakers are used to detect proximal tubular injury.
    • e.g – NGAL , 2-4 hrs
    • - IL - 18 , 4 – 6 hrs
    • - KIM – I , 12 – 24 hrs
  • 30. Management of AKI
    • Indications for RRT in Patients with AKI
    • BUN > 27 mmol/L Relative
    • BUN > 35.7 mmol/L Absolute
    • Hyperkalemia > 6 Relative
    • Hyperkalemia > 6 with ECG change Absolute
    • Acidosis pH > 7.15 Relative
    • Acidosis pH < 7.15 Absolute
    • Fluid overload (diuretic sensitive) Relative
    • Fluid overload (diuretic resistant) Absolute
    • RIFLE (R.I.F) Relative
  • 31. Is Early Start of RRT Better ?
    • A tend toward a better outcome with early RRT, however , the quality of this trials favoring early timing is poor.
  • 32. Pharmacological Treatment of AKI
    • Recombinant human IGF–1 (rh IGF–I )
    • - Reduced kidney injury
    • - Decrease apoptosis and inflammation
    • Atrial naturitic peptide
    • - Dilate afferent arterioles
    • - Constrict efferent arterioles
    • Duo to narrow therapeutic window
    • - Failed to reduce AKI in human trials.
  • 33. Drugs on the Horizon
    • Anti-apoptosis/necrosis * Caspas inhibitors
    • * PARP inhibitors
    • Anti-inflammatory * Activated protein C
    • * L-MSH,anti PPAR-yr
    • Antisepsis * Activated protein e
    • * ethyl pyruvate
    • Growth factors * Erythroprotein
    • * HGF
    • Vasodilaters * ANP
    • * Co release
    • New anti-coagulants * anti factor lla (r-hiridum)
    • * Anti factor Xa (danaparoid)
    • Combination (nafamostat)To prevent
    • HITinCVVH patients.
  • 34. Conclusion :
    • AKI is common complication in hospitalized patients.
    • AKI has strong impact on morbidity and mortality.
    • Even mild degree of renal dysfunction may have a negative impact on outcome.
    • RIFIE classification is a good outcome predictor.
    • There are promising biomakers for early diagnosis and outcome predictor.
    • Drugs on horizon (no effective pharmacological therapy).
  • 35. SHUKRAN!!!

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