Program Information

1. Program Information

2. Acute Kidney Injury in the ICU Susan L. Evans, MD Associate Director Surgical ICU Assistant Professor of Trauma, Surgical Critical Care and Acute Care Surgery The F. H. Sammy Ross Trauma Center Carolinas Medical Center Charlotte, NC Based on the 2005 presentation byJohn A. Kellum, MD Professor of Critical Care Medicine and Medicine Vice Chair for Research Director, Molecular Core, CRISMA Laboratory Department of Critical Care Medicine University of Pittsburgh Slide Sub-Title

3. Learning Objectives • Upon completion of this module you should: • Be able to define acute kidney Injury and sub-classify it into its main forms. • Understand the clinical consequences of acute kidney Injury. • Be able to list common risk factors for acute kidney Injury. • Be able to identify which agents are likely to be useful and which agents are likely to be ineffective or harmful in the prevention and treatment of acute kidney Injury. • Understand the basic principals of Renal Replacement Therapy

4. Outline • Epidemiology and Definitions • Etiology/Diagnosis • Outcome • Prevention • Treatment

5. Acute Kidney Injury • Glomerularfiltrationrate(GFR)=rateoftransferofproteinfreeplasmafiltrate(ultrafiltration)acrossthewallsoftheglomerularcapillaries. • InitsmostsevereformAKIisreferredtoasacuterenalfailure.

6. Defining Acute Kidney Injury International, interdisciplinary consensus panel Acute Dialysis Quality Initiative RIFLE Criteria

7. RIFLE Criteria for Acute Kidney Injury GFR Criteria* Urine Output Criteria Increased creatinine x 1.5 or GFR decrease >25% UO <.5ml/kg/h x 6 hrs High Sensitivity Risk UO <.5ml/kg/h x 12 hrs Increased creatinine x 2 or GFR decrease >50% Injury Increase creatinine x 3 or GFR dec >75% or creatinine 4mg/dl (Acute rise of 0.5 mg/dl) UO <.3ml/kg/h x 24hrs or anuria x 12 hrs High Specificity Oliguria Failure Loss Persistent AKI** = complete loss of renal function > 4weeks End Stage Renal Disease ESRD Bellomo R, et al. Crit Care Med. 2004;8:R204-R212 www.ADQI.net

8. Baseline 0.5 (44) 1.0 (88) 1.5 (133) 2.0 (177) 2.5 (221) 3.0 (265) Risk 0.75 (66) 1.5 (133) 2.3 (200) 3.0 (265) 3.8 (332) --- Injury 1.0 (88) 2.0 (177) 3.0 (265) --- --- --- Failure 1.5 (133) 3.0 (265) 4.0 (350) 4.0 (350) 4.0 (350) 4.0 (350) RIFLE Comparisons Creatinine is expressed in mg/dL and (mcmol/L). BellomoR,etal.CritCareMed.2004;8:R204–R212.

9. Epidemiology of AKI Uchino et al. Crit Care Med. 2006;34:1913-1917.

10. Epidemiology of AKI Evans et al. Crit Care Med. 2008;35:A156.

11. Epidemiology of AKI • The prevalence of AKI among patients in the intensive care unit is not known. • As many as 70% of critically ill patients experience some degree of AKI. • Approximately 5% of patients in the ICU receive renal replacement therapy (e.g., hemofiltration, hemodialysis). • Hospital mortality in this group is 40 - 80%. Cruz Clin J Am Soc Nephrol 2007;2:418-425 Bagshaw Nephrol. Dial Transplant 2008;23(4):1204-1210 Hoste CCM 2006;10(3):R73

12. Risk Factors for AKI • Hypovolemia • Hypotension • Sepsis • Frequentlyaspartofmultipleorganfailure • Pre-existingrenal,hepatic,orcardiacInjury • Diabetesmellitus • Exposuretonephrotoxins • Aminoglycosides,amphotericin,immunosuppressiveagents,nonsteroidalanti-inflammatorydrugs,angiotensinconvertingenzymeinhibitors,intravenouscontrastmedia • Twoormoreriskfactorsareusuallypresent!

13. Pre-renal (40 - 80%) renal artery disease systemic hypotension Dehydration Intra-renal (10 - 50%) acute tubular necrosis interstitial nephritis Post-renal (< 10%) obstruction TypesofAcuteKidneyInjury Significant overlap

14. Types of Kidney Injury pre - renal renal osm u (mOsm/kg) > 500 < 400 Na u (mmol/L or meq/L) < 20 > 40 BUN/s creatinine > 20 < 10 u/s creatinine > 40 < 20 u/s osmolality > 1.5 > 1 FeNa (%)* < 1 > 2 ________________________________________________________________ * ( (u Na / s Na) / (u creat / s creat) ) X 100 u for urinary, s for serum, Fe = fractional excretion

15. Etiology of (intra-renal) AKIand Typical* Urinalysis Findings • Acute Tubular Necrosis (ATN) [~ 90% of AKI cases] • urine sediment benign, mild proteinuria/hematuria • muddy-brown casts • Allergic Interstitial Nephritis • urine eosinophils • variable urine sediment, proteinuria and hematuria • Rhabdomyolysis • brown urine, dip stick (+) blood but RBC (-) by microscopy • myoglobin (+) • Glomerulonephritis • marked proteinuria • RBC casts (highly specific) * urinalysis is often non-diagnostic

16. Cellular Injury and Repair in acute tubular necrosis (ATN) Injury Proliferation And Redifferentiation Normal Tubular Cells Propagation Inflammation Recovery (rapid) Injured Cells Recovery (slow) De- Differentiated Cells Necrotic * Cells Apoptotic Cells Exfoliation Into the Urine * very few necrotic cells are observed from patients with ATN

17. Presence of AKI is Strongly Associated with Hospital Mortality AKI = 5.5x mortality!!

18. Metnitz et al. Crit Care Med. 2002

19. Renal Replacement Therapy (RRT) The need for renal replacement therapy (rrt) is strongly associated with hospital mortality Metnitz et al. Crit Care Med. 2002

20. Effective Hydration Prevent hypotension Avoid nephrotoxins Unknown N-acetylcysteine Sodium Bicarbonate Prophylactic Hemofiltration Ineffective/harmful Diuretics Dopamine Other renal vasoactive drugs DA-1 agonists PDE inhibitors Ca++ blockers Adenosine antagonists Natriuretic peptides Prevention of AKI Goals of therapy are to prevent AKI or need for RRT Kellum et al. Clinical Evidence. 2004;11:1094-118.

21. Prevention • Maintain hydration (Isotonic IVF) • Reducing risk from nephrotoxins • Single vs. multiple daily doses of aminoglycosides • Lipid complex vs. standard amphotericin • Iso-osmomotic vs. standard or “low” osmolality radiocontrast media • Maintain perfusion pressure Kellum JA, et al. Clinical Evidence. 2004;11:1094-118.

22. Radiocontrast ATN For prevention (no) Ischemic ATN Vascular surgery (no) Other settings (?) Strength of Evidence Level I Level I * No data in humans Should We Use Loop Diuretics to Prevent ATN? * diuretics were begun after surgery Kellum JA. Crit Care Med. 1997;1:53-59

23. Dopamine Can Increase Urine Output by Various Mechanisms • Direct renal vasodilatation (DA-1 receptors) • Increased cardiac output (-receptors) • Increased renal perfusion pressure (-receptors) • Inhibition of Na-K ATPase at the tubular epithelial cell level resulting in natriuresis Seri I et al. Am J Physiol. 1988;255:F666-73.

24. Dopamine is not Effective 328 patients in 23 ICUs Bellomo et al. Lancet. 2000;356:2139-43.

25. 0.1 1 10 Death All Studies Excludes Radio-contrast Heart Disease Only ARF All Studies Excludes Radio-contrast Heart Disease Only Excludes Outliers Hemodialysis All Studies Excludes Radio-contrast Heart Disease Only Excludes Outliers Dopamine is not Effective Kellum & Decker, Crit Care Med. 2001;29:1526-1531. Harm Benefit

26. Risks of “Low-dose” Dopamine • Bowel mucosal ischemia • Digital necrosis • Pro-arrhythmic • Hypo-pituitarism • Immune suppression

27. DA-1 Agonists Dopexamine Fenoldapam Natriuretic Peptides Atrial natriuretic peptide Urodilatin B-type natriuretic peptide Adenosine Antagonists Theophylline Pentoxifylline Rolipram Calcium Antagonists Nifedipine Diltiazem Other Vasoactive Agents

28. N-acetylcystein (NAC) 83 patients with CRI (mean Creat. 2.4) CT scans with low-osmolal contrast agent Tepel M et al. N Engl J Med. 2000;343:180-184.

29. Tepel et al. N Engl J Med.2000;343:180-184.

30. NAC reduces the risk of AKI (increased creatinine) by 50%. Birck et al. Lancet. 2003;362:598-603.

31. Does NAC prevent AKI or just decrease Serum creatinine? • Hoffman et al. J Am Soc Nephrol. 2004;15:407-410. • Healthy volunteers given NAC showed a fall in serum creatinine without any change in cystatin C • NAC increases creatinine kinase activity • Increases tubular secretion of creatinine? • Decreased muscle production of creatinine?

32. Bicarbonate as Prophylaxis for RCN? N=154 Merten et al. JAMA. 2004;291(19):2328-2334.

33. Hemofiltration for RCN? Pro • Marenzietal.NEnglJMed.2003;349(2)1333-40. • n=114,hydrationalonevs.hydrationplushemofiltration • >25%riseinScrt:5%vs.50%P<0.001 • NeedforacuteRRTpost-procedure:3%vs.25%P<0.001 • In-hospitalmortality:2%vs.14%P=0.02 • Resultsnotconsistentwithhemodialysisstudies Con • Hsiehetal.IntJCardiol.2005;101(3):407-413. • N=40,hemodialysisafterPCI • Nodifferencein3&6monthcreatininerise • Nodifferencein#patientsprogressingtoESRD

34. Radio-contrast • So-called “low osmolality” radio-contrast • Iohexol: 700 - 800 mOSM • Iodixanol: 200 - 300 mOSM (iso-osmolar) • Incidence of AKI was 3% (iodixanol) compared with 26% (iohexol) (p = 0.002). Aspelin et al. N Engl J Med. 2003;348:491-99.

35. Effective Hemodialysis Biocompatible membranes More dialysis Unknown CRRT vs. IHD Earlier dialysis Ineffective/harmful Diuretics * Dopamine Treatment of AKI * Diuretics are never a treatment for oliguria but are sometimes required for management of volume overload. Kellum J et al. Clin Evid.2004;11:1094-118.

36. Goals of Renal Replacement Therapy (RRT) • Substitute for renal function • Control Volume • Correct acid-base abnormalities • Improve Clearance of toxins (e.g. uremia) • Reduce complications • Hasten/Permit Recovery • Prevent death

37. Techniques of RRT • Fluid Removal • water efflux through semi-permeable membrane • Solute Removal • Convection – ultrafiltrate • Diffusion - dialysis

38. Hemofiltration Forni et al. NEJM 336(18): 1303-1309, 1997.

39. Hemodialysis Forni et al. NEJM 336(18): 1303-1309, 1997.

40. Word Salad of RRT • CVVH – Continuous VenoVenous Hemofiltration • CVVHD – Continuous VenoVenous HemoDialysis • CVVHDF – Continuous VenoVenous HemoDiaFiltration • IHD – Intermittent HemoDialysis • SLEDD – Sustained Low-Efficiency Daily Dialysis

41. 100 90 p < 0.001 80 70 p < 0.001 p n.s. 60 50 40 30 58 % 41 % 57 % 20 10 0 Group 1(n=146) Group 2 (n=139) Group 3 (n=140) ( Uf = 20 ml/h/Kg) ( Uf = 35 ml/h/Kg) ( Uf = 45 ml/h/Kg) Cumulative Survival vs. Ultrafiltration Rate Ronco et al. Lancet. 2000; 355:26-30.

42. 100 90 80 70 60 50 40 72 % 30 54 % 20 10 0 3/wk HD 7/wk HD wKT/V = 3.6 wKT/V = 7.4 Survival vs. Dialysis Dose In Intermittent Hemodialysis Adapted from Shiffl et al. N Engl J Med. 2002;346:305-10.

43. Intensity of RRT Odds Ratio: 1.09 95% CI: 0.86-1.40 P=0.47 Intensive – 53.6% Less-Intensive – 51.5%

44. Intensity of RRT

45. Favors standard dose Favors higher dose More Intensive RRT Is Not Associated With Increased Survival

46. What is Standard Dose RRT? • In the ATN study • Control patients received thrice weekly IHD with a delivered Kt/Vurea of 1.3. • Control patients received 95% of the prescribed dose of CRRT • In practice • IHD patients in the ICU receive a delivered Kt/Vurea of 1.1 or less • CRRT patients in the ICU receive ~80% of the prescribed dose.

47. Continuous vs. Intermittent RRT Bagshaw et al. Crit Care Med. 2008;36(2):610-617.

48. Treatment: Diuretics • Diuretics: Effects on outcome (small RCTs) • 66 patients randomized to receive furosemide (1.5 - 6.0 mg/kg) • No significant differences in recovery or need for HD. ~ Kleinknecht et al. Nephron. 1976;17:51-58. • 58 patients randomized to single dose (1g) vs. continued dosing of furosemide (3g/day). • Oliguria was reversed in 2/30 vs. 24/28. • No differences in mortality, renal recovery, or need for RRT. • Permanent deafness in one patient. ~ Brown et al. Clin Nephrol. 1981;15:90-6.

49. Treatment: Diuretics • Diuretics:Effectsonoutcome(largeobservationalstudies) • 4-center,retrospectiveanalysisofpatientsreferredfornephrologyconsults(1989-1995;n=552) • Withadjustmentsforco-variatesandpropensityscore,diureticusewasassociatedwith: • Significantlyincreasedriskofdeathornon-recoveryofrenalfunction(oddsratio1.77;95%CI1.14-2.76) ~Mehtaetal.JAMA.2002;288:2547-53. • 52-center,prospectiveinceptioncohortofICUpatients(n=1743) • Nodifferencesinmortality,orrenalrecovery,evenafteradjustmentforthesameco-variatesandpropensityscore • Oddsratio1.22(p=0.15) • However,nobenefitassociatedwithdiureticseither! ~Uchinoetal.CritCareMed.2004;32:1669–77.

50. Conclusions/Recommendations • AKI is a common ICU syndrome. • As many as 70% of ICU patients develop AKI. • Approximately 5% of ICU patients receive RRT. • AKI in the critically ill carries a very high mortality, and current treatment is disappointing. • Inflammation likely plays a significant role in the development of AKI.