1. October 2010 Acute Kidney Injury Michael Clarkson Department of Renal Medicine Cork University Hospital

2. “Acute Renal Failure” Syndrome is not dichotomous Dynamic process initiation, maintenance and recovery phases. Undue emphasis on whether or not renal function has overtly failed. Minor decrements in glomerular filtration associated with adverse clinical outcomes. October 2010

3. Terminology Acute Renal Failure (ARF) Acute Kidney Injury (AKI) Acute Tubular Necrosis (ATN)

4. May 2007AKI for the General Physician Bellomo R, Ronco C, Mehta RL, Palevsky P; ADQI workgroup. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8:R204-12. www.ADQI.net

5. R.I.F.L.E. R ISK I NJURY F AILURE L OSS E SKD October 2010

6. Levels for definition R [Creat] x 1.5<0.5 ml/kg/h x 6 h I [Creat] x 2.0<0.5 ml/kg/hr x 12 h F [Creat] x 3.0 350 umol/l anuria x 12 h L complete loss of function > 4 weeks E End Stage Kidney Disease > 13 weeks October 2010

7. AKI Network Definition AKI stage Creatinine criteria Urine output criteria I ↑ by >/= 25 µmol/L or ↑ to >/= 150% – 200% Urine output 6 hours II ↑ > 200% – 300% from baseline Urine output 12 hours III ↑ > 300% or Creat>/= 350 µmol/L after a rise of at least 50µmol/L or RRT Urine output 24 hours or anuria for 12 hours

8. October 2010 RIFLE Criteria - Validity The outcome of acute renal failure in the intensive care unit according to RIFLE: model application, sensitivity, and predictability. Abousaif et al. AJKD 2005. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Hoste et al. Crit Care 2005. An assessment of the RIFLE criteria for acute renal failure in hospitalized patients. Uchino et al. Crit Care Med. 2006.

9. Consequences of AKI Acute metabolic complications Acute cardiovascular complications Prolonged hospitalisation Resource consumption Patient DeathCommon ESKDUncommon October 2010

10. Epidemiology October 2010

11. Madrid Acute Renal Failure Study Liano F; Pascual J. Kidney Int 1996; 50: 811-8 Prospective, multi-centre, community-based 9 month period Creatinine >177mol/L 13 hospitals (4.2 million aged >14yrs) 209(195,223) cases pmp 48% normal function at admission 36% received RRT 45% hospital mortality October 2010

12. What kind of AKI? (Madrid Study) October 2010

13. Uchino S, Kellum JA, Bellomo R, et al. Acute Renal Failure in Critically Ill Patients: A Multinational Multicentre Study JAMA 2005;294: 813-818. BEST Kidney Investigators 54 Study Centres, 23 Countries, 15 months ~30 000 ICU admissions 5.5 to 6.0% AKI ( 30mmol/l) 4.0 to 4.4% RRT (80% CRRT) 30% pre-existing renal dysfunction October 2010

14. Uchino S, Kellum JA, Bellomo R, et al. Acute Renal Failure in Critically Ill Patients: A Multinational Multicentre Study JAMA 2005;294: 813-818. October 2010

15. Uchino S, Kellum JA, Bellomo R, et al. Acute Renal Failure in Critically Ill Patients: A Multinational Multicentre Study JAMA 2005;294: 813-818. ICU mortality 52% Subsequent hospital mortality 8% Total mortality 58-62.5% SAPS-II predicted 45.6% Independent of dialysis 83.7-88.8% Septic shock, vasopressors, mechanical ventilation, HRS October 2010

16. Nash K, Hafeez A, Hou S. Hospital-Acquired Renal Insufficiency. AJKD 2002;39(5): 930-6 4622 consecutive patients. Tertiary Referral Hospital. AKI 7.2% Risk Factors: CKD, Age, Race. October 2010

17. Nash K, Hafeez A, Hou S. Hospital-Acquired Renal Insufficiency. AJKD 2002;39(5): 930-6 Causal Factors Renal Hypoperfusion ECV, CHF, BP Medications / Contrast / Post-op / Sepsis / Non-renal Tx Medications Aminoglycosides>NSAID>Pip-Tazo>Ampho>SMX- TMP>Cya Outcome Complete recovery 38%, Death 20%, HD 4%, CKD 38% October 2010

18. Causes of Severe AKI Feest TG, Mistry CD, Grimes DS, Mallick NP. ( from RA Study on Incidence of CRF) October 2010

19. Treatment October 2010

20. How should AKI be treated..? General therapy Prevention Specific therapy RRT October 2010

21. How should AKI be treated..? General Measures Discontinue offending agents Avoid nephrotoxins if possible Forensic attention to current / previous Rx Meticulous attention to assessment of ECV status October 2010

22. P.E. Stevens, et al. Non-specialist management of acute renal failure. QJM 2001; 94: 533-40 East Kent (593 000) 12 month prospective study 486 cases p.m.p. [Creat]>300umol/l Focus on initial assessment/management October 2010

23. Rayner HC. A model undergraduate core curriculum in adult renal medicine. Med Teacher 1995; 17:409–2. CVP / fluid status Urinalysis Ultrasound October 2010

24. AKI – Minimum Data Set Serial assessment / record of ECV status Renal profile, Ca 2+, PO 4-, ABG Urinalysis / urine output Nephrotoxic medication review Renal Ultrasound Focused investigations (vasculitis, myeloma, uric acid, CPK etc.) October 2010

25. Prevention of AKI

26. Optimisation of ECV is single most important manoeuvre Volume depletion is risk factor for AKI in multiple clinical situations Endogenous Toxins Myoglobin Light chains Uric Acid Exogenous Toxins Radiocontrast Aminoglycosides Cisplatin October 2010

27. Which fluid? Crystaloid vs. Colloid

28. Schierhout G et al. Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: a systematic review of randomized trials. BMJ 1998;316:961-4. 37 RCTS 26 colloids vs. crystalloids (n = 1622). 10 colloid in hypertonic crystalloid vs. isotonic crystalloid (n = 1422) 1 colloid in isotonic crystalloid with hypertonic crystalloid (n = 38) MortalityRR 1.19(0.98-1.45) No benefit from colloid Cost more. October 2010

29. Finfer S et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247-56. Saline versus Albumin Fluid Evaluation (SAFE) Study 16 ICUs in Australia and New Zealand. n=6997 4% Albumin vs. 0.9% NaCl Outcomes: 28 Day MortalityRR 0.99 (0.91-1.09) Days of RRT: Not significant October 2010

30. Schortgen, F et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet 2001;357:911-16. 6% hydroxyethylstarch or 3% fluid-modified gelatin. RCT, n=129 Acute renal failureRR 2·32 (CI 1·02–5·34). 6% hydroxyethylstarch is an independent risk factor for development of AKI Do not use! October 2010

31. Rivers E, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77 ‘Goal-directed’ resuscitation in sepsis. Mean creatinine 230mol/L on admission. Defined hemodynamic targets: MAP > 65mmHg, CVP 10-12, Urine output>0.5mls/kg/hr, ScvO2>70%). Significant decrease in mortality. October 2010

32. Renal Replacement Therapy October 2010

33. Please, Sir…..what’s the prescription….? 1.Remove the bad stuff 2.Leave the good stuff 3. Don’t be too rough 4.Don’t keep clotting 5. Don’t keep bleeding 6. Don’t be too expensive 7. Don’t be too complicated October 2010

34. Some Physics (the fundamentals) Haemodialysis Solute removal by Diffusion Haemofiltration Solute removal by Convection October 2010

35. What kind of RRT…….? Diffusion Haemodialysis Fast Sometimes not well tolerated Small molecules Clearance of drugs variable Requires dialysis expertise Convection Haemofiltration Slow Usually well tolerated Medium-sized molecules Clearance of most drugs Can be ‘run’ with less knowledge/expertise More expensive !!!!!!!!!!!!! October 2010

36. Intermittant HD vs. CRRT Swartz, et al. Comparing continuous haemofiltration with hemodialysis in patients with severe acute renal failure. Am J Kidney Dis 1999; 34: 424-32 Mehta, et al. A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure. Kidney Int 2001; 60:1154-63. Uehlinger, et al. Comparison of continuous and intermittent renal replacement therapy for acute renal failure. Nephrol Dial Transplant 2005;20:1630-7. October 2010

37. Tonelli, et al. Acute renal failure in the intensive care unit: a systematic review of the impact of dialytic modality on mortality and renal recovery. Am J Kidney Dis 2002;40:875-85 6 RCTs CRRT vs. HD N=624 Mortality RR 0.96 (0.85-1.05) Renal death RR 1.02 (0.85-1.08) ESKD RR 1.02 (0.89-1.17) October 2010

38. Kellum JA, et al. Continuous versus intermittent renal replacement therapy: a meta- analysis. Intensive Care Med 2002; 28: 29-37 Randomised & Observational Studies CRRT v HD Primary end-point RR cumulative mortality 13 studies (3 randomised) – 1400 patients Poor quality – only 6 corrected for severity Overall RR 0.93 (0.79, 1.09) Adjusted for qualityRR 0.72 (0.60, 0.87) Similar severityRR 0.48 (0.34, 0.69) October 2010

39. Renal Replacement Therapy Choice often dictated by… Resources of the institution CVVH not available Technical expertise of the physician Intensivist vs. nephrologist Clinical status of the patient Cerebral edema Bleeding risk October 2010

40. How much? How often? Renal Replacement Therapy October 2010

41. May 2007AKI for the General Physician Specific therapies for ATN Diuretics Dopamine / Fenoldopam ANP / ANP analogues Growth factors

42. October 2010 Cantarovich F, et al. High-dose furosemide for established ARF: a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Am J Kidney Dis. 2004; 44: 402-9. 338 AKI patients, stratified by severity 25mg/kg/day iv or 35mg/kg/day po v Placebo Survival/renal recoveryNo difference 2litre diuresis achieved57% v 33% Mehta RL, et al; PICARD Study Group Diuretics, mortality, and non-recovery of renal function in acute renal failure. JAMA 2002; 288: 2547-53. Uchino S, et al; BEST Kidney Investigators Diuretics and mortality in acute renal failure. Crit Care Med 2004; 32: 1669-77.

43. Ho KM, Sheridan DJ. Meta-analysis of frusemide to prevent or treat acute renal failure BMJ 2006; 333:420. 9 RCTs 849 patients In-hospital mortality, RRT, number of RRT treatments, persistent oliguria No benefit Deafness and tinnitus (RR 1.00,15.78) October 2010

44. Diuretics in AKI Diuretics are not nephrotoxic Doctors prescribing habits are nephrotoxic! October 2010

45. Kellum JA, Decker JM. Use of dopamine in acute renal failure: a meta-analysis. Crit Care Med 2001; 29: 1526-31. 1966-2000 Prevention/Treatment 58 (n=2149) studies 24 (n=1019) outcome 17 (n= 854) RCT Mortality0.44-1.83 AKI0.55-1.19 RRT0.55-1.24 Power for >50% effect on AKI/RRT October 2010

46. May 2007AKI for the General Physician Renal-dose dopamine: from hypothesis to paradigm to dogma to myth and, finally, superstition? Jones D, Bellomo R J Intensive Care Med 2005;20: 247-8

47. Other Pharmacotherapies Recombinant Growth Factors Maybe good if you are small, white & furry with a long tail Not so good if you are anything else Calcium Channel Blockers No RCT suggest benefit Risk hypotension Theophyline No RCT suggest clinically important benefit Narrow therapeutic window October 2010

48. Is there hope……………?

49. October 2010 If I end up in your ICU with AKI…………. There is no pharmacologic treatment for established ATN Excellence in generic supportive management If you give me dopamine or thoughtlessly prescribed diuretics I’ll sue you (I mean, haunt you………..) Adequate dose CVVH Intermittent HD only by an expert My kidneys will get better if I do