OMG: Not Another Biomarker Talk - Forni
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1) Over 50% of patients in intensive care units develop acute kidney injury (AKI), which is associated with high mortality rates. 2) Creatinine is an imperfect biomarker for detecting AKI, as it is influenced by many non-renal factors and rises slowly after injury. 3) Novel biomarkers that detect early cellular changes in the kidney, such as TIMP-2 and IGFBP7, may help identify patients at high risk of developing AKI earlier than creatinine.
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OMG: Not Another Biomarker Talk - Forni
- 1. Lui G Forni : Consultant Intensivist & Nephrologist Faculty of Health Sciences : University of Surrey The Injured Kidney: AKI: Who Will Get It ?? OMG : Not Another Biomarker Talk…
- 2. Disclosures Research Funding Commercial Trials: Honorarium/Travel Expenses: Astute Medical SBRI/D4D’s Renal Technologies Patientrack BRS/BKPA Roche Fresenius; Astute Medical; Ortho Clinical Diagnostics; Baxter/Gambro/Renal
- 3. AKI : What’sThe Problem ? • Common • High Mortality • Heavy Burden of Illness • Acute • ‘Chronic’ • Expensive!!! AcuteKidneyInjury:WhoWillGetIt?
- 4. No AKI = 1.99% Mortality AKI = 28.11 % Mortality AcuteKidneyInjury:WhoWillGetIt?
- 6. AcuteKidneyInjury:WhoWillGetIt? Epidemiology 40% Europe 92% Northern Hemisphere 75% High Income
- 9. HT, Heart Failure, Cirrhosis, Diabetes, Mechanical Ventilation Who Will Get It ? : Risk Factors?
- 10. AcuteKidneyInjury:WhoWillGetIt? So Which Of Our Patients Are At Risk of AKI ?
- 11. AcuteKidneyInjury:WhoWillGetIt? Who Is At Risk ?…
- 12. 141 Pages Long 132 Page Appendix 64 Pages of Tables AcuteKidneyInjury:WhoWillGetIt?
- 15. Incidence and outcomes of acute kidney injury in intensive care units: AVeterans Administration study CV Thakar et al, Crit Care Med 2009 Risk Dependent on Cause AcuteKidneyInjury:WhoWillGetIt?
- 17. Author/Study Year Number AKI (?) Rasmussen 1985 148 SCr > 160 Lohr 1988 126 50% Elevation Schaefer 1991 134 RRT Liano 1993 328 RRT Paganini 1996 506 SCr > 160 Chertow 1998 256 RRT Lins 2000 197 Rise SCr > 80 Mehta 2002 605 SCR > 160 Lins 2004 293 SCr > 160 Dharan 2005 265 50% rise in SCr Chertow 2006 618 SCr > 40 Demirjian 2011 1122 SCr > 2 / RRT Poorly Performing Variable Definitions AcuteKidneyInjury:WhoWillGetIt?
- 18. What about in well defined populations? • Cardiac Surgery –Known Baseline –Timed Insult –Accurate Data Collection AcuteKidneyInjury:WhoWillGetIt?
- 20. AcuteKidneyInjury:WhoWillGetIt? Predictive Scoring Systems • Variable Endpoints • Poorly Performing • Not applicable to the majority of our patients • Is there another way to identify AKI early?
- 21. AcuteKidneyInjury:WhoWillGetIt? The Race For The AKI Biomarker…
- 22. AcuteKidneyInjury:WhoWillGetIt? “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” Biomarkers…..
- 24. AcuteKidneyInjury:WhoWillGetIt? Biomarkers for AKI : The Dream
- 25. AcuteKidneyInjury:WhoWillGetIt? So What Went Wrong ?
- 26. AcuteKidneyInjury:WhoWillGetIt? • Can Novel Biomarkers Help to Identify High Risk Patients & Improve Clinical Practice?
- 27. AcuteKidneyInjury:WhoWillGetIt? The Problem May be…. • Creatinine • Under stable steady state conditions…... • Excellent for CKD • Useless for AKI….
- 28. ©2000 by American Physiological Society AcuteKidneyInjury:WhoWillGetIt? Dietary Intake Muscle Bulk Tubular Secretion Renal Reserve
- 29. AcuteKidneyInjury:WhoWillGetIt? Why is Creatinine Imperfect? • Poor Specificity in Pre-Renal Disease • Levels Dependant on Dietary Intake/Sepsis • Drug Induced Changes inTubular Secretion • Poor Sensitivity with Adequate Renal Reserve • Slow Kinetics Post Injury • Poor Sensitivity Where Histologicl damage is Mild
- 31. AcuteKidneyInjury:WhoWillGetIt? AKI No AKI 800 200 Lets Assume We Know Which Patients In This Cohort Have AKI…
- 32. AcuteKidneyInjury:WhoWillGetIt? Total 200 800 1000 AKI + (SCr) 180 80 260 AKI - (SCr) 20 720 740 90% Sensitivity 90% Specificity If We Assume SCr has a S&S of 90%
- 33. AcuteKidneyInjury:WhoWillGetIt? Total 260 740 1000 AKI (PT+ve) 180 20 260 No AKI (PT-ve) 80 720 720 69% Sensitivity 97% Specificity “AKI” As Determined by PT Even the perfect test would give imperfect results…...
- 36. Initial Cellular Insults Oxidative/Inflammatory Stress DNA damage G1 Cell-Cycle arrest G1 G2 S (DNA synthesis) InterphaseCytokinesis Mitosis Mitotic phase (M) [TIMP-2] [IGFBP7] Peroxidized lipids Chemical exposure PAMPSDAMPS Reactive oxygen species Oxidized proteins [IGFBP7] [TIMP-2] P53 P21 P27 CyclE CDK2 CyclD CDK4 Markers of Cell-Cycle Arrest p53/p21 signaling involved in CCA G1 = Gap 1 (Cell Growth/Preparation for DNA Synthesis)
- 37. Conclusions • Over 50% of our Patients Currently Get AKI • Overall Poor Outlook Probably Reflects – Multisystem effects of renal injury – Underlying cause of the AKI • We Should Probably Abandon the Slavish Chase for a RenalTroponin…. AcuteKidneyInjury:WhoWillGetIt?
- 38. Conclusions • We need to start listening to what the new molecules are telling us.. AcuteKidneyInjury:WhoWillGetIt?
Editor's Notes
- Major routes of Cr metabolism in the mammalian body. The most part (up to 94%) of Cr is found in muscular tissues. Because muscle has virtually no Cr-synthesizing capacity, Cr has to be taken up from the blood against a large concentration gradient by a saturable, Na+- and Cl−-dependent Cr transporter that spans the plasma membrane (□). The daily demand for Cr is met either by intestinal absorption of dietary Cr or by de novo Cr biosynthesis. The first step of Cr biosynthesis probably occurs mainly in the kidney, whereas the liver is likely to be the principal organ accomplishing the subsequent methylation of guanidinoacetic acid (GAA) to Cr. It must be stressed that the detailed contribution of different bodily tissues (pancreas, kidney, liver, testis) to total Cr synthesis is still rather unclear and may vary between species (see text). The muscular Cr and PCr are nonenzymatically converted at an almost steady rate (∼2% of total Cr per day) to creatinine (Crn), which diffuses out of the cells and is excreted by the kidneys into the urine.