2. Risk prediction models of AKI DR.F.Haghverdi MD

3. Outline AKI epidemiology and definition(brenner2016) Biomarkers Risk prediction models of AKI (post CABG, non cardiac surgery, post contrast)

4. 4 AKI: About 5% of hospital admissions. 30 % of ICU patients have AKI and 5% of ICU populations requiring RRT.

5. AKI: The most frequent cause of hospital AKI is ATN because of decreased renal perfusion,observed in 39% of episodes, followed by medication associated AKI (16%), radiocontrast media–induced AKI (11%), postoperative AKI (9%), and sepsis-associated AKI (6.5%).

6. AKI: The crude short-term mortality rate among patients with intrinsic AKI approximates 50% and has changed little over the past 3 decades.

7. AKI: 10-40% surviving patients remaining dialysis dependent. 50% of recover kidney function patients have subclinical function defect 5% of patients who survive an episode of AKI are at increased risk for CKD and ESKD.

10. Is there any doubt that we need better markers for AKI?

12. Biomarkers: Prediction of AKI Prognosis Novel therapy Surrogate endpoint in clinical trials

13. Why we need newer biomarkers? Diagnosis of AKI is Often Delayed Elevation in serum creatinine is the current gold standard, but this is problematic. Normal serum creatinine varies widely with age, gender, diet, muscle mass, muscle metabolism, medications, and hydration status. In AKI, serum creatinine can take several days to rise.

14. Why we need newer biomarkers? Up to 50% of kidney function may be lost before serum creatinine even begins to rise.

15. Early detection may decrease mortality in AKI

18. Clinically useful Biomarkers: Validation in different setting of AKI ( cardiac surgery, sepsis,contrast nephropathy) and in different clinical centers. Development and testing of rapid assays. Development of a panel of biomarkers.It is unlikely that a single biomarker will suffice so a panel of biomarkers will be necessary.

19. x

20. Novel biomarkers Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G 1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P 0.72.

26. Key messages Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2) are new biomarkers for AKI and perform better than existing markers for predicting the development of moderate or severe AKI (KDIGO stage 2 or 3) within 12 hours of sample collection. [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Risk for major adverse kidney events (death, dialysis or persistent renal dysfunction) within 30 days (MAKE30) elevated sharply for [TIMP-2]·[IGFBP7] above 0.3 and doubled when values were >2.0. Both IGFBP7 and TIMP-2 are inducers of G1 cell-cycle arrest, a key mechanism implicated in AKI.

27. FDA has approved use of (TIMP2/IFBP7) for development of AKI

28. Biomarkers and ATN phases:

29. Relative changes in AKI biomarker concentration in humans over time after surgery. Alge and Arthur, JM, 2015 ACUTE KIDNEY INJURY BIOMARKERS

32. Risk prediction models of AKI AKI after CABG AKI after major noncardiac surgery AKI post contrast

33. 33 What are risk score/prediction models? A “prediction” is a statement or claim that a particular event will occur in the future. A “prediction” is a statement or claim that a particular event will occur in the future. Mathematical equation can be used to model the rate (or probability or likelihood) of event. Mathematical equation can be used to model the rate (or probability or likelihood) of event. Mathematical equation and/or scoring system can be used to stratify subjects (e.g., high vs. low risk ) Mathematical equation and/or scoring system can be used to stratify subjects (e.g., high vs. low risk )

34. Post CABG AKI 34

35. Post CABG AKI Acute kidney injury (AKI) is a serious and potentially lethal complication of cardiac surgery. Acute kidney injury (AKI) is a serious and potentially lethal complication of cardiac surgery. Severe kidney failure requiring dialysis occurs in 1% to 2% of cardiac surgery patients and is associated with a mortality rate in excess of 60%. Severe kidney failure requiring dialysis occurs in 1% to 2% of cardiac surgery patients and is associated with a mortality rate in excess of 60%. 35

36. Post CABG AKI Importantly, less severe AKI not requiring dialysis, which can occur in up to 17% of patients,remains independently associated with a 19-fold increase in short term mortality. Importantly, less severe AKI not requiring dialysis, which can occur in up to 17% of patients,remains independently associated with a 19-fold increase in short term mortality. 36

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42. Post CABG AKI 42

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50. NRI: Net RECLASSIFICATION Improvement IDI: integrative DISCRIMINATION Improvement 50

51. AKI after major noncardiac surgery 51

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58. AKI post contrast 58

59. Definition, clinical features, and differential diagnosis RCN is defined as “an acute decline in kidney function after the administration of intravascular contrast material, in the absence of other causes. The most commonly used criteria to define RCN is an increase of 25% or 0.5 mg/dL in sCr concentration, between 48 -72 hours after the administration of contrast media. sCr concentration usually begins to increase within 24 hours after administration of contrast media and generally peaks between days 3 -5, returning to baseline 7 - 10 days later. Radiocontrast Nephropathy, 2006.Vo l u m e 4, I s s u e 7 By ALVARO ALONSO, MD, AND MARK J. SARNAK, MD, MS

63. AKI post contrast

66. Conclusion: Diagnosis of AKI is Often Delayed Elevation in serum creatinine is the current gold standard, but this is problematic. We need new validated Biomarkers for early detection and prediction op AKI. FDA has approved use of (TIMP2/IFBP7) for early detection of AKI. Risk prediction models of AKI need to be validated in new large studies.