1. AKI to CKD: How Should We Look For It Prasad Devarajan, MD Professor of Pediatrics and Developmental Biology University of Cincinnati College of Medicine Director, Nephrology and Hypertension Director, Nephrology Clinical Laboratory CEO, Dialysis Unit Cincinnati Children’s Hospital Medical Center

2. The Center for Acute Care Nephrology Cerda CJASN 2008; 3:881-886 Natural History of AKI

3. The Center for Acute Care Nephrology Hypothesis: AKI markers for AKI to CKD transition Natural History of AKI

4. The Center for Acute Care Nephrology Outline Look for AKI to CKD transition by measuring markers of Decreased function Glomerular damage Tubulo-interstitial damage

5. The Center for Acute Care Nephrology Outline Look for AKI to CKD transition by measuring markers of Decreased function GFR estimation using serum creatinine and cystatin C Glomerular damage Albuminuria Tubulo-interstitial damage Albuminuria and other Novel AKI biomarkers

6. The Center for Acute Care Nephrology Estimating GFR from serum creatinine 0.43 X height (cm)/s. creat Barratt formula eGFR in ml/min/1.73 m2 Children 0.2-14 years Cr-EDTA Only CKD S creat by Jaffe Counahan et al, Arch Intern Med 51:875-8, 1976 0.413 X height (cm)/s. creat New Schwartz formula eGFR in ml/min/1.73 m2 Children 1-16 years Iohexol Only CKD S creat by Enzymatic Schwartz et al, JASN 20:629-37, 2009 (For older kids: use MDRD formula or CKD-EPI formula or the new combined creat plus cystatin C formula)

7. The Center for Acute Care Nephrology Advantages Widely available Inexpensive Convenient bedside estimate Disadvantages Confounded by age, gender, race, hydration, diet, muscle mass, time Many medications increase serum creat (TMP, aspirin, steroids) Overestimates GFR in CKD Confounded by “renal reserve” Colorimetric vs Enzymatic Estimating GFR from serum creatinine

8. The Center for Acute Care Nephrology Advantages of cystatin C Much less affected by age, gender, race, diet, hydration, muscle mass, and medications than serum creatinine Cystatin C levels are nearly identical in adults and children over 1 year old (unlike creatinine levels) – so a single reference range can be used for all individuals greater than 1 year of age Detects the early state of hyperfiltration Estimating GFR using Cystatin C

9. The Center for Acute Care Nephrology Advantages of cystatin C Compared to gold standards, almost always outperforms serum creatinine in children and adults, with normal kidney function, AKI, or CKD from various etiologies (three published meta-analyses) Estimating GFR using Cystatin C Dharnidharka AJKD 40:221-6, 2002 Roos Clin Biochem 40:383-91, 2007 Zhang AJKD 58:356-65, 2011

10. The Center for Acute Care Nephrology Cystatin C in AKI Zhang AJKD 58:356-65, 2011 (13 AKI publications)

11. The Center for Acute Care Nephrology Cystatin C in CKD Roos Clin Biochem 40:383-91, 2007 (23 CKD publications)

12. The Center for Acute Care Nephrology Disadvantages of cystatin C Cystatin C levels are higher in hyperthyroidism, and in patients receiving steroids or other immunosuppressants Two commonly used methods for measuring cystatin C (nephelometry and turbidimetry) can give discrepant results More expensive than serum creatinine GFR equations incorporating both cystatin C and creatinine may perform better than either one Estimating GFR using Cystatin C

13. The Center for Acute Care Nephrology Outline Look for AKI to CKD transition by measuring markers of Decreased function GFR estimation using serum creatinine and cystatin C Glomerular damage Albuminuria Tubulo-interstitial damage Albuminuria and other Novel AKI biomarkers

14. The Center for Acute Care Nephrology Albuminuria Associates with Community-Acquired AKI Grams JASN 2010; 21:1757-64 ARIC Cohort 8 year follow up 11,200 subjects with baseline ACR 356 (3.2%) developed AKI

15. The Center for Acute Care Nephrology Albuminuria Predicts AKI After Cardiac Surgery Molnar CJASN 2012 ePub (TRIBE-AKI adults) Zappitelli CJASN 2012 ePub (TRIBE-AKI children) AUCClinical ModelPost-op ACRCombination Adults (n=1198)0.75 (0.04)0.59 (0.04)0.81 (0.03) Children (n=294)0.79 (0.04)0.63 (0.05)0.82 (0.04) (< 2 yrs) (> 2 yrs) No AKI AKI

16. The Center for Acute Care Nephrology Albuminuria Predicts AKI Progression After Cardiac Surgery Koyner JASN 2012 23:905-14 (TRIBE-AKI adults) PredictorCut PointAdjusted ORAdjusted AUC Clinical Model0.75 (0.04) Urine ACR>1333.41 (1.27, 9.11)0.78 (0.04) Urine NGAL>1412.02 (0.86, 4.73)0.79 (0.04) Urine IL-18>1853.63 (1.64, 8.03)0.77 (0.04) Plasma NGAL>32211.66 (4.49, 30.27)0.80 (0.04)

17. The Center for Acute Care Nephrology Advantages Widely available Inexpensive Established marker of CKD and CKD outcomes Disadvantages Mechanisms unclear (glomerular versus tubular) May reflect non-specific changes in capillary permeability and/or a non- specific inflammatory response Limited diagnostic accuracy in AKI (AUCs in the 0.6 to 0.65 range) Many patients with CKD progress despite having only mild proteinuria Many patients with significant proteinuria do not progress Albuminuria for AKI to CKD Transition

18. The Center for Acute Care Nephrology Outline Look for AKI to CKD transition by measuring markers of Decreased function GFR estimation using serum creatinine and cystatin C Glomerular damage Albuminuria Tubulo-interstitial damage Albuminuria and other Novel AKI biomarkers

19. The Center for Acute Care Nephrology Novel Biomarkers for AKI to CKD Transition Novel inducible urinary biomarkers of AKI are being evaluated for use in the AKI-to-CKD progression Unbiased gene expression profiling studies in animal models of AKI-to-CKD transition show NGAL and KIM-1 as two most persistently upregulated genes (and proteins) in the kidney Ko et al, AJP Renal 298:F1472-83, 2010 Viau et al, JCI 120: 4065-76, 2010

20. The Center for Acute Care Nephrology NGAL – 2 Months After 75% Nephrectomy Viau et al, JCI 120: 4065-76, 2010 NGAL mRNA NGAL protein

21. The Center for Acute Care Nephrology NGAL – Expression in PDK Models Mouse Human Viau et al, JCI 120: 4065-76, 2010

22. The Center for Acute Care Nephrology NGAL in Human CKD NGAL protein expression is increased in kidney biopsies from humans with CKD, correlating with histologic damage and degree of CKD Increased levels of urinary NGAL and an inverse correlation with GFR have been documented in patients with CKD from PDK, HIV, FSGS, and diabetic nephropathy Devarajan Adv Chr Kid Dis 2010; 17:469-79 Goldstein Pediatr Nephrol 2011; 26:509-22

23. The Center for Acute Care Nephrology NGAL in Human CKD Progression Nickolas: 78 patients with CKD followed up for 200 days – urine NGAL at baseline correlated with future worsening of serum creatinine (r=0.77; p<0.001) Yang: 74 patients with diabetic nephropathy followed for 1 year – urine NGAL at baseline correlated with follow-up eGFR (r=-0.57, p<0.001) Bolignano: 96 patients with CKD stages 2-4 followed up for 18.5 months – 32% reached the composite end point of doubling of serum creatinine or onset of ESRD – urine and plasma NGAL at baseline independently predicted CKD progression with AUC 0.78 Nickolas et al, Curr Opin Nephrol Hypertens 17:127-32, 2008 Yang et al, Endocrine 36:45-51, 2009 Bolignano et al, CJASN 4:337-44, 2009

24. The Center for Acute Care Nephrology NGAL in Human CKD Progression Bhavsar: case-control study (n=143 each) from ARIC cohort prospectively followed for 8 years Cases progressed to CKD Stage 3 High baseline urine NGAL values independently associated with progression Bhavsar AJKD 2012; 60:233-40 Urinary BiomarkerOdds of CKD 3P for trend NGAL2.36 (1.12-5.01)0.01 KIM-11.51 (0.72-3.17)0.2 Albumin1.8 (0.95-3.43)0.07

25. The Center for Acute Care Nephrology KIM-1 in Human CKD Progression Peralta: case-control study (n=343 each) from MESA cohort prospectively followed for 5 years Cases progressed to CKD Stage 3 High baseline urine KIM-1 values independently associated with progression Peralta AJKD 2012; EPub Urinary BiomarkerOdds of CKD 3 KIM-12.35 (1.08-5.14) NGAL1.52 (0.76-3.05)

26. The Center for Acute Care Nephrology Other Novel AKI-CKD Biomarkers Devarajan Adv Chr Kid Dis 2010; 17:469-79 Fassett KI 2011; 80:806-821

27. The Center for Acute Care Nephrology AKI to CKD – Studies in Progress Claes, Goldstein et al: Long term follow up of children with AKI after cardiac surgery - no evidence of hypertension, proteinuria, or decreased eGFR NGALL-FABPIL-18KIM-1 Pre-op (n=54) 168.70.81258 Post-op Day 2 (n=54) 99244541010 5-8 years later (n=14) 9.17.657*473* *P<0.05 compared to pre-op baseline

28. The Center for Acute Care Nephrology AKI to CKD – Studies in Progress AKI after cardiac surgery (adult/pediatric), ICU (adult), community-acquired (adult)

29. The Center for Acute Care Nephrology AKI to CKD – Studies in Progress

30. The Center for Acute Care Nephrology AKI to CKD – Future Directions Targeted longitudinal assessments are required to assess the implications of AKI for CKD progression AKI severity and cumulative burden should be tracked for all patients at risk for AKI Biomarkers such as NGAL and KIM-1 should be tested for their ability to stratify subjects who are at greatest risk for AKI to CKD progression, who might benefit from increased surveillance, early prevention, and specific interventions Goldstein & Devarajan, Pediatr Nephrol 26:509-22, 2011

31. The Center for Acute Care Nephrology Acknowledgement of Collaborators Chirag Parikh (Yale U)Jon Barasch (Columbia U) Charles Edelstein (U Colorado)Tom Nickolas (Columbia U) Stuart Goldstein (CCHMC)Joseph Bonventre (Harvard) Didier Portilla (U Arkansas)Karina Soto (U Lisbon) Pat Murray (U Dublin)Sarah Faubel (U Colorado) Jay Koyner (U Chicago)Catherine Krawczeski (CCHMC) Rinaldo Bellomo (Austin Hosp)David Askenazi (UAB) Zoltan Endre (U Otago)Michael Haase (Charité Hosp) David Humes (U Mich)Christoph Westenfelder (U Utah) Adeera Levin (U Br Columbia)Uptal Patel (Duke U) Amit Garg (U London) Tim Bunchman (VCU) Sean Bagshaw (U Alberta)Kiyoshi Mori (Kyoto U) Mike Zappittelli (McGill U)Abbott Diagnostics Neesh Pannu (U Alberta)Biosite/Alere Funding: Thank You for your Attention!