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Novel Diagnostics and Treatments of AKI

Novel Diagnostics and Treatments of AKI. Paul J. Scheel, Jr., M.D. Director, Division of Nephrology The Johns Hopkins University School of Medicine. Learning Objectives. Understand increasing incidence of AKI Identify the new definitions of AKI

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Novel Diagnostics and Treatments of AKI

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  1. Novel Diagnostics and Treatments of AKI Paul J. Scheel, Jr., M.D. Director, Division of Nephrology The Johns Hopkins University School of Medicine

  2. Learning Objectives • Understand increasing incidence of AKI • Identify the new definitions of AKI • Understand use and limitations of new biomarkers for AKI • Review recent treatment trials of AKI

  3. Incidence: AKI Hsu et al , JASN 2013, 24:37-42

  4. Incidence: AKI By Age Hsu et al , JASN 2013, 24:37-42

  5. Does AKI Lead to CKD ? • The higher the serum creatinine • The longer the duration of AKI • Recurrent AKI * Strongly Associated with CKD and Death

  6. AKI and Survival Chawla et al. Kid Int. 2012;82: 516-524

  7. KDIGO Definition of AKI

  8. Diagnosis • Based on Change in Serum Creatinine • Assay Interference • Altered metabolism of creatinine in AKI • Dilution by volume overload • Alteration in secretion by drugs ( cimetidine) • Late and Indirect Marker

  9. Bio-Markers of AKI • Predict and Diagnose AKI • Identify Location of Injury • Identify Type and Etiology of Injury • Predict Outcomes

  10. Biomarkers of AKI

  11. AKI Bio-Markers • Cystatin C • Microalbumin • N-Acety-β-Glucose-Amidase (NAG) • Kidney Injury Molecule-1 ( KIM-1) • Neutrophil Gelatinase-Associated Lipocalcin (NGAL) • IL-18 • Liver Fatty Acid Binding Protein

  12. Cystatin C • Found in all nucleated cells • Freely filtered • Not protein bound • Not normally secreted in urine • Competes with albumin for endocyticreabsorbtion • Analysis affected by: • DM • Corticosteroids • Hyperthyroidism • Elevated Bilirubin • Inflammation Charlton et al. NDT ( 2014) 0:1-11

  13. MicroAblbumin • Normal < 30 mg/L • ↑Albuminuria secondary to tubular dysfunction • Non specific as to site of injury • Need to know baseline • Can be non pathologic ( fever, exercise)

  14. MicroAlbuminuria and AKI Adults AKI /Cardiac Surgery Children AKI /Cardiac Surgery Age 1 month to 2 years Age > 2 years Zappitelli et al. CJASN;2012;7:1761-1769 Molnar et al. CJASN 2012;7:1749-1760

  15. N-Acetyl-β-D-Glucose AmidaseNAG • Proximal Tubule Protein • Appears in Urine with proximal tubular injury • Appears 12h to 4 days before rise in serum creatinine • Inhibited by Urea • False + : Glucose intolerance,RA, Hyperthyroid Charlton et al. NDT ( 2014) 0:1-11

  16. KIM-1 • Increased more than any other gene in AKI • Shed from proximal tubular cells into urine • Urine KIM-1 ↑within 12hrs of ischemic injury Charlton et al. NDT ( 2014) 0:1-11

  17. Parikh et al. CJASN 2013; 8:1079-1088

  18. NGAL • Produced by tubular epith cells and neutrophils • Filtered at glomerulus • Filtered NGAL captured by proximal tubular cells • Rise in serum and urine NGAL predictor of AKI • Infusion of NGAL may prevent AKI ? Charlton et al. NDT ( 2014) 0:1-11

  19. NGAL in Diagnosis and Prognosis of AKI Predict AKI Predict Initiation of RRT Haase et al. Am J Kid Dis 2009;54(6):1012-1024

  20. IL-18 • Levels ↑2x in AKI • Source: • Proximal tubular cell Charlton et al. NDT ( 2014) 0:1-11

  21. Urinary IL-18 In AKI Parikh et al, Am J. Kid Dis. 2004, 43: 405-414

  22. Liver Fatty Acid –Binding ProteinL-FABP • Increased 4 hours after ischemic injury from cardiac surgery Charlton et al. NDT ( 2014) 0:1-11

  23. Urinary FABP and NAG as Predictors of AKI Following Cardiac Surgery Katagiri et al. Ann of thoracic Surgery 2012;93:577-583

  24. Treatment Trials • Dopamine for prevention of delayed graft function • N-accetycysteine to prevent RCIN • Chloride-poor IV fluids in ICU • ANP to prevent AKI

  25. Dopamine For Delayed Graft Function • Randomized, Open label, Multicenter • 264 Deceased Donors • Dopamine at 4 micrograms/Kg/min • Outcome: Need for Dialysis

  26. Dopamine For Prevention of Delayed Graft Function Schnuelle et al. JAMA. 2009 Vol 302(10):1067-1075

  27. Dopamine For Prevention of Delayed Graft Function Schnuelle et al. JAMA. 2009 Vol 302(10):1067-1075

  28. Treatment Trials • Dopamine for prevention of delayed graft function • N-accetycysteine to prevent RCIN • Chloride-poor IV fluids in ICU • ANP to prevent AKI

  29. N-acetylcysteine To Prevent RCIN • 180 patients with GFR < 60 ml/min having PCI • Randomized, placebo controlled , double blind • NAC 2000 mg/day or 3 days vspalcebo

  30. N-accetycysteine to prevent RCIN Miner, et al Am Heart Journal 2004;148:690-695

  31. N-accetycysteine to prevent RCIN Miner, et al Am Heart Journal 2004;148:690-695

  32. Treatment Trials • Dopamine for prevention of delayed graft function • N-accetycysteine to prevent RCIN • Chloride-poor IV fluids in ICU • ANP to prevent AKI

  33. Is Chloride Bad in Intravenous fluids ? • Normal saline has 40% higher Chloride than plasma • High Serum Chloride Associated with Renal vasoconstriction and decreased GFR • Normal Saline also associated with “ dilutional” metabolic acidosis

  34. Chloride Liberal vs Chloride Restrictive IVF Administration • 1533 patients admitted to ICU • NS vs Lactate (Chloride 109nmol), Balanced Buffered soln ( Chloride 98 mmol) • Outcome: AKI

  35. Chloride –Liberal Vs Restricted Chloride i.v. Fluid in ICU Patients Development of Stage 2 or 3 AKI Yunos et al. JAMA 2012; 308 (15): 1576-1572

  36. Chloride –Liberal Vs Restricted Chloride i.v. Fluid in ICU Patients Need for RRT in ICU Yunos et al. JAMA 2012; 308 (15): 1576-1572

  37. Treatment Trials • Dopamine for prevention of delayed graft function • N-accetycysteine to prevent RCIN • Chloride-poor IV fluids in ICU • ANP to prevent AKI ( NU-HIT Trial)

  38. ANP Nu-HIT Trial • RCT 303 patients with CKD undergoing CABG • Intervention hANPvs Placebo • Outcome: postoperative AKI

  39. hANP During CABG for CKD Dialysis Free Rate Sezai et al, JACC . 2011Vol 58 (9):897-203

  40. Summary • Clinical use of biomarkers for early diagnosis of AKI is promising but awaits prospective clinical trials . • While several trials have demonstrated the ability to reduce AKI in randomized trials only hANP has demonstrated ability to reduce AKI and decrease risk of CKD and Dialysis

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