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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 • Understand use and limitations of new biomarkers for AKI • Review recent treatment trials of AKI Incidence: AKI Hsu et al , JASN 2013, 24:37-42 Incidence: AKI By Age Hsu et al , JASN 2013, 24:37-42 Does AKI Lead to CKD ? • The higher the serum creatinine • The longer the duration of AKI • Recurrent AKI * Strongly Associated with CKD and Death AKI and Survival Chawla et al. Kid Int. 2012;82: 516-524 KDIGO Definition of AKI KDIGO STAGE Serum Creatinine Increase Urine Output Criteria 1 1.5-1.9 x baseline or >0.3 mg/dl increase < 0.5 ml/kg per hr for 6-12h 2 2-2.9 x baseline < 0.5 ml/kg per hr for > 12 hrs 3 3x baseline or increase serum creatinine > 4 < 0.3 ml/kg per hr for > 24 hrs mg/dl or Initiation of Dialysis Or anuria for > 12 hrs 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 Bio-Markers of AKI • • • • Predict and Diagnose AKI Identify Location of Injury Identify Type and Etiology of Injury Predict Outcomes Biomarkers of AKI Functional Biomarkers Tubular Enzymes Upregulated Proteins Creatinine Alanine Amino Peptidase KIM-1 Cystatin C Alkaline Phosphatase Clusterin Β-2 Microglobulin α-Glutathione-S-Transferase NGAL Retinol-binding Protein ϒ-Glutamyl Transpeptidase IL-18 Microalbumin N-Acetyl-β-Glucosamidase Cysteine-Rich Protein 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 Cystatin C - Found in all nucleated cells Freely filtered Not protein bound Not normally secreted in urine Competes with albumin for endocytic reabsorbtion - Analysis affected by: - DM Corticosteroids Hyperthyroidism Elevated Bilirubin Inflammation Charlton et al. NDT ( 2014) 0:1-11 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) MicroAlbuminuria and AKI Adults AKI /Cardiac Surgery Children AKI /Cardiac Surgery Age 1 month to 2 years Molnar et al. CJASN 2012;7:1749-1760 Age > 2 years Zappitelli et al. CJASN;2012;7:1761-1769 N-Acetyl-β-D-Glucose Amidase NAG • 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 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 Parikh et al. CJASN 2013; 8:1079-1088 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 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 IL-18 • Levels ↑2x in AKI • Source: – Proximal tubular cell Charlton et al. NDT ( 2014) 0:1-11 Urinary IL-18 In AKI Parikh et al, Am J. Kid Dis. 2004, 43: 405-414 Liver Fatty Acid –Binding Protein L-FABP • Increased 4 hours after ischemic injury from cardiac surgery Charlton et al. NDT ( 2014) 0:1-11 Urinary FABP and NAG as Predictors of AKI Following Cardiac Surgery Katagiri et al. Ann of thoracic Surgery 2012;93:577-583 Treatment Trials • Dopamine for prevention of delayed graft function • N-accetycysteine to prevent RCIN • Chloride-poor IV fluids in ICU • ANP to prevent AKI Dopamine For Delayed Graft Function • • • • Randomized, Open label, Multicenter 264 Deceased Donors Dopamine at 4 micrograms/Kg/min Outcome: Need for Dialysis Dopamine For Prevention of Delayed Graft Function Schnuelle et al. JAMA. 2009 Vol 302(10):1067-1075 Dopamine For Prevention of Delayed Graft Function Schnuelle et al. JAMA. 2009 Vol 302(10):1067-1075 Treatment Trials • Dopamine for prevention of delayed graft function • N-accetycysteine to prevent RCIN • Chloride-poor IV fluids in ICU • ANP to prevent AKI 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 vs palcebo N-accetycysteine to prevent RCIN Miner, et al Am Heart Journal 2004;148:690-695 N-accetycysteine to prevent RCIN NAC Placebo P Value Death, MI, Dialysis, Hospitalization, n (%) 23 (24.2) 18 21.2) NS Death, n %) 4 (4.2) 3 (3.5) NS Non fatal MI, n( %) 6 (6.3) 4 (4.7) NS Need for Dialysis, n (%) 1(1.1) 1 (1) NS Repeat Hospitalizations, n (%) 13 (13.7) 13 (15.3) NS Miner, et al Am Heart Journal 2004;148:690-695 Treatment Trials • Dopamine for prevention of delayed graft function • N-accetycysteine to prevent RCIN • Chloride-poor IV fluids in ICU • ANP to prevent AKI 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 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 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 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 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) ANP Nu-HIT Trial • RCT 303 patients with CKD undergoing CABG • Intervention hANP vs Placebo • Outcome: postoperative AKI hANP During CABG for CKD Dialysis Free Rate Sezai et al, JACC . 2011Vol 58 (9):897-203 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