A08 Using Kidney Biomarkers for AKI 2: Differential Diagnosis, Interventions and Prognosis
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1 A08 Using Kidney Biomarkers for AKI 2: Differential Diagnosis, Interventions and Prognosis Kent Doi, MD, PhD Emergency and Critical Care Medicine, The Univ of Tokyo, Japan
2 Using kidney biomarkers: Key questions for differential diagnosis 1. Can biomarkers distinguish a pre-renal state' from AKI? 2. Can biomarkers differentiate etiology of AKI? 3. Can biomarkers identify the mechanism and time course of AKI? 4. Can biomarkers distinguish AKI from CKD? 5. Can biomarkers distinguish de novo AKI from AKI superimposed on CKD? 6. What is role of biomarkers from other organs in the context of determining etiology of AKI?
3 Using kidney biomarkers: Key questions for differential diagnosis 1. Can biomarkers distinguish a pre-renal state' from AKI? 2. Can biomarkers differentiate etiology of AKI? 3. Can biomarkers identify the mechanism and time course of AKI? 4. Can biomarkers distinguish AKI from CKD? 5. Can biomarkers distinguish de novo AKI from AKI superimposed on CKD? 6. What is role of biomarkers from other organs in the context of determining etiology of AKI?
4 Pre-renal AKI acute renal success?? The renal tubules conserve salt and water in the face of sensed renal hypoperfusion. Because this is undoubtedly a good response (a means of organ protection), prerenal syndrome could be called acute renal success.
5 Pre-renal vs Renal AKI Concept Rapid recovery Na reabsorption Pre-renal Physiological reaction against hypoperfusion Yes (Reversible) Increased (low FENa) Renal Structural damage in renal tissue No (Irreversible) Decreased (high FENa) Location Outpatient Inpatient
6 Pre-renal vs Renal AKI 1. Pre-renal AKI Reversible, volume-responsive retrospective diagnosis 2. Ischemic renal AKI As a result of prolonged ischemia, the tubular epithelial cells undergo injury and, if it is severe, cell death by apoptosis and necrosis (=acute tubular necrosis [ATN]), will be observed with organ functional impairment. 3. When pre-renal transforms into renal AKI??
7 Ischemic renal AKI not transient but persistent Sutton TA/Molitoris BA, Kidney Int 2002
8 Ischemic renal AKI Extension phase occurs even after RBF completely recovered. Case: AKI after left ventricular assist device (LVAD) implantation 24 y.o. Male of dilated cardiomyopathy (DCM), no CKD For Decompensated heart failure, IABP+MV+CRRT were used Emergent LVAD implantation
9 2012/6/ /6/ /6/ /6/ /6/ /6/ /6/ /7/2 2012/7/4 2012/7/6 2012/7/8 2012/7/ /7/ /7/ /7/ /7/ /7/ /7/ /7/ /7/ /7/ /7/30 (ml) (mg/dl) AKI after LVAD implantation extension phase of ischemic AKI 2500 LVAD CHDF/IHD plasma NGAL Serum Cre NGAL Urine RRT Cre Urine volume Tsukamoto M/Doi K, Circ J 2015
10 Ischemic renal AKI and Biomarker monitor tubular injury in AKI New AKI biomarkers NGAL, IL-18, KIM-1, L-FABP, TIMP-2/IGFBP-7, etc Ischemia Vaidya VS. Annu Rev Pharmacol Toxicol 2008
11 Function Glomerular (scre) New spectrum of AKI combo of function and damage Damage Tubular biomarkers Pre-renal Renal McCullough PA/Ronco C, Contrib Nephrol 2013
12 New spectrum of AKI combo of function and damage
13 Urinary L-FABP FABPs (Fatty acid-binding proteins) 1. L-FABP : Liver, Kidney (proximal tubule) 2. H-FABP: Heart, Kidney (distal tubule) 3. A-FABP (ap2) : Adipocyte, Macrophage 4. I-FABP : Intestine, Liver fatty acids mitochondrion fatty acids transporter FABP Normal Ischemic (1h Bx) peroxisome ER PPAR RXR PPAR FABP gene expression Yamamoto T/Doi K/Noiri E. JASN 2007 Wolfrum C. PNAS 2001
14 Urinary L-FABP in Pre-renal AKI Volume depletion model shows 1. transient BUN elevation 2. no pathological finding in PAS 3. pimonidazole incorporation BUN (mg/dl) # Hypoxia induced by dehydration (A) (B) 0 0h 24h 48h 72h 7d 14d (C) (D) Pimonidazole Doi K, Kidney Int 2012
15 Urinary L-FABP in Pre-renal AKI Urinary L-FABP discriminates pre-renal from renal AKI. (A) (B) Urinary L-FABP (ng/ml) * * * * * 100~1000x Acute tubular necrosis (C) CDDP (D) I/R ~10x h 24h 48h 72h 0h 72h 0h 24h Dehydration CDDP I/R Doi K, Kidney Int 2012
16 Urinary NGAL Neutrophil gelatinase-associated lipocalin The normal kidney had little staining for NGAL in distal tubules and collecting ducts (<10%). Ischemic ATN produced intense but heterogeneous staining of the cortical tubules (>50%). Mori K and Barash J. JCI 2005
17 Urinary NGAL in pre-renal AKI No expression of NGAL in the dehydrated kidney Renal ischemia reperfusion Dehydration Paragas N and Barash J. Nat Med 2011
18 Urinary NGAL in pre-renal AKI Patients (>18 y.o.) who visited ED of Columbia University Medical Center at 6am~12am from March to August Nickolas TL, Ann Intern Med. 2008
19 Urinary NGAL in pre-renal AKI Higher urinary NGAL level in AKI vs pre-renal or CKD U-NGAL Serum Cre Nickolas TL, Ann Intern Med. 2008
20 Urinary NGAL in pre-renal AKI Urinary NGAL level >130 μg/gcre identified more nephrology consult, dialysis, or ICU admission. Nickolas TL, Ann Intern Med. 2008
21 Combo of U-NGAL and Cystatin C 345 pediatric pts after CPB, 62 (18%) severe AKI (= stage 2, 3) ungal, pcysc at 2h after CPB ΔScre >50% from pre-opp JACC 64 ; , 2014
22 ΔScre, pcysc Combo of U-NGAL and Cystatin C Double-positive biomarker showed significantly better prediction for severe AKI (stage 2,3). U-NGAL Sens Spec + LR - LR ΔScre ungal+ pcysc ( ) 34.2 (13-94) 0.8 ( ) 0.5 ( ) JACC 64 ; , 2014
23 Combo of U-NGAL and Cystatin C Identifying transient AKI (<48h) by U-NGAL+/pCysCi.e., Loss of function without damage JACC 64 ; , 2014
24 Summary Biomarkers can distinguish a pre-renal state' from AKI in animal AKI model and human AKI. Two-dimension approach with functional change' and kidney damage' will help to understand pathophysiology of AKI better than the old classification using the terms prerenal, renal and post-renal AKI.
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