PHYSIOLOGICAL BIOMARKERS OF AKI

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1 PHYSIOLOGICAL BIOMARKERS OF AKI Mark D. Okusa, MD Division of Nephrology Center for Immunity, Inflammation and Regenerative Medicine University of Virginia Charlottesville, VA

2 Work Group 4 Dr. Bertrand Jaber, Kidney and Dialysis Research Laboratory, Division of Nephrology, Department of Medicine, St. Elizabeth s Medical Center, Tufts University, School of Medicine, Boston, MA Dr. Peter Doran, UCD Clinical Research Centre UCD School of Medicine and Medical Science, University College Dublin, Dublin, Ireland Dr. Jacques Duranteau, Hôpitaux de Paris, Hôpital Bicetre, Département d Anesthésie-Réanimation, Université Paris Sud XI, Le Kremlin-Bicêtre Dr. Li Yang, Renal Division Peking University First Hospital Beijing, China Dr. Can Ince, Department of Intensive Care, Erasmus Medical Centre, Erasmus University of Rotterdam, and the Department of Translational Physiology, Academic Medical Centre, University of Amsterdam, The Netherlands.

3 Acute Dialysis Quality Initiative Consensus Conference on Acute Kidney Injury Biomarkers Acute Dialysis Quality Initiative (ADQI) Consensus Conference on Acute Kidney Injury Biomarkers held in Dublin, Ireland, in August 2011 Prevention Renal reserve Stress Test Continuous

4 The ADQI breakout group 4 identified important new clinical needs in AKI 1. Do physiological markers improve the risk assessment of AKI? If so what set or group of physiological markers are essential for assessment of the functional state of the kidney? 2. Do real-time physiological markers improve the early diagnosis and aid in the differential diagnosis of AKI? 3. What is the interplay or added value of physiological markers to biochemical markers of AKI and clinical characteristics? 4. Can real-time monitoring of physiological markers be used to guide therapy?

5 Tissue Oxygenation and Microcirculation Critical Physiological Biomarkers Microcirculation is to ensure adequate oxygen delivery to meet the metabolic demand of every single cell. Unique microvasculature architecture of the kidney, high oxygen demand from the tubular salt-water reabsorptionhighly sensitive to hypoxia. The chief function of the kidney (i.e. filtration of plasma and formation of urine) necessitates RBF higher than necessary to meet the metabolic- oxygen tensions in the kidney 70 mmhg in the cortex and 20 mmhg in the medulla. RBF is variable in AKI.

6 Physiological Biomarkers Treatment Decision Clinical Factors Outcomes Clinical Factors + Biochemical Biomarkers Outcomes Clinical Factors + Biochemical Biomarkers+ Physiological Biomarkers Outcomes

7 Physiological Markers to Assess Kidney Function in AKI Glomerular Filtration Rate/Urine Flow Monitoring Urine indices Real-time GFR measurement Serum creatinine revisited (serial measurement, correction for fluid balance [bioimpedance]) Continuous urine flow Renal Perfusion Doppler ultrasound (visualization of macro-circulation) Contrast enhanced ultrasound (visualization of micro-circulation) Renal Oxygenation Bladder urine PO2 (measure of renal medullary oxygenation) Near infrared spectroscopy (measure of renal O2 bioavailability) Bold MRI (measure of renal O2 bioavailability) PET (measure of renal metabolism) Other complimentary markers to assess kidney function in AKI Kidney ultrasound Renal venous O2 saturation (measure of renal oxygen consumption) Urinalysis (renal indices, urine sediment, flow cytometry) Endothelial markers (e.g., endothelial microparticles, glycocalyx degradation) Inflammatory markers (e.g., cytokines; immune cells) Oxidative stress markers

8 Clinical Applications for GFR Determination Drug-dosage adjustments in patients with acute or chronic kidney dysfunction Screening test for hospital-acquired kidney injury in patients with or without preexisting kidney damage, Assess therapeutic response Rate of progression of kidney disease, Monitor patients requiring repeated administration of nephrotoxic drugs, Indirect assessment of visceral organ perfusion, such as during prolonged anesthesia

9 Realtime GFR In vivo rapid detection and instantaneous calculation of GFR Portable analyzer developed for this purpose allowed point-of-care determination of GFR Ratiometric emission at 490nm and 590 nm. 2 compartment model. Within 60 min of administration of the fluorescent conjugates, Minimal adverse effects and excellent agreement with the 6-h iohexol-based GFR technique E. Wang G.J. Schwartz and B.A. Molitoris et al. Kidney int 81: , 2012

10 Contrast Enhanced Ultrasound

11 CEUS in AKI and DGF Authors Rim et al Vogel et al Schneider Bellomo Kalantarina Kishimoto Fischer Schwenger Benozzi Organ/S pecies Brain/Do g Heart/H umans Kidney/ Humans Kidney/ Humans Kidney/ Humans Kidney/ Humans Kidney/ Humans Kidney/ Humans Description Cerebral circulation in response to hypo-, hypercapnea A microsphere measurement of flow correlated with Myocardial perfusion hyperemia induced by adenosine and CEUS derived parameters correlated with intracoronary Doppler measurements. Normal human volunteers- iv infusion of AII after oral captopril, dosedependent decrease in perfusion index during increasing doses of AII compared to baseline. The decreases in PI were already detectable when the renal plasma flow (as estimated by para-amino-hippurate clearance) decreased by 15% Healthy volunteers-rbf increased after high protein meal by 43% (A β parameter) compared with baseline. Seven healthy volunteers - increase in microbubble velocity after oral administration of valsartan which correlated with RBF measured by PAH clearance. Reference Circulation 2001 JACC 2005 Critical Care 2011 AJP 2009 Hypertens Res 2004 Transplantation Eur Radiol transplant patients, highly significant correlation (P = ) between RBF as estimated by CEUS and Scr. RBF by CEUS reached a higher sensitivity (91 versus 82%), specificity (82% versus 64%) and accuracy (85 versus 73%) for the diagnosis of chronic allograft nephropathy than conventional Doppler ultrasound 39 kidney recipients, CEUS at 5, 25 and 30 days after grafting. Distinguish between ATN and AR. Am J. Transplant 2006 Transplant Proceed 2009 Fischer Kidney/ Humans 32 patients 5 to 7 days after kidney tx - temporal difference in the contrast agent arrival slopes between two main territories. Differentiated acute rejection from a normal clinical course. NDT 2006

12 Functional MRI BOLD-MRI imaging relies on the different magnetic properties of oxyhemoglobin and deoxyhemoglobin to achieve tissue contrast on T2*-weighted images, which therefore noninvasively assesses tissue oxygen bioavailability by measuring relative changes in deoxyhemoglobin. DW-MRI measures apparent diffusion coefficient (ADC) values and quantifies the combined effects of blood microcirculation and Brownian motion of water molecules within tissues. High-resolution ASL perfusion images of the whole kidney were able to be obtained with good image quality by means of a 3 Tesla MR setting within a clinically applicable measuring time, thus providing an alternative to conventional perfusion imaging involving potentially nephrotoxic contrast media.

13 Functional MRI in AKI Authors Organ Description Specie s Reference Inoue et al Kidney AKI-prerenal, AIN, AGN Human J Am Soc Nephrol 2011 Sadowski et al Kidney Transplantation-ATN or AR Human Radiology 2005 Djamali et al Kidney Transplantation-ATN or AR Human Transplantation 2006 Fei et al Kidney Transplantation-ATN or AR Human Nephrol Dial Transplant 2008 Textor et al Kidney Renal arterial stenosis Human J Am Soc Nephrol 2008 Juillard et al Kidney AKI-intra renal ischemia Pig Kidney Int 2004 Pedersen et al Kidney AKI-UUO Pig Kidney Int 2005 Togao et al Kidney AKI-UUO Mouse Radiology 2010 Prasad et al Kidney Diuresis in healthy subjests Human Circulation 1996 Epstein et al Kidney Diuresis in healthy subjests and diabetes Human Diabetes Care 2002 Winter et al Kidney Quantification of renal perfusion:- Comparison of ASL and DCE-MRI Lanzman et al Kidney Transplantation-ASL-MRI detected decreased perfusion in acute dysfunction Rabbit J Magn Reson Imaging 2011 Human Eur Radiol 2010

14 F. Mangione et al. AJKD 56: , 2012 Renal Blood Flow in AKI Fig 1 Fig 3 Fig 2 Fig 4

15 Noninvasive Evaluation of Kidney Hypoxia and Fibrosis Using Magnetic Resonance Imaging T. Inoue et al. JASN.2011 Aug;22(8): Epub 2011 Jul 14.

No injection Inflammation in IRI: MRI-ferumodextran-10 Sham Sham 16 Small dextran-coated iron particles internalized preferentially by monocytes and macrophages.

16 No injection Inflammation in IRI: MRI-ferumodextran-10 Sham Sham 16 Small dextran-coated iron particles internalized preferentially by monocytes and macrophages. MRI images before and 24 hours after injection of ferumodextran-10 particles in normal and ischemic animals IRI subjected to 60 min bilateral IRI. Iron particles decrease the MRI signal on T 2 -weighted images 24 Hrs IRI S.K. Jo R.A. Star, Kidney Int. (2003) 64, 43 S.K. Jo R.A. Star 51 Kidney Int. (2003) 64, 43 51; 24 Hrs

17 Laser Speckle Imaging Microvascular perfusion in the renal cortex Perfusion Histogram M. Legrand C.Ince Intensive Care Med. 37:1534, 2011`

18 Tissue Oxygen Tension Measurement Techniques Polarographic method Dynamic fluorescence quenching method Magnetic resonance imaging Wang ZJ et al: Acad Radiol 15: , 2008 Ragheb J & Buggy DJ. Br J Anaesth 92:464-8, 2004

19 Physiology of Urine po 2 Urine passing through the tubule and collecting duct equilibrates with O 2 of surrounding cells Urine po 2 entering the calyces reflects oxygen tension of the renal medulla Renal-pelvis urine PO 2 = mm Hg Bladder urine PO 2 = mm Hg

20 Determinants of Urine po2 Urine po2 Oxygen supply Renal medullary blood flow Oxygen consumption

21 Potential Benefits and Technical Pitfalls of Urine PO 2 Measurement Potential Benefits Indirect measure of renal medullary oxygenation Relatively non-invasive technique Bladder urine polarographic probe commercially available in Europe (LICOX) Technical Pitfalls Bladder urine measurement may not reflect renal pelvis urinary po2 May not be sensitive to non-homogeneous renal oxygen distribution Requires clinical evaluation in AKI as an early marker of ischemic injury

22 Urine Oxygen Tension (PuO 2 ) Defined as the local partial pressure of O2 in the urine (renal pelvis, ureter or bladder) May be the most reliable quantitative index of renal medullary perfusion Its monitoring and modulation may be of critical importance in the prevention and treatment AKI

23 Urine microscopy in early diagnosis of AKI 267 hospitalized patients with a diagnosis of AKI. Findings on urine microscopy led change in the initial diagnosis of PRA to ATN in 27 patients (23%) ATN to PRA in 15 patients (14%) MA Perazella et al. Clin J Am Soc Nephrol 3: , 2008

24 Urinary Sediment Authors Organ Description Species Reference Bagsaw et al Kidney Urine Microscopy in sepsis UMS higher in sepsis Urine biochem poor correlation with UMS Santos et al Kidney Urinary Enzymes (LDH, Alk Phosp, g-gt) When determined early after liver transplant these markers are predictors of AKI Perazella et al Kidney Urine Sediment predictive of worsening AKI Human Human Human Nephrol Dial Transplant, 2011 Tranplantation Proceedings, 2011 Clin J Am Soc Nephrol 2010 Chawla et al Kidney Cast Scoring Index for AKI Human Nephron clin Pract, 2008 Perazella et al Kidney Diagnosic value of urine microscopy Predictive of ATN with score >=2 Human Clin J Am Soc Nephrol, 2009

25 Characteristics of Physiological Markers for the Assessment of AKI Physiological Marker Parameter Unit Bedside Invasive Continuous Clinical Performance scr (serial, TBW adjusted) BJ egfr mg/dl + - -? + RT-mGFR LY/BM mgfr ml/min + + -? ++++ RT-Urine flow PD Urine output ml/kg/hour + - +? + Doppler US (imaging) JD CEUS (imaging) MO Urine po2 BJ Bladder po2 CI BOLD MRI (imaging) LY Macrocirculation Macro-/microcirculation Renal medullary O2 tension Tissue O2 tension Renal O2 availability 64 Cu PET (imaging) PD O2 uptake/renal metabolism Near infrared spectroscopy CI Renal O2 availability Resistive index Cost + - -? ++ A.U ? +++ mm Hg + - +? ++ mm Hg + + +? ++ Hb O2/Hb - - -? ++++ mci/mcg - + -? ++++ Hb O2/ Hb + - +? ++++ Renal venous O2 Renal O2 Hb O2/Hb + + +? ++++

26 Utility of Physiological Markers in AKI Physiological Marker [reference] Risk Assessme nt Early Diagnos is Differential Diagnosis Prognos is Therapy Guidanc e Urine indices - - Serial Creatinine Real time measured GFR Continuous Urine flow? Doppler US? Contrast enhanced US? Urine po2?? Bladder po2? BOLD MRI??? PET??? Near infrared spectroscopy???

27 Physiological Clinical Phases Phases of Acute of Acute Kidney Kidney Injury Injury 100 Prerenal Initiation Extension Maintenance Repair 0GFR, % Perfusion Oxygenation Structural/Anatomic Hibernation Regeneration Vasomotor ATP Depl Nephropathy Endothelium Epithelium Early Microvascular Injury Obstruction Inflammation Coagulation Dedifferentiation Migration Proliferation Time after Insult Adapted from T. A. Sutton, et al. Kidney Int. 62: 1539, 2002 Redifferentiation Repolarization Late

28 Prioritizing the Research Agenda: Currently Available Techniques To test the hypothesis that the currently available techniques may be valuable for risk stratification renal reserve, early diagnosis, differential diagnosis, prognostication, and therapy guidance of AKI: GFR/Urine Flow Serial serum creatinine Measured GFR Continuous urine flow Renal Circulation 1. Duplex US (resistive index) 2. Contrast-enhanced US (macro-/micro-circulation) Renal Oxygenation 1. Bladder urine po2 (renal medullary O2 tension)

29 Prioritizing the Research Agenda: Emerging Technologies To test the hypothesis that the following emerging techniques may be valuable for risk stratification renal reserve, early diagnosis, differential diagnosis, prognostication, and therapy guidance of AKI: Renal Circulation 1. Duplex US (resistive index) 2. Contrast-enhanced US (macro-/micro-circulation) Renal Oxygenation 1. Bladder tissue PO2 2. Renal venous O2 saturation (renal O2 consumption) 3. Near infrared spectroscopy (renal O2 availability) 4. Bold MRI (renal O2 availability) 5. PET (renal metabolism)

Biomarkers in Acute Kidney Injury

Biomarkers in Acute Kidney Injury Mark D. Okusa, M.D. Chief, Division of Nephrology Center for Immunity, Inflammation and Regenerative Medicine University of Virginia Health System Population incidence