AKI Biophysical Basis of Decreased GFR

Transcription

1 ASN BOARD REVIEW 2014 AKI Pathogenesis, Diagnosis, Biomarkers and Risk Assessment Anupam Agarwal, MD Division of Nephrology University of Alabama at Birmingham Outline Pathogenesis of Acute Kidney Injury and Repair Prerenal and Ischemic AKI Sepsis Toxin Pathogenesis of AKI in the Elderly Definition, Incidence Diagnosis, Biomarkers Clinical Risk Assessment of AKI Vasculature Vasoconstriction Focal Ischemia Vasodilation Thrombosis Coagulation Inflammation Plugging No Reflow Intermittent flow Microenvironment Innate immunity Adaptive immunity Paracrine factors Autocrine factors Pathogenesis of AKI Tubules Apoptosis Necrosis Mitochondrial dysfunction Back-leak Detachment Obstruction Systemic factors Proinflammatory cytokines Antiinflammatory cytokines AKI Biophysical Basis of Decreased GFR Prowle, J. R. et al. Nat. Rev. Nephrol.;6(2): Effect of Ischemia on Regional Blood and Medullary PO 2 Pathogenesis of AKI Renal Artery PO 2, mm Hg 100 Pre-ischemia Postischemia Renal Vein 80 Cortex Inner Cortex Medulla O 2 Diffusion Relative Blood Flow Cortex Outer medulla Inner medulla P GC P.O.A. Hellberg, et.al. Kidney Int. 40:625,1991

2 PreRenal AKI Intrarenal Mechanisms for Autoregulation of the Glomerular Filtration Rate NSAIDS ACEI/ARB RC Blantz 53: , 1998 Abuelo JG. N Engl J Med 2007;357: Hepatorenal Syndrome Severe Vasoconstriction HRS: antemortem HRS: postmortem Intrahepatic Resistance Low SVR Abnormal Distribution Of Blood Volume Cirrhosis Splanchnic Vasodilators Portal Hypertension and Splanchnic Arterial Vasodilation Cardiac Preload Cirrhotic Cardiomyopathy Impaired effective arterial blood volume Low Arterial Pressure Activation of Vasoconstrictor System Renal Vasoconstriction M. Epstein Am J. Med: 49: , 1970 HEPATORENAL SYNDROME Intraabdominal Compartment Syndrome Cardiac Index (L/min/m 2 ) Hemodynamic effect of IAH Abdominal Pressure (mmhg above baseline) Wedge Pressure (mmhg) Physiologic Sequelae Elevated intra-abdominal pressure causes: Compression of renal veins and IVC Reduced cardiac output to kidneys Renal failure, oliguria/anuria The Result: Reduced blood flow to kidney Renal congestion and edema Decreased glomerular filtration rate (GFR) Acute tubular necrosis (ATN) Ridings, et al 1995 Pickhardt et al Patel et al 2007

3 Microvascular Injury Ischemia Innate Immunity Acute Tubular Injury Endothelium Microvascular endothelial injury and dysfunction during IRI Ischemia Endothelial Cell activation, Dysfunction, Injury and/or Detachment Vasoconstriction Leukocyte Adhesion Permeability Microvascular Congestion DAMPS Immune Cells Cytokines Inflammation Apoptosis Necrosis Tubular Obstruction Backleak Inflammation Impaired Vasodilation Coagulation Leukocyte Adhesion Capillary Obstruction and Continued Ischemia Adapted from Bonventre and Weinberg JASN 14: , 2003 Courtesy of Bruce Molitoris Continued Ischemia DECREASED GFR TA Sutton, CJ Fisher, BA Molitoris Kidney Int (2002) 62, Extension of ARF Microvascular Blood Flow at 24h Post Ischemia Effect of stm Early Pathogenic Mechanisms of AKI Endothelial, Epithelial, Immune Cells and Interstitium Blood Flow velocity (µm/sec) Saline treated stm treated / / * Sharfuddin, A. A. & Molitoris, B. A. (2011) Nat. Rev. Nephrol. Injury and Repair in Ischemic Acute Kidney Injury Human Acute Kidney Injury Backleak Regenerating Cell NonReplacement Site J. V. Bonventre and L. Yang J. Clin Invest. 2011;121(11): TS Olsen, HS Olsen, HE Hansen Vichows Arch 1985, 406:75

4 Outline Pathogenesis of Acute Kidney Injury and Repair Prerenal and Ischemic AKI Sepsis Toxin Definition, Incidence Diagnosis, Biomarkers Clinical Risk Assessment of AKI DEAD CELLS, GRANULAR CASTS, REGENERATING EPITHELIUM Courtesy of MA Venkatachalam Sepsis Related AKI Hyperdynamic Circulation in Experimental Septic AKI: Systemic Parameters Mechanisms Ecoli MAP Ecoli HR Pro-inflammatory State Systemic Vasodilation Impaired Microcirculation Cytokine mediated cell injury CO TPC Conductance (Schrier, RW, NEJM, 2004) C Langenberg R Bellomo, Kidney Int (2006) 69, Hyperdynamic Circulation in Experimental Septic AKI: Renal Parameters Hyperemic AKI: Loss of glomerular filtration pressure E Coli Septic AKI may represent a unique form of AKI: hyperemic AKI. GFR is determined by glomerular filtration pressure. If afferent arteriole dilates and the efferent arteriole dilates even more, RBF will markedly increase, yet pressure within the glomerulus will fall. GFR will also decrease. C Langenberg R Bellomo, Kidney Int (2006) 69,

5 Sepsis is a Disorder of the Microcirculation PO 2 Outline Pathogenesis of Acute Kidney Injury and Repair Prerenal and Ischemic AKI Sepsis Toxin Pathogenesis of AKI in the Elderly Definition, Incidence Diagnosis, Biomarkers Clinical Risk Assessment of AKI Trzeciak S et al. Acad Emerg Med 2008; 15: Site Specificity of Common Nephrotoxins Hemodynamics ACEI/ARB TMA Distal Tubule Injury Ampho B Calcineurin Inh Calcineurin inh Ampho B Clopidogrel Calcineurin inh Diuretics Cocaine Lithium NSAIDS Mitomycin Sulfadiazine Contrast Quinine Proximal Tubule Injury Tubular Obstruction Acyclovir Acyclovir Aminoglycosides Indinavir Cadmium Methotrexate Cidofovir Sulfonamides Cisplatin Foscarnet Lead Mercuric chloride Interstitial Nephritis Allopurinol Aristolochic acid Cephalosporins Ciprofloxacin V.S. Vaidya, J.V. Bonventre Diuretics NSAIDS Comprehensive Toxicology Penicillins 2010, Pages Phenytoin PPIs Aminoglycosides GFR is not apparent until 7 10 days after initiating therapy. Occurs in setting of hypotension, prerenal azotemia other nephrotoxins U Na >20 meq/l, FE NA >2 Usually reversible Risk factors: prolonged treatment, volume depletion, preexisting renal disease, hypokalemia, old age, other nephrotoxins Monitor drug levels and creatinine every 2 3 days Aminoglycoside Nephrotoxicity Aminoglycoside binds to the anionic phospholipid of the PTC, it is transferred to the transmembrane protein megalin and endocytosed Megalin-expressed in the renal proximal tubules, podocytes and ciliary and inner ear epithelium After endocytosis, endosomes - accumulate in organelles such as the mitochondria and the nucleus- disrupting in mitochondrial function Aminoglycoside Nephrotoxicity Myeloid bodies 1.Nagai J; Takano M. Drug Metab Pharmacokinet Jun;19(3): Ford DM et al. Am J Physiol Jan;266(1 Pt 1):C Sandoval RM; Molitoris BA, Am J Physiol Renal Physiol Apr;286(4):F J.M. Lopez-Nova et al, Kidney Int 79:33, 2011

6 Sodium Diatrizoate-ionic monomer ( mosm/kg) Structure of Contrast Media Iohexol-nonionic monomer (780 mosm/kg) Contrast Media-Nephrotoxicity Contrast Media PGE 2 Endothelin ANP Vasopressin Ado PGI 2 Systemic Hypoxemia Blood viscosity Osmotic Load Iodixanol-nonionic dimer (290 mosm/kg) Blood Flow Oxygen Delivery Oxygen Consumption Adapted from C.M. Sandler N.Engl.J.Med 348:551, 2003 Direct Cellular Toxicity modified from Rudnick et. al. Seminars in Nephrology 17:15-26, 1997 Renal Medullary Hypoxia Pathogenesis of CIAKI Progession of AKI to CKD/ESRD Calvin, A. D. et al. (2010) Contrast-induced acute kidney injury and diabetic nephropathy Nat. Rev. Nephrol. doi: /nrneph J. Cerdá et al. Clin J Am Soc Nephrol 3: , Loss of Peritubular Capillaries Lead to Chronic Hypoxia MSCs Repair Kidney Decreased oxygen diffusion from peritubular capillaries to tubular and interstitial cells Stagnation of peritubular capillary blood flow Decreased peritubular capillary blood flow as a result of imbalance of vasoactive substances Inappropriate energy usage as a result of uncoupling of mitochondrial respiration induced by oxidative stress Increased metabolic demands of tubular cells Decreased oxygen delivery as a result of anemia Nangaku M JASN 2006;17:17-25 Florian E. Tögel & Christof Westenfelder Nature Reviews Nephrology 6, (March 2010)

7 What is the origin of myofibroblasts in the kidney? Molecular Mechanisms of Fibrosis Cell Cycle and Epigenetic Modification 10% 60% Rasal 1 RAS inactivation Cell Proliferation Hypermethylation Rasal 1 RAS activation Cell Proliferation 5% 30% VS LeBleau R. Kalluri et al. Nature Medicine 19, (2013) T.A.Wynn Nature Medicine 16, (2010); L. Yang Nature Med 16: , 2010 W. Bechtel Nature Med 16: , 2010 Outline Pathogenesis of Acute Kidney Injury and Repair Prerenal and Ischemic AKI Sepsis Toxin Pathogenesis of AKI in the Elderly Definition, Incidence Diagnosis, Biomarkers Clinical Risk Assessment of AKI Population incidence of dialysis-requiring AKI in the United States by age groups from 2000 to 2009 Hsu R K et al. JASN 2013;24:37-42 AKI Susceptibility in Elderly Prevention of AKI in elderly depends on awareness of reduced GFR Age dependent decline in GFR; worse with clinical risk factors CKD is risk factor for AKI Prevention depends on awareness of reduced GFR in elderly despite normal creatinine Anderson S et al. JASN 2011;22:28-38 M. C. Odden et al. Nephrol Dial Transplant (2010) 25(2): Redrawn from USRDS 2009, P. Eggers

8 Senile Nephrosclerosis Among 1,203 living kidney donors Glomerulosclerosis Tubular atrophy Interstitial fibrosis >5% Arteriosclerosis 20 yo kidney donor Renal Reserve in Elderly yo kidney donor GFR ml/min Baseline Meat Meal Renal Reserve 50 0 Young Old Oldest Old AD Rule et al. Nephron Physiol August; 119(Suppl 1): p6 p11. CG Musso et al. Int Urol Nephrol (2011) 43: Pathogenesis of AKI Key Points Ischemic, septic or toxin induced AKI often occur concomitantly Ischemic AKI results is a summation of events that involve capillary endothelium, tubular epithelial cells, and inflammatory cells and humoral mediators (cytokines and chemokines). Nephrotoxins-site specificity Sepsis models of AKI Pro-inflammatory cytokines due to host response. Disorder of microcirculation AKI in aging Due to comorbid factors (heart failure, diabetes) and Due to noncomorbid factors that relate to age related changes in kidney function. Due in part to decrease in renal reserve Chronic medullary hypoxia and activation of myofibroblasts are thought to contribute to mechanisms by which AKI leads to CKD. Pathogenesis of AKI: Key Points: Update Role of mesenchymal stem cells i) Immediate effects ameliorate injury (paracrine) ii) late effects in recovery ( homing ) Single episode of kidney injury triggers long-term changes to structure & function. Epithelial regeneration leads to repair and fibroblast/pericyte proliferation leads to fibrosis. Outline Pathogenesis of Acute Kidney Injury and Repair Prerenal and Ischemic AKI Sepsis Toxin Pathogenesis of AKI in the Elderly Definition, Incidence Diagnosis, Biomarkers Clinical Risk Assessment of AKI Population incidence of dialysis-requiring AKI in the United States by sex from 2000 to 2009 Overall Age Gender Hsu R K et al. JASN 2013;24:37-42

9 Over 30 definitions of AKI/ ARF exist in the literature ADQI Rifle Criteria Consensus Definition 1. Creat 0.1 mg/dl 2. Creat increase >0.5 mg/dl 3. Creat>= 0.5 mg/dl 4. Creat >= 1.7 mg/dl 5. Creat >= 1.5 mg/dl 6. Creat >= 2 mg/dl 7. Creat>= 2.1 mg/dl and x 2 8. Creat >= 177µmol/L >62µmol/L 9. Creat > 200µmol/L (2.36 mg/dl) 10. Creat> 3.2 mg/dl or x Creat>5 mg/dl or K > RIFLE 13. Creat increase >= 25% 14. Creat increase >= 50% 15. Creat increase >= 100% 16. Cr72h >0µmol/L 17. Cr72h >25µmol/L 18. Cr72h >44µmol/L 19. Cr72h >50µmol/L 20. Cr72h >100µmol/L 21.Cockcroft-Gault Cr Cl < 30 ml/min 22.Cockcroft-Gault Cr Cl ml/min 23. Cockcroft-Gault72hr <0% 24. Cockcroft-Gault72hr <-15% 25. Cockcroft-Gault72hr <-25% 26. Cockcroft-Gault72hr <-50% 27.MDRD: 50% change in GFR 28.UO <100 q 8hr 29.U α1-microglob 30.U β2- microglobulin 31.U N-acetyl- β-d-glucosaminidase 32.U gluthation transferase-π 33.U gluthation transferase- α 34.NGAL 35.RRT Bellomo et al Crit Care 2004 Mortality Risk in Hospitalized Patients AKIN Criteria (Rifle V2.0) Multivariable OR Chertow et al, JASN 16: , 2005 >0.3 >0.5 >1.0 >2.0 SCr mg/dl R (I) R (I) I (II) F (III) F (III) Increased SCr x1.5 OR > 0.3 mg/dl Increased SCr x2 Increase SCr x3 or SCr 4mg/dl (Acute rise of 0.5 mg/dl) RRT Started UO <.5ml/kg/h x 6 hr UO <.5ml/kg/h x 12 hr UO <.3ml/kg/h x 24 hr or Anuria x 12 hrs Modifications proposed by AKIN Amsterdam, 2005 High Sensitivity High Specificity Criterion must be reached within 48hr KDIGO Definition of AKI Failure vs Non-AKI Increase in All-Cause Mortality with worse RIFLE Class Increase in SCr by 0.3 mg/dl within 48 hours; or Increase in SCr to 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or Injury vs Non-AKI Urine volume <0.5 ml/kg/hour for 6 hours. Risk vs Non-AKI n=71, Relative Risk Ricci et al KI 2008 Examples Baseline Day 1 Day 2 Day 3 Day 7 RIFLE AKIN YES NO NO YES

10 5 Problems (at least) with Serum Creatinine RIFLE/AKIN/KDIGO-Creatinine based Serum Creatinine and GFR In AKI 1. Not sensitive: There is lot of cellular injury that does not affect (GFR)/creatinine 2. Not Specific: Creatinine can increase without kidney injury (pre-renal state) 3. Delayed: The rise is serum creatinine is delayed by 2-3 days 4. Fluid therapy may dilute serum creatining delaying diagnosis 5. Inter-laboratory variation in measuring creatinine, and bilirubin and other compounds interfere with the colorimetric modified Jaffe assay hence affect serum creatinine levels. Nutrition Drugs Tubular excretion Muscle mass Protein metabolism Serum creatinine Renal excretion Infection Edema Volume of distribution Nonlinear Filtration (GFR) Star RA, Kidney Int, 1998 Definition and Incidence: Summary RIFLE or AKIN Definitions Increase in stage associated with increase in mortality Both have important limitations KDIGO Definition Consensus definition- Combines RIFLE and AKIN into a single definition Limitations-number of limitations Need to integrate biomarkers of injury Outline Pathogenesis of Acute Kidney Injury Definition, Incidence Diagnosis, Biomarkers Clinical Risk Assessment of AKI Primary Prevention High risk Primary and Secondary Prevention Risk Profiling and Biomarkers Therapeutic Window Secondary Prevention Prerenal AKI Sensitive Biomarkers Glomerular Filtration Rate AKI Creatinine What Can An Ideal AKI Biomarker Teach Us? Predict and diagnose AKI early (before increase in serum creatinine) Identify the primary location of injury (proximal tubule, distal tubule, interstitium) Pinpoint the type (pre-renal, AKI, CKD), duration and severity of kidney injury Identify the etiology of AKI (ischemic, septic, toxic, combination) Predict clinical outcomes (dialysis, death, length of stay) Monitor response to intervention and treatment Expedite the drug development process (safety) Jo, S.K. M.H. Rosner and M.D. Okusa, Clin. J. Am. Soc. Nephrol. 2: , Prasad Devarajan: Biomarkers in Acute Kidney Injury :Search for a Serum Creatinine Surrogate

11 Biomarkers after AKI Early Detection Idealized Value of Damage Biomarkers Differential Diagnosis of AKI Urinary NGAL Serum Creatinine SCr Kim-1 IL-18 NGAL L-FABP 635 patients admitted to the hospital with AKI, prerenal azotemia, CKD, or normal kidney function. RIFLE criteria for AKI used. At a cutoff value of 130 g/g creatinine, sensitivity and specificity of NGAL for detecting acute injury were (95% CI, 0.73 to 0.98) and (CI, to 1.00), TK. Nicholas et al. Ann Intern Med. 2008;148: Combined use of damage biomarkers and functional biomarkers Predicts clinical events Diagnosis of AKI: Combination of Functional and Damage Markers NGAL KIM-1 Clinical events (initiation of dialysis or in-hospital mortality) T.K. Nicholas, et al. J Am Coll Cardiol January 17; 59(3): Dublin, Ireland, August 30th-September 1st, 2011 ZH Endre et al Contrib Nephrol. 2013;182:30-44 RenaStick Point of Care Testing for AKI V.S. Vaidya J. V. Bonventre, et al. Kidney International (2009) 76, Timing in Secondary Prevention EarlyARF Study Double-blind placebo-controlled trial - early treatment with erythropoietin (E) could prevent the development of AKI in ICU setting. Urinary levels of two biomarkers, γ-gt and AP (46.3) triggered randomization to either placebo or two doses of E Primary outcome of relative average plasma creatinine increase from baseline over 4 to 7 days. Of 529 patients, 162 were randomized within an 3.5 h of a positive sample. Early intervention with high-dose erythropoietin did not alter the outcome. randomization Randomization Av 3.5 h Placebo or E 1 hr 12 hr 24 hr 7 d ZH Endre, et al,kidney Int. (2010) 77,

12 Thresholds for Detection of AKI Caveats? Urine microscopy in early diagnosis of AKI Healthy Adult Adult with CKD?? Pediatric Elderly Adult?? AKI AKI AKI AKI No AKI No AKI No AKI No AKI What are the cut points for: L-FABP, KIM-1, and IL-18 Surgery, contrast-induced AKI, sepsis and critical illness. 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 Biomarkers: Summary Biomarkers General Transition from discovery to validation to clinical use: IL-18; Cystatin C; KIM -1; NAG Combination of functional and damage biomarkers Optimal context specific cut-points for the diagnosis of AKI need to be developed for L-FABP, KIM-1, and IL-18 and other Biomarkers - Older patients The use of serum creatinine is the current gold standard but its use necessitates a clear understanding of its limitations especially the older population Validation of lead biomarkers need testing in the older population L-FABP, KIM-1, and IL-18 and others Cut-points need to be identified in the older population Outline Pathogenesis of Acute Kidney Injury Definition, Incidence Diagnosis, Biomarkers Clinical Risk Assessment of AKI Risk Assessment Pre-Exposure Risk Factors Susceptibility Normal Demographics Co-morbidities Medications Exposure Acute Kidney Injury GFR Damage Outcomes ESRD/Death CKD Recovery Shared Susceptibility Factors Chronic Co-morbidities Dehydration Hypoalbuminemia Medications CKD Advanced Age Diabetes Mellitus Female Gender NSAIDs Heart Disease Black race? ACEI/ARBs Pulmonary Previous AKI Statins? Multiple myeloma Acoholism Preexposure medications Pre-Exposure Risk Factors Intervention Before Exposure After Exposure During Development of AKI After Recovery from AKI Adapted from KDIGO; appendix C, Kidney Int. 2012

13 Risk Prediction for RCIN Risk Factors Hypotension IABP CHF Age>75 Diabetes Contrast volume Cr>1.5 mg/dl egfr<60 ml/min/1.73 m 2 Score for each 100ml 4 2 for for for <20 Risk Score Risk of RCIN Risk of Dialysis 5 7.5% 0.04% % 0.12% % 1.09% % 12.6% 5,561 pts in development set 2,786 pts in the validation set Mehran et al. JACC 2004;44: Risk factors Score Female gender 1 Congestive heart failure 1 Left ventricular ejection fraction 1 <35% Preoperative use of IABP 2 COPD 1 Insulin-requiring diabetes 1 Previous cardiac surgery 1 Emergency surgery 2 Valve surgery only (reference to 1 CABG) CABG + valve (reference to 2 CABG) Other cardiac surgeries 2 Preoperative creatinine 1.2 to 2 <2.1 mg/dl (reference to 1.2) Preoperative creatinine (reference to 1.2) Minimum score, 0 Maximum score, 17 Risk Assessment of ARF Post CABG ( ) C. Thakar J. Am Soc. Nephrol 16: , 2005 Risk Factors for AKI: Importance of CKD Kaiser Permanente Northern California Hyperglycemia increases AKI Risk 1,746 hospitalized AKI-D and 600,820 hospitalized with no AKI Documented Proteinuria Diagnosed Hypertension Diabetes Mellitus <15 Baseline GFR 60 Reference Unadjusted Odds ratio C.Y. Hsu GM. Chertow and AS Go Kidney Int. 74, , 2008 Van den Berghe, JASN, March 08 Proteinuria increases AKI Risk Obesity and Risk of Acute Kidney Injury Following Cardiac Surgery Examined body mass relationship between BMI and AKI in 445 patients undergoing cardiac surgery. Higher BMI independently associated with increased odds of AKI 26.5% increase per 5 kg/m 2 ( %; P- 0.02). Baseline and intraop F 2 -isoprostane, and intraop PAI-1 independently predicted AKI Obesity independently predicts AKI after cardiac surgery in part through oxidative stress. T. Huang, et al. JASN Jan 1, : F. T. Billings IV et al. JASN 23: , 2012

14 Predictive and intraoperative Risk Assessment. Non Dialysis AKI Associates with Increased Long Term Mortality Demirjian S, et al. AJKD; 59(3): 382-9, J-P Lafrance and D. R. Miller J Am Soc Nephrol 21:435-42, 2010 Clinical Risk Assessment: Summary Understanding individual risk factors may help in preventing AKI Interaction of susceptibility of AKI and type/extent of exposure that determines risk of occurrence of AKI Susceptibility factors may be modified Exposures can be avoided or tailored to reduce risk Most patients are seen after exposure-still opportunity for risk assessment closer monitoring, general support measures AKI-recovery may lead to CKD/ESRD Post AKI monitoring and transition of care is important Cirrhotic Cardiomyopathy 50 ys ago Kowalski and Abel described hyperdynamic circulation in cirrhotic patients Gould 1969 demonstrated cardiac contractile response was depressed in alcoholic cirrhosis, confirmed in several other studies (alcoholic cirrhosis).alcohol cardiomyopathy? Depressed cardiac function due to cirrhosis -adrenergic receptor density of lymphocytes of patients Animal studies confirmed Nonalcoholic cirrhosis with blunted cardiac inotropic and chronotropic response to exercise, drugs, hemorrhage, surgery and stress. Conduction abnormalities