Disclosures

Diagnosis and Management  Consultant for Baxter of Acute Kidney Injury  Patent on 0.5% citrate anticoagulant solution for CRRT

Ashita Tolwani, M.D., M.S. Professor of Medicine University of Alabama at Birmingham 2017

AKI Outline

 Epidemiology

 Definition Epidemiology of AKI

 Pathophysiology and differential diagnosis

 Overview of prevention and management

1 Acute Kidney Injury: Why Do We Care?

 AKI is common (KDIGO definition)  21% of all hospital admissions  >50% of ICU patients  AKI is associated with increased risk of CKD, ESKD, CV disease, and death Worldwide, 2,000,000  Dialysis‐requiring AKI ICU patients have the worst outcomes  11% of ICU patients with AKI require dialysis and 10‐30% survivpeople will die this year ors remain dialysis dependent at time of hospital discharge of AKI!  AKI can be preventable, treatable, and reversible

 Healthcare workers are not well informed about AKI and its consequences

Mehta RL et al. Lancet 2015 Pannu et al. CJASN 2013 Cerda, et al. CJASN 2015

2 Definition

 More than 30 different definitions exist with a variety of quoted incidence rates, risk factors, and morbidity and mortality rates  A staging system is needed to stratify patients so that both accurate identification and prognostication are possible Definition of AKI

www.ADQI.net

Using RIFLE, Patients with AKI Mortality Risk in Hospitalized Patients Have Poorer Outcomes

Analysis of 71,000 pts/13 studies to validate RIFLE Criteria

Mild AKI have poor outcomes

> 0.3 > 0.5 > 1.0 > 2.0 ↑SCr mg/dL

Source: Ricci Z. Kidney Int. 73: 538-546, 2008 Chertow et al, JASN 16: 3365-3370, 2005

3 AKIN Criteria (Rifle V2.0) KDIGO AKI Guidelines: Definition of AKI

Increased SCr x1.5 UO < .5ml/kg/h OR > 0.3 mg/dL R (I) x 6 hr High Sensitivity

Increased SCr x2 UO < .5ml/kg/h I (II) x 12 hr

Increase SCr x3 UO < .3ml/kg/h or SCr 4mg/dl x 24 hr or High F (III) (Acute rise of 0.5 mg/dl) Anuria x 12 hrs Specificity RRT Started

Modifications proposed by AKIN Criterion must be Amsterdam, 2005 reached within 48hr KDOQI Commentary AJKD 2013

Problems with Serum Creatinine Serum Creatinine and GFR in AKI

 Creatinine is influenced by age, muscle mass, gender, and Muscle mass ethnicity Nutrition Infection  Creatinine does not reflect the presence or absence of structural injury and thus provides no guidance on AKI etiology or the Protein metabolism likelihood of response to various targeted therapies Edema  The rise is serum creatinine is delayed by 2‐3 days after the injury has occurred Serum creatinine Volume of  Fluid therapy may dilute serum creatinine and therefore delay distribution diagnosis  Inter‐laboratory variation in measuring creatinine, and bilirubin Renal excretion and other compounds interfere with the colorimetric modified Drugs Nonlinear Jaffe assay hence affect serum creatinine levels Tubular excretion Filtration (GFR)

Star RA, Kidney Int, 1998

4 Relationship Between GFR and Creatinine Conceptual Model for AKI

120

80 GFR (mL/min) 40

Increased Kidney 0 Normal Damage  GFR Death risk failure 6 Serum 4 Creatinine (mg/dL) 2 Ideal Creatinine 0 0 7 14 21 28 Biomarker Days Gill, N. et al. Chest 2005;128:2847-2863

What Can an Ideal AKI Biomarker Teach Us? Potential Biomarkers for AKI Proximal Tubule Injury •Urine IL-18 •Urine KIM-1 •Urine L-FABP Distal Tubule . Predict and diagnose AKI early (before increase in serum •Urine Cystatin C •Urine NGAL •α1-microglobulin •Urine π-GST creatinine) •β2-microglobulin •Urine α-GST . Identify the primary location of injury (proximal tubule, distal •Urine Netrin-1 •Urine NAG tubule, interstitium) Glomerular Injury • Urine albumin excretion . Pinpoint the type (pre‐renal, AKI, CKD), duration and severity Glomerular Filtration • Serum Creatinine of kidney injury • Blood urine Nitrogen • Serum Cystatin C . Identify the etiology of AKI (ischemic, septic, toxic, • Plasma NGAL

combination) Loop of Henle Injury •Uromodulin . Predict clinical outcomes (dialysis, death, length of stay) . Monitor response to intervention and treatment Other Mechanisms / Sites of Injury not specific to the Adapted from Koyner . Expedite the drug development process (safety) Nephron and Parikh‐ Brenner and •Hepcidin – Iron trafficking Rector’s The Kidney •TIMP-2/ IGFBP7 – G1 cell cycle arrest Courtesy of J. Koyner Prasad Devarajan: Biomarkers in Acute Kidney Injury :Search for a Serum Creatinine Surrogate

5 Biomarkers after AKI Early Detection New Paradigm for the Spectrum of AKI Idealized

SCr Kim‐1 STRUCTURAL IL‐18 NO AKI (subclinical) AKI Creat (‐) Creat (‐) Biomarker (‐) Biomarker (+)

NGAL FUNCTIONAL AKI INTRINSIC AKI (structural & functional) L‐FABP Creat (+) Creat (+) Biomarker (‐) Biomarker (+)

Urinary Biomarkers Associated with Tubular Damage

Classification of the Etiologies of AKI

AKI Pathophysiology and Differential Diagnosis of AKI Prerenal Intrinsic Post-renal AKI AKI AKI

Acute Acute Acute Acute Intratubular Tubular Interstitial Vascular GN Obstruction Necrosis Nephritis Syndromes

6 Non ‐ICU ICU Evaluation of Cause of AKI

Form of AKI BUN:Cr UNa (mEq/L) FENa Urine Sediment

Prerenal >20:1 <10 < 1% Normal, hyaline casts Post‐renal >20:1 >20 variable Normal or RBC’s Intrinsic ATN <10:1 >20 > 2% Muddy brown casts; tubular epithelial cells, granular casts AIN <20:1 >20 >1% WBC’s WBC casts, RBC’s, eosinophils AGN variable <20 <1% Dysmorphic RBC’s, RBC casts Vascular variable >20 variable Normal or RBC’s

Fractional Excretion of Na+ (FENa) Fractional Excretion of Urea (FEurea)

(Urine Na x Serum Cr) X 100 < 1% = pre‐renal (Serum Na x Urine Cr) > 2% = ATN (Urine UN x Serum Cr) X 100 < 35% = Pre‐renal (Serum UN x Urine Cr) > 50% = ATN  Normal renal function <1%  Most accurate with oliguric AKI . Better than FENa in patients on diuretics

 Caveat: . Rationale: Urea reabsorbed in proximal tubule + inner . < 1% without volume depletion medulla, not affected by loop and thiazide diuretics . Contrast nephropathy . Acute GN . Rhabdomyolysis . Possibly > 2% with prerenal state: . Diuretics, severe CKD

Steiner AJM 1984:77:699-702

7 Pre-renal AKI – Decreased Renal Blood Flow Pre-renal Urine Sediment

Cause Examples Volume depletion Renal losses; GI fluid losses; hemorrhage; burns Decreased cardiac output Heart failure; massive pulmonary embolus; acute coronary syndrome Systemic vasodilation Sepsis; cirrhosis; anaphylaxis; anesthesia Intrarenal vasoconstriction Drugs (NSAIDs, COX‐2 inhibitors, amphotericin B, calcineurin inhibitors, contrast agents); hypercalcemia; hepatorenal syndrome Efferent arteriolar vasodilation Renin inhibitors; ACE inhibitors; ARBs Hyaline Casts A prolonged pre‐renal state can lead to ATN

Pathogenesis of Pre-renal AKI Impaired Autoregulation Can Lead to “Normotensive AKI”

Congestive Heart Failure Liver Volume Failure Depletion Sepsis

+ Renal Angiotensin II Vasoconstriction - + Nitric oxide Adrenergic nerves - + Prostaglandins Vasopressin

Decreased GFR

Abuelo JG. N Engl J Med 2007;357:797-805

8 Intrarenal Mechanisms for Autoregulation of the GFR Pre-renal Azotemia: Medications

Angiotensin‐converting enzyme inhibitors

Nonsteroidal anti‐inflammatory drugs NSAIDS ACEI/ARB

Abuelo JG. N Engl J Med2007;357:797-805.

Systemic Effects of Increased Abdominal Abdominal Compartment Syndrome Pressure

 Intra‐abdominal hypertension:  Cardiac  GI  Intra‐abdominal pressure ≥12 mm Hg; or   venous return   splanchnic perfusion  Abdominal perfusion pressure <60 mm Hg   cardiac output  CNS   CVP, PCWP & SVR   intracranial pressure,  Abdominal compartment syndrome  Pulmonary   perfusion pressure  Intra‐abdominal pressure ≥20 mm Hg; and   intrathoracic &  Renal  One or more new organ failures airway pressures   renal perfusion   PaO2   GFR   PaCO2   urinary output

9 Clinical Settings for ACS Abdominal Compartment Syndrome

 Diagnosis  Trauma patients following massive volume  Measurement of intra‐abdominal pressure resuscitation  Clamp drainage tube of Foley catheter  Massive ascites  Instill 25 mL sterile water into the bladder via the aspiration port  Measure pressure using a manometer or transducer attached to  Post liver transplant the aspiration port.  Mechanical limitations to the abdominal wall  The manometer or transducer should be zeroed at the level of the mid‐axillary line at the iliac crest  Tight surgical closure  Burn injuries  Treatment  Bowel obstruction  Abdominal decompression  Pancreatitis

Intrinsic Renal Disease Treatment of Pre-renal AKI Glomerulonephritis Interstitial • Postinfectious GN nephritis  Correction of volume depletion • Endocarditis‐associated GN • Systemic vasculitis •drugs  Discontinuation/dose adjustment of medications • Membranoproliferative GN –penicillins •  NSAIDs Rapidly progressive GN –sulphonamides • IgA nepropathy –rifampin  RAAS blockers –NSAID's  CNIs –phenytoin  Evaluation for causes of “effective” volume depletion –allopurinol  Heart failure •infections Small blood vessels •systemic disease  Cirrhosis • Malignant hypertension –SLE  Nephrotic syndrome • HUS/TTP –sarcoid  Sepsis • (Pre)Eclampsia –sjogrens • DIC •malignancy  Treat hypercalcemia • Scleroderma •idiopathic  Recognize and treat abdominal compartment syndrome • Vasculitis • Cholesterol emboli Acute tubular necrosis

10 Pathogenesis of Ischemic AKI Acute Tubular Necrosis Ischemia Causes Ischemic: causes of prolonged prerenal AKI Innate Acute Tubular Drug‐induced: aminoglycosides; vancomycin; polymyxins; lithium; Microvascular Injury Immunity Injury amphotericin B; pentamidine; cisplatin; foscarnet; tenofovir; Vasoconstriction DAMPS Apoptosis cidofovir; carboplatin; ifosfamide; zoledronate; contrast agents; Leukocyte Adhesion Immune Cells Necrosis sucrose; immunoglobins; mannitol; hydroxyethyl starch; dextran; ↑ Permeability Cytokines

NSAIDs; synthetic cannabinoids; amphetamines Microvascular Tubular Obstruction Inflammation Congestion Backleak Pigment: rhabdomyolysis; intravascular hemolysis

Sepsis Continued Ischemia DECREASED GFR

Adapted from Bonventre and Weinberg JASN 14:2199-2210, 2003

Histology: Normal Kidney/Tubules Acute Tubular Necrosis

Interstitial edema

‐ “Back‐to‐Back” tubules Flattened Epithelial Cells

‐ “Plump” Epithelial Cells Loss of Brush Border

‐ Intact Brush Border Colloidal intra‐tubular casts ‐ Minimal Intra‐tubular material

11 Acute Tubular Necrosis Urine Sediment Contrast Media-Nephrotoxicity

Increase in serum creatinine occurs within 24 to 48 Contrast Media hours following contrast exposure

PGE2  Endothelin Systemic Osmotic ANP Vasopressin Hypoxemia Load

Ado PGI2 Blood viscosity

 Oxygen Oxygen Blood Flow Delivery Consumption

Direct Cellular Toxicity Renal Medullary Hypoxia

Muddy Brown Granular Casts and Renal Tubular Epithelial Cells Rudnick et. al. Seminars in Nephrology 17:15-26, 1997

Strategies for Prevention of Contrast- Risk Factors for Contrast-Associated AKI Associated AKI  Effective  Patient Related  Low- or Iso-osmolal contrast agents  Intravenous isotonic fluids  Preexisting renal insufficiency  Avoidance of concomitant nephrotoxins  Diabetes mellitus  Ineffective or harmful  Intravascular volume depletion  Furosemide  Mannitol  Reduced cardiac output  Dopamine  Concomitant nephrotoxins  Fenoldopam  Prophylactic RRT  Procedure related  Uncertain  Intravenous sodium bicarbonate  Increased dose of radiocontrast  N-acetylcysteine  Multiple procedures within 72 hours  Theophyliine  ANP  Intra‐arterial administration  Statins  Type of radiocontrast  Iron chelators  RIPC

12 Acute Interstitial Nephritis Acute Interstitial Nephritis

. Clinical Suspicion . Urine Studies Causes . Fever, Rash . Dipstick/low grade proteinuria Drug‐induced: cephalosporins; penicillin; methicillin; . Culprit Drug or Disease . fluoroquinolones; sulfonamides; rifampin; NSAIDs; COX‐2 Process Pyuria, hematuria, WBC casts inhibitors; proton pump inhibitors; 5‐aminosalicylates; indinavir; . Blood Tests . Eosinophiluria abacavir; allopurinol; phenytoin; triamterene; furosemide; thiazide diuretics; phenytoin; carbamazepine; Chinese herb . Increased serum creatinine . Imaging Tests (AKI) nephropathy . Renal US/CT Scan . Leukocytosis, eosinophilia, . Gallium Scan Infection: pyelonephritis; viral nephritides; leptospirosis; anemia, elevated ESR, transaminitis . FDG‐PET Scan Legionella; Mycobacterium tuberculosis . Kidney Biopsy Autoimmune: Sjögren syndrome; sarcoidosis; SLE; TINU . Gold Standard syndrome; IgG4‐related disease The triad of Fever, Rash and Eosinophilia: <5‐10% Malignancy: lymphoma; leukemia; multiple myeloma

Acute Interstitial Nephritis Urine Sediment Acute Interstitial Nephritis

White Blood Cell Cast

13 Acute Interstitial Nephritis: Acute Interstitial Nephritis - Summary Eosinophiluria

 Most commonly drug induced Drug Induced-AIN All Etiologies of AIN  All cases (n=548) Pyuria (n=452) All cases (566) Pyuria ( 467) Complete “classic” triad is rarely present >1% >5% >1% >5% >1% >5% >1% >5%  Common urinary findings include Sensitivity 35.6 23.3 44.8 29.3 30.8 19.8 38.4 24.7  Pyuria Specificity 68.2 91.2 61.7 89.3 68.2 91.2 61.7 89.3  WBC casts PPV 14.7 28.8 14.7 28.8 15.6 30.0 15.6 30.0 NPV 87.3 88.6 88.4 89.6 83.7 85.6 84.4 86.5  Eosinophiluria neither sensitive nor specific Positive LR 1.1 2.6 1.2 2.7 0.97 2.3 1.0 2.3  Primary treatment is discontinuation of offending Negative LR 0.9 0.8 0.9 0.8 1.01 0.9 1.0 0.8 agent/treatment of underlying etiology Insensitive test with specificity and positive LR only potentially  Role of glucocorticoids remain uncertain acceptable using Urine Eos >5% cutoff in setting of high pretest probability Muriithi AK, et al. CJASN 2013; 8: 1857-1862

Acute Glomerulonephritis: Acute Glomerulonephritis Dysmorphic RBCs and RBC Casts

. Nephritic presentation . Proteinuria (may be in nephrotic range (> 3.5 g/day)) . Hematuria (dysmorphic RBCs) . RBC casts

. Diagnosis usually requires renal biopsy . Infection‐related glomerulonephritis . Cryoglobulinemia . RPGN

14 Acute Vascular Syndromes Atheroembolic Disease Causes Macrovascular: renal artery occlusion; renal vein thrombosis; polyarteritis nodosa Microvascular: TMA; HUS; TTP; APLS; HELLP; scleroderma renal crisis; hypertensive emergency; drugs (clopidogrel, cyclosporine, tacrolimus, anti‐angiogenesis drugs, interferon, m‐TOR inhibitors); drug‐induced TMA (caused by quinine, cancer therapies [gemcitabine, mitomycin, bevacizumab, bortezomib, sunitinib], calcineurin inhibitors [cyclosporine, tacrolimus], drugs of abuse [cocaine, ecstasy, intravenous extended‐release oxymorphone]) Atheroembolic disease

Atheroembolic Disease: Atheroembolic Disease Non-Renal Manifestations

 Risk factors  Precipitating factors  General  Gastrointestinal  Fever  Anorexia  Atherosclerosis  Arterial catheterization  Myalgias  Nausea and vomiting  CAD  Arteriography  Weight loss  Nonspecific abdominal pain  AAA  GI bleeding  Vascular surgery  Cutaneous  PVD  Livedo reticularis  Ileus  Anticoagulation  Hypertension  Digital ischemia  Bowel ischemia/infarction  Thrombolytic therapy  Neurologic  Pancreatitis  Hypercholesterolemia  TIA/CVA  Hepatitis  Diabetes Mellitus  Altered mental status  Musculoskeletal  Peripheral neuropathy  Myositis  Spinal cord infarct  Eyes  Amaurosis fugax  Retinal cholesterol emboli

15 Atheroembolic Disease: Atheroembolic Disease: Renal Manifestations Laboratory Features

 Serum chemistries  Serologic  Renal infarction   BUN and creatinine   ESR  Acute kidney injury  Amylase  Serum complement  Subacute kidney injury   CPK  Urine   LFTs  Exacerbation of hypertension  Eosinophiluria  Hematology  Proteinuria  Proteinuria (may be nephrotic)  Leukocytosis  Hematuria  Hematuria  Eosinophilia  Pyuria  Anemia  Thrombocytopenia

Atheroembolic Disease: Intrinsic Renal Disease: Treatment Intratubular Obstruction  Common factors:  Avoid anticoagulation  Include high excretion in urine  Low solubility in acidic urine  Avoid vascular interventions  Exacerbated by hypovolemia  ACE inhibitors / angiotensin receptor blockers  Common crystals  Statin therapy  Uric acid (tumor lysis syndrome)  Nutrition support  Acyclovir  Sulfa  Dialysis for management of volume status and uremia  Methotrexate  Role of steroid therapy is uncertain  Ethylene glycol (calcium oxalate deposition)  Intratubular protein deposition  Multiple myeloma (Bence‐Jones protein deposition)

16 Tumor Lysis Syndrome Tumor Lysis Syndrome

 Rapid lysis of malignant cells leads to hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and AKI  Management of patients at risk or presenting with TLS  Aggressive volume expansion to achieve a urine output of at least 80 to 100 mL/m2/h  Allopurinol to prevent formation of new uric acid (recommended as prophylaxis for patients at low/intermediate risk for TLS)  Rasburicase for patients at high risk of TLS or with TLS (contraindicated in patients with G6PD deficiency)  Urinary alkalinization is no longer recommended due to an increase in calcium phosphate crystal deposition  Management of hyperkalemia and hyperphosphatemia  RRT in refractory cases

Interventions in AKI

Drug Biological Animal Uncontrolled Small Large rationale experiments human data RCT RCT Loop diuretics Present Favorable Favorable Negative N/A Low-dose dopamine Present Favorable Favorable Variable Negative Mannitol Present Favorable Favorable N/A N/A Prevention and Management of Ca antagonist Present Favorable Favorable Variable N/A Theophylline PresentThe Favorable only FavorableFDA Positive N/A AKI Prostaglandins Present Favorable Favorable N/A N/A Natriuretic peptide Presentapproved Favorable treatment Favorable of Negative N/A -receptor antagonist PresentAKI N/A is dialysis N/A Positive N/A Endothelin antagonist Present Favorable N/A N/A N/A Thromboxane antagonist Present Favorable N/A N/A N/A Thyroxine Present Favorable N/A Negative N/A Saline Present Favorable Favorable Positive N/A NAC Present Favorable N/A Positive N/A Non-ionic media Present Favorable Favorable Positive positive

17 Prevention of ATN

 Recognition of underlying risk factors  Diabetes  CKD  Age  Cardiac/liver dysfunction  Early recognition is key  Changes in creatinine are a late manifestation of renal injury  A “normal” normal serum creatinine may reflect significant renal insufficiency, particularly in the elderly  Maintenance of renal perfusion  Avoidance of nephrotoxins

AKI Summary

 AKI is defined by a standardized creatinine‐based definition

 AKI is common

 AKI is associated with mortality in a stage‐dependent fashion

 Methods for earlier diagnosis of AKI and its progression may result in improved outcomes by facilitating targeted and timely treatment of AKI

 There is no treatment of ATN and prevention of precipitating factors is paramount

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