The Pathophysiology of Acute Kidney Injury 2022 PDF

The Pathophysiology of Acute Kidney Injury Juliette Bouillon, DMV, MVSc, DACVIM (Small Animal Internal Medicine) [email protected] ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 1 Review 2 Definition 3 Causes of AKI TODAY’S AGENDA 4 The 4 phases of AKI 5 Clinical prese...

The Pathophysiology of Acute Kidney Injury Juliette Bouillon, DMV, MVSc, DACVIM (Small Animal Internal Medicine) [email protected] ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 1 Review 2 Definition 3 Causes of AKI TODAY’S AGENDA 4 The 4 phases of AKI 5 Clinical presentation, diagnosis & treatment 6 Example – clinical case ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Learning objectives Acute Kidney Injury Review physiology Define acute kidney injury Describe causes of acute kidney injury and categorize them Describe the 4 phases of acute kidney injury Be familiar with clinical presentation, diagnosis and treatment ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Review One of the kidney functions Excretion of unwanted solute (urea, creatinine, minerals and other metabolic garbage) in a volume of water that is not itself required to maintain homeostasis It is the result of carefully regulated glomerular filtration, tubular reabsorption and tubular secretion. ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Review Laboratory parameters measured to evaluate kidney function Serum urea and serum creatinine Predominantly dependent on the glomerular filtration rate (GFR) Provide an estimation of GFR = flow of plasma from the glomerulus into Bowman’s space over a specified period Urine specific gravity (USG) Provides an estimation of urine osmolality Index of tubular reabsorption = kidney's "response ability" to concentrate (remove water in excess of solute) or dilute (remove solute in excess of water) urine ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Acute Kidney Disease AKI Definition ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Definition Acute Kidney Injury Acute Kidney Injury Abrupt damage to the renal parenchyma resulting in reduction in kidney function reflected by alterations in glomerular filtration, urine production and tubular function Previously named ‘acute renal failure’ Consequences - Failure of the kidneys to meet the excretory, metabolic and endocrine demand of the body: Retention of uremic wastes that may lead to azotemia Deranged fluid status, electrolyte imbalances and acid-base disorders ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Definition Acute Kidney Injury Schemes exist to aid recognition of AKI RIFLE scheme & AKIN criteria (humans) IRIS AKI grading criteria (veterinary) FYI ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 FYI Definition Schemes exist to aid recognition of AKI Uniform characterization and recognition Facilitate evaluation and management A “moment” in the course of the disease Worsening Improvement Transition to CKD ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Acute Kidney Disease Causes of AKI AKI ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Normal CKD Acute Kidney Injury Causes of AKI Prerenal and postrenal disease can coincide with intrinsic renal injury! Acute Kidney Injury Category Pre-renal (hemodynamic) Intrinsic renal ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Post renal Acute Kidney Injury Causes of AKI Intrarenal azotemic renal failure may be caused by many disease processes that destroy ≥ ¾ of the parenchyma of both kidneys Category Pathophysiology Acute Kidney Injury Pre-renal (hemodynamic) Insufficient delivery of blood to the kidneys Intrinsic renal Damage to any section of the kidney: glomeruli, tubules, interstitium, or vessels Post renal Urine leakage within tissue or urinary obstruction Reversible provided compromised renal perfusion is corrected before the onset of ischemic nephron damage ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Causes of AKI Acute Kidney Injury Category Pathophysiology Examples Pre-renal (hemodynamic) Intrinsic renal Post renal Insufficient delivery of blood to the kidneys Damage to any section of the kidney: Glomeruli, tubules, interstitium, or vessels Urine leakage within tissue or urinary obstruction Dehydration, hypovolemia, hypotension, decreased effective circulating volume, trauma, shock, drugs (NSAIDs, ACEi), etc. Ischemia, toxins, infectious, immunemediated, neoplasia, etc. ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Trauma, calculi, mucous plugs, tumors, blood clots, urethral/ureteral strictures Azotemia (first time/acute onset) Causes Acute Kidney Injury How to categorize? Prerenal azotemia is a functional abnormality that is potentially reversible depending on primary cause Prerenal disease can coincide with intrinsic renal injury Suspicion of AKI Pre-renal (hemodynamic) Intrinsic renal Prognosis associated with prerenal azotemia Early treatment  prognosis favorable Prolonged prerenal azotemia  structural damage  intrinsic, irreversible renal failure > Elevated serum BUN or creatinine concentrations > Oliguria > High urine specific gravity (1.035 in dogs; 1.040 in cats) > Detection of underlying cause > Rapid correction of azotemia after administration of appropriate therapy to restore renal perfusion ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Post renal Causes Azotemia (first time/acute onset) How to categorize? Pre-renal (hemodynamic) Total loss of ability to concentrate and dilute urine often develops gradually A USG between 1.007 to 1.029 in dogs or 1.007 to 1.039 in cats associated with clinical dehydration or azotemia is indicative of intrarenal azotemia Total inability of the nephrons to concentrate or dilute urine (isosthenuria) results in the formation of urine that is similar to that of glomerular filtrate (approximately 1.008 to 1.012) Acute Kidney Injury Suspicion of AKI Intrinsic renal Post renal > Hydrated patient, with elevated BUN and creatinine concentrations and impaired ability to concentrate or dilute urine > Dehydrated patient, with increased BUN and creatinine and impaired ability to concentrate urine. > More definitive studies (e.g., ultrasonography, radiography, biopsy, exploratory surgery) to establish the underlying cause > Azotemia does not resolve after appropriate therapy ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Azotemia (first time/acute onset) Causes How to categorize? Pre-renal (hemodynamic) Acute Kidney Injury Suspicion of AKI Intrinsic renal Post renal Obstruction of the excretory pathway Rupture of the excretory pathway > Elevated serum BUN and creatinine concentrations > Oliguria or anuria, dysuria and tenesmus > Obstructive lesions detected by physical examination (e.g., urethral plug, herniated bladder), radiography, ultrasonography, etc. > Variable urine specific gravity values ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Prognosis associated with obstructive lesions Total obstruction for 3-6 days  death If obstruction rapidly removed  favorable prognosis Long-term prognosis depends on the reversibility of the underlying cause Azotemia (first time/acute onset) Causes How to categorize? Pre-renal (hemodynamic) Acute Kidney Injury Suspicion of AKI Intrinsic renal Post renal Obstruction of the excretory pathway Rupture of the excretory pathway > Progressively elevated serum BUN or creatinine concentrations > Progressive depression, painful abdomen, ascites > A history of trauma and associated physical examination findings Prognosis associated with excretory pathway rupture If persistent leakage  progressive azotemia  death If leakage rapidly repaired or heals  favorable prognosis Long-term prognosis depends on the reversibility of the underlying cause ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 > Inability to palpate the urinary bladder > Detection of a modified transudate or exudate by abdominocentesis > Abnormalities detected by ultrasonography or retrograde contrast (positive or negative) cystography or urethrocystography. Causes Azotemia (first time/acute onset) How to categorize? Pre-renal (hemodynamic) If azotemia resolves = pre-renal azotemia superimposed on inability to concentrate urine (e.g., endocrine disease, etc.) Acute Kidney Injury Suspicion of AKI Intrinsic renal Post renal > Hydrated patient, with elevated BUN and creatinine concentrations and impaired ability to concentrate or dilute urine > Dehydrated patient, with elevated BUN and creatinine and impaired ability to concentrate urine. > More definitive studies (e.g., ultrasonography, radiography, biopsy, exploratory surgery) to establish the underlying cause > Azotemia does not resolve after appropriate therapy ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Causes Acute Kidney Injury How to categorize? Combinations of azotemia Pathogenesis Patient with previously compensated primary renal disease Kidneys have impaired ability to compensate Uremic crisis Extrarenal mechanisms that may be associated with uremic crises Protein by-products, stress states (fever, infection, change of environment), prerenal uremia, nephrotoxic drugs ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Causes Acute Kidney Injury How to categorize? Combinations of azotemia Diagnosis Patients with a previous history of compensated primary renal failure Detection of primary extrarenal disease processes & generalized renal disease Detection of clinical dehydration associated with azotemia and impaired urine concentration  a portion of the azotemia is prerenal Response to therapy Prognosis. Withhold formulating a prognosis until the magnitude of azotemia is reassessed after correcting the prerenal or postrenal components of azotemia ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Disease The 4 phases of AKI ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 4 Phases Phase 1 - Initiation Renal insult – damage initiation Phase 2 - Extension phase Localized ischemia, inflammation and cellular injury leading to cell apoptosis or necrosis, causing further damage Phase 3 - maintenance phase Phase 4 - recovery phase Renal tubules repair and heal if the basement membrane of the nephron is intact ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Acute Kidney Injury Phase 1 - initiation ↓ATP ↑Ca2+ Renal insult Ischemic, nephrotoxic, obstructive ROS Direct damage to renal tubular cells and ischemia Hypoxia  depletion in ATP  increased cellular calcium concentration  activates proteases and phospholipases  free radicals  cellular damage  inflammatory reaction ROS and Inflammation Nephrons within the renal medulla (proximal convoluted tubule and the thick ascending loop of Henle) are particularly vulnerable to ischemia, due to decreased perfusion and increased energy demands compared with the rest of the kidney ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Phase 1 - initiation Consequences: loss of apical microvilli & absorptive brush border  loss of cell polarity Abnormal solute and electrolyte handling Increased sodium delivery to macula densa in distal tubule Tubuloglomerular feedback activated  vasoconstriction afferent arteriole  worsened renal ischemia Integrin dysfunction Desquamation into tubular lumen  obstruction (casts, debris)  peritubular interstitium + increased glomerular pressure  ↓ GFR back-leak of filtrate into the Renal tubular cells unable to support their energy needs  activation of intracellular mechanisms cause cellular swelling  further obstruction of renal tubules Clinically: Clinical signs often absent This phase lasts from hours to a few days During this stage, early intervention may prevent progression ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Phase 2 – extension phase Amplification of the initial renal insult by ongoing hypoxia from ischemia and the resulting inflammatory response Damage to peritubular capillary endothelial cells  enhanced vascular reactivity to vasoconstrictive agents and decreased vascular reactivity to vasodilating agents  exacerbation of ischemia and hypoxia Intrinsic cellular protections may block these programmed events and spare the cell ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Phase 2 – extension phase Clinically Changes continues until there is a definable change in renal function such as decreased urine output or azotemia This is when clinical signs appear! Length of time necessary to see changes is variable, depending on the insult's nature and severity Routine laboratory tests and clinical examination findings may not detect evidence of AKI Lack of baseline renal values Non-specific signs such as lethargy, inappetence and abdominal pain Intervention may not be successful in this phase ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Phase 3 – maintenance phase In this stage, a critical amount of irreversible damage has occurred - stabilization of the GFR at its nadir Apoptosis continues but renal blood flow returns to normal, leading to cellular repair Proliferation and migration of renal tubular cells occurs, beginning the process of re-establishing cell polarity and tubular integrity Clinically 1 to 3 weeks (days to weeks, variable) Stage when AKI is generally detected Urine output may be increased or decreased and it resembles the ultrafiltrate, with little modification by tubular processes ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Phase 4 – recovery phase GFR rises as cellular repair continues GFR may fully recover - renal tubules repair and heal if the basement membrane of the nephron is intact Residual chronic kidney disease - scar formation resulting in longterm dysfunction Clinically Can last for weeks to months Onset of polyuria is sometimes a marker for the onset of the recovery phase Very important to avoid any additional renal injury during this period Possible sodium losses because the proximal tubules and ascending limbs of the loops of Henle have reductions in the number of sodium transporters and aquaporin-2 proteins Extreme Na losses lead to volume depletion that can delay or interrupt renal recovery ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Acute Kidney Disease Clinical presentation, diagnosis & treatment ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Diagnosis Acute Kidney Injury Prompt recognition – a priority! History Time course Attempt to identify an underlying cause medication history, toxin exposure Physical examination Lethargy and depression Oral ulceration and a ‘uremic breath’ Melena if secondary gastrointestinal ulceration and bleeding Size of the urinary bladder (obstruction, hint towards urine production) Kidneys’ size, shape, symmetry, pain ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Diagnosis Bloodwork BUN & creatinine – normal vs increased Electrolytes disturbances Urinalysis Isosthenuria Proteinuria, glucosuria, hematuria, pyuria, bacteriuria, crystalluria or casts Culture and sensitivity - in all patients with unknown cause of AKI prior to treatment with antibiotics Doppler blood pressure measurement & fundic examination High prevalence of hypertension ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Diagnosis Imaging tests Radiography Evaluation of kidney size and shape Identification radiopaque stones within the urinary tract Abdominal ultrasound Evaluate further for obstruction (particularly with nonradiopaque calculi) Neoplasia, Pyelonephritis Antegrade pyelography or computed tomography (obstruction) Biopsy/FNA (rare) ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Treatment and monitoring Intravenous fluid therapy Cornerstone of therapy Caution – volume overload! – close monitoring of hydration status Correct dehydration, electrolyte disturbances, acid-base disturbances More directed treatments may be necessary if severe derangements such as hyperkalemia Oliguria-anuria Closely monitor urine production Diuretics (furosemide, mannitol) Dopaminergic agonists (fenoldopam) ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Treatment and monitoring Hypertension Amlodipine (dihydropyridine calcium channel blocker) Gastrointestinal sequelae Uremic toxins, hypergastrinemia Antiemetics (maropitant, ondansetron, metoclopramide) Inhibitors of gastric acid production (famotidine, ranitidine, omeprazole, pantoprazole) Nutritional support Renal replacement therapies (dialysis) ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Prognosis Guarded Mortality 47-64% ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Acute Kidney Disease Example – Clinical cases ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 History Juno - 6-year-old Labrador Retriever cross Ingested approximately 10 x 400mg Advil Extra Strength capsules during the course of the day while the owner was not at home Ingestion was at an unknown time, with a possible maximum ingestion time of about 12 hours prior to presentation She vomited 6 times prior to presentation (no blood) One normal bowel movement since event Recent history of TPLO surgery one month ago on her left hind limb Up to date on vaccines, endo/ectoparasite preventatives Indoor/outdoor Only dog in house ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Physical examination BAR HR 140 bpm RR panting T 38.8 °C (101.8°F) Pink, mildly tacky mucous membranes and an adequate/delayed capillary refill time indicating appropriate tissue perfusion and mild dehydration Bladder moderately filled Juno was also intermittently lame on her left hind limb All other physical exam parameters were within normal limits Blood pressure: 144/88 (101) ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Diagnosis NSAID intoxication ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Problem list Vomiting Dehydration ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Diagnosis NSAID intoxication ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Diagnosis NSAID intoxication Toxic dose 125mg/kg Risk for gastrointestinal compromise and acute kidney injury Ibuprofen is not recommended for use in dogs and cats Any dose can lead to vomiting, anorexia, and depression In dogs, - Doses of 50mg/kg can lead to GI ulceration - Doses of 125-150mg/kg and higher can lead to AKI - Doses of 400mg/kg and higher may lead to ataxia, tremors, central nervous system depression, hypotension, coma, seizures - Doses of 600mg/kg and higher can be fatal ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Diagnosis Diagnostic test Bloodwork and urinalysis: baseline, 24h, 48h Treatment Control vomiting and treat/prevent ulceration Maropitant (Cerenia) 1mg/kg IV q24h Misoprostol 3 mcg/kg PO q8h for 3-5 days Pantoprazole 1 mg/kg IV q12h for 10 days Sucralfate 1g q8h for 5 days Prevent further absorption One dose of activated charcoal once vomiting is controlled Correct dehydration and maintain normal fluid intake Fluid therapy 2x maintenance for 48h ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Acute Kidney Injury Juno 24h ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 72h Acute Kidney Injury Juno 1 week Urinalysis: isosthenuria, no proteinuria anymore! BP: normotensive ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 1 month Urinalysis: isosthenuria BP: normotensive History and physical examination Granny, 10-year-old spayed female German Wirehaired History of ingesting 10 x Deracoxib (75 mg tablets) within 1 hour prior to presentation No clinical signs All physical exam parameters were within normal limits ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Problem list Ingestion of 10 x Deracoxib (75 mg tablets) within 1 hour prior to presentation ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Problem list Ingestion of 10 x Deracoxib (75 mg tablets) within 1 hour prior to presentation Toxic dose 34 mg/kg, which can cause GI upset (> 15 mg/kg) or renal damage (> 30 mg/kg) ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury Diagnosis and Treatment Diagnosis Bloodwork and urinalysis Baseline, 24h, 48h Treatment Apomorphine (0.02 mg/kg intravenous [IV], repeated with 0.03 mg/kg IV) was given to induce vomiting She vomited 5-6 times and about 3 tablets and plastic pieces were found Prevent further absorption Two doses of activated charcoal once vomiting is controlled Control vomiting and treat/prevent ulceration Maropitant (Cerenia) 1mg/kg IV q24h Pantoprazole 1 mg/kg IV q12h for 10 days Sucralfate 1g q8h for 5 days Encourage renal excretion of the drug and maintain normal fluid intake Fluid therapy 2x maintenance for 48h Elimination half-life of deracoxib is approximately 8 hours, drug elimination time = 5 - 10 x elimination half-lives. In Granny's case, this will be 40 hours (1.6 days) or longer ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury History and physical examination ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury History and physical examination ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 Acute Kidney Injury THANK YOU VETERINARY.ROSSU.EDU ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE – Juliette B. , VMS 5687 ©2021 Ross University School of Veterinary Medicine. All rights reserved.