Acute Kidney Injury and Kidney Function

• Acute Kidney Injury (AKI) refers to abrupt damage to the renal parenchyma It results in reduced kidney function It is reflected in altered glomerular filtration, urine production, and tubular function It was previously known as 'acute renal failure'

Kidney Function

• Kidneys play an important role in total body homeostasis via multiple functions
• These functions include:
• Excretion of metabolic waste products and foreign chemicals
• Regulation of water and electrolyte balance
• Regulation of body fluid osmolality and electrolyte concentrations
• Regulation of arterial pressure
• Regulation of acid-base balance
• Secretion, metabolism, and excretion of hormones and gluconeogenesis

Laboratory Parameters

• Laboratory parameters are measured to assess kidney function
• Serum urea and serum creatinine levels are tested
• They are predominantly dependent on the glomerular filtration rate (GFR)
• They provide an estimation of GFR (flow of plasma from the glomerulus into Bowman’s space over a specific period)
• Urine specific gravity (USG) is also tested
• It provides an estimation of urine osmolality
• It is an index of tubular reabsorption and the kidney's ability to concentrate (remove water in excess of solute) or dilute (remove solute in excess of water) urine

Consequences of AKI

• AKI results in the failure of the kidneys to meet the excretory, metabolic, and endocrine demands of the body
• Potential consequences:
• Retention of uremic wastes which may lead to azotemia
• Deranged fluid status
• Electrolyte imbalances
• Acid-base disorders

Causes of AKI

• Acute kidney injury has three categories
• Pre-renal (hemodynamic)
• Intrinsic renal
• Post-renal
• Intrarenal azotemic renal failure is linked to disease processes that damage ≥ ¾ of the parenchyma of both kidneys
• Prerenal and postrenal diseases can coincide with intrinsic renal injury

Pathophysiology

• Pre-renal AKI involves insufficient delivery of blood to the kidneys
• Dehydration, hypovolemia, hypotension, decreased effective circulating volume, trauma, shock, and certain drugs, like NSAIDs and ACE inhibitors, can be examples
• Intrinsic renal AKI involves damage to any section of the kidney
• The glomeruli, tubules, interstitium, or vessels can be affected
• Can be caused by ischemia, toxins, infection, immune-mediated issues, or neoplasia
• Post-renal AKI involves urine leakage within tissue or urinary obstruction
• Causes include trauma, calculi, mucous plugs, tumors, and urethral/ureteral structures
• Reversible if compromised renal perfusion is corrected before ischemic nephron damage

Azotemia

• Azotemia can have a few different causes that must be categorized
• These include prerenal, intrinsic, and postrenal causes
• Prerenal azotemia is a functional abnormality and potentially reversible
• Prognosis increases with early treatment
• Prolonged prerenal azotemia can cause structural damage → intrinsic, irreversible renal failure
• Prerenal azotemia has the following signs
• Elevated serum BUN or creatinine concentrations
• Oliguria
• High urine specific gravity (≥1.030 in dogs; ≥1.040 in cats)
• Detection of underlying cause
• A rapid correction of azotemia after the administration of appropriate therapy to restore renal perfusion
• Intrinsic Azotemia has the following signs
• 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 that does not resolve after appropriate therapy
• Elevated serum BUN and creatinine concentrations show obstruction of the excretory pathway
• Oliguria or anuria, dysuria, and tenesmus may be present
• Obstructive lesions may be detected by physical examination (e.g., urethral plug, herniated bladder), radiography, ultrasonography, etc.
• Variable urine specific gravity values are usually present
• Rupture of the excretory pathway shows progressively elevated serum BUN or creatinine concentrations
• There would also be progressive depression, a painful abdomen, and ascites
• Will also show a history of trauma and associated physical examination findings
• Inability to palpate the urinary bladder means there is a rupture of the excretory pathway
• Detection of a modified transudate or exudate by abdominocentesis
• Abnormalities are detected by ultrasonography or retrograde contrast (positive or negative) cystography or urethrocystography.
• Prognosis associated with obstructive lesions
• Death occurs with total obstruction for 3-6 days
• Favorable prognosis results from rapid removal of the obstruction
• Long-term prognosis depends on the reversibility of the underlying cause
• Excretory pathway rupture may cause:
• Persistent leakage → progressive azotemia → death
• Rapidly repaired leakage or heals → favorable prognosis
• Long-term prognosis depends on the reversibility of the underlying cause

Phases of AKI

• AKI has four phases:
• Phase 1 - Initiation indicates renal insult and damage initiation
• Phase 2 - Extension phase involves localized ischemia, inflammation, and cellular injury. It leads to cell apoptosis or necrosis, which causes further damage
• Phase 3 - Maintenance phase involves more AKI in the kidney
• Phase 4 - Recovery phase occurs as renal tubules repair and heal if the basement membrane of the nephron is intact
• Renal insults are ischemic, nephrotoxic, and obstructive
• Direct damage to renal tubular cells and ischemia can also occur
• The following process happens during Renal Insult - Direct damage to renal tubular cells and ischemia
• Hypoxia → depletion in ATP → increased cellular calcium concentration → activates proteases and phospholipases → ROS and free radicals → cellular damage → inflammatory reaction
• The loop of Henle (proximal convoluted tubule and the thick ascending loop) are particularly vulnerable to ischemia

Diagnosis of AKI

• Prompt recognition is important!
• Diagnosis involves:
• History (time course, possible underlying causes, medication history, and exposure to toxins)
• Physical examination (lethargy, depression, oral ulceration and a ‘uremic breath’, secondary gastrointestinal ulceration and bleeding via melena, kidney size and shape, symmetry, pain, urinary bladder size)
• Bloodwork (normal to increased BUN & creatinine and electrolyte disturbances)
• Urinalysis
  • Isosthenuria
  • Proteinuria, glucosuria, hematuria, pyuria, bacteriuria, crystalluria, or casts
  • Must perform a culture and sensitivity tests on all patients with unknown cause of AKI prior to treatment with antibiotics
• Doppler blood pressure measurement & fundic examination, because hypertension is common
• Imaging tests like radiography (kidney size and shape, identification of radiopaque stones within the urinary tract) and abdominal ultrasound (obstruction or non-radiopaque calculi/neoplasia and pyelonephritis
• Rarely a Biopsy/FNA

Visible Lesions

• Tongue - ulcerative stomatitis, uremia occur
• Stomach -hemorrhagic gastritis - uremia is seen
• Auricular mineralization and hemorrhages occur secondary to uremia

Treatment and Monitoring

• Treatment includes the following
• Intravenous fluid therapy (cornerstone of therapy)
• Caution - Volume can cause overload. Must closely monitor hydration levels.
• Correct dehydration, electrolyte disturbances, and acid-base disturbances
• Severe derangements, like hyperkalemia, may need more directed treatments
• Closely monitor urine production to resolve Oliguria-anuria
• Use Diuretics (furosemide, mannitol)
• Use Dopaminergic agonists (fenoldopam)
• High blood pressure
• Use the calcium channel blocker Amlodipine (dihydropyridine)
• Gastrointestinal sequelae
• Uremic toxins and hypergastrinemia require antiemetics (maropitant, ondansetron, metoclopramide) and inhibitors of gastric acid production (famotidine, ranitidine, omeprazole, pantoprazole)
• Nutritional support
• Renal replacement therapies (dialysis)

Prognosis

• AKI has a guarded prognosis
• Mortality is high, between 47-64%

Nephrotoxic Agents

• Some of the agents which are nephrotoxic are:
• Metals
  • Mercury, Arsenic, Copper, Cadmium, Lead, Fluorine, Zinc
• Mycotoxins
  • Ochratoxin and Citrinin
• Plants
  • Oxalate, Halogeton, Rhubarb, Sorrel, Oak, Amaranthus, Bracken fern, Easter lily, Red maple, White snake root, Vitamin D, Cestrum diurnum, Solanum, Trisetum, and Sorghum
• Antifungals -Amphotrecin B
• Antibacterials -Neomycin, Gentamicin, Tetracycline, Sulfonamide, and Furazolidone
• NSAIDs/analgesics - Phenyl butazone, Flunixin meglumine, and Multiple NSAIDs
• Antineoplastics -Cisplastin and Cyclophosphamide
• Rodenticides Diquat, Zinc phosphide, and Cholecalciferol
• Ethylene glycol, Pine oil, Vitamin K3, Cyclosporine, Blister beetle, Raisin, and Snake venom
• Aminoglycosides (antibiotics) accumulate in the proximal tubular epithelial cells
• This causes cellular damage, altered mitochondrial function, and inhibition of protein synthesis
• Gentamicin toxicity has been reported in dogs - tubular epithelial necrosis with regeneration and mineralization
• Neomycin toxicosis has been reported in calves – renal tubular epithelial degeneration and necrosis
• NSAIDs cause renal toxicity through inhibiting prostaglandin synthesis and renal blood flow, causing renal papillary necrosis

Vitamin D3

• Vitamin D3 toxicity in veterinary medicine is caused by vitamin supplement overdosage or rodenticide ingestion
• Histological findings: Mineralization in multiple organs including the kidneys, lungs, myocardium, stomach and vessels.
• In kidneys, mineralization of arteries and mineral deposition are observed in the tubular basement membranes.

Ethylene Glycol

• Ethylene glycol intoxication occurs through consuming antifreeze
• Urine analysis shows proteinuria, glucosuria, hematuria, calcium oxalate and hippurate crystalluria, renal epithelial cells, white blood cells and granular and cellular casts in the urine sediment
• Grossly the kidneys are firm, with pale streaks at the corticomedullary junction
• Degeneration and necrosis and of the renal tubular epithelium with birefringent crystals is likely to occur

Clinical Case: Juno The Labrador

• A 6-year-old labrador retriever named Juno ingested approximately 10 x 400mg Advil Extra Strength capsules
• During the course of the day while the owner was not at home
• About 12 hours prior to presentation (no blood) Juno vomited 6 times
• Juno had a history of TPLO surgery one month ago and the veterinarian was up to date on vaccines/preventative care
• Physical examination showed all normal values, except the following
• HR 140 bpm
• Mildly tacky mucous membranes
• Intermittent lameness
• Normal dose of Ibuprofen/Advil is not recommended in dogs and cats
• Toxic dose of ibuprofin is 125 mg/kg and risk for gastrointestinal compromise and acute kidney injury
• In this case, with Juno's weight and other signs, the diagnosis was NSAID intoxication
• The primary cause of which is ibuprofen and naproxen toxicosis
• The mechanism being that NSAIDs inhibit the COX enzymes
• COX enzymes are important for the production of various PGs (prostaglandins)
• Loss of the vasodilative actions of PGE2 and PGI2 in the kidneys through inhibition of COX1 leads to hypoxic renal injury
• During examination, it was noted that Juno showed GI signs and some level of gastrointestinal ulceration
• Bloodwork and urinalysis occurred at baseline, 24h, and 48h
• To control vomiting, the veterinary staff treated and prevented ulceration
• Maropitant (Cerenia) 1mg/kg IV q24h was administered
• Misoprostol 3 mcg/kg PO q8h for 3-5 days was given
• Pantoprazole 1 mg/kg IV q12h for 10 days was administered
• Sucralfate 1g q8h for 5 days was prescribed
• The veterinarian administered one dose of activated charcoal once vomiting
• Fluid therapy 2x maintenance for 48hh was given to ensure the patient was well hydrated
• After one week, urinalysis showed isosthenuria, with no proteinuria
• Blood pressure was deemed normotensive