Renal Failure: Acute and Chronic

• The urinary system is vulnerable to toxic injury because of high blood flow, high metabolic demand, concentration of toxicants and metabolic activation of xenobiotics.
• The proximal tubule is the most sensitive part of the nephron to toxic injury.
• Serum renal function markers BUN (blood urea nitrogen) and creatinine are used to clinically measure kidney function.
• There can be significant nephron damage (50-70%) before BUN and creatinine levels become significantly elevated because of the kidney's reserve capacity.
• Mild renal toxicity can be completely reversible.
• Acute Renal Failure (ARF) can be reversible with treatment.
• Chronic Renal Failure (CRF) is frequently irreversible, progressing to end-stage renal disease (ESRD) involving permanent loss of renal function.

Acute Renal Failure (ARF)

• Decreased Glomerular Filtration Rate (GFR)
• Increased BUN (BUN)
• Increased creatinine (creatinine)
• Glucosuria
• Azotemia occurs
• Aminoaciduria occurs
• Oliguria or anuria occurs
• Renal enlargement and pain occurs
• Systemic signs: increased thirst, nausea/vomiting, lethargy, anorexia, and weakness
• Systemic sequelae: dehydration and metabolic acidosis

Chronic Renal Failure (CRF)

• Results from long-term exposure to toxicants
• Progressive deterioration of renal function
• Exhaustion of reserve capacity
• Polyuria/polydipsia occurs
• Isosthenuria occurs
• Increased BUN occurs
• Increased creatinine occurs
• Uremia occurs
• Dehydration occurs

Ethylene Glycol

• It is a colorless, odorless, sweet-tasting liquid found in antifreeze solutions (95% EG), windshield de-icing agents, brake and transmission fluids, polishes, photographic solutions, and paint solvents.
• It is highly toxic (mortality rate of 78% in cats and dogs)
• Cats are more sensitive than dogs
• Cats: 1.5 ml/kg (Small Animal Tox), 0.9 ml/kg (Clinical Vet Tox)
• Dogs: 6.6 ml/kg (Small Animal Tox), 4.4 ml/kg (Clinical Vet Tox)
• Toxicity is common due to its abundance in households, lack of public awareness, and potential palatability.
• Rapid absorption from the GI tract and lungs (delayed by food in the stomach)
• Distributes quickly throughout the body with peak plasma concentration in dogs within 1-4 hours
• Metabolized in the liver and kidney by alcohol dehydrogenase (ADH) to toxic metabolites
• Excreted mainly through the kidney with an elimination half-life of approximately 11 hours

Ethylene Glycol Metabolism

• EG is oxidized by alcohol dehydrogenase (ADH) to glycoaldehyde (1st rate-limiting reaction).
• Glycoaldehyde is metabolized to glycolic acid.
• Glycolic acid is converted to glyoxylic acid (2nd rate-limiting reaction), leading to accumulation, acidosis, and nephrotoxicosis.
• Glyoxylic acid is metabolized to oxalic acid, formic acid, glycine, and α-hydroxy-β-ketoadipate.
• Oxalic acid combines with calcium to form calcium oxalate crystals that deposit in renal tubules, brain vasculature, and other tissues.

Ethylene Glycol Mechanism of Toxicity

• GI tract irritation
• CNS depression, inducing metabolic acidosis and electrolyte imbalance
• Cytotoxicity and mechanical damage

Ethylene Glycol Clinical Signs

Stage I (CNS Stage)

• 30 minutes - 12 hours
• Mimics acute alcohol toxicosis with inebriation, ataxia, nausea, vomiting, increased thirst and urination (PD/PU), hypothermia

Stage II (Cardiopulmonary/acidotic stage)

• 12-24 hours
• Severe metabolic acidosis due to glycolic acid accumulation and hypocalcemia which leads to vomiting, changes in heart rate, rapid breathing, muscle twitching, depression, hypothermia.
• Polydipsia may subside.

Stage III (Renal toxicity)

• 24-72 hours
• Characterized by the formation of calcium oxalate crystals in the kidneys and cytotoxicity of EG metabolites to renal tubular epithelium, leading to oliguric renal failure (initially polyuria, then oliguria or anuria), uremia (lethargy, vomiting, oral ulceration, seizures, coma, death), enlarged and painful kidneys, and potential anterior uveitis

Ethylene Glycol Diagnosis

• History of exposure
• Clinical signs
• Clinical pathology (e.g., elevated BUN and creatinine, metabolic acidosis, increased anion and osmolar gaps)
• Ethylene glycol analysis (GC, HPLC)
• Point-of-care ethylene glycol test kits
• Examination with Wood's lamp (urine may fluoresce due to added fluorescein dye)
• Ultrasonography (increased renal cortical echogenicity)