History

A 14-year-old 200-kg Dartmoor pony gelding was presented to the North Carolina State University (NCSU) Veterinary Hospital because of a 2-day history of being down with acute colic. No other ponies on the premise were reportedly ill. A red maple leaf tree (Acer rubrum) had fallen into the pasture 3 days prior to clinical signs with several bite marks noted on the bark.

Clinical and Gross Findings

On the initial physical examination, the referring veterinarian reported markedly icteric mucous membranes with an elevated rectal temperature of 39.6 °C (reference interval [RI], 37.2 °C to 38.6 °C) performed on October 14, 2020. The serum biochemistry profile following the initial 48 hours of veterinary attention is summarized (Table 1). A CBC and serum biochemistry profile showed a PCV of 36% (RI, 30% to 50%) with the presence of Heinz bodies noted, marked hyperlactatemia > 12 mmol/L (RI, < 2 mmol/L), and hyperbilirubinemia (no value reported). No urine was produced for collection at this time. The primary veterinarian did not instigate treatment prior to referral.

The patient continued to decline overnight and was referred to NCSU Veterinary Hospital on October 15, 2020, for further workup. On presentation, the gelding had a rectal temperature of 38.4 °C, respiratory rate of 16 rbpm (RI, 8 to 16 breaths/min), and pulse of 80 (RI, 24 to 48 beats/min) combined with icteric sclera and muddy brown, tacky mucous membranes. Gastrointestinal borborygmi were auscultated in all four quadrants but notably decreased. Dark red-brown urine was collected, and urine specific gravity was 1.035 (RI, 1.020 to 1.050) with the presence of white blood cells (0 to 5 cells/LPF) and fine granular casts (5 to 10 casts/LPF) on urinalysis. Additionally, the PCV had further decreased (29.8%), with marked hemolysis, and occasional eccentrocytes on the blood smear. A serum biochemistry panel was performed and revealed increasing hyperlactatemia (> 15 mmol/L), mildly increased creatinine (2.6 mg/dL [RI, 0.2 to 2.2mg/dL]), hyperbilirubinemia (7.3 mg/dL [RI, 0.5 to 2.3]), hyperglycemia (191 mg/dL [RI, 65 to 110 mg/dL]), elevated AST (670 IU/L [RI, 202 to 338 IU/L]), and elevated CK (1,191 IU/L [RI, 120 to 470 IU/L]). The patient was placed on intravenous fluids containing supplemental electrolytes (ascorbic acid) and flunixin meglumine (1.1 mg/kg, IV).

On October 16, 2020, the PCV further decreased to 20% (moderate anemia) but did not decrease further. In contrast, the lactate drastically improved to 3.3 mmol/L. Simultaneously, the initial clinical signs were getting less severe. The pony started eating hay and passing appropriately formed feces was observed. However, during the night, the horse began to decline once more, developed pipe stream diarrhea, and became increasingly dull. The lactate increased to 12 mmol/L and the patient was anuric. Multiple doses of furosemide (1 mg/kg, IV) were administered with no urine produced. Blood gas analysis revealed a marked hyperkalemia (7.7 mmol/L [RI, 2.5 to 5.2 mmol/L]), elevated lactate (> 15 mmol/L), and marked hypoglycemia (17 mg/dL), elevated AST (541 IU/L) and CK (1,779 IU/L). Serum biochemistry values, anuria despite furosemide administration, and hyperkalemia suggested anuric renal failure. A urinary catheter was placed under sedation. Only a small amount of dark red urine was obtained. Following sedation, the horse went down and remained in lateral recumbency. Fluids with dextrose and calcium were administered to lower the potassium and protect the heart from severe electrolyte derangement, but the patient began to have seizures and died naturally.

Postmortem examination revealed a diffuse brown discoloration in all the internal organs and splenomegaly (Figure 1). The kidneys were swollen with diffuse hemoglobinuric nephrosis, with a red to brown discoloration of the renal cortex and medulla. The cortex has multifocal dark red radial streaks that extend into the capsular surface. The medulla is diffusely red, with irregular dark red patchy areas and yellow discoloration of renal pelvis adipose tissue.

View Full Size

Necropsy images of the thoracic and abdominal organs (A) and cut sections of the kidneys (B) of a 14-year-old 200-kg Dartmoor pony gelding evaluated for a 2-day history of being down with acute colic. A—Diffuse brown discoloration was evident in all the internal organs. B—The kidneys were swollen with diffuse red-to-brown discoloration. The renal cortices had multifocal dark red radial streaks; the medullae are diffusely red, with irregular dark red patchy areas; and the adipose tissue in each renal pelvis has yellow discoloration. C = Colon. J = Jejunum. L = Lung. Li = Liver. K = Kidney.

Citation: Journal of the American Veterinary Medical Association 261, 8; 10.2460/javma.23.02.0122

• Download Figure
• Download figure as PowerPoint slide

Histopathologic findings

Microscopically the lumen of renal tubules in the cortex and medulla had a brightly eosinophilic to red, hyaline to granular material (hemoglobin and hyaline casts) occasionally mixed with sloughed epithelial cells and necrotic cellular debris (granular cast; Figure 2). Tubules often exhibited one or more of the following changes: mild ectasia with attenuated epithelium; epithelial cell swelling with cytoplasmic vacuolization (degeneration); karyorrhectic and pyknotic nuclei with hypereosinophilic cytoplasm (necrosis); fragmentation of tubular basement membranes (tubulorrhexis); intratubular mineralization; tubular epithelial cells with intracytoplasmic, globular, hypereosinophilic material (protein). Okajima stain highlighted tubular casts orange confirming the presence of hemoglobin. The hepatic parenchyma had portal tracts with mildly expanded mature fibrosis and often infiltrated by scattered lymphocytes. The centrilobular to midzonal hepatocytes had an expanded swollen cytoplasm, containing microvesicular lipid vacuoles.

View Full Size

Photomicrographs of renal tissue sections from the gelding described in Figure 1. A—The renal tubules within the cortex and medulla contain brightly eosinophilic to red, hyaline to granular material (hemoglobin and hyaline casts), occasionally mixed with sloughed epithelial cells and necrotic cellular debris (granular cast). H&E stain; bar = 100 µm. B—Tubules often exhibit mild ectasia with attenuated epithelium, sloughed epithelial cells with karyorrhectic and pyknotic nuclei, hypereosinophilic cytoplasm (necrosis), and fragmentation of tubular basement membranes (tubulorrhexis; arrowhead). H&E stain; bar = 25 µm. C—Scattered renal tubules have intraluminal mineralization (arrowheads). H&E stain; bar = 100 µm. D—Highlighted orange to orange-red tubular casts confirm the presence of hemoglobin. Okajima stain; bar = 50 µm.

Citation: Journal of the American Veterinary Medical Association 261, 8; 10.2460/javma.23.02.0122

• Download Figure
• Download figure as PowerPoint slide

Morphologic Diagnosis and Case Summary

Morphologic diagnoses: 1) severe diffuse subacute tubular degeneration and necrosis with hemoglobin, hyaline, and granular casts; 2) mild diffuse chronic portal fibrosis and mild multifocal centrilobular microvesicular lipidic hepatocellular vacuolization.

Case summary: Acer rubrum (Red Maple) toxicity in a Dartmoor pony.

Comments

Red maple leaf toxicity is primarily seen in equine species but has been also reported in ducks, zebras, donkeys, and alpacas.^1,2 Affected animals will develop acute, severe hemolysis with hemoglobinemia and/or methemoglobinemia within 18 to 48 hours post-consumption of the fallen leaves, as seen in this particular case.^1–3 Toxicity is typically seen in the fall or early spring when the melting snow uncovers previously fallen leaves.^1–3 There is a correlation between the amount of leaf decay and the toxic potency of the leaves to horses.² Typically, the disease only develops with the consumption of partially decayed to completely dead leaves, which may remain toxic for weeks.² It is estimated that consumption of 0.5% to 0.8% of body weight or 1.5 to 3.0 g/kg of body weight of partially decayed dry leaves is enough to cause intoxication with a fatality rate greater than 60%.^1,2

The exact toxin in red maple leaves is not definitively identified, although it is hypothesized to be a nitrogenous compound, gallic acid, or polyphenicol.^1,2 It is believed that the dead leaves generate potent oxidants which overcome the glutathione-reducing system in red blood cells resulting in the formation of Heinz bodies.^2,3 Heinz bodies weaken the integrity of the red blood cell membrane allowing for osmotic lysis and the release of hemoglobin (hemoglobinemia). Hemoglobinuria develops once the renal reabsorption threshold for hemoglobin is surpassed.⁴ The proximal tubule and the medulla of the kidney are highly metabolic and thus exquisitely sensitive to decreased oxygenation.⁴ In addition to anemia, oxygen delivery is further exacerbated by the oxidation of free hemoglobin to form methemoglobin.³ Reduced oxygen-carrying capacity deprives the horse of oxygen and results in shock and renal nephrosis. Pooled hemoglobin casts within the tubules may block the tubules and lead to partial or complete obstruction.⁴ A cycle is created as obstruction creates further tubular necrosis and degeneration which leads to decreased resorption and increased pooling of hemoglobin.³

Clinical signs associated with red maple toxicity include depression, lethargy, anorexia, colic, dark brown or red urine (hemoglobinuria or methemoglobinuria), muddy brown or cyanotic membranes, anemia, icterus, and Heinz bodies on cytology.^1–3 The disease most commonly manifests as a hemolytic crisis with hemoglobinuria or methemoglobinuria, but both can occur leading to a poorer prognosis.^1–3 The disease progresses quickly, and the onset of clinical signs may occur within 18 hours of ingestion.¹ If the disease progresses past 48 hours, laminitis may occur due to systemic hypoxia.^1–3

Gross lesions associated with red maple toxicity include renal edema and pigment nephrosis, brown discoloration of other tissues and blood, splenomegaly, icterus, and serosal petechiation.^1–4 Microscopically, red maple toxicity is most often characterized by tubular dilation and necrosis with hemoglobin casts.^3–5 Staining with Okajima stain will differentiate hemoglobin from methemoglobin. The liver and spleen will often exhibit centrilobular hepatocellular necrosis (due to hypoxia) and erythrophagocytosis (due to hemolysis), respectively.¹

Differential diagnoses should include leptospirosis, babesiosis, exertional rhabdomyolysis, end-stage liver disease, equine infectious anemia, and nitrate toxicity.^3,4 Diagnosis relies on clinical testing for hemolysis and methemoglobinemia, a good clinical history, and ruling out the other etiologies with laboratory testing.^1–4

Treatment of red maple toxicity is rarely rewarding due to the rapid clinical course and the unidentified toxin. Therapies are aimed at palliative care and addressing sequelae to severe hemolysis. Blood transfusions and colloidal fluids are the hallmark of treatment but may lose efficacy in the face of devastating oxidative hemolysis.^1–3 Fluid therapy, activated charcoal (if timely), mineral oil to inhibit further absorption of the toxin, and as a gastroprotectant, non-steroidal, and corticosteroids have all been described with varying outcomes.^1–3 While administration of methylene blue is considered non-efficacious in horses and may even worsen the condition, ascorbic acid (vitamin C) has recently shown promise in reducing methemoglobin.^1–3