History

A 4-year-old 32.0-kg (70.4-lb) sexually intact male German Wirehaired Pointing Griffon was evaluated on emergency referral to the Louisiana State University Veterinary Teaching Hospital because of complications related to cottonmouth envenomation of the muzzle 4 days prior. Initially, the dog was treated with 5 mL of dexamethasone and 5 mL of penicillin (day 0) by the referring veterinarian; it was then sent home, and treatment with amoxicillin (500 mg, PO, q 12 h) was initiated. Two days after that initial visit (day 2), the dog developed considerable swelling, signs of pain, anorexia, and vomiting. On reexamination, treatment with carprofen (50 mg, PO, q 12 h) for 3 days was started. On day 5, the dog was again evaluated by the referring veterinarian because of anorexia, vomiting, icterus, and marked subcutaneous edema. The owners reported they had not seen the dog urinate for at least 24 hours. Results of initial clinicopathologic analyses revealed marked neutrophilia, severe azotemia, hyponatremia, hyperkalemia, and hypochloremia. The dog was administered 2 L of fluids IV and referred to the veterinary teaching hospital.

Clinical and Clinicopathologic Findings

At the referral evaluation (day 5), the dog was quiet, alert, and responsive. Rectal temperature revealed hypothermia (37°C [98.6ºF]); heart rate and respiratory rate were within reference limits. The dog's mucous membranes, skin, and sclera were icteric, and it was estimated to be 10% dehydrated. The muzzle was extremely swollen and erythematous with 1 puncture wound immediately adjacent to the left naris. Multiple oral ulcerations were present, as was severe pitting edema of all 4 limbs, the prepuce, and the ventral aspect of the neck and thorax. The skin overlying the thorax and prepuce was darkly erythematous with evidence of sloughing.

A CBC yielded an inflammatory leukogram and evidence of regenerative anemia and mild thrombocytopenia. Serum biochemical analysis revealed severe azotemia, muscle damage, hyperbilirubinemia, hypoalbuminemia, and high liver enzyme activities. Serum electrolyte concentrations were also deranged with hyperkalemia and hyponatremia. Pertinent laboratory findings for the first week that the dog was in the veterinary teaching hospital (days 5 through 13) are summarized (Table 1). An ultrasound-guided renal biopsy was performed on day 9 and submitted to the International Veterinary Renal Pathology Service.

Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page→

Histopathologic Findings

Three needle-core biopsy specimens were evaluated histologically. Two core specimens were composed entirely of medulla, and the third was composed of medulla and corticomedullary junction. The lumens of collecting ducts were mildly dilated and contained granular to globular casts that stained red with H&E stain and bright red with Masson's trichrome stain. In some tubules, sloughed necrotic epithelial cells were present. Periodic acid–Schiff staining verified that there was loss of the apical brush border in many tubules but that tubular atrophy was not present. The interstitium was mildly expanded by edema and scattered aggregates of neutrophils and macrophages. There was a small focus of interstitial fibrosis surrounding a ruptured tubule. Otherwise, interstitial fibrosis was not a feature. There were 3 glomeruli available for evaluation, all of which appeared within normal limits (Figure 1).

Photomicrographs of renal biopsy tissue sections from a dog with pigmentary nephropathy secondary to snake bite envenomation. Hematoxylin and eosin staining and Masson trichrome staining of serial sections (A and B, respectively) reveal red globular material consistent with hemoglobin and myoglobin pigments in collecting ducts. In panel C, sloughed cellular debris (arrow) is visible. In panel D, periodic acid–Schiff staining of the corticomedullary junction reveals a normal glomerulus, vacuolar degeneration and necrosis of proximal tubules (arrowheads), and absence of tubular atrophy. In each panel, bar = 20 µm.

Citation: Journal of the American Veterinary Medical Association 249, 8; 10.2460/javma.249.8.901

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Photomicrographs of renal biopsy tissue sections from a dog with pigmentary nephropathy secondary to snake bite envenomation. Hematoxylin and eosin staining and Masson trichrome staining of serial sections (A and B, respectively) reveal red globular material consistent with hemoglobin and myoglobin pigments in collecting ducts. In panel C, sloughed cellular debris (arrow) is visible. In panel D, periodic acid–Schiff staining of the corticomedullary junction reveals a normal glomerulus, vacuolar degeneration and necrosis of proximal tubules (arrowheads), and absence of tubular atrophy. In each panel, bar = 20 µm.

Citation: Journal of the American Veterinary Medical Association 249, 8; 10.2460/javma.249.8.901

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Photomicrographs of renal biopsy tissue sections from a dog with pigmentary nephropathy secondary to snake bite envenomation. Hematoxylin and eosin staining and Masson trichrome staining of serial sections (A and B, respectively) reveal red globular material consistent with hemoglobin and myoglobin pigments in collecting ducts. In panel C, sloughed cellular debris (arrow) is visible. In panel D, periodic acid–Schiff staining of the corticomedullary junction reveals a normal glomerulus, vacuolar degeneration and necrosis of proximal tubules (arrowheads), and absence of tubular atrophy. In each panel, bar = 20 µm.

Citation: Journal of the American Veterinary Medical Association 249, 8; 10.2460/javma.249.8.901

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Interpretation and Case Summary

Diagnostic interpretation: acute tubular necrosis with intratubular red granular casts consistent with either hemoglobin or myoglobin.

Case summary: pigmentary nephropathy secondary to Crotalid (Agkistrodon piscivorus) envenomation.

Comments

The cottonmouth or water moccasin is a Crotalid snake with hematoxic and proteolytic venom. Reported hematologic changes associated with Crotalid envenomation include echinocytosis, thrombocytopenia, hemolysis, and coagulopathies.¹ Hemolysis is preceded by erythrocyte swelling with an increase in Hct² and may be delayed for up to 1 to 3 weeks after the snake bite.³ The overall mortality rate for snake envenomation in dogs has been reported as high as 19%.¹ Death as a result of nephropathy secondary to snake envenomation has not been reported in the veterinary medical literature, to our knowledge.

Hemolysis causes bilirubinemia leading to bilirubinuria. In dogs, pigmentary nephropathy is rarely reported and is very uncommon secondary to snake envenomation. In 1 study,¹ acute renal failure was reported in 1 of 31 (3%) dogs after envenomation by Eastern Diamondback Rattlesnakes. There is a single report⁴ of pigmentary nephropathy in a dog secondary to envenomation by a myotoxic-hemolytic-neurotoxic snake, the red-bellied black snake (Pseudechis porphyriacus). Although the frequency of pigmentary nephropathy in dogs appears low, it is likely underreported. If the dog dies with other systemic complications, the renal lesions can be subtle and easily overlooked if the tissue is mildly autolyzed. The ability to detect the lesion and determine prognosis in the case described in the present report was based on the excellent quality of the biopsy samples.

In the United States, there are only 2 snake species—the rattlesnake and the moccasin—that are hemotoxic, causing pigmenturia in bite victims. There are no myotoxic snakes in the United States; however, the proteolytic nature of some venoms can also induce muscle degeneration and increase the pigment load. It is impossible to distinguish hemoglobin from myoglobin casts in histologic samples. In human nephropathology, immunohistochemical analysis is used for definitive identification of the pigment. Given the evidence of severe hemolysis and the high serum creatine kinase activity in the dog of the present report, it is likely that both pigments were involved in the tubular injury.

Although acute renal failure with pigmentary nephropathy is uncommonly reported in the veterinary medical literature, there is a potential for development of this condition with any type of snake envenomation. In 31 dogs with snake bites, anemia attributable to intravascular hemolysis developed in 7 (23%) with another 7 (23%) having unclassified anemia, some of which were severely affected.¹ Dogs may not develop secondary pigmentary nephropathy if promptly treated with antivenin. It is important to be aware that acute renal failure can have a delayed onset and that dogs with snake bites should be monitored and treated immediately if clinical signs do develop.

In the human medical literature, a mortality rate of 1% to 20% is reported with snake-bite nephropathy. With intensive care, usually some form of dialysis initially, recovery of humans with snake-bite nephropathy occurs within 2 to 3 weeks, but this period could be longer with more extensive tubular damage.⁵

The dog of the present report had profound oliguria (urinary output, < 0.1 mL/kg/h [0.05 mL/lb/h]) for 6 days. The dog's severe electrolyte disturbances, acid base status, azotemia, and fluid imbalance were initially corrected with continuous renal replacement therapy over 3 days. Given the lack of interstitial fibrosis and tubular atrophy in the renal biopsy specimens, the dog's prognosis for recovery of renal function was good. The dog received a combination of continuous renal replacement therapy and intermittent hemodialysis over a period of 11 days. The dog's renal function rapidly improved by day 10, with a peak urinary output of approximately 9 mL/kg/h (4.1 mL/lb/h) on day 15. The dog required several weeks of intensive care to manage other medical issues including anorexia-cachexia and hypercoagulability with thrombosis of the right jugular vein and a vessel in the tongue (leading to lingual infarction). Four months later, the dog was fully recovered with resolution of all hematologic abnormalities and return to normal renal function.

Acute kidney injury can have a guarded-to-grave prognosis; however, histologic examination of renal biopsy specimens is helpful in assessing the damage to the kidneys and determining prognosis. In the case described in the present report, pigmentary nephropathy was confirmed on the basis of the results of histologic examination of renal biopsy specimens and had characteristics identical to the lesion observed in affected humans. The histologic findings indicated that the acute kidney injury was reversible and scarring had not yet developed, thereby helping to guide the therapeutic plan for this dog. Dogs with this type of acute kidney injury can make a full recovery with appropriate supportive care.