Wilson K. Rumbeiha,     Ames, Iowa

Michael J. Murphy,     Stillwater, Minnesota

Pathophysiologic Considerations

Renal failure is common, but only a small percent of cases of renal insufficiency are caused by chemical toxicants. The kidney constitutes only 1% of body weight in most mammals but receives about 25% of normal cardiac output. This high cardiac output exposes the kidney to many substances foreign to the body, including food additives, drugs, and other foreign chemicals (i.e., xenobiotics). These chemicals often reach relatively high concentrations in the renal ultrafiltrate. Kidneys also possess unique transporters that concentrate toxicants in this organ. In many instances a high concentration of xenobiotics is associated with nephrotoxicity, but other factors may also play a role.

The kidneys also conduct substantial metabolism of endogenous and exogenous chemicals. Bioactivation of some chemicals can lead to nephrotoxicity, although metabolism of most chemicals leads to detoxification.

Animals may be predisposed to nephrotoxicity. Young and geriatric animals generally are believed to be more susceptible to the nephrotoxic effects of xenobiotics. Young animals may not have fully developed detoxifying enzyme systems, and these systems may be diminished in geriatric animals. Malnutrition, dehydration, shock, preexisting renal conditions, and concurrent exposure to multiple nephrotoxins are some of the factors that may influence the potential for nephrotoxicity.

Causes of acute renal failure in dogs and cats generally can be classified as hemodynamic-related, infectious, or toxic. Toxicant-induced acute renal failure is most commonly encountered in small animals. Younger animals are the most frequently involved. In dogs the most common causes of nephrotoxicosis are ethylene glycol (EG), nonsteroidal antiinflammatory drugs (NSAIDs), cholecalciferol (CCF), and aminoglycoside antibiotics. In cats the most common causes of nephrotoxicity are EG, CCF, and Easter lilies. An expanded list of known nephrotoxins is presented in Web Box 5-1. Only the most common causes of nephrotoxicosis are discussed here, with additional comments directed toward the issue of pet food–related toxicosis.

Establishing a Diagnosis of Nephrotoxicosis

The causes of acute renal failure in dogs and cats are so extensive (see Web Box 5-1) that refinement of the etiologic diagnosis usually relies on the history, clinical signs, physical examination, and results of toxicology laboratory testing. The goal in toxicology cases is establishing a cause. Often the facts necessary for such a conclusion are not evident, and morphologic, presumptive, or clinical diagnoses are made.

Two tenets of toxicology are exposure and dose response. Pets must first be exposed to a toxicant for it to cause a toxicosis. Further, they must be exposed to a potentially toxic dose and have the adverse effect previously demonstrated for that toxicant before a clinician can reach a conclusive diagnosis of a toxicosis.

In veterinary patients the history and specific laboratory tests are normally used to determine whether an animal has been exposed to a nephrotoxin. The history is often the less reliable of the two methods. For example, does the owner know if his or her pet was exposed to a potentially toxic dose of a drug (NSAIDs, aminoglycosides) with demonstrated nephrotoxicity? Specifically one might inquire if EG, aminoglycosides, or Lilium spp. of plants are present in or around the home. If so, the next step is to confirm or rule out exposure by specific toxicology laboratory testing when available in order to arrive at an etiologic diagnosis. Tests should identify the parent compound and/or its metabolites. Quick screening tests are often used to make treatment decisions, but analytic laboratory tests may be required to confirm an etiologic diagnosis. The availability of such confirmatory tests may be investigated by contacting an accredited veterinary diagnostic laboratory (see www.aavld.org or www.abvt.org).

Serum or urine is usually the specimen of choice in live animals. For example, although calcium oxalate crystals in urine might be present in toxicoses in a dog or cat with renal failure, this finding is nonspecific; therefore serum and/or urine glycolic acid or EG concentrations would better support a diagnosis of EG exposure. Similarly, serum concentrations of 25-hydroxycholecalciferol are used to indicate exposure to CCF; serum or urine concentrations of NSAIDs and aminoglycosides may be used for the same purpose.

The clinical signs, physical examination findings, and routine laboratory tests may be instructive. Clinical signs of renal toxicosis often include gastrointestinal upset, central nervous system depression, cardiopulmonary involvement, anuria, oliguria, and polydypsia, as observed with EG toxicosis. For example, signs of NSAID toxicosis often may include gastrointestinal bleeding and ulceration, acidosis, and mild elevations of hepatic enzymes. Clinical signs of CCF toxicosis include dark bloody feces, oliguria, or polyuria. Ultrasound may show renal cortical damage. Involvement of other organ systems may provide additional diagnostic leads as to the toxicant involved.

Laboratory testing often is required to establish the adverse effects of toxicity. Obviously increased serum urea nitrogen and creatinine concentrations, along with urinalysis, are used clinically to indicate renal injury. Urine specific gravity, cellular casts, and presence of crystals can aid in the diagnosis of acute nephrotoxicity. Calcium abnormalities are common with EG and with CCF toxicosis. Values within the normal range for all these tests would be interpreted as arguing against a diagnosis of nephrotoxicity. Such findings may not exclude exposure to a subtoxic dose of a nephrotoxic chemical.

When a patient dies or is euthanatized, necropsy and histopathology findings can in some instances support an argument of exposure to a toxicant. For example, the finding of EG solution, CCF rodenticide bait, medications, or lily plant parts supports exposure to the respective toxicants. The observation of birefringent crystals histologically is very suggestive of EG exposure, but even in this case the findings are not specific. For example, such crystals can occur following exposure to soluble oxalates (Oxalis spp. plants). Similarly renal mineralization is compatible with, but not specific for, CCF exposure. Renal mineralization can be present in hypercalcemia of malignancy, for example.

Thus the diagnosis of nephrotoxicity must rely on evidence of exposure to a sufficient quantity of a toxic chemical, clinical or analytic laboratory findings that confirm or strongly suggest toxicosis, and clinical or necropsy findings of compatible illness. These same principles should be applied to the diagnosis of emerging toxicities, such as melamine-cyanuric acid intoxication, associated with pet foods, and the recently recognized Fanconi syndrome in dogs that have consumed dog treats.