Why no pee? Renal Toxicants Tina Wismer, DVM, MS, DABVT, DABT ASPCA Animal Poison Control Center, Urbana, IL

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1 Why no pee? Renal Toxicants Tina Wismer, DVM, MS, DABVT, DABT ASPCA Animal Poison Control Center, Urbana, IL There are many toxicants that can directly and indirectly affect the kidneys (see table 1). The kidney is susceptible to toxicants because of its high relative blood flow (~25% of cardiac output) compared with its low percentage of total body weight. Blood borne toxicants are delivered at the highest rates to cortical tissues, whereas the medullary and papillary regions are exposed to the highest luminal concentration of toxicants and for a longer period of time. Different portions of the kidney vary in their susceptibility to toxicant damage. The proximal tubule is highly involved in active transport of substances and is the most sensitive portion the nephron to both hypoxia and toxicosis. The kidney also has enzymes for detoxification, some ability to regenerate and considerable reserve capacity. The renal response to toxicosis is limited to only four categories: glomerular lesions, nephrosis, mineralization and papillary necrosis. Glomerular lesions are rarely reported with toxicosis (primarily associated with immune disease). Acute tubular necrosis (tubular nephrosis) is the most commonly recognized form of toxicant-induced renal damage. Mineralization or nephrocalcinosis results from excessive amounts of vitamin D or its analogs. Papillary necrosis, or ischemic necrosis, occurs secondary to inhibition of prostaglandin synthesis. Cholecalciferol (Vitamin D) and its analogs Vitamin D and vitamin D analog toxicosis is on the rise. In addition to prescription strength vitamin D capsules (50,000 IU), and psoriasis creams (Dovonex, Taclonex ), there has also been an increase in cholecalciferol containing rodenticides (D-Con, Quintox, Rampage, etc.). These products cause elevations of serum Ca ++ and P, leading to soft tissue mineralization and renal failure. Cholecalciferol is metabolized to 25-hydroxycholecalciferol (calcifediol) and then to 1,25-dihydroxycholecalciferol (calcitriol = active metabolite). Calcitriol increases intestinal absorption of calcium, stimulates bone resorption, and increases renal tubular reabsorption of calcium. Elevations in P can be seen within 12 hours, and Ca ++ elevations within 24 hours. Animals usually begin to exhibit vomiting, depression, polyuria and polydipsia by hours post ingestion. Anorexia, bloody vomiting and diarrhea may also be seen. Renal failure can occur within hours. Problematic doses can be as low as 0.1 mg/kg. Emesis is recommended if pills/creams have been ingested for less than minutes; with bait ingestion, emesis can be induced within 4 hours. Decontamination should continue with one dose of activated charcoal, followed by cholestyramine (300 mg/kg q 8 h for 4 days). Obtain baseline (< 8 hr. post exposure) Ca ++, P, BUN, and creatinine for future comparison. If Ca ++ is rising, start the animal on 0.9% NaCl IV at 2x maintenance. Sodium competes for reabsorption with calcium in renal tubules. If the Ca ++ continues to rise while on fluids, animals should also be started on furosemide and prednisolone (adjust fluids accordingly). Steroids reduce bone resorption, decrease intestinal absorption, and increase renal excretion of calcium. Phosphate binders should also be administered. The animal should be maintained on a low calcium diet (K/D, U/D, S/D, or macaroni and lean ground beef). If these treatments are not effective, calcitonin (inhibits osteoclastic bone resorption and reduces tubular reabsorption of calcium), pamidronate or zoledronate (inhibits osteoclastic bone resorption) can be administered. Monitor blood values frequently for 5-6 weeks. Treatment may be prolonged because of the long half-life of calcifediol (16-30 days). Prognosis decreases with

2 prolonged elevations in Ca ++. Lesions from soft tissue mineralization (renal, cardia, GI) are poorly reversible and may result in long term sequelae or sudden death. Lily Members of the Lilium and Hemerocallis genera (Easter lilies, tiger lilies, day lilies, etc.) have been incriminated in causing acute renal failure in cats. The water soluble toxic principle is unknown. Even minor exposures (bite on a leaf, ingestion of pollen) may result in toxicosis, so all feline exposures to lilies should be considered potentially life-threatening. It should be noted that not all plants with lily in the name are the true lilies of the Liliaceae family. Affected cats often vomit within a few hours after exposure. Within 24 to 72 hours of ingestion, oliguric to anuric renal failure develops, accompanied by vomiting, depression, anorexia, and dehydration. Elevations in BUN, creatinine, P and K + are detectable as early as 12 hours post ingestion. Creatinine elevations may be especially high. Abundant casts, proteinuria, glucosuria, and isosthenuria are usually detectable on urinalysis within 24 hours of ingestion, reflecting lily-induced damage to renal tubular cells. In severe cases, death or euthanasia due to acute renal failure generally occurs within 3 to 6 days of ingestion. When initiated within 18 hours of ingestion, fluid diuresis at 2x maintenance for 48 hours has been effective in preventing lily-induced acute renal failure. Conversely, delaying treatment beyond 18 hours frequently results in death or euthanasia. Baseline renal values should be obtained upon presentation and then repeated at 24 and 48 hours. Because the tubular injury from lily ingestion spares the renal tubular basement membrane, regeneration of damaged tubules may be possible. In severe cases, dialysis may aid in managing renal failure until tubular regeneration occurs (10-14 days or longer). Grapes/raisins There have been numerous well-documented reports of dogs developing polyuric/oliguric/anuric renal failure within 72 hours of ingesting grapes and raisins, usually in large quantities. At this time the mechanism of action and toxic principle are unknown. Grapes and raisins have come from various sources. Analysis of grapes and raisins involved in some of these cases have tested negative for heavy metals, pesticides, and known mycotoxins. Histopathologic examination has shown proximal renal tubular degeneration or necrosis with the basement membrane remaining intact. The distal convoluted tubules are usually less frequently and less severely affected. The lowest documented grape dose leading to renal failure is 0.7 oz/kg and the lowest documented raisin dose leading to renal failure is 0.11 oz/kg, however, there are reports that as little as 1 grape/raisin has caused renal failure. Some dogs are exposed and never develop signs and some only develop mild GI signs and recover. Vomiting usually begins within 6 hours of ingesting the grapes/raisins. BUN and creatinine begin to elevate in hours. Treatment is the same as for lily toxicosis. Dogs developing severe oliguria or anuria generally are poorly responsive to attempts to increase urine production (mixed results with peritoneal and hemodialysis). If renal values are normal at 48 hours, the animal can be weaned off fluids and sent home. Symptomatic care for vomiting, diarrhea, or other signs may be required. Ethylene glycol Ethylene glycol (EG) is present in automotive radiator antifreeze, brake fluids, aircraft deicers, condensers, heat exchangers, home solar units and portable basketball goal post bases.

3 Ethylene glycol may also be used to winterize toilets in RVs and summer homes in colder latitudes. Cats, rabbits and humans are the most sensitive to EG, with dogs, cattle, pigs and rodents having an intermediate sensitivity. Unfortunately, reliable toxic doses of EG have not been established for most animals. Much of the acute toxicity data available is based on lethal doses and do not take into account the fact that many animals may survive the initial stages of toxicosis only to succumb to kidney failure days later. Because of this, any suspected exposure of an animal to EG should be considered a potential toxicosis. When doubt exists, treat as if potentially toxic. It is important to remember that EG is a potent alcohol and many of the signs of toxicosis will relate to severe alcohol intoxication. Because of the different mechanisms involved in EG toxicosis, clinical signs frequently change throughout the course of the toxicosis. It is sometimes easier to break the clinical signs into 3 different stages, although considerable overlap between these stages may be seen and some animals will not experience each stage; death can occur at any stage. The stages are 1) neurologic the initial inebriation due to the effects of alcohol on the CNS, 2) cardiopulmonary due to severe acidosis and electrolyte disturbances, and 3) renal due to renal tubular injury from calcium oxalate crystals. The neurologic stage generally begins within 30 minutes of exposure and lasts up to 12 hours. In some cases, this stage may pass quickly and may not be noted by the pet owner. Animals are initially ataxic, disoriented, stuporous, PU/PD (more pronounced in dogs) and hypothermic (especially cats). They then may appear to recover. By 6-12 hours, the neurologic status may worsen due to severe metabolic acidosis from EG metabolites. The cardiopulmonary stage generally occurs from hours following exposure. Tachypnea, tachycardia, depression, and pulmonary edema may be seen. The renal stage can be seen as early as 12 hours, especially in cats, but is generally seen within hours following exposure. Clinical signs include azotemia, depression, anorexia, vomiting, abdominal pain, oral ulcers, oliguria/anuria and seizures. Urinalysis shows low urine SG, glucosuria, and possibly calcium oxalate crystals (absence of crystalluria does NOT rule out EG toxicosis). BUN and creatinine become elevated but usually not before 12 hours post exposure; therefore BUN and creatinine are of minimal benefit in diagnosing early exposures. Diagnosis is based on history, clinical signs, and confirmatory laboratory testing. In dogs, the ethylene glycol test kit can be an invaluable aid to determine whether an exposure is significant enough to warrant treatment. There are two available patient side ethylene glycol tests: VetSpec (Catachem) and Kacey. The VetSpec test is a colorimetric qualitative test. It will be positive for any cis-1-diol (ethylene glycol, propylene glycol, glycerol, sorbitol, etc.). It has both canine and feline tests. The Kacey strip test will be positive for any alcohol (see above, plus ethanol, methanol, etc.). It has both canine and feline tests on the same strip. It is important to remember that some forms of activated charcoal and most diazepam injectable products contain propylene glycol that may interfere with the interpretation of the test. For this reason blood for testing should be taken prior to administration of propylene glycolcontaining activated charcoal (check the label) or diazepam. Other means of diagnosing EG exposure in pets include having EG levels run at a human hospital. Levels of 50 mg/dl or greater in dogs would be considered significant. In cats, any level above zero should be treated. Measuring anion gap (> 25 meq/l) or serum osmolality (> 20 mosm/kg) may assist in diagnosing EG toxicosis. Observation, via Wood s lamp, of fluorescence in urine, stomach contents or on paws/muzzle may suggest exposure (fluorescein dye is added to automotive antifreeze to help in detecting radiator leaks).

4 Treatment of EG toxicosis must be timely and aggressive. Failure to institute appropriate therapy within the first several hours may result in irreversible renal damage or death of the animal. For recent (within 45 minutes) exposures and asymptomatic animals, induce vomiting or perform gastric lavage. The use of activated charcoal is somewhat controversial, as aliphatic alcohols are not thought to be well adsorbed by charcoal. Based on exposure history and/or diagnostic test results, the use of either fomepizole or ethanol infusion is indicated. Symptomatic animals should be stabilized as needed. IV fluids are extremely important, high infusion rates of crystalloids are necessary to correct dehydration and hypoperfusion. Treat acidosis and renal failure as needed. Oliguric or anuric animals may require peritoneal dialysis. IV ethanol and fomepizole (4-MP, 4-methylpyrazole) are used to delay the breakdown of EG to its more toxic metabolites. Best results with either of these treatments require initiation of treatment as soon as possible following ingestion. Ethanol has the advantages of being inexpensive and readily available, but it has some serious drawbacks, including worsening of metabolic acidosis and CNS depression. Fomepizole will not cause these signs and in contrast to ethanol, which is administered every 4 hours or as a CRI, fomepizole is administered every 12 hours for 36 hours. The main drawback with fomepizole is the cost and the need to have it compounded. Treatment should be continued until animals are clinically normal and have had at least 24 hours with normal renal function and acid base parameters. Alternatively, for dogs, a negative EG test indicates that ethanol/fomepizole treatment may be discontinued (although treatment may need to be continued for any residual renal impairment). The prognosis for recovery depends on degree of exposure, length of time between exposure and treatment, and aggressiveness of treatment. The presence of oliguria/anuria indicates a grave prognosis. NSAIDs Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis by blocking the conversion of arachidonic acid to various prostaglandins. Decreased prostaglandins mean decreased pain but also decreased secretion of the protective mucus layer in the stomach and small intestine and vasoconstriction in gastric mucosa. NASIDs inhibit renal blood flow, glomerular filtration rate, tubular ion transport, renin release and water homeostasis. NSAIDs have a narrow margin of safety. GI ulcers and renal failure can be seen after an acute ingestion. Cats are thought to be twice as sensitive as dogs due to their limited glucuronyl-conjugating capacity. Intravenous fluids and gastroprotectants are the mainstays of therapy. Ibuprofen Ibuprofen (Motrin, Advil, Midol, etc.) is available in 50 to 800 mg tablets and 100 mg/5 ml suspension. In addition to gastric ulcers and AKI, ibuprofen can cause CNS signs, affect platelet aggregation and rarely hepatic function. Ibuprofen has a narrow margin of safety. Even at the therapeutic dog dosage of 5 mg/kg, ibuprofen may cause gastric ulcers and perforations with chronic use. In dogs, an acute exposure of mg/kg can result in GI signs (vomiting, diarrhea, abdominal pain, anorexia), > 175 mg/kg can result in more severe GI signs (hematemesis, melena) plus renal damage (PU/PD, oliguria, uremia), > 400 mg/kg results in GI, renal, and CNS signs (seizure, ataxia, coma). Ferrets that ingest ibuprofen are at high risk for CNS depression and coma, with or without GI upset. The onset of GI upset is generally within the first 2-6 hours after ingestion, with GI hemorrhage and ulceration occurring 12 hours to 4 days post ingestion. Renal failure often occurs within the first hours after exposure.

5 Assisted ventilation and supplemental oxygen may be required if animal is comatose. Seizures should be treated with diazepam. Both naloxone and lipids have been used to reverse the coma seen in ibuprofen toxicosis with mixed results. Prognosis is good if the animal is treated promptly and appropriately. Gastrointestinal ulceration usually responds to therapy. Acute renal insufficiency resulting from ibuprofen administration has been considered reversible, but development of papillary necrosis is generally considered irreversible. Naproxen (Naprosyn, Aleve ) Half-life in the dog is 74 hours, as the drug undergoes extensive enterohepatic recirculation. Ulcerative gastritis is possible in dogs at 5 mg and doses of > 10 mg/kg can cause acute renal failure. Due to the prolonged half-life, fluids need to be continued for at least 72 hours and GI protectants for days. Carprofen Dogs can develop GI ulcers at 20 mg/kg and acute renal failure at 40 mg/kg. Cats develop ulcers at 4 mg/kg and ARF at 8 mg/kg. Deracoxib Dogs can develop GI ulcers at 15 mg/kg and acute renal failure at 30 mg/kg. Grapiprant Grapiprant is a prostaglandin E (PGE) EP4 receptor antagonist; a non-cyclooxygenase inhibiting, non-steroidal, anti-inflammatory drug. The therapeutic index is wider with grapiprant when compared to other NSAIDs, but GI ulcers and AKI can still occur. Dogs can develop GI ulcers at 55 mg/kg and acute renal failure at 125 mg/kg. Miscellaneous Any toxin that causes hemoglobinuria (pit viper venom, onions/garlic, brown recluse spiders, zinc) can cause hemolysis. Free hemoglobin is toxic to the kidney. Hemoglobinuria can induce acute tubular necrosis through the formation of hemoglobin casts. IV fluids should be started to combat hypovolemia and protect the kidneys. Toxins that cause tremors/seizures can lead to myoglobinuria. Myoglobin, a monomer containing a heme molecule similar to hemoglobin, when excreted in the urine can precipitate, causing tubular obstruction and acute kidney injury. References available upon request. Table 1. Nephrotoxicants in Dogs and Cats Pharmaceuticals ACE inhibitors Acyclovir Alkylating antineoplastics Allopurinol Alpha-lipoic acid Aminoglycosides Amphotericin B BAL Calcipotriene and related compounds Calcium EDTA Cephalosporins Cimetidine

6 Cisplatin Cocaine Conjugated estrogens Cyclosporine Furosemide Interleukin-2 Methotrexate NSAIDs Penicillin Phenytoin Radiocontrast agents Rifampin Sulfonamides Tacrolimus Tetracyclines Thiazide diuretics Household/Industrial Boric acid Ethanol Ethylene glycol Oxalic acid Phenol Pine oil Toluene Pesticides Cholecalciferol rodenticides Diquat Paraquat Metals Arsenic Cadmium Mercurial salts Zinc Mycotoxins Citrinin Ochratoxin Plants Cortinarius mushrooms Lilium and Hemerocallis (cats) Grapes/raisins Oxalis Rhubarb Other Pit vipers Any other cause of hemolysis or rhabdomyolysis