Acute Renal Failure

By Dr. Elisabeth Snead VSAC 465, 2010 Objectives 1. The student must be able to list the principle causes of ARF 2. The student should have a basic understanding of the pathogenesis of ARF. 3. The student should understand the appropriate diagnostic tests used to establish the diagnosis of ARF. 4. The student must understand what factors can predispose a patient to development of ARF. 5. The student should be able to formulate a therapeutic plan for a patient with ARF. 6. The student should now how to treat a small animal patient with ARF secondary to ethylene glycol toxicity. Introduction 1. Definition: ARF is a clinical syndrome characterized by the sudden onset (within hours to days) of hemodynamic, filtration, and excretory failure of the kidneys leading to accumulation of metabolic toxins (BUN, creatinine, phosphorous, etc.) and disruption of fluid, electrolyte, and acid-base homeostasis. 2. ARF must be distinguished from other causes of acute uremia, including causes of prerenal azotemia, postrenal azotemia, CRF, or combinations of these. 3. In contrast to CRF, ARF is potentially reversible if diagnosed early and aggressively treated. Delay in implementing therapy, can result in irreversible renal damage or death. Etiology of ARF 1. Ischemia and nephrotoxins are the most common causes of ARF, but the etiology is often multifactorial. Causes can be classified into one of three main categories: prerenal, intrinsic renal parenchymal diseases, and postrenal disorders. See Table 1. 2. The kidneys are susceptible to the effects of ischemia and toxins because of some of their unique anatomic and physiologic features. Some of these are listed in table 2. Pre-existing Risk Factors for ARF 1. Several risk factors that predispose dogs and cats to the development of ARF have been identified. See below for a partial list of risk factors. Risk factors are additive.
Preexisting renal disease or renal insufficiency Dehydration and hypovolemia from any cause Decreased cardiac output Hypercalcemia/hypocalcemia Concurrent use of nephrotoxic drugs with diuretics Use of multiple nephrotoxic drugs in the same patient Prolonged anesthesia with inadequate fluid therapy Trauma Sepsis DIC and vasculitis Fever Diabetes mellitus Advanced age Systemic hypertension Heat stroke Pancreatitis

2. The importance of identifying these risk factors is that it allows a risk-benefit analysis to be carried out for an individual patient in which an elective anesthetic procedure or treatment is being contemplated to minimize the incidence of iatrogenic ARF.

Table 1. Examples of Causes of ARF

Prerenal hemodynamic disorders Shock/Hypovolemia Hemorrhage, septic Shock, cardiogenic shock, heat stroke, severe 3rd degree burns Systemic Diseases - pancreatitis, peritonitis (acute abdomen), DIC, hypoadrenocorticism Renal vascular/hypoperfusion Anatomical - renal artery occlusion Functional - Drugs - NSAIDS, ACE inhibitors, anesthetic drugs, hepatorenal syndrome Renal vein occlusion Infectious Leptospirosis, Pyelonephritis, FIP, Leishmaniasis, Fungal, Lyme dz, etc Sepsis Renal Disorders MODS, Glomerulonephritis, Hemolytic uremic syndrome, SLE, trauma, Renal neoplasia, Renal transplant rejection (graft vs host), acute interstitial nephritis Nephrotoxins Antimicrobial agents: aminoglycosides, idiopathic rxns to ALL other classes Antifungal drugs: amphotericin B Chemotherapy drugs: methotrexate, cisplatin, doxorubicin in cats, bisphosphonates Others: Radiocontrast agents, NSAIDS, ACE Inhibitors Heavy metals: Hg, Pb, etc Toxins: Ethylene glycol Plants: some lilies (cats), mycotoxins Endogenous toxins: hemoglobin, myoglobin, hypercalcemia Miscellaneous: streptokinase, acetaminophen, snake venom, Bee venom, grapes (dogs) Partial or complete obstruction of the urethra or bladder by uroliths, mucous plugs, blood clots, strictures, or an intra or extraluminal mass Bilateral ureteral obstruction or unilateral ureteral obstruction with a single kidney Bilateral renal pelvis obstruction or unilateral renal pelvis obstruction with a single kidney

Intrinsic Renal Parenchymal Disorders

Postrenal Disorders

Table 2. Factors that make the Kidney Vulnerable to Ischemic and Toxic Injury
Factors that May Predispose the Kidney to Ischemic and Toxicant-Induced Injury

Large renal blood flow (20 % of cardiac output) results in increased delivery of blood-borne toxicants to the kidney; the renal cortex is also especially susceptible as it receives 90 % of the renal blood flow and contains a large metabolically active endothelial surface area (i.e., glomerular capillaries, proximal tubules). Renal tubular epithelial cells, especially in the proximal tubules and ascending thick Loop of Henle are particularly vulnerable to ischemic and toxic injury because of their high metabolic rates. Toxicants that are subject to renal tubular secretion and reabsorption may accumulate in high concentrations within renal tubular cells leading to injury (e.g., gentamicin). The countercurrent multiplier system may also concentrate toxins in the renal medulla. Xenobiotic metabolism by the kidneys can, rarely, result in intrarenal formation of toxic metabolites.

Pathogenesis of ARF: 1. Pathophysiology of ischemic ARF in a nutshell: the kidneys can maintain adequate renal perfusion pressure by autoregulation as long as the systemic arterial blood pressure is above 60 to 70 mmHg. If BP drops below this renal ischemia occurs; glomerular filtration and cellular delivery of nutrients and oxygen to renal tissues is impaired. Depletion of cellular ATP stores, leads to dysfunction of Na/K ATPase pumps and the inability of cells to maintain osmotic homeostasis. Cellular swelling leads to further contraction of the ECF volume, which further exacerbates renal ischemia and impairs nutrient delivery. As tubular epithelial swelling progresses, the lumen of the renal tubule start to occlude, function diminishes and the patient becomes oliguric. If the insult is severe and progressive, epithelial death and sloughing occurs, inflammatory cells migrate into the tubules; the tubule becomes 2

occluded and anuria occurs. Back-leak of filtrate into the interstitium from the tubule causes more inflammation and damage. Lysosomal enzymes and free radicals released from activated inflammatory cells called into the tissue contribute to the damage. Intrarenal vasoconstriction results from an imbalance of vasoconstrictive and vasodilatory mediators and exacerbates renal hypoxia. The end result is a rapidly declining GFR, with the whole process taking place over hours to days. Reperfusion injury may also add to the renal damage once treatment is instituted. 3. Pathophysiology of Nephrotoxic ARF: the pathophysiology will depend to some extent on the toxin involved, but direct damage to either the renal tubules or glomerulus can result in tubular obstruction, tubular back leak, renal arteriolar vasoconstriction, and possibly decreased glomerular capillary permeability. 4. ARF classically proceeds through three distinct phases: a. Initiation phase b. Maintenance phase c. Recovery phase. 5. Initiation phase: a. Spans the time from initiation of renal damage to the onset of azotemia (hrs to days). b. Clinical signs may not be obvious; therapeutic measures to reduce the renal insult have the potential to prevent the development of established ARF. 6. Maintenance phase: a. Characterized by tubular epithelial lesions and established nephron dysfunction. Even with removal of the inciting cause and re-establishment of renal blood flow improvement there is often no noticeable improvement in renal function. This stage usually persists for days to weeks. b. The urine volume produced during this phase is variable. Patients with severe damage to the kidneys will be anuric or oliguric; those with less severe damage will have normal urine production or more likely be polyuric. c. It is not uncommon for patients to die in this phase. d. Hemodialysis can be lifesaving for patients in this phase. 7. Recovery phase: a. Characterized by repair of renal lesions and improved function. b. Repair is only possible if the tubular basement membrane is intact and epithelial cells are still viable; the remaining surviving nephrons will undergo hypertrophy to compensate for the loss of irreversibly injured nephrons. c. Complete or incomplete renal functional recovery may be the end result. d. The recovery phase may take up to 6-8 weeks or longer. Clinical Presentation 1. Clinical signs of ARF are nonspecific and include acute onset of lethargy, anorexia, dehydration, depression, vomiting, and diarrhea. Occasionally, uremic breath, oral ulcers or tongue tip necrosis, bilaterally enlarged and possibly painful kidneys may be present and should increase clinical suspicion of ARF. 3

2. Oliguria (< 0.5 ml/kg/hr) or, less frequently, anuria (< 0.1 ml/kg/hr) may be present, but nonoliguric forms of ARF where the patients urine production is normal or increased are not uncommon. 3. Patients with ARF are typically in good body condition; they may be hypothermic, and may have an increased respiratory rate secondary to a resulting metabolic acidosis. Clinical Evaluation 1. Rule out postrenal and prerenal causes of azotemia. Check for signs of lower urinary tract obstruction (especially if patient is anuric) or rupture. Q: How would you rule out both of these possibilities? 2. Whenever possible try to obtain a urine sample to measure the USG prior to fluid therapy in order to allow localization of the cause of a patients azotemia. However, do not delay IV fluid therapy for this if the patient is sick and clinically dehydrated or you suspect ARF. Fluid therapy induces diuresis, often leading to production of dilute urine; this can delay and frustrate attempts to localize azotemia. 3. Most prerenal causes of azotemia can be ruled out with a baseline urinalysis, with the exception of those disorders where prerenal azotemia is superimposed on an inability to concentrate urine (e.g., hypoadrenocorticism, hypercalcemia, etc). These can mimic ARF; the azotemia should promptly resolve with fluid therapy. 4. Rule out environmental exposure to toxins (especially ethylene glycol) or medical exposure to drugs (aminoglycoside or ibuprofen) which might induce ARF. 5. Differentiate from CRF using the history, physical exam and laboratory findings, etc. See table below. Table 3. Distinguishing ARF from CRF
History Acute Renal Failure Ischemic episode, toxicant exposure, nephrotoxic drug use Acute illness Good Normal to large May be painful Absent Chronic Renal Failure Long-standing signs of weight loss, possibly PU/PD, vomiting, diarrhea Poor History of weight loss Small, irregular contour Sometimes present especially in young, immature dogs with CRF Decreased nonregenerative anemia Normal to decreased Variable: often polyuric Animals with ARF may be anemic from other concurrent diseases, or if ARF is caused by intravascular hemolysis, etc. Urine output is the major determinant of serum [K+] Urine output does not differentiate ARF from CRF Exceptions/Comments FYI ONLY Animals with ARF that develops secondary to another long-standing disease may have a more protracted history. If patients with ARF have other concurrent diseases then they may be in poor body condition. Some CRF diseases cause renal enlargement (amyloidosis)

Body condition Renal Size Osteodystrophy (renal hyperparathyroidism ) Pack Cell Volume Serum potassium Urine volume

Normal or increased Normal to increased Variable: anuria, oliguria more common

Clinicopathologic Findings with ARF 1. Electrolyte abnormalities a. Moderate to marked azotemia, hyperkalemia, and hyperphosphatemia are expected. Bradycardia and cardiac arrhythmias may result from profound hyperkalemia. 4

b. Hypocalcemia may be evident with ethylene glycol toxicity. 2. Moderate to marked metabolic acidosis from accumulation of uremic and or lactic acid. 3. The urine formed will be physiologically inappropriate - the specific gravity < 1.030 in dogs and < 1.035 in cats; often it is in the isosthenuric range 1.007 1.015. The fractional excretion of Na > 1 % and there is lower than expected creatinine in the urine for the degree of azotemia. 4. Renal tubular damage may be indicated by the presence of increased granular and cellular casts, and possibly proteinuria and glucosuria (with normal serum glucose). The presence of high numbers of calcium oxalate dihydrate or monohydrate crystals is highly suggestive of ethylene glycol poisoning. A serum test for ethylene glycol should be performed. 5. Renal ultrasonographic findings with ARF are nonspecific; echogenicity may be normal or diffusely hyperechoic. With ethylene glycol poisoning, renal cortices may be markedly hyperechoic and a medullary rim sign seen, however, this is not pathognomonic. 6. Histopathologic examination of renal cortical biopsy specimens will reveal varying degrees of tubular necrosis and acute inflammation. Tubular regeneration may also be seen and is a positive prognostic sign. Management of ARF 1. Basic goal is to buy time for the remaining nephrons to repair and hypertrophy. To do this you must: a. Minimize further renal damage and correct the underlying disease. b. Correct alterations in ECF volume. c. Minimize hyperkalemia. d. Correct acid/base disturbances. e. Establish urine production to reduce accumulation of uremic toxins. f. Good supportive care and nutritional management. 2. Time is of the essence so work quickly. These patients need 24-hr intensive care. 3. Minimize further renal damage: a. Discontinue all potentially nephrotoxic drugs and consider measures to reduce their absorption if appropriate (induction of emesis, gastric lavage, cathartics, etc.). b. Start specific antidotal therapy if applicable (i.e., alcohol dehydrogenase inhibitor 4methylpyrazole for ethylene glycol toxicity, penicillin for Leptospirosis). c. Identify and eliminate any prerenal or postrenal abnormalities that exist. 4. Correct Alterations in ECF volume a. Replace fluid deficits intravenously within the first 2 - 6 hours provided there are no contraindications to do so (i.e., underlying cardiac disease). 1. 0.9% NaCl is preferred for hyperkalemic patients 2. LRS or equivalent replacement fluid for normokalemic patients 3. Half strength saline (0.45 %) in 5 % dextrose if hyperkalemic and hypernatremic. 5

b. Monitor the patient carefully for signs of overhydration (respiratory rate and character, body weight, lung sounds, PCV/TP), as oliguric/anuric patients may not be able to excrete excess fluids. Monitoring central venous pressure is the gold standard for assessing for overhydration but trending body weight is the next best thing. GET A BASELINE BODY WEIGHT before fluid therapy is initiated, reweigh patient at least 2X daily. Significant changes in BW reflect changes in fluid status in these patients; inappetence will not cause loss of more than 0.5% - 1% body weight/day. c. Once rehydrated, if urine production is re-established be sure that fluid administration is matched to ongoing losses (ins-and-outs fluid therapy). MEASURE URINE OUTPUT AND OTHER FLUID LOSSES so that fluid requirements can be properly assessed. d. Switch to a maintenance fluid if possible, and administer a fluid rate of at least 1.5 to 2 X maintenance. e. If urine flow is not reestablished, and there are no signs of overhydration, continue administration another bolus of fluids over 4 to 5 hours equivalent to 5% dehydration to achieve mild volume expansion. If patient is hypernatremic or hyperkalemic give 0.45 % NaCl in 2.5 % dextrose. f. If urine production is still not reestablished or is subnormal (<0.3 1.0 ml/kg/hr), a diuretic dopamine can be administered to promote diuresis. 5. Minimize hyperkalemia a. Hyperkalemia can cause cardiac conduction abnormalities and is the main lifethreatening electrolyte disturbance that occurs with ARF. b. Best diagnosed based on measurement of the serum potassium concentration; if lytes can not be monitored evaluate for bradycardia and consistent electrocardiographic findings (see below). If present treat for hyperkalemia. Electrocardiographic Findings seen with Hyperkalemia Bradycardia Decreased P-wave amplitude, Increased PR interval, Widened QRS complexes, Tall, spiked T waves If severe: atrial standstill, ventricular tachycardia, ventricular fibrillation and asystole. c. Hyperkalemia requires prompt treatment. Several therapeutic strategies can be used to combat hyperkalemia depending on the severity see notes on FLUTD. 1. Mild hyperkalemia IV fluids alone 2. Moderate hyperkalemia insulin/glucose, sodium bicarbonate 3. Severe calcium gluconate and aggressive fluids 6. Correct acid-base disturbances a. A moderate to severe metabolic acidosis is very common with oliguric ARF. b. Treatment other than IV fluids, is reserved for patients with a pH of < 7.15. NaHCO3is the treatment of choice, but administer carefully. Overzealous use can result in ionized calcium deficits, paradoxical CNS acidosis (hyperventilation abates and CO2 6

diffuses into the CSF), and metabolic alkalosis. Goal of treatment is to return the pH to 7.2 not back to the normal range. c. Calculate the dose of NaHCO3, and give to the dose over 1-4 hrs, then reassess

Table 6. Treatment Recommendations for Metabolic Acidosis

Severity Mild Moderate Severe pH 7.3 - 7.35 7.15- 7.3 < 7.15 Serum [HCO3-] > 16 mmol/L 12-16 mmol/L < 12 mmol/L Therapeutic Intervention Volume replacement Establish urine flow and initiate diuresis Administration of an alkalinizing fluid with measures taken for mild acidosis Sodium bicarbonate 84 mg/ml or 1 mmol/ml Formula Dose [HCO3-] (mmol/L) = 0.4 x [HCO3-]deficit x BW Where [HCO3-] deficit = (desired [HCO3-] patient [HCO3-]) Desired [HCO3-] is 12 corresponding to a pH of 7.2 not a normal [HCO3-]

Example calculation: 15 kg dog with a HC03 of 8 Dose [HCO3-] (mmol/L) = 0.4 x 4 x 15 = 24 mmol Based on a concentration of 1 mmol/ml the dog needs 24 mls total Give 6 mls as a CRI over 4 hrs = 1.5 mls/hr 7. Reduce Accumulation of Nitrogenous Wastes and Uremic Toxins a. If fluid therapy alone fails to induce diuresis, then either a diuretic or a combination of a diuretic and dopamine in the case of dogs can be tried in an attempt to improve renal blood flow and GFR. However, major benefits are rarely seen. b. Mannitol, an osmotic diuretic, (0.25 0.5 g/kg IV slowly over 20 minutes) is preferred for initial diuretic therapy provided there are no signs of severe fluid overload, pulmonary edema, or congestive heart failure. If urine production occurs then the dose of mannitol can be repeated every 4 hours, or as a constant rate infusion (CRI) (1-2 mg/kg/min). c. Furosemide, a loop diuretic, can also be tried. Give initially at a dose of 2-6 mg/kg IV. If adequate diuresis is not induced in 30 min repeat the initial dose alone or in combination with dopamine for a dog. Some animals will respond to furosemide, but not mannitol or visa versa. If diuresis is achieved, the initial dosage can be repeated q 6 to 8 hours, or furosemide can be administered as a CRI (0.25 1.0 mg/kg/hr). Furosemide can promote gentamicin-induced ARF; avoid in these cases and in other forms of toxicant induced ARF. d. Dopamine, is a catecholamine, capable of stimulating dopaminergic receptors in the renal vasculature and inducing vasodilation in dogs (not cats). This has the potential of increasing renal blood flow and GFR. Only a low dose CRI (0.5 3.0 ug/kg/min) will induce renal vasodilation. Higher doses cause vasoconstriction, tachycardia and potentially cardiac arrhythmias. In people, there is growing evidence that dopamine treatment has no benefit; however, there are species differences with respect to distribution of dopamine receptors. e. Diltiazem - antiendothelin effects leads to increased renal blood flow. May also have some other renoprotective effects (via decreased tubular cell death). Monitor patient for hypotension. Has shown some benefit in ARF induced by Leptospirosis. f. Doses of all drugs are included for your information only. 7

8. Good Supportive Care and Symptomatic Management of Sequela of ARF a. Control Vomiting and Combat Uremic Gastritis 1. Administer of H2 receptor blockers and a central acting antiemetics. 2. Use lower doses (metoclopramide, H2 blockers) if renally excreted. b. Nutritional Support 1. Provision of daily caloric requirements is very important for improving outcome. 2. Inappetence resulting from gastric hyperacidity and vomiting; this can usually be controlled with administration of antiemetics and H2-receptor blockers. 3. The use of enteral feeding techniques (nasoesophageal tube, esophagostomy tube, gastrotomy tube) should be considered if the patient is not vomiting. Parenteral (IV) nutrition can be used for animals that are vomiting. 4. Reduced protein diets and enteric phosphate binders (aluminum hydroxide or calcium acetate) should be used with all methods of enteral nutrition. 5. Azodyl could be added to enteral nutrition food to promote enteric dialysis 9. Other Supportive Measures a. Treat infections aggressively. ARF patients are prone to sepsis; adjust doses as needed. Select antibiotic based on culture and sensitivity results. Prophylactic antibiotic administration is NOT warranted for prevention of an iatrogenic UTI from urinary catheter placement it is ineffective and promotes colonization with a more resistant bacterial population. 10. Renal Replacement Therapy: Dialysis 1. Dialysis can be used to remove uremic toxins and levels of nitrogenous wastes in order to buy time for renal function to recover. 2. Two types of dialysis are possible - peritoneal and hemodialysis. 3. Dialysis should be considered based on whether or not the initiating disorder is reversible and whether or not adequate renal tissue remains (best based on biopsy results). 4. Warn owners that dialysis is very expensive and time consuming. 5. There are currently several centers where hemodialysis is performed: UC Davis (Dr. Larry Cowgill and Dr. Thierry Francey), UC Veterinary Medical Center - San Diego (Dr. Julie Fischer), The Animal Medical Center (Dr. Kathy Langston), and Tufts University (Dr. Mary Ann Labato and Dr. Linda Ross) Prognosis 1. In general, the prognosis for patients with well established ARF is guarded to poor but aggressive therapy in the first few days is required in order to establish an accurate prognosis. 2. The use of hemodialysis has improved the outcome in dogs with ARF. In a case series of 124 dogs with ARF who underwent dialysis, the overall survival rate was 41 %. The underlying cause for the ARF was a major factor determining survival; only 18 % of dogs with ARF induced by toxins survived, 76 % of those with infectious causes (i.e., Leptospirosis) and 56 % of those with metabolic and hemodynamic causes survived. 3. Prognosis depends on various factors, including: 8

a b c d e f

Severities of the azotemia and the histopathological lesions, as well as the response to therapy, are the most important prognostic indicators for ARF. Urine output: nonoliguric ARF has a better prognosis that oliguric/anuric ARF. Cause ARF secondary to infectious and hemodynamic causes tends to have a better prognosis than if induced by a toxin. Other organ failure or disease states (e.g., sepsis, CHF) Age: older animals are more likely to have underlying renal disease or other systemic diseases. Access to hemodialysis.

Ethylene Glycol (EG) Poisoning

Introduction 1. EG is one of the most common toxins encountered in small animal practice. It often results in death unless diagnosed early and treated aggressively. Mortality rate is 60-70 % in dogs; even higher in cats. It is a colorless, odorless, sweet tasting liquid found in antifreeze. 2. FYI only - the minimum lethal dose is 6.6 ml/kg in dogs and 1.5 ml/kg in cats. Metabolism and Pathophysiology of EG Toxicity 1. Following ingestion EG is rapidly absorbed from the GI tract. Peak plasma levels occur 3 to 6 hours after ingestion and remain significantly elevated for at least 12 hours, but are usually undetectable by 48 hours after ingestion. 2. Most of the ingested EG is metabolized by the liver. The metabolites are the real demons, not EG itself. EG, however, will lead to CNS depression, ataxia, vomiting (direct gastric irritation), and osmotic diuresis. 3. The metabolites result in a severe high anion gap metabolic acidosis, and toxic renal tubular epithelial damage. In the renal tubules and in tissues, calcium may combine with oxalate to form calcium oxalate crystals that precipitate out, obstruct the renal tubules and lead to ARF. Taken from the Compendium of Continuing Education: Gaynor et al, 1999, Vol 21 Clinical Stages of EG Toxicity 1. EG can be divided into three fairly distinct clinical stages. 2. Stage I - CNS Signs a. Occurs 30 minutes to 12 hours after ingestion of EG. b. Within the first few hours the serum osmolality increases significantly, and a severe normochloremic metabolic acidosis with a high anion gap develops. Signs resemble those seen with alcohol intoxication: depression, incoordination, ataxia and stupor. Focal or generalized seizures, coma, and death may also be seen. c. Vomiting is common and may be from EG causing gastric irritation, or from the acute rise in serum osmolality. 9

d. In dogs, but not cats, marked and progressive polydipsia is also common in the first 1-2 hours. This occurs in response to the increase in serum osmolality. e. Severe polyuria often develops in both cats and dogs, secondary to a marked osmotic diuresis; this contributes to dehydration and hypoperfusion. After the initial CNS depression, many animals appear to recover, only to then rapidly deteriorate. 3. Stage II - Cardiopulmonary Signs a. Occurs 12 -24 hours after EG ingestion. Tachypnea and tachycardia are common signs. In dogs and cats, pulmonary edema despite being a common finding on necropsy, does not cause clinical signs. 4. Stage III Renal Signs a. Establishment of oliguric renal failure marks the final stage. This occurs in 12 to 24 hrs (cats) and 48 to 72 hours (dogs) following ingestion of EG. b. Cats tend to produce more oxalates than dogs as they metabolize EG more rapidly. This may account for their increased sensitivity to EG intoxication. c. Unfortunately, most pets are presented during this stage when most of the EG has been metabolized. d. c/s include depression, anorexia, vomiting, azotemia, and oliguria or anuria. Renal pain maybe detectable and seizures may occur secondary to uremia or hypocalcemia. Clinicopathologic Findings 1. CBC: nonspecific finding. 2. Serum biochemistry profile: a. Metabolic acidosis characterized by a low pH, low bicarbonate, and a high anion gap. b. Hypocalcemia is seen in about 50 % of affected dogs and cats. c. Azotemia d. Hyperphosphatemia e. Hyperkalemia f. Hyperglycemia is common (seen in approximately 70 % cases) and is thought to be caused by inhibition of glucose metabolism by aldehyde metabolites and from physiologic stress. 3. Urinalysis a. Calcium oxalate crystalluria is a consistent finding and can be detected as early as 3 hours after ingestion in cats and by 4-6 hours after ingestion in dogs. b. The monohydrate crystals (picket fence or dumbbell shaped) are more common.

Picket fence or dumbbell shaped crystals; their presence is usually associated with ethylene glycol toxicity.

Envelope shaped crystals and can be normal in dogs and cats, but if there is support for ARF and large numbers are present ethylene glycol should be considered.

c. Isosthenuria may be observed as early as 3 hours after EG ingestion. d. Glucosuria secondary to injury to the proximal tubules may be seen. 10

e. Aciduria, hematuria, renal epithelial cells, and cellular and granular casts are common. Diagnosis 1. Due to the nonspecific signs and because a history of ingestion is often not available with EG toxicity, early diagnosis is challenging. The prognosis for recovery is directly related to the time elapsed between ingestion and initiation of therapy; early and rapid diagnosis is critical. 2. YOU MUST maintain a healthy high index of suspicion for this toxicity. Consider in any animal, especially a young animal, with access to the outdoors with compatible signs. 3. A few key features may aid in a more rapid diagnosis: clinical signs of depression, vomiting, ataxia, polyuria, polydipsia, in combination with a metabolic acidosis characterized by a high anion gap, isosthenuria, calcium oxalate monohydrate or dihydrate crystalluria, and hyperosmolality (if available). 4. All these are early findings, so the minimum data base needs to include a CBC, serum biochemistry, UA and ideally a venous blood gas determination with ionized calcium included. Specific Diagnostic Aids 1. Measurement of Serum Osmolality a) This can be a helpful diagnostic aid in the early stages. Normal serum osmolality is 280310 mOsm/kg. EG is very osmotically active but once EG has been metabolized the serum osmolality will return to normal. b) Formula for calculating serum osmolality: Osmc = 1.86 ([Na+] + [K+]) + (urea) + (glucose) Urea and glucose in mmol/L Osmo Gap = Osmm osmc When there is an Osmo Gap there is an unmearsured osmole 2. Metabolic Acidosis a) The metabolic acidosis associated with EG is characterized by a high anion gap due to the presence of unmeasured serum anions. Normal anion gap = 15 to 26 mEq/L. The anion gap can be calculated using the following formula: Anion gap (mEq/L) = (Na+ + K+) (Cl- + HCO3-) b) An elevated anion gap may not be evident early on but will be in the later stages. 3. EG SERUM Detection a) A commercially available kit, the Glycol Test Kit, is available for use in dogs and appears to accurately measure serum EG concentrations 50 mg/dl. b) This test takes 30 minutes to run and is most useful in the first 12 hours after ingestion, but may help document exposure up to 24 hours after ingestion. c) The test kit is not sensitive enough for use in cats and false-negative results in dogs, despite ingestion of lethal doses of EG, have been documented. d) Blood samples for testing should be drawn before treatment is initiated; false positives may occur with propylene glycol, an additive in activated charcoal and some anticonvulsants such as diazepam. 4. Detection of Sodium Flourescin in the Urine/Gastric Contents a) Antifreeze contains sodium flourescin for detection of radiator leaks. This substance fluoresces under a Woods lamp so looking at the urine or gastric contents using a Woods lamp may be helpful. 11

5. Renal Ultrasonography a) Although the findings on ultrasound are not pathognomonic they can be helpful. Increased cortical echogenicity is an early finding (within 4-6 hours of ingestion); in the later stages a distinct corticomedullary rim sign or halo sign may be seen. 6. Renal Biopsy a) Renal biopsy will be diagnostic (acute tubular necrosis with calcium oxalate crystals within the renal tubules) although it is rarely needed to establish a diagnosis. Treatment 1. Goals of treatment are as follows: a) Prevent further absorption b) Increase excretion of both EG and its metabolites and provide good supportive care (see earlier section for generic treatment of ARF). c) Prevent additional metabolism of EG. 2. Prevention of further Absorption a) Induce vomiting using apomorphine or hydrogen peroxide if an animal presents within 12 hours of ingestion. Contraindicated if the patient is depressed or stuporous. Activated charcoal can also be administered, but is not very effective at absorbing EG. b) If owners call you immediately after witnessing their pet ingest EG, instruct them to make the dog vomit by administering hydrogen peroxide and to seek veterinary care ASAP. 3. Increase Excretion a) Intensive supportive care and monitoring is required. Provide thermal support if hypothermic; eye lubrication, a well-padded bed; turn patient if recumbent q 4 hours. b) Aggressive IV fluid therapy is essential. Diuresis will also increase renal perfusion and help promote excretion of EG and its metabolites. c) Sodium bicarbonate therapy to combat the metabolic acidosis is recommended if the acidosis is severe pH < 7.15. Alkalinizing the urine also promotes glycolate excretion. 4. Preventing Additional Metabolism a) Inhibition of the enzyme alcohol dehydrogenase (ADH) responsible for initiating metabolism of EG is the cornerstone of specific therapy for EG intoxication. b) The specific antidotes available for EG intoxication are ethanol or 4- methylpyrazole. Cats - ethanol is considered the best option because they metabolize EG too quickly for the doses of 4MP used in dogs to be effective. Higher doses of 4MP (125 mg/kg) would be effective in cats if given within the first few hours of EG ingestion. c) Ethanol i. Ethanol is a competitive inhibitor of ADH, with a higher affinity for the enzyme than EG. Because of the CNS depression, exacerbation of serum hyperosmolality, and osmotic diuresis resulting from ethanol therapy, patients will require very intensive monitoring and support. ii. A continuous rate of infusion (CRI) rather than bolus administration is preferred. iii. FYI only the dose of 20 % ethanol: Cats 5 ml/kg IV q 6 hrs for 5 treatments then q 8 hrs for 4 more treatments or the total dose given as a CRI. 12

Dogs: 5.5 ml/kg IV q 4 hrs for 5 treatments, then q 6 hrs for 4 more treatments or 300 mg/kg IV bolus followed by 100 mg/kg/hr CRI. Cost per ml (VTH Pharmacy) = $ 25 /500 mls they will ship this to an outside clinic. c) 4-Methylpyrazole (4MP) i. 4MP is a strong inhibitor of alcohol dehydrogenase and is safe and effective. The duration of activity of 4-MP is longer than for ethanol, allowing for a more practical dosing schedule. The other main advantage of 4-MP over ethanol is that it does not cause CNS depression. ii. Dose for Dogs: initial loading dose: 20 mg/kg IV over 20 minutes followed by 15 mg/kg IV at 12 and 24 hours, and 5 mg/kg IV at 36 hours. iii. Expensive - costs $7.25/ml; cost to treat a 15 kg is $90. 5. Supportive Care a) Treatment of hypocalcemia induced seizures or tetany is occasionally required; 10 % Calcium gluconate at a dose of 0.5-1.5 ml/kg, administered slow IV to effect. If possible, monitor an ECG while administering. If ionized Ca 2+ is normal treat seizures with conventional anticonvulsants. b) Nutritional support c) Combat vomiting and anorexia d) Dialysis 6. Prognosis a) The prognosis for recovery once ARF has developed is very poor. In one study involving 36 dogs with EG intoxication treated with 4MP, all dogs that were azotemic at the time of presentation (18/36 dogs) died. If animals present within the first 3-5 hours and are treated aggressively, the prognosis is good. Leptospirosis-FYI Only A. Etiologic Agent 1 Various servovars of Leptospira interrogans. Increasing incidence of canine leptosporosis in Canada attributed to increased contact with wild-life. B. Pathophysiology 1 Maintained in wild life or other reservoir hosts (raccoons, shunks, voles, rats, pigs, cattle) and transmitted either directly or indirectly (contaminated fomites, feed, water, soil). Leptospira can penetrate mucous membranes and abraded skin. 2 Renal involvement hepatic involvement occurs with some servovars L. grippotyphosa, canicola, pomona, and bratislava. C. Clinical Signs and Findings 1 Clinical signs include: fever, lethargy, stiff sore muscles, vomiting, dehydration, diarrhea (may be hemorrhagic), polyuria/polydipsia (can be followed by oliguria), renal pain, icterus, bloody urine, petechial and ecchymotic hemorrhages (can cause vasculitis and DIC), and acute death. D. Diagnosis: Serology, histology or by PCR. E. Treatment 13

1 Penicillin (20, 000 40, 000 IU/kg IV q 6hrs) in the acute phase. 2 Good supportive care (intravenous fluid support and nutritional support) for ARF. 3 Doxycycline (10 mg/kg PO q 24 hrs) to eliminate the carrier state at discharge. F. Zoonotic Potential and Prevention 1 Warn owners about the zoonotic potential and take measures to prevent transmission to staff, owners, and other patients (barrier nursing techniques - wear gloves, gowns, protective eye wear, walk animal outside in a place where other patients are not walked, etc). 2 Vaccination new vaccine contains all 4 leptospira servovars. Older vaccines do not protect against pomona, grippotyphosa, or Bratislava - just against icterohemorrhagiae and canicola. Vaccine reactions are common. Tainted Pet Food- FYI Only 1. March 2007: numerous reported cases of ARF in dogs and cats associated with ingestion of commercial pet foods manufactured mostly by Menu Foods. Toxic compounds proposed to be melamine and cyanuric acid present in wheat gluten, rice protein, and corn gluten imported from China. 2. Melamine first implicated but considered relatively nontoxic. Intentional additive to boost nitrogenous content. Cyanuric acid also identified as co-contaminant in pet food. Also relatively nontoxic on its own. In combination with melamine, insoluble crystals form that obstruct and damage renal tubules. 3. In a small study involving cats feed diets with varying concentrations of melamine, cyanuric acid, or both, only cats feed diets containing both developed ARF. Histopathologic findings limited to the kidneys, and included crystals primarily in the lumen of the distal tubule, severe interstitial edema, and hemorrhage at the corticomedullary junction. 4. Similar outbreak of ARF seen in 2004 in Asia with identical clinical, histological, and toxicological findings seen in NA 2007 outbreak. Mycotoxin incriminated in the Asian outbreak but not proven.

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