Proceedings of the World Small Animal Veterinary Association Sydney, Australia 2007 Hosted by: Australian Small Animal Veterinary Association (ASAVA) Australian Small Animal Veterinary Association (ASAVA) Australian Small Animal Veterinary Association (ASAVA) Next WSAVA Congress
ACUTE INTRINSIC RENAL FAILURE (AIRF) - CAUSES AND PREVENTION Dennis J. Chew, DVM, Diplomate, ACVIM (Internal Medicine) College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA Definition and Introduction Acute renal failure is a clinical syndrome characterized by an abrupt increase of serum creatinine and blood urea nitrogen (BUN) concentrations to above normal (azotemia). An inability to regulate solute and water balance is often present and renal synthetic and degratory functions are impaired to varying degrees. The term acute renal failure is commonly used to connote acute intrinsic renal failure, but it is important to consider all possible causes, including pre-renal, intrinsic (primary) renal, and post-renal. The finding of acute renal failure is not a specific diagnosis. Older definitions of AIRF required that oliguria be documented during the clinical course-+, but this is no longer included. Oliguria, normal urine production, or polyuria can all occur depending on the specific cause and severity of renal injury sustained during AIRF. Differential Diagnosis and Frequency of AIRF The frequency of underlying conditions associated with AIRF varies with the nature of the veterinary practice. Nephrotoxicity is the leading cause for AIRF at The Ohio State University Veterinary Hospital, followed by nephritis and ischemia. The aggressive use of potentially nephrotoxic antibiotics, particularly the aminoglycosides, can contributes to nephrotoxic AIRF. The exposure to cholecalciferol rodenticides, indiscriminate use of non-steroidal anti-inflammatory drugs (NSAID), and exposure of veterinary patients to extensive surgical procedures and aggressive post-traumatic resuscitative maneuvers as emergency patients can result in AIRF. Ischemic and nephrotoxic AIRF occur more readily in patients that have underlying chronic renal disease or renal failure. An increased frequency of AIRF has recently been noticed in cats given NSAID at the time of routine desexing. Potential Causes for AIRF due to Renal Ischemia (Hypoperfusion) Dehydration Trauma Anesthesia Sepsis Hyperthermia Hemolysis ACE Inhibitors Shock Hemorrhage Surgery Burns Hypothermia Myoglobinuria Non-Steroidal Anti-Inflammatory Drugs (NSAID) Note that renal ischemia can occur in the absence of systemic arterial hypotension. Potential Nephrotoxins as a Cause for AIRF More Common Glycols (Ethylene Glycol) Antimicrobials Aminoglycosides Amphotericin-B Sulfonamides - dehydration Dennis J. Chew, DVM, ACVIM; The Ohio State University College of Veterinary Medicine 2006
2 Tetracyclines - IV Easter Lilly Cats Less Common Grapes/Raisin Toxicity dogs Hypercalcemia/Hypercalciuria Cholecalciferol Rodenticide Cholecalciferol Diet Calcipotriene Cancer Chemotherapeutics Radiocontrast Agents - IV Heavy Metals Hydrocarbons Fluorinated Inhalational Anesthesia Miscellaneous Causes of AIRF Glomerular/Vascular Acute glomerulonephritis Rapidly progressive glomerulonephritis (Borrelia associated) Cutaneous and renal glomerular vasculopathy (Greyhounds Alabama Rot ) Hemolytic uremic syndrome (HUS) Systemic vasculitiis Renal thromboembolism renal infarction Acute-on-chronic renal failure Renal amyloidosis with acute papillary necrosis Acute Hyperphosphatemia Tumor lysis syndrome Phosphate enema Phosphate acidifier Massive soft tissue trauma Sepsis/DIC Pancreatitis Food-associated renal failure Pathophysiology of AIRF due to Nephrosis Exposure to nephrotoxins or ischemia causes tubular injury exhibited microscopically along a spectrum from degeneration to necrosis, and is referred to as nephrosis or acute tubular necrosis (ATN). Some patients, however, exhibit minimal or no light microscopic lesions yet exhibit severe renal excretory failure. Factors that can contribute to azotemia and or oliguria during AIRF include tubular backleak, intraluminal and extraluminal tubular obstruction, and primary filtration failure (afferent arteriolar vasoconstriction, efferent arteriolar vasodilatation, and or a decrease in glomerular permeability). Diagnosis of AIRF Rapid increases of BUN, serum creatinine, and serum phosphorus may be observed during AIRF. This is particularly helpful to document AIRF in the absence of recent serum biochemistry values for comparison. For example, a patient s serum creatinine of 4.3 mg/dl, 6.0 mg/dl, and 7.5 mg/dl sequentially over three consecutive days supports a diagnosis of AIRF. Serum creatinine and BUN do not increase
3 over this short a time period in hydrated patients with chronic renal failure. Hyperphosphatemia may be out of proportion to the degree of increase in BUN or serum creatinine in those with acute renal failure compared to chronic renal failure. The magnitude of elevation in BUN or serum creatinine concentrations is not generally helpful in the diagnosis of AIRF vs CRF or in the differentiation of prerenal, intrinsic renal, or post-renal azotemia. Urinalysis reveals a low specific gravity (SG) during the maintenance phase of AIRF (SG less than 1.030, but most-often in the 1.007 to 1.015 range). Dipstrips may show proteinuria, hematuria or glucosuria on occasion. Urinary sediment is typically active at early stages of the maintenance phase exhibiting increased numbers of casts (particularly cellular casts) and small epithelial cells compatible with renal tubular epithelium. Animals with AIRF should have smooth kidneys with normal or increased kidney size whereas those with chronic renal failure may show small and or irregular kidneys both on palpation and abdominal radiographs. Renal ultrasonography can provide additional anatomic information to confirm intrarenal lesions, but cannot be relied on to distinguish acute from chronic renal failure or to suggest a specific microscopic lesion. Failure to document ultrasonographic renal changes does not exclude a diagnosis of AIRF. Kidneys may enlarge during AIRF but this may not be detected if they are still within the normal range for kidney size; kidneys tend to become plump before they measure elongated. Renal biopsy may be helpful to determine that an azotemia is due to primary renal lesions and to characterize the changes as acute or chronic. Urine culture can be helpful in selected cases to evaluate for upper or lower urinary tract infection. Prognosis of AIRF The attending veterinarian and client often have greater expectations for immediate improvement following treatment than is realistic, remembering that the maintenance phase of AIRF can last weeks in some cases before adequate renal repair and function can occur. The most likely causes for death during the initial management of the AIRF patient in the maintenance phase are from the effects of hyperkalemia, metabolic acidosis, and severe azotemia. Overhydration and resulting pulmonary edema are the next major causes of death during vigorous fluid therapy. Over half of dogs with AIRF will either die or be euthanized due to poor response to treatment, while about 20% will return to normal serum creatinine levels and the others will survive with chronic renal failure. Animals with AIRF that remain oliguric following intravevous rehydration fluids are much more likely to die or to be euthanized but non-oliguria does not guarantee survival either. In the absence of dialysis, anuric animals (e.g. ethylene glycol intoxication in dogs or cats; easter lilly ingestion in cats) cannot survive. Lower levels of serum phosphorus have been associated with greater survival in some dogs with AIRF. The level of azotemia during the maintenance phase of AIRF is related to the potential to survive those with minimal increases in serum creatinine are least likely to die while those with serum creatinine in excess of 10 mg/dl are at increased risk to die in the absence of dialysis. The prognosis for recovery from AIRF is related to the specific cause - those in which AIRF is attributed to ethylene glycol or associated with DIC are very unlikely to recover (grave prognosis). Recovery from AIRF following aminglycoside neprhotoxicity is generally poor. Recovery of AIRF from leptospirosis is fair to good provided that supportive treatments and penicillin are started early enough. In the absence of dialysis, persistence of oliguria or development of oliguria during fluid
4 and diuretic treatments of dogs with ARF is associated with a poor prognosis. Though the prognosis is worse for dogs with oliguric forms of aminoglycoside nephrotoxity, the presence of non-oliguria does not guarantee survival either. A grave prognosis is warranted for dogs or cats that develop anuric ARF, a situation most-likely to develop in ethylene glycol intoxication but may also be encountered in cats following ingestion of Easter or day lilies. It should be noted that dogs and cats with severe oliguric ARF have recently been shown to survive with return of renal function and urine production following several months of hemodialysis. Due to the overall poor to grave prognosis for most cases with AIRF, prevention is far preferred to the often-unrewarding management of AIRF. General Goals for Treatment of AIRF During the Maintenance Phase Prophylaxis is far superior to any treatment for cases with established AIRF. Placement of an indwelling intravenous catheter is necessary to adequately administer fluids and drugs in the management of AIRF. Rapid correction of dehydration is indicated and can be individually calculated (estimated % dehydration x body weight in kg = Liters of dehydration) or given as 2 to 3 times maintenance fluid needs (60 to 90 ml / pound per day). Further fluids are given to match sensible (urinary volume ), insensible (respiratory losses at about 10 ml/lb/day), and contemporary (an estimated volume from vomiting and diarrhea) fluid losses. Since urine output is widely variable in AIRF, it is advisable to place an indwelling urinary catheter to monitor urine output to facilitate fluid therapy decisions for the initial 24 to 48 hours. The recognition of oliguria is important initially as it dictates the volume of IV fluid therapy that can be safely given. Urine production less than 1.0 ml/kg/hour (24 ml/kg/day) qualifies for oliguria in our hospital prior to rehydration and volume expansion. Relative oliguria exists if urine production is form 1.0 to 2.0 ml/kg/hour while on IV fluids. Urine output should be from 2.0 to 5.0 ml/kg/hour during vigorous administration of IV fluids if the kidneys are healthy. Conversion from Oliguria to Non-Oliguria The use of diuretics to convert oliguria to non-oliguria is often advocated following rehydration fluids and body weight gain. It is easier to manage patients that are non-oliguric because hyperkalemia and overhydration are less likely to occur and the severity of nitrogenous waste product retention may be less. It is not certain whether conversion from oliguria to non-oliguria following diuretics changes the natural course of the disease, or whether successful conversion identifies those cases with less severe renal tubular lesions. Veterinary patients that remain oliguric despite diuretics have a poor prognosis due to the relative unavailability of dialysis. Mannitol, furosemide, dopamine, or combinations of these are the diuretics most often employed in attempts to convert oliguria to non-oliguria. Rehydration prior to use of diuretics should occur first to allow greater delivery of the diuretic to its site of action. Since furosemide has been shown to enhance severity of renal lesions following exposure to aminoglycosides in experimental dogs, furosemide is not recommended as a diuuretic agent in these cases. The so-called renal-dose of dopamine (below the vasopressor dose, often from 2 to 5 micrograms/kg/minute) has surprisingly little clinical documentation to support its use in either human or veterinary medicine. Treatment with atrial natriuretic peptide (ANP) holds promise as it can induce diuresis, natriuresis, increased GFR, and maintenance of RBF shortly after periods of ischemia or during maintenance phases of post ischemic or
5 nephrotoxic AIRF. Independent of its hemodynamic effects, ANP limits renal tubular cell exfoliation, necrosis, and cast formation; ATP regeneration is enhanced at the same time. SELECTED REFERENCES Dial SM, Thrall MA, Hamar DW: Efficacy of 4-methylpyrazole for treatment of ethylene glycol intoxication in dogs. Am J Vet Res 55(12): 1762-1770, 1994. Gwaltney-Brant S, Holding JK, Donaldson CW, Eubig PA, Khan SA. Renal failure associated with ingestion of grapes or raisins in dogs. J Am Vet Med Assoc 2001; 218:1555-6. Langston CE: Acute renal failure caused by lily ingestion in six cats. J Am Vet Med Assoc 220(1): 49-52, 36, 2002. Poortinga EW, Hungerford LL. A case-control study of acute ibuprofen toxicity in dogs. Prev Vet Med 1998; 35:115-24. Vaden SL, Levine J, Breitschwerdt EB. A retrospective case-control of acute renal failure in 99 dogs. J Vet Intern Med 1997; 11:58-64.