43 Acute Renal Failure
1. What is acute renal failure (ARF)?
• Hemodynamic, filtration, and excretory failure lead to the accumulation of metabolic toxins as well as fluid, electrolyte, and acid-base imbalances.
• Acute renal failure, as compared with chronic renal failure, is potentially reversible with early diagnosis and supportive treatment.
• ARF must be differentiated from prerenal azotemia, which is usually mild and occurs when there is a decline in glomerular filtration rate (GFR) resulting from decreased renal blood flow, perfusion pressure, or excessive vasoconstriction.
• Damage to the kidney vasculature, tubular epithelium, or interstitium can lead to ARF. Any alterations in renal blood flow can affect GFR and lead to renal damage and disease.
• It is the rate of change in renal lesions and function, not the abruptness with which signs appear, that differentiates acute and chronic renal failure.
2. Why are the kidneys prone to injury?
• The kidneys receive about 20% of the cardiac output, with the renal cortex receiving about 90% of that flow.
• Mechanisms that are thought to lead to renal injury include tubular obstruction, increased tubular permeability, and altered renal blood flow.
3. What phases of acute renal failure have been identified?
• Initiation, maintenance, and recovery have been identified as the three phases of acute renal failure.
• Initiation refers to the time of initial insult to the kidneys with parenchymal and tubular epithelium injury. As cell death or necrosis occurs, there is a decline in GFR, loss of urinary concentrating ability, and development of oliguria or polyuria and azotemia. Appropriate therapy during this initial phase may decrease the insult to the kidneys and avoid the development of acute renal failure. This period may last from hours to days, but abnormalities may not be clinically evident.
• Tubular lesions and nephron dysfunction occur during the maintenance phase, which may last for weeks to months. GFR and renal blood flow are decreased, urine production decreases, and uremia may develop.
• During the recovery phase, damaged nephrons may be repaired and there may be compensatory hypertrophy of undamaged nephrons. Tubular injury can be repaired if the basement membranes remain intact and there are viable epithelial cells. Through this phase, which can last weeks to months, there may be improved renal function, but normal function may not be regained. Polyuria often occurs as a response to accumulated water, salt, and osmotically active solutes. Azotemia may resolve during this phase.
4. What are the major causes of acute renal failure?
• Inadequate renal perfusion (e.g, thromboses of renal arteries, severe hypotension from any cause, hyperthermia [heat stroke])
• Rapidly progressive forms of specific renal diseases (e.g., glomerulonephritis, infection [pyelonephritis], leptospirosis, urinary tract obstruction)
5. What drugs have been identified as common causes of acute renal failure?
• Aminoglycosides (e.g., neomycin, gentamicin, amikacin) can have a toxic effect on the kidneys by causing tubular necrosis. Interference with phospholipid metabolism in the proximal renal tubule cells leads to release of proteolytic enzymes with resulting cellular damage and cell death. Damage can also occur from increased production of free radicals and altered filtration though the glomerular capillaries. This is a dose- and duration- dependent toxic effect and the damage may be reversible with discontinuation of the drug. High or repeated daily dosing, preexisting renal disease, volume depletion, or exposure to other nephrotoxins can enhance the nephrotoxic effects of aminoglycosides. Concurrent administration of other drugs such as furosemide or misoprostol can worsen the renal damage and their use is contraindicated in treatment of toxicity cases.
• Nonsteroidal antiinflammatory drugs (NSAIDs) act by reducing prostaglandin and thromboxane production via cyclooxygenase inhibition. Prostaglandins PGE2 and PGI2 have vasodilatory actions and help to maintain renal blood flow when systemic blood pressure decreases. NSAIDs can interfere with the kidney’s ability to compensate when systemic hypotension occurs. Animals with other risk factors such as dehydration or underlying renal disease have a poorer prognosis. Risk of toxicity can also be higher in animals with congestive heart failure, nephrotic syndrome, diabetes mellitus, renal insufficiency, hypertension, cirrhosis, and those under anesthesia. Renal function should be evaluated before beginning long-term treatment using an NSAID.
• Angiotensin-converting enzyme inhibitors act by preventing the formation of angiotensin II, a potent vasoconstrictor in the renin-angiotensin-aldosterone system. These substances can preferentially cause dilation of the glomerular efferent arteriole, leading to a decrease in glomerular filtration rate. Animals at greater risk include those with sodium depletion, congestive heart failure, chronic renal insufficiency, or those receiving diuretics.
• The antifungal drug amphotericin B can have direct toxic effects on renal epithelial cells. It can also cause renal arterial vasoconstriction resulting in a reduction in GFR. Renal function should be evaluated prior to initiating use and during therapy. Maintaining adequate hydration during administration, diluting the drug, and administering the dose slowly over several hours may decrease the risk of acute renal failure. Liposome-encapsulated or lipid-complexed formulations are thought to be less nephrotoxic.
• The alkylating chemotherapeutic agent cisplatin is concentrated within and mainly excreted by the kidney. It can have dose-dependent, progressive, and irreversible toxic effects by causing renal tubular necrosis. Diuresis with intravenous fluids should be a component of administration to reduce the toxic effects of the drug. Carboplatin, a less nephrotoxic drug, should be considered as an alternative.
6. What other toxins have been implicated in causing acute renal failure?
• Ethylene glycol, which is found in most antifreeze products and in some chemicals used for photographic developing, can cause acute renal failure and gastrointestinal, respiratory, and central nervous system signs. The lethal dose in dogs is 6.6 ml/kg and acute renal failure can occur within 24 to 72 hours of ingestion. Renal tubular injury is caused by the glycolate metabolite of ethylene glycol. The formation of oxalate crystals also causes direct renal tubular damage and can cause obstruction. Other changes with ethylene glycol toxicity include calcium oxalate crystalluria, metabolic acidosis with a high anion gap, azotemia, hyperphosphatemia, hypocalcemia, and hyperkalemia. Diagnosis is based on history of ingestion as well as clinical signs and biochemical abnormalities. Within 12 hours of exposure, serum testing may aid in making the diagnosis. Therapy is aimed at preventing further absorption and to decrease conversion of the ethylene glycol to its toxic metabolites. Use of 4-methylpyrazole or 20% ethanol is considered specific therapy for dogs.
• Elevated calcium can occur from renal failure or can be a cause of acute renal failure. Presence of hypercalcemia can lead to further renal damage from mineralization of the renal parenchyma. A calcium-phosphorus product greater than 60 is considered a risk factor for tissue mineralization. Further investigation into causes of hypercalcemia should be initiated.
• There have been published reports of renal toxicity related to ingestion of large quantities of raisins or grapes. A specific toxin or contaminant in products has not been identified. Acute renal failure developed within 24 to 72 hours of ingestion and aggressive management is warranted in cases of known ingestion. Evidence of renal tubular necrosis, metastatic mineralization of tissues, and renal tubular epithelial regeneration has been seen in reported cases.
• Members of the genus Lilium, a plant family that includes the Easter lily and tiger lily, can cause nephrotoxicity when portions of the plant are ingested. Animals may show gastrointestinal signs, neurologic signs, and acute renal failure.
• Vitamin D toxicosis has historically occurred through exposure to rodenticides containing cholecalciferol (vitamin D3). The resulting hypercalcemia can lead to acute renal failure. Ingestion of medications containing vitamin D can also be a source of toxin. Management should include saline diuresis, furosemide, and may include the use of bisphosphonates.
7. What infectious diseases can cause acute renal failure?
• Leptospirosis is an infectious, zoonotic disease that can cause acute renal failure as well as hepatic disease. Multiple serovars of Leptospira interrogans have been identified as causing acute renal failure including icterohaemorrhagiae, canicola, pomona, bratislava, and grippotyphosa. Leptospiral organisms can be transmitted through contact with infected urine or exposure to contaminated water or soil. Colonization and replication in the renal tubular epithelium cause direct damage and there can be immune-mediated renal damage through antigenic stimulation. Serologic testing can aid diagnosis by demonstrating rising titers. Supportive care involving fluid support as well as antibiotic therapy are indicated (procaine penicillin, ampicillin, doxycycline).
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