Evolution of Terminology and Incidence of Acute Renal Failure

Prerenal failure has long been used to describe an acute, reversible increase in nitrogenous waste products (azotemia) in the bloodstream, associated with a transient decrease in renal function secondary to renal hypoperfusion. Although this term is entrenched in both the human and veterinary medical literature, its use likely contributes to the lack of recognition of subclinical renal damage that may accompany a number of medical problems. This can be attributed to the large reserve capacity of the kidneys, in which nearly 75% of nephron function must be compromised before dysfunction is recognized clinically. With prerenal failure, adequacy of renal function is characterized by maintenance of concentrating ability (urine specific gravity >1.035) and normal serum and urine electrolyte concentrations. Unfortunately, urine samples are rarely collected from horses at the time of hospital admission to document specific gravity: urine tonicity declines and urine Na⁺ concentration increases rapidly with supportive fluid therapy. As a consequence, it can be challenging to distinguish between prerenal failure and intrinsic renal damage (renal azotemia, for which loss of concentrating ability is a hallmark) by measuring urine specific gravity in horses that have been receiving fluids for 6 to 12 hours. Nevertheless, suspicion of changes in glomerular and tubular function and integrity can be supported by detecting pigmenturia, proteinuria, or glucosuria with reagent strip analysis or cast formation on microscopic examination of urine sediment.

Despite the reversible nature of azotemia and urinary alterations with prerenal failure, nephron injury (and a degree of nephron loss) likely occurs in most instances of prerenal failure. To increase awareness of subclinical renal damage in patients with decreased renal blood flow (RBF) and glomerular filtration rate (GFR), the term acute kidney injury (AKI) has been introduced in human and, subsequently, small animal medicine. Acute kidney injury is defined as an increase in serum creatinine concentration of as little as 0.3 mg/dL (25 µmol/L) or a 50% increase from the baseline value, yet creatinine may remain within reference range, and serum electrolyte concentrations are usually normal. Furthermore, the mild increase in creatinine is reversible with appropriate supportive treatment. When AKI progresses to overt acute renal failure (ARF), abnormalities in serum electrolyte concentrations (hyponatremia, hypochloremia, and occasionally hyperkalemia), more substantial azotemia (creatinine >2.5 mg/dL or >220 µmol/L), loss of concentrating ability (urine specific gravity <1.020), and clinical signs of renal failure may become apparent. In the author’s hospital, the incidence of significant azotemia is slightly under 5% for horses that have a serum chemistry profile performed as part of their evaluation; however, mortality rate is high for horses with severe azotemia (creatinine >10 mg/dL or 880 µmol/L), with the exception of neonates with spurious hypercreatininemia (Table 110-1).

Causes of Acute Kidney Injury and Acute Renal Failure

Acute kidney injury usually develops as a complication of another disease process or activity that leads to hypovolemia and a prolonged period of decreased RBF and GFR (e.g., colic, enterocolitis, hemorrhage, or endurance exercise). Acute kidney injury may progress to ARF when renal hypoperfusion persists or renal damage is exacerbated by exposure to nephrotoxic agents. Nephrotoxins that can cause AKI and ARF include endogenous pigments (myoglobin or hemoglobin), vitamin D or vitamin K₃, heavy metals (e.g., mercury, cadmium, zinc, arsenic, and lead), and acorns (tannins). Treatment with nephrotoxic medications, including nonsteroidal antiinflammatory drugs (NSAIDs), aminoglycoside antimicrobials, or oxytetracycline (most commonly when administered for correction of flexural deformities in neonatal foals), remains a significant risk factor for development of iatrogenic ARF in horses. Hemodynamically mediated AKI/ARF is often associated with oliguria (urine output <0.5 mL/kg for longer than 6 hours), whereas urine production with nephrotoxin-associated AKI/ARF often remains normal (nonoliguric AKI). In neonates, ARF can also develop as a complication of septicemia, particularly with disseminated Actinobacillus equuli infection. Acute renal failure can also develop with Leptospira spp infections in equids.

Nonsteroidal Antiinflammatory Drugs

Most horses do not experience appreciable adverse effects from NSAID use as long as the drugs are administered at the proper dosage and treated animals are not dehydrated. When RBF decreases as a consequence of dehydration or diversion of cardiac output away from the kidneys (as during exercise), vasodilatory prostaglandins (PGE₂ and PGI₂) are produced within the kidney. Production of renal prostaglandins through cyclooxygenase (COX) pathways is greatest in medullary tissue, the region of the kidney that normally has the lowest blood flow and functions in a relatively hypoxic environment. Thus it should not be surprising that the lesion associated with NSAID use is inner medullary (medullary crest or papillary) necrosis (Figure 110-1). As with adverse gastrointestinal effects of NSAIDs, it appears that certain individuals are more sensitive to the adverse renal effects of these drugs. Consequently, the author prefers use of “NSAID sensitivity” rather than “NSAID toxicosis” when adverse effects are observed with NSAID treatment. Recent development of more COX-2–selective NSAIDs has received considerable attention, and it would be logical to assume that these NSAIDs may be less nephrotoxic than nonspecific NSAIDs. However, this new generation of COX-2–selective NSAIDs has not been demonstrated to be renoprotective in studies in other species, and their use should not be assumed to be renoprotective in equids.