Table. Potential risk factors for AKI/ARF in dogs and cats
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Acute kidney injury (AKI) often results from ischemic or toxic insults and usually affects the most metabolically active tubular
portions of the nephron. If the ischemic or toxic insult is severe enough, acute renal failure (ARF) may result. In many cases,
AKI and ARF inadvertently develop in the hospital setting in conjunction with diagnostic or therapeutic procedures. For example,
renal damage may result from decreased renal perfusion associated with anesthesia and surgery or with the use of nonsteroidal
anti-inflammatory drugs (NSAIDs). Similarly, renal damage may occur in patients treated with potential nephrotoxicants like
gentamicin, amphotericin, and cisplatin. The nephron damage that occurs with ischemic or toxic insults is not always reversible;
animals that do recover adequate renal function usually require prolonged and expensive intensive care. Several retrospective
studies have documented the poor prognosis associated with ARF in dogs and cats. In a study of hospital-acquired ARF, the
survival rate was only 40%. In another retrospective study of 99 dogs with all types ARF, 22% died, 34% were euthanized, 24%
survived but progressed to chronic kidney disease (CKD), and only 19% regained normal or adequate renal function. Similarly,
in a retrospective study of 32 cats with all types of ARF, 16% died, 31% were euthanized, 28% survived but progressed to CKD,
and only 25% regained normal or adequate renal function. These studies underscore the importance of early detection of AKI
and prevention of ARF. Several risk factors have been identified that predispose dogs to gentamicin-induced ARF (Table), however
it is likely that many of these risk factors also predispose dogs and cats to other types of toxicant-induced ARF as well
as ARF induced by ischemia. A combination of decreased renal perfusion and/or use of nephrotoxic therapeutic agents superimposed
on more chronic, pre-existing risk factors is usually responsible for AKI/ARF in the clinical setting. Early detection of
AKI facilitates appropriate intervention that can arrest or at least attenuate tubular cell damage and the development of
established ARF. Pathophysiology
Acute renal failure has three phases, which are categorized: 1) initiation, 2) maintenance, and 3) recovery. The initial insult
occurs resulting in sub-lethal cellular injury in the initiation phase. Therapeutic measures started during this initiation
phase may reduce the renal insult and prevent development of established ARF. The maintenance phase is characterized by tubular
cell death and established nephron dysfunction. Therapeutic intervention during the maintenance phase, although often life
saving, usually does little to diminish existing renal lesions or improve renal function. The recovery phase is the period
when renal lesions resolve and renal function improves. Tubular damage may be reversible if the tubular basement membrane
is intact and viable epithelial cells are present. Although additional nephrons cannot be produced and irreversibly damaged
nephrons can not be repaired, functional hypertrophy of surviving nephrons may adequately compensate for the decrease in nephron
numbers. Even if renal functional recovery is incomplete, adequate function may be reestablished in some cases.
Risk factors for AKI/ARFDehydration and volume depletion are perhaps the most common and most important risk factors for ARF (Table). Studies in human
beings indicate volume depletion increases a patient's risk of developing ARF by a factor of ten. Hypovolemia not only decreases
renal perfusion, but also decreases the volume of distribution of nephrotoxic drugs and results in decreased tubular fluid
flow rates and enhanced tubular absorption of toxicants. In addition to hypovolemia, renal hypoperfusion may be caused by
decreased cardiac output, decreased plasma oncotic pressure, increased blood viscosity, systemic hypotension, and decreased
renal prostaglandin synthesis. Any of these conditions can increase the risk of ARF in the hospital setting.
Pre-existing renal disease and advanced age, which is often associated with some degree of decreased renal function, can increase
the potential for nephrotoxicity by several mechanisms. The pharmacokinetics of potentially nephrotoxic drugs can be altered
in the face of decreased renal function. Gentamicin clearance has been shown to be decreased in dogs with sub-clinical renal
dysfunction, and the same is probably true for other nephrotoxicants. Animals with renal insufficiency also have reduced urine
concentrating ability and, therefore, decreased ability to compensate for prerenal influences. Renal disease may also compromise
production of prostaglandins that help maintain renal vasodilation and blood flow.
Decreased serum concentrations of several electrolytes can increase the risk of ARF. For example, hyponatremia potentiates
IV contrast media-induced ARF in dogs. Additional studies in dogs have demonstrated that dietary potassium restriction exacerbates
gentamicin nephrotoxicity, possibly because potassium depleted cells are more susceptible to damage. It is important to note
that gentamicin administration in dogs is associated with increased urinary excretion of potassium. This increased urinary
excretion of potassium could result in reduced intracellular concentrations and increased nephrotoxicity in clinical patients.
Therefore, serum electrolyte concentrations should be closely monitored in patients receiving potentially nephrotoxic drugs,
especially if these patients are anorexic, vomiting, or have diarrhea.
