The diagnostic approach to the patient with renal failure is to first identify life-threatening problems, then to localize the azotemia to differentiate between acute kidney injury (AKI) and chronic kidney disease (CKD). The next steps are to determine the urine volume and potential causes of the injury. It is important to obtain a complete history, perform a thorough physical examination and then obtain the appropriate laboratory tests (complete blood count, chemistry profile, urinalysis and culture), imaging, serology and possibly biopsy. The management of the patient with AKI may have unique challenges when compared to the patient with CKD.
Acute Kidney Injury
The definition of AKI is the sudden inability of the kidneys to regulate water and solute balance. Oliguria is considered when urine output is less than 2 ml/kg/hr. Acute kidney injury may be from pre-renal, renal, or post-renal causes. Pre-renal AKI is most commonly the result of decreased renal perfusion such as with shock or dehydration. Post-renal most often results from an obstruction to urine flow or tears in the urinary tract. Acute kidney injury may be the result of renal injury from ischemia, toxin or infectious agent. The other causes may be from vascular derangement or cellular injury secondary to decreased renal blood flow (RBF), decreased glomerular filtration rate (GFR) or decreased excretion.
Several retrospective studies have documented the poor prognosis associated with AKI in dogs and cats. In a study of hospital-acquired AKI, the survival rate was 40%.1 In another retrospective study of 99 dogs with all types of AKI, 22% died, 34% were euthanized, 24% survived but progressed to CKD, and 19% regained normal kidney function.2 Similarly, in a retrospective study of 25 cats with all types of AKI 20% died, 36% were euthanized, 20% survived but progressed to CKD and 24% returned to normal function.3 These studies underscore the importance of early detection of acute tubular damage and prevention of AKI.4
There are a variety of potential risk factors that may predispose to the development of AKI (Chart 1). The clinical signs of AKI include lethargy, depression, anorexia, and vomiting, typically with a duration of less than one week. Laboratory findings may include a normal or increased hematocrit, blood urea nitrogen (BUN) and creatinine that are progressively increasing, a normal to increased serum potassium, moderate to severe metabolic acidosis and an active urine sediment.
Chart 1.Potential risk factors for the development of AKI.
1. Pre-existing renal disease
2. Advanced age
5. Liver disease
6. Multiple organ involvement
8. Diabetes mellitus
11. Decreased cardiac output
13. Electrolyte imbalance
15. Nephrotoxic drugs
16. Hyperviscosity syndrome
17. Dietary protein level
Problematic Conditions to Monitor
Conditions that may generate anxiety to the technical staff, especially anesthesia technicians, and warrant addressing include acidosis, hyperkalemia, hypocalcemia, hypovolemia or fluid overload and hypertension.
The AKI patient may present with a severe metabolic acidosis which may cause physiologic effects in the pulmonary, cardiovascular or neurologic systems. A severe acidosis of a pH< 7.0 will trigger changes in the respiratory system that will increase the breathing rate and the depth of each tidal volume. This will lead to an increase in minute ventilation as a form of compensation. Effects on the cardiovascular system includes ventricular arrhythmias, decreased contractility and a poor response to catecholamines. This will ultimately result in poor tissue perfusion. Acidosis effects the neurologic system resulting in signs varying from mild depression to coma. Treatment consists of relieving obstruction, establishing a fluid diuresis, restoring renal function or dialysis and bicarbonate therapy. Acidosis should be corrected when the pH is less than 7.0. Sodium bicarbonate should be supplied utilizing the formula 0.3x bw(kg)x base deficit. Administer 1/3 dose intravenously slowly and then the remainder of the dose in the IV fluids over several hours. Avoid rapid intravenous boluses as it may generate the production of CO2 which diffuses into the CNS and can worsen CSF acidosis. Immediate determination of a recheck blood gas may over estimate the effect of therapy. Diffusion and buffering may take 2-4 hrs.
Potassium homeostasis is the result of a balance between dietary intake, transcellular shifts, excretion in feces and primarily excretion in urine. The causes of hyperkalemia are the metabolic acidosis and decreased urinary excretion. The metabolic acidosis causes shifts of intracellular potassium to the extracellular space. The major determinant of the resting membrane potential is the ratio of intracellular potassium to the concentration in the extracellular fluid. Severe hyperkalemia reduces the magnitude of the resting membrane potential, to the extreme that the resting membrane potential may become less than the threshold potential. This results in an inability of the cell to repolarize after a single depolarization. The cell becomes no longer excitable. Muscle weakness occurs. Cardiac abnormalities develop. Serum potassium concentration greater than 6.5-7.0 mEq/l can cause cardiac conduction disturbances (bradycardia, atrial standstill, idioventricular rhythms, ventricular tachycardia, fibrillation and asystole) and electrocardiographic changes (peaked T waves, loss of P waves).4
Treatment for hyperkalemia consists of fluid therapy and rehydration. Urine production must be reestablished. If severe hyperkalemia exists then there is the need for direct antagonism of the high potassium levels on membrane actions. This can be accomplished by lowering the potassium concentration by driving the potassium intracellularly or by removing the potassium from the body via dialysis. Treatments include intravenous calcium gluconate, insulin, or sodium bicarbonate.
Significant hypocalcemia can be observed in dogs and cats with AKI associated with ethylene glycol intoxication. Clinical consequences include increased neuromuscular excitability, decreased cardiac contractility, and peripheral vasodilation. Treatment consists of intravenous calcium gluconate.
Disorders of calcium balance can also be present in patients with AKI with resultant hypercalcemia. If moderate to severe hypercalcemia develops, a primary hypercalcemic disorder (e.g., neoplasia or vitamin D3 intoxication) should be considered as the cause of the renal failure. Immediate treatment for hypercalcemia includes rehydration with saline and diuresis induced with furosemide. Glucocorticoids will also help lower calcium concentrations by decreasing intestinal absorption and facilitating excretion.4
Fluid Volume Overload
Fluid volume overload is a common problem seen in dogs and cats with azotemia and oliguric/anuric AKI or in those with protein-losing nephropathies. There is often great difficulty in assessing the hydration status. The tendency is to give fluids. It is difficult to break old habits. Treatment for volume overload is to avoid fluids. If you must administer fluids, than supply insensible losses only (10 ml/kg/day). The administration of diuretics works only if the kidneys do. The extra fluids need to be removed by another method, i.e., dialysis (hemodialysis or peritoneal dialysis).
Most dogs and cats with AKI are volume depleted because of gastrointestinal fluid loss in addition to the loss of urine concentrating ability. Replacement of these losses will correct the pre-renal component and protect against any additional ischemic renal tubular damage.4 The goal of fluid therapy for established AKI is correction of water and solute imbalances. A positive response to therapy is indicated by an increase in glomerular filtration and increases in urine production. The increased urine production observed with diuresis is usually a result of a relative decrease in the tubular reabsorption of filtrate. Increased urine production alone does not indicate an improvement in glomerular filtration.
During the rapid rehydration phase the patient should be closely observed for signs of volume overload. Frequent assessment of body weight, CVP, PCV, and plasma total protein will help detect early volume overload. An increase in the CVP of > 5-7 cm of water over baseline values suggests the likelihood of volume overload.4 Clinical signs of volume overload include: increased bronchovesicular sounds, tachycardia, restlessness, chemosis, and serous nasal discharge.
Patients with AKI as well as CKD have a high incidence of hypertension. In the oliguric or hypoproteinemic patient volume overload will increase the blood pressure. It is imperative to avoid a hypertensive emergency. Consequences of hypertension are end organ damage especially to the eyes, brain, heart and kidney.
Angiotensin converting enzyme inhibitors (ACEi) are the first line of therapy for the management of hypertension. The mechanism of action for ACEi is the inhibition of the conversion of angiotensin I to angiotensin II. They are balanced vasodilators and decreased afterload. ACEi also have a variety of other effects. These include: 1) decrease aldosterone secretion, 2) decrease plasma angiotensin II levels, 3) dilate efferent renal arterioles, 4) decrease proteinuria, and 5) increase urine concentration of PGE2 and bradykinin. Renal effects of ACEi include: 1) reduce systemic and glomerular hypertension, 2) improve glomerular permselectivity, 3) reduce proteinuria, and 4) limit glomerular hypertrophy by reducing mesangial cell proliferation and reducing production of extracellular matrix. Side effects of ACEi include decreased renal perfusion, hyperkalemia, vomiting, myelosuppression and seizures.
Calcium channel blockers (CCB) are another family of drugs used commonly in the management of hypertension . Mechanisms of action of CCB include: 1) arteriolar smooth muscle relaxant, 2) inhibit the slow transmembrane calcium influx into cell via voltage-gated L-type transmembrane calcium channels (calcium antagonists), 3) vasodilation at arterioles and coronary arteries, 4) antiarrhythmic and cardiodepressant effects. Amlodipine has the most systemic antihypertension and renal effects. There is minimal effect on the heart. Amlodipine does not seem to be as renal protective as ACEi. Side effects include hypotension, nausea and constipation.
Anemia is defined as an inadequate level of red blood cells or hemoglobin and is a common clinical finding in CKD and may occur in patients with AKI. Anemia has been reported as a complication in 32-65% of cats with CKD.5 Although the underlying cause of anemia in CKD is multifactorial, the primary contributing factor is an inadequate production of erythropoietin by the kidneys. Erythropoietin is a glycoprotein hormone that regulates red blood cell generation and is produced by the peritubular interstitial cells of the kidney in response to a decrease in tissue oxygenation.
Treatment of anemia may consist of blood transfusion or hormone replacement therapy. Recombinant human erythropoietin (Epogen®)has been used to correct nonregenerative anemia in both CKD and AKI in dogs and cats.6 Darbepotin alfa is a novel erythopoiesis stimulating protein that may be beneficial in the management of veterinary patients with CKD associated anemia. Structural differences may make darbepoetin less immunogenic. A longer half-life allows it to be administered less frequently than Epogen.
1. Behrend EN, et al. JAVMA, 1996; 208:537.
2. Vaden SL. et al. JVIM 1997; 11:58,
3. Worwag S, LangstonC. JVIM 2004; 18:416.
4. Grauer GF. BSAVA Manual of canine and feline nephrology and urology, 2nd edition 2007; 215.
5. Lulich JP, et al. Compend Continu Edu Pract Vet 1992: 14-127.
6. Cowgill LD et al. J AM Vet Med Assoc 1998; 212:521