The regulatory function of the kidney involves regulation of body fluids, electrolytes and minerals by a combination of glomerular filtration, tubular secretion, and tubular reabsorption. Maintaining fluid, electrolyte and acid-base homeostasis is the basis of the regulatory function. The most obvious clinical evidence of regulatory failure is decreased urine concentrating and diluting capacity manifest as polyuria and polydipsia. Regulatory failure is assessed by measuring urine concentrating ability. Urine specific gravity values less than 1.030 in dogs or less than 1.040 in cats should prompt consideration of primary renal failure. Specific gravity values between 1.030 and 1.040 in dogs and between 1.040 and 1.045 in cats should be viewed with suspicion.

The biosynthetic function of the kidneys involves the formation of a variety of hormones and other chemicals which have both local and systemic effects. In chronic renal failure (CRF), the most important examples of biosynthetic failure include inadequate formation of erythropoietin and 1,25-dihydroxycholecalciferol. The clinical effect of failure to produce erythropoietin is the hypoproliferative anemia of CRF. The clinical impact of inadequate renal production of 1,25-dihydroxycholecalciferol is development of renal osteodystrophy and renal secondary hyperparathyroidism. It is usually not necessary to demonstrate biosynthetic failure to confirm the diagnosis of primary renal failure, but clinical evidence of biosynthetic failure is useful in confirming the diagnosis of CRF because the chronic absence of these hormones is necessary to produce clinical effects.

Diagnosis of primary renal failure is based on demonstrating concurrent excretory and regulatory failure. Detection of inadequate urine concentrating ability (urine specific gravity values less than 1.030 in dogs and less than 1.035 in cats) in an azotemic patient usually confirms the diagnosis of primary renal failure. Note that other causes of dilute urine can be associated with prerenal azotemia, but this is unusual and often apparent by examining the case history and other laboratory findings. Also note that renal failure patients do not typically have urine specific gravity values less than 1.006. Values below this specific gravity indicate urine diluting capacity and are usually inconsistent with a diagnosis of primary renal failure.

Chronic renal failure is primary renal failure that has persisted for an extended period, usually months to years. It is characterized by irreversible loss of nephrons with associated compensatory hypertrophy and hyperfunction. The diagnosis of chronic renal failure is based on identifying historical, physical, or laboratory findings which suggest that renal failure has been present for an extended time. The medical history and physical examination are often the most revealing and reliable clues to chronicity. A history of signs as polyuria, polydipsia, weight loss, selective appetite, deteriorating haircoat occurring over several months is strong evidence for CRF. Physical exam findings of poor nutritional status, poor haircoat, small kidneys, or renal osteodystrophy (most likely evident clinically as "rubber jaw") strongly suggest chronicity. Laboratory findings are often not helpful in establishing the diagnosis of chronic renal failure, although the presence of a hypoproliferative anemia may be suggestive of chronicity. Radiology may be useful in establishing kidney size or presence of renal osteodystrophy.

Acute renal failure is often diagnosed by the absence of signs of chronicity. In some instances, the history of a potential renal insult (such as exposure to aminoglycoside therapy or ethylene glycol consumption) is helpful in making a tentative diagnosis of acute renal failure. The patient with acute renal failure may be in good nutritional health because the onset of renal failure is recent. However, for a given level of azotemia, acute renal failure patients may be more clinically affected. Acute renal failure may be nonoliguric or oliguric; detection of normal to increased urine production does not rule-out acute renal failure.

Conservative medical management of CRF consists of supportive and symptomatic therapy designed to correct deficits and excesses in fluid, electrolyte, acid-base, endocrine, and nutritional balance and thereby minimize the clinical and pathophysiological consequences of reduced renal function. Goals of conservative medical management of patients with chronic primary renal failure are to: (1) ameliorate clinical signs of uremia, (2) minimize disturbances associated with excesses or losses of electrolytes, vitamins, and minerals, (3) support adequate nutrition by supplying daily protein, calorie, and mineral requirements, and (4) modify progression of renal failure. The components of conservative medical management are summarized in table 1. Conservative medical management is most beneficial when combined with specific therapy directed at correcting the primary cause of renal disease.

Dietary constituents other than protein should be modified to optimize the benefits of diet therapy. For example, dietary content of electrolytes and minerals which require renal excretion should generally be reduced in patients with CRF (e.g. phosphorus, sodium, magnesium, hydrogen ions). Dietary supplementation may be necessary or useful for some minerals and electrolytes (e.g. potassium and calcium). Although the principal benefit ascribed to dietary therapy in patients with CRF has been amelioration of clinical signs of uremia due to reduced retention of nitrogenous waste products, diet therapy may also benefit renal failure patients in other ways:

1. Diet therapy may influence progression of renal failure.
   1. Protein restriction may minimize spontaneous, progressive renal damage in patients with CRF by modifying renal hemodynamics or compensatory renal growth.
   2. Dietary phosphorus restriction appears to slow progression of experimentally induced canine CRF.
   3. Other dietary factors which may influence progression of chronic renal failure include: dietary lipid content and composition, sodium intake, total calorie intake, the acidifying nature of the diet, and potassium content.
2. Because proteinaceous foods are a major dietary source of phosphorus, dietary protein restriction is associated with a simultaneous reduction in phosphorus intake with potential amelioration of renal secondary hyperparathyroidism.
3. Severity of polyuria and polydipsia is usually moderated when renal failure patients are fed reduced protein diets.
4. Moderate protein restriction may reduce the severity of anemia of CRF.
5. Because hydrogen ions are a by-product of protein catabolism, protein restriction may minimize metabolic acidosis.

The decision as to when to intervene with dietary therapy in patients with CRF is based, in part, to the severity of renal dysfunction and the goals of dietary therapy. There is little controversy as to the value of reduced protein diets in dogs with overt clinical signs of uremia when fed normal or high protein diets. The therapeutic value of dietary protein restriction for dogs and cats with early or mild renal failure is currently under investigation. The argument that protein restriction impairs nutrition and enhances morbidity and mortality has not been borne out in studies in our clinical trial center. In fact, renal diets restricted in protein reduce the incidence or uremia, renal-related mortality and all cause mortality when compared to no dietary intervention. This difference is evident at all levels of renal dysfunction. The caveat not to restrict protein intake until CRF is more advanced is not supported by current clinical trials.

Dogs with CRF should initially be fed a diet designed for dogs with renal failure or its nutritional equivalent. Cats with CRF should initially be fed a diet designed for cats with renal failure or its nutritional equivalent. Note that diets designed for dogs with renal failure do not contain sufficient protein for cats and therefore must not be fed to normal cats or cats with renal failure. Diets designed for cats with renal failure contain too much protein to be considered appropriate for dogs with renal failure. Because of the intrinsic variability of protein requirements of normal dogs and cats and the probable varied influence of uremia on protein requirements of uremic dogs and cats, dietary protein should be adjusted to meet individual patient needs. Sufficient calories should be provided to maintain a normal, stable body weight. Supplementing B-complex vitamins may be considered for dogs and cats with CRF, particularly during periods of reduced food consumption.

Potassium supplementation may be necessary to prevent or correct hypokalemia in some cats with CRF. Hypokalemia is a relatively frequent complication of renal failure with a reported incidence of 19% in one clinical study of feline renal failure. Although an association between renal failure and development of hypokalemia has been confirmed in cats, the mechanism of hypokalemia has not been established.

Potassium replacement therapy is indicated for cats with hypokalemia, even in absence of clinical signs of hypokalemia. Oral administration is the safest and preferred route of administration for potassium replacement therapy. Potassium gluconate is generally regarded as the potassium salt of choice for replacement therapy. Potassium may be administered orally as potassium gluconate in a palatable powder form (Tumil-K, Daniels Pharmaceuticals, Inc.), potassium gluconate elixir (Kaon Elixir, Adria Laboratories, Columbus, OH), or potassium citrate solution (Polycitra-K, Willen Drug, Baltimore, MD). Depending on the size of the cat and severity of hypokalemia, potassium gluconate is given initially at a dose of 2 to 6 mEq per cat per day. Potassium dosage should thereafter be adjusted based on the clinical response of the patient and serum potassium determinations performed during the initial phase of therapy. Serum potassium concentrations should be monitored every 24 to 48 hours during the initial phase of therapy. Serum potassium concentrations should be monitored every 7 to 14 days during the maintenance phase of therapy. Routine supplementation of all cats with CRF has been recommended, regardless of serum potassium concentrations. The goal of such therapy is to prevent or correct hypokalemia-induced renal dysfunction. The safety and efficacy of this approach has not been evaluated. Diets that are acidifying and restricted in magnesium content may promote hypokalemia, and should therefore generally be avoided in cats with CRF. Potassium depletion and metabolic acidosis may promote potentially fatal reductions in plasma taurine concentrations in cats.

Alkalinizing agents should be administered when necessary to correct the metabolic acidosis of CRF. Because even mildly reduced plasma bicarbonate concentrations may promote some of the adverse effects of chronic metabolic acidosis, oral alkalinization therapy is probably indicated when serum bicarbonate concentration declines to 17 meq/l or below (total CO2 concentrations of 18 meq/l or below). Oral sodium bicarbonate is the most commonly used alkalinizing agent for patients with metabolic acidosis of CRF. The suggested initial dose of sodium bicarbonate is 8 to 12 mg/kg body weight given every 8 to 12 hours. A solution containing approximately 84 mg of sodium bicarbonate per ml (1 meq/ml) of solution can be prepared by adding 2.5 ounces of sodium bicarbonate to 1 quart of water (84 mg added to 1 liter of water). This solution may be stored capped and refrigerated for several months. This solution may be administered at a starting dose of 1 to 1.5 ml per 10 kg of body weight. The solution may be administered orally by syringe or mixed with the food. Potassium citrate is a useful alkalinizing agent that limits sodium intake and provides supplemental potassium. Potassium citrate may administered orally at a dosage of 40 to 60 mg/kg every 12 hours. Alkalinizing agents should be given in several smaller doses rather than a single large dose to minimize fluctuations in blood pH. The patient's response to alkalinization therapy should be determined by measuring blood bicarbonate or serum (plasma) total CO2 concentrations 10 to 14 days after initiating therapy. Ideally, blood should be collected just prior to administration of the drug. Dosage of alkalinizing agents should be adjusted so that blood bicarbonate (or serum total CO2) concentrations are maintained between 18 and 24 meq/l.

Most dogs and cats with CRF benefit from therapy designed to minimize calcium and phosphorus imbalances. The objectives of management of abnormal divalent ion metabolism in CRF are to: 1) maintain serum levels of calcium and phosphorus as close to normal as possible, 2) prevent or suppress excessive secretion of parathyroid hormone (PTH), 3) prevent or ameliorate renal osteodystrophy, 4) prevent or reverse extraskeletal mineralization, and 5) limit progressive renal dysfunction. Calcium and phosphate balance in patients with renal failure may be improved or corrected by limiting phosphate intake and providing adequate quantities of dietary calcium and metabolically active forms of vitamin D.

Limiting dietary intake of phosphate and, if necessary, administering intestinal phosphate binding agents should minimize phosphate retention and hyperphosphatemia. The ultimate goal of therapy is to prevent or minimize renal secondary hyperparathyroidism and its various adverse consequences. Dietary phosphate restriction is an important and effective first step toward normalizing phosphate balance because it may normalize serum phosphate concentrations in mild to moderate CRF, and it reduces the quantity of phosphate that must be bound by intestinal phosphate binding agents if their use becomes necessary. Serum phosphate concentrations should be determined after the patient has been consuming the phosphate-restricted diet for about 2 to 4 weeks. Samples obtained for determinations of serum phosphate concentration should be collected after a 12-hour fast to avoid postprandial effects.) Phosphate binding agents should be used in conjunction with dietary phosphate restriction when dietary therapy alone fails to reduce serum phosphate concentrations to within the normal range.

Intestinal phosphate binding agents render ingested phosphate and the phosphate contained in saliva, bile, and intestinal juices unabsorbable. Because the primary goal is limiting absorption of phosphate contained in the diet, administration of phosphate binding agents should be timed to coincide with feeding. These agents are best administered with or mixed into the food, or just prior to each meal. Currently available phosphate binding agents include aluminum-based and calcium-based compounds. Aluminum-containing intestinal phosphate binding agents include aluminum hydroxide, aluminum carbonate, and aluminum oxide. Although quite effective for binding phosphate, an important disadvantage of long-term use of aluminum-containing antacids in humans with CRF has been development of aluminum toxicity. The potential for toxicity of aluminum salts in dogs and cats has been confirmed, but clinical evidence of toxic accumulation of aluminum has not been reported in these species.

Calcium salts such as calcium acetate, calcium carbonate, or calcium citrate may be highly effective as phosphate binding agents. Calcium-based phosphate-binding agents do not entail the risk of aluminum toxicity that accompanies use of aluminum-based phosphate-binding agents. Unfortunately, calcium-based products may promote clinically significant hypercalcemia; therefore, it is necessary to carefully monitor serum calcium concentrations intermittently when using these drugs. Calcium acetate is the most effective calcium-based phosphate-binding agent as well as the agent least likely to induce hypercalcemia because it releases the least amount of calcium compared to the amount of phosphate it binds. It is particularly important that calcium-based phosphate-binding agents be administered with meals both to enhance the effectiveness of phosphate binding and to minimize absorption of calcium and the risk of hypercalcemia. Administration of calcium-based phosphorus binding agents between meals promotes absorption of calcium and increases the risk of inducing hypercalcemia

Dosage of phosphate binding agents should be individualized so that serum phosphate concentrations are normalized. It has been suggested that a dose of approximately 100 mg/kg/day divided into two or three doses is an appropriate starting dose for aluminum or calcium based phosphate binding agents when serum phosphorus concentration exceeds 6.0 mg/dl. The effect of therapy should be monitored by serial evaluation of serum phosphate concentrations at about 10 to 14 day intervals. Dosage should be increased until serum phosphate concentrations are reduced to or near normal. Dosage of calcium-based phosphate binding agents should be decreased if serum calcium concentrations exceed normal limits; additional aluminum-based agents should be used in these patients if hyperphosphatemia persists. Thereafter, serum calcium and phosphate concentrations should be monitored every 4 to 6 weeks or as needed.

Intestinal malabsorption of calcium is common in CRF, but can be overcome by increasing dietary calcium intake. Because increasing calcium intake may elevate serum calcium concentration and thereby reduce serum PTH activity, calcium supplementation may play an important role in preventing or ameliorating renal osteodystrophy and systemic toxicities resulting from hyperparathyroidism. The optimum time for initiating calcium supplementation during the course of CRF is uncertain. In any case, the increased risk of inducing extraskeletal mineralization attending calcium supplementation dictates that it should generally be withheld at least until serum phosphate concentration are normalized by other therapeutic means.

Oral calcium supplementation should be considered in patients with hypocalcemia; clinical, radiographic, or histologic evidence of renal osteodystrophy; or patients with inadequate dietary calcium intake. Oral administration of a variety of calcium salts may be used to improve calcium balance. Calcium carbonate may be the preferred calcium salt in many patients with CRF because it contains a high fraction of calcium and is inexpensive, tasteless, and usually well tolerated. Initially, calcium carbonate should be administered at a dose of 100 mg/kg/day. In order to maximize calcium absorption, calcium salts should be given in small quantities throughout the day. Administration of one or two large doses is likely to be substantially less effective and more likely to induce complications such as gastrointestinal side-effects. Administration of calcium carbonate with meals that contain large quantities of phosphate should be avoided because it will limit calcium absorption because of the phosphate-binding effect.

Vitamin D supplementation may be considered for dogs and cats with proven renal secondary hyperparathyroidism. In mild renal failure, calcitriol deficiency results predominantly from the inhibitory effects of phosphate retention on renal 1a-hydroxylase activity. As renal failure progresses, loss of viable renal tubular cells limits calcitriol synthetic capacity. Therefore, over time, phosphate restriction alone may fail to prevent renal secondary hyperparathyroidism, necessitating vitamin D supplementation for complete PTH suppression.

Although potentially beneficial in CRF patients, vitamin D therapy must be undertaken with great caution because hypercalcemia is a frequent and potentially serious complication of vitamin D therapy. Vitamin D therapy does not directly impair renal function, but sustained vitamin D-induced hypercalcemia can result in reversible or irreversible reduction in GFR. Hypercalcemia reportedly occurs in 30% to 57% of humans treated with 1,25-dihydroxycholecalciferol. Chew and colleagues reported that hypercalcemia was an uncommon side-effect in dogs with CRF when calcitriol was administered at low dosages. However, hypercalcemia was reported to occur when calcitriol therapy was combined with calcium-containing phosphate binding agents. Because hyperphosphatemia enhances the tendency for vitamin D therapy to promote renal mineralization and injury, serum phosphate concentration must be normalized before initiating vitamin D therapy. In general, patients should not receive vitamin D therapy unless serum calcium and phosphate concentrations will be carefully monitored throughout treatment.

Vitamin D may be administered as calcitriol, 1a-hydroxyvitamin D, or 25-hydroxyvitamin D (calcidiol). Calcitriol (Rocaltrol Capsules, 0.25 mcg and 0.50 mcg; Roche Laboratories, Nutley, NJ) rapidly and effectively suppresses renal secondary hyperparathyroidism in dogs and humans. An important advantage of calcitriol therapy in CRF is that it does not require renal activation for maximum efficacy. Dogs and cats appear to require lower dosages of calcitriol than those recommended for humans (on a per weight basis). Nagode and colleagues have recommended a dosage of 1.5 to 3.5 ng/kg body weight per day given orally to dogs with CRF. Preliminary findings suggest similar doses may be effective in cats with CRF as well. Brown and colleagues have recommended a dosage of 6.6 ng/kg given orally once daily. Vitamin D therapy may enhance intestinal absorption of calcium and phosphorus and therefore should not be given with meals.

Serum calcium concentrations must be monitored during therapy with calcitriol to prevent hypercalcemia. Hypercalcemia may develop at any point during therapy with calcitriol. Calcitriol's rapid onset (about 1 day) and short duration of action (half-life less than 1 day) permits rapid control of unwanted hypercalcemia, but early detection of hypercalcemia is indicated to limit the extent of renal injury. The recommended endpoint of calcitriol therapy is normalization of PTH activity.

A progressive hypoproliferative anemia which contributes substantially to the debilitation and adverse clinical signs associated with uremic syndrome is characteristic of CRF. Although affected by the patient's age, species, specific renal diagnosis, and concurrent diseases, the severity and progression of the anemia correlates with the degree of renal failure and worsens with progressive renal failure in both dogs and cats. Anemia in patients with CRF is multifactorial and may be exacerbated by concurrent illness. Although experimental and clinical evidence exists for the supporting roles of shortened red cell life span, nutritional abnormalities, erythropoietic inhibitor substances in uremic plasma, blood loss, and myelofibrosis, erythropoietin deficiency has clearly emerged as the lead player in the pathophysiology of the anemia of CRF in both humans and animals.

Androgens were once the premier options available for the treatment of anemia in CRF. Although controlled safety and efficacy studies in veterinary medicine are lacking, clinical impression is that therapy with androgens has been disappointing. With the advent of rHuEPO therapy, androgens have largely fallen out of favor for treatment of renal anemia in human and veterinary medicine. Based on studies in human patients and clinical experience with veterinary patients, androgens appear to work in only a small percentage of patients (usually those mildly affected), have a long delay to onset of action, and are associated with undesirable side effects. Consideration of androgens for treatment of dogs and cats with CRF should now be limited to only those patients with symptomatic anemia in which all other factors adversely affecting erythropoiesis (nutritional deficiency, blood loss, hemolysis, concurrent disease) have been eliminated and the other treatment options (erythropoietin, transfusion) have been exhausted.

When given to dogs and cats with CRF, treatment with rHuEPO causes a dose-dependent increase in hematocrit and correction of anemia. A transient, moderate reticulocytosis is initially observed within the first week of therapy in most animals. The bone marrow myeloid/erythroid ratio decreases further illustrating the increased erythropoietic response. Some animals show a transient thrombocytosis during therapy. Correction of hematocrit to low normal takes approximately 2 to 8 weeks depending on the starting hematocrit and dose given. Associated with the correction of anemia, most clients report that their animals show improved clinical status manifest as a increases in appetite, body weight, energy level and sociability. Intravenous or subcutaneous administration of rHuEPO has been shown to be effective in both veterinary and human trials. Subcutaneous administration is the preferred route and most clients can be taught to give the injections at home. Starting doses of 50 - 150 units/kg subcutaneously three times weekly are recommended. Most animals should be started at 100 units/kg and monitored weekly until a target hematocrit of approximately 33 - 40 % in dogs and 30 - 35% in cats is achieved. In animals with severe anemia (hematocrit <14) but not requiring transfusion, daily therapy with 150 units/kg may be preferred for the first week. In hypertensive patients or when the anemia is not severe, the lower dose of 50 units/kg three times per week may help to prevent increases in blood pressure and iron-deficient erythropoiesis. When a hematocrit at the low end of the target range is reached, the dosing interval should be decreased to twice weekly. Most animals require 50 -100 units/kg two to three times weekly to maintain their hematocrit in the target range; however, the dose and dosing interval required to maintain patients in the normal range can be highly variable. Ongoing monitoring of hematocrit will be necessary to allow adjustments in dose and dosing interval. Occasional animals will require dosing intervals as low as once weekly and doses as low as 25 units/kg. Animals requiring more than 150 units/kg three times weekly should be evaluated for erythropoeitin resistance. Because of the lag time between dosage adjustment and effect on hematocrit, patience must be exercised so as not to adjust the dose too frequently resulting in rapid, unpredictable changes in hematocrit and an inability to find a stable dosing regimen. Caution to avoid polycythemia is especially important.

In preliminary trials of rHuEPO therapy, the following adverse events were noted, although for some a causal relationship has not been established: (1) refractory anemia, (2) polycythemia, (3) vomiting, (4) seizures, (5) discomfort at the site of injection, and (6) transient cutaneous or mucocutaneous reactions often with fever. The problem of refractory anemia is directly related to rHuEPO therapy due to the development of neutralizing anti-rHuEPO antibodies. The human protein appears to be immunogenic in most, but not all, dogs and cats with antibody titers developing at variable times (4 weeks to several months) after the onset of therapy. Antibody titers decline after cessation of therapy; rare attempts at immunosuppressive therapy have not been successful in abrogating the response. Bone marrow myeloid/erythroid ratios provide the best method to ascertain if rHuEPO resistance is due to antibody formation, After therapy is stopped and antibody titers decline, suppressed erythropoiesis is reversible and pre-treatment levels of erythropoiesis are attained.

Systemic hypertension is among the most common complications of CRF. It has been reported to occur in about 60 to 65% of cats with CRF and in 50 to 93% of dogs with CRF. It may occur even more frequently with primary glomerulopathies. Although the actual effects of hypertension in dogs and cats remain to be confirmed, it is suspected that sustained hypertension may be associated with serious cardiovascular, ocular, neurologic, and renal complications.

Diagnosis of systemic hypertension should be based on determination of arterial blood pressure. Blood pressure should be routinely determined in dogs and cats with renal disease using either direct or indirect methods. Normal values for blood pressure depend somewhat on the method used. Diagnosis of hypertension should generally be based on results of 3 independent determinations of blood pressure which are free of excitement or anxiety induced artifacts. Values consistently greater than 160/120 (mean 135) probably indicate hypertension in cats and 180/130 (mean 156) probably indicates hypertension in dogs. Evidence of hypertensive organ damage supports a diagnosis of systemic hypertension.

Therapy designed to reduce blood pressure may be considered for dogs and cats with blood pressures consistently above the values cited above. It is cautiously recommended that the goal of antihypertensive therapy should be to lower arterial pressure to 160/120 or below in cats based on the apparent risk of hypertensive retinopathy with systolic values above 160 mm Hg (i.e. defined as "effective therapy"). The ideal goal for pressure reduction is dogs is less clear, but may be similar. Normalizing blood pressure may reverse many of the acute ocular manifestations of hypertension, but the effect of such therapy on the renal, neurologic, or cardiovascular manifestations of hypertension in dogs and cats with CRF has not been determined. However, antihypertensive therapy is not without risk. Overzealous therapy may promote hypotension, volume depletion, and additional renal injury. Pharmacological management of hypertension also entails risks of drug reactions.

Specific guidelines for treatment of systemic hypertension have not been established for dogs and cats. Until clinical data concerning effectiveness of various forms of therapy become available, therapy should be directed primarily at limiting extracellular fluid volume expansion and counteracting the vasoconstrictor effects of angiotensin II and norepinephrine (table 2). Therapy should be initiated in a step-wise fashion beginning with non-pharmacological therapy (sodium restriction and obesity control) followed by pharmacological therapy if necessary.

Sodium intake should probably be reduced to about 0.3% of the diet or less (canine maintenance requirement for sodium is about 0.06% of diet). Changes in sodium intake should always be made gradually over a period of one to two weeks or more. Abrupt changes in dietary sodium may be associated with transient imbalances between intake and urine loss. Too rapid a reduction in sodium intake may reduce extracellular fluid volume leading to poor renal perfusion and further reduction in renal function. It is unclear whether sodium restriction alone is effective in normalizing systemic hypertension in dogs and cats with CRF. However, without sodium restriction, administration of some antihypertensive drugs such as beta-adrenergic antagonists and vasodilators may lead to sodium retention, extracellular fluid volume expansion, and attenuation of the antihypertensive effects of the drugs.

Pharmacological management of hypertension should be considered when sodium restriction alone has proven ineffective in maintaining blood pressures at or below the desired end-point. In patients with mild to moderate renal failure, antihypertensive therapy should ideally be effective as monotherapy (i.e. using a single drug), cause minimal side-effects, promote regression of left ventricular hypertrophy (or prevent its development), and limit progression of renal failure. Angiotensin converting enzyme inhibitors, calcium channel blockers, and beta-adrenergic antagonists appear to most favorably fit the needs of renal failure patients and should be regarded as first-choice drugs. Drug therapy should only be used when the effect of therapy can be monitored by serial determinations of blood pressure. Antihypertensive therapy should be administered at the lowest effective dose with the dose titrated according to blood pressure response. Hypotension is usually the first sign that drug dosage needs to be reduced. Therapy should begin with a single antihypertensive drug. Response to therapy should be determined after 7 to 14 days by measuring blood pressure. If therapy has not reduced blood pressure to the target range within 2 to 4 weeks, therapy may be changed in one of three ways: 1) dosage of the current drug may be increased to a higher but non-toxic level, 2) the drug may be discontinued and therapy begun with another class of drug, or 3) a second drug may be added to the treatment regimen. In both dogs and cats, the calcium channel blocking agent amlodipine has been our first drug of choice. When unsuccessful in correcting hypertension, we usually add the ACE inhibitor enalapril and the second drug. Enalapril may be of particular utility when proteinuria is an important component of the patient's clinical disease.

Response to treatment should be monitored at appropriate intervals so that treatment can be individualized to the specific, and often changing, needs of the patient. The database obtained before initiation of conservative medical management should be used as a baseline for comparison of the patient's progress. This evaluation should be repeated at appropriate intervals which vary according to specific needs of the patient. Immediately following initiation of therapy, patients should be monitored every 2 to 4 weeks to assess the response to therapy. The frequency of evaluation may vary depending on severity of renal dysfunction, complications present in the patient, and response to treatment. Certain forms of therapy, such as administration of rHuEpo, may also necessitate more frequent patient monitoring. Recommendations for monitoring are summarized in table 3.

The term urinary tract infection is used in preference to more localizing terms such as cystitis or pyelonephritis to emphasize the fact that infection at one location potentially places the entire urinary tract at risk for infection. Further, the extent of involvement of various parts of the urinary tract may be unclear based on clinical presentation alone. Most UTI appear to be superficial infections of the lower urinary tract and manifest clinically as signs of pollakiuria and dysuria. Such infections are typically benign and readily respond to routine antimicrobial therapy. However, UTI occasionally leads to systemic or life-threatening infections, particularly in immunocompromised patients. In addition, some patients diagnosed as having bacterial UTI fail to respond to antimicrobial therapy or develop recurrent UTI following withdrawal of antimicrobial therapy. In these patients, the diagnosis may be incorrect, therapeutic failure may have occurred, or complicating factors may be present which must be identified and corrected in order to facilitate successful therapy.

It is believed that in excess of 95% of all UTI arise from ascent of bacteria through the urethra into the bladder. Urinary tract infections results from a complex interaction between the patient's urinary tract defense mechanisms (table 1) and invading bacteria. Disruption of normal host defense mechanisms is believed to be necessary for UTI to occur. Impairment in defense mechanisms may be transient (e.g. catheter-induced urothelial trauma) or persistent (e.g. urothelial neoplasia). In addition, certain bacteria have specific characteristics, termed virulence factors, which enhance their ability to colonize and persist within the urinary tract (table 2). These characteristics explain, in part, why most UTI result from a predictable few bacterial species (figure 1).

The diagnosis of UTI should be confirmed by urine culture because diagnosis based solely on clinical signs and the presence of inflammatory changes on urinalysis (white and/or red blood cells and protein) results in over-diagnosis. For example, although commonly treated with antimicrobial agents, lower urinary tract signs in cats typically do not result from bacterial UTI. Recurrence of clinical signs is common in these cats, but recurrence rarely results from bacterial UTI except when urinary catheterization has been performed. Likewise, recurrent signs of lower urinary tract disease may occur in the absence of bacterial UTI in dogs with urolithiasis, neoplasia, or other urinary disorders. It is desirable to avoid antimicrobials when their use is not warranted. Inappropriate use of antibiotics exposes the patient to the risk of unnecessary drug reactions and potentially promotes development of resistant strains of bacteria. Overuse of antibiotics in humans and animals is becoming an increasingly controversial issue of which veterinarians should take note.

It is essential to obtain urine cultures whenever antimicrobial therapy fails to ameliorate clinical signs or UTI recurs. Antimicrobial therapy should be withdrawn three to five days prior to collection of the urine sample for bacterial culture. Urine samples should ideally be cultured within 30 minutes after collection because multiplication or destruction of bacteria may be detected as early as one hour after urine collection. If immediate culture is not possible, urine may be stored refrigerated for up to six hours or in commercially available collection tubes containing preservatives for up to 72 hours.

Pyuria, hematuria, proteinuria and bacteriuria are not reliable indicators of bacterial UTI. The presence of bacteria in urine is not synonymous with UTI because the bacteria may be contaminants or pathogens. The normal urethra sustains a substantial resident population of bacteria. Thus, bacteria may contaminate any urine sample collected by a method involving passage of urine or catheter through the urethra. Urine for culture should be obtained by cystocentesis whenever possible because this method minimizes the risk of contaminating the sample. Nonetheless, even samples obtained by cystocentesis could be contaminated by skin bacteria, penetrating a loop of intestine, or on transfer of urine to culture media.

Differentiation between bacterial pathogens versus contaminants can usually be made with quantitative urine cultures. Significant bacteriuria is a term coined to describe bacteriuria that likely represents UTI. A high bacterial count in a properly collected urine sample is evidence of UTI (table 3). Small numbers of bacteria cultured from urine of untreated patients usually indicate contamination. When bacterial numbers are in the suspicious range, the urine culture should be repeated. If the same bacterial organism is cultured in similar or greater number, infection is confirmed since contamination is unlikely to yield reproducible results.

Antimicrobial therapy is usually successful in ameliorating signs of UTI eradicating infection. However, when the patient fails to respond to antimicrobial therapy or signs recur following therapy, it is inappropriate and unwise to respond simply by changing antibiotics. While inadequate response to treatment may simply be due to therapeutic failure, other possibilities should be considered (Figure 2). As a minimum, the diagnosis should be confirmed by urine culture 3 to 5 days after withdrawing the antibiotic. When infections recur after treatment, additional diagnostic evaluations of the patient are indicated.

Recurrence of clinical and/or laboratory signs of UTI may occur as a consequence of relapse (persistent infection), reinfection, or superinfection. Classifying recurrent UTI in this fashion is clinically useful because it provides guidance as to the possible cause for recurrent UTI (table 4). The type of recurrence can usually be established by comparing the results of follow-up urine cultures to results of the pre-treatment urine culture. Relapses (persistent infections) are defined as recurrences caused by the same species and serologic strain of microorganism(s) shortly after cessation of antimicrobial therapy (usually within several days to weeks). Urine cultures may or may not be sterile immediately following treatment. In contrast, reinfections are recurrent infections caused by a pathogen different from that causing the previous infection. Reinfections usually occur at a longer interval after cessation of antimicrobial therapy, and urine cultures are sterile immediately following initial treatment. Reinfections are the most common form of recurrent UTI. Superinfections, a relatively uncommon form of recurrent UTI, are new infections which develop during the course of antimicrobial therapy. Urine cultures will be positive during or immediately after terminating therapy.

Patients with recurrent UTI require additional diagnostic efforts because of the increased probability that conditions predisposing to or complicating infection are present. Therapy of UTI in these patients is most likely to succeed when these conditions are recognized and corrected. Initial patient evaluation should include a review of the medical history, physical examination, urinalysis, urine culture and susceptibility testing, renal function tests (serum urea nitrogen and/or creatinine concentrations), and survey abdominal radiographs. As described above, results of previous urine cultures make it possible to establish whether recurrence is due to relapse or reinfection. If initial tests confirm the diagnosis of bacterial UTI but fail to identify the cause or type of recurrence, consider recommending a four to six week course of antimicrobial therapy.

If infection recurs despite a properly performed course of antimicrobial therapy, further diagnostic efforts are indicated. Differentiating relapse from reinfection provides guidance in selecting appropriate diagnostic tests. Consider performing appropriate contrast radiographic or ultrasound procedures to rule-out urolithiasis, neoplasia, or structural abnormalities, or involvement of the upper urinary tract. Combined urethrography and double contrast cystography appears to be the most sensitive means of evaluating the lower urinary tract. Prostatic involvement may be investigated using ultrasound examination and cytology and culture of semen or prostatic biopsies. Intravenous urography and/or renal ultrasonography are indicated for evaluation of the upper urinary tract.

Definitive diagnosis of pyelonephritis is often difficult. Only bacterial isolation from renal parenchyma or urine obtained from the renal pelvis provide conclusive proof of renal infection. Pyelonephritis may be suspected on the basis of clinical or laboratory findings suggesting renal involvement. While pyelonephritis is most commonly confirmed clinically by diagnostic imaging, these techniques appear to be quite insensitive. Intravenous urography is often used to support a diagnosis of pyelonephritis, but findings are frequently inconclusive and the diagnosis remains tentative. Classic excretory urography findings consistent with pyelonephritis include dilation of the renal pelvis, and blunting, asymmetry, or distortion of the pelvic diverticula. Changes in renal size and shape, presence of renoliths, vesicoureteral reflux, and evidence of urinary outflow obstruction also support the diagnosis of pyelonephritis. Nephrosonography may also be used to support a diagnosis of pyelonephritis. Principal nephrosonographic findings with pyelonephritis include renal pelvic dilatation, usually with proximal ureteral dilatation, and a hyperechoic mucosal margin line within the renal pelvis, proximal portion of the ureter, or both. Additional nephrosonographic findings supporting the diagnosis of pyelonephritis include generalized renal hyperechogenicity, foci of medullary hyperechogenicity, and renal cortical hyperechoic or hypoechoic foci. Normal findings by excretory urography and/or nephrosonography do not exclude a diagnosis of pyelonephritis.

Hyperadrenocorticism is a relatively common yet overlooked cause for reinfections. Dogs with Hyperadrenocorticism are predisposed to UTI because of immunosuppression and reduced urine concentrating ability. Urinalysis findings of dogs with UTI associated with hyperadrenocorticism are often characterized by a lack of inflammatory reaction despite the presence of bacteriuria. Many affected dogs do not have clinical signs of urinary tract disease (asymptomatic bacteriuria). Diagnosis of hyperadrenocorticism should be confirmed by appropriate diagnostic testing (e.g. dexamethasone suppression or ACTH response testing).

Most UTI are easily eliminated by antimicrobial therapy. Antibiotic selection should be based on several factors including ease of administration, risk of toxicity, side-effects, or drug interaction, effectiveness against offending organism(s), and whether the antibiotic reaches therapeutic concentrations in the affected tissues (e.g. urine, kidneys, prostate, or bladder wall). When clients find the recommended antimicrobial therapy to be too expensive, the administration of medication too difficult, or the side-effects of therapy too unacceptable, they are unlikely to follow recommendations, complete therapy and return for necessary follow-up evaluations. Lack of owner compliance is an important cause for therapeutic failure and relapsing UTI (table 4).

The frequency with which a drug must be administered is an important consideration for many owners. Drugs that can be administered orally once daily are more likely to be reliably administered by owners. Urine concentration of enrofloxacin following once daily oral administration is remarkable and urinary levels many times bactericidal concentrations are attained for most uropathogens (table 5; figure 3). Thus, empirical therapy with enrofloxacin can be expected be associated with a high rate of success in treatment of uncomplicated a UTI. Administering the dose of antimicrobial after evening voiding and before bedtime is potentially advantageous in that it allows the bladder to fill with and retain urine with a high concentration of antibiotic for an extended interval period of time, thus maximizing the potential to eradicate pathogens from the excretory pathway. For drugs requiring multiple daily doses, at least one of the doses should be administered after voiding and before bedtime or other extended period of enclosure.

Another important characteristic of drugs selected for managing UTI is a low incidence of toxicity or side-effects. Adverse effects are uncommon with enrofloxacin and largely limited to mild gastrointestinal signs such as anorexia and vomiting. However, they should not be used in young, growing dogs because of the potential for articular cartilage damage.

Although drug interactions are uncommon with fluoroquinolones, several drugs have the potential to interact with fluoroquinolones impairing their absorption from the gastrointestinal tract, thereby promoting therapeutic failures. Cations interact with fluoroquinolones causing significant reduction in drug absorption. Implicated cations include aluminum, magnesium, calcium, iron, and zinc. These compounds are principally of concern in patients with chronic renal failure being treated with phosphate-binding agents (antacids) containing aluminum or calcium, sucralfate for gastric ulcers, or oral iron supplements for anemia. It has been suggested that a 4- to 6-hour interval between administration of these drugs and fluoroquinolones could prevent the interaction.

Two critical factors to consider when selecting an antimicrobial are the activity of the drug against the infecting organism, and the ability of the antimicrobial to reach the site of infection. Fluoroquinolones, including enrofloxacin, are effective against a broad spectrum of both gram positive and gram negative bacteria. However, they are ineffective against anaerobic bacteria. With few exceptions, uropathogens are aerobic bacteria against which enrofloxacin appears to be highly effective (figure 3). Currently available quinolones are reportedly less active against streptococcal species and their activity against Enterococcus may be variable to poor in human isolates. Nonetheless, the high urine concentrations achieved with enrofloxacin therapy may mitigate these limitations. Enrofloxacin and other quinolones are excreted into the urine by both glomerular filtration and tubular secretion and their concentration in urine is increased as water is extracted from the renal tubules.

Recurrent UTI and recent antimicrobial therapy are clear indications for bacterial susceptibility testing. Efficacy of an antimicrobial in treatment of bacterial UTI is best predicted by determining the minimum inhibitory concentration (MIC) of bacteria isolated from the urinary tract. The MIC is defined as the least amount of an antimicrobial agent that inhibits growth of a specific species or strain of bacteria in a defined and reproducible set of in vitro conditions. Efficacy of a drug in treatment of bacterial UTI may be estimated by multiplying the determined MIC of the bacteria isolated from the UTI by four; if this product is less than the predicted mean urine concentration for the drug (table 4), therapy will likely be effective.

Despite the high urine levels attained by many antimicrobials, treatment failures do occur, particularly when the treatment interval is short. At least some treatment failures may be a result of unrecognized pyelonephritis. As previously described, diagnosis of pyelonephritis is at best difficult. It has been estimated that up to 30% of women in a primary care setting and up to 80% of indigent patients seen in emergency rooms with a clinical diagnosis of cystitis also have silent, invasive bacterial infections of the renal parenchyma. Although the classic signs of acute pyelonephritis include pollakiuria, dysuria, pyrexia, systemic signs such as anorexia and vomiting, and flank (renal) pain, with or without septicemia, clinical signs may be limited to dysuria and pollakiuria as a consequence of involvement of the lower urinary tract. In fact, pyelonephritis almost always results from ascent of bacteria from the lower urinary tract. This entity in humans has been termed "subclinical pyelonephritis" and is clinically indistinguishable from lower UTI. The most reliable clue to occurrence of subclinical pyelonephritis is detection of treatment failure on follow-up urine cultures. These patients may also have reduced urine concentrations due to impaired renal tubular function. Although subclinical pyelonephritis has traditionally been referred to as chronic pyelonephritis in veterinary medicine, it has been suggested that the term "chronic pyelonephritis" should be used to describe the pathologic process rather than the clinical syndrome.

The failure rate for treatment of pyelonephritis in humans is very high. Respective rates for relapse and reinfection in acute pyelonephritis have been reported to be 17% and 18% and 44% and 21% with chronic pyelonephritis. Similar data are unavailable for dogs and cats, largely because of the difficulty in identifying patients with pyelonephritis.

Bacterial species responsible for pyelonephritis in dogs and cats have not been well characterized because of difficulty in differentiating from upper and lower UTI. In humans, E. coli is responsible for over 80% of cases of acute uncomplicated pyelonephritis, presumably due to uropathogens that have specific affinity for the kidneys.

In absence of obstruction or renoliths, therapeutic failure for pyelonephritis has been hypothesized to result from bacterial resistance, the presence of L-form bacteria, reinfection with a new pathogen, or use of antibiotics for an insufficient time. Clinical evidence validating any of these causes remains lacking, but the usual therapeutic approach has been to select an antimicrobial based on bacterial susceptibility testing and administer it at an appropriate therapeutic dosage for at least 4 to 6 weeks. To be effective in treatment of pyelonephritis, antibiotics must reach therapeutic levels in renal tissue, particularly within the medulla. Pyelonephritis actually enhances renal tissue accumulation of aminoglycosides and quinolones, while renal tissue accumulation of beta-lactams is reduced. In normal kidneys, enrofloxacin achieves renal tissue levels that exceed serum concentrations. Some new fluoroquinolones have been found to concentrate in the renal parenchyma at levels at least 10 times those of serum and are maintained within the renal medullary tissue for extended intervals after discontinuing therapy.

A strategy that has proven effective in managing humans with difficult pyelonephritis is sequential antimicrobial therapy. This approach combines aminoglycoside therapy with subsequent oral therapy with an additional antimicrobial. Aminoglycosides may reach renal tissue concentrations more than 100 times those observed in serum and levels far in excess of the MIC for most gram negative uropathogens persist for up to 1 year following cessation of therapy. This unique pharmacology of aminoglycosides can be used to reduce their potential nephrotoxicity by limiting their administration to 3 days and continuing therapy with an appropriate oral and less toxic antimicrobial drug such as enrofloxacin, trimethoprim-sulfa, or a beta-lactam. The key point here is that to cure pyelonephritis, it is necessary to achieve inhibitory drug levels in both renal tissue and urine. If pyelonephritis is complicated by septicemia, drugs must be inhibitory in serum as well. Enrofloxacin's excellent in vitro activity combined with good serum, renal tissue, and urine concentrations following oral or parenteral administration make it an excellent choice for these patients. Further, fluoroquinolones may ultimately supplant use of aminoglycosides for managing pyelonephritis in most patients because of their effectiveness of in achieving both renal and urine concentrations with minimal toxicity.

Therapy is successful only if the urine does not contain any pathogenic organisms. Treatment is ineffective and relapse will occur if the bacterial colony count has only been reduced. To confirm that therapy is at least effective in sterilizing urine, a urine sample collected by cystocentesis should be cultured three to five days following initiation of antimicrobial therapy. Performing urine culture at this time is designed to recognize treatment failure so that a prolonged period of unnecessary and expensive antimicrobial therapy can be avoided. If bacterial growth is detected 3 to 5 days after initiating therapy, treatment should be reevaluated. If the urine is sterile 3 to 5 days after initiating therapy, treatment may be continued.

Data concerning the minimum and optimum duration of antimicrobial therapy for UTIs are not available. It is recommended that acute, uncomplicated UTIs and some reinfections be treated for a period of 10 to 14 days whereas most recurrent UTI, complicated infections, pyelonephritis, and prostaitis should be treated for at least 4 to 6 weeks. Infections involving the kidney(s) and prostate gland may require even more prolonged therapy. The client should be informed that amelioration of clinical signs is not a reliable indicator of successful eradication of UTI, and medication should be administered throughout the recommended treatment interval.

Urine may be cultured immediately before discontinuing therapy to ensure that infection has been eradicated and that superinfection has not developed. Bacterial culture should then be performed on urine obtained by cystocentesis 7 to 10 days after completing therapy to detect relapses. Urine should also be cultured approximately 1, 2, 3, 6, and 12 months after terminating therapy to detect reinfections or delayed relapses.