CHAPTER 32 Urinary Tract Disorders
The Upper Urinary Tract
The recognition and management of renal disease are important in small animal practice: Cats are popular companions, and the average life expectancy has increased. The purpose of this chapter is not only to explore renal disease in depth but also to remind veterinarians that although the clinical signs may look the same, they should strive to identify specific etiologies insofar as these may have specific treatments.
Various diagnostic methods are available for evaluation of the upper urinary tract, including imaging, renal function tests, urinalysis, urine culture, urine protein : creatinine ratio, and renal biopsy. Table 32-1 describes how diagnostic tests can be used to localize disorders.
Renal size is measured radiographically relative to the length of the second lumbar (L2) vertebra. Although there is no difference between the sexes in this parameter, there is an effect of gonadectomy on kidney size. A significant size difference was determined between intact and neutered cats, with intact cats having larger kidneys. Normal feline renal length ratios range from 1.9 to 2.6 for neutered cats and 2.1 to 3.2 for intact cats, which suggests that reproductive status should be taken into consideration when interpreting renal size.202 Box 32-1 lists the causes of renomegaly in the cat.
Assessment of renal function using the standard measures of urine specific gravity (USG), creatinine (Cr), and blood urea nitrogen (BUN) is extremely crude because these parameters are not altered until significant renal function has been lost (approximately 75%) and because they also reflect nonrenal factors. BUN can be especially difficult to interpret because it reflects ammonia intake, production, and excretion. Urea is a by-product of ammonia metabolism that is excreted in bile, reabsorbed by way of enterohepatic recirculation, and also is eliminated by the kidney. The majority of the ammonia produced in the body is by bacterial fermentation in the gut, with lesser amounts produced by catabolism of endogenous protein and other molecules such as heme and some of the cytochromes that are rich in nitrogen. Because dietary factors can be important—there have been reports of animals fed organ meats as treats that produced spuriously high urea readings—everything the patient is ingesting must be taken into consideration. Bleeding into the gastrointestinal tract is one of the most common pathologic causes because of the large amount of nitrogen in blood, which is broken down by the bacteria. Other potential causes include factors that could change the amount of ammonia being produced by the bacteria in the gut, such as shifts in bacterial populations and changes in motility and gastrointestinal transit of food. Any metabolic derangement that causes excessive catabolism of protein in the body as an energy substrate has the potential to increase urea levels. Increases in urea (independent of Cr) are common in diabetes mellitus (DM) and hyperthyroidism. Interestingly, urea can be elevated in renal disease when Cr is normal, especially in neonates or animals with muscle wasting insofar as these patients have decreased muscle mass compared with the normal population and therefore correspondingly lower Cr levels. In this situation urea may be more sensitive than Cr for predicting renal disease. In most cases, a diagnosis of renal insufficiency will be made based on elevations in BUN and/or Cr along with a dilute USG.
Numerous tests have been evaluated for the assessment of glomerular filtration rate (GFR) or renal function. The standard 24-hour Cr clearance test is unwieldy, and renal scintigraphy is not widely available.121 One group evaluated a single injection of either inulin or Cr in normal cats and then compared plasma inulin and Cr clearances.The results showed that inulin may be a better indicator of GFR than Cr.166 The same researchers subsequently assessed iohexol and found that plasma clearance of this marker not only is a sensitive test for the detection of diminished renal function before changes in either BUN or Cr but also can be performed noninvasively in conscious cats.167 Another single-injection inulin clearance study compared inulin and iohexol clearance and showed excellent correlation between the two methods in their ability to detect alterations in GFR. The investigators concluded that an “inulin excretion test” sampling blood 3 hours after the administration of 3000 mg/m2 body surface area can be used for the assessment of renal function in daily practice.100 Excretory urography is another method to determine GFR; one study compared iohexol with amidotrizoate and concluded that iohexol was safer and produced better-quality urograms.6
Renal hemodynamics (resistance and pulsatility index) of intrarenal arteries has been studied using pulsed-wave Doppler; quantitative scintigraphy (99mTc-MAG3) was used to study relative renal function and relative renal blood flow. Of clinical relevance is that significant differences were found between awake and isoflurane-anesthetized cats for all pulsed-wave Doppler and quantitative renal scintigraphic measurements.165 Recently, a group evaluated an enzyme-linked immunosorbent assay (ELISA) test for gadolinium diethylenetriamine pentaacetic acid as a means to determine GFR. This test did not offer a sufficiently accurate estimation of GFR in cats when compared with plasma clearance of iohexol and plasma concentrations of BUN and Cr.203 Box 32-2 lists additional tests for renal function.
BOX 32-2 Diagnostic Tests for Evaluation of Renal Function
A urinalysis is indicated as part of a minimum database in any ill cat. For example, pyelonephritis is an occult condition without necessarily any clinical signs referable to the urinary tract. Urinalysis results reflect the health and function of many body systems because urine is, in essence, filtered blood. Examples of some of the non–urinary tract conditions with significant changes detected through urine evaluation include DM (glucosuria) and ketoacidosis (ketonuria), diabetes insipidus (hyposthenuria), hepatic disease and hemolytic disease (bilirubinuria), prerenal azotemia (concentrated urine), and severe inflammation or multiple myeloma (proteinuria).
Throughout this chapter the term urinalysis refers to a complete urinalysis consisting of macroscopic evaluation (e.g., appearance, concentration, semiquantitative urine biochemical dip strip tests for pH and urine constituents: protein, glucose, blood) a USG assessment, and microscopic evaluation of spun urine sediment (e.g., cells, crystals, bacteria).
As with any laboratory test, it is possible to generate invalid and misleading results. The usefulness of a urine specimen is significantly affected by the timing of collection and the way it is collected, handled, stored, and examined. Additionally, the veterinarian should note all the drugs that a patient is receiving because many therapeutic agents affect the results of urinalysis (Box 32-3).177
BOX 32-3 Effects of Drugs on Urine Sample
Samples collected after fasting or in the early morning may show highest concentrating ability and highest yield of sediment. The exception to this is the cat with access at all times to a litter box. This sample is also least likely to show glucosuria. Cytologic quality of the cells will be altered by prolonged exposure to waste products, osmolality, and pH variations.
Recently formed urine provides better cytologic detail, and bacteria are more easily identified. If the sample is dilute, tubular concentrating ability cannot be evaluated. Dilute samples also may distort cells.
The most reliable method for collecting urine from cats is by cystocentesis. Cystocentesis samples reflect prerenal, renal, ureteral, and bladder health. Voided samples reflect the aforementioned, as well as the urethra, prostate, vagina, and perineal fur. Further, voided samples reflect where the cat has urinated (e.g., the litter box, consultation table, or floor). The yield of the sediment must also be interpreted in light of collection technique. The bladder contracts circumferentially; however, sediment depends on gravity. Thus, for a cystocentesis-collected sample, the sediment yield may be improved by gently shaking the bladder just before inserting the needle.178 Voided samples also do not reflect sediment proportionately because of sediment remaining in the bladder as it contracts; thus samples collected in this manner may underestimate the degree of inflammation, crystalluria, and so on.
Cystocentesis: The bladder must contain a sufficiently large volume of urine for the veterinarian to be able to identify it by palpation and immobilize it manually. The two approaches used are either through the lateral abdominal wall with the cat on its side or ventrally with the cat in dorsal recumbency. Ideally, the hair is shaved and the skin disinfected; however, as this adds to stress for the patient, it is often not performed. After the bladder is agitated, the needle should be inserted in the caudoventral direction on an angle so that the layers of the bladder wall seal the puncture better. By using a smaller-gauge needle (e.g., 23 to 25 G) and not applying pressure to the bladder with the mobilizing hand, the veterinarian can reduce the risk of urine leakage.
If a swirl of blood is seen to enter the hub of the syringe, collection should be discontinued and the blood (an iatrogenic cause for hematuria) should be noted in the medical record. This bleeding is extremely unlikely to result in postcollection complications, however. Iatrogenic hematuria is commonly seen in cystocentesis samples and may be differentiated from true hematuria by comparison with a free catch–voided sample collected by the client at home 24 to 48 hours later. Clients can use a long-handled spoon such as a soup ladle or put clean aquarium gravel or Nosorb in a clean, empty litter box to collect the sample. Penetration of a bowel loop during cystocentesis is unlikely to cause problems other than in the interpretation of bacteriuria (discussed later). The most disconcerting postprocedural complication is the rare occurrence of vomiting and hypotensive collapse. Although the mechanism is unclear, it is believed to be a vasovagal response. With standard fluid therapy (to support volume and systemic blood pressure [BP]) and quiet, patients recover within 30 minutes to 1 hour.
Voided sample: Midstream collection reduces the chance of collecting debris (particulate material including feces and bacteria) from the perineal region; however, a voided sample is never completely free from risk of contamination. Veterinarians often make do with samples collected from the examination table, examination room floor, cage, litter box, or carrier base. These may also be used as long as the veterinarian is aware that the sample is likely to include artifacts (and know which types are most likely).
Catheter collection is another possibility; however, it requires sedation in both sexes to ensure humane treatment and minimize potential trauma to the urethra. In the very young kitten (younger than 3 or 4 weeks of age), a urine sample may be obtained by stimulating the anogenital region with a warm moist cotton ball.
In an ideal world urine should be kept at room temperature and evaluated within 30 minutes of collection. Storage time and temperature alter and affect pH, USG, and crystal formation.7 If it cannot be examined in this time frame, the following suggestions will help preserve the integrity of the specimen.
1 Refrigerate at 41° F (5° C) for 2 to 3 hours or possibly overnight. The sample should be warmed to room temperature before analysis for accuracy of USG and for glucose assessment. Do not freeze the sample.
To minimize interassay variation, a standardized protocol should be used for every sample. Refrigerated samples should be rewarmed to room temperature before evaluation. Urine strips and other reagents should be kept cool but not refrigerated. These and the urine should not be exposed to sunlight or other light for significant amounts of time. It is important to read and interpret the test results at the times designated by the test manufacturer. Centrifugation of urine sediment should be at 1000 to 1500 rpm for 3 to 5 minutes. Most important, the timing and method of collection should be taken into consideration when interpreting the significance of the results relative to the patient.
Volume: The normal 24-hour urine volume production for an adult cat is 20 to 40 mL/kg per day. When the USG is greater than 1.040, polyuria is unlikely. Occasionally, cats with renal insufficiency may paradoxically concentrate their urine above 1.040.
Color: Clarity and color are affected by many things, which, in turn, affect the USG value perceived with an optical refractometer. Conversely, urine color should also be interpreted in light of the USG. The color of the sample may be important insofar as it can affect interpretation of the colorimetric dry chemistries (urine strips). Color comparisons are subjective and are affected by colored urine constituents. Color should be assessed by a trained professional, in a consistently well-lit area and using fresh urine (Figure 32-1). Urine color may provide valuable information, including the following:
• Normal urine color ranges from transparent to light yellow, medium yellow, and amber. Normally, highly concentrated urine is amber as a result of increased urochrome or urobilin. Urochrome levels are also high in states of fever or starvation. Nitrofurantoin and riboflavin (vitamin B2) will cause urine to appear deep yellow.
• Red, pink, red-brown, red-orange, or orange color suggests hematuria, the presence of hemoglobin, myoglobin, porphyrin, or warfarin. In humans ingestion of rhubarb, beets, phenothiazines, and other substances may cause this discoloration.
Turbidity: Transparency is assessed by holding a clear glass tube against a printed page and assessing the legibility of the print. Concentrated urine is more likely to be turbid than dilute urine. Refrigeration changes clarity, as do substances affecting pH. Most commonly, turbidity is caused by sediment—namely, crystals, cells (red blood cells, white blood cells, epithelial cells), bacteria, yeast, semen, or contaminants from the collection container (as well as litter box, carrier, table top, floor) or feces. If there is lipid (from pericystic fat) in the urine, it will rise to the surface of the sample.
Crystal formation is affected by temperature; these may form as urine cools from body temperature to room or refrigerator temperature. Hematuria results in brownish to reddish (rarely black) turbid urine. Myoglobin and hemoglobin create a similarly colored, but clear, urine.
Odor: Cat urine has a characteristic odor that is stronger when the urine is concentrated. Tomcat urine has an almost pathognomonic smell that helps identify an intact cat or a cat that has been incompletely castrated (e.g., retained testicle) or a cat with a testosterone-secreting tumor. It has been speculated that felinine, the amino acid unique to cats, is responsible for this smell.
Abnormal odors may indicate infection with urease-producing bacteria. Warm temperature facilitates transformation of ammonium [NH4] to ammonia [NH3], resulting in odor. The odor of urine ketones may be detected by some humans. A putrid smell suggests bacterial degradation of protein.
USG: USG is a measure of the density of the urine relative to the density of water measured at the same temperature. The density of water is 1.000 under set circumstances of temperature and pressure. Temperature affects USG inversely (i.e., increasing urine temperature causes a decrease in its USG, whereas decreasing the urine temperature increases the USG). Solutes affect the density of urine, and each solute may affect it to a different degree, even when each one is present in equal amounts.
The accepted method for determining USG in cats is by using a refractometer. This tool assesses refractive index (ratio of velocity of light in air to the velocity of light in a solution). The refractive index is affected by the type and quantity of solutes present. Although refractometers are calibrated to a reference temperature, they compensate to a certain degree. They should be stored at room temperature. Veterinary refractometers measure a wider range of specific gravity and are therefore best suited for cat urine that may have USG in excess of 1.080. Human refractometers read only to 1.050. Digital refractometers appear to correlate with optical refractometers and have the advantage of less subjectivity.22 Some reagent strips include a pad for USG. Because these are developed for human urine, the highest value they detect is 1.030, which is inadequate for feline urine. Urinometers, devices that float in urine to measure USG, are imprecise. Osmometers assess osmolality rather than specific gravity. Regardless of the method used, all factors that affect refraction still should be taken into consideration.
The normal USG for a cat depends on hydration status and age. By the time a kitten is 4 weeks of age, USG is 1.020 to 1.038; full concentrating ability (up to 1.080) is reached by 8 weeks of age. In a dehydrated cat normal renal function (specifically, concentrating ability), is suggested by USG of 1.040 or above, depending on the diet fed. In cats fed exclusively canned food, a “normal” USG may be 1.025 or greater, whereas in cats fed exclusively dry food, USG should be 1.035 to 1.040 or higher.52 In a well-hydrated cat, it may fall between 1.035 and 1.060. Specific gravity varies within the same individual throughout the day; therefore a single urine sample with a low USG is not reliable evidence of a decline in renal function.
When nephrons are no longer able to modify glomerular filtrate, a fixed USG of 1.008 to 1.012 develops. USG of 1.007 to 1.039 in a dehydrated cat with or without azotemia is highly suggestive of renal insufficiency (or renal failure, depending on the degree of azotemia once the patient is rehydrated).176 Hypoadrenocorticism and hyperaldosteronemia are less common causes of such a drop in urine concentration. There is a subgroup of cats with impaired renal function that paradoxically remain able to concentrate urine to greater than 1.045, such that renal azotemia precedes a decline in USG.177 Because these patients are uncommonly identified, veterinarians must rely on finding USG of 1.045 or greater in the face of azotemia as indicating a prerenal cause for the azotemia.
Urine pH: Urine pH can be used as an index of body acid–base balance; however, this parameter changes so rapidly to provide homeostatic balance to the body that it is a rough guide at best. Obligate carnivores create a great deal of acidic metabolic waste. They regulate their acid–base balance by excreting hydrogen (H+), ammonium ion (NH4+), and phosphates (PO4+) in urine (metabolic route) and by exhaling CO2 (respiratory route). pH is one of the factors affecting crystal formation and may be manipulated to encourage dissolution of some crystal types. Acidic urine inhibits bacterial growth.
Stress affects urine pH. In one study it was reported that the urine pH of a cat increased by 1.4 U when the cat was transported from home to a veterinary clinic. The authors concluded that the most likely cause was anxiety-induced hyperventilation (excessive panting).43 Another study suggested the opposite—namely, that increasing activity of the sympathetic nerves and the adrenal glands will most likely lead to increased metabolism, including catabolic conversion of proteins, which in turn increases sulfuric acid production and lowers urinary pH. This effect can also be seen in the fasted, inappetent, or anorectic cat.60
Eating affects urine pH. Postprandial alkaline tide (alkaline urine) is believed to be a result of increased hydrochloride acid secretion after a meal. In their feral state cats eat many (8 to 15) small meals per day rather than two, as are fed in many homes, making the effect of this pH swing much smaller. Frequency of feeding along with quality of food ingested and the composition of the meal will affect urine pH. Higher-protein, meat- and fish-based diets create more acidic urine; lowerprotein, grain- and vegetable-based diets create more alkaline urine.
The pH of urine in the healthy “normal” cat generally ranges between 6.0 and 7.5. The pH of urine least likely to result in crystal formation is 6.2 to 6.4. The method used to measure urine pH is critical; pH meters are inexpensive and are most accurate. Hydrogen paper (pH 5.5 to 9.0) is satisfactory. The urine reagent strips most commonly used in clinics are extremely unreliable. pH values measured with reagent strips are accurate only to within 0.5 units, meaning that the color subjectively translated into a pH value may vary by +/− 0.5, resulting in one whole unit variability.
Acidic urine may be a result of an acidifying diet, respiratory or metabolic acidosis, diabetic ketoacidosis, renal failure, starvation or anorexia, pyrexia, protein catabolism, hypoxia, or severe diarrhea. Severe vomiting resulting in chloride depletion may cause paradoxical acidosis.
Alkaline urine is associated with an alkalinizing diet; drug therapy; respiratory or metabolic alkalosis; vomiting; renal tubular acidosis; chronic metabolic acidosis resulting in ammonium ion (NH4+) secretion; and infection with urease-producing bacteria, such as Proteus and Staphylococcus, organisms seen infrequently in the urinary tract of cats.
Drugs may alter urine pH. Acidifiers include DL-methionine, furosemide, ammonium chloride (NH4Cl), ascorbic acid at supertherapeutic doses, and phosphate salts. Alkalinizing agents include sodium bicarbonate (NaHCO3), potassium citrate, sodium lactate, and chlorothiazide.
Artifacts affecting urine pH include containers contaminated with detergents or disinfecting agents, CO2 loss resulting from storing urine at room temperature, and contamination of the sample by urease-producing bacteria from the environment or the distal urethra.
Glucose: The glucose pad on a urine strip is a colorimetric test based on glucose oxidase activity. Although it is easy to use, several points are worth noting. Because the test involves multiple enzymatic steps, it must be performed according to label instructions. The colorimetric indicators can react with substances other than glucose, and some substances may inhibit the test; this means that false-positive and false-negative results are possible. Glucose oxidase is labile, so the expiration date of the strips should be respected. The reaction is also pH dependent. Because the test is temperature dependent, the urine has to be tested at room or body temperature.
Glucose is filtered by the glomerulus and reabsorbed by the proximal tubules. Physiologic or stress glucosuria occurs when serum glucose exceeds the renal threshold for glucose of greater than 260 mg/dL (14 mmol/L). Pharmacologic agents that can result in transient glucosuria include epinephrine, phenothiazines, glucagon, adrenocorticotropic hormone (ACTH) and morphine. Persistent glucosuria may be a result of DM, hyperprogesteronemia, acromegaly, hyperadrenocorticism, and pheochromocytoma. Renal glucosuria may be caused by acute tubular injury.
Ketones: Ketones (ketone bodies) are produced when metabolism shifts to using stored fat as a source of energy, such as in cellular starvation (unregulated DM or lack of eating) or when excessive fat is ingested. In other species it also occurs with insufficient carbohydrate metabolism. The three ketones produced are acetoacetic acid, acetone, and beta-hydroxybutyric acid. The first two are detectable in urine using the reagents in urine strips; beta-hydroxybutyric acid is not. All three types can be measured in blood. Another colorimetric reaction on urine strips, ketone pad color interpretation, is subjective and is affected by colored urine constituents.
Bilirubin: Bilirubin is a by-product of heme (from hemoglobin) catabolism. The portion that is bound to albumin (unconjugated/indirect bilirubin) is removed from circulation by the liver where it is conjugated. Once conjugated, it is water soluble. The majority of the conjugated portion is transported in bile to the intestinal tract, where bacteria convert it into urobilinogen. It is oxidized to urobilin, the pigment that provides the brown color to feces. A small amount of the urobilinogen is reabsorbed into circulation and is excreted into urine. The small quantity of conjugated bilirubin that evades the bile is excreted into glomerular filtrate.
An increase in urinary bilirubin is associated with increased destruction of red blood cells (hemolytic disease), hepatocellular disease preventing normal elimination of this product, or bile duct obstruction (cholestatic disease). Altered selective permeability of glomerular capillaries in glomerulonephropathy can also potentially cause bilirubinuria by changing the renal threshold of affected nephrons. Bilirubinuria may precede clinically recognizable icterus and even bilirubinemia. Unlike in dogs, bilirubinuria is not found in normal cats, even in highly concentrated urine samples, presumably because of a higher renal threshold for bilirubin in this species.177
Bilirubin is an unstable compound, especially when exposed to room air or light. The degradation products formed under those circumstances (including biliverdin) do not react with the test, causing false-negative test results. To avoid this, urine should be evaluated within 30 minutes of collection or be refrigerated, kept dark, and (for other tests) brought to room temperature just before analysis. This test should also be run before centrifugation (or filtration) because precipitates in the centrifuged (or filtered) sample may absorb bilirubin.
Urobilinogen: The reagent strip test detects normal and increased amounts but not the absence of urobilinogen. Because of this, it cannot be used to detect complete bile duct obstruction. Increased concentration is suggestive of hemolytic disease or decreased hepatic function. For results to be meaningful, a fresh urine specimen is required.
Occult blood, hemoglobin, and myoglobin: Hemoglobinuria (red to brown urine) is suggestive of intravascular hemolysis; a serum sample from the patient collected concurrently should have a reddish discoloration. Myoglobinuria (brownish urine) is suggestive of muscle disease; the serum from the patient may be clear.
Free hemoglobin and myoglobin, but not intact red blood cells, cause a positive reaction. This urine strip chemical reaction augments and complements the microscopic findings of red cells on urine sediment evaluation. This test must be interpreted in concert with the USG as well as the microscopic sediment evaluation. Very dilute or very alkaline urine may lyse red cells. Serum creatinine kinase should be assessed when a positive reaction occurs and hemoglobinemia has been ruled out to differentiate between myoglobinuria and hemoglobinuria.
Lack of red cells in the sediment with a positive test reaction implies hemoglobinuria, myoglobinuria, low urine concentration, low pH causing red cell lysis, or misidentification of red cells in the sediment. When red blood cells are seen on microscopic examination but the urine test pad is negative, it suggests that the strips are outdated, the sample was improperly mixed or centrifuged, there are too few red cells in the sediment to hemolyze, or red cells have been misidentified in the sediment.
Hematuria indicates blood loss into any part of the urinary tract. Identification of the site of bleeding is the next step. Idiopathic renal hematuria has been recognized in cats and dogs. It is not known whether it is due to a vascular bed abnormality or to an abnormality in podocyte attachment, as occurs in humans.220
Protein: Numerous types of protein (as many as 40 kinds) may be found in the urine of cats. Hemoglobin and myoglobin have already been mentioned. Protein detected in urine may be prerenal, glomerular, or postglomerular in origin. Small amounts of protein are routinely found in the urine of healthy individuals, but under normal circumstances plasma proteins included in urine are restricted by size and are 66,000 daltons or lower. Because protein loss may be transient, it is essential to verify that proteinuria is persistent before considering appropriate diagnostics and therapeutics. Sample-to-sample variation may be considerable. Centrifugation removes cells that may be causing positive reactions; therefore if protein is detected on an uncentrifuged sample, the test should be repeated on the supernatant after centrifugation.
The aspects of the glomeruli that determine whether protein leaves the glomerular capillaries are size, electrical charge, and hemodynamics. In general, proteins at or below 45,000 daltons with a positive charge are most likely to pass through. Albumin is 66,000 daltons and has a negative charge, which is why there are negligible amounts of albumin in the urine of a cat with normally functioning glomeruli despite high plasma concentrations (Table 32-2). Plasma hemoglobin is normally bound to haptoglobin, making it too large to cross the glomeruli. When this binding capacity is exceeded, as may occur in hemolysis, then unbound hemoglobin can enter urine.
|Protein||Approximate Molecular Weight (Daltons)||Implication When Found in Urine|
|Smaller proteins (e.g., beta2-microglobulin, muramidase)||11,800-14,400||Unknown|
|Myoglobin||17,600||Ischemic or traumatic injury to muscles (heat stroke, electrocution, severe muscular exertion, snake bite, crush injury)|
|Bence Jones proteins||22,000-44,000||Multiple myeloma|
|Hemoglobin (unbound to haptoglobin)||64,500||Low urine specific gravity, alkaline urine, intravascular hemolysis|
|Albumin||66,000||Significant glomerular disease|
Adapted from Osborne C, Stevens J, Lulich J et al: A clinician’s analysis of urinalysis. In Osborne C, Finco D, editors: Canine and feline nephrology and urology, ed 1, Baltimore, 1995, Williams & Wilkins.
Because tubules reabsorb filtered protein, a great deal of protein has to be lost through the glomeruli, exceeding the capacity of the functional or impaired tubules to reabsorb it, for it to be present in the ultrafiltrate. Some proteins originate from the urinary tract. The distal tubules and collecting ducts secrete Tamm–Horsfall mucoprotein. The urothelium secretes immunoglobulins as necessary (e.g., to protect against ascending infection).
Interpretation of the significance of protein in urine depends on the USG. For example, mild 1+ proteinuria with USG of 1.010 implies greater protein loss than 1+ protein in a sample with USG of 1.040. Localization of the protein source requires knowledge of collection technique and the urine sediment constituents (Table 32-3).
|Urinary Protein Source||Findings|
|Hemorrhage into urinary tract (trauma, inflammation, neoplasia)||Occult blood test +, TNTC red blood cells + white blood cells in sediment, high protein|
|Inflammation in urinary tract||Variable number of white blood cells in sediment, protein rarely >2+ unless concurrent hemorrhage|
|Infection in urinary tract||Many white blood cells and bacteria in sediment, protein rarely >2+ unless concurrent hemorrhage|
|Glomerular and/or tubular disease||No occult blood, no significant sediment findings, +/− casts, protein higher in glomerular than tubular disease|
|Functional extrarenal causes for transient glomerular changes (e.g., fever, stress, extreme environmental temperatures, seizures, venous congestion of kidneys, exercise)||No occult blood, lack of significant sediment findings, +/− casts, high protein, transient|
|Hemoglobinuria, myoglobinuria||Variable amounts protein, no significant sediment findings|
TNTC, Too numerous to count.
Adapted from: Osborne C, Stevens J, Lulich J et al: A clinician’s analysis of urinalysis. In Osborne C, Finco D editors: Canine and feline nephrology and urology, ed 1, Baltimore, 1995, Williams & Wilkins.
Numerous test methods exist to detect urine protein, each having a different specificity and sensitivity. It should be noted that small amounts of protein normally found in urine are not detected by routine methods. When 4+ (approximately 1000 mg/dL) protein is found in the supernatant of a centrifuged specimen, a urine protein : Cr ratio (UPC) should be performed. The UPC should be repeated two to three times at 2-week intervals to verify the persistence of the problem before pursuing additional diagnostics (e.g., biopsy) or therapeutics.
The reader is referred to the ACVIM Consensus Statement143 for a comprehensive discussion of causes, significance, identification, and management of proteinuria in dogs and cats. This topic is discussed in greater detail later in this chapter.
Urine sediment: Microscopic examination of urine sediment is akin to exfoliative cytology of the urinary tract. It is critically important in the interpretation of color, specific gravity, turbidity, protein, pH, occult blood, and so forth. Without this procedure it is not possible to differentiate, for example, proteinuria caused by glomerular disease from that of inflammatory response to bacterial insult at any level of the urinary tract or the genital tract. Conversely, the sediment cannot be interpreted without knowledge of the physical and biochemical characteristics of the sample.
To minimize interassay variation, a standardized procedure should be followed. Centrifugation speed for urine sediment is slow: 1000 to 1,500 rpm for 3 to 5 minutes. Faster or longer centrifugation will lead to artifacts. Normal constituents in urine sediment include a few epithelial cells, red and white blood cells, hyaline casts, some fat, mucus, sperm, and some struvite or oxalate crystals. Yeast bodies are contaminants. Abnormal constituents in urine sediment include more than a few red or white blood cells; hyperplastic or neoplastic epithelial cells; more than a few hyaline or granular, cellular, hemoglobin, fatty, or waxy casts; a large number of crystals; any parasite ova; bacteria in a properly collected, transported, and prepared sample; or many yeast organisms.
Storage of urine can alter crystalluria dramatically and therefore the clinician’s diagnosis and treatment planning. A study performed to look at the effects of storage on the diagnosis of crystalluria and casts in cats with no history of urinary tract disease was performed. Crystalluria was detected in at least one aliquot in 92% of stored samples as opposed to only 24% of samples examined fresh. Regardless of whether the sample was stored or fresh, urine from cats fed an exclusively canned diet did not have crystals.208
Pitfalls of interpretation may be avoided by examining unstained sediment using a reduced microscope light intensity. This can be achieved by either lowering the condenser or closing the iris diaphragm. Stain artifact may include bacteria growing in the stain and foreign material. Stain should be filtered weekly or monthly (depending on the number of samples being examined) and should be kept in the refrigerator. Additionally, staining procedures that require washing and counterstaining may result in loss of sediment in the process. Ideally, some of the sediment should be examined unstained, and if there is enough, some of it should be saved for staining. A lack of bacteria on examination does not mean that bacteria are not present.
In cats with chronic kidney disease (CKD), the prevalence of urinary tract infections (UTIs) is 22%; in cats with uncontrolled DM and in cats with hyperthyroidism, it is 12%. Many cats with UTIs have no clinical signs of lower urinary tract disease or changes in their laboratory values indicative of infection.156 Because UTI is so common in cats with hyperthyroidism, DM, and CKD, urine culture and sensitivity is recommended as part of the minimum database for cats with these conditions, especially if the USG is 1.030 or lower regardless of sediment and, in more concentrated samples, if significant numbers of white blood cells or bacteria are seen. Box 32-4 shows causes of negative growth on urine culture in the face of the detection of bacteria in the sediment.
BOX 32-4 Factors that May Explain Lack of Growth on Urine Culture when Bacteria Were Identified in the Sediment
Renal proteinuria occurs by one of two mechanisms. The first is a loss of integrity of the glomerular filtration barrier in excess of tubular reabsorption capacity; this may cause mild to marked proteinuria. The second occurs when the tubules fail to reabsorb normal proteins; this may cause mild to moderate proteinuria. Cr is excreted by the kidneys exclusively by glomerular filtration. Comparing these two urine components gives a measure of protein loss relative to renal function. The equation is simple:
In cats a UPC below 0.2 is considered nonproteinuric. Values between 0.2 and 0.4 reflect borderline proteinuria and should be reassessed within 2 months and reclassified as appropriate. A UPC above 0.4 is considered clinically significant proteinuria.
In humans microalbuminuria is predictive of future renal health. In cats the predictive significance of microalbuminuria is not understood at present. The recommendation of the International Renal Interest Society (IRIS; www.iris-kidney.com/) is to continue to monitor this level of proteinuria.96
The reader is referred to the ACVIM Consensus Statement143 for a comprehensive discussion of the causes, significance, identification, and management of proteinuria in dogs and cats. (This topic is also discussed later in this chapter.)
Imaging studies commonly used in the assessment of the upper urinary tract of cats include survey radiography, contrast excretory studies, and ultrasound. The normal signal intensities have been determined for magnetic resonance imaging (MRI) of the normal feline cranial abdomen.173 Each test has a role to play in patient diagnostics. Plain radiographs allow assessment of the number, size, location, and density of the kidneys. The limitations of survey radiography include an inability to visualize kidneys in the thin cat lacking retroperitoneal fat or if retroperitoneal fluid is present. Moreover, survey radiography cannot delineate problems of the renal pelvis or of the ureters unless there is radio-opaque material present (e.g., renoliths or ureteroliths, dystrophic mineralization) (Figure 32-2). Fecal material may obscure the outflow tract. Abdominal compression (e.g., using a wooden spoon over the organ of interest or a general abdominal wrap) may help enhance the image of a specific area by eliminating some of the superimposition encountered with survey radiographs.11
FIGURE 32-2 This radiograph shows a cluster of radio-opaque calculi in the bladder lumen as well as five smaller densities in the kidney. On ultrasound two calculi were also seen in the ipsilateral ureter.
Excretory urography is the technique of choice when the renal parenchyma, renal pelvis, or ureters are of concern. This study may be useful to establish the relationship between a renal mass and the pelvis or ureter, to locate an avulsed or congenitally displaced kidney, to identify and possibly distinguish between acute and chronic pyelonephritis, to detect a nonfunctional kidney, to diagnose hydronephrosis, and to outline radiolucent uroliths.119
Ultrasound has the advantage of being noninvasive and quick. It is safer for the patient because no contrast material is needed and safer for the patient and owner because there is no exposure to ionizing radiation. It can be used to guide renal biopsy should this be indicated. This modality is useful for evaluating renal masses, cysts, diseases of the renal pelvis (calculi, hydronephrosis, pyonephrosis53) and adjacent abdominal structures. Although it is difficult to visualize the normal feline ureters ultrasonographically, various abnormalities associated with ureteral dilation may be revealed, including ectopic ureter, ureterocele, and certain causes of ureteral obstruction. Ultrasonographic evidence of hypoechoic subcapsular thickening in feline kidneys is associated with renal lymphosarcoma.215 Ultrasound guidance facilitates certain interventional diagnostic procedures for the ureters.135 Its limitations include the inability to visualize structures through abdominal air or bone (i.e., pelvic structures occlude the urethra).
Histopathology of a kidney biopsy sample can provide information by revealing a pathologic process other than chronic interstitial nephritis. Patient selection is important. This procedure should be recommended in those individuals whose treatment will change because of information the results provide. Thus those with proteinuria believed to be of glomerular origin, those with ultrasound evidence of infiltrative disease, or those in ARF are appropriate candidates. The benefits of biopsy in patients with renomegaly outweigh risks; in general, however, for patients with small, scarred kidneys, it is unlikely to be of use. To obtain the best possible results, the veterinarian must be well prepared and understand the laboratory’s sample-handling requirements.214 The laboratory should ideally be able to perform not just light microscopy but also electron microscopy (EM). The latter requires a specific transport medium, gluteraldehyde, which is available through the laboratory.
Two centers that provide this comprehensive service are the Texas Veterinary Renal Pathology Service (Texas A&M University, College Station, Tex) and the Veterinary Pathology Diagnostic Centre (Utrecht University, Utrecht, The Netherlands). They encourage submission as part of the World Small Animal Veterinary Association (WSAVA) Renal Standardization study in order to increase understanding of glomerular diseases of dogs and cats. EM is needed for complete histologic examinations, especially to define early stages of kidney diseases (minimal changes disease, epithelial tubular pathologies, and tubular basement membrane and glomerular basement membrane changes). Along with clinical, histologic, histochemical, and immunologic examinations, it is an essential method for diagnosis and prognosis of renal disease.198 Because complications after renal biopsy are usually minor, provided the biopsy is performed properly, this tool for diagnostic evaluation should be encouraged.164,214
A sample may be collected by tissue-core biopsy (e.g., Tru-Cut) percutaneously with ultrasound guidance or surgically by laparotomy or keyhole approach. The first technique requires only very good sedation and local analgesia, whereas the latter requires general anesthesia. Regardless of technique, monitoring for postprocedural bleeding is critical. This and other possible complications (e.g., peritonitis, local infection, neoplastic seeding) still occur in fewer than 2% of patients undergoing percutaneous sampling. Unless the procedure inadvertently interferes with significant vasculature, GFR is not substantially affected.74 By guiding the biopsy needle through cortex only from pole to pole, the veterinarian is able to avoid the medulla and the medullary-cortical junction and significant vascular supply (Figure 32-3). The patient should be monitored to ensure that adequate analgesia is being used; palpation over and around the biopsy site will be a good guide. Renal biopsy is contraindicated in patients with coagulopathy, those receiving drugs affecting bleeding, and those with cavitated lesions (e.g., vascular lesion, cyst, abscess, hydronephrosis) to avoid leakage of contents or bleeding.26 More information on performing renal biopsy can be found later in this chapter.
FIGURE 32-3 This drawing depicts the correct way to direct the renal biopsy needle. The needle should remain in the renal cortex and not cross the corticomedullary junction or enter the medulla or the renal pelvis.
(From Vaden SL: Renal biopsy: methods and interpretation, Vet Clin North Am Small Anim Pract 34:887, 2004.)
Renal anomalies are rare in cats. The most common familial disorders in cats include renal amyloidosis, renal dysplasia, polycystic kidney disease, glomerular basement membrane disorders, and tubular dysfunction (Fanconi’s syndrome).98 Errors of embryologic development that have been recognized in cats include agenesis, renal fusion, ectopic kidney, and cysts.
In reports of renal agenesis, the right kidney is more likely to be absent along with its ureter (in toto or partially). In affected females the uterine horn on the same side is also partially or completely missing. The ovary, having a different cellular origin, is present. In affected males the vas deferens and epididymis may be lacking, but the ipsilateral testicle will be normal.81
In the recent literature, two cases with urogenital abnormalities have been reported. The first, a 9-month-old female domestic shorthair, was lacking the right kidney and ureter and a segment of the uterine horn on the same side. The cat was brought in because of acute vomiting, depression, and shivering caused by hydrometra of the right uterine horn segment.51 The second case described was of a 1.5-year-old female Persian with azotemia and inappetence. Like the earlier case, the cat also had renal and ureteral agenesis with segmental aplasia of the uterine horn on the right side; however, in this cat the affected uterine segment was caudal, resulting in cranial uterine horn distention.91 In a study in which 257 Ragdoll cats were screened for polycystic kidney disease, 0.8% were identified with renal agenesis/aplasia.179 In a large study of more than 53,000 cats presented for ovariohysterectomy, uterine anomalies were detected in 0.09% of cats (n = 49). The kidneys were also evaluated in 34 of the affected cats, and ipsilateral renal agenesis was found in 29% (10 of 34).158
Crossed renal ectopia with fusion was identified in an adult neutered male cat that was presented for polyuria and polydipsia and shown to have renal disease and hypertension. Imaging revealed an ectopic left kidney fused with an orthotopic right kidney.8 Bilateral renal dysplasia was found in a 5-month-old Norwegian Forest Cat; histopathology revealed primary tubular disorganization and changes in the glomeruli.10
Membranoproliferative glomerulonephritis (GN) was reported in a 9-month-old domestic shorthair cat in Japan.15 In another report a series of 8 young, related Abyssinian cats of both sexes presented with hematuria and were found to have varying degrees of proteinuria. Six of the eight developed nephrotic syndrome with peripheral edema. Histopathology revealed mild glomerular changes, including mesangial hypercellularity with adhesions between Bowman’s capsule and the glomerular tuft consistent with focal proliferative glomerulopathy. Genetic analysis was not available in this report.222
In Norway, 11 Ragdoll cats were evaluated after two unrelated queens were found suddenly dead as a result of oxalate nephrosis with chronic or acute-on-chronic underlying renal disease.105 Renal abnormalities were found on ultrasound of five cats. Although investigated as an inherited condition, the etiology and mode of inheritance were not elucidated. Primary hyperoxaluria was ruled out by urine oxalate and liver enzyme analysis.
Polycystic kidney disease (PKD) is found in Persian, Himalayan, and Exotic Shorthair cats around the world and is reported extensively in the United States,58 United Kingdom,46 Australia,17,20 France,18 Italy,31 and Slovenia.69 The prevalence rates in these studies are between 40% and 50%. Many young Persian cats are asymptomatic, and renal function may not begin to decline until the cat is 7 or 8 years of age. Other breeds of cats manifest this condition rarely; a case report describing a Chartreux cat was recently published.217 It has been shown to have an autosomal dominant mode of inheritance in all of these breeds.27,153 All affected individuals are heterozygous for the causative mutation; homozygous individuals die in utero. Concurrent with the renal cysts, unilocular or multilocular cysts may be seen in the liver with or without congenital hepatic fibrosis,33 as well as other abdominal organs (Figure 32-4).69
(Courtesy Dr. Susan Little.)
Cats may exhibit no clinical disease, slowly progressive renal insufficiency as adults, or significant disease as young cats, with marked renomegaly. Because of the variable clinical picture and because of the autosomal dominant inheritance in a pedigreed population, screening to identify affected individuals is essential. The condition may be unilateral or bilateral with irregular, enlarged kidney (or kidneys) on palpation. Radiographically, the affected kidney will be irregularly enlarged; on excretory urogram multiple radiolucent areas will be seen. Ultrasound is readily available and may help identify affected cats long before they show clinical signs. Thus sonographic screening is recommended in kittens older than 13 weeks of age; a skilled ultrasonographer can detect cysts in affected kittens as young as 6 to 8 weeks of age. Absence of cysts at a young age does not predict that the kitten will not develop them at a later age. Conversely, a cat with cysts may never show clinical disease. Cysts are located in the medulla or cortex (or both) and are anechoic to hypoechoic, round to irregularly shaped structures of variable size that may grow over time (Figure 32-5). Affected kidneys have indistinct corticomedullary junctions and may have mineralized foci. Further evaluation using intravenous contrast medium allows more definitive identification of cysts with computed tomography (CT), as well as identification of distortion of the renal pelves by cysts.189
FIGURE 32-5 A, Ultrasound of the left kidney of a cat with polycystic kidney disease. Note the anechogenicity of the cyst. B, This ultrasound is of the right kidney and shows that cysts are of variable sizes within the same cat.
(Courtesy Dr. Edward Javinsky.)
Genetic testing has been developed to detect a C→A transversion at position 3284 on exon 29 of the PKD1 gene, resulting in a stop mutation. A real-time polymerase chain reaction (PCR) assay using fluorescent hybridization probes and melting curve analysis has recently (2009) been developed that may be as reliable but faster than previous methods.63 It is, however, recommended to use both ultrasound as well as genetic testing to improve sensitivity and specificity32 to decrease the prevalence of the disease in the Persian population.58 PKD is the leading cause of renal disease in Persian and Persian-related breeds.
Therapy for hepatic and renal cysts is warranted when there is significant compression of adjacent tissue or pain from capsular stretch. Drainage may be performed using ultrasound guidance. In one study of dogs and cats, the drained cysts were infused with alcohol for two periods of 3 minutes. Short-term discomfort was noted in all the patients, with anorexia, lethargy, or vomiting occurring in some.229
Interestingly, although dogs with renal cysts and humans with PKD have hypertension, cats with PKD are normotensive. One study that looked at the effects of the angiotensin-converting enzyme inhibitor (ACE-I) enalapril on BP, renal function, and the renin-angiotensin-aldosterone system (RAAS) in affected cats compared with healthy controls found that the ACE-I reduced BP in all and resulted in changes in RAAS enzyme activities and hormone concentrations with minimal effects on renal function.163
Much less common than PKD, perinephric pseudocysts (PNPs) surround one or both kidneys, which may be normal or subnormal in size. Not a true cyst, the fibrous sac lacks an epithelial lining; thus the fluid it contains is extravasated rather than secreted. There is no single etiology, and this condition may follow renal trauma (urine leakage resulting in scarification) or perirenal fat necrosis (resulting in inflammation), may be associated with neoplasia (e.g., transitional cell carcinoma186), or may be categorized as idiopathic. Regardless of the initiating cause, anechoic fluid accumulates between the renal capsule and the parenchyma. The sac is often at a pole, but the fluid dissects between the kidney and its capsule or is extracapsular. Fluid cytology reveals a transudate with urea nitrogen close to that of serum. Because the structure does not communicate with renal parenchyma, contrast does not fill it, and on ultrasound it is seen to envelop the kidney rather than exist within it. One report describes a case in which the pseudocyst communicated with the pleural space, resulting in hydrothorax. Unilateral nephrectomy of the affected kidney resulted in resolution of the hydrothorax.191
Affected cats are generally older (older than 8 years of age); there is no sex or breed predisposition.21,175 The lesion is initially detected on palpation; renal insufficiency may be diagnosed on the basis of serum biochemistries and urinalysis, either due to associated interstitial fibrosis or the effect of compression. Imaging reveals the nature of the lesion (Figure 32-6).
(Courtesy Dr. Edward Javinsky.)
Surgical resection of cyst walls is recommended, although reduction by drainage may provide temporary relief. There is one report of cyst wall omentalization with good long-term outcome.108 Another case report describes laparoscopic fenestration of the capsule wall with resulting improvement in GFR of the affected kidney; no relapse was seen.157 In other cases renal disease progresses, with the outcome being related to the severity of the renal disease.