Symmetric dimethylarginine is a biomarker that has the potential to supplant other GFR assessments in terms of ease of use and detection of early CKD. This biomarker is a byproduct of protein methylation that is freely filtered through the glomerulus and excreted primarily by renal clearance and it is correlated with serum Cr and GFR. It has been demonstrated to increase earlier than serum Cr as GFR decreases, making it potentially useful in early detection of disease.11 Unlike Cr, SDMA is not affected by muscle mass, so it is a more sensitive measurement of renal function in patients with muscle loss. However, like Cr, SDMA is affected by dehydration, and therefore should be interpreted in conjunction with USG.

The International Renal Interest Society (IRIS) CKD staging schema ( e-Box 35.1) has incorporated SDMA to aid in assessment of patients with muscle loss with the caveat that the comments are preliminary and based on early data. A persistent increase in SDMA above 14 µg/dL may be consistent with early renal dysfunction and may be a reason to consider a cat in IRIS stage 1. In muscle-wasted IRIS stage 2 patients, an SDMA >25 µg/dL may indicate that renal dysfunction has been underestimated and recommendations for IRIS stage 3 should be considered. Similarly, in ­muscle-wasted IRIS stage 3 patients, an SDMA >45 µg/dL may indicate renal dysfunction more consistent with IRIS stage 4.

The utility of SDMA has been assessed in certain ­disease situations:

Our understanding of SDMA is still developing, and several caveats should be considered when interpreting results. Although it can be helpful in early detection of disease, it may not always be elevated in cats with early CKD. The influence of various disease states on SDMA is also still being explored. Urine specific gravity should also be considered, and a patient is best assessed using all available information. Finally, it is important to note that there are other influences on SDMA and Cr that may produce conflicting results (e.g., high SDMA with normal Cr) or results that vary over time such as normal individual variation, variability in reference ranges among laboratories, and the potential for other influences on SDMA that are not yet well-explored.¹⁷

Penetration of a bowel loop during cystocentesis is unlikely to cause problems other than in interpretation of bacteriuria. The most disconcerting postprocedural complication is the rare occurrence of vomiting and hypotensive collapse.18 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 rest in a quiet location, patients recover within 30 minutes to 1 hour.

Collecting a midstream voided sample 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. Artifacts reported in the analysis must be interpreted in context of sampling technique.

Another possible technique is collection with a catheter. It requires sedation in both sexes to ensure humane treatment and minimize potential trauma to the urethra. In kittens 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.

Urine should be kept at room temperature and evaluated within 30 minutes of collection. Storage time and temperature affects crystal formation.19 If it cannot be examined within this time frame, the following suggestions will help preserve the integrity of the specimen.

To minimize interassay variation, a standardized protocol should be used for every sample. Most important, the timing and method of collection should be taken into consideration when interpreting the significance of the results relative to the patient. Key points for examination of urine include:

A summary of the key points in interpretation is presented here; more information may be found in published articles.23,24

Volume: the normal 24-hour urine production for an adult cat is 20 to 40 mL/kg. When the USG is greater than 1.040, polyuria is unlikely. Occasionally, cats with kidney disease 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 considering 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 (Fig. 35.1). Urine color may provide valuable information, including:

USG: Urine specific gravity 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 may affect the density of urine, and each solute may affect it to a different degree, even when each one is present in equal amounts. However, in a study where glucose was added to urine samples from 102 dogs and 59 cats, there was minimal alteration in USG in most samples (the greatest difference was 0.008).25 This suggests USG can be used to assess renal concentrating ability in most, but not all, cats with glucosuria (e.g., cats with DM).

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. The device should be stored at room temperature. Veterinary refractometers measure a wider range of specific gravity than those designed for humans and may be better suited for cat urine where a USG >1.080 can occur. Refractometers for human urine read only to 1.050. However, human and veterinary refractometers may also provide slightly different readings. There is some controversy about which is more accurate when trying to establish cutoff values for normal concentrating ability. In a study of urine samples from 27 cats and 31 dogs, USG was determined using five refractometers (including two designed for cats) and compared with the precise weight of total solids.²⁶ Each refractometer reported a different USG value and the two refractometers designed for cat urine reported falsely low USG values. The authors commented that the imprecision of refractometers makes it difficult to use precise cutoff values for normal USG and recommended that the variability of refractometer performance should be considered in clinical assessments. Therefore, monitoring trends in USG in an individual patient may be more helpful than a single USG value.

Digital refractometers appear to correlate with optical refractometers when used with cat urine and have the advantages of ease of use and less subjectivity.²⁷ Some reagent strips include a pad for USG. These are developed for human urine; because the highest value they detect is 1.030, they are not accurate 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 must be taken into consideration.

The normal USG for a cat depends on hydration status and age. Kittens do not have fully developed urine concentrating ability, and the age at which this is reached may be variable. In a well-hydrated adult cat, USG may fall between 1.035 and 1.060. In a dehydrated cat, normal concentrating ability is suggested by a USG of 1.040 or above. The cat’s diet may also affect USG. Healthy cats fed exclusively canned foods may have a USG as low as 1.030.^28,29 Specific gravity varies throughout the day; therefore, a single sample with a low USG is not reliable evidence of a decline in renal function (Box 35.2).

Stress affects urine pH in cats. In one case report, the urine pH of a cat increased by 1.4 U when the cat was transported from home to a veterinary clinic.30 The authors concluded that the most likely cause was anxiety-induced hyperventilation (excessive panting). 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.³¹ This effect can also be seen in the fasted, inappetant, or anorectic cat.

Eating affects urine pH. Postprandial alkaline tide (alkaline urine) is believed to be a result of increased hydrochloride acid secretion after a meal. In a feral state, cats eat 8 to 15 small meals per day rather than two, as many pets are fed, 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. High protein meat- and fish-based diets create more acidic urine while lower protein 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 urine pH 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. H⁺ paper (pH 5.5 to 9.0) is satisfactory. The urine reagent strips commonly used in veterinary 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 of variability.

Acidic urine may be a result of a diet that is animal protein–based, 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 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, ascorbic acid at supertherapeutic doses, and phosphate salts. Alkalinizing agents include sodium bicarbonate, 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 distal urethra or from the environment.

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 must 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 (>260 mg/dL [>14 mmol/L]). Pharmacologic agents that can result in transient glucosuria include epinephrine, phenothiazines, glucagon, adrenocorticotropic hormone, or morphine. Persistent glucosuria may be a result of DM, hyperprogesteronemia, acromegaly, hyperadrenocorticism, and pheochromocytoma. Renal glucosuria may be caused by acute tubular injury and anecdotally has also been observed in late-stage CKD.

Urine glucose monitoring should not be used for titration of insulin dose in a diabetic cat because the relationship between serum glucose concentration and that in the urine is variable. However, it may be helpful in monitoring for onset of diabetic remission in cats treated with insulin.

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, hepatic lipidosis, or lack of food intake) 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 test strips but beta-hydroxybutyric acid is not. Another colorimetric reaction on urine strips, ketone pad color interpretation, is subjective and is affected by colored urine constituents.

Bilirubin: bilirubin is a byproduct of heme (from hemoglobin) catabolism. The portion that is bound to albumin (unconjugated or indirect bilirubin) is removed from circulation by the liver where it is conjugated. Once conjugated, it is water soluble. Most of the conjugated portion is transported in bile to the intestinal tract where bacteria convert it to urobilinogen. It is oxidized to urobilin, the pigment that provides the brown color to feces. A small amount of 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 RBCs (hemolytic disease), hepatocellular disease preventing normal elimination of bilirubin, or bile duct obstruction (cholestatic disease). Altered selective permeability of glomerular capillaries in glomerulonephropathy can 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.

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 strip, causing false-negative test results. To avoid this, urine should be evaluated within 30 minutes of collection or be refrigerated, kept dark, and (as 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 present after centrifugation) 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 patient’s serum may be clear. Note that hemoglobinuria and myoglobinuria may cause a false positive bilirubin result with urine reagent strips and laboratory assays due to color interference.

Free hemoglobin and myoglobin, but not intact RBCs, 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 creatine 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 RBCs are seen on microscopic examination, but the urine test pad is negative, it suggests 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.

Protein: as many as 40 types of protein may be found in the urine of cats. Hemoglobin and myoglobin have already been mentioned. Protein detected in urine may be preglomerular, glomerular, or postglomerular in origin. Small amounts of protein are routinely found in the urine of healthy individuals, but under normal circumstances plasma proteins in urine are restricted by size to 66,000 daltons or less. 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 in an uncentrifuged sample, the test should be repeated on the supernatant after centrifugation.

The factors 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 normal glomerular function despite high plasma concentrations (Table 35.2). 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, unbound hemoglobin can enter urine.

Because tubules reabsorb filtered protein, a great deal of protein must 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 when necessary (e.g., to protect against ascending infection).

Interpretation of the significance of proteinuria depends on USG and sediment characteristics. For example, mild (1+) proteinuria with a USG of 1.010 implies greater protein loss than finding 1+ protein in a sample with a USG of 1.040. Localization of the protein source requires knowledge of collection technique and the urine sediment constituents (Table 35.3). One study showed that the presence of blood in feline urine may result in increased UPCR even if hematuria is not visible; therefore, urine sediment examination should be considered when interpreting UPCR.³²

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