History

Clinical history is essential to the diagnosis and assessment of risk for renal injury. The signalment can direct diagnostic efforts to breed‐related (such as Fanconi’s syndrome in Basenjis, Samoyed hereditary glomerulopathy) or congenital and hereditary disorders such as polycystic kidneys. Intact male and female patients may show signs of urinary tract disorders secondary to vaginal, uterine or prostatic disease. Past medical history, including preexisting renal disease, as well as chronic medication history is assessed. Queries are particularly made regarding any medications that may alter renal hemodynamics or have the potential to be nephrotoxic, such as nonsteroidal antiinflammatory drugs (NSAIDS), angiotensin converting enzyme (ACE) inhibitors (ACEi), antihypertensive drugs, and chemotherapeutic agents. Potential exposure to environmental nephrotoxins, including lilies (toxic to cats), raisins or grapes (toxic to dogs), ethylene glycol or dietary supplements such as alpha‐lipoic acid, vitamin D‐containing toxins, supplements or medications should be identified. Environmental and housing history may highlight the risk of infection with leptospirosis [1,2].

Patients with uremia may have shown signs of hyporexia to anorexia, nausea, vomiting, weight loss, and blood in vomitus (suggestive of gastrointestinal (GI) ulcerations) [1,2,5,6]. The history pertaining to water intake (polydipsia or adipsia) and urination of the animal is essential. Information regarding the estimated amount of urine passed with each effort, the frequency of urination and presence of pain or straining during urination provides essential clues to the underlying disorder. Pollakiuria (increased frequency of urination), polyuria (increase in quantity of urine), and oliguria (reduced urine quantity) are signs of urinary tract problems that the owner has likely observed [7]. The appearance of the urine may direct diagnostic efforts as well; cloudy urine suggests infection, blood in the urine is possible with stones, trauma, hemoglobin or infection, and dark‐colored urine suggests bilirubin, hemoglobin or myoglobin [7,8].

Physical examination

Establishing a baseline for temperature, pulse, and respiratory rate can provide important information regarding any systemic effects of urinary tract disorders. A high body temperature may be present with infectious or inflammatory causes of renal dysfunction. Hypothermia is a common consequence of endogenous renal toxins causing a reset of the thermoregulatory center. Heart or pulse rate can be affected by poor perfusion (tachycardia in dogs, normal rate or bradycardia in cats) or significant hyperkalemia (bradycardia in dogs, tachycardia or bradycardia in cats) secondary to renal failure or urinary tract obstruction or disruption. Severe metabolic acidosis can cause Kussmaul type breathing, while uremic pneumonitis or fluid overload can cause tachypnea and labored breathing.

Physical evaluation of effective circulating volume includes heart rate, pulse quality, mentation, mucous membrane color, and capillary refill time to allow stratification of patients into the categories of compensatory, early decompensatory, and late decompensatory shock [9]. The physical assessment of hydration will include skin turgor, mucous membranes, and corneal moisture [9]. Additional physical examination findings that may indicate the presence of renal disease include oral mucosal ulcerations, decreased body condition in patients with chronic renal failure, and uremic odor to the breath. Special focus should be placed on renal palpation during abdominal palpation to note renal size, symmetry, or the presence of pain. Urinary bladder palpation should be performed to detect pain or a turgid urinary bladder that may suggest obstructive disease. If the urinary bladder is empty of urine and urinary stones are large, they may be palpable on transabdominal palpation. Digital rectal examination can detect some urethral masses, stones, or urethral distension. In male dogs and cats, the penis should be extruded to evaluate for discharge, discoloration, penile or distal urethral masses. In female dogs, digital vaginal exam can be performed if the clinical history warrants it. Fundic examination should be performed to evaluate for signs of hypertensive retinopathy, including tortuous retinal vessels, retinal hemorrhage, or detachment [1,2].

Point of care testing

The initial POC testing begins with the minimum database consisting of packed cell volume (PCV), total protein (TP), blood urea nitrogen (BUN), glucose, electrolytes, blood gas for acid–base analysis, coagulation profile with buccal mucosal bleeding time (BMBT), and urinalysis (UA). Hemoconcentration may indicate dehydration. Anemia indicated by a low PCV can be a result of bleeding or CKD. Hypoproteinemia (low TP) can be present due to albumin loss through the urine (glomerular disease) or concurrent liver disease.

Urea nitrogen is a byproduct of endogenous and exogenous protein metabolism by the liver. Since urea nitrogen is freely filtered from the blood at the glomerulus, the BUN can be useful as a marker of renal glomerular filtration rate (GFR). However, the BUN level will also elevate due to a reduction in renal blood flow in an adequately functioning kidney. Extrarenal influences should be considered when renal function and renal blood flow are adequate [1,2,10]. The BUN can also be elevated due to an increased rate of urea production (postprandial from dietary protein) or GI bleeding. A low BUN warrants assessment of hepatic function.

The blood glucose is evaluated and correlated with the presence or absence of urine glucose. The renal threshold for glucose in the cat is 300 mg/dL (17 mmol/L) and 180 mg/dL (10 mmol/L) in dogs. Glucose found in the urine when the blood glucose is below the renal threshold localizes the problem to a renal proximal tubular disorder [7].

Acid–base and electrolyte abnormalities in patients with renal failure contribute to the clinical manifestations of uremia and are potential therapeutic targets. A high anion gap metabolic acidosis is the most common acid–base derangement in patients with renal failure [2]. However, metabolic alkalosis may be present in patients with renal failure that are experiencing severe vomiting. The acid–base status should be monitored at least daily in any critically ill patient (see Chapter 7) [2].

Serum electrolytes may be abnormal due to kidney failure or postrenal obstruction or disruption. Of emergent interest is serum potassium since it can increase with a relative decrease in urine output. The presence of hyperkalemia warrants evaluation of the electrocardiogram and urine output, and may require immediate intervention to stabilize myocardial conduction. In contrast, patients with chronic renal failure often have low potassium levels due to chronic polyuria, chronically decreased potassium intake and total body potassium depletion (see Chapter 6) [11].

Hypercalcemia can be the cause of acute renal failure or the result of chronic renal failure. The clinical signs associated with hypercalcemia are dependent on the rate and magnitude of rise in serum calcium. Acute, severe increases or long‐standing increases in serum calcium are more likely to result in kidney injury and resultant clinical signs of polyuria, polydipsia, uremia, and lab‐detected azotemia. Differentials for hypercalcemia include hyperparathyroidism, neoplasia including osteolytic processes, hypoadrenocorticism, vitamin D toxicities, some types of granulomatous infections, and chronic renal failure [1,2]. Mild increases in serum calcium do not require specific therapy except to treat the underlying cause. However, severe hypercalcemia resulting in azotemia may require specific interventions, discussed under the acute kidney injury section below. Mild hypocalcemia is a common result of chronic renal failure as renal secondary hyperparathyroidism progresses [11,12]. Hypocalcemia can occur with severe hypoalbuminemia in patients with protein‐losing nephropathies. Clinical signs of hypocalcemia including tremors, tetany, and seizures are uncommon in patients with hypocalcemia associated with renal insufficiency (see Chapter 6).

The BMBT measures the ability to form an initial platelet plug after capillary injury with a lancet. The components of the coagulation system assessed during BMBT measurement are the endothelial and vascular response to injury, including contribution to the platelet plug by platelets and functional von Willebrand factor. The BMBT can be prolonged with severe thrombocytopenia so results of BMBT should be evaluated in conjunction with a platelet count. Uremic coagulopathy is characterized by platelet dysfunction and BMBT may be useful as a screening tool for uremic coagulopathy (see Chapter 9).

The UA provides results that are integral in the diagnosis and monitoring of urinary tract disorders [4]. The testing is best performed on urine that is collected by aseptic methods of cystocentesis or urinary bladder catheterization. The gross character of urine can indicate the presence of hematuria/hemoglobinuria (red urine), bilirubinuria (bright yellow or greenish urine), methemoglobinuria or myoglobinuria (brown to black urine) [7,8].

Differentiating from hemoglobinuria and myoglobinuria can be challenging but because hemoglobin binds tightly to haptoglobin and does not clear as readily from the serum as myoglobin, a patient with a dark pigmented urine and a red coloration to the serum is more likely to have hemoglobinuria, whereas a patient with dark pigmented urine but with clear serum is more likely to have myoglobinuria. Evaluation of urinary and serum pigments in the face of urinary tract disease is important because excretion of an excess of serum pigments can contribute to nephropathy and renal failure [7,8].

Isosthenuria, demonstrated by a urine specific gravity of 1.008–1.020, concurrently with elevation of the BUN and creatinine, is the classic diagnostic criterion for intrinsic renal disease. Urine that is highly concentrated (>1.035) may indicate a prerenal component to the azotemia. Hyposthenuria (<1.008) can narrow the differential list to problems such as psychogenic polydipsia, iatrogenic medullary washout, or nephrogenic or central diabetes insipidus. The UA results beyond urine specific gravity are valuable in determining some etiologies of intrinsic renal insult. The urinary dipstick has test pads for qualitative or semiquantitative assessment for urine protein, glucose, bilirubin, red cells, and leukocytes. The finding of glucosuria without serum hyperglycemia can suggest renal proximal tubular injury [8]. The presence of proteinuria with noninflammatory urinary sediment usually localizes the problem to the glomerulus and is further tested with the urine protein:creatinine ratio [13,14].

Examination of the urine sediment for the presence of casts, crystals, cells, and bacteria provides a reflection of the urine contained in renal tubules and the urinary bladder. The presence of inflammatory cells combined with bacteria supports urinary tract infection and possibly pyelonephritis (white cell casts). Urine cytology can be diagnostic of urinary tract neoplasms if there is exfoliation of neoplastic cells. The finding of crystalluria may assist in the diagnosis of urolithiasis. The presence of calcium oxalate crystals (octahedral or envelope shaped) can be a normal finding in dogs or cats but may also be the result of ethylene glycol toxicity, or indicative of calcium oxalate urolithiasis. Triple phosphate crystals, also called magnesium ammonium phosphate, or struvite crystals (“coffin lid” shaped) can be present in alkaline urine associated with stone formation or bacterial urinary tract infections. Ammonium biurate crystals (yellow‐brown “thorn‐apple” shaped) can be found with portosystemic shunts. Ammonium biurate crystals may also be the result of a genetic defect of the urate transporter, a finding in some normal Dalmations and English Bulldogs [7].

Urinary casts are composed of a matrix of Tamm–Horsfall protein secreted by renal tubular cells, which often contain imbedded cells or cellular debris. Casts mirror the lumen of renal tubules, and are easily identified on urinalysis. Urinary casts are categorized as cellular (red blood cell, white blood cell, tubular cell), granular, waxy or hyaline. Cellular, granular, and waxy casts represent different states of breakdown of the cellular component imbedded in the cast mucoprotein matrix. Cellular casts contain intact and discernible cells including red blood cells, renal tubular epithelial cells or white blood cells. The cells within granular casts have partially broken down, contributing to the granular appearance. The cells within waxy casts have disintegrated and are not discernible, contributing to the waxy appearance. Small quantities of hyaline or waxy casts may be a normal finding on urinalysis. The presence of cellular or granular casts represents tubular pathology. Tubular necrosis and tubular cell sloughing will contribute to tubular casts. Severe hematuria with trauma, coagulopathy, or idiopathic renal hemorrhage may result in red blood cell casts. White blood cell casts may be seen in severe pyelonephritis [7].

In addition to being a diagnostic aid, urinalysis can also be a valuable monitoring tool for the ICU patient. A high urine specific gravity during fluid therapy indicates that dehydration is still present. A lower urine specific gravity during fluid diuresis is appropriate. A daily examination of the urine sediment for tubular casts is a sensitive indicator of tubular injury and is of particular utility when monitoring for nephrotoxicity associated with aminoglycoside or other drug therapy [1,2,4].

Initial clinicopathological testing

A complete blood count (CBC) and serum biochemistry should be performed in patients with azotemia. Red blood cell (RBC) levels should always be interpreted in light of the patient’s fluid balance. Chronic renal failure is associated with normochromic, normocytic nonregenerative anemia secondary to decreased erythropoietin production [11]. If GI bleeding is contributing to anemia, the red cells are typically microcytic and hypochromic because of iron deficiency. Chronic anemia of renal failure can be mild to moderate in severity (see Chapter 10). The presence of leukocytosis may indicate an infectious or inflammatory component to the urinary tract injury.

The serum biochemistry results will assist in the diagnosis of renal failure and, when interpreted with urinalysis, may help with localization to specific parts of the kidney. Creatinine elevation is the most widely used clinical marker of renal function, providing the most rapid and readily available surrogate for GFR [10]. Because serum creatinine is influenced by fewer extrarenal factors than BUN, changes in creatinine can be interpreted as proportional to the degree of renal insult and a reflection of the GFR and rate of tubular flow [1,2,10]. The serum biomarker symmetric dimethylarginine (SDMA) has been evaluated in dogs and cats [15–17]. SDMA has been shown to have a linear and reciprocal relationship to GFR and may be more sensitive than serum creatinine for the detection of chronic kidney disease in cats [15–17]. When the BUN and creatinine are interpreted in conjunction with UA results (such as abnormal specific gravity, proteinuria, renal casts), they remain the standard for the diagnosis of renal failure [1,2,4,10,18].

Increases in serum BUN and creatinine during therapy may signify progressive or ongoing renal injury, may be a warning for the development of oliguria, or may be a marker of inadequate fluid therapy. Decreases in BUN and creatinine during therapy can indicate improved hydration, improved GFR and tubular flow, renal recovery or a combination of these factors [1,2,4,10]. Monitoring the trend of change of BUN and creatinine in hospitalized patients could facilitate early detection of AKI as well as assessing the response to treatment.

Serum phosphorus levels are the result of dietary intake of phosphorus balanced with renal excretion. Hyperphosphatemia is common in patients with acute and chronic renal failure due to decreases in GFR [4]. However, postrenal obstruction or disruption can also cause hyperphosphatemia. Elevations in serum phosphorus can cause a decrease in ionized calcium through renal secondary hyperparathyroidism (rHPTH). Renal secondary hyperparathyroidism has been demonstrated to occur early in renal disease. Calcium‐phosphorus changes have been associated with an increased mortality in CKD in humans, cats, and dogs. When the total calcium and phosphorus product exceeds 60–70, there is an increased risk of malignant calcification of tissues [11].

Evaluation of hepatic function is important when assessing for problems that affect both renal and hepatic function (such as leptospirosis or life‐threatening hepatorenal syndrome). Hepatorenal syndrome is characterized by renal failure as a consequence of end‐stage cirrhotic liver failure. Evidence of hepatic failure such as hypoalbuminemia, alterations in serum cholesterol, low BUN, high blood ammonia, and prolonged clotting times, in association with evidence of renal failure, supports the hepatorenal syndrome diagnosis. Hypoalbuminemia may occur as a consequence of albumin loss secondary to glomerulopathies. Since antithrombin may also be lost through the diseased glomerulus, patients with severe hypoalbuminemia should be assessed for hypercoagulability or for evidence of thrombus formation.

The presence of proteinuria with an active urinary sediment including the presence of red blood cells, white blood cells  + bacteria on the initial urinalysis warrants submission of a urine sample for culture and susceptibility testing. The presence of proteinuria without a reactive sediment directs the submission of urine for a urine protein:creatinine (UPC) ratio to identify potential glomerular sources of urine protein [13,14].

Diagnostic imaging

Urinary tract imaging modalities from plain to contrast radiographs and abdominal ultrasound are complementary in the diagnosis and management of patients with urinary tract pathology. No single imaging technique is preferred as the gold standard of evaluation. Patients with renal failure often undergo several imaging modalities to fully evaluate the upper and lower urinary tract, and to assist in therapeutic recommendations [19].

Radiographic studies

Abdominal radiographs will allow assessment of the size and symmetry of the kidneys and retroperitoneal space, the size of the urinary bladder, the size and position of reproductive organs associated with the urinary tract and the location and shape of other abdominal organs. Canine kidneys will appear as bean‐shaped on radiographs and measure 2.5–3.5 times the length of the second lumbar vertebra. The right kidney is usually one‐half length cranial to the left kidney. Renal size in the cat as measured on the VD radiograph varies from 2.4 to 3.0 times the length of the second lumbar vertebral body (L2). However, it is fairly common for older cats (over 10 years of age) to have kidneys that range from 2.0 to 2.4 times the length of L2, without biochemical changes indicative of renal disease [19].

Abdominal radiographs remain the standard of care for evaluation of the presence of radiopaque urolithiasis (such as calcium phosphate, calcium oxalate, silicate, struvite) anywhere in the urinary tract. Urate and occasionally cysteine uroliths may be radiolucent [19].

Excretory urography is an intravenous (IV) contrast radiographic study that can provide a subjective assessment of renal function [20]. It also detects the presence of pyelectasia or hydronephrosis and can demonstrate urine leakage from the level of the kidneys to the urethra. Table 13.2 provides guidelines for performing urinary contrast studies. The risk of the procedure must be evaluated due to the potential for contrast‐induced renal failure from IV iodinated contrast agents. The patient undergoing the procedure must be well hydrated with adequate perfusion prior to the administration of any contrast agent [20].

Contrast study	Indications	Patient preparation	Procedure	Notes
Excretory urogram	Subjective evaluation of GFR Determination of renal size and position Evaluation of size, and shape of renal pelvis Evaluation for ureteral patency Evaluation for ectopic ureter Evaluation for patency or leaks from the level of the bladder to the ureters and urinary bladder	12–24‐hour fast Serial enemas as needed to clear the colon of fecal material Place IV catheter for contrast injection Sedation as needed to achieve radiographs	Obtain survey lateral and VD abdominal radiographs to ensure clearance of fecal material Administer undiluted iodinated contrast at 400–800 mg/kg IV single bolus Take immediate lateral and VD abdominal radiograph and then timed radiographs at 5, 20, and 40 minutes Oblique radiograph views may be taken to evaluate for ectopic ureter	Iodinated contrast should not be administered to patients who are dehydrated Allergic reactions to iodinated contrast are uncommon and anaphylactic reactions rare Contrast‐induced vomiting is transient and treated with supportive care Contrast‐induced renal failure is uncommon but use of nonionic contrast is advocated to minimize complications IV fluid administration post contrast is recommended to maintain hydration and induce diuresis
Negative‐contrast cystogram or pneumocystogram	Identify size, shape, and location of urinary bladder	12–24‐hour fast Serial enemas as needed to clear the colon of fecal material Sedation as needed to achieve urinary catheter placement and radiographs Sterile urinary catheter placement for contrast injection	Obtain survey lateral and VD abdominal radiographs Pass a urinary catheter with aseptic technique Inject 10 mL/kg of negative contrast Take lateral and VD abdominal radiographs immediately post injection Remove negative contrast from the bladder post procedure for patient comfort	Radiographs can be taken with urinary catheter in place or removed The negative contrast used can be air or medical carbon dioxide Vascular air embolism from diseased urinary bladder wall is a rare but possible complication Use of carbon dioxide may reduce the risk of air embolism
Positive contrast cystourethrogram	Identify size, shape, and location of urinary bladder Evaluate for urinary bladder or urethral diverticula Evaluate for urinary bladder or urethral patency or leakage Evaluate for filling defects for urolith detection or hematomas Evaluate for some bladder mucosal filling defects such as polyps or masses	Same patient preparation as a negative‐contrast cystogram	Obtain survey lateral and VD abdominal radiographs Pass a urinary catheter with aseptic technique Inject 10 mL/kg of sterile iodinated contrast solution Take lateral and VD abdominal radiographs immediately post injection For the urethrogram, pull the catheter back to the distal urethra and take a lateral caudal abdominal radiograph while simultaneously injecting contrast to achieve good filling of the urethra Alternatively a voiding urethrogram can be performed by removing the urinary catheter and taking a radiograph while the patient is voiding or when the bladder is actively being expressed	Iodinated contrast can be diluted with sterile saline (1:2 or 1:5 depending on the original concentration of iodinated contrast agent) and still achieve good opacification of urinary bladder and urethra Radiographs with the pelvic limbs of the patient moved to different positions (pulled cranially or caudally) may be needed for good evaluation of the entire urethra Contrast agent can be removed from the urinary bladder post procedure or the patient can be allowed to void the contrast
Double‐contrast cystogram	Identify size, shape, and location of urinary bladder Evaluate for urinary bladder diverticula Evaluate for urinary bladder leakage Evaluate for filling defects for urolith detection or hematomas Increased resolution for detection of bladder mucosal filling defects such as polyps, masses, and thickenings compared to positive contrast cystogram	Same patient preparation as a negative‐contrast cystogram	Obtain survey lateral and VD abdominal radiographs Pass a urinary catheter with aseptic technique Inject 10 mL/kg of negative contrast Inject sterile iodinated contrast (most have a concentration >/= 200 mg/mL) at a dose of 1 mL/cat, 1–3 mL for dogs <25 lbs, or 3–6 mL for dogs >25 lbs Take lateral and VD abdominal radiographs post injection of positive contrast Remove positive and negative contrast from the bladder post procedure for patient comfort	Undiluted iodinated contrast provides a better study than diluted contrast The negative contrast used can be air or medical carbon dioxide Vascular air embolism from diseased urinary bladder wall is a rare but possible complication Use of carbon dioxide may reduce the risk of air embolism

GFR, glomerular filtration rate; IV, intravenous; VD, ventrodorsal.

Positive contrast and double‐contrast cystourethrograms can be performed to detect bladder and urethral lithiasis caused by radiolucent calculi (see Table 13.2). Positive contrast placed into the urinary bladder can also be used to demonstrate urinary bladder rupture (Figure 13.2). Urinary bladder wall thickness, mural and luminal masses, strictures and polypoid diseases can be highlighted with a double‐contrast cystourethrogram [21].

Glomerular filtration rate

Methods to measure GFR are feasible in clinical practice and include nuclear scintigraphy (using radionucleotides and gamma camera) and iohexol clearance measurements. Iohexol is an iodinated contrast agent that was found to be a suitable marker for GFR. After IV injection, iohexol is eliminated in the urine by glomerular filtration, with no tubular secretion or reabsorption. Plasma iohexol clearance can be calculated with collection and measurement of iohexol in serial blood samples. Laboratory quantitation of iohexol is required by liquid chromatography or x‐ray absorption [25]. Nuclear scintigraphy and iohexol clearance methods of GFR measurement, though accurate, are unable to assess ongoing changes in GFR, and with the time and equipment needed for results, this gives them little clinical utility over the endogenous creatinine clearance in the veterinary ICU [10].

While the standard in human medicine for measuring GFR is the iohexol clearance test, the endogenous creatinine clearance can provide a reasonable estimation. A decrease in clearance indicates a decrease in GFR [25]. When performed correctly, a creatinine clearance test provides the benefit of detecting approximately 20% decrease in renal function, compared to the 75% functional loss that is necessary before elevations in BUN and creatinine concentrations are detected. In order to increase the diagnostic accuracy of creatinine clearance for GFR assessment, this test should only be performed in well‐hydrated, nonazotemic animals. The procedure for performing and calculating the endogenous creatinine clearance is provided in Table 13.4. Inaccuracies with the endogenous creatinine clearance test are possible due to incomplete evacuation of the bladder, tubular secretion of creatinine in some male dogs, possible increased extrarenal secretion of creatinine (such as in the GI tract), and measurement of noncreatinine chromagens in the serum. Creatinine clearance is useful to rule in or out kidney disease in patients with polyuria and polydipsia but without azotemia [25].

The fractional excretion of urinary electrolytes is the fraction of the filtered electrolyte that is then excreted in urine. This urine parameter has been used to assess the appropriateness of renal electrolyte handling by the kidney and aids in localizing the cause of renal azotemia in humans. The fractional sodium excretion is used most commonly [10]. Fractional excretion is easy to measure clinically with spot urine and serum electrolyte measurements normalized by simultaneous urine and serum creatinine measurement [26]. The formula is:

where FE = fractional excretion, Na = sodium, Cr = creatinine. In humans, the results are used to help differentiate prerenal disease (FE <1%) from acute tubular necrosis or other kidney disease (FE >2–3%) [10,26]. Interpretation of fractional sodium excretion in veterinary medicine is challenged by lack of normal reference intervals and due to large intra‐ and inter‐patient variability reported in fractional excretion [10]. Fractional excretion measurement has not been shown to be of additional value over monitoring BUN and creatinine trends in the veterinary ICU [10,26].

Urine biomarkers

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