Azotemia is defined as an abnormal concentration of urea, creatinine, and other nonprotein nitrogenous substances in blood, plasma, or serum. Azotemia can be associated with several fundamentally different causes. Because nonprotein nitrogenous compounds (including urea and creatinine) are endogenous substances, abnormally elevated serum concentrations may be caused by an increased rate of production (by the liver for urea; by muscles for creatinine) or by a decreased rate of clearance (primarily by the kidneys).1
Azotemia should not be used as a synonym for kidney disease since it may be caused by lower urinary tract abnormalities or other nonrenal factors, and kidney disease can be present in the absence of azotemia. Although blood urea nitrogen (BUN) and creatinine concentrations are commonly used as crude indices of the glomerular filtration rate (GFR), meaningful interpretation of these parameters depends on recognizing and evaluating prerenal, primary renal, and postrenal factors that may reduce GFR.
Creatinine is a nonenzymatic breakdown product of phosphocreatine in muscle, and daily creatinine production is determined largely by individual muscle mass. In dogs and cats, creatinine excretion is accomplished almost exclusively by glomerular filtration, and the creatinine concentration is inversely related to GFR.2
Measurement. Creatinine concentrations can be measured by several methods. The alkaline picrate method is most commonly used. It measures the rate of color development (typically orange) when creatinine is complexed with alkaline picrate. Results may tend to be higher than those obtained with autoanalyzers that use an enzymatic method (e.g. i-Stat [Abaxis]) because of the presence of noncreatinine chromogens. The Jaffe reaction is a form of the alkaline picrate method. Some autoanalyzers (including portable analyzers such as VetScan [Abaxis]) use an adaptation of the Jaffe reaction that can separate creatinine from noncreatinine chromogens.3 Thus, results from different measurement techniques cannot be directly compared.
A number of plasma constituents can interfere with creatinine measurement in dogs and cats.4,5 High serum bilirubin concentrations (3 mg/dl) can falsely lower creatinine concentrations.4,5 Glucose, fructose, pyruvate, acetoacetate, uric acid, ascorbic acid, and plasma proteins can all cause the Jaffe colorimetric assays to yield falsely high creatinine concentrations in people.3 As a rule, interfering chromogens increase the creatinine result by about 20%, but with some diseases, the interference can be much greater. For example, people with diabetic ketoacidosis can have marked spurious elevations in serum creatinine concentrations.3 Cefazolin can increase the serum creatinine concentration in dogs and cats by 50% to 300% when it is measured by using the Jaffe reaction.5 With marked renal insufficiency, as serum creatinine concentrations rise, noncreatinine chromogens contribute proportionally less to the total reaction.3,5 Noncreatinine chromogens do not affect the variability of plasma creatinine concentrations.3 Therefore, clinicians should be less concerned about noncreatinine chromogen interference when serum creatinine concentrations are markedly elevated, and measurement methods using enzymatic reactions are less affected by interference from most substances except bilirubin.4,5
Normal serum creatinine concentrations in dogs and cats vary depending on the laboratory used. Trends should be interpreted from values from a single laboratory and its reference ranges because results from different laboratories cannot be precisely compared.6
Limitations of measurement. Measurement is fast and inexpensive; however, a serum creatinine concentration has low sensitivity and specificity as an endogenous marker of GFR. It is influenced not only by GFR but also by factors affecting creatinine production such as muscle mass and cachexia. Young animals have lower creatinine concentrations, whereas males and well-muscled individuals have higher concentrations. Greyhounds have slightly higher serum creatinine concentrations than do non-greyhounds.7 If a greyhound's GFR is normal, an increase in creatinine concentration is probably attributable to increased muscle mass.7 The serum creatinine concentration is not affected appreciably by diet.
Blood urea nitrogen
Urea production and excretion do not occur at a constant rate. While renal dysfunction can cause increased BUN concentration, nonrenal causes also often result in increased BUN concentration. In the liver, BUN is a byproduct of the urea cycle and protein catabolism. Urea production and excretion increase after a high-protein meal, so an eight- to 12-hour fast is recommended before measuring BUN concentration to avoid the effect of feeding on urea production. Clinical conditions characterized by increased catabolism (e.g. starvation, infection, fever) also can increase BUN concentrations.
Gastrointestinal (GI) hemorrhage may also increase BUN concentrations because blood is an endogenous protein source. In 52 dogs with hematemesis, melena, or both, BUN concentrations and BUN:creatinine ratios were significantly higher than in age-matched control dogs, suggesting that GI hemorrhage contributes to increased BUN concentrations in dogs as a consequence of increased GI absorption of nitrogenous compounds.9 BUN concentrations may be increased by prerenal factors such as dehydration, which increases urine volume, and some drugs that increase tissue catabolism (e.g. glucocorticoids, azathioprine) or decrease protein synthesis (e.g. tetracyclines), but these effects are usually minimal.9
In contrast, BUN concentrations may decline in patients with portosystemic shunts or hepatic failure and those receiving low-protein diets. Reduced BUN concentrations may be an undesirable finding in patients with CKD because this may indicate protein calorie malnutrition from inadequate protein intake as a consequence of improperly formulated diets or patients not consuming adequate amounts of food. Because many extrarenal factors influence the BUN concentration, creatinine concentrations are often used as a more reliable measure of GFR in patients with CKD.
BUN concentrations should be interpreted with knowledge of simultaneously obtained serum creatinine concentrations, particularly in patients consuming reduced-protein diets. The ratio of BUN to serum creatinine concentration should decline to the lower end of the reference range when dietary protein intake is reduced (usually to around 10 to 15; reference range = 7 to 37).9 In patients consuming reduced-protein diets, an increased ratio may suggest poor dietary compliance, enhanced protein catabolism, GI hemorrhage, dehydration, anorexia, or declining muscle mass.2
Potassium is excreted primarily by the kidneys; 90% to 95% of ingested potassium is excreted in the urine.10,11 Potassium is filtered by the glomerulus, with 70% reabsorbed in the proximal tubule, an additional 10% to 20% reabsorbed in the ascending loop of Henle, and a final 10% to 20% delivered to the distal tubule for final determination of urinary potassium concentration.
Serum potassium concentration can vary depending on whether the kidney failure is acute or chronic. In patients with acute oliguric or anuric kidney failure, the potassium concentration is typically elevated because of decreased excretion and may occur for several reasons. First, there is insufficient time for the kidneys to adapt to nephron loss, which occurs in CKD but not in acute kidney disease. Second, effective urinary excretion of potassium is altered because of decreased distal tubule blood flow in states of severely decreased GFR. Third, metabolic acidosis and release of potassium from tissues during a catabolic state also contribute to hyperkalemia.
In cats with CKD, hypokalemia is attributed to chronic potassium wasting, whereas most dogs with CKD have normal potassium concentrations. Determining the fractional excretion of potassium (FEK+ ) may help differentiate renal and nonrenal sources of potassium loss.
This index relates the amount of potassium excreted to the amount filtered.11 Because urine potassium and creatinine concentrations are typically much higher than serum concentrations, these values are usually determined by sending samples to a commercial laboratory instead of by using cage-side analyzers. Random measurement of the urinary potassium concentration is simple to perform but may be less accurate than measurement from a 24-hour urine collection, since it is influenced by two independent factors: potassium secretion and water reabsorption in the medulla. The FEK+ should be < 4% for nonrenal sources of loss. Values > 4% may indicate inappropriate renal loss.10,11
HYPERPARATHYROIDISM AND CALCIUM
Calcium metabolism is regulated by parathyroid hormone (PTH), calcitriol (1,25-dihydroxycholecalciferol), and calcitonin. The major organs involved in its regulation are the kidneys, the small intestine, and bone. The total calcium concentration is composed of three fractions: protein-bound calcium (35%), ionized calcium (50%), and complexed calcium (15%).10 Ionized calcium is the biologically active form.
Fewer than 10% of dogs with CKD have increased serum ionized calcium concentrations. When ionized calcium concentrations were measured in 490 dogs with CKD, 9% were hypercalcemic, 55% were normocalcemic, and 36% were hypocalcemic.12 The use of adjustment formulas to correct total calcium based on serum protein or albumin concentrations are an inaccurate way to determine ionized calcium and are not recommended.13
Calcium disturbances in patients with CKD are a result of decreased vitamin D metabolism through multiple mechanisms. In the later stages of CKD, the loss of functional renal mass leads to decreased production of 1-alpha-hydroxylase, an enzyme that converts calcidiol to calcitriol (the active form of vitamin D). However, studies in people have also shown a suppression of enzyme activity due to associated aspects of the disease, including metabolic acidosis, hyperphosphatemia, and uremic toxins that accumulate in CKD.14
In dogs and cats with secondary (renal) hyperparathyroidism, laboratory tests may reveal previous hypocalcemia or normocalcemia and hyperphosphatemia. In addition, dogs and cats with secondary hyperparathyroidism have extremely elevated intact PTH concentrations and decreased vitamin D concentrations. In contrast, dogs and cats with tertiary hyperparathyroidism, which occurs after a prolonged period of secondary hyperparathyroidism and excessive PTH stimulation, will have normal or elevated serum calcium concentrations in combination with moderately elevated intact PTH concentrations.10 Laboratory tests in patients with tertiary hyperparathyroidism may also reveal decreased vitamin D (1,25-dihydroxycholecalciferol, calcitriol) and phosphorus concentrations and elevated alkaline phosphatase activities.15
Hypercalcemia promotes soft tissue mineralization, which is most pronounced when the calcium-phosphorus product is > 50.16 Acute intrinsic renal failure occasionally develops as a consequence of hypercalcemia; however, chronic intrinsic renal failure is far more common.10 The main cause of hypercalcemia in dogs with potential subsequent hypercalcemic nephropathy is pseudohyperparathyroidism secondary to neoplasia, such as lymphoma, anal sac adenocarcinoma, mammary carcinoma, and multiple myeloma.10,16 Azotemia caused by hypercalcemia may result from a combination of renal vasoconstriction, prerenal reduction in extracellular fluid volume (anorexia, hypodipsia, vomiting, and polyuria), and acute tubular necrosis from the ischemic and toxic effects of hypercalcemia. With CKD, nephrocalcinosis, tubulointerstitial inflammation, and interstitial fibrosis cause progressive nephron loss.
Phosphorus metabolism is regulated by the same hormones as calcium: PTH, calcitriol, and calcitonin. It is absorbed primarily in the duodenum, and absorption is increased by the influence of calcitriol. Intestinal phosphorus absorption is decreased with glucocorticoids, increased dietary magnesium, and hypothyroidism.
Phosphorus is primarily excreted by the kidneys. Most (80% to 90%) of the filtered load is reabsorbed by the proximal tubules. PTH decreases phosphorus reabsorption and is the most important regulator of renal phosphate transport.17
Hyperphosphatemia is commonly seen in patients with acute and chronic kidney disease because of decreased renal excretion. Other potential causes of hyperphosphatemia include increased intestinal absorption (vitamin D toxicosis, increased dietary phosphorus), from transcellular shifts (hemolysis, tumor lysis syndrome), or growth (juveniles, neonates).17 Hyperphosphatemia is not typically associated with clinical signs, but high concentrations leading to an elevated calcium x phosphorous product (> 50) may contribute to soft tissue mineralization.
URINE SPECIFIC GRAVITY
Urine osmolality and urine specific gravity (USG) are used to assess the kidneys' ability to concentrate or dilute urine. Although urine osmolality is the most accurate method to detect urine solute concentration, USG is an easier, cheaper, and more practical measurement in a clinical setting. A USG > 1.030 in dogs and > 1.035 in cats indicates adequate urine concentration. Generally, primary renal disease can be excluded if azotemia is seen with adequate concentrating ability; however, a small percentage of cats develop azotemia and clinical signs of CKD yet maintain urine-concentrating ability.18,19
Always interpret USG in light of an animal's drinking habits in the context of its physiologic state.20 Hyposthenuric urine may be seen with primary (psychogenic) polydipsia and central diabetes insipidus, but it can also occur secondary to conditions that cause nephrogenic diabetes insipidus such as hypercalcemia, pyometra, heavy metal toxicosis, and hyperadrenocorticism. Medications such as glucocorticoids, phenobarbital, and diuretics may also cause dilute urine.21 Use caution when interpreting USG after hetastarch administration as it may lead to an overestimation of urine concentration.22 Kidney failure is commonly misdiagnosed in dogs with hypoadrenocorticism. Mineralocorticoid deficiency and subsequent hyponatremia lead to decreased tonicity of the renal medullary interstitium, leading to inappropriate USG in the face of azotemia (secondary to hypovolemia).
In dogs, persistent renal proteinuria with urine protein:creatinine (UPC) values ≥ 2 is usually due to glomerular disease. UPC values ≥ 0.5 are evidence of persistent renal proteinuria when they are found repeatedly in three or more samples obtained two or more weeks apart and cannot be attributed to prerenal or postrenal causes. In dogs, relative risks of development of uremic crises and death were three times higher in dogs with UPC ≥ 1 compared with dogs with UPC < 1.23
In cats, UPC values ≥ 1 should prompt suspicion of glomerular disease; however, values ≥ 1 may be seen with progressive tubular disease and end-stage CKD. Proteinuria is highly related to survival in cats with CKD. The current conventional definition of persistent proteinuria in cats is > 0.4, which is associated with reduced survival. Even cats with mild proteinuria of 0.2 to 0.4 have been shown to have decreased survival when compared with cats with UPC < 0.2.24
When elevated UPC is treated and monitored in proteinuric animals, the UPC must change by at least 35% at high UPC values (near 12) and 80% at low UPC values (near 0.5) to demonstrate a significant difference between serial values.25
Microalbuminuria testing is generally reserved as an adjunctive test when albuminuria is suspected despite previous negative test results, in cases of renal disease or hypertension, or as an additional screening test. In-house semiquantitative test kits such as the E.R.D. HealthScreen (Heska) are species-specific for dogs and cats. In cats, microalbuminuria and UPC do not always correlate, and repeatability is an issue with semiquantitative testing.26
Anemia of CKD is typically nonregenerative, normochromic, and normocytic. The anemia is normally proportional to the degree of nephron loss. Deformed red blood cells (echinocytes or burr cells) may be noted.
The cause of anemia of CKD is multifactorial. The primary mechanism is an absolute or relative loss of erythropoietin, a hormone produced by the kidney that stimulates red blood cell progenitor cells to begin erythropoiesis in the bone marrow. In one study, dogs with CKD had low to normal erythropoietin concentrations despite being anemic, which is an inappropriate response to anemia.27 In cats with anemia of CKD, erythropoietin concentrations may be in the normal range.28 A diagnostic problem is that erythropoietin assays are not readily available commercially.
Other mechanisms of anemia include shortened red blood cell lifespan, nutritional abnormalities, erythropoietic inhibitor substances in uremic plasma, blood loss, and bone marrow fibrosis secondary to a previous insult to the marrow.1 Additional clinically important causes of anemia in dogs and cats with CKD are iron deficiency and chronic GI blood loss.
A gradual decrease in the mean corpuscular volume (MCV) may indicate development of iron deficiency. Mean corpuscular hemoglobin (MCH) may also decrease, and the mean corpuscular hemoglobin concentration (MCHC) is the last of the red blood cell indices to decrease.1 The reticulocyte hemoglobin content and reticulocyte volume can be evaluated with automated complete blood count machines in reference laboratories, but these values are not routinely reported. Initial reports indicate these may prove to be useful in evaluating for iron deficiency, but more work remains to validate these tests.30,31
An elevated BUN:creatinine ratio in conjunction with sudden development of anemia may be a clue that GI blood loss is present. An increase in hematocrit and a decrease in the BUN:creatinine ratio after treatment with gastroprotectant medications (e.g. H2-blockers, proton-pump inhibitors, or sucralfate) provides evidence of GI hemorrhage as a cause of the anemia.
OTHER TESTS OF GFR
The ideal substance for measuring GFR should be a) exclusively cleared by glomerular filtration, b) neither secreted nor reabsorbed by the kidney tubules, and c) easily measured.32 Unfortunately, a substance meeting all these criteria is not available as a simple or routine test on most commercially available veterinary biochemical profiles. The crudest estimates of GFR on a serum chemistry profile are BUN and creatinine concentrations; however, as discussed above, measuring and interpreting these values have their limitations.
Cystatin C has been investigated as a marker of GFR in dogs. This cysteine protease inhibitor is freely filtered by the glomerulus and unaffected by nonrenal factors such as inflammation and sex. It correlates well with GFR measurements and may be a reasonable alternative to creatinine concentration measurement.33 The main limitation of cystatin C measurement in people is intraindividual variation. It has lower sensitivity than serum creatinine concentration in detecting changes in the same individual, even though cystatin C may be a better indicator of early decreases in GFR.34 Cystatin C measurement is not available for veterinary patients outside a research setting.
Multiple tests are typically reserved for a laboratory or university setting that provides accurate measurements of GFR. Many of these methods have several disadvantages, including high cost, labor intensiveness, risks caused by anesthesia, or need for specialized equipment or licensing. The gold standard is the urinary clearance of inulin. Other tests include nuclear scintigraphy, clearance tests of endogenous and exogenous creatinine, clearance of chromium-51 EDTA, and the iohexol clearance test.35 Of the aforementioned tests, the iohexol clearance test is probably the most practical and easiest to perform (see the Related Link "Case study: Acute kidney failure from hypotension in a dog" below). It does not require any specialized equipment or urine collection and can be completed in four hours.36,37 (Iohexol measurement for the iohexol clearance test is available at the Diagnostic Center for Population and Animal Health, Michigan State University, 4125 Beaumont Road, Lansing, MI 48910-8104; phone: (517) 353-1683; FAX: (517) 353-5096; www.animalhealth.msu.edu .)
A combination of routine blood and urine tests, along with more specialized laboratory tests, can provide a wealth of information about the presence of kidney disease and clues about its cause. In addition, these tests may help detect complications associated with kidney disease.
Michael Geist, DVM, DACVIM
VCA Animal Specialty Group
5610 Kearny Mesa Road, Suite B
San Diego, CA 92111
Cathy Langston, DVM, DACVIM
The Animal Medical Center
510 East 62nd St.
New York, NY 10065
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