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Evaluation of the Rabbit Urinary Tract
Review Article
Evaluation of the Rabbit Urinary Tract Jeffrey R. Jenkins, DVM, Dip. ABVP (Avian)
Abstract Urinary tract disease is not an uncommon presentation for pet rabbits. It is beneficial for the veterinarian treating these patients to have a thorough understanding of a rabbit’s urogenital anatomy, renal physiology, and diseases that affect the kidney and urinary tract. The evaluation of the rabbit urinary tract requires a multidisciplinary approach including the procurement of a thorough history, signalment, assessment of clinical signs, physical examination, and diagnostic test results. To obtain a definitive disease diagnosis, more intensive diagnostic testing may be required, including contrast radiography, ultrasound evaluation, and histopathological assessment of biopsy samples. This article will provide information to aid in the diagnosis and treatment of rabbit urinary tract diseases. © 2010 Published by Elsevier Inc. Key words: diagnostic testing; kidney; rabbit; renal disease; urinary tract
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ignalment plays an important role in directing veterinarians with the management of their patients. In most cases, the wide variety of diseases impacting the renal system of rabbits extends across the animal’s age, sex, and breed; however, there are exceptions. A few of these exceptions include renal disease caused by Encephalitozoon cuniculi, which is typically diagnosed in older rabbits because E. cuniculi requires a prolonged period of time to establish an infection that causes significant disease, and most renal and bladder neoplasia, which are most common in geriatric patients. Because of their smaller urethra, male rabbits are predisposed to develop large urinary calculi, whereas both sexes are affected by “sludge” or micro urinary calculi (MUC). Intact female rabbits may develop reproductive tract disease that also involves the urinary tract (e.g., uterine neoplasia). Rabbit breeds with long lumbar areas (e.g., lop breeds) have a higher incidence of intervertebral disc problems and associated pain, paresis, and paralysis. Urinary tract problems associated with intervertebral disc disease include urine scald, cystitis, MUC, and renal infections. The anamnesis should include questions of the overall health and behavior of the patient, as well as
those more specific to the urinary tract. Questions directed at frequency and volume of urination, appropriate use of litter box, volume and frequency of water consumption, and straining or vocalizing during urination are necessary to understand the overall condition of the urogenital tract of a patient. Other important questions that would suggest complications of urinary tract disease include: loss of weight and/or muscle mass, anorexia, and change of odor and/or color of urine.
Physical Examination As with any disease presentation, a complete physical examination is paramount in the formulation of a From the Avian & Exotic Animal Hospital, San Diego, CA USA. Address correspondence to: Jeffery R. Jenkins, DVM, Dip. ABVP (Avian), Avian & Exotic Animal Hospital, 2317 Hotel Circle South, Ste C, San Diego, CA 92108-3310. E-mail: DrExotic@ aol.com. © 2010 Published by Elsevier Inc. 1557-5063/10/1904-$30.00 doi:10.1053/j.jepm.2010.10.006
Journal of Exotic Pet Medicine, Vol 19, No 4 (October), 2010: pp 271–279
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272 plan to diagnose and properly treat a patient. It is possible to palpate most of the rabbit’s urinary tract. Both kidneys are freely movable within the abdominal cavity and may be evaluated for size, texture, and shape. Careful, gentle palpation, beginning with the renal pelvis, will reveal the renal artery and vein, and in many rabbits, the ureters. The distal cecum and its appendix may, at times, extend into the pelvic cavity and is often confused with the bladder by those unfamiliar with rabbit anatomy. When the cecum is in an extremely caudal position, it extends cranial and is frequently ventral to the urinary bladder. Similarly, the bladder may be confused with the large vaginal vestibule of female rabbits.
Radiograph and Ultrasonic Evaluation The rabbit urinary tract is well suited for evaluation with both conventional radiographic and ultrasound imaging. Fat is stored in the rabbit’s paralumbar space, thereby enhancing the image quality from both of these modalities. With the increased availability and sophistication of ultrasonography, the author performs fewer contrast techniques on rabbit patients. More detailed descriptions of diagnostic imaging techniques used on rabbit patients are published in other literature sources, and a further review is beyond the scope of this article.
Clinical Pathology Blood Collection The central auricular artery is a commonly used blood collection site (Fig 1). The author prefers to
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gently stroke, flick, or “pop” the artery with a finger or blood collection tube to dilate the vessel and aid in the collection of a 1- to 5-mL sample with a 1- to 5-mL syringe and a 23- to 25-gauge needle. Alternatively, blood may be allowed to flow freely from a needle hub into a blood collection tube after the needle has been placed in the artery. One should not apply too much negative pressure on the syringe because this can result in the collapse of the artery or damage blood cells passing through the needle. A 23- to 25-gauge blood collection needle and vacuum blood-collection tubes such as the Kendall Monoject (Covidien, Mansfield, MA USA) or Becton Dickinson Vacutainer Blood Collection Set (Becton Dickinson, Franklin Lakes, NJ USA) are effective when collecting blood from healthy large breed rabbits. The central auricular artery frequently collapses when collecting larger volumes (10-15 mL) of blood. Stroking the artery from the base of the ear toward the tip may help induce blood flow when collecting from the central auricular artery. Another method of dilating the central auricular artery when collecting large volumes of blood is to apply 2% nitroglycerine ointment to the skin over the artery. Follow the manufacturer’s safety recommendations when handling nitroglycerine ointment and carefully remove any ointment from the ear after the blood collection procedure. Nitroglycerine ointment can be used to allow large volumes of blood to be collected for a transfusion or for serological products. The jugular vein is another common site for blood collection from rabbit patients. The rabbit may be gently restrained in dorsal or lateral recumbency for this venipuncture technique, whereas fractious animals may need to be anesthetized or lightly sedated. The area from which the blood will be collected is prepped with aseptic technique and the vein occluded at the thoracic inlet. Entering the jugular vein from a cranial to caudal direction may be easier for some practitioners because of the short neck and depth of the jugular vein found in many rabbit patients. Small volumes of blood suitable for a complete blood cell count (CBC) may be obtained from the marginal auricular vein or the cephalic vein; however, these vessels are better suited for injection than phlebotomy.
Hematology
Figure 1. The auricular artery is the most common site used to collect blood from rabbit patients in the author’s practice. The vein is more often used for injection and the artery for collection of blood samples. Pictured is the ear of a New Zealand rabbit.
The CBC is the most important diagnostic tool available to the veterinarian next to a good history and physical examination. Moreover, it is of great importance that the CBC be performed and interpreted by a veterinarian that has a thorough knowledge of the species they are examining.
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Erythrocytes. Rabbit erythrocytes or red blood cells (RBC) are biconcave disks averaging 6.7 to 6.9 m in diameter and 2.15 m in thickness. A natural anisocytosis occurs in rabbit blood, with reports of diameters ranging from 5.0 to 7.8 m (Fig 2). In general, rabbit erythrocytes are larger than those found in feline, equine, or bovine species, with diameters averaging 5.8 m, 5.5 m, and 5.7 m, respectively, and smaller than those of the dog, which average 7.0 m. Rabbit erythrocyte counts and hematocrit (Hct) percentages vary with age, sex, and breed; however, most normal rabbits have erythrocyte counts of 5.1 to 7.6 ⫻ 106/m3 and Hct percentages of 33% to 50% (Table 1). Both male and geriatric rabbit patients tend to have higher erythrocyte counts and Hct percentages. Rabbit hemoglobin (Hb) values range from 10 to 15 g/dL and vary on technique used. Mean corpuscular volume ranges from 60 to 69 m3, reflecting the larger diameter of rabbit cells compared with that of the cat: 39 to 55 m3, horse: 34 to 58 m3, and cow: 40 to 60 m3. Despite differences in RBC number, size, and volume, values for Hct, Hb, and mean corpuscular hemoglobin concentration (MCHC), computed from the Hb and the Hct, are relatively constant in healthy rabbits. With few exceptions, MCHC is close to 33% in all healthy mammals and birds.1 Mean corpuscular hemoglobin (MCH), Hb by weight in the average erythrocyte, is calculated by multiplying the Hb (g/dL) ⫻ 10 and dividing by the RBC count. This value is typically similar to that reported in other mammals.
Figure 2. Rabbit erythrocytes, small lymphocyte, and platelet. Note anisocytosis and polychromasia typical of rabbits. Photomicrograph courtesy of Terry W. Campbell, MS, DVM, PhD.
Table 1. Normal hematologic values in the domestic rabbit Parameter
Reference range
Erythrocytes (count) 5.4 to 7.6 ⫻ 106/m3 Hematocrit/Packed cell volume 33%-50% Hemoglobin 10.0-17.4 g/dL Mean corpuscular volume 60-69 m3 Mean corpuscular hemoglobin 19-22 pg Mean corpuscular hemoglobin 30%-35% concentration Leukocytes 5.2 to 12.5 ⫻ 106 Lymphocytes 30%-85% Neutrophils 20%-75% Eosinophils 1%-4% Basophils 1%-7% Monocytes 1%-4% Platelets 250 to 650 ⫻ 103/mm3
The rabbit Hct is most often determined by centrifugation (e.g., packed cell volume [PCV]). The determination of a PCV using centrifugation is rapid and accurate within the acceptable parameters of clinical medicine. There has been a recent increase in the use of automated flow cytometry instruments by many commercial laboratories. The hematocrit, along with MCH and MCHC, are calculated based on direct measurements by these instruments.2 Anisocytosis is commonly observed in rabbit erythrocytes and is normal up to 2%. Nucleated cells and cells with Howell-Jolly bodies may be occasionally identified in rabbit blood samples. Reticulocyte counts typically range from 2% to 4% and may be somewhat higher in young animals. Reticulocyte counts will increase with blood loss. Rabbit erythrocytes are reported to have a mean lifespan of 57 days and a potential lifespan of 67 days. Erythrocyte lifespans appear to be linked to metabolic rate, as illustrated by the average lifespan of the cat (70 days), dog (120 days), horse (145 days), and cow (170 days).3 Rabbit anemia may be classified by size (mean corpuscular volume) and hemoglobin concentration (MCH, MCHC). Anemia may be normocytic, macrocytic, or microcytic, as well as normochromic or hypochromic. It is helpful to classify the anemic condition in diagnosing the origin of the disease process. Bone marrow evaluation is often necessary to fully characterize anemia to determine a definitive diagnosis and develop a treatment plan. Rabbits with urinary tract disease often have qualitative changes in their erythrocytes, as well as
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changes in the total number of RBC and other RBC parameters. In the author’s practice, rabbits with acute bladder or renal infections frequently have no RBC changes. There may be an increased erythrocyte count and PCV associated with the hemoconcentration related to dehydration. Chronic bladder or renal disease (e.g., chronic inflammatory disease) is often associated with some degree of blood loss, resulting in a mild to moderate anemia. Most anemic conditions associated with chronic bladder or renal disease in rabbits are normocytic to macrocytic, hypochromic, may or may not have an increased reticulocyte count, and have a decreased Hb resulting in a decreased MCH and MCHC. Rabbits with endstage renal disease are often diagnosed with a microcytic, hypochromic anemia.
Platelets. Rabbit platelets occur singularly and in clumps. They have a pale blue cytoplasm and small cluster of azurophilic granules. Most rabbit platelets are 1 to 3 m in diameter, but larger forms may be seen. Normal platelet numbers range from 170 to 1120 ⫻ 103/mm3, but most rabbits have platelet counts between 250 and 650 ⫻ 103/mm3.4 Rabbits with end-stage renal disease may have low platelet counts; however, it is uncommon to see clinical signs of hemorrhage. The relationship between platelet-activating factor and platelets in renal disease is currently an active area of study.
Leukocytes/White Blood Cells. White blood cell (WBC) counts in rabbits are similar or slightly lower than those of other domestic animals. Normal WBC counts in rabbits, 5.2 to 12.5 ⫻ 106, vary with age, sex, breed, and season (Table 1).4
Lymphocytes. Lymphocytes are the most common WBC found in rabbits and comprise 30% to 80% of the total leukocyte count. Rabbit lymphocytes do not appear significantly different from those of other mammals. Although they are predominantly small in size, 7 to 10 m, larger cells, 10 to 15 m, may also be observed. The lymphocyte nucleus is round to oval and stains dark purple-blue with Romanowsky stains; the cytoplasm stains medium to dark blue. A perinuclear halo and azurophilic granules may be present in large lymphocytes. It is reported that lymphocytes from a healthy rabbit consist of 39% B lymphocytes, 44% T lymphocytes, and 8% null cells.5 Monocytes. Monocytes are the largest cell in the peripheral blood of the normal rabbit, measuring 15 to 18 m in diameter. Monocytes have a large, variably shaped nucleus that contains a less-condensed
Figure 3. Rabbit monocyte, erythrocytes, and platelet. Monocytes have a large, variably shaped nucleus with chromatin that appears less condensed than that of heterophils. Cytoplasm is abundant and stains gray to blue-gray. A few cytoplasmic vacuoles may be observed. Photomicrograph courtesy of Terry W. Campbell, MS, DVM, PhD.
chromatin than that of heterophils (Fig 3). The monocyte cytoplasm is abundant and stains gray to blue-gray; a few cytoplasmic vacuoles may be observed within the cytoplasm. Large, dark red granules have been described in the cytoplasm of some monocytes in association with nonspecific toxicity.6 Monocytes comprise 1% to 4% of the normal rabbit WBC.4
Neutrophils (Heterophils). When Romanowsky stain or Giemsa and Wright stain is used to stain WBC, the granules of rabbit neutrophils appear bright pink to red. This staining phenomenon has resulted in the use of the terms heterophil, amphophil, and pseudoheterophil when referring to the rabbit neutrophil. Functionally and morphologically, the rabbit neutrophil is equivalent to the neutrophil of other domestic mammals (Fig 4). The rabbit neutrophil is 10 to 15 m in diameter and has a polymorphous nucleus that stains light blue to light purple. The cytoplasm stains diffusely pink because of the presence of large dark pink to red granules, with small granules staining less intensely than the larger granules. These granules have been identified as primary or azurophilic (larger) and secondary or specific (smaller) granules. Neutrophils may be present in the peripheral blood as immature or band forms; however, band forms do not frequently increase with bacterial infections. Neutrophils are not as numerous as lymphocytes in rabbits and typically constitute 20% to 75% of the total leukcocyte count.
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is reported to be aleukemic with a relative lymphophilia, which can include the observation of immature and atypical lymphocytes.10,11
Clinical Chemistries of Rabbits As with other domestic animals, blood chemistry values have long been used as an important diagnostic test to assess the overall health of rabbit patients. Changes in these plasma/serum chemistry parameters may be helpful in the diagnosis of diseases that involve the urinary tract. Normal plasma chemistry values important for assessing kidney function are listed in Table 2. The clinical chemistry parameters discussed in this article are limited to those that are most meaningful to the diagnosis of urinary tract disease. Figure 4. Rabbit blood smear showing neutrophil (heterophil) and basophil. Several platelets are present as well. Photomicrograph courtesy of Terry W. Campbell, MS, DVM, PhD.
Eosinophil. Rabbit eosinophils are larger than neutrophils and have a diameter range of 12 to 16 m (Fig 5). The eosinophilic granules of rabbits are larger than neutrophil granules, they stain intensely pink or a dull pink-orange, and most often fill the cytoplasm of the cell. The nucleus of the rabbit eosinophil is bilobed or horseshoe shaped. Eosinophils comprise 1% to 4% of total leukocyte count of the rabbit. Basophil. Unlike most exotic small mammals kept as pets, the rabbit commonly has circulating basophils in the peripheral blood (up to 2%-5% of the total WBC). Basophils are similar in size to the neutrophil and have a light purple, lobulated nucleus and dark purple to purple-black or occasionally metachromatc cytoplasmic granules. In general, the number of circulating basophils is inversely proportional to the number of tissue mast cells of that patient.7,8
WBC Response to Renal Disease. Rabbits experiencing an infectious disease rarely present with an elevated WBC count. The most common finding in the WBC count of a rabbit diagnosed with an infectious disease is a shift in the percentages of the various leukocytes to a neutrophil-dominated differential. Rabbits with an acute infection may present with 60% or greater neutrophils and 30% or fewer lymphocytes. Occasionally, rabbits with an acute infectious process will have a normal WBC count and a decrease in total leukocyte numbers. Stress or endogenous corticosteroid administration can induce a significant lymphopenia.9 Rabbit renal lymphoma
Blood Urea Nitrogen. Blood urea nitrogen (BUN) is commonly used to assess renal function in mammals. Urea is the principal end-product of protein catabolism formed in the liver of mammals and excreted by the kidneys. The BUN is filtered through the glomerulus and 25% to 40% is reabsorbed by the renal tubules. Rabbit BUN has a diurnal fluctuation, peaking in the late afternoon and early evening. This is thought to be correlated to the ingestion of cecotrophs.12 A decrease in BUN may be caused by anabolic steroids, diminished protein intake (e.g., anorexia, cessation of cecotrophy), and severe hepatic insufficiency. Increased BUN may be indicative of a variety of renal perfusion or function problems and/or increased protein catabolism (e.g., high protein diets, vigorous exercise). Increases in BUN relative to re-
Figure 5. Rabbit blood smear showing eosinophil and small lymphocyte. Photomicrograph courtesy of Terry W. Campbell, MS, DVM, PhD.
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Table 2. Normal blood chemistry values for the domestic rabbit Parameter
Reference range conventional units
Blood urea nitrogen Creatinine Calcium Phosphorus
28.3-47.9 mg/dL 0.8-1.9 mg/dL 8.8-15.6 mg/dL 3.1-6.8 mg/dL
Reference range SI units 10.1-17.1 mmol/L 74-171 mol/L 2.2-3.9 mmol/L 1.0-2.2 mmol/L
nal function may be divided into prerenal, renal, and postrenal causes. An elevation in BUN relative to a prerenal condition may include reduced renal blood flow and factors that reduce net filtration pressure at the glomerulus (e.g., dehydration). When BUN is elevated because of a renal condition, it suggests that there is a loss of 50% to 70% of the functional nephrons. Postrenal uremia is associated with obstruction, renal and cystic calculi, neoplasia, and perforation of the urinary system.
Circulating Enzymes. The specificity of a plasma
Creatinine. Creatinine is formed in the metabo-
Urinalysis
lism of muscle creatine and phosphocreatine. The creatinine level is far less influenced by external factors than BUN and is not affected by dietary proteins, protein catabolism, age, sex, or exercise. Creatinine is freely filtered through the glomerulus and excreted in the urine. Creatinine levels may be increased by severe renal insufficiency or severe muscle damage. Similar to BUN, creatinine is insensitive at detecting modest renal damage, as levels are increased only in cases where there is a greater than 50% to 70% loss of nephrons.
The urinalysis (UA) is a simple and quick procedure that can yield valuable information regarding the function of a rabbit’s urinary system, as well as other organs and systems in the body. In the author’s practice, a UA is part of the basic diagnostic information collected on any rabbit that presents with a disease condition. Collecting a UA from a rabbit patient is similar to that described for cats. With house-trained rabbits, urine should be collected in the early morning. Consumption of water during the day may dilute cellular components in the urine and lower the overall specific gravity of the sample. Urine may be collected by free catch, manual expression, catheterization, or cystocentesis. When obtaining a sample by free catch, an effort should be made to avoid the first part of the urine stream because it will contain exudate flushed from the urethra and the vaginal vestibule of female rabbits. Overzealous manual expression of the urinary bladder can result in artifactual blood in the urine sample. Urine obtained for bacterial cultures should be collected by catheterization or cystocentesis. For the best results, the UA should be processed as soon as the urine is collected; however, urine preserved by refrigeration for 2 to 3 hours can still provide reliable data.
Calcium. Rabbits typically have a higher total plasma calcium concentration than other mammals; however, the ionized fraction of calcium in the rabbit is comparable with that of other mammals.13 The rabbit appears to maintain its serum ionized calcium concentration against hypocalcemia and hypercalcemia by rapid changes in parathyroid hormone secretion and calcitonin. However, unlike other mammalian species, the changes in parathyroid hormone occur in the presence of relatively high levels of calcium, suggesting that the parathyroid gland of the rabbit is reset to respond to changes in ionized calcium within their physiological range. The relative insensitivity of the rabbit parathyroid to extracellular calcium is analogous to that observed in primary hyperparathyroidism.14 In support of this statement, wild members of the pet rabbit species, Oryctolagus cuniculus, also have relatively elevated calcium concentrations as opposed to other mammals. (Karen Rosenthal, DVM, personal communication, 2006).
enzyme as an indicator of injury or disease of a specific tissue or organ depends on both the concentration of an enzyme in the tissue or the organ of question. Although helpful in diagnosing diseases that affect other tissues, the plasma enzymes commonly evaluated with commercial analyzers are not of benefit in diagnosing rabbit urinary tract disease.12
Physical Examination of Urine. The color of normal rabbit urine is variable (e.g., white, yellowish white, light brown). One should always consider color and turbidity in association with urine-specific gravity. Rabbits that eat hay or vegetables or that have been recently treated with antibiotics may temporarily pass porphyrins in their urine, creating an
Evaluation of the Rabbit Urinary Tract
orange- or red- tinged coloration that may be confused as blood. Myoglobin or methemoglobinuria may cause rabbit urine to appear dark brown. Normal rabbit urine usually contains large amounts of light-colored sediment that may appear abnormal to inexperienced clinicians. Rabbits with low urine-specific gravity often have clear urine and less sediment. Cloudy urine must always be evaluated based on a microscopic examination. The most common cause of cloudy urine is calciuria, which is normal in rabbits. Other causes of cloudy urine include contamination due to white and red blood cells, epithelial cells, bacteria, and mucous.
Specific Gravity. Refractometer measurements of urine-specific gravity are accurate and only require a single drop of urine. The author has found the urine-specific gravity measurements from the commercial urine test strips to be highly inaccurate. Normal rabbit urine-specific gravity ranges from 1.003 to 1.035, with an average of 1.015.15 A fixed urine-specific gravity (1.008-1.012), combined with clinical dehydration, increased BUN and creatinine levels (uremia), or an abnormally high PCV, is an indication that the functional competence of the kidneys may be compromised. Reaction (pH). Normal rabbit urine is markedly alkaline, typical of hindgut-fermenting herbivores. The pH of healthy rabbits normally ranges from 8 to 9. Low urinary pH may result from high protein diets (i.e., rabbits eating cereal grains or cat food), catabolic states, starvation, and fever. Urine stored at room temperature becomes more alkaline with time because of the decomposition of urea.
Protein. Young healthy rabbits can have small amounts of albumin16 and adults trace amounts of protein, often from mucous, in their urine. Increased amounts of protein in the urine may indicate renal damage due to both increased permeability of the glomerulus to proteins and impaired reabsorption of protein due to tubular disease. Transient proteinuria may be found after excessive muscular activity, seizure activity, and with stress. Protein levels must be interpreted along with the urine-specific gravity and sediment analysis. Very dilute urine that tests positive for protein is more significant than a concentrated urine sample with the same level of protein.
Urine Glucose. Glucose is not present in normal rabbit urine; however, the author has experienced trace to even moderate amounts of glucose in the
277 urine of otherwise healthy rabbits after acutely painful or frightening experiences or with some chronic stressful condition (pain). Glucosuria may also occur when there is significant hematuria. As noted above, spontaneous diabetes mellitus has been documented in New Zealand White rabbits, but rarely affects companion rabbits.17,18
Urine Ketone. Ketones, most often acetone, acetoacetic acid, and beta-hydroxybutyric acid, are found in rabbit urine after prolonged anorexia or starvation, including that associated with pregnancy. Rabbits with severe dental disease and rabbits on a hayonly diet that have a severely impacted cecum are common disease presentations in which urinary ketones are identified.
Urine Bilirubin. Rabbits rarely have increased levels of circulating bilirubin and are less likely to have increased levels of bilirubin in their urine. This is partially because most bile is secreted as biliverdin in the rabbit. Positive urinary bilirubin is associated with the destruction of heme from blood cells and/or muscles and may be a sign of nephritis or cystitis.
Hematuria. Blood may be found in rabbit urine with chemical reagent test strips and by examination of urine sediment. Urinalysis strips will diagnose hematuria by testing positive for hemoglobin, myoglobin, and RBCs in the urine. The distinction between hematuria and hemoglobinuria or myoglobinuria requires examination of sediment and provides significant diagnostic information. Normal rabbit urine has very few RBCs (0-3 cells/high-power field), and an increase in the number of erythrocytes occurs with inflammation or damage of the urinary or reproductive systems caused by infection, calculi, or neoplasia. Table 3 provides a list of the common causes of hematuria in rabbits.
Urine Sediment. Calciuria is common in the rabbit and is associated with the unique calcium metabolism of rabbits. Rabbit urine often appears cloudy and turbid. Microscopically, this turbidity is the result of calcium carbonate crystals. The mean fractional excretion of calcium in a rabbit being fed a conventional pellet diet is 44%. The fractional excretion of calcium in most mammals is less than 2%.19 Other crystals, most often triple phosphate and amorphous phosphate crystals, are also commonly seen in rabbit urine. Rabbits being treated with sulfonamide drugs may have sulfadiazine crystals (trimethoprim-sulfadiazine), observed as “shocks
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Table 3. Causes of hematuria in the rabbit Cystitis, urethritis Pyelonephritis Urolithiasis (urethra, bladder, ureter or renal pelvis) Renal neoplasia Renal infarcts Bladder polyps Uterine adenocarcinoma Endometrial hyperplasia Endometrial venous aneurysm Endometrial hemangiomatosis
References 1. 2.
3. 4.
5.
of wheat” or radially striated spherules or sulfonamide crystals, which are yellow in color and resemble uric acid crystals. Many drugs excreted in the urine have the potential to form crystals. Consequently, a review of the patient’s drug history is useful when an unidentified crystal is recognized. Erythrocytes, WBCs, casts (cylinduria), and bacteria may be found in rabbit urine and have the same interpretation and importance as with other companion mammal patients. Urine collected by manual expression of the bladder may contain an abundance of RBCs. The presence of WBCs in the urine suggests infection, whereas casts are often indicative of glomerular or renal tubular disease.
6.
7. 8. 9. 10. 11.
Calciuria versus MUC/“Sludge”. It is the author’s opinion that there is a distinct difference between normal calciuria and the fine calcium urinary calculi often described as “sludge.” The author suggests the more accurate descriptive name of MUC for sludge. Normal calciuria is the result of a high calcium diet, but the distinction is that the calcium in the normal rabbit does not precipitate to form calculi within the bladder. MUC are calcium-based calculi, not just crystals. These calculi form in response to cystitis or other conditions that provide the nidus for their formation. MUC may even form in greater quantities in rabbits fed a low calcium diet. Intermittent or partial outlet obstruction of the rabbit bladder by MUC leads to damage of bladder smooth muscle. When prolonged, the damage to the bladder smooth muscle becomes irreversible.20-22 Preventing bladder damage in rabbits with MUC requires early intervention, flushing, and prolonged treatment with an appropriate antibiotic. Unfortunately, once the bladder is damaged, these rabbits require long-term management, including regular expression, long-term antibiotic therapy, and care of perineum to prevent urine scald, dermatitis, and myiasis.
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13. 14. 15.
16.
17. 18. 19.
Hawkey CM, Dennett TB: Color Atlas of Comparative Veterinary Hematology. Ames, IA, Iowa State University Press, pp 58-107, 1989 Kabata J, Gratwohl A, Tichelli A, et al: Hematologic values of New Zealand white rabbits determined by automated flow cytometry. Lab Anim Sci 41:613-619, 1991 Benjamin MM: Outline of Veterinary Clinical Pathology (ed 3). Ames, IA, Iowa State Press, 1978 McLaughlin RM, Fish RE: Clinical biochemistry and Hematology, in Manning PJ, Ringler DH, Newcomer CE (eds): The Biology of the Laboratory Rabbit (ed 2). San Diego, CA, Academic Press, Inc., pp 111-127, 1994 Curiel TJ, Perfect JR, Durack DT: Leukocyte subpopulations in cerebrospinal fluid of normal rabbits. Lab Anim Sci 32:622-624, 1982 Benson KG, Paul-Murphy J: Clinical pathology of the domestic rabbit: acquisition and interpretation of samples. Vet Clin North Am (Exotic Anim Pract) 2:539-552, 1999 Jain NC: Shalm’s Veterinary Hematology (ed 4). Philadelphia, PA, Lea & Fibiger, 1986 Parmley RT: Mammals, in Rowley AF, Ratcliff NA (eds): Vertebrate Blood Cells. Cambridge, UK, Cambridge University Press, pp 337-424, 1988 Harkness JE, Wagner JE: The Biology and Medicine of Rabbits and Rodents (ed 4). Philadelphia, PA, Williams and Wilkins, 1995 Fox RR, Laird CW, Blau EM, et al: Biochemical parameters of clinical significance in rabbits. 1. Strain variations. J Hered 61:261-265, 1970 Fox RR, Meier H, Crary DD, et al: Lymphosarcoma in the rabbit: genetics and pathology. J Natl Cancer Inst 45:719-729, 1970 Hoffmann WE, Solter PF, Wilson BW: Clinical enzymology, in Loeb WF, Quimby FW (eds): The Clinical Chemistry of Laboratory Animals (ed 2). London, Taylor and Francis, pp 399-454, 1999 Munoz ME, Gonzales J, Esteller A: Bile pigment formation and excretion in the rabbit. Comp Biochem Phys 85A:67-71, 1986 Warren HB, Lausen NC, Segre GV, et al: Regulation of calciotropic hormones in vivo in the New Zealand white rabbit. Endocrinology 125:2683-2690, 1989 Kozma C, Macklin W, Cummins LM, et al: The anatomy, physiology, and biochemistry of rabbits, in Weisbroth SH, Flatt RE, Kraus AL (eds): The Biology of the Laboratory Rabbit. New York, NY, Academic Press, pp 50-72, 1974 Kraus AL, Weisbroth SH, Flatt RE, et al: Biology and diseases of rabbits, in Fox JG, Cohen BJ, Lowe FM (eds): Laboratory Animal Medicine. San Diego, CA, Academic Press, pp 207-240, 1984 Conway HH, Brown CJ, Sanders LL, et al: Spontaneous diabetes mellitus in the New Zealand rabbit. J Hered 71:179-181, 1980 Conway HH, Fass FH, Smith DS, et al: Spontaneous diabetes mellitus in the New Zealand rabbit: physiological characteristics. Metabolism 30:50-56, 1981 Buss SL, Bourdeau JE: Calcium balance in labora-
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20.
21.
tory rabbits. Miner Electrolyte Metab 10:127-132, 1984 Guven A, Kalorin C, Onal B, et al: Novel biomarkers of bladder decompensation after partial bladder obstruction. Neurourol Urodyn 26:1036-1042, 2007 Nigro DA, Haugaard N, Wein AJ, et al: Metabolic
22.
basis for contractile dysfunction following chronic partial bladder outlet obstruction in rabbits. Mol Cell Biochem 200:1-6, 1999 Yang L, He D, Wang S, et al: Effect of long-term partial bladder outlet obstruction on caldesmon isoforms and their correlation with contractile function. Acta Pharmacol Sin 29:600-605, 2008
Evaluation of the Rabbit Urinary Tract Jeffrey R. Jenkins, DVM, Dip. ABVP (Avian)
Abstract Urinary tract disease is not an uncommon presentation for pet rabbits. It is beneficial for the veterinarian treating these patients to have a thorough understanding of a rabbit’s urogenital anatomy, renal physiology, and diseases that affect the kidney and urinary tract. The evaluation of the rabbit urinary tract requires a multidisciplinary approach including the procurement of a thorough history, signalment, assessment of clinical signs, physical examination, and diagnostic test results. To obtain a definitive disease diagnosis, more intensive diagnostic testing may be required, including contrast radiography, ultrasound evaluation, and histopathological assessment of biopsy samples. This article will provide information to aid in the diagnosis and treatment of rabbit urinary tract diseases. © 2010 Published by Elsevier Inc. Key words: diagnostic testing; kidney; rabbit; renal disease; urinary tract
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ignalment plays an important role in directing veterinarians with the management of their patients. In most cases, the wide variety of diseases impacting the renal system of rabbits extends across the animal’s age, sex, and breed; however, there are exceptions. A few of these exceptions include renal disease caused by Encephalitozoon cuniculi, which is typically diagnosed in older rabbits because E. cuniculi requires a prolonged period of time to establish an infection that causes significant disease, and most renal and bladder neoplasia, which are most common in geriatric patients. Because of their smaller urethra, male rabbits are predisposed to develop large urinary calculi, whereas both sexes are affected by “sludge” or micro urinary calculi (MUC). Intact female rabbits may develop reproductive tract disease that also involves the urinary tract (e.g., uterine neoplasia). Rabbit breeds with long lumbar areas (e.g., lop breeds) have a higher incidence of intervertebral disc problems and associated pain, paresis, and paralysis. Urinary tract problems associated with intervertebral disc disease include urine scald, cystitis, MUC, and renal infections. The anamnesis should include questions of the overall health and behavior of the patient, as well as
those more specific to the urinary tract. Questions directed at frequency and volume of urination, appropriate use of litter box, volume and frequency of water consumption, and straining or vocalizing during urination are necessary to understand the overall condition of the urogenital tract of a patient. Other important questions that would suggest complications of urinary tract disease include: loss of weight and/or muscle mass, anorexia, and change of odor and/or color of urine.
Physical Examination As with any disease presentation, a complete physical examination is paramount in the formulation of a From the Avian & Exotic Animal Hospital, San Diego, CA USA. Address correspondence to: Jeffery R. Jenkins, DVM, Dip. ABVP (Avian), Avian & Exotic Animal Hospital, 2317 Hotel Circle South, Ste C, San Diego, CA 92108-3310. E-mail: DrExotic@ aol.com. © 2010 Published by Elsevier Inc. 1557-5063/10/1904-$30.00 doi:10.1053/j.jepm.2010.10.006
Journal of Exotic Pet Medicine, Vol 19, No 4 (October), 2010: pp 271–279
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272 plan to diagnose and properly treat a patient. It is possible to palpate most of the rabbit’s urinary tract. Both kidneys are freely movable within the abdominal cavity and may be evaluated for size, texture, and shape. Careful, gentle palpation, beginning with the renal pelvis, will reveal the renal artery and vein, and in many rabbits, the ureters. The distal cecum and its appendix may, at times, extend into the pelvic cavity and is often confused with the bladder by those unfamiliar with rabbit anatomy. When the cecum is in an extremely caudal position, it extends cranial and is frequently ventral to the urinary bladder. Similarly, the bladder may be confused with the large vaginal vestibule of female rabbits.
Radiograph and Ultrasonic Evaluation The rabbit urinary tract is well suited for evaluation with both conventional radiographic and ultrasound imaging. Fat is stored in the rabbit’s paralumbar space, thereby enhancing the image quality from both of these modalities. With the increased availability and sophistication of ultrasonography, the author performs fewer contrast techniques on rabbit patients. More detailed descriptions of diagnostic imaging techniques used on rabbit patients are published in other literature sources, and a further review is beyond the scope of this article.
Clinical Pathology Blood Collection The central auricular artery is a commonly used blood collection site (Fig 1). The author prefers to
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gently stroke, flick, or “pop” the artery with a finger or blood collection tube to dilate the vessel and aid in the collection of a 1- to 5-mL sample with a 1- to 5-mL syringe and a 23- to 25-gauge needle. Alternatively, blood may be allowed to flow freely from a needle hub into a blood collection tube after the needle has been placed in the artery. One should not apply too much negative pressure on the syringe because this can result in the collapse of the artery or damage blood cells passing through the needle. A 23- to 25-gauge blood collection needle and vacuum blood-collection tubes such as the Kendall Monoject (Covidien, Mansfield, MA USA) or Becton Dickinson Vacutainer Blood Collection Set (Becton Dickinson, Franklin Lakes, NJ USA) are effective when collecting blood from healthy large breed rabbits. The central auricular artery frequently collapses when collecting larger volumes (10-15 mL) of blood. Stroking the artery from the base of the ear toward the tip may help induce blood flow when collecting from the central auricular artery. Another method of dilating the central auricular artery when collecting large volumes of blood is to apply 2% nitroglycerine ointment to the skin over the artery. Follow the manufacturer’s safety recommendations when handling nitroglycerine ointment and carefully remove any ointment from the ear after the blood collection procedure. Nitroglycerine ointment can be used to allow large volumes of blood to be collected for a transfusion or for serological products. The jugular vein is another common site for blood collection from rabbit patients. The rabbit may be gently restrained in dorsal or lateral recumbency for this venipuncture technique, whereas fractious animals may need to be anesthetized or lightly sedated. The area from which the blood will be collected is prepped with aseptic technique and the vein occluded at the thoracic inlet. Entering the jugular vein from a cranial to caudal direction may be easier for some practitioners because of the short neck and depth of the jugular vein found in many rabbit patients. Small volumes of blood suitable for a complete blood cell count (CBC) may be obtained from the marginal auricular vein or the cephalic vein; however, these vessels are better suited for injection than phlebotomy.
Hematology
Figure 1. The auricular artery is the most common site used to collect blood from rabbit patients in the author’s practice. The vein is more often used for injection and the artery for collection of blood samples. Pictured is the ear of a New Zealand rabbit.
The CBC is the most important diagnostic tool available to the veterinarian next to a good history and physical examination. Moreover, it is of great importance that the CBC be performed and interpreted by a veterinarian that has a thorough knowledge of the species they are examining.
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Erythrocytes. Rabbit erythrocytes or red blood cells (RBC) are biconcave disks averaging 6.7 to 6.9 m in diameter and 2.15 m in thickness. A natural anisocytosis occurs in rabbit blood, with reports of diameters ranging from 5.0 to 7.8 m (Fig 2). In general, rabbit erythrocytes are larger than those found in feline, equine, or bovine species, with diameters averaging 5.8 m, 5.5 m, and 5.7 m, respectively, and smaller than those of the dog, which average 7.0 m. Rabbit erythrocyte counts and hematocrit (Hct) percentages vary with age, sex, and breed; however, most normal rabbits have erythrocyte counts of 5.1 to 7.6 ⫻ 106/m3 and Hct percentages of 33% to 50% (Table 1). Both male and geriatric rabbit patients tend to have higher erythrocyte counts and Hct percentages. Rabbit hemoglobin (Hb) values range from 10 to 15 g/dL and vary on technique used. Mean corpuscular volume ranges from 60 to 69 m3, reflecting the larger diameter of rabbit cells compared with that of the cat: 39 to 55 m3, horse: 34 to 58 m3, and cow: 40 to 60 m3. Despite differences in RBC number, size, and volume, values for Hct, Hb, and mean corpuscular hemoglobin concentration (MCHC), computed from the Hb and the Hct, are relatively constant in healthy rabbits. With few exceptions, MCHC is close to 33% in all healthy mammals and birds.1 Mean corpuscular hemoglobin (MCH), Hb by weight in the average erythrocyte, is calculated by multiplying the Hb (g/dL) ⫻ 10 and dividing by the RBC count. This value is typically similar to that reported in other mammals.
Figure 2. Rabbit erythrocytes, small lymphocyte, and platelet. Note anisocytosis and polychromasia typical of rabbits. Photomicrograph courtesy of Terry W. Campbell, MS, DVM, PhD.
Table 1. Normal hematologic values in the domestic rabbit Parameter
Reference range
Erythrocytes (count) 5.4 to 7.6 ⫻ 106/m3 Hematocrit/Packed cell volume 33%-50% Hemoglobin 10.0-17.4 g/dL Mean corpuscular volume 60-69 m3 Mean corpuscular hemoglobin 19-22 pg Mean corpuscular hemoglobin 30%-35% concentration Leukocytes 5.2 to 12.5 ⫻ 106 Lymphocytes 30%-85% Neutrophils 20%-75% Eosinophils 1%-4% Basophils 1%-7% Monocytes 1%-4% Platelets 250 to 650 ⫻ 103/mm3
The rabbit Hct is most often determined by centrifugation (e.g., packed cell volume [PCV]). The determination of a PCV using centrifugation is rapid and accurate within the acceptable parameters of clinical medicine. There has been a recent increase in the use of automated flow cytometry instruments by many commercial laboratories. The hematocrit, along with MCH and MCHC, are calculated based on direct measurements by these instruments.2 Anisocytosis is commonly observed in rabbit erythrocytes and is normal up to 2%. Nucleated cells and cells with Howell-Jolly bodies may be occasionally identified in rabbit blood samples. Reticulocyte counts typically range from 2% to 4% and may be somewhat higher in young animals. Reticulocyte counts will increase with blood loss. Rabbit erythrocytes are reported to have a mean lifespan of 57 days and a potential lifespan of 67 days. Erythrocyte lifespans appear to be linked to metabolic rate, as illustrated by the average lifespan of the cat (70 days), dog (120 days), horse (145 days), and cow (170 days).3 Rabbit anemia may be classified by size (mean corpuscular volume) and hemoglobin concentration (MCH, MCHC). Anemia may be normocytic, macrocytic, or microcytic, as well as normochromic or hypochromic. It is helpful to classify the anemic condition in diagnosing the origin of the disease process. Bone marrow evaluation is often necessary to fully characterize anemia to determine a definitive diagnosis and develop a treatment plan. Rabbits with urinary tract disease often have qualitative changes in their erythrocytes, as well as
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changes in the total number of RBC and other RBC parameters. In the author’s practice, rabbits with acute bladder or renal infections frequently have no RBC changes. There may be an increased erythrocyte count and PCV associated with the hemoconcentration related to dehydration. Chronic bladder or renal disease (e.g., chronic inflammatory disease) is often associated with some degree of blood loss, resulting in a mild to moderate anemia. Most anemic conditions associated with chronic bladder or renal disease in rabbits are normocytic to macrocytic, hypochromic, may or may not have an increased reticulocyte count, and have a decreased Hb resulting in a decreased MCH and MCHC. Rabbits with endstage renal disease are often diagnosed with a microcytic, hypochromic anemia.
Platelets. Rabbit platelets occur singularly and in clumps. They have a pale blue cytoplasm and small cluster of azurophilic granules. Most rabbit platelets are 1 to 3 m in diameter, but larger forms may be seen. Normal platelet numbers range from 170 to 1120 ⫻ 103/mm3, but most rabbits have platelet counts between 250 and 650 ⫻ 103/mm3.4 Rabbits with end-stage renal disease may have low platelet counts; however, it is uncommon to see clinical signs of hemorrhage. The relationship between platelet-activating factor and platelets in renal disease is currently an active area of study.
Leukocytes/White Blood Cells. White blood cell (WBC) counts in rabbits are similar or slightly lower than those of other domestic animals. Normal WBC counts in rabbits, 5.2 to 12.5 ⫻ 106, vary with age, sex, breed, and season (Table 1).4
Lymphocytes. Lymphocytes are the most common WBC found in rabbits and comprise 30% to 80% of the total leukocyte count. Rabbit lymphocytes do not appear significantly different from those of other mammals. Although they are predominantly small in size, 7 to 10 m, larger cells, 10 to 15 m, may also be observed. The lymphocyte nucleus is round to oval and stains dark purple-blue with Romanowsky stains; the cytoplasm stains medium to dark blue. A perinuclear halo and azurophilic granules may be present in large lymphocytes. It is reported that lymphocytes from a healthy rabbit consist of 39% B lymphocytes, 44% T lymphocytes, and 8% null cells.5 Monocytes. Monocytes are the largest cell in the peripheral blood of the normal rabbit, measuring 15 to 18 m in diameter. Monocytes have a large, variably shaped nucleus that contains a less-condensed
Figure 3. Rabbit monocyte, erythrocytes, and platelet. Monocytes have a large, variably shaped nucleus with chromatin that appears less condensed than that of heterophils. Cytoplasm is abundant and stains gray to blue-gray. A few cytoplasmic vacuoles may be observed. Photomicrograph courtesy of Terry W. Campbell, MS, DVM, PhD.
chromatin than that of heterophils (Fig 3). The monocyte cytoplasm is abundant and stains gray to blue-gray; a few cytoplasmic vacuoles may be observed within the cytoplasm. Large, dark red granules have been described in the cytoplasm of some monocytes in association with nonspecific toxicity.6 Monocytes comprise 1% to 4% of the normal rabbit WBC.4
Neutrophils (Heterophils). When Romanowsky stain or Giemsa and Wright stain is used to stain WBC, the granules of rabbit neutrophils appear bright pink to red. This staining phenomenon has resulted in the use of the terms heterophil, amphophil, and pseudoheterophil when referring to the rabbit neutrophil. Functionally and morphologically, the rabbit neutrophil is equivalent to the neutrophil of other domestic mammals (Fig 4). The rabbit neutrophil is 10 to 15 m in diameter and has a polymorphous nucleus that stains light blue to light purple. The cytoplasm stains diffusely pink because of the presence of large dark pink to red granules, with small granules staining less intensely than the larger granules. These granules have been identified as primary or azurophilic (larger) and secondary or specific (smaller) granules. Neutrophils may be present in the peripheral blood as immature or band forms; however, band forms do not frequently increase with bacterial infections. Neutrophils are not as numerous as lymphocytes in rabbits and typically constitute 20% to 75% of the total leukcocyte count.
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is reported to be aleukemic with a relative lymphophilia, which can include the observation of immature and atypical lymphocytes.10,11
Clinical Chemistries of Rabbits As with other domestic animals, blood chemistry values have long been used as an important diagnostic test to assess the overall health of rabbit patients. Changes in these plasma/serum chemistry parameters may be helpful in the diagnosis of diseases that involve the urinary tract. Normal plasma chemistry values important for assessing kidney function are listed in Table 2. The clinical chemistry parameters discussed in this article are limited to those that are most meaningful to the diagnosis of urinary tract disease. Figure 4. Rabbit blood smear showing neutrophil (heterophil) and basophil. Several platelets are present as well. Photomicrograph courtesy of Terry W. Campbell, MS, DVM, PhD.
Eosinophil. Rabbit eosinophils are larger than neutrophils and have a diameter range of 12 to 16 m (Fig 5). The eosinophilic granules of rabbits are larger than neutrophil granules, they stain intensely pink or a dull pink-orange, and most often fill the cytoplasm of the cell. The nucleus of the rabbit eosinophil is bilobed or horseshoe shaped. Eosinophils comprise 1% to 4% of total leukocyte count of the rabbit. Basophil. Unlike most exotic small mammals kept as pets, the rabbit commonly has circulating basophils in the peripheral blood (up to 2%-5% of the total WBC). Basophils are similar in size to the neutrophil and have a light purple, lobulated nucleus and dark purple to purple-black or occasionally metachromatc cytoplasmic granules. In general, the number of circulating basophils is inversely proportional to the number of tissue mast cells of that patient.7,8
WBC Response to Renal Disease. Rabbits experiencing an infectious disease rarely present with an elevated WBC count. The most common finding in the WBC count of a rabbit diagnosed with an infectious disease is a shift in the percentages of the various leukocytes to a neutrophil-dominated differential. Rabbits with an acute infection may present with 60% or greater neutrophils and 30% or fewer lymphocytes. Occasionally, rabbits with an acute infectious process will have a normal WBC count and a decrease in total leukocyte numbers. Stress or endogenous corticosteroid administration can induce a significant lymphopenia.9 Rabbit renal lymphoma
Blood Urea Nitrogen. Blood urea nitrogen (BUN) is commonly used to assess renal function in mammals. Urea is the principal end-product of protein catabolism formed in the liver of mammals and excreted by the kidneys. The BUN is filtered through the glomerulus and 25% to 40% is reabsorbed by the renal tubules. Rabbit BUN has a diurnal fluctuation, peaking in the late afternoon and early evening. This is thought to be correlated to the ingestion of cecotrophs.12 A decrease in BUN may be caused by anabolic steroids, diminished protein intake (e.g., anorexia, cessation of cecotrophy), and severe hepatic insufficiency. Increased BUN may be indicative of a variety of renal perfusion or function problems and/or increased protein catabolism (e.g., high protein diets, vigorous exercise). Increases in BUN relative to re-
Figure 5. Rabbit blood smear showing eosinophil and small lymphocyte. Photomicrograph courtesy of Terry W. Campbell, MS, DVM, PhD.
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Table 2. Normal blood chemistry values for the domestic rabbit Parameter
Reference range conventional units
Blood urea nitrogen Creatinine Calcium Phosphorus
28.3-47.9 mg/dL 0.8-1.9 mg/dL 8.8-15.6 mg/dL 3.1-6.8 mg/dL
Reference range SI units 10.1-17.1 mmol/L 74-171 mol/L 2.2-3.9 mmol/L 1.0-2.2 mmol/L
nal function may be divided into prerenal, renal, and postrenal causes. An elevation in BUN relative to a prerenal condition may include reduced renal blood flow and factors that reduce net filtration pressure at the glomerulus (e.g., dehydration). When BUN is elevated because of a renal condition, it suggests that there is a loss of 50% to 70% of the functional nephrons. Postrenal uremia is associated with obstruction, renal and cystic calculi, neoplasia, and perforation of the urinary system.
Circulating Enzymes. The specificity of a plasma
Creatinine. Creatinine is formed in the metabo-
Urinalysis
lism of muscle creatine and phosphocreatine. The creatinine level is far less influenced by external factors than BUN and is not affected by dietary proteins, protein catabolism, age, sex, or exercise. Creatinine is freely filtered through the glomerulus and excreted in the urine. Creatinine levels may be increased by severe renal insufficiency or severe muscle damage. Similar to BUN, creatinine is insensitive at detecting modest renal damage, as levels are increased only in cases where there is a greater than 50% to 70% loss of nephrons.
The urinalysis (UA) is a simple and quick procedure that can yield valuable information regarding the function of a rabbit’s urinary system, as well as other organs and systems in the body. In the author’s practice, a UA is part of the basic diagnostic information collected on any rabbit that presents with a disease condition. Collecting a UA from a rabbit patient is similar to that described for cats. With house-trained rabbits, urine should be collected in the early morning. Consumption of water during the day may dilute cellular components in the urine and lower the overall specific gravity of the sample. Urine may be collected by free catch, manual expression, catheterization, or cystocentesis. When obtaining a sample by free catch, an effort should be made to avoid the first part of the urine stream because it will contain exudate flushed from the urethra and the vaginal vestibule of female rabbits. Overzealous manual expression of the urinary bladder can result in artifactual blood in the urine sample. Urine obtained for bacterial cultures should be collected by catheterization or cystocentesis. For the best results, the UA should be processed as soon as the urine is collected; however, urine preserved by refrigeration for 2 to 3 hours can still provide reliable data.
Calcium. Rabbits typically have a higher total plasma calcium concentration than other mammals; however, the ionized fraction of calcium in the rabbit is comparable with that of other mammals.13 The rabbit appears to maintain its serum ionized calcium concentration against hypocalcemia and hypercalcemia by rapid changes in parathyroid hormone secretion and calcitonin. However, unlike other mammalian species, the changes in parathyroid hormone occur in the presence of relatively high levels of calcium, suggesting that the parathyroid gland of the rabbit is reset to respond to changes in ionized calcium within their physiological range. The relative insensitivity of the rabbit parathyroid to extracellular calcium is analogous to that observed in primary hyperparathyroidism.14 In support of this statement, wild members of the pet rabbit species, Oryctolagus cuniculus, also have relatively elevated calcium concentrations as opposed to other mammals. (Karen Rosenthal, DVM, personal communication, 2006).
enzyme as an indicator of injury or disease of a specific tissue or organ depends on both the concentration of an enzyme in the tissue or the organ of question. Although helpful in diagnosing diseases that affect other tissues, the plasma enzymes commonly evaluated with commercial analyzers are not of benefit in diagnosing rabbit urinary tract disease.12
Physical Examination of Urine. The color of normal rabbit urine is variable (e.g., white, yellowish white, light brown). One should always consider color and turbidity in association with urine-specific gravity. Rabbits that eat hay or vegetables or that have been recently treated with antibiotics may temporarily pass porphyrins in their urine, creating an
Evaluation of the Rabbit Urinary Tract
orange- or red- tinged coloration that may be confused as blood. Myoglobin or methemoglobinuria may cause rabbit urine to appear dark brown. Normal rabbit urine usually contains large amounts of light-colored sediment that may appear abnormal to inexperienced clinicians. Rabbits with low urine-specific gravity often have clear urine and less sediment. Cloudy urine must always be evaluated based on a microscopic examination. The most common cause of cloudy urine is calciuria, which is normal in rabbits. Other causes of cloudy urine include contamination due to white and red blood cells, epithelial cells, bacteria, and mucous.
Specific Gravity. Refractometer measurements of urine-specific gravity are accurate and only require a single drop of urine. The author has found the urine-specific gravity measurements from the commercial urine test strips to be highly inaccurate. Normal rabbit urine-specific gravity ranges from 1.003 to 1.035, with an average of 1.015.15 A fixed urine-specific gravity (1.008-1.012), combined with clinical dehydration, increased BUN and creatinine levels (uremia), or an abnormally high PCV, is an indication that the functional competence of the kidneys may be compromised. Reaction (pH). Normal rabbit urine is markedly alkaline, typical of hindgut-fermenting herbivores. The pH of healthy rabbits normally ranges from 8 to 9. Low urinary pH may result from high protein diets (i.e., rabbits eating cereal grains or cat food), catabolic states, starvation, and fever. Urine stored at room temperature becomes more alkaline with time because of the decomposition of urea.
Protein. Young healthy rabbits can have small amounts of albumin16 and adults trace amounts of protein, often from mucous, in their urine. Increased amounts of protein in the urine may indicate renal damage due to both increased permeability of the glomerulus to proteins and impaired reabsorption of protein due to tubular disease. Transient proteinuria may be found after excessive muscular activity, seizure activity, and with stress. Protein levels must be interpreted along with the urine-specific gravity and sediment analysis. Very dilute urine that tests positive for protein is more significant than a concentrated urine sample with the same level of protein.
Urine Glucose. Glucose is not present in normal rabbit urine; however, the author has experienced trace to even moderate amounts of glucose in the
277 urine of otherwise healthy rabbits after acutely painful or frightening experiences or with some chronic stressful condition (pain). Glucosuria may also occur when there is significant hematuria. As noted above, spontaneous diabetes mellitus has been documented in New Zealand White rabbits, but rarely affects companion rabbits.17,18
Urine Ketone. Ketones, most often acetone, acetoacetic acid, and beta-hydroxybutyric acid, are found in rabbit urine after prolonged anorexia or starvation, including that associated with pregnancy. Rabbits with severe dental disease and rabbits on a hayonly diet that have a severely impacted cecum are common disease presentations in which urinary ketones are identified.
Urine Bilirubin. Rabbits rarely have increased levels of circulating bilirubin and are less likely to have increased levels of bilirubin in their urine. This is partially because most bile is secreted as biliverdin in the rabbit. Positive urinary bilirubin is associated with the destruction of heme from blood cells and/or muscles and may be a sign of nephritis or cystitis.
Hematuria. Blood may be found in rabbit urine with chemical reagent test strips and by examination of urine sediment. Urinalysis strips will diagnose hematuria by testing positive for hemoglobin, myoglobin, and RBCs in the urine. The distinction between hematuria and hemoglobinuria or myoglobinuria requires examination of sediment and provides significant diagnostic information. Normal rabbit urine has very few RBCs (0-3 cells/high-power field), and an increase in the number of erythrocytes occurs with inflammation or damage of the urinary or reproductive systems caused by infection, calculi, or neoplasia. Table 3 provides a list of the common causes of hematuria in rabbits.
Urine Sediment. Calciuria is common in the rabbit and is associated with the unique calcium metabolism of rabbits. Rabbit urine often appears cloudy and turbid. Microscopically, this turbidity is the result of calcium carbonate crystals. The mean fractional excretion of calcium in a rabbit being fed a conventional pellet diet is 44%. The fractional excretion of calcium in most mammals is less than 2%.19 Other crystals, most often triple phosphate and amorphous phosphate crystals, are also commonly seen in rabbit urine. Rabbits being treated with sulfonamide drugs may have sulfadiazine crystals (trimethoprim-sulfadiazine), observed as “shocks
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Table 3. Causes of hematuria in the rabbit Cystitis, urethritis Pyelonephritis Urolithiasis (urethra, bladder, ureter or renal pelvis) Renal neoplasia Renal infarcts Bladder polyps Uterine adenocarcinoma Endometrial hyperplasia Endometrial venous aneurysm Endometrial hemangiomatosis
References 1. 2.
3. 4.
5.
of wheat” or radially striated spherules or sulfonamide crystals, which are yellow in color and resemble uric acid crystals. Many drugs excreted in the urine have the potential to form crystals. Consequently, a review of the patient’s drug history is useful when an unidentified crystal is recognized. Erythrocytes, WBCs, casts (cylinduria), and bacteria may be found in rabbit urine and have the same interpretation and importance as with other companion mammal patients. Urine collected by manual expression of the bladder may contain an abundance of RBCs. The presence of WBCs in the urine suggests infection, whereas casts are often indicative of glomerular or renal tubular disease.
6.
7. 8. 9. 10. 11.
Calciuria versus MUC/“Sludge”. It is the author’s opinion that there is a distinct difference between normal calciuria and the fine calcium urinary calculi often described as “sludge.” The author suggests the more accurate descriptive name of MUC for sludge. Normal calciuria is the result of a high calcium diet, but the distinction is that the calcium in the normal rabbit does not precipitate to form calculi within the bladder. MUC are calcium-based calculi, not just crystals. These calculi form in response to cystitis or other conditions that provide the nidus for their formation. MUC may even form in greater quantities in rabbits fed a low calcium diet. Intermittent or partial outlet obstruction of the rabbit bladder by MUC leads to damage of bladder smooth muscle. When prolonged, the damage to the bladder smooth muscle becomes irreversible.20-22 Preventing bladder damage in rabbits with MUC requires early intervention, flushing, and prolonged treatment with an appropriate antibiotic. Unfortunately, once the bladder is damaged, these rabbits require long-term management, including regular expression, long-term antibiotic therapy, and care of perineum to prevent urine scald, dermatitis, and myiasis.
12.
13. 14. 15.
16.
17. 18. 19.
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20.
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tory rabbits. Miner Electrolyte Metab 10:127-132, 1984 Guven A, Kalorin C, Onal B, et al: Novel biomarkers of bladder decompensation after partial bladder obstruction. Neurourol Urodyn 26:1036-1042, 2007 Nigro DA, Haugaard N, Wein AJ, et al: Metabolic
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basis for contractile dysfunction following chronic partial bladder outlet obstruction in rabbits. Mol Cell Biochem 200:1-6, 1999 Yang L, He D, Wang S, et al: Effect of long-term partial bladder outlet obstruction on caldesmon isoforms and their correlation with contractile function. Acta Pharmacol Sin 29:600-605, 2008