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Urology Jody P. Lulich, DVM, PhD and Carl A. Osborne, DVM, PhD University of Minnesota Diagnostic Pitfalls: Misdiagnosising Causes of Urinary Tract Signs Jody P. Lulich, DVM, PhD and Carl A. Osborne, DVM, PhD Optimal patient care depends on an accurate diagnostic assessment of clinical information and thoughtful analysis of the trade offs between the benefits and risks of further diagnostic testing and treatment. Because of limitations imposed by time, finances, and risks associated with diagnostic testing, diagnosis is often an unstructured and frenzied process of data collection followed by inference. As a result, clincians are compelled to make a diagnosis in the face of varying degrees of uncertainty. It is our hope, in the following sections, to provide a more structured approach to the diagnostic process by providing a few guiding principles, likelihoods of common diseases, and systematic approaches to data collection. We have also provided common diagnostic errors and solutions to some problems we have encountered. MISSING THE OBVIOUS What's Common and What's Not Of 15,349 cats with lower urinary tract disease, the five most frequent diagnoses were feline urologic syndrome, cystitis, urethral obstruction, urethrolithiasis and urocystolithiasis.1 The most common diagnosis, feline urologic syndrome (now called idiopathic lower urinary tract disease or idiopathic cysistis), does not represent a specifically treatable disease, but a syndrome caused by a variety of etiologies. In a prospective diagnostic study of 143 cats with hematuria and dysuria using conventional diagnostic techniques, urethral plugs were diagnosed in 22.4% and uroliths in 22.4% of the cats.2 In 53.8% of the cases, however, a cause for lower urinary tract signs could not be further refined. Less frequent diagnoses for LUTD in cats included urinary incontinence, bacterial cystitis, urethral strictures, urachal diverticula, and neoplastic disorders. Of 24,087 dogs diagnosed with lower urinary tract disease using conventional diagnostic procedures, urinary incontinence, urolithiasis, urinary tract infection, and neoplasia were diagnosed most often.3 The majority of dogs with urinary incontinence were female (72%); the majority of female dogs with urinary incontinence were neutered (79%). In contrast, urolithiasis predominated in males; 63% were male and 37% were female. Renal failure is the most commonly recognized upper urinary tract disease of dogs and cats. The cause of most forms of renal failure remain an enigma; however, recognized causes include glomerulonephritis, toxins (e.g ethylene glycol), adverse drug reactions (e.g. gentamicin, nonsteroidal antiinflammatory agents), ischemia (e.g. hypoperfusion associated with traumatic shock, anesthesia or dehydration), urinary outflow obstruction, and bacterial infection. A Stich In Time Saves Nine Early diagnosis and appropriate intervention may result in cure of many diseases or at least minimize their progression. For example, mild chronic renal failure may go unnoticed in patients that have time to compensate for gradual reduction in renal function. Likewise, disease that affects only one kidney may remain clinically silent. If renal failure is due to infection, urinary outflow obstruction, or glomerular disease, early detection and treatment may restore adequate and sometimes complete renal function. To avoid overlooking subclinical renal failure, we routinely perform diagnostic screening tests in animals at risk. High risk groups include breeds with a history of familial renal failure, dogs 7 years and older, cats 10 years and older, and patients receiving drugs with potential nephrotoxicity (e.g. gentamicin, nonsteroidal antiinflammatory agents, Cis platinum, and amphotericin B). Early diagnosis will also greatly improve patient outcomes for other diseases, especially urolithiasis, acute renal failure, urinary tract infection, and urinary tract neoplasia. MISSING THE EASILY TREATABLE AND LIFE THREATENING Deciding when diagnostic testing is adequate to provide sufficient information to safely begin treatment is influenced by the degree of diagnostic uncertainty that each clincian will accept. To optimize patient care, evaluations should routinely include tests that identify easily treatable and life threatening conditions . Consider the following example. A 3 year old male cat is admitted to your clinic because the owners are concerned about acute onset of vomiting. Following diagnostic evaluation, you make a diagnosis of acute renal failure. Despite intensive parenteral fluid therapy, diuretics and adequate control of acid/base and electrolyte abnormalities, the cat remains oliguric and dies three days later. At necropsy, you discover that the cat's right kidney was hypoplastic. However, the left kidney appeared normal except for a calcium oxalate urolith obstructing urine outflow at the junction of the renal pelvis with the proximal ureter. Had radiography been performed, surgical urolith removal in combination with the patient's previous therapy, likely would have reversed this cat's acute renal failure. DIAGNOSTIC INERTIA Sometimes we create our own diagnostic inertia, that is, we tend to move in the same direction despite warning signs that we may be moving in the wrong direction. By not listening to client's observations and interpretations or by prematurely considering client's comments unreliable when they are accurate, we often lose valuable diagnostic information. Sometimes, we diagnose by intuition (so called gut feelings) or premonition (the mystical 6th sense) without properly evaluating the patient or reasonable diagnostic tests. Even worse, when our therapy fails, we remain overconfident and steadfastly adhere to our original diagnosis rather than considering that our diagnostic observations and interpretations may have been partially or totally innaccurrate. Consider that following example. An 8 year old female spayed female Golden Retriever is evaluated for hematuria and dysuria. Routine physical examination reveals no abnormalities. It was not possible to obtain a urine sample at the time of initial examination. Based on the patient's clinical signs and disease probabilities you diagnose a urinary tract infection and accordingly prescribe a broad spectrum antibiotic. After 7 days of therapy, the owner informs you that the dog is still urinating in the house. At that time you prescribe a different antibiotic. The owner again calls you 3 days later because she is concerned that the dog is still urinating in the house. You suggest that additional time is needed for the medication to work. The client stops calling you and you assume that all is well. A few weeks later while having lunch with a colleague, she informs you that one of your clients made an appointment to visit her hospital. You learn that the 8 year old female dog evaluated for hematuria and dysuria had a transitional cell carcinoma of the bladder. This scenario illustrates the necessity to reassess diagnostic conclusions when treatment outcomes differ from expected results. A Well Defined Problem Is Half Solved A fundamental step in the diagnostic process is our capacity to define the patient's medical problems without overstating them. We should continually focus on this crucial step, since we must be able to define problems before we can help solve them. Even if we do not have immediate solutions, by properly identifying the patient's problems, we will be able to utilize other resources, such as textbooks, journals, and colleagues for consultation to help solve the problem. In the process of defining problems, one must use care not to mix observations with interpretations. Observations and interpretations represent distinctly separate facets of diagnosis. Even when observations are correct, interpretations of these observations may be erroneous. If misinterpretations are accepted as facts, the result may be misdiagnosis and formulation of inappropriate or contraindicated therapy. Garbage In - Garbage Out Diagnostic chaos can also be created by relying on information from inappropriately collected samples. Sometimes conditions of sample collection or client impatience may result in less than ideal sampling conditions. For example, the pH of a urine sample collected from the examination table may reflect the pH of the disinfectant used to clean the table rather than that of the urine in the patient. When questionable results occur in samples collected under less than ideal conditions, interpretion of results should encompass the possibility (or probability) that in vitro factors may have influenced the test result. To clarify ambiguities, repeat the test under more suitable conditions. Don't Be Fooled And Don't Fool Around Verifying a diagnosis usually requires interpretations of test results. But not all tests are created equal. In fact, some diagnostic test results should not be relied upon at all. For example, reagent strips are routinely used for analysis of canine and feline urine; however, most of these products are designed for evaluating human urine. Therefore, some of the results of these tests may not be valid for companion animals. For example, when evaluating urine from cats, the leukocyte reagent pad is routinely positive, even if there are no white blood cells in the sample. Don't be fooled by this false positive result when evaluating cat urine by the reagent strip method. Microscopic evaluation of urine sediment should always be included in a complete urinalysis. Other diagnostic pitfalls to avoid: Diagnostic Pitfall: Hematuria is synonymous with lower urinary tract disease. Diagnostic Safeguard: Hematuria can originate from any portion of the urinary tract as well as from generalized coagulation disorders (e.g. Von Willebrand's disease). Avoid diagnosis of lower urinary tract disease before localizing the origin of bleeding. Diagnostic Pitfall: Ease of transurethral catheterization during cystotomy indicates that uroliths are not in the urethral lumen. Diagnostic Safeguard: Some uroliths, especially those with an irregular contour (e.g. uroliths composed of calcium oxalate) may allow passage of catheters and flushing solutions. Comparing urolith numbers detected by radiography prior to surgery, to the number of uroliths removed will be helpful. As a safeguard, radiograph patients following cystotomy to insure complete urolith removal. Diagnostic Pitfall: Urethral obstruction in cats is synonymous with plug formation. Diagnostic Safeguard: Approximately 25% of cats with lower urinary tract disease have uroliths. Flushing and catheterization of the urethra may be sufficient to disrupt urethral plugs; however, they may be ineffective in preventing reobstruction caused by uroliths. A lateral survey radiograph prior to unobstructing the urethra will help differentiate most urethral plugs from uroliths. For many cats we do not know the cause of obstruction. Diagnostic Pitfall: Hyperamylasemia in dogs is pathognomic with pancreatitis. Diagnostic Safeguard: In addition to pancreatitis, serum concentrations of amylase and lipase are also elevated 2 to 3 times greater than the normal value in azotemic dogs without pancreatitis. Radiography and ultrasonography of the cranial abdomen are helpful to differentiate pancreatitis from azotemia in patients with hyperamylasemia and hyperlipasemia. PLAN YOUR WORK To maximize diagnostic efficiency and avoid the pitfalls of frenzied data collection, develop a diagnostic plan to search for the common causes, identify the treatable problems and rule out life threatening conditions. Avoid diagnostic chaos and inertia by defining the problem first, collecting appropriate samples under proper conditions, and understanding the meaning of a positive test.
Biopsy of the Lower Urinary Tract Jody P. Lulich, DVM, PhD and Carl A. Osborne, DVM, PhD Differentiation of potentially reversible disease from progressive irreversible disease is the single most important factor in the management of persistent or recurrent lower urinary tract signs. Biopsy of the urinary bladder and urethra is helpful to make this distinction in the living patient. Many options are available to obtain tissue for microscopic evaluation (table 1). If structures to be biopsied can be palpated, they are usually accessible for aspiration with a needle and syringe. If larger samples are desired, minimially invasive techniques, such as transurethral catheter biopsy have been commonly recommended (Osborne 1995). A practical alternative to catheterization biopsy is use of flexible endoscopy forceps to retrieve tissue samples from the lower urinary tract (Lulich 2000). Obtaining samples using endoscopy forceps has the advanthage of procuring samples with minimal architectural disruption. Likewise, the procedure is as convenient as urinary catheterization. MATERIALS NEEDED FOR BIOPSY Flexible endoscopy biopsy forceps can be obtained from a variety of vendors in a a variety of sizes and lengths. We have had the best results using forceps with a fenestrated oval or elongated cup (figure 1). The fenestrated cup minimizes tissue crushing. Although some prefer biopsy forceps with a central spear to help anchor the biopsy cup to the biopsy site, in our experience the spear becomes dull after several uses. Once damaged, the spear no longer anchors tissue, but inadvertently pushes the target tissue away from the grasping cup. For this reason, we nolonger use biospy forceps with a central spear. Depending on the location and size of the lesion, additional equipment can be used to guide the biopsy forceps and visualize the procedure. For example, biopsy forceps inserted through the biopsy channel of a cystoscope greatly facilitates procurement of samples from the lateral walls of the urinary bladder. If operators are not familiar with cystoscopy, ultrasound can be used to guide the biopsy forceps (Figure 2). PERFORMING FORCEPS BIOPSY Obtaining tissue samples using the endoscopy forceps is similar to methods used to obtain gastrointestinal mucosal with an endoscope. Since the endoscope is not inserted into the urethra, other methods, such as palpation, cystoscopy, or medical imaging, are needed to localize the lesion and direct the biopsy forceps.
Following bladder biopsy, hematuria and dysuria may be more pronounced. In most cases, bleeding quickly stabilizes (hours to a day) without treatment. Administration of antibiotics is indicated because the integrity of the mucosal surface of the lower urinary tract is disrupted by this procedure, further altering normal host defenses. If possible, infections diagnosed during initial evaluation should be eradicated prior to biopsy. Eliminating infection prior to biopsy will minimize hematuria and dysuria associated with sampling of inflamed tissues and also the potential of extending the infection into the biopsy site and adjacent tissues. In the absence of prior infection, we routinely administer antibiotics orally for the next 3 to 5 days. The need for medication to minimize pain and inflammation should be deteremined on the basis of the underlying disease and the degree of tissue disruption during procurement of the sample, and the type and dose of preanesthetic agents used. LIMITATIONS OF FORCEPS BIOPSY Standard flexible biopsy forceps are approximately the diameter of an 8 french catheter (2.7mm). As a general rule, you should be able to insert the biopsy forceps into the urethral lumen of most male dogs greater than 4 kilograms, and into the urethral lumen of most, if not all, female cats and dogs. The lumen of the penile urethra of male cats is usually too narrow to accommodate insertion of standard flexible biopsy forceps used for endoscopy. For male cats, consider using forceps with a shaft diameter less that 1 to 1.67mm in diameter (i.e less than 3.5 to 5 Fr). Most cystoscopes cannot be inserted in the urethra of male cats, and those scopes that fit into the uretha generally do not have a biopsy channel. Therefore, consider transurethral palpation or medical imaging to direct the biopsy procedure. It is possible that a thin or weakened bladder wall could be perforated by this procedure. For this reason we do not recommend biopsy of the lower urinary tract at sites proximal to sites of partial or complete obstruction because increases in intravesicular pressure may result in extravasation of urine into the abdominal cavity or retroperitoneal space. If a tissue sample proximal to a urinary obstruction is desired, constant bladder evacuation by indwelling urethral catheterization or antepubic percutaneous catheterization (Stone 1992) of the urinary bladder should be considered. Minimizing intravesicular pressure should allow small perforations of the bladder wall to spontaneously heal. FOOTNOTES a. Anestacon, Polymedica Indeustries, Divison of Alcon Labs Inc., Woburn, MA 01801 REFERENCES
Improving Diagnosis and Therapy of Chronic Kidney Disease in Cats Jody P. Lulich, DVM, PhD and Carl A. Osborne, DVM, PhD Kidney disease (damage) is defined as any pathological abnormality or marker of injury (i.e. abnormalities in hematology and serum chemical values, abnormal urine sediment, proteinuria, aberrations in medical imaging studies, and hypertension) with or without azotemia. Kidney failure is loss of sufficient functional nephrons (usually ¾ or more) to impair homeostasis. A diagnosis of primary renal failure (rather than prerenal or postrenal azotemia) is usually confirmed by detecting azotemia and inappropriate urine concentrating capability (specific gravity of 1.007 to approximately < 1.035). Early detection of kidney failure is difficult because mild forms of disease typically remain sub-clinical. In addition, many clinical findings associated with renal failure are not specifically referable to the urinary system. However, some trends may help selection of patients likely to benefit from further evaluation. For example, cats between 10 and 15 years old are five times more likely to have renal failure than cats of younger age groups. Cats greater than 15 years have the highest incidence of kidney failure. Particular breeds (British short-hair, Somali, Birman, Siamese, Abyssinian, Main Coon, Burmese) have also been identified to be at increased risk. We emphasize, however, that the best predictor of future clinically significant disease is detection of existing minor disease. The aforementioned risk factors are not collectively as strong a predictor of kidney failure as are laboratory findings of early kidney damage or dysfunction. Therefore, we recommend that older cats be periodically screened even in the absence of clinical signs. Even though not specifically related to the urinary tract, kidney disease should be considered in cats with anorexia, weight-loss, dehydration, depression, vomiting, polyuria and constipation. Lastly, when detected, kidney disease can be staged to prioritize identification of correctable causes and implementation of effective therapeutic strategies to minimize progressive deterioration of kidney function. 
STAGING CHRONIC KIDNEY DISEASE Chronic kidney disease (CKD) in dogs and rats typically progresses and culminates in end stage kidney failure and death. Although cats with CKD may survive for months to years after their initial diagnosis with minimal clinical signs attributable to CKD, many cats ultimately develop signs associated with advanced CKD consistent with progression as observed in other species. Mechanisms responsible for progression include the pathological consequences of the initiating event, functional maladaptaions to preserve renal perfusion, the superimposition of uremic complications, and the inherent susceptibility of the diseased kidney to repeated damage. Because these problems appear sequentially as disease progresses, cats can be managed according to disease severity. A useful approach is to categorize cats with CKD into stages. The International Renal Interest Society has proposed a staging scheme based on the level of azotemia (table 1) that takes into consideration diagnostic and therapeutic interventions. Table 1. Identify Stage of Feline Chronic Kidney Disease to Prioritize Diagnostic and Therapeutic Interventions.
Modified from Grauer GF and Brown SA. Chronic kidney disease and the role of phosphorus binders. Clinician's update, November 2005 Supplement. RELATED DEFINITIONS KIDNEY FAILURE is the inability of the kidneys to maintain homeostasis (e.g. acid-base balance, water balance, electrolyte balance, hormone balance, and metabolic waste removal). Pathophysiologically it implies destruction of at least ¾ of the functioning mass of both kidneys. Classically the diagnosis is determined on the basis of azotemia with inappropriate urine concentration (i.e. urine specific gravity of 1.007 to approximately 1.035); however, some cats in early kidney failure may concentrate their urine above 1.035. PROTEINURIA is a laboratory finding indicating urine protein excretion in excess of normal (urine protein to creatinine ratio of greater than 0.4 to 0.5). Determining its clinical significance requires knowledge of its origin, magnitude, and persistence. Pre-renal proteinuria (e.g. hemoglobinemia, myoglobinemia, Bence Jones proteinuria) and post-renal proteinuria (e.g. lower urinary tract or genital tract trauma, hemorrhage, inflammation and cancer) have minimal if any adverse consequences on the long-term health of feline kidneys. However, the magnitude of renal proteinuria (e.g. glomerular and/or tubular) is inversely related to survival. In a cross sectional epidemiological study of 94 cats with chronic kidney disease and 42 non-azotemic cats, survival was significantly shorter in cats with UP/UC >0.43 compared to cats with UP/UC <0.13.a It is important to recognize that the cause of the death in approximately half of the cats was not related to the kidney failure. How proteinuria promotes progressive renal injury is not completely understood. However, urine protein, sufficient to overwhelm tubular resorptive mechanisms, initiates a sequence of events (i.e. activation of proinflammatory genes) leading to interstitial fibrosis. Some have hypothesized that proteinuria is merely a marker of maladaptive consequence of up-regulation of the rennin-angiotensin system in the damaged kidney (i.e. with the loss of functioning nephrons, local activation of the renin-angitoensin system within the kidney leads to cellular hypertrophy and glomerular hyperfiltration; the rise in glomerular capillary hydrostatic pressure is accompanied by an increased in urine protein). Regardless of the role of urine protein, the use of angiotensin converting enzyme inhibitors minimized proteinuria and prolonged survival. In a randomized, double-blind clinical trial of 193 cats with chronic kidney disease, benazepril significantly improved survival when the UP/UC was greater than 1.b When treating cats with ACEI, several questions remain. Should ACEI be administered to all cats with chronic kidney disease? What should the target post-ACEI treatment urine protein level be to minimize progressive deterioration of kidney function? HYPERTENSION is clinically significant when sustained elevations in blood pressure cause or are likely to cause end organ damage (e.g. left ventricular hypertrophy, hypertensive encephalopathy, retinal detachment and ocular hemorrhage, and glomerular hyperfiltration resulting in interstitial fibrosis and progressive kidney damage). A recent study indicated that the prevalence of hypertension on initial evaluation of cats with chronic kidney disease was 20%. It is believed that hypertension is a consequence of, rather than an underlying cause for chronic kidney disease. The general consensus among veterinary urologists is that systolic blood pressure exceeding 160 to 180 mm Hg may lead to end-organ injury and progressive deterioration of kidney function. Therefore, hypertension of this magnitude warrants treatment. Amlodipine is considered the primary antihypertensive medication to manage elevations in blood pressure. When doubling the dose of Amlodipinie does not effectively control blood pressure, angiotension converting enzyme inhibitors are concomitantly administered. UREMIA is the entire consternation of signs and symptoms of chronic kidney failure, including nausea, vomiting, anorexia, characteristic odor of the breath, prutitis, neuromuscular disorders, muscle pain, muscle twitching, hypertension, edema, mental confusion, and acid-base and electrolyte abnormalities.
Table 2. Markers of Kidney Damage
Markers require confirmation of renal origin to be evidence of kidney damage. Modified from Polzin DP, Osborne CA, Ross SJ: Chronic kidney failure in Ettinger JS, Feldman EC, editors: Textbook of veterinary internal medicine, ed 6, Philadelphia, 2005, Elsevier Table 3. Diagnostic Considerations for Cats with Kidney Disease
Table 4. Renoprotective Therapy to Minimize Progression
Table 5. Additional Supportive and Symptomatic Therapy to manage Feline Kidney Disease
Calcium Oxalate: Biologic Behavior and Risk Factor Management Jody P. Lulich, DVM, PhD BIOLOGIC BEHAVIOR Epidemiological studies have revealed that the risk of calcium oxalate (CaOx) uroliths is approximately 7 times greater in Bichon Frise dogs admitted to veterinary hospitals than dogs admitted without urinary tract disease. However, the frequency and time of recurrence of CaOx uroliths in Bichons has not been evaluated in a systematic fashion. This information is needed to determine whether therapy designed to prevent recurrence of CaOx uroliths is warranted. Records of 50 Bichons (34 males and 16 females) with CaOx uroliths admitted to our hospital between 1990 and 2002 were reviewed. Mean age of Bichons at initial urolith detection was 7.6±2.4 years. Urinalyses (n=27) revealed that specific gravity was 1.027±1.012 and pH was 7.3±0.8; only 37% had CaOx crystalluria. Thirty-four Bichons were evaluated following surgery. CaOx recurrence occurred in 25. Recurrence rate increased with length of time that Bichons were evaluated. After 1 year, 37% had their first recurrence; after 2 years, 64% had their first recurrence and 8% had their second recurrence; after 3 years, 90% had their first recurrence, 15% had their second recurrence, and 4% had their third recurrence. Urolith recurrence was detected in 100% of dogs evaluated ? 4 years. At first recurrence; neither age, gender, urine specific gravity, urine pH, CaOx crystalluria, nor serum calcium concentration was associated with the propensity for urolith formation. These observations indicate that following urolith removal CaOx recurrence is imminent. Therefore, long-term monitoring and therapy is needed to prevent repeat urolith removal. SELECTING AN APPROPRIATE DIET Results of experimental and clinical investigations have confirmed the importance of dietary modifications in medical protocols to prevent urolith recurrence. However for calcium oxalate, selection of an appropriate diet is challenging because: 1) the exact mechanisms underlying calcium oxalate urolith formation are not completely known, 2) results of epidemiological studies do not always match physiology response of diet characteristics, and 3) diet efficacy has not been evaluated using clinically relevant endpoints. The Exact Mechanisms Underlying Calcium Oxalate Urolith Formation Are Not Completely Known. Although formation of CaOx uroliths is associated with a complex and incompletely understood sequence of events, it is accepted that initial crystal formation and subsequent crystal growth are at least partly a reflection of urine supersaturation. However, unlike other stone types, the urinary concentrations of calculogenic minerals may not be the predominant driving force for CaOx urolith formation. For example, 68 proteins were recently identified in matrix of CaOx uroliths from humans (Canales 2008). We have identified over 30 proteins in CaOx uroliths from dogs. The function of many of these proteins is unknown. Those proteins known to influence crystal nucleation, growth, and aggregation include osteopontin, nephrocalcin, Tamm-Horsfall, bikunin, and ?1-antitripsin. In experimentally induced hyperoxaluria, intratubular CaOx crystalluria was detected in ostoeopontin and Tamm-Horsfall knockout mice, but did not occur in wild-type controls. These findings indicate the importance of other substances besides the concentrations of minerals in urine in the generation of CaOx uroliths. Results of Epidemiological Studies Do Not Always Match Physiology Response of Diet Characteristics Few studies have evaluated the risk of dietary ingredients on CaOx urolith formation. In these studies, the most influential dietary attributes are urine acidifying potential and the concentrations of calcium, protein, and sodium. (Table 1). Of the many dietary attributes only two results of epidemiologic studies are consistently corroborated by results of experimental studies: diets formulated to promote more acidic urine and diets with low moisture content (i.e. kibble) increase the risk of CaOx formation. Therefore, canned diets designed to promote formation of neutral or alkaline urine should be considered to minimize CaOx urolith recurrence. Table 1. Evaluation of dietary risk factors for calcium oxalate formation in dogs
Diet Efficacy Has Not Been Evaluated Using Clinically Relevant Endpoints. Ideally, studies to prevent CaOx urolith formation should be performed in dogs with a history of forming calcium oxalate stones. In addition, investigators and clients should be masked as to which dogs are randomly assigned the therapeutic food and the control food. Lastly, studies should report reliable endpoints of urolith recurrence (i.e. medical imaging). We are not aware of any reported studies meeting these basic criteria. So how can veterinarians make recommendations? The two most commonly prescribed diets to prevent CaOx urolith recurrence in dogs are Prescription Diet u/d® and Urinary SO™. How do these diets compare (table 2)? Table 2. Comparing the Dietary Characteristic of Diets Commonly Used to Prevent CaOx urolith Recurrence
* Lulich 2001, †Stevenson 2004
Therapeutic Strategies for Managing the Four Most Difficult Urinary Tract Infections Jody P. Lulich, DVM, PhD Effective management of persistent urinary tract infections (table 1) requires an understanding of the underlying cause, the invading organism and its antimicrobical susceptibility, the location of the infection, and the bioavailability and activity of antimicrobic drugs. We use several steps to identify and control disease: STEP ONE: VERIFY INFECTION Clinicians are commonly faced with the problem of lack of response to what appears to be adequate antimicrobic therapy. This is usually manifested clinically by lack of clinical improvement, partial clinical improvement, or clinical deterioration. The usual response, selection of a different antimicrobic, assumes that your original therapeutic choice was inadequate. This is possible; however, a common cause for persistence of clinical signs is noninfectious disorders mimicking infectious disease. When are urine cultures and bacterial susceptibility testing mandatory? Poor response to antimicrobic therapy is a clear indication to evaluate urine culture results. Diagnosis of bacterial UTI solely on the basis of clinical signs usually results in overdiagnosis. Once antibacterial therapy has already been initiated, therapy should be discontinued for three to five days before urine is cultured. Discontinuing therapy for five days minimizes false negative results associated with therapeutic inhibition of in vivo and in vitro bacterial growth. Ideally, in this situation, urine cultures should be performed just prior to termination of therapy and five days after termination of therapy. The former urine culture potentially identifies bacteria resistant to present antimicrobic therapy and the latter culture aids verification of bacterial infection as a contributing cause of clinical disease. STEP TWO: LOCALIZE INFECTION Bacterial infection of the urinary tract encompasses a wide variety of clinical entities whose common denominator is microbial invasion of any of its components. Infection may predominate at a single site such as the kidney (pyelonephritis), ureter (ureteritis), bladder (cystitis), urethra (urethritis), or prostate gland (prostatitis), at two or more of these sites, or it may be restricted to the urine (bacteriuria). Although terms such as pyelonephritis, cystitis, and urethritis are commonly used, they reflect localized expressions of urinary tract infection that have the potential of affecting the entire urinary tract. The important point is that the entire system is at risk of invasion once any of its parts becomes colonized with bacteria. Because bacterial infections are unlikely to be confined to the urinary bladder without affecting the urethra, it is more appropriate to utilize the terminology of "lower urinary tract infection" or "urethrocystitis" rather than "cystitis". Likewise, because bacterial infections are unlikely to be confined to the renal parenchyma and renal pelvis without affecting portions of the ureters, it may be more appropriate to utilize the terminology of "upper urinary tract infection" rather than pyelonephritis. Localization of infection is critical to successful antimicrobic selection and administration. For example, lipid soluble antimicrobics are recommended to treat infections of the prostate and renal medulla because recommended doses of antimicrobics with low lipid solubility may not achieve therapeutic concentrations in these locations. In addition, duration of antimicrobic administration varies with location of infection. Uncomplicated infections of the lower urinary tract usually require 7 to 14 days of therapy while longer periods are recommended for infections in the kidney or prostate gland. STEP THREE: IDENTIFY AND CORRECT UNDERLYING CAUSES Conceptual understanding of the interaction between the various host defense mechanisms and uropathogenic microorganisms permits development of a diagnostically and therapeutically significant classification of urinary tract infections. The common denominator of this classification is the presence or absence of detectable abnormalities in host defense mechanisms, which allows differentiation of complicated from uncomplicated urinary tract infections. An uncomplicated (or simple) urinary tract infection is defined as an infection in which no underlying structural, neurologic, or functional abnormality can be identified. Although useful, this classification may be somewhat misleading in that it infers that bacterial infection is always the primary abnormality. This may be the situation if normal host defenses are overwhelmed by a large inoculum of pathogens. However, it is becoming increasingly apparent that most bacteria will multiply and survive only when urinary tract host defenses are disrupted. It is reemphasized that a urinary tract infection usually represents a transient or persistent defect in the innate defense mechanisms of the patient, even though the underlying cause may escape detection. The clinical relevance of identification of an uncomplicated urinary tract infection is that it is more likely to be caused by a transient, self-limiting, and potentially reversible abnormality in host defenses. Complicated urinary tract infection occurs as a result of bacterial invasion of the urinary system secondary to identifiable diseases that interfere with normal host defense mechanisms. Causes of complicated urinary tract infection include interference with normal micturition, anatomic defects, alterations of urothelium, altered volume, frequency, or composition of urine, and impaired immunocompetence. In general, the underlying cause must be removed or corrected if secondary bacterial infection is to be eradicated. Failure to do so is a common cause of recurrent (relapse, reinfection, or superinfection) urinary tract infections. STEP FOUR: ADMINISTER APPROPRIATE ANTIMICROBIC THERAPY Evaluation of the susceptibility of infecting bacteria to antimicrobial drugs is advisable as a general guide for choice of therapeutic agents because bacteria isolated from dogs and cats with UTI may vary widely in their susceptibility to specific antimicrobial agents. Treatment of an acute onset of uncomplicated bacterial UTI may be formulated without results of antimicrobial susceptibility tests provided patients have not been given antibacterial drugs in the past 4 to 6 weeks. In this situation, choice of drug should be based on know properties of antimicrobial agents in combating UTI caused by commonly isolated organisms, and their ability to attain a high concentration in urine. Data concerning the minimum and optimum duration of antimicrobial therapy for urinary tract infections are not available. Therefore, no rigid generalities concerning the duration of treatment for acute, chronic and recurrent UTI can be established. Duration of therapy must be individualized on the basis of serial clinical and laboratory findings, and therefore is dependent on patient response to therapy. The goals of therapy are to: 1) eliminate bacteria from urine and tissue, and 2) allow the urinary tract and its defense mechanisms time to recover sufficient function to prevent recurrence of UTI. STEP FIVE: MONITOR THERAPEUTIC EFFICACY Although results of susceptibility tests are valuable for predicting antimicrobic success, clinical and laboratory evidence of response to an antimicrobial drug is the ultimate parameter of success. Repeat urine cultures are essential for monitoring therapeutic efficacy because factors other than in vitro susceptibility may affect in vivo effectiveness of an antimicrobial agent. The following recommendations extrapolated from studies in human beings are based on uncontrolled clinical observations. They are guidelines only and should not be interpreted as rigid facts. Culture a urine sample collected by cystocentesis 3 to 5 days following initiation of therapy (so-called "test for cure"). Therapy is considered to be successful only if urine does not contain any viable pathogenic organisms. Treatment is ineffective if the bacterial colony count has only been reduced. Hematuria, pyuria, and proteinuria is likely to be present at this stage, although it may be of lesser magnitude. Consider evaluation of a urine culture and urinalysis 3 to 5 days (or sooner if necessary) prior to the scheduled discontinuation of therapy, especially if prophylactic antibiotics are to be used to prevent frequently recurrent UTI. Therapy may be discontinued if the urine is sterile and the urine sediment is normal. If results indicate persistent infection, reevaluation of therapy is essential. STEP SIX: CONTROL RECURRENT INFECTIONS Recurrence of clinical and/or laboratory signs of urinary tract infection following withdrawal of therapy may be classified as relapses, reinfections, or superinfections. Relapses (persistent infections) are defined as recurrences caused by the same species and serological strain of microorganism within several weeks of the date of cessation of therapy. Relapses are usually associated with antimicrobic failure and persistence of the original organism. Reinfections are defined as recurrent infections caused by a different pathogen(s). In contrast to relapses, most reinfections occur at a longer interval following cessation of therapy. Reinfections are usually associated with failure to recognize or eliminate underlying causes. Superinfections are defined as infections with an additional organism during the course of antimicrobial treatment. They are most likely to occur in association with indwelling urethral catheters, or as a sequelae to urinary diversion techniques in which the urinary tract communicates with the intestinal tract, and when proximal portions of the urethra, the urinary bladder, or the kidneys communicate directly with the exterior (antepubic urethrostomy, tube cystostomy, percutaneous nephropyelostomy, etc). If therapy has been successful, follow-up evaluation is required to detect recurrences. Relapse caused by the same organism would be expected to occur shortly after cessation of antimicrobial therapy. Therefore the results of a urinalysis and culture should be reevaluated 7 to 10 days following the discontinuation of therapy to detect recurrent relapses at a subclinical stage. Recovery of the same organism from previously sterile urine is presumptive evidence that antimicrobial therapy failed to eradicate the infection and suggests lack of compliance or deep-seated infection. If the relapse occurred following a brief period of therapy, continue treatment for a longer period. If the relapse occurred 10 or more days following therapy, repeat therapy with a different antimicrobial agent selected on the basis of susceptibility tests and continue therapy for a longer period. An antimicrobic with greater tissue penetration (lipid soluble agents with low protein binding) is usually more effective. The procedures to evaluate efficacy described above should be repeated. Infections of the canine prostate gland are a common cause of recurrent UTI. Relapses appear to be related to poor penetration of antimicrobial drugs into prostatic secretions, but may also be related to drug resistance. Reinfections may be associated with persistent abnormalities in prostatic defenses against bacterial infections. Reinfection caused by a different organism would be expected to occur later than a relapse. Therefore, the results of a urinalysis and culture should be reevaluated approximately 4 (and in some instances repeatedly) weeks after cessation of antimicrobial therapy. Detection of frequent reinfections following antimicrobial therapy is an absolute indication to evaluate the patient for a predisposing cause. Reinfections should be managed by choosing antimicrobial agents on the basis of antimicrobial susceptibility tests. Each agent should be used for a sufficient period of time (3 to 5 days) to evaluate its effectiveness in sterilizing urine. Elimination of bacterial pathogens associated with reinfections may require therapy of shorter duration than recurrences associated with relapses. Infrequent recurrences (2 or 3 times per year) may be treated as single episodes (i.e. short course of a suitable antimicrobial agent). In some patients with chronic UTI, elimination of predisposing causes may be impossible. The result is recurrent reinfections. In such cases it may be helpful to provide low dose (preventative) antibacterial therapy for an indefinite period (6 months or more) with drugs primarily eliminated in urine. Reduced dosages (about 1/3 of the therapeutic dosage) of drugs excreted in high concentration in urine may be utilized provided there has been complete eradication of bacterial pathogens by therapeutic dosages of appropriate drugs. Logically, preventative antimicrobial therapy would be inappropriate for management of patients with recurrent bacterial UTI due to relapses (reinfection with the same organism). Even though this preventative dosage regime does not result in MIC's throughout the day, low concentrations of some drugs apparently interfere with producing of fimbriae by some uropathogens. This in turn interferes with the ability of potential pathogens to adhere to uroepithial cells. It is best to give one daily preventative dose of the antibiotic at a time when the drug is likely to be retained in the urinary tract for several hours (i.e. prior to bedtime). During preventative therapy, urine samples collected by cystocentesis (not by catheterization or voiding) should be recultured approximately once each month. If bacteria are identified, a "breakthrough" infection may have occurred. This may be associated with poor compliance. The patient should be treated again with therapeutic dosages of an antimicrobial drug selected on the basis of susceptibility tests. Once the infection has been eradicated and the associated inflammatory response subsides, preventative therapy may be resumed. Following 6 to 9 months of consecutive negative urine cultures, therapy may be discontinued on a trial basis to determine if a relapse or reinfection will occur. If abnormalities in host defenses have healed, UTI may not recur. If UTI develops within a short period, the procedures outlined above should be repeated. Long-term use of antimicrobial agents is not without risk of adverse effects. For example, sulfadiazine-trimethoprim combinations have been associated with keratoconjunctivitis sicca, folate deficiency anemia; and immune-complex reactions. EXTRA TABLES Test Conditions That Can Produce Worthless Results
Some Diagnostic Tests That Are Potentially Life Threatening If Performed Improperly
Practically Worthless Tests
Diagnostic Plans for a Variety of Disease Scenarios
Table 1. Managing the four most resistant bacteria colonizing the urinary tract
Antimicrobic siesta: discontinue antimicrobics with the goal of spontaneous resolution or decreased antimicrobic resistance. Urine Creatinine Ratios
ELISA-enzyme linked Immunoassy; FPIA-Fluorescence polarization immunoassay;   | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||