An Isolated Cryptococcal Urinary Tract Infection in a Cat

Introduction

Cryptococcosis is an important infectious disease that affects humans and a variety of animals worldwide.¹ It is caused by a saprophytic, yeast-like fungus that has the ability to form a large polysaccharide capsule.¹ In North America, the causative agent is primarily Cryptococcus neoformans var. neoformans.² Avian excrement, especially that of the pigeon, is the chief reservoir, and the most likely natural route of transmission of cryptococcal infection is via inhalation of aerosolized spores.¹ In contrast to many other fungal infections, cryptococcosis occurs with equal or greater frequency in cats compared to dogs.^1,3 The age range of affected cats is broad (1 to 13 years; average 5 years), and males may be predisposed, likely because of their increased roaming behavior.⁴ Cryptococcosis in cats usually involves the nasal cavity and upper respiratory tract, skin, central nervous system, and eyes.^1,3

The most reliable method of establishing a presumptive diagnosis of cryptococcosis is direct visualization of the organism on cytological or histopathological evaluation.^3,5 Serological testing is useful for diagnosis when the organism cannot be isolated or when obtaining tissue or fluid samples may jeopardize the health of the animal. A latex agglutination test that detects cryptococcal capsular antigen is highly specific and sensitive and can be used on serum, cerebrospinal fluid, and urine.⁶ Serial serology can be useful to assess response to therapy, and declining titers or return to a negative titer are considered good prognostic indicators.^5,6 Serial monitoring of serum cryptococcal antigen titers during treatment may also be useful in determining duration of antifungal therapy.⁶

Cryptococcuria is a relatively infrequent presentation in human patients and may occur as a manifestation of disseminated disease or as an isolated urinary tract infection (UTI).⁷ When cryptococcuria is recognized in people, patients often have an underlying, immunocompromising condition.⁷ Renal involvement with cryptococcosis in animals is uncommon and has only occasionally been confirmed in cats with systemic cryptococcosis by the discovery of fungal elements on urine sediment examination or at necropsy.^1,4 Isolated cryptococcal UTIs have rarely been reported in companion animals.⁸ An ascending urethral route of infection is likely an important source of isolated fungal UTIs.⁸

Case Report

A 13-year-old, 3.5-kg, castrated male, indoor/outdoor domestic shorthaired cat was presented for evaluation of stranguria and pollakiuria. The cat had a 4-year history of intermittent, nonobstructive lower urinary tract disease occasionally associated with bacterial cystitis. Treatments previously administered included urinary catheterization on two occasions and intravenous or subcutaneous fluids. Amoxicillin/clavulanic acid^a was administered orally when a bacterial UTI was present and on three other occasions as treatment for bite wounds. The cat also had a history of presumed pyelonephritis and chronic renal failure first documented 3 years earlier.

On physical examination, the cat was of thin body condition. A mildly distended urinary bladder and a small left kidney could be felt on abdominal palpation. The remainder of the physical examination was unremarkable. Systolic blood pressure was measured by use of the Doppler method and was within normal limits.

A complete blood cell count was within normal limits. A serum biochemical profile revealed mild elevations in blood urea nitrogen (45.1 mg/dL; reference range 10 to 35 mg/dL) and creatinine (2.7 mg/dL; reference range 0.6 to 1.6 mg/dL), which were similar to previously recorded renal values in this cat. Total serum thyroxine concentration was within normal limits. Urinalysis revealed isosthenuria (urine specific gravity of 1.012); a pH of 7.0; 50 to 60 red blood cells (RBCs) per high-power field; one to two white blood cells (WBCs) per high-power field; and two or more budding yeast per high-power field [Figures 1, 2]. Prior urinalysis had also revealed the presence of yeast 10 and 20 months previously that had been assumed to be contaminants. No therapy or further investigation had been instituted on either occasion. A urine fungal culture revealed Cryptococcus spp. Serology^b for Cryptococcus antigen was also positive (titer 1:128).

Enzyme-linked immunosorbent assays for feline leukemia virus antigen and feline immunodeficiency virus antibody were negative. Thoracic radiographs and a fundic examination were within normal limits. Abdominal ultrasonography revealed a diffusely hyperechoic right kidney and a small (2.2 cm), hyperechoic, irregularly shaped left kidney with a cortical cyst at the caudal margin. Other abdominal structures appeared sonographically to be within normal limits.

Fluconazole^c was administered at 50 mg (14 mg/kg) orally q 12 hours as a treatment for fungal UTI. Given the presence of concurrent renal failure, the cat was monitored closely for overt manifestations of any adverse effects of fluconazole (e.g., anorexia), as kidney disease can alter excretion of the drug.⁹ Serum biochemical profiles were performed every 4 weeks during therapy to detect worsening azotemia or hepatotoxicity, and no appreciable change was revealed. Monthly fungal urine cultures were performed during therapy, and the drug was continued until two consecutive negative cultures were obtained. Six months of therapy was required. The clinical signs of cystitis resolved within the first 2 weeks of starting therapy, and no recurrent episodes were reported. Mild to moderate azotemia persisted on serum biochemical panels. Complete recovery of renal function was not expected, however, because of the ultrasonographic evidence of chronic renal damage.

Discussion

In cats, primary fungal UTIs are rare.¹⁰ However, the true incidence may be underestimated due to the insensitivity of urine sediment analysis in detection of yeast or hyphae and to the possibility of occult infections.¹⁰ Candida spp. are the most common fungal organisms reported to cause UTIs in companion animals; cryptococcal UTIs have been reported only occasionally.^4,8,11 Like disseminated fungal disease, urinary fungal infections are believed to be associated with impaired local or systemic host defenses.¹⁰ Discovery of a fungal UTI should prompt an investigation for systemic involvement and potential underlying diseases. Factors that alter local defense in the urinary tract include glucosuria, aciduria, indwelling urinary catheters, urethrostomy, and lower urinary tract diseases such as urolithiasis and chronic bacterial cystitis.^8,10 Other predisposing factors include prolonged antibiotic and/or glucocorticoid therapy, blood dyscrasias, neoplasia, diabetes mellitus, and other chronic diseases that may depress immune responses.⁸

Fungi should not be found in the urine of healthy animals.¹⁰ Therefore, fungi identified in properly collected urine samples, particularly serial samples, should be considered pathogens.¹⁰ Cryptococcal organisms, when present, may often be mistaken for fat droplets or WBCs or RBCs on urine sediment evaluation, thereby hindering diagnosis.^4,10 Lipid droplets found during urinalysis are generally considered to be of little diagnostic importance and are common in domestic cats, as triglycerides are stored in renal tubular cells in this species.¹² A previous retrospective study reported a much higher percentage of fat droplets seen in the urine of cats with cryptococcosis than in the urine of cats without cryptococcosis, suggesting some of the reported fat droplets may have been fungal organisms.⁴ Fat droplets were frequently identified on urinalysis of the cat in this report, as well as the discovery of yeast on two prior occasions. The misidentification of yeast or the assumption that yeast seen on urine sediment evaluation are contaminants, either through sampling contamination or contamination of cytological stains, may lead to the underdiagnosis of fungal UTIs and a delay in or an absence of the administration of appropriate therapy. A delay in therapy may have a detrimental effect on an animal demonstrating clinical signs of a fungal UTI.

Other than the presence of organisms, urinalyses in animals with fungal UTIs may also reveal aciduria, proteinuria, hematuria, glucosuria, and pyuria.^8,10 Pyuria is not necessarily present in clinical infections, however, and an absence of WBCs may be associated with impaired immune defenses.¹⁰ Urine culture provides a definitive diagnosis of fungal UTI.¹⁰

Animals not demonstrating any clinical signs should be allowed to spontaneously clear fungi from the urinary tract before antifungal therapy is initiated.¹⁰ These animals should be monitored closely for the development of clinical signs, and routine evaluation of the urine and renal function is warranted. Identifiable predisposing risk factors should be addressed; indwelling urinary catheters should be removed; and, when possible, antibacterial and immunosuppressive therapy should be discontinued. Concurrent bacterial UTIs are common and should be treated if present.⁸ Alkalinization of the urine may hasten the elimination of the infection.¹⁰

More aggressive therapy is warranted in animals exhibiting clinical signs associated with funguria (e.g., evidence of cystitis or pyelonephritis) and in animals with debilitating diseases or those requiring chemotherapy.¹⁰ Experience with treatment of fungal UTIs in cats is limited.⁸ Flucytosine, amphotericin B, ketoconazole, itraconazole, and fluconazole have been used to treat fungal UTIs in people, but no studies have confirmed the safety or efficacy of these agents in cats being treated for fungal UTIs.⁸ Single or combination therapy with amphotericin B was not an acceptable option in this case because of the presence of renal failure. Fluconazole therapy was chosen over other azole derivatives, such as ketoconazole or itraconazole, because it is excreted primarily through the kidneys and reaches high concentrations in the urine. Fluconazole has been shown to be effective in the treatment of systemic cryptococcosis in cats.¹³

At the time of diagnosis, the cat in this report showed no evidence of concurrent systemic involvement and had no historical complaints consistent with systemic cryptococcosis. The origin of the fungal UTI in this cat is unknown. It is possible that fungal pyelonephritis was the cause of chronic renal failure in this cat. Isolation of Cryptococcus spp. from renal tissue with a renal biopsy may have confirmed an upper UTI, but a biopsy was not attempted. Another possibility is that the chronic renal failure and previously documented UTIs were not results of cryptococcosis, but that prior urinary catheterization and administration of systemic antibiotics created an environment that predisposed to a fungal UTI.

Antifungal therapy was discontinued in this cat after two consecutive negative urine fungal cultures. Although not performed in this case, serial serum antigen testing may also have been appropriate to determine duration of therapy. Continuing treatment for 1 month after a decrease in antigen titer by two orders of magnitude or, preferably, until serum antigen is undetectable has been recommended.⁶ In this cat, treatment with fluconazole resulted in the resolution of funguria with no adverse effects. No recurrent episodes were reported prior to the cat being lost to follow-up 12 months after the discontinuation of antifungal therapy.

Conclusion

Fungal UTIs may occur as manifestations of disseminated disease or as isolated UTIs. Cryptococcus spp. may be mistakenly identified as other translucent structures, such as fat droplets or as contaminants during urine sediment analysis, causing a delay in or the absence of accurate diagnosis and treatment. Urine fungal cultures are warranted in animals with recurrent UTIs or signs of cystitis, particularly if the animal is immunocompromised or has any urinary tract abnormalities predisposing to infection.