Feline-feline Idiopathic Lower Urinary Track Disease.part Ii

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Vol. 21, No. 2 February 1999

Refereed Peer Review

FOCAL POINT ★Although specific causes have not yet been identified, we hypothesize that more than one cause may be involved in the pathogenesis of feline idiopathic lower urinary tract disease (iLUTD).

KEY FACTS ■ Popular hypotheses regarding potential causes of iLUTD include immune-mediated disease, altered urothelial permeability, stress, bladder mastocytosis, and neurogenic inflammation. ■ In many cats, iLUTD occurs in the absence of crystalluria, suggesting that factors other than crystalluria must be involved. ■ Uropathogens have not been eliminated as potential causes of iLUTD. ■ Further investigation is necessary to determine which of the following factors represents causes or effects of iLUTD: alterations in urinary bladder light microscopic features, permeability, neuropeptide concentrations, and urine biochemical composition.

Feline Idiopathic Lower Urinary Tract Disease. Part II. Potential Causes* Michigan State University

University of Minnesota

Tina S. Kalkstein, DVM, MA John M. Kruger, DVM, PhD

Carl A. Osborne, DVM, PhD

ABSTRACT: The cause(s) of hematuria, dysuria, and pollakiuria cannot be identified in most male and female cats with commonly used clinical techniques. Suggested, but still unproven, causes of idiopathic lower urinary tract disease include uropathogens, increased permeability of the bladder mucosa to urine constituents that stimulate inflammatory responses, and inflammation triggered by neurogenic mechanisms.

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esearch in the past 30 years has revealed that feline lower urinary tract disease (LUTD) may result from a variety of different causes, including uroliths; urethral plugs; bacterial, fungal, or parasitic urinary tract infections; congenital or acquired anatomic abnormalities of the bladder and urethra; and iatrogenic or idiopathic causes. Idiopathic LUTD (iLUTD) is currently recognized as the most common cause of hematuria, dysuria, and pollakiuria in male and female cats. Although clinical studies of naturally occurring iLUTD have by exclusion allowed definition of what is not the cause, the underlying cause has not been identified in the majority of patients. Detection of functional and structural abnormalities of the urinary bladder wall, alterations in urine composition, and isolation of viruses from the urine of cats with iLUTD have prompted multiple theories regarding the etiopathogenesis of iLUTD (Table I). Hematuria, dysuria, and pollakiuria subside within 3 to 7 days in most cats with iLUTD. This is the second article in a four-part series on the clinical features (Part I), causes (Part II), diagnostic evaluation (Part III), and management (Part IV) of feline iLUTD. Part I reviewed the clinical manifestations of feline iLUTD; this article reviews possible causes.

CRYSTALS One hypothesis of the cause of iLUTD is that crystalluria, struvite crystalluria *Part I of this four-part presentation appeared in the January 1999 (Vol. 21, No. 1) issue of Compendium.

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in particular, can induce cyspatients. In one study, bacTABLE I titis and urethritis in cats.1 terial nucleic acid sequences Predictive Roles of Factors in the Etiopathogenesis Our observations and those were detected in 29% of 14 of Feline Idiopathic Lower Urinary Tract Disease of others, however, indicate urinary bladder tissue speciLikelihood of that variability exists in the mens obtained from IC paFactors Involvement a prevalence, magnitude, and tients.9 In addition, a novel unclassified microbe was mineral composition of crys- Causative factors isolated from the biopsy tistals in urine collected from Uropathogens sue of all 14 IC patients. normal cats and those with Bacteria + These findings support curiLUTD or other naturally Viruses +++ Immune-mediated disease + rent hypotheses that (1) IC occurring LUTDs.2–4 ++ In a prospective study of Altered urothelial barrier patients may have an active + 141 cats with naturally oc- Leaking of urine substances infection with noncurring LUTDs conducted Other? culturable, difficult to culin the mid-1980s, crystalture, or atypical bacteria or Precipitating factors luria was observed in 50% (2) bacterial DNA, in the Stress + of 62 cats with nonobstrucabsence of active infection, tive iLUTD. 2 The preva- Response/effect factors may stimulate immunologic lence of crystalluria in cats Inflammation and/or biochemical patholowith nonobstructive iLUTD gy.10–12 Although these findMast-cell–mediated +++ ings are encouraging, a causawas not significantly differNeurogenic-mediated +++ ++ tive relationship between ent from that of unaffected Altered urothelial barrier + bacterial pathogens and hucontrol cats. In a more re- Leaking of urine substances man IC has yet to be estabcent uncontrolled study of lished. Nevertheless, these 109 cats with naturally oc- Concomitant unrelated factors – observations suggest that the curring LUTDs, struvite Crystalluria causative role of bacteria in crystalluria was observed in a – = unlikely; + = likely; ++ = very likely; +++ = extremely likely at least some cats with 13% of cats with nonobiLUTD should be reexamstructive iLUTD5 (Table II). The lower prevalence of crystalluria observed in the ined using contemporary diagnostic methods. newer study may be related to the increased use of Viruses were implicated as potential causative agents manufactured diets designed to minimize struvite crysin the etiopathogenesis of feline iLUTD approximately talluria. The observation that hematuria, dysuria, and 30 years ago. This hypothesis was supported by the isourethral obstruction commonly occur in cats in the ablation of gamma herpesvirus (bovine herpesvirus type sence of crystalluria indicates that causative factors oth4), calicivirus (feline calicivirus), and retrovirus (feline er than crystalluria must be involved.2,5,6 syncytium-forming virus) from the urine and tissue of cats with naturally occurring LUTDs.13–17 Herpesviruses, UROPATHOGENS adenoviruses, polyomaviruses, and retroviruses have In cats with iLUTD, results of TABLE II urine culture for aerobic bacteria are invariably negative.2,5 Efforts to isoPrevalence and Compositiona of Crystalluria in Cats with Idiopathic Lower Urinary Tract Disease late uncommon bacteria (e.g., anaerobes, mycoplasmas, ureaplasmas, Time Period Frequency Mineral Type spirochetes) from the urine of cats with iLUTD have also been uni- 1981–19852 31 of 62 cats (50%) Struvite (96%) formly unsuccessful. 2,3,7,8 Based on Struvite + calcium oxalate (1%) Calcium oxalate (1%) these observations, bacteria have been Uric acid (1%) excluded as causative agents in the Amorphous phosphate (1%) etiopathogenesis in feline iLUTD. There is increasing evidence, how5 9 of 70 cats (13%) Struvite (100%) ever, that bacteria may have a role in 1993–1995 the etiopathogenesis of interstitial a Mineral composition determined by light microscopic observation of crystal habit. cystitis (IC) in at least some human STRUVITE CRYSTALLURIA ■ AEROBIC BACTERIA ■ VIRUSES

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been similarly incriminated oratory models of immuneas causes of hemorrhagic mediated cystitis in guinea cystitis in humans.18 pigs and rats share many Despite considerable evigross morphologic and light dence that viral agents can microscopic features with induce LUTD in cats in labhuman IC 30–32 and feline iLUTD 33 Results of other oratory settings, reproducstudies, however, do not ible evidence that viruses support the role of immunecause naturally occurring mediated disease in human symptomatic LUTD is still IC.34–37 The etiopathogenic lacking.19,20 However, an inability to detect viruses in role of immune-mediated LUTD patients must be disease in feline iLUTD has viewed with caution. Neganot been investigated. tive findings may represent URINE TOXINS insensitive or inappropriate Concentrated urine is a virus-detection methods, consistent clinical feature of the viricidal nature of feline cats with nonobstructive urine, or improper sample iLUTD. 2,5 It has been hyhandling.21 The recent discovery of viruslike particles pothesized that high concententatively identified as calitrations of normal and/or abcivirus in a substantial num- Figure 1—Transmission electron micrograph of feline cali- normal components in urine ber of crystalline–matrix ure- civirus particles isolated by cell-culture inoculation with may be toxic to urinary bladthral plugs obtained from urine (negatively stained with phosphotungstic acid) ob- der tissue in human patients male cats with naturally oc- tained from a 2-year-old, spayed female cat with nonobstruc- with IC.22,38 The exact mechcurring urethral obstruction tive idiopathic lower urinary tract disease. (Original magnifi- anism of bladder-wall injury is noteworthy.21 In addition, cation, ×73,000; courtesy of Dan Taylor, Animal Health is unknown but may involve we recently isolated a cali- Diagnostic Laboratory, Michigan State University, East direct cytotoxic, immunologcivirus from urine obtained Lansing, MI) ic, or neurogenic processes. from a nonobstructed cat Studies evaluating urinary with naturally occurring substances as potential toxins iLUTD (Figure 1). Although these observations do not and/or irritants in cats with iLUTD have not been reestablish a cause and effect relationship, they emphasize ported. the need for reexamining the roles of known viral LEAKY UROTHELIUM pathogens and continuing to search for other Transitional epithelium of the urinary bladder is covuropathogens. ered by a thin mucus layer composed of hydrated glyAUTOIMMUNE DISEASE cosaminoglycans (GAGs), which play an important Autoimmune disease and nonspecific immune-medirole in preventing adherence of microorganisms and ated inflammation have been proposed as potential crystals to the bladder urothelium and in limiting causative factors in the etiopathogenesis of human IC.22 transepithelial movement of urine proteins and ionic Abnormal immune reactions may be incited by autolosolutes.39 Quantitative or qualitative defects in surface gous (i.e., self ) antigens or by foreign (e.g., bacterial or GAGs and subsequent increased uroepithelial permeviral) antigens within the bladder wall or urine. Alability have been hypothesized to be causative factors in though definitive evidence is lacking, findings supportthe pathogenesis of feline iLUTD and human IC.39,40 Chronic exposure of bladder-wall tissue to urine conive of an immunopathologic cause of human IC instituents could result in sensory nerve stimulation, clude (1) detection of serum autoantibodies directed mast-cell activation, and/or induction of immune-meagainst urine, bladder-wall components, Tamm-Horsdiated or neurogenic inflammatory responses. Comfall protein, and nuclear antigens; (2) identification of pared with normal cats, some cats with iLUTD seem to immunoglobulin deposits in the bladder wall; and (3) have increased urinary bladder permeability to salicyincreased major histocompatibility complex antigen exlates, decreased surface GAG expression, and decreased pression in some affected patients.23–29 In addition, labCALICIVIRUS ■ CONCENTRATED URINE ■ GLYCOSAMINOGLYCANS

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total urinary GAG excretion.40–43 Similar abnormalities have been identified in humans with IC.39,44,45 Some investigators, however, have failed to detect altered urothelial GAG layers, decreased urine GAG excretion, or enhanced urothelial permeability in humans with IC.46–49 The controversy surrounding the role of GAGs in IC has been compounded by the fact that increased urothelial permeability has been associated with urolithiasis, chemical cystitis, and bladder overdistention.50–52 Although decreased GAG excretion and enhanced bladder permeability may be observed in cats with iLUTD, it is unknown whether these abnormalities are a specific cause of disease or a result of underlying causative mechanisms.

STRESS Stress has been defined as any physical, chemical, or emotional force that disturbs or threatens homeostasis and the accompanying adaptive responses to restore homeostasis.53 Although stress may be beneficial, the adaptive responses to stress may themselves become stressors capable of inducing pathologic changes. Stress has been implicated as a potential pathogenic factor in disease in general and in autoimmune and neuroinflammatory diseases in particular. Such stressful events as earthquakes,54 seasonal weather changes, residence changes,55 major holidays, and diet changes have been associated with recurrent episodes of LUTD in cats.56 In humans with IC, stress seems to be a significant factor associated with the precipitation or exacerbation of clinical signs.57 Although the exact mechanism(s) by which stress influences the course of IC is unknown, recent studies in rodents suggest that psychologic stress results in rapid activation of urinary bladder mast cells. 58 Mast-cell activation may have a role in the pathogenesis of IC in humans (see Mast Cells).52,59 The role of stress in the etiopathogenesis of feline iLUTD is difficult to define. Although it is unlikely that stress per se is a primary cause of iLUTD, stress-induced immune, endocrine, and inflammatory responses could precipitate or exacerbate signs of iLUTD regardless of underlying cause. Systematic evaluation of stress factors and their influence on the incidence and pathogenesis of feline iLUTD requires further investigation. MAST CELLS Compared with normal cats, increased numbers of mast cells have been identified within the bladder submucosa of some cats with iLUTD.60,61 Mast-cell infiltrates are also often seen in bladder biopsy results obtained from human IC patients.62,63 Mast cells secrete a variety of preformed biologically active molecules (e.g., histamine, heparin, serotonin, kinins, proteases, phos-

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pholipases, chemotactic factors, cytokines, vasoactive intestinal peptide) as well as molecules synthesized de novo (e.g., leukotrienes, platelet-activating factor, prostaglandins, thromboxanes).62,64 Mast-cell secretion can be triggered by anaphylatoxins (C3a, C5a), antigens, bradykinin, cytokines/lymphokines (IL-1, TNF), hormones (ACTH, PTH, progesterone), IgE, neurotransmitters (ACH), neuropeptides (neurotensin, somatostatin, substance P), bacterial toxins, viruses, drugs, and stress.58,62,65 The products of activated mast cells could be responsible for the inflammation, fibrosis, pain, vasodilation, and smooth muscle contraction associated with human IC and feline iLUTD.52,60,62 Histamine and its metabolites have been found in higher concentrations in the urine of human IC patients66–68 and the cystoscopic effluent of cats with iLUTD.60 Despite these observations, the role of mast cells in human IC and feline iLUTD remains controversial. Excessive numbers of mast cells have been observed in bladder biopsy results obtained from humans with bladder diseases other than IC, such as bacterial urinary tract infections, neoplasia, outflow obstruction, and stress incontinence.62,63,69–71 These observations suggest that urinary bladder mastocytosis may not be specific for IC. However, recent electron microscopic studies indicate that, in contrast to non-IC disorders, the majority of urinary bladder mast cells in humans with IC are activated and are often located in proximity to neuropeptide-containing sensory nerves.59,68,71,72 The close biochemical and anatomic relationship between urinary bladder mast cells and neuropeptide-containing neurons has led to the hypothesis that neurohormonal triggering of mast-cell activation and subsequent release of mast-cell mediators play a central role in a multifactorial pathogenesis of IC.52,71,72 Similar ultrastructural studies of mast cells and their spatial relationship to sensory nerves in cats with iLUTD have not been performed.

NEUROGENIC INFLAMMATION Neurogenic inflammation is a process initiated by excitation of small c-fiber sensory afferent neurons and mediated by neuropeptides (substance P, neurokinin, and calcitonin gene-related peptide) released from stimulated nerves.52 Neurogenic inflammation may also be triggered by histamine and other mediators released by independently activated mast cells in proximity to neuropeptide-containing sensory neurons.52 Interaction of neuropeptides with tissue receptors results in vasodilation, increased vascular and epithelial permeability, increased leukocyte migration, and mast-cell activation. 73–76 Consequently, the combined effects of neuropeptides and mast-cell mediators may induce a wide range of biologic effects culminating in pain, in-

MAST-CELL ACTIVATION ■ HISTAMINE ■ NEUROPEPTIDES

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flammation, tissue injury, and fibrosis.52,77 Observations of increased numbers of substance-P–containing nerve fibers and their close anatomic association with mast cells in urinary bladders of humans with IC have led to the hypothesis that neurogenic inflammation and subsequent mast-cell activation represent the central common pathway in a multifactorial pathogenesis of IC.52,59,68,71,72 Increased numbers of substance-P–containing sensory afferent neurons and high-affinity substance-P receptors have been observed in the bladder submucosa of some cats affected with iLUTD.56 These observations suggest that increased numbers of neuropeptide-containing neurons and increased expression of high-affinity substance-P receptors are associated with inflammation in feline urinary bladders.56 However, the questions of whether these phenomena are a cause or effect of inflammation and if they have a role in the etiopathogenesis of feline iLUTD require further investigation.

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76. Church MK, Lowman MA, Rees PH, et al: Mast cells, neuropeptides and inflammation. Agents Actions 27:8–16, 1989. 77. Galli SJ: New concepts about the mast cell. N Eng J Med 328:257–265, 1993.

About the Authors Dr. Kalkstein is currently a resident in Small Animal Internal Medicine and Dr. Kruger is affiliated with the Department of Small Animal Clinical Sciences at the College of Veterinary Medicine, Michigan State University, East Lansing, Michigan. Dr. Osborne is affiliated with the De-

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