FELINE-Feline Idiopathic Lower Urinary Track Disease.part II

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20TH ANNIVERSARY Vol. 21, No. 2 February 1999

Refereed Peer Review

FOCAL POINT

KEY FACTS

Feline IdiopathicLower Urinary TractDisease. Part II.

Potential Causes*

Michigan State University University of Minnesota

Tina S. Kalkstein, DVM, MA Carl A. Osborne, DVM, PhDJohn M. Kruger, 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, caus-

es of idiopathic lower urinary tract disease include uropathogens, increased permeability of

the bladder mucosa to urine constituents that stimulate inflammatory responses, and inflam-

mation triggered by neurogenic mechanisms.

Research in the past 30 years has revealed that feline lower urinary tractdisease (LUTD) may result from a variety of different causes, includinguroliths; urethral plugs; bacterial, fungal, or parasitic urinary tract infec-

tions; congenital or acquired anatomic abnormalities of the bladder and urethra;and iatrogenic or idiopathic causes. Idiopathic LUTD (iLUTD) is currently rec-ognized as the most common cause of hematuria, dysuria, and pollakiuria inmale and female cats. Although clinical studies of naturally occurring iLUTDhave by exclusion allowed definition of what is not the cause, the underlyingcause has not been identified in the majority of patients. Detection of functionaland structural abnormalities of the urinary bladder wall, alterations in urine

composition, and isolation of viruses from the urine of cats with iLUTD haveprompted multiple theories regarding the etiopathogenesis of iLUTD (Table I).Hematuria, dysuria, and pollakiuria subside within 3 to 7 days in most cats withiLUTD. 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 (PartIV) of feline iLUTD. Part I reviewed the clinical manifestations of felineiLUTD; this article reviews possible causes.

CRYSTALSOne hypothesis of the cause of iLUTD is that crystalluria, struvite crystalluria

CE

5Although specific causes havenot yet been identified, we

hypothesize that more than one

cause may be involved in the

pathogenesis of feline idiopathiclower urinary tract disease

(iLUTD).

s Popular hypotheses regarding

potential causes of iLUTD include

immune-mediated disease,

altered urothelial permeability,

stress, bladder mastocytosis,

and neurogenic inflammation.

s In many cats, iLUTD occurs

in the absence of crystalluria,

suggesting that factors other

than crystalluria must be

involved.

s Uropathogens have not been

eliminated as potential causes

of iLUTD.

sFurther investigation is necessaryto 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.

*Part I of this four-part presentation appeared in the January 1999 (Vol. 21, No. 1) issueofCompendium.


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in particular, can induce cys-titis and urethritis in cats.1

Our observations and thoseof others, however, indicatethat variability exists in the

prevalence, magnitude, andmineral composition of crys-tals in urine collected fromnormal cats and those withiLUTD or other naturallyoccurring LUTDs.24

In a prospective study of141 cats with naturally oc-curring LUTDs conductedin the mid-1980s, crystal-luria was observed in 50%of 62 cats with nonobstruc-

tive iLUTD.

2

The preva-lence of crystalluria in catswith nonobstructive iLUTD was not significantly differ-ent from that of unaffectedcontrol cats. In a more re-cent uncontrolled study of109 cats with naturally oc-curring LUTDs, struvitecrystalluria was observed in13% of cats with nonob-structive iLUTD5 (Table II).

The lower prevalence of crystalluria observed in thenewer study may be related to the increased use ofmanufactured diets designed to minimize struvite crys-talluria. The observation that hematuria, dysuria, andurethral obstruction commonly occur in cats in the ab-sence of crystalluria indicates that causative factors oth-er than crystalluria must be involved.2,5,6

UROPATHOGENSIn cats with iLUTD, results of

urine culture for aerobic bacteria areinvariably negative.2,5 Efforts to iso-

late uncommon bacteria (e.g., anaer-obes, mycoplasmas, ureaplasmas,spirochetes) from the urine of cats

with iLUTD have also been uni-formly unsuccessful.2,3,7,8 Based onthese observations, bacteria have beenexcluded as causative agents in theetiopathogenesis in feline iLUTD.

There is increasing evidence, how-ever, that bacteria may have a role inthe etiopathogenesis of interstitialcystitis (IC) in at least some human

patients. In one study, bac-terial nucleic acid sequences

were detected in 29% of 14urinary bladder tissue speci-mens obtained from IC pa-

tients.

9

In addition, a novelunclassified microbe wasisolated from the biopsy tis-sue of all 14 IC patients.These findings support cur-rent hypotheses that (1) ICpatients may have an activeinfection with non-culturable, difficult to cul-ture, or atypical bacteria or(2) bacterial DNA, in theabsence of active infection,

may stimulate immunologicand/or biochemical patholo-gy.1012 Although these find-ings are encouraging, a causa-tive relationship betweenbacterial pathogens and hu-man IC has yet to be estab-lished. Nevertheless, theseobservations suggest that thecausative role of bacteria inat least some cats withiLUTD should be reexam-

ined using contemporary diagnostic methods.Viruses were implicated as potential causative agentsin the etiopathogenesis of feline iLUTD approximately30 years ago. This hypothesis was supported by the iso-lation of gamma herpesvirus (bovine herpesvirus type4), calicivirus (feline calicivirus), and retrovirus (felinesyncytium-forming virus) from the urine and tissue ofcats with naturally occurring LUTDs.1317 Herpesviruses,adenoviruses, polyomaviruses, and retroviruses have

Compendium February 1999 20TH ANNIVERSARY Small Animal/Exotics

S T R U V I T E C R Y S T A L L U R I A s A E R O B I C B A C T E R I A s V I R U S E S

TABLE I

Predictive Roles of Factors in the Etiopathogenesisof Feline Idiopathic Lower Urinary Tract Disease

Likelihood ofFactors Involvement a

Causative factorsUropathogens

Bacteria +Viruses +++

Immune-mediated disease +Altered urothelial barrier ++Leaking of urine substances +Other?

Precipitating factorsStress +

Response/effect factorsInflammation

Mast-cellmediated +++Neurogenic-mediated +++

Altered urothelial barrier ++Leaking of urine substances +

Concomitant unrelated factorsCrystalluria

a = unlikely; + = likely; ++ = very likely; +++ = extremely likely

TABLE II

Prevalence and Compositionaof Crystalluria in

Cats with Idiopathic Lower Urinary Tract DiseaseTime Period Frequency Mineral Type

198119852 31 of 62 cats (50%) Struvite (96%)Struvite + calcium oxalate (1%)Calcium oxalate (1%)Uric acid (1%)

Amorphous phosphate (1%)

199319955 9 of 70 cats (13%) Struvite (100%)

aMineral composition determined by light microscopic observation of crystal habit.


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been similarly incriminatedas causes of hemorrhagiccystitis in humans.18

Despite considerable evi-dence that viral agents can

induce LUTD in cats in lab-oratory settings, reproduc-ible evidence that virusescause naturally occurringsymptomatic LUTD is stilllacking.19,20 However, an in-ability to detect viruses inLUTD patients must beviewed with caution. Nega-tive findings may representinsensitive or inappropriatevirus-detection methods,

the viricidal nature of felineurine, or improper samplehandling.21 The recent dis-covery of viruslike particlestentatively identified as cali-civirus in a substantial num-ber of crystallinematrix ure-thral plugs obtained frommale cats with naturally oc-curring urethral obstructionis noteworthy.21 In addition,

we recently isolated a cali-

civirus from urine obtainedfrom a nonobstructed cat with naturally occurringiLUTD (Figure 1). Although these observations do notestablish a cause and effect relationship, they emphasizethe need for reexamining the roles of known viralpathogens and continuing to search for otheruropathogens.

AUTOIMMUNE DISEASEAutoimmune disease and nonspecific immune-medi-

ated inflammation have been proposed as potential

causative factors in the etiopathogenesis of human IC.22

Abnormal immune reactions may be incited by autolo-gous (i.e., self) antigens or by foreign (e.g., bacterial orviral) antigens within the bladder wall or urine. Al-though definitive evidence is lacking, findings support-ive of an immunopathologic cause of human IC in-clude (1) detection of serum autoantibodies directedagainst urine, bladder-wall components, Tamm-Hors-fall protein, and nuclear antigens; (2) identification ofimmunoglobulin deposits in the bladder wall; and (3)increased major histocompatibility complex antigen ex-pression in some affected patients.2329 In addition, lab-

oratory models of immune-mediated cystitis in guineapigs and rats share manygross morphologic and lightmicroscopic features with

human IC

30 32

and felineiLUTD33 Results of otherstudies, however, do notsupport the role of immune-mediated disease in humanIC.3437 The etiopathogenicrole of immune-mediateddisease in feline iLUTD hasnot been investigated.

URINE TOXINSConcentrated urine is a

consistent clinical feature ofcats with nonobstructiveiLUTD.2,5 It has been hy-pothesized that high concen-trations of normal and/or ab-normal components in urinemay be toxic to urinary blad-der tissue in human patients

with IC.22,38 The exact mech-anism of bladder-wall injuryis unknown but may involvedirect cytotoxic, immunolog-

ic, or neurogenic processes.Studies evaluating urinarysubstances as potential toxins

and/or irritants in cats with iLUTD have not been re-ported.

LEAKY UROTHELIUMTransitional epithelium of the urinary bladder is cov-

ered by a thin mucus layer composed of hydrated gly-cosaminoglycans (GAGs), which play an importantrole in preventing adherence of microorganisms andcrystals to the bladder urothelium and in limiting

transepithelial movement of urine proteins and ionicsolutes.39 Quantitative or qualitative defects in surfaceGAGs and subsequent increased uroepithelial perme-ability have been hypothesized to be causative factors inthe pathogenesis of feline iLUTD and human IC.39,40

Chronic exposure of bladder-wall tissue to urine con-stituents could result in sensory nerve stimulation,mast-cell activation, and/or induction of immune-me-diated or neurogenic inflammatory responses. Com-pared with normal cats, some cats with iLUTD seem tohave increased urinary bladder permeability to salicy-lates, decreased surface GAG expression, and decreased

Small Animal/Exotics 20TH ANNIVERSARY Compendium February 1999

C A L I C I V I R U S s C O N C E N T R A T E D U R I N E s G L Y C O S A M I N O G L Y C A N S

Figure 1Transmission electron micrograph of feline cali-civirus particles isolated by cell-culture inoculation withurine (negatively stained with phosphotungstic acid) ob-tained from a 2-year-old, spayed female cat with nonobstruc-tive idiopathic lower urinary tract disease. (Original magnifi-cation, 73,000; courtesy of Dan Taylor, Animal HealthDiagnostic Laboratory, Michigan State University, EastLansing, MI)


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total urinary GAG excretion.4043 Similar abnormalitieshave been identified in humans with IC.39,44,45 Some in-vestigators, however, have failed to detect alteredurothelial GAG layers, decreased urine GAG excretion,or enhanced urothelial permeability in humans with

IC.4649

The controversy surrounding the role of GAGsin IC has been compounded by the fact that increasedurothelial permeability has been associated withurolithiasis, chemical cystitis, and bladder overdisten-tion.5052 Although decreased GAG excretion and en-hanced bladder permeability may be observed in cats

with iLUTD, it is unknown whether these abnormali-ties are a specific cause of disease or a result of underly-ing causative mechanisms.

STRESSStress has been defined as any physical, chemical, or

emotional force that disturbs or threatens homeostasisand the accompanying adaptive responses to restorehomeostasis.53 Although stress may be beneficial, theadaptive responses to stress may themselves becomestressors capable of inducing pathologic changes. Stresshas been implicated as a potential pathogenic factor indisease in general and in autoimmune and neuroin-flammatory diseases in particular. Such stressful eventsas earthquakes,54 seasonal weather changes, residencechanges,55 major holidays, and diet changes have beenassociated with recurrent episodes of LUTD in cats.56

In humans with IC, stress seems to be a significant fac-

tor associated with the precipitation or exacerbation ofclinical signs.57 Although the exact mechanism(s) by

which stress influences the course of IC is unknown, re-cent studies in rodents suggest that psychologic stressresults in rapid activation of urinary bladder mastcells.58 Mast-cell activation may have a role in thepathogenesis of IC in humans (see Mast Cells).52,59

The role of stress in the etiopathogenesis of felineiLUTD is difficult to define. Although it is unlikelythat stress per se is a primary cause of iLUTD, stress-in-duced immune, endocrine, and inflammatory responsescould precipitate or exacerbate signs of iLUTD regard-

less of underlying cause. Systematic evaluation of stressfactors and their influence on the incidence and patho-genesis of feline iLUTD requires further investigation.

MAST CELLSCompared with normal cats, increased numbers of

mast cells have been identified within the bladder sub-mucosa of some cats with iLUTD.60,61 Mast-cell infil-trates are also often seen in bladder biopsy results ob-tained from human IC patients.62,63 Mast cells secrete avariety of preformed biologically active molecules (e.g.,histamine, heparin, serotonin, kinins, proteases, phos-

pholipases, chemotactic factors, cytokines, vasoactiveintestinal peptide) as well as molecules synthesized denovo (e.g., leukotrienes, platelet-activating factor,prostaglandins, thromboxanes).62,64 Mast-cell secretioncan be triggered by anaphylatoxins (C3a, C5a), anti-gens, bradykinin, cytokines/lymphokines (IL-1, TNF),

hormones (ACTH, PTH, progesterone), IgE, neuro-transmitters (ACH), neuropeptides (neurotensin, so-matostatin, substance P), bacterial toxins, viruses,drugs, and stress.58,62,65 The products of activated mastcells could be responsible for the inflammation, fibro-sis, pain, vasodilation, and smooth muscle contractionassociated with human IC and feline iLUTD.52,60,62 His-tamine and its metabolites have been found in higherconcentrations in the urine of human IC patients6668

and the cystoscopic effluent of cats with iLUTD.60

Despite these observations, the role of mast cells inhuman IC and feline iLUTD remains controversial.

Excessive numbers of mast cells have been observed inbladder biopsy results obtained from humans withbladder diseases other than IC, such as bacterial urinarytract infections, neoplasia, outflow obstruction, andstress incontinence.62,63,6971 These observations suggestthat urinary bladder mastocytosis may not be specificfor IC. However, recent electron microscopic studiesindicate that, in contrast to non-IC disorders, the ma-

jority of urinary bladder mast cells in humans with ICare activated and are often located in proximity to neu-ropeptide-containing sensory nerves.59,68,71,72 The closebiochemical and anatomic relationship between urinary

bladder mast cells and neuropeptide-containing neu-rons has led to the hypothesis that neurohormonal trig-gering of mast-cell activation and subsequent release ofmast-cell mediators play a central role in a multifactori-al pathogenesis of IC.52,71,72 Similar ultrastructural stud-ies of mast cells and their spatial relationship to sensorynerves in cats with iLUTD have not been performed.

NEUROGENIC INFLAMMATIONNeurogenic inflammation is a process initiated by ex-

citation of small c-fiber sensory afferent neurons andmediated by neuropeptides (substance P, neurokinin,and calcitonin gene-related peptide) released from stim-ulated nerves.52 Neurogenic inflammation may also betriggered by histamine and other mediators released byindependently activated mast cells in proximity to neu-ropeptide-containing sensory neurons.52 Interaction ofneuropeptides with tissue receptors results in vasodila-tion, increased vascular and epithelial permeability, in-creased leukocyte migration, and mast-cell activa-tion. 73 76 Consequently, the combined effects ofneuropeptides and mast-cell mediators may induce a

wide range of biologic effects culminating in pain, in-


M A S T - C E L L A C T I V A T I O N s H I S T A M I N E s N E U R O P E P T I D E S


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flammation, tissue injury, and fibrosis.52,77 Observationsof increased numbers of substance-Pcontaining nervefibers and their close anatomic association with mastcells in urinary bladders of humans with IC have ledto the hypothesis that neurogenic inflammation and

subsequent mast-cell activation represent the centralcommon pathway in a multifactorial pathogenesis ofIC.52,59,68,71,72

Increased numbers of substance-Pcontaining sensoryafferent neurons and high-affinity substance-P receptorshave been observed in the bladder submucosa of somecats affected with iLUTD.56 These observations suggestthat increased numbers of neuropeptide-containingneurons and increased expression of high-affinity sub-stance-P receptors are associated with inflammation infeline urinary bladders.56 However, the questions of

whether these phenomena are a cause or effect of in-

flammation and if they have a role in the etiopathogene-sis of feline iLUTD require further investigation.

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About the Authors

Dr. Kalkstein is currently a resident in Small Animal Inter-nal Medicine and Dr. Kruger is affiliated with the Depart-

ment of Small Animal Clinical Sciences at the College of

Veterinary Medicine, Michigan State University, East

Lansing, Michigan. Dr. Osborne is affiliated with the De-


FELINE-Feline Idiopathic Lower Urinary Track Disease.part II

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Transcript of FELINE-Feline Idiopathic Lower Urinary Track Disease.part II