By Kerry Rolph, BVM&S, CertVC, PhD, FANZCVS (feline chapter), DipECVIM-Ca, MRCVS

It has been reported 4.6 percent of cats evaluated in private practices in the U.S. and seven to eight percent of cats seen at veterinary teaching hospitals present for lower urinary tract disorders (Forrester and Roudebush, 2007). Clinical signs frequently include: hematuria, stranguria, dysuria, periuria, pollakiuria, behavioral changes (such as aggression), and excessive grooming of the perineum and/or ventrum. Unfortunately, as the bladder can only respond to insult in a limited number of ways, the clinical signs are not predictive of the underlying disease process.

There are several diseases that can result in clinical signs of FLUTD. In cats older than 10 years of age, the most likely differentials are:

• urinary tract infection (UTI) (45 percent of cases);
• uroliths (10 percent of cases); and
• uroliths and UTI (16 percent of cases), with neoplasia, trauma, idiopathic disease, and urinary incontinence occurring in the remaining cases (Bartges, 2002).

Conversely, in cats younger than 10 years of age, the most common cause of lower urinary tract signs is idiopathic FLUTD (iFLUTD or feline interstitial cystitis [FIC]), which accounts for more than 50 percent of cases, with some further 20 percent of patients demonstrating urethral plugs. These are thought to arise from inflammation with crystal amalgamation. This has led many clinicians to believe this is a subset of iFLUTD, with these two forms accounting for approximately 75 percent of cases (Caney, 2011). Between 15 and 21 percent of cases under 10 years of age will have urolithiasis, while only one to two percent of cats younger than 10 years old are found to have UTIs. Dietary management is important in the control of both urolithiasis and iFLUTD (Bartges, 2002).

Understanding uroliths

Formation of uroliths is not a disease per se, but can occur as a complication of another disorder. For example, 35 percent of cats presenting with calcium oxalate uroliths have been reported to be hypercalcemic. In other cases, the underlying etiopathogenesis may not be elucidated (Bartges and Kirk, 2006).

There are many minerals that can precipitate within the urinary tract to form crystals. The most common are struvite (magnesium ammonium phosphate hexahydrate) or calcium oxalate. However, crystals are found in many normal cats, and are not necessarily pathogenic. Factors influencing crystal formation include the amount of mineral saturated within the urine (i.e. whether or not supersaturation is present), urine pH, urine temperature, the presence or absence of various inhibitory factors such as citrate or pyrophosphate, and the occurrence of promoters of crystallization, including dead cells, cellular debris, protein, bacteria, or other crystals (Matsumoto and Funaba, 2008, Bartges and Callens, 2015). For urolith formation to occur, there must first be an initiation phase, which involves the formation of a crystal nidus (nucleation). Crystal growth depends on the ability of the nidus to remain within the urinary tract, the duration of supersaturation of the urine, and the crystal's physical ultrastructure. The actual rate of growth of the urolith depends on numerous factors, including mineral composition and risk factors such as infection (Bartges and Callens, 2015).

Struvite uroliths account for more than 50 percent of all feline uroliths (Bartges and Callens, 2015). These can occur as a consequence of infection of the urinary tract with a urease-producing bacterium (bacterial-associated uroliths) or can occur in sterile urine, where they are considered a dietary-induced urolith. Infection-induced struvite uroliths are reported to occur more commonly in cats younger than one year or older than 10 years of age (Bartges and Kirk, 2006). In cats, the majority of struvite uroliths are sterile. However, infection should always be ruled out as an underlying cause.

Dietary considerations

Sterile struvite uroliths occur most commonly in cats between one and 10 years of age. In at-risk cats (i.e. those with a lack of urolith inhibitors) fed a diet that leads to supersaturation of the urolith constituents, stone formation can occur. Decreasing urine concentration (and therefore retention time) has been shown to markedly lower the risk of urolith formation (Bartges and Callens, 2015). Experimentally, diets containing excessive amounts of magnesium phosphate have led to the formation of sterile struvite uroliths in normal cats (Osborne et al. 1985). However, the influence of magnesium depends on the urinary pH, with alkaluria predisposing to struvite formation (Queau, 2019).

Struvite uroliths can be dissolved by feeding a diet that is acidifying, and one restricted in magnesium, phosphorus, and protein. In cats with sterile struvite uroliths, such a diet has been shown to lead to dissolution in approximately 36 days (range 14 to 141 days). However, in infection-induced struvite urolithiasis, this was increased to approximately 79 days (Bartges and Kirk, 2006). It is recommended that when infection-associated struvite urolithiasis is treated, the cat should remain on an appropriate antibiotic for the duration of dissolution and a further two weeks thereafter.

Diets manufactured for the dissolution of struvite uroliths should not be fed long term, as they are not balanced and the acidification will predispose to calcium oxalate (or other) forms of urolithiasis. Therefore, after dissolution of sterile-struvite, the cat should be switched to a maintenance lower urinary tract diet that will do the following:

• dilute the urine, avoiding supersaturation;
• provide the nutritional requirements for the formation of urolith inhibitors; and
• maintain an appropriate pH to decrease the risk of either calcium oxalate or struvite uroliths.

Recently, one such diet has been shown to provide dissolution of struvite uroliths (albeit over approximately double the time frame of the dissolution diet) (Lulich et al. 2013). Infection-induced struvite uroliths do not require a maintenance diet, as once the infection is adequately treated, the risk for urolith formation is removed.

Calcium oxalate uroliths form when urine is supersaturated with calcium and oxalate. In addition, large molecular-weight proteins occurring in the urine, such as nephrocalcin, uropontin, and Tamm-Horsfall mucoprotein, affect the formation of calcium oxalate uroliths (Dijcker et al. 2011, Lulich et al. 2016). They account for approximately 35 percent of all feline uroliths submitted to one veterinary analysis laboratory (Minnesota Urolith Center, 2020). Hypercalcemia is present in 35 percent of cases with calcium oxalate uroliths; however, of cats presenting with idiopathic hypercalcemia, 35 percent have calcium oxalate uroliths (Bartges and Kirk, 2006).

Hypercalciuria can occur from excessive intestinal absorption of calcium, impaired renal reabsorption, or excessive skeletal mobilization. While hypercalciuria has not been well-defined in normocalcemic cats with calcium oxalate uroliths, it is thought to occur. Metabolic acidosis promotes hypercalciuria. As buffers are released from the bone, there is concurrent release of calcium, which, in turn, increases urinary calcium excretion (Lekcharoensuk et al. 2000, Bartges et al. 2013).

It is recognized that consumption of diets supplemented with urinary acidifiers (e.g. ammonium chloride) is associated with increased urinary calcium excretion. Significant aciduria (urine pH <6.2) is thought to predispose to calcium oxalate formation, in part due to the associated academia and hypercalciuria. However, it is also recognized that acidic urine alters the function and concentration of crystal inhibitors (aciduria promotes hypocitraturia and leads to functional impairment of endogenous urolith inhibitors) (Bartges and Kirk, 2006). Substances such as citrate, magnesium, and pyrophosphate—which form soluble salts with calcium or oxalic acid—reduce the availability of these substances for precipitation (Bartges and Callens, 2015). Other inhibitors, such as Tamm-Horsfall glycoprotein and nephrocalcin, interfere with the ability of calcium and oxalic acid to combine and thereby minimize crystal formation, aggregation, and growth (Bartges and Kirk, 2006).

Oxalic acid is a metabolite of ascorbic acid (vitamin C) and several amino acids, including glycine and serine. If oxalic acid combines with potassium or sodium ions, it forms soluble salts. However, if it combines with calcium ions, the salt is insoluble. It is recognized an increase in dietary intake of oxalic acid (or vitamin B6 deficiency) can predispose to calcium oxalate formation (Dijcker et al. 2011).

Calcium oxalate uroliths cannot be dissolved by adjusting the patient's diet. Instead, they require interventional or surgical procedures if they are to be removed from the urinary tract. However, there are medical and nutritional interventions that are recommended to decrease the recurrence of these uroliths in at-risk cats (Lulich et al. 2016). The mainstay of treatment is to decrease urine concentration (and therefore supersaturation). In addition, diets have been formulated to promote high concentrations and activity of urolith inhibitors, reduce urine acidity, and decrease calcium and oxalate concentration within the urine (Lulich et al. 2016). Achieving a urine concentration below 1.030 not only leads to decreased saturation, but results in an increased urine transit time and voiding frequency (Bartges and Kirk, 2006). This can be achieved by feeding wet food and adding water, or feeding a prescription diet designed to lower urine concentration and prevent urolith formation.

It has long been recognized that acidifying diets predispose to the formation of calcium oxalate uroliths. It is thought persistent aciduria leads to low-grade metabolic acidosis, and thereby increases bone metabolism and calciuria (Bartges et al. 2013). In addition, aciduria promotes hypocitraturia and functional impairment of endogenous urolith inhibitors. Therefore, feeding an acidifying diet or administering urinary acidifiers to a cat that is predisposed to calcium oxalate uroliths is contraindicated. To prevent recurrence of calcium oxalate urolithiasis, a urinary pH of 6.6 to 7.5 is advised (Lulich et al. 2016).

Aside from reducing urinary concentration and optimizing pH, decreasing urinary substrate can aid in lowering stone recurrence. Therefore, it is advised the patient's diet contain a moderate level of calcium (marked restriction has been reported to increase urinary calcium levels in normal cats) and relatively low level of oxalate. Excessive amounts of vitamin D (which can increase calcium absorption and therefore cause calciuria) should be avoided. Since phosphate restriction can increase activation of vitamin D and in turn promote intestinal calcium absorption, it is recommended low phosphate diets are avoided (Bartges and Callens, 2015).

Urinary oxalate is derived from the following:

• endogenous metabolism of various amino acids (including glycine and serine);
• the metabolism of ascorbic acid (vitamin C); and
• dietary oxalic acid.

If there is inadequate vitamin B6 within the diet, oxalic acid production and urinary excretion is increased. Kittens fed a B6-deficient diet have been shown to develop calcium oxalate urolithiasis (Blanchard et al. 1991). Therefore, cats with a history of calcium oxalate urolithiasis should receive a diet low in oxalic acid and with adequate B6, while excess intake of vitamin C should be avoided. For this reason, cranberry concentrate should be avoided, as it not only provides mild acidification, but also contains high levels of oxalate and vitamin C (Bartges and Kirk, 2006).

In refractory cases of calcium oxalate urolithiasis, potassium citrate may be included in the diet or as an additional medication. As stated previously, citric acid can combine with calcium to form a soluble complex, thereby reducing the amount of calcium available for urolith formation. In addition, citric acid inhibits nucleation of calcium and oxalate crystals (Bartges, 2002). In a similar manner, urinary magnesium complexes with oxalic acid, decreasing the amount available to form uroliths. Cats receiving a diet deplete in magnesium have been shown to be at increased risk of calcium oxalate urolithiasis. However, excess magnesium should be avoided, as it can predispose to struvite formation (Osborne et al. 1985).

Idiopathic feline lower urinary tract disease

In young to middle-aged cats presenting with signs of FLUTD, idiopathic disease is the most likely differential. Studies have highlighted several predisposing factors for this condition. The cats are:

• male, neutered, and overweight;
• use a litter tray;
• rarely go outside;
• have limited exercise; and
• typically live in a multi-cat household (Gunn-Moore, 2003).

In addition, black and white cats, as well as Persians, demonstrate an increased incidence of disease (Gunn-Moore, 2003). Bladder signs are typically self-limiting, and unless obstruction occurs, usually resolve without treatment in three to five days. However, our understanding of this condition has evolved in recent years. Current belief is that this is in fact a systemic condition, with clinical signs attributed to the urinary bladder and abnormalities identified within the brain, spinal cord, and adrenal glands in addition to the bladder wall (Buffington, 2011). Cats with idiopathic cystitis demonstrate alterations within the glycosaminoglycan (GAG) layer. Although a generalized decrease in the GAG layer and a reduction in the GAG GP-51 have both been reported in cats, studies attempting to replenish the former have failed to demonstrate a benefit above that seen with placebo medications (Press et al. 1995, Buffington et al. 1996, Gunn-Moore and Shenoy, 2004, Pereira et al. 2004). In addition, the urothelium, which normally forms a tight barrier to ion and solute flux, is more permeable in cats with idiopathic cystitis; on electron microscopy, a denuded urothelium has been identified (Lavelle et al. 2000).

Within the submucosa, signs consistent with neurogenic inflammation (vasodilation and vascular leakage in the absence of significant mononuclear or polymorphonuclear infiltration) have been reported, along with increased mast cell numbers in some cases (Buffington, 2011). However, changes are not limited to the bladder wall, with multiple neuroendocrine abnormalities being present. For example, the mechanoreceptor bladder afferent neurons appear to be more sensitive to stimuli in affected cats. In addition, there is an increase in the expression of substance P (a sensory neurotransmitter) receptors (Gunn-Moore, 2003), enlargement of the cell bodies within the dorsal root ganglion, and abnormal neuropeptide profiles within the dorsal root ganglion. This is not restricted to the cells from bladder-identified neurons, but affects cells throughout the lumbosacral spinal cord (Buffington, 2011).

The role stress plays

It is well documented in both laboratory studies and client-owned cats that exacerbations of lower urinary tract signs occur with external environmental stressors. It is known that cats with idiopathic cystitis have increased levels of tyrosine hydroxylase (the rate-limiting enzyme involved in catecholamine synthesis) within the locus coeruleus and paraventricular nucleus of the hypothalamus (Buffington and Pacak, 2001). In addition, it has been shown there is greater activity in the locus coeruleus, an area of the brain that not only deals with vigilance and arousal, but in which the highest number of noradrenergic neurons are found. It is also an important source of noradrenaline within the central nervous system (CNS). In addition, chronic external stress is known to escalate the activity of tyrosine hydroxylase with accompanying increases in autonomic outflow (Buffington, 2011). Cumulatively, these alterations lead to an altered response to stress.

Normal cats respond to stress with activation of the hypothalamic-pituitary-adrenal (HPA) axis. This is seen as increased activity in the locus coeruleus, higher plasma catecholamine concentrations, enhanced adrenal sensitivity to adrenocorticotropic hormone (ACTH), greater secretion of glucocorticoids from the adrenal cortex, and increased urine cortisol concentrations. The role of glucocorticoids and other alpha-2 adrenoceptor agonists is complex. However, one of their essential functions is to provide negative feedback to control the stress response, which they do by inhibiting further transmission of noxious signals to the brain.

In contrast, cats with idiopathic cystitis respond to stress in a different manner. They are likely to demonstrate displacement activity such as increased eating, drinking, grooming, and urinating. While they do show markedly increased activity in their locus coeruleus and significantly increased sympathetic activity compared to normal cats, this does not appear to be restrained by adrenocorticotrophic output; an inappropriate activation of the adrenal cortex and decreased sensitivity to ACTH are seen in cats with idiopathic cystitis (Gunn-Moore, 2003). This uncoupling of the hypothalamic-pituitary-adrenal axis is also seen in some chronic pain syndromes in humans and is believed to result from desensitization or down-regulation of the alpha-2 adrenoceptor agonist receptors, secondary to chronic stimulation. While a recent study has shown cats with idiopathic cystitis have multiple abnormalities in their alpha-2 adrenoceptor-mediated signal transduction pathway, it is still unclear whether this represents adaptation to living with chronic stress or indicates these cats have an innate defect in their ability to cope with stress (Buffington, 2011).

In addition to the changes within the bladder and neuroendocrine system, it has been documented that cats with idiopathic cystitis are more likely to demonstrate a range of other abnormalities that together have been termed "sickness behaviors." Studies of confined animals have shown sickness behaviors can occur with activation of the stress response system and result in a variety of signs such as anorexia, sickness, inappetence, diarrhea, enhanced pain behavior, and general ill-thrift (Buffington, 2011). Putting these findings together, it becomes evident that while cats with idiopathic cystitis appear to have disease of the urinary bladder, they are, in fact, suffering from a far more complex syndrome with wide-reaching effects. This is important to keep in mind when treatment decisions are being made.

Approach to a cat with hematuria/dysuria/stranguria

When presented with a cat with clinical signs consistent with lower urinary tract disease, it is important to gain an accurate history. Is the cat at increased risk of UTI? This condition accounts for about two percent of cases of cystitis in cats under 10 years of age, and is rare in concentrated urine (Gunn-Moore, 2003). To rule out UTI, a urine sample should be obtained, and urine specific gravity (USG) and culture of the urine performed.

The second big rule out is whether uroliths are suspected. Consider first the cat's diet. Could the food predispose the patient to urolith formation? Does the cat have a history of uroliths or is it a breed known to be predisposed to urolith formation such as the ragdoll or British short-haired breeds? (Lekcharoensuk et al. 2000). If a cat is thought to be at risk of calcium oxalate uroliths, blood calcium (ideally ionized calcium) should be obtained to rule out systemic hypercalcemia as the cause of urinary supersaturation and secondary stone formation. Where possible, diagnostic imaging (ideally a double contrast pneumocystogram) should also be performed to rule in/out urolith formation. If uroliths are identified, examining the urine for crystals and assessing the pH might be suggestive of the type of urolith. This, however, does not definitely prove the type of stone. If a suspected struvite urolith doesn't respond appropriately to medical management, surgery and stone analysis may be indicated. Any cat with uroliths should have a urinary culture performed to rule out primary or secondary infection.

If neither UTI nor uroliths is suspected and the cat is younger than 10 years of age (making neoplasia less likely), treatment for idiopathic cystitis can be instigated. Cases should be reviewed regularly—if the response is not optimal, further investigations may be needed.

As discussed, idiopathic FLUTD is a multisystem disease, requiring a multimodal approach to treatment. Dealing with bladder signs alone will not demonstrate an overall benefit to the cat, who will continue to have abnormal stress response and may demonstrate sickness behaviors (Buffington, 2011). Provided the cat is not obstructed and renal function is adequate (as assessed by the USG at a minimum), environmental enrichment to decrease stress, dietary alterations, and pharmacological intervention can be considered. The owner should be aware this is a disease of unknown cause, with no known cure. Therefore, the goal of therapy is to reduce the severity and recurrence rate of subsequent episodes.

Considering the evidence stress plays in this syndrome's etiology, stress reduction is thought to be of great importance. Measures that should be taken include:

• a complete assessment of the cat's environment, ensuring the individual has minimal interactions with more playful cats in the household;
• making sure the cat isn't exposed to loud or sudden noises and has "safe passage" to a litter tray (which should be of a design and incorporate a substrate the patient finds preferable);
• situating trays close to the cat's "safety zone" within the home, away from high-traffic areas with at least one tray per cat, preferably with one extra tray in multi-cat households; and
• identifying the cat's stressors and providing ample "safe zones" away from these to encourage the cat to move around more, enhancing his or her quality of life in general.

This final point can be a lengthy process and might involve asking the owner to draw a map of the cat's territory and core zones, identifying where interactions and stressors might be located. In addition, synthetic pheromones or supplements aimed at stress reduction (i.e. the milk protein, hydrolysate alpha-casozepine) may help decrease stress in some individuals, and therefore decrease clinical signs (Gunn-Moore and Cameron, 2004, Beata et al. 2007).

Lowering the cat's urine specific gravity has demonstrated the greatest benefit. Cats with a USG less than 1.030 have a significantly reduced recurrence of signs compared to those with a USG greater than 1.030 (Buffington, 2011). Therefore, implementing changes in diet and water consumption can greatly decrease recurrence. This can be achieved by providing alternative sources of water around the home (water fountains, glasses, rain water), flavoring water with tuna juice, etc., or feeding a wet diet or a diet designed to promote diuresis (Gunn-Moore, 2003). Recently, commercially available prescription diets have been introduced that are designed to dilute urine. Studies have demonstrated a significant decrease in the recurrence of idiopathic FLUTD with such diets, even when dried formulations are fed. In addition, some manufacturers have supplemented these diets with glycosaminoglycans (GAGs) and substances aimed at reducing stress such as alpha-casozepine and tryptophan (as a serotonin precursor) (Naarden and Corbee, 2020). These formulations, which decrease urolith formation by avoiding supersaturation of the urine with the composite minerals, dissolve struvite uroliths (although more slowly than the diets designed specifically for this) and decrease the incidence of iFLUTD. As such, they are appropriate for long-term management of many feline lower urinary tract diseases (Lulich et al. 2013, Naarden and Corbee, 2020).

Kerry Rolph, BVM&S, CertVC, PhD, FANZCVS (feline chapter), DipECVIM-Ca, MRCVS, is an associate professor of small animal internal medicine at Ross University School of Veterinary Medicine (RUSVM). She graduated from Edinburgh University and worked in small animal practice for two years before returning to Edinburgh to study for her PhD. Dr. Rolph gained both her certificate in veterinary cardiology and PhD in 2004. In 2010, she passed the Feline Medicine Australian College of Veterinary Scientists Fellowship examinations. Four years later, Rolph gained her European diploma in companion animal medicine and became a European specialist in companion animal medicine. She then worked at a private referral hospital in Bristol, England, for three years before joining RUSVM in January 2019. Rolph can be contacted via email at KRolph@rossvet.edu.kn.

References

Forrester, S. D. & Roudebush, P. 2007. Evidence-Based Management of Feline Lower Urinary Tract Disease. Veterinary Clinics of North America Small Animal Practice, 37, 533-558.

Bartges, J. W. What's new in feline LUTD? ECVIM, 2002.

Caney, S. 2011. Pathogenesis and Treatment of Feline Lower Urinary Tract Disease. Veterinary Times.

Bartges, J. W. & Kirk, C. A. 2006. Nutrition and Lower Urinary Tract Disease in Cats. Veterinary Clinics of North America Small Animal Practice, 36, 1361-1376.

Matsumoto, K. & Funaba, M. 2008. Factors affecting stuvite (MgNH4PO4·6H2O) crystallization in feline urine. Biochimica et Biophyscia Acta, 1780, 233-239.

Bartges, J. W. & Callens, A. J. 2015. Urolithiasis. Veterinary Clinics of North America Small Animal Practice, 45, 747-768.

Osborne, C. A., Polzin, D. J., Abdullahi, S. U., Leininger, J. R., Clinton, C. W. & Griffith, D. P. 1985. Struvite Urolithiasis in Animals and Man: Formation, Detection, and Dissolution. Advances in Veterinary Science and Comparative Medicine, 29, 1-101.

Queau, Y. 2019. Nutritional Management of Urolithiasis. Veterinary Clinics of North America Small Animal Practice, 49, 175-186.

Lulich, J. P., Kruger J.M., Macleay, J. M., Merrills, J. M., Paetau-Robinson, I., Albasan, H. & Osborne, C. A. 2013. Efficacy of Two Commercially Available, Low-Magnesium, Urine-Acidifying Dry Foods for the Dissolution of Struvite Uroliths in Cats. Journal of the American Veterinary Medical Association, 243, 1147-1153.

Dijcker, J. C., Plantinga, E. A., Van Baal, J. & Hendriks, W. H. 2011. Influence of nutrition on feline calcium oxalate urolithiasis with emphasis on endogenous oxalate synthesis. Nutrition Research Reviews, 24, 96-100.

Lulich, J. P., Berent, A. C., Adams, L. G., WESTROPP, J. L., Bartges, J. W. & Osborn, T. M. 2016. ACVIM Small Animal Consensus Recommendations on the Treatment and Prevention of Uroliths in Dogs and Cats. Journal of Veterinary Internal Medicine, 30, 1564-1574.

Minnesota Urolith Center 2020. 2019 Minnesota Urolith Center Global Data.

Lekcharoensuk, C., Lulich, J. P., Osborne, C. A., Koehler, L. A., Urlich, L. K., Carpenter, K. A. & Swanson, L. L. 2000. Association between patient-related factors and risk of calcium oxalate and magnesium ammonium phosphate urolithiasis in cats. Journal of the American Veterinary Medical Association, 217.

Bartges, J. W., Kirk, C. A., Cox, S. K. & Moyers, T. D. 2013. Influence of acidifying or alkalinizing diets on bone mineral density and urine relative supersaturation with calcium oxalate and struvite in healthy cats. American Journal of Veterinary Research, 74, 1347-1352.

Blanchard, P. C., BAI, S. C., Rogers, Q. R. & Morris, J. G. 1991. Pathology Associated With Vitamin B-6 Deficiency in Growing Kittens. Journal of Nutrition, 121, S77-78.

Gunn-Moore, D. A. 2003. Feline lower urinary tract disease. Journal of Feline Medicine & Surgery, 5, 133-138.

Buffington, C. A. T. 2011. Idiopathic Cystitis in Domestic Cats-Beyond the Lower Urinary Tract. Journal of Veterinary Internal Medicine, 25, 784-796.

Press, S. M., Moldwin, R., Kushner, L., Buffington, C. A. T. & Schupp-Byrne, D. 1995. Decreased expression of GP-51 glycosaminoglycan in cats afflicted with feline interstitial cystitis. Journal of Urology, 153, 288A.

Buffington, C. A. T., Blaisdell, J. L., Binns, S. P. & Woodworth, B. E. 1996. Decreased urine glycosaminoglycan excretion in cats with interstitial cystitis. Journal of Urology, 155, 1801–1804.

Gunn-Moore, D. A. & Shenoy, C. M. 2004. Oral glucosamine and the management of feline idiopathic cystitis. Journal of Feline Medicine & Surgery, 6, 219-225.

Pereira, D. A., Aguiar, J. A. K., Hagiwara, M. K. & Michelacci, Y. M. 2004. Changes in cat urinary glycosaminoglycans with age and in feline urologic syndrome. Biochem Biophys Acta-Gen Subj, 1672, 1-11.

Lavelle, J. P., Meyers, S. A., Ruiz, W. G., Buffington, C. A. T., Zeidel, M. L. & Apodaca, G. 2000. Urothelial pathophysiological changes in feline interstitial cystitis: A human model. . American Journal of Physiology: Renal Physiology, 278, F540-553.

Buffington, C. A. T. & Pacak, K. 2001. Increased plasma norepinephrine concentration in cats with interstitial cystitis. Journal of Urology, 165, 2051-2054.

Buffington, C. A. T., Chew, D. J. & Dibartola, S. P. 1996. Interstitial cystitis in cats. Veterinary Clinics of North America Small Animal Practice, 26, 317-326.

Gunn-Moore, D. A. & Cameron, M. E. 2004. A Pilot Study Using Synthetic Feline Facial Pheromone for the Management of Feline Idiopathic Cystitis. Journal of Feline Medicine & Surgery, 6, 133-138.

Beata, C., Beaumont-Graff, E., Coll, V., Cordel, J., Marion, M., Massal, N., Marlois N. & Tauzin, J. 2007. Effect of alpha-casozepine (Zylkene) on anxiety in cats. Journal of Veterinary Behavior, 2, 40-46.

Naarden, B. & Corbee, R. J. 2020. The effect of a therapeutic urinary stress diet on the shot-term recurrence of feline idiopathic cystitis. Veterinary Medicine and Science, 6, 32-38.