BVSc (Hons) MMedVet (Med) PhD Dipl. ECVIM (Internal Medicine)
Bryanston Veterinary Hospital
PO Box 67092, Bryanston, 2021, South Africa
Presentation done for Royal Canin
FELINE IDIOPATHIC CYSTITIS
Feline lower urinary tract diseases are a heterogeneous group of disorders that may result from fundamentally different causes such as anatomic defects, behaviour abnormalities, neoplasia, urolithiasis, or urinary tract infection. In most cats, however, the cause(s) is (are) unknown and therefore referred to as feline idiopathic cystitis (FIC). Typical clinical signs are dysuria, pollakiuria, stranguria, haematuria, or inappropriate urination.
Feline idiopathic cystitis is similar to interstitial cystitis (IC), which is an idiopathic lower urinary tract disorder of humans. It is characterised by difficult, painful, and frequent urination without a diagnosable cause and is most commonly reported in woman. To be diagnosed with IC, patients must have either bladder pain or urinary urgency and show either glomerulations (submucosal petechial haemorrhages) or a classic Hunner’s ulcer on cystoscopic examination. Cats with FIC meet all the inclusion and exclusion criteria for diagnosis of IC that can be applied to animals.
The pathophysiology of FIC is not fully understood and may involve complex interactions between a number of body systems as a variety of abnormalities have been found in the bladders, nervous system, and hypothalamic-pituitary-adrenal axis of cats with FIC. Thus it is important that this syndrome is not just considered a “bladder disease” amenable to simple diet or drug therapies.
In both IC and FIC smaller amounts of total urinary glycosaminoglycan (GAG) and a specific GAG (GP-51) are secreted. GAG and GP-51 contribute to the surface mucus covering the urothelium that is believed to inhibit bacterial adherence and urothelial injury from the constituents of the urine. A defective GAG layer or damaged urothelium could permit hydrogen, calcium, potassium ions, or other constituents of urine to come into contact with sensory neurons innervating the urothelium. These ions can stimulate local release of neurotransmitters and result in neurogenic bladder inflammation. Sensory neurons reach the bladder via the pelvic and hypogastric nerves, and the central processes of these nerves synapse in the dorsal horn of the sacral and lumbar spinal cord, respectively. These neurons include unmyelinated nociceptive fibres, commonly referred to as C fibres.
Increased sensory nerve fibre density is found in the bladder of patients with IC. These fibres contain a variety of neuropeptides, which suggests a role for neurogenic inflammation in the pathophysiology of IC. In both IC and FIC, Substance P containing fibres are increased in the submucosa of bladders. Mammalian bladders usually express either the NK1 (high affinity) or the NK2 (low affinity) Substance P receptor, or both. In normal cat bladders, the NK2 receptor is identified, whereas NK1 receptors are at or below the threshold of detectability. In contrast, inflamed bladders have higher concentrations of NK1 Substance P-binding sites and are associated with inflammatory events in urinary bladders of cats.
Abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis have been observed in cats with FIC as they show decreased serum cortisol response to ACTH as well as lower adrenal gland size and volume. Therefore it appears that although the sympatho-neural system is fully activated in FIC the HPA axis is not. The significance of this finding is however, not known.
The clinical signs of FIC and IC both include pain and increased frequency and urgency of urination. The increased “grooming” of the caudal abdomen and genitalia by cats with FIC is consistent with reports of bladder pain. Cats with FIC can also “barber” the hair in the region of the caudal abdomen and proximal inner thighs, which is suggestive of increased perception of pain or irritation in the region. In addition cats with FIC usually resent handling and resist abdominal palpation, often attempting to bite during such examination. In both IC and FIC, clinical signs of the disease follow a waxing and waning course.
Cats with FIC show frequent attempts to urinate causing some clients to confuse the disorder with constipation because of the frequency with which the cat “squats”. Urine volume produced during these episodes often is less than 2 ml. There is often an urgency to urinate, which can result in urination outside the litter box.
Haematuria (either macroscopic or microscopic) is the most consistent finding. Micro-organisms cannot reliably be cultured from the urine, and the urine is cytologically nondescript. Although IC and FIC are not thought to be of infectious origin, novel organisms have been cultured from some humans with IC. Whether these organisms are a cause or an effect of the disease remains to be determined. Moreover, some micro-organisms could be involved as an original inciting cause, but are no longer present by the time the disease is recognised.
Although radiographic studies (survey and contrast) and ultrasonography are not helpful in the diagnosis of FIC, they are important in ruling out anatomic defects, neoplasia, or urinary calculi.
Cystoscopy is required for the diagnosis of IC in humans, although the typical cystoscopic findings of prominent vasculature and submucosal petechial haemorrhages (glomerulations) are shared with other bladder diseases. In cats the cystographic changes with FIC are submucosal petechial haemorrhages.
Common findings of a relatively normal epithelium and muscularis with submucosal oedema and vasodilatation without significant infiltration of inflammatory cells are consistent with findings in many cats with FIC. Mast cells also have been found in bladder biopsy specimens from cats with FIC. Problems with the study of mast cells include different subsets of mast cells that affect their detection by standard histological techniques, and the fact that their granules, to which commonly used stains bind, may be released before the biopsy specimen is collected.
The clinical diagnosis of FIC rests on the same criteria, as does the diagnosis of IC in humans, namely: “chronic irritative voiding symptoms, sterile and cytologically negative urine, and characteristic cystoscopic findings along with failure to find a more objective cause”.
Amitriptyline, a tricyclic antidepressant, is advocated as it has anticholinergic, antihistaminic, anti-alpha-adrenergic, anti-inflammatory, and analgesic properties. The drug is used extensively for treatment of IC in humans. In cats the dose, frequency, and duration of therapy is entirely empirical. Data shows that there is amelioration of clinical signs within 24-48 hours after the administration of amitriptyline. The proposed beneficial effects of the drug are its analgesic properties, potential to stabilise mast cells, and ability to decrease inflammation.
The dosage is between 2.5 to 12.5mg orally oid, usually at night, with the final dose adjusted to produce a barely perceptible calming effect on the cat. The reduction in clinical signs can be dramatic in some cats, but in others, little or no beneficial effect is observed. Despite an improvement in clinical signs, underlying bladder pathology may persist.
Synthetic GAGs have the potential to relieve the clinical signs of IC, as they act by adhering to the luminal side of the mucosa, thus helping to maintain or enhance the permeability barrier of the adluminal cells to the urine.
Pheromones are fatty acids that seem to transmit highly specific information between animals of the same species. Pheromones induce changes in both the limbic system and hypothalamus, altering the emotional state of the animal. The use of Feliway®, a facial pheromone has been shown to reduce anxiety–related behaviours in cats. Thus its use in FIC may be of benefit, as it will reduce anxiety, which may be a precipitating factor in FIC. Controlled trials are, however, needed to fully evaluate Feliway® as a therapy for FIC.
To reduce environmental stress there should be sufficient clean litter trays, individual food and water bowels, sufficient places to hide, and opportunities to express the natural predatory behaviour of cats.
Diets of these patients should remain constant to further reduce stress. The moisture content should be increased, either by feeding canned food or moistening the dry food.
There is no rationale for the use of antibiotics, urinary tract antiseptics, urinary tract analgesics, urinary acidifiers, anti-spasmodics, corticosteroids, and DMSO in the management of FIC.
URINARY TRACT INFECTIONS
A urinary tract infection (UTI) develops when a breach occurs in the host defence mechanisms allowing a virulent organism to adhere, multiply, and persist in the urinary tract. The entire urinary tract is at risk of microbial invasion once any part of it becomes colonised with bacteria; however, the majority of cases involve bacterial infection of the lower urinary tract. Bacterial UTI occurs more frequently in dogs than in cats. In cats it is often associated with renal failure, immune-suppressive diseases, and following perineal urethrostomy.
The most common bacterial pathogens associated with UTI are: E. coli, Staphylococci, Streptococci, Enterobacter, Proteus, Klebsiella, and Pseudomonas. Mycoplasmal, chlamydial, viral, and fungal UTI are rare.
The urinary tract defence mechanisms are important factors that influence the pathogenesis of UTI. Defence mechanisms of the urinary tract include:
- Flushing and dilutional effects of voiding.
- Unidirectional flow of urine.
- Vesico-ureteral junction.
- Urethral length in males.
- Bactericidal properties of prostatic secretions.
- Colonisation by non-pathogenic bacterial flora.
- Mucosal secretions.
- Bacteriostatic properties of urine (pH and osmolalilty).
Uncomplicated UTI is defined as an infection in which no underlying structural, neurological or functional abnormalities can be identified. Complicated UTI is associated with a defect in the host’s urinary defence system, such as interference with normal micturition, anatomic defects, damage to mucosal barriers, or alterations in urine volume or composition.
Lower UTI often results in pollakiuria, stranguria or dysuria, and haematuria (gross or microscopic). Acute bacterial pyelonephritis may manifest with non-specific systemic signs such as pyrexia, depression, anorexia, and leukocytosis.
Urine analysis findings with a UTI include bacteriuria, proteinuria, haematuria, or pyuria. The presence of RTE cell or leukocyte casts, together with bacteriuria is highly suggestive of pyelonephritis. Urine culture with antibiotic sensitivity is required to confirm the presence and type of bacteria as well as indicate the antibiotic of choice.
Abdominal palpation of the bladder as well a rectal palpation may help diagnose a thickened bladder wall, a bladder mass, or urolithiasis. Excretory urograms, ultrasonography, and pyelocentesis may be required to confirm pyelonephritis.
The cornerstone of therapy is antibiotic treatment, which should be based on urine culture and sensitivity, especially with chronic and complicated cases. Antibiotics that have a good volume of distribution in the urinary tract are broad-spectrum penicillins, cephalosporins, and potentiated sulphonamides. Duration of therapy must be individualised and should be based on the cessation of clinical signs and elimination of abnormal urine sediment, as well as a negative urine culture. An uncomplicated lower UTI should be treated for 10-14 days, whereas recurrent UTI and pyelonephritis should be treated for a minimum of 6 weeks.
Recurrent infections can be classified as:
- Relapses – recurrence with the same strain within 1-2 weeks after stopping antibiotic therapy.
- Re-infections – recurrence with a new strain.
Recurrent infections required should be fully investigated to identify an underlying cause. Diagnostic testing would include:
- Urine culture and sensitivity.
- Survey and contrast radiographs.
- Semen and prostatic wash cytology, culture and sensitivity.
- Prostatic and/or renal FNA/biopsy.
Long-term (> 6 weeks) antibiotic treatment is required for recurrent UTI and regular urine analysis and cultures are required to ensure resolution of the UTI. If predisposing factors cannot be corrected, antibiotic therapy may have to be continued indefinitely, often administered once a day at night.
Urolithiasis is defined as the formation of urinary calculi from the less soluble crystalloids of urine, as a result of multiple congenital and/or acquired physiological and pathological processes. Uroliths are organized concretions found in the urinary tract that contain primarily organic or inorganic crystalloid and a much smaller amount of organic matrix. When 70% or more of the urolith is composed of one type of crystal it is named for that crystal. Secondary crystalloids can comprise up to 30% of the total weight. Urine is commonly supersaturated with crystalloids, and observation of individual crystals in the urine does not mean the animal is at risk for urolithiasis. Super saturation of urine with crystalloids depends on the interaction of mineral elements in the urine that are derived from the amount of solute ingested and excreted, as well as the volume of urine produced.
Urolithiasis should not be a final diagnosis but should rather be seen as a sequel of one or more underlying abnormalities. In dogs and cats, the majority of uroliths are found in the bladder or urethra.
Urolith formation is often erratic and unpredictable with several interrelated physiologic and pathologic factors involved. Conditions that contribute to crystallisation and urolith formation include:
- Presence of a high urine concentration of crystalloid material.
- A degree of urinary retention of crystalloid material.
- Urinary stasis.
- Favourable urine pH for crystallisation to occur.
- Presence of UTI will favour the development of a urolith.
- Metabolic factors.
Clinical signs are dependent on the number, type, and location of the urolith within the urinary tract. As the majority of uroliths occur in the urinary bladder signs of cystitis are frequently observed.
In male dogs, small uroliths may lodge within the urethra, usually at the caudal end of the os penis, resulting in complete or partial obstruction with signs of bladder distension and post renal azotaemia. Occasionally the urinary bladder or urethra may rupture resulting in ascites or subcutaneous perineal fluid accumulation, respectively, and post-renal azotaemia.
Unilateral renal uroliths may be asymptomatic or associated with haematuria and chronic pyelonephritis. Bilateral renal uroliths often lead to renal failure, because they are usually associated with pyelonephritis or obstruction.
Ureteral uroliths may be asymptomatic or associated with haematuria or abdominal pain. Unilateral complete obstruction results in a unilateral hydronephrosis with no evidence of decrease in renal function.
Urine analysis findings are typical for urinary tract inflammation. Crystalluria may be observed and may occur as an incidental finding without uroliths. However, if the 2 exist concurrently the identity of the crystal is usually the same as that of the urolith. Ultrasonography and survey and contrast radiographs can be used to diagnose and localise uroliths. Urine culture is important to exclude concurrent UTI.
Once a urolith is collected it is imperative that it is quantitatively analysed to identify its composition, as this is important in preventative therapy.
Cystotomy and/or urethrotomy are often used in the management of urolithiasis. It is important to remember that surgery is often associated with a high rate of recurrence if the underlying cause is not addressed.
The medical dissolution of struvite, urate, and cystine uroliths is effective, however, it requires a high degree of owner compliance over a long period of time (weeks to months). In both the dog and cat, a diet appropriate for the type of urolith should be fed.
FELINE URETHRAL OBSTRUCTION
Urethral plugs are the most common cause of obstruction in male cats because of the narrow penile urethral lumen that predisposes to obstruction with a urolith or urethral plug. Many urethral plugs are composed of struvite with a proteinaceous matrix. In the past struvite urethroliths were the sole type but calcium oxalate urethroliths are currently more commonly reported.
Urethral plugs form when vasodilatation and leakage of plasma proteins from the suburothelial capillary plexus (bladder weeping) and secondary urethritis, which can be seen cystoscopically in cats with FIC, trap crystals within the lumen of the urethra and may result in obstruction. It is likely that oozing of plasma proteins into urine during active inflammation increases the urinary pH that contributes to the precipitation of struvite crystals that participate in urethral plug formation. Mineral components of urethral plugs continue to be predominantly composed of struvite despite the increase in frequency of calcium oxalate urolithiais. This may be due to the narrow range of metabolic super saturation of struvite in urine.
Regardless of the underlying cause or causes, relief of obstructions, re-establishment of urine flow, and correction of fluid, electrolyte, and acid-base imbalances associated with obstruction and post-renal azotaemia are the first steps in proper management. Cats with urethral obstruction should be managed aggressively with medical treatment unless recurrent obstructions occur. A perineal urethrostomy surgery may be needed to prevent future episodes of urethral obstruction. Surgery does not correct the underlying problem and recurrent uroliths and FIC episodes can still occur. As struvite crystals play an important role, the use of urinary acidifying diets are advocated in the management of urethral plugs.
Disorders of the prostate are fairly common in the dog with prostamegally evident in two-thirds of dogs, over five years of age.
As a dog ages spontaneous enlargement (benign prostatic hyperplasia) occurs. Despite this enlargement, the prostatic secretory capacity decreases as the benign hyperplasia develops. There are two distinct types of hyperplasia:
- Glandular hyperplasia begins at 1-2 years of age and its prevalence peaks at 5-6 years. During this time the prostate develops a proliferation of secretory structures that are distributed uniformly throughout the gland. There is an increase in the number and size of the epithelial cells, accompanied by a smaller but significant proliferation of stromal fibroblasts and smooth muscle.
- Complex hyperplasia generally develops later, but the first evidence appears at 2-3 years of age. Cystic, dilated alveoli filled with eosinophilic material are a characteristic feature and can give the surface of the gland an irregular contour. The cysts can be distributed throughout the gland but are more numerous in the peri-urethral areas. Cell infiltration (lymphocytes and plasma cells) is common, appearing as clusters or nodules of cells in the stroma. Frequent epithelial atrophy and occasional epithelial squamous metaplasia are associated with these areas of cell infiltration.
Excessive androgen or oestrogen (iatrogenically, neoplastic lesions, or testicular dysfunction) can cause prostatic enlargement. An androgen imbalance leads to cystic hyperplasia of the acini and ducts together with hypertrophy of the fibromuscular framework. An oestrogen imbalance, on the other hand, causes hyperplasia of the ducts together with squamous metaplasia of the epithelial lining and desquamation into the lumens. The acini may or may not become hyperplastic. In time, prostatic secretions pool in multiple small to large cysts, which dilate the ducts and the gland.
Diagnosis Of Prostatic Disorders
Most dogs with prostatic disorders are middle-aged or older intact animals. Although neutered dogs are at a reduced risk for prostatic disease, prostatic neoplasia is still possible.
Prostatic disease can present with clinical signs attributed to the urinary tract (haematuria, pyuria, dysuria, incontinence), colon (constipation, diarrhoea, tenesmus, dyschezia), locomotory (hindquarter stiffness or lameness), as well as non-specific systemic signs (fever, weight loss, anorexia, PuPd, vomition).
Due to the variety of prostatic disorders that occur in dogs, each necessitating a different therapeutic approach and prognosis, an accurate diagnosis is of great importance. If the history and clinical findings (including a rectal examination) suggest that a patient may have prostatic disease, one or more of the following diagnostic procedures should be performed:
- Cytological evaluation and bacterial culture of semen/prostatic fluid wash/urine/fine needle aspirate.
- Survey and contrast radiography.
- Prostate biopsy.
Benign prostatic hyperplasia
Benign prostatic hyperplasia (BPH) is the most common prostate abnormality in intact male dogs and is estimated to occur in 100% of old, intact dogs. Androgens are essential for the development and maintenance of BPH. However, with age, a modest decrease in the serum testosterone concentration, combined with no change in the serum estradiol-17-beta concentration, results in a relative decrease in the serum androgen to oestrogen ratio. This altered hormonal milieu is believed to contribute to the pathogenesis of BPH by increasing androgen receptor expression.
The diagnosis of BPH is made indirectly by elimination of other types of prostatic disease. A definitive diagnosis of BPH requires histopathologic confirmation. However, it is difficult to justify a prostatic biopsy when the results of less invasive methods strongly support the diagnosis of BPH and the absence of more sinister prostatic diseases. A presumptive diagnosis of BPH is based on the history, clinical signs, prostatic imaging, and prostatic fluid cytology and culture. Clinical signs associated with BPH include haemorrhagic urethral discharge, haematuria, haemospermia, and tenesmus. Many dogs with BPH show no clinical signs. BPH may only become a clinical problem once it results in pressure on the colon or if it encroaches on the muscles and nerves in the pelvic canal.
For non-breeding males, the recommended treatment for BPH is castration with prostatic size significantly decreasing within 7-10 days after castration. Anti-androgenic drugs (progesterone, finasteride, chloradinone acetate, osaterone acetate, delmadinone acetate, flutamide, and megestrol acetate) are effective at reducing prostatic size but can adversely affect gonadal function. Oestrogens have also been used to treat BPH; however, because of the risk of myelosuppression and prostatic abscess formation, they are no longer a recommended treatment. The liposterolic extract of saw palmetto plant berries or the American dwarf palm tree (Serenoa repens) reportedly improves urinary flow rates in humans with BPH but has little effect (positive or negative) in dogs.
This is an acute inflammatory condition, which may occur with or without hyperplasia of the prostate. Bacteria most frequently isolated are E. coli, Proteus, Pseudomonas, Staphylococcus and Streptococcus. Prostatic infection can either be ascending from the lower urinary tract, descending from the kidney or bladder, or of haematogenous origin.
Analgesics and catheterisation may be indicated for urethral spasm, resulting in urine retention. Antibiotic selection is of paramount importance, with effective antibiotics being penicillins, cephalosporins, potentiated sulphonamides, and quinolones. The antibiotic choice should ideally be based on a culture and given at high doses for 4-6 weeks. Urine culture will frequently isolate the infective organism and should be repeated at the completion of therapy. As castration is effective in decreasing gland size, it should be considered with recurrent infections.
This occurs less frequently than acute prostatitis, however, owing to the relative lack of clinical signs it is most likely under-diagnosed. It is often considered as a sequel to acute prostatitis.
Therapy is aimed at intensive antibiotic therapy, based on culture and antibiogram. Treatment is continued until the causative organism is eliminated, which can be determined by intermittent urine or prostatic fluid culture. Castration should be considered and prostatectomy only done in cases completely refractory to medical treatment.
This is defined as a localized accumulation of pus within the parenchyma of the prostate. Abscesses may be small or large, focal or diffuse. Usually smaller abscess coalesce to form one or more larger abscess. Prostatic abscessation has been associated with BPH, oestrogen therapy, and extension of acute prostatitis.
Conservative antibiotic therapy is often unrewarding. Castration is advocated in all cases to reduce gland size. The abscess can be treated by marsupialisation or percutaneous drainage, under ultrasound guidance.
Paraprostatic cysts originate near the prostate and represents embryonic structures (vestiges of the mullerian ducts). The cyst is not in direct communication with the prostate and can be completely removed via blunt dissection. Clinical signs of prostatic cysts are usually absent until the cyst becomes large enough to impinge on the bladder and/or rectum, leading to dysuria and constipation, respectively.
Prostatic neoplasia is an uncommon condition with no breed predilection. The aetiology is unknown, however, the aging process and the associated hormonal imbalances appear to be of prime importance in prostatic carcinogenesis. In comparison to man squamous metaplasia has been shown not to be a pre-neoplastic change. Metastasis is common, usually developing in the sublumbar lymph nodes, lumbar vertebral bodies, and lungs.
The diagnosis of prostatic carcinoma is made based on the history, clinical signs, and results of prostatic imaging, fluid analysis, and histopathology. In intact dogs, prostatic carcinoma is not always associated with prostatomegaly. However, in castrated dogs, prostatomegaly is highly associated with prostatic carcinoma. On palpation, the prostate may be normal in size but may feel firm and asymmetric and adhered to the pelvic canal. Tumour markers used in human medicine, such as PSA and prostatic acid phosphatase, are not useful in the diagnosis of prostatic neoplasia in the dog.
The prognosis for dogs with prostatic neoplasia is poor. Treatment is primarily palliative and includes complete or partial resection of the prostate, castration, and intraoperative orthovoltage radiotherapy. Piroxicam, a specific cyclo-oxygenase-1 (COX-1) inhibitor, administered at a dosage of 0.3 mg/kg given orally once a day, has been used successfully to reduce the size of several canine carcinomas. Combining cisplatin with piroxicam appears to have a synergistic effect therapy.