Publicatiedatum: Exoticscon, september 2022
Lower Urinary Tract Disease in Guinea Pigs as it Relates to Nutrition
Authors: Eva Stoffels, BVSC, DVM, PhD,
Affiliation: From the Marumoto Veterinary Practice, Hoevenweg 18, 7722 PN Dalfsen, The Netherlands.
Abstract: Lower Urinary Tract Disease (LUTD) is very common in pet guinea pigs. LUTD comprises cystitis (bacterial or sterile), “sludge” (crystalluria) and urolithiasis. Symptoms such as stranguria, hematuria and weight loss may be present. Bacterial cystitis is more common in female animals. Typical pathogens are Corynebacterium spp., Streptococcus spp., and sometimes coliforms. Chronic interstitial cystitis is associated with structural changes in the bladder wall, with or without the bacterial component. Urolithiasis occurs in both sexes but in males it usually requires surgical intervention. Radiology and ultrasound imaging are the diagnostics of choice. Treatment options include antimicrobials, multimodal pain management, exogenous progestogens and neuromodulatory drugs. The occurrence of LUTD is highly influenced by the diet. Excessive consumption of leafy vegetables and certain types of pelleted food increases calcium excretion and the risk of cystitis and urolithiasis. It is argued that dietary nitrogen compounds contribute to this condition.
Introduction
Lower urinary tract disease (LUTD) comprising cystitis and urolithiasis is one of the most common disorders in pet and laboratory guinea pigs. Urinary discomfort and dental problems account for nearly 90% of all author’s veterinary consultations.
LUTD is truly frustrating: it is persistent, painful, compromising the animal’s life quality and often not responsive to treatment. Therefore, it is important to answer the following: is LUTD “idiopathic” and just inherent to guinea pigs? Are there serious problems associated with the diet and husbandry of guinea pigs kept in captivity?
Guinea pigs are obligate herbivores. Their diet in captivity consists of hay, plant-based pelleted chow and various vegetables and fruits. Fresh vegetables may provide minimal hydration and decrease the free consumption of water.1 Guinea pigs produce diluted, alkaline urine. Crystalluria, or urinary “sludge” is so common that some sources consider it physiological.2 On the other hand, nutrition seems to have a major influence on the amount of excreted sludge and the incidence of LUTD.
This paper attempts a systematic description of the disease. It is based on a compilation of clinical findings in about 100 guinea pig patients treated by the author in the past two years (2020-2022). Furthermore, observations of the author’s own guinea pigs (more than 150 animals), their eating and drinking habits, and the prevalence of LUTD are included in the statistics. Clinical presentations and diagnostic methods are described, followed by treatment options (pharmacotherapy and surgery). Finally, the underlying mechanisms of LUTD and nutritional risk factors are discussed.
Figure 1. “Sludge” containing mainly CaCO3
CYSTITIS
Infectious cystitis
Uncomplicated bacterial cystitis makes up to 80% of all the author’s presented cases. Guinea pig urine is rich in protein (see discussion in ETIOLOGY AND PATHOGENESIS) and it often contains glucose. Proteinuria and glucosuria provide an efficient culture medium for bacteria. Infectious cystitis more prevalent in female guinea pigs (sows) than in males (boars). This can be attributed to a short and relatively wide urethra in sows. Sows housed together with a (neutered) boar may be at higher risk because the infection is readily transmitted sexually.3
Affected animals usually have a good body condition score. Intermittent painful micturition – stranguria or pollakiuria are the most obvious signs observed by the owner. Alternatively, micturition may be uneventful but the animal exhibits pain symptoms (straining and vocalizing) while passing feces. In the author’s experience, about 30% of the cases there are no specific symptoms, but the owner might notice weight loss and/or subtle changes in the animal’s behavior.
Cystitis is diagnosed by detecting hematuria, pyuria and/or urinary nitrite. Blood in urine is not always easy to assess by the owner. Urine often appears normal because only occult blood is present. Conversely, urine may be red-colored after consumption of certain plant dyes; the most common example is the red beetroot. Therefore, urinalysis is always necessary. Commercial human or veterinary urine test strips (e.g. Combur by Roche) can be used. The dipstick urinalysis has to be repeated after obtaining one negative result, because hematuria may be intermittent. Nitrite and leukocytes are not always detectable. Because the strips are not always sensitive enough to evaluate low numbers of cells 1,2, urine cytology is necessary to detect blood cells and other objects such as epithelial cells, sludge (Figure 1) and bacteria.
The author does not submit urine for bacterial culture, because many owners do not consent to the cost. However, when cystitis persists despite treatment, it is advisable to obtain an antibiogram or to confirm the absence of infection (see Chronic interstitial cystitis). Representative urine samples are readily obtained by bladder catheterization with a thin (No. 1) flexible Rüsch catheter. In boars, accessing the bladder may be more challenging, because the catheter is easily deflected into one of the seminal vesicles. Ultrasound-guided cystocentesis must be performed either with sedation or anesthesia, with an analgesic administered prior to the procedure. This sample is preferred for bacterial culture and sensitivity testing.
Pathogen identification can be performed in-clinic using kits such as Uricult® (Aidian Finland). However, for more detailed information and a reliable antibiogram, a specialized veterinary laboratory familiar with normal biomes in exotic species should be used. The most common bacterial pathogens encountered by the author are (in decreasing order of prevalence): Corynebacterium renale, Streptococcus spp., Staphylococcus spp., Enterococcus spp., Escherichia coli and other enterobacteria (non-ESBL), and very rarely Proteus mirabilis. These bacteria, with the exception of Enterococcus spp. usually (so far) have only a low-level antibiotic resistance. Bacterial cystitis has features of a secondary/opportunistic infection. It is treatable with antibiotics (see PHARMACOTHERAPY), but relapses are very common.
Figure 2. Chronic interstitial cystitis. A. necropsy B. histopathology (H&E stain).
Chronic Interstitial Cystitis (IC)
About 20% of presented cystitis cases presented to the author for a second opinion are unresponsive to a prolonged antibiotic treatment. In the author’s experience, this seems more likely to occur after a prolonged treatment with trimethoprim-sulfonamide (TMPS). The incidence of female patients is higher in this group. In some cases, no discomfort is seen and (intermittent) hematuria may be the only sign. However, most animals with IC are in pain and vocalize during urination and/or defecation. Urine may appear thick and slimy and have a foul odor. It usually contains desquamated epithelial cells and large amounts of blood and calcium carbonate sludge. There may be an intermittent infection but in many cases the urine is sterile. The animals often suffer from secondary contact dermatitis (“urine scalding”) in the genital area and hind legs; the skin may be severely eroded. Although most guinea pigs with IC never become truly anorexic, their condition gradually deteriorates.
A striking feature of IC is the loss of bladder compliance due to thickening of the bladder wall. A wall thickness of 1 mm or more, determined by ultrasonography, cystoscopy, surgery or at necropsy, can be considered pathological. In severe cases, desquamation of the urothelium leads to formation of pseudomembranes. Pseudomembranes may be expelled in the urine, or they may mineralize and form uroliths. On necropsy and histopathology, the detrusor muscle is hyperplastic, and the submucosa contains multifocal cystic lesions (Figure 2).
Diagnosis is based on the epicrisis and ultrasonographic examination. Ultrasonography allows detection of various abnormalities: crystalluria/sludge, structural changes of the bladder, neoplasia and uroliths. In Figure 3, normal and affected guinea pig bladders are shown. It is advisable to perform an ultrasonographic examination of the kidneys at the same time. The presence of chronic kidney disease (medullary fibrosis, multifocal cystic lesions) worsens the prognosis of IC. Cystic kidneys may be caused by micro-obstructions of tubules and collecting ducts with calcium salts.1
Although ultrasonography is excellent to evaluate soft tissue pathology, it does not always provide the full clinical picture. For example, not all uroliths (if present) can be readily detected. In animals with chronic cystitis, especially in boars, adjunct radiographic examinations are necessary because these animals are at high risk of developing uroliths that can lead to obstructions (see UROLITHIASIS).
Figure 3. Ultrasound imaging of the bladder. A. Normal; B, C. interstitial cystitis (note the organ wall thickness); B. an urolith; C. desquamated pseudomembranes (arrow).
UROLITHIASIS
Urolithiasis is the presence of macroscopic (> 1 mm) calculi in the urinary tract. In guinea pigs they usually consist of relatively pure calcium carbonate. Cavies fed a low-calcium diet and in cases of vitamin D intoxication, calcium phosphate can be found as well (author’s own analyses). The author has never observed calcium oxalate sludge nor calculi, although oxalate crystals are commonly seen in feces. Struvite has not been found.4
Bladder and urethra
Urolithiasis affects sows and boars to an equal extent, but in sows it is often less apparent. This is due to the anatomical differences. The relatively short (2-3 cm) and wide urethra in females facilitates the excretion of sludge and calculi. Anecdotally, uroliths up to 1 cm in diameter can be spontaneously expelled per vias naturales. An interesting finding in female guinea pigs is the accumulation of sludge in the distal urethral diverticulum, without urethra obstruction (Figure 4). Such “stones” are usually soft and easy to crumble. In males the urethra is much longer (> 8 cm) and has two flexures: the proximal, pelvic flexure and the distal, preputial flexure. Symptoms of urolithiasis in boars may be severe: Stranguria usually leads to exhaustion and in the author’s experience, the animal may die of pain if not treated on time. Uroliths of 4-6 mm pose a risk of acute urethral obstruction with fatal sequelae. The flexures and the os penis segment are the predilection sites for obstruction. Nevertheless, some male guinea pigs have been able to expel calculi as large as 5 mm in diameter.
Ureter
Urolithiasis can occur within the ureters, with the calculi causing partial or total ureteral obstruction. The symptoms are often inapparent because there is no stranguria. The affected animals are usually unwell: They may lose weight, have a decreased appetite and frequent secondary gastrointestinal disorders. Hematuria (occult blood) tends to be intermittent. When uroliths are present bilaterally, the animals will eventually succumb to kidney failure.5
Medical imaging
Since all guinea pig calculi contain calcium, they are readily visualized in radiographs. At least two radiographic projections are necessary views: dorsal recumbency for VD (dorsoventral is also possible but not as accurate) and lateral. Radiography is required to decide on the optimal treatment. For example, total urethral obstruction with a relatively small urolith (Figure 5a) is a medical emergency. Paradoxically, large calculi (Figure 5b) do not require immediate intervention. However, surgery should be planned as soon as is feasible, in order to relieve the discomfort. Often no large uroliths, but only small calculi, calcified pseudomembranes and excessive sludge are seen (Figure 5c). Oddly shaped (fusiform or irregular) radiopaque objects that are not lying in the midline on the dorsoventral projection need further investigation, because they may be located in the ureter (Figure 5d). Additional ultrasonographic examination is needed to locate the stone accurately; usually it appears as an echogenic structure with an acoustic shadow (Figure 6), or at least a strongly dilated ureter is visible.
Treatment options
Treatment of urolithiasis can be conservative as well as surgical, dependent on the size and location of the calculi, the gender and the general condition of the patient. In females, a stone-expelling therapy consisting of a diuretic and a spasmolytic drug is often successful (see PHARMACOTHERAPY). However, this can be suggested only for a sow in good clinical condition and the calculi are smaller than 5 mm in diameter. Larger calculi usually require surgical intervention or at least a cystoscopic procedure (see SURGERY). In males the decision to proceed with the surgery is usually made earlier because of the risk of total urethral obstruction. Ureteral calculi can spontaneously descend into the bladder. They can be treated conservatively in both sexes, provided they are smaller than 4 mm and the animal’s condition is satisfactory.
Treatment can relieve the symptoms temporarily, but relapses are very common. In one case known to the author, a new urolith was formed in the two weeks following the surgery. Thus, additional effort must be undertaken (dietary adaptations, diuretics, nutraceutics etc.) to prevent recurrent urolithiasis. Periodic monitoring is also recommended.
Figure 4. Accumulation of sludge in the distal urethral diverticulum in a sow. The “stone” is visible in the urethral opening. It does not cause obstruction.
Figure 5. A. pelvic urethra obstruction in a male; B. a large bladder stone; C. an ureter stone; D. multiple calculi (arrow) in the bladder.
Figure 6. An ultrasound image showing an empty bladder and bilateral ureter stones (arrows).
PHARMACOTHERAPY
Infectious cystitis
Uncomplicated bacterial cystitis can be treated with antimicrobials, but the choice of the drug is usually limited. The antimicrobial must not be toxic to the commensal intestinal flora nor to internal organs, it must reach therapeutic levels in the target organ (bladder), it must be easy to administer by the owner, and free from legal issues. In practice, only orally administered nitrofurans, fluoroquinolones and the trimethoprim-sulfonamide combination fulfil these requirements.
Trimethoprim-sulfonamide (TMPS). TMPS is considered the first-line veterinary treatment in the Netherlands; the usual dose is 4-20 mg/kg po q12. Unfortunately, it usually fails to eliminate the infection even when used for several weeks or longer. This is attributed to the unfavorable pharmacokinetics of TMPS in rodents. The elimination half-life time in the plasma is less than one hour.6 The drug is excreted in urine where it may persist depending on urinary retention, but its concentration is not well-defined. TMPS is time-dependent and bacteriostatic: Continuous exposure to concentrations above the minimum inhibiting concentration (MIC) is necessary to suppress bacterial growth. Since the levels of TMPS in urine strongly depend on the efficiency of bladder emptying, bacteria might be exposed to sublethal doses. This is also the mechanism behind the widespread resistance to TMPS in rodents. The efficacy of TMPS might be improved by increasing the frequency of administration, but this often faces practical issues. Moreover, sulfonamides, being weak acids, form anions in alkaline guinea pig urine which further reduces their activity. Trimethoprim might contribute to crystalluria because it is poorly soluble at high pH values.7
Nitrofuran antimicrobials. The author’s treatment of choice is nitrofurantoin or furazidin, 50 mg/kg po q12 or q24. Similar to TMPS, these broad-spectrum drugs have a short plasma half-life and are predominantly excreted in urine, but they are concentration-dependent and exert a bactericidal effect.8 Moreover, they are weak bases, so they can assume the unionized (biologically active) form in alkaline guinea pig urine. Furazidin has a higher efficacy in vivo than nitrofurantoin, presumably due to its higher pKa (more basic character) and more lipophilic properties, allowing it to penetrate the (sub)mucosa of the bladder. No adverse effects on the digestive system have been observed with both drugs. A treatment of 10 consecutive days eliminates the infection in about 80% of cases. A prolonged treatment of another 10 days results in a nearly complete elimination of the infection. However, relapses can occur, especially when the owner does not follow the dietary advice (see ETIOLOGY AND PATHOGENESIS). Therefore, a follow-up with frequent urinalysis is necessary. Some cases of Enterococcus spp. cystitis respond poorly, even though most strains of Enterococcus are in vitro susceptible to nitrofurans.
Other treatment options. When nitrofurans are ineffective, fluoroquinolones (enrofloxacin or ciprofloxacin, 10 mg/kg po q12) may offer another treatment option. Antimicrobial susceptibility testing is required. A last resort remedy is fosfomycin (300 mg/kg po single dose), a drug that inhibits the bacterial cell wall synthesis, similar to beta-lactam antibiotics. Although it is much less toxic than penicillin, caution is recommended because it can affect the commensal intestinal flora. The author has had no fatalities from using this drug, but several animals have had a reduced appetite and fecal output which returned to normal after administration of metoclopramide.
Chronic cystitis and urolithiasis
Treatment of chronic cystitis and recurrent urolithiasis is usually unrewarding. Pathological changes to the bladder (Figure 2 and 3) and to the kidneys are irreversible. Only in rare cases, and exclusively when the diet is drastically revised (see the discussion in ETIOLOGY AND PATHOGENESIS), the animal may remain free from symptoms for the rest of its life, without medications. The life expectancy of guinea pigs with LUTD is not necessarily shorter (unless the kidneys are affected), but there may be lifelong discomfort that has to be managed.
The primary goal of the treatment is the long-term management of pain. Pain that is associated with the urinary tract can be classified as visceral pain and more specifically, as colic pain. Therefore, the treatment should not only suppress the inflammatory response, but also the smooth muscle spasms. Multimodal pain management provides the best outcome. Below is a list of therapeutics used by the author.
Non-steroidal anti-inflammatory drugs (NSAIDs). Not every NSAID is suitable for treatment of visceral pain. Meloxicam (0.5-1 mg/kg PO or SC q12h) is a first-line remedy, but it is not particularly effective for cystitis. Metamizole (100 mg/kg PO q12h) appears to be a better option, because of its spasmolytic properties.9 NSAIDs can be used in acute situations, such as pain relief after surgery of the urinary tract, but long-term use should be avoided due to the potential for renal damage and gastric ulceration.
Acetaminophen. Acetaminophen (100 mg/kg PO q6 or q-12h) offers good analgesia for visceral pain. It can be given to relieve acute pain symptoms but is also suitable for prolonged use. Caution is required in animals with compromised liver function. A combination of acetaminophen, an opioid (tramadol 10-20 mg/kg PO q12h) and an NSAID is a good option for post-operative multimodal pain management. If necessary, metoclopramide (1 mg/kg PO or SC q3-12h) can be added to combat the secondary gastrointestinal atony.
Phenazopyridine. This drug is a specific urinary analgesic. Its mechanism of action is not yet fully elucidated. Phenazopyridine (25 mg/kg PO q12h) is especially applicable in acute cases, such as post-surgery or in urolithiasis when the calculi are passing through the urethra. Prolonged use is not recommended because of the risk of methemoglobinemia.10 As it is a dye, owners must be aware that the urine will be highly colored (yellow orange to reddish), and soiled bedding should be removed as soon as possible.
Spasmolytics. As a selective a PD4 (phosphodiesterase) inhibitor, drotaverine facilitates smooth muscle relaxation exerted by stimulation of beta-adrenergic receptors in various visceral organs. It is a widely used antispasmodic for the urogenital system, the intestines and the biliary tract.11 It is found particularly effective in relieving colic pain associated with IC and urolithiasis. A dose of 20 mg/kg PO q12h is well-tolerated. When combined with a diuretic drug (e.g., furosemide 10 mg/kg PO q12h or hydrochlorothiazide 1-2 mg/kg PO q12h) it facilitates the passage of uroliths, sludge and pseudomembranes from the entire urinary tract. It is the author’s treatment of choice for bladder stones up to 5 mm in females, and small ureteral stones in both sexes. In this way, surgical intervention can be often avoided. When drotaverine cannot be accessed, phloroglucinol may be used as a substitute. However, its efficacy is lower. Spasmolytics and diuretics can be given for 10 consecutive days and then the cavy closely observed for a relapse of clinical signs. If the uroliths are still present, surgery should be considered.
Alpha blockers. Tamsulosin is another spasmolytic drug, which exerts its action on the bladder and the prostate by blocking the alpha-adrenergic receptors. It might also facilitate the passage of urinary calculi.12 A dose of 0.02 mg/kg PO q24h has relieved the pain in three guinea pigs treated by the author. The drug has been given for 2 months without any apparent side effects. The author does not yet have enough data to compare the efficacy of this drug with other antispasmodics.
Oxybutynin. Oxybutynin blocks the effects of acetylcholine on the muscarinic receptors in the bladder. It increases the bladder compliance thus combatting urinary retention. Moreover, it is shown to prevent fibrosis of the bladder wall, which makes it a curative remedy and not a mere analgesic.13 It is particularly applicable in management of pollakiuria in IC. A dose of 2.5 mg/kg PO q12h is well-tolerated and there are no adverse effects caused by its anticholinergic properties (e.g., gastrointestinal stasis). The therapy can be prolonged for several months.
Neuromodulatory agents. Gabapentin and pregabalin are structural analogues of the gamma-aminobutyric acid (GABA), but not direct agonists of the GABA receptor. They are used to combat a variety of neuropathies.14 Gabapentin (25 mg/kg PO q12h) or pregabalin (20 mg/kg PO q24h) are effective in suppressing severe pain associated with advanced IC in the author’s experience. There is a marked sedative effect, especially with pregabalin, but on a positive note, the drugs stimulate the appetite and improve the general condition of the animal. This palliative therapy can be given lifelong.
Progestogens. Topical formulations of progesterone are commonly used in human medicine, for the management of interstitial cystitis. The author has observed that female guinea pigs with chronic cystitis are free from symptoms during gestation, and relapse after delivery. The mechanism of action of progesterone is dual: It causes smooth muscle relaxation which improves the bladder compliance15 (through a different mechanism than oxybutynin), and it reduces histamine secretion by mast cells.16 Synthetic progestogens are readily available, because they are used in farm animals. Altrenogest (Regumate, MSD Animal Health) at a dose of 0.4 mg q24h has proven very effective in managing chronic interstitial cystitis in female guinea pigs. With only a few exceptions, sows receiving altrenogest together with oxybutynin can be maintained free from pain for several months. The appetite is usually improved and the animals may gain weight.
NK1 antagonists. Since the afferent innervation of the bladder contains numerous substance-P rich nerve fibers,17 central or peripheral antagonization of the NK1 receptor may be beneficial. Maropitant (2 mg/kg PO q24h) can be used to treat acute pain. The author often uses maropitant (2 mg/kg SC) as premedication in the urinary tract surgery.
Nutraceuticals. Several nutraceuticals have been administered to guinea pigs with persistent cystitis and crystalluria. Unbiased assessment of their efficacy is difficult because it usually relies on the long-term feedback from the owner.
Potassium citrate dihydrate is used as a calcium-complexing and urine alkalizing agent in treatment of human kidney stones and is shown to reduce urinary excretion of calcium oxalate in a rat model.18 It is also anecdotally used in guinea pigs and rabbits. The author has supervised the treatment of 20 guinea pigs (100 mg/kg PO q24h) with this agent. Although owners have reported some improvement in animal’s behavior, no apparent reduction of sludge has been seen upon microscopic examination. Possibly, potassium citrate is helpful in prevention of calcium oxalate calculi, but it does not remove calcium carbonate crystals formed in the alkaline guinea pig urine (see ETIOLOGY AND PATHOGENESIS). Besides, one animal developed dental disease (resolved after cessation of citrate), presumably due to a lowered serum calcium and a hyperparathyroid response.19 Therefore, the author has abandoned using this supplement altogether.
Ammonium chloride is used to control urolithiasis in farm animals, by acidifying the urine.20 A dose of 100 mg/kg q24h PO (the same as in cattle) reduces sludge to some extent; the urinary pH remains alkaline. On the other hand, ammonium chloride is another source of nitrogen and might contribute to proteinuria (see ETIOLOGY AND PATHOGENESIS). This issue needs to be investigated further.
Anecdotally, unsweetened cranberry juice is reported to relieve cystitis symptoms in some cases.
SURGERY
Surgery of guinea pigs can be challenging. Therefore, the author considers it a salvage solution in cases when pharmacotherapy is deemed impossible or has already failed. The patients must be screened to exclude serious conditions such as circulatory issues, gastrointestinal stasis, (metabolic) acidosis etc. Surgery on debilitated animals is doomed to fail. Medical imaging (radiographs and ultrasonography) is imperative prior to surgery. The urolith(s) must be localized very accurately.
Premedications and anesthesia
The author’s protocol consists of preoperative administration of an NSAID (meloxicam 1 mg/kg SC) and tramadol (20 mg/kg SC) and an antimicrobial (enrofloxacin 10 mg/kg SC). The animal is sedated with midazolam (1 mg/kg SC). When a more invasive surgery is planned (e.g. ureterotomy), maropitant (2 mg/kg SC) is added. Anesthesia is induced with 5% isoflurane and maintained at 1.5%. The site is prepared and infiltrated with a local anesthetic (lidocaine 2%, epinephrine 1:200.000, max. 16 mg/kg lidocaine or 0.8 ml/kg of the lidocaine-epinephrine solution).
Urolith removal per vias naturales
In sows, small bladder stones can be removed by retrograde hydropropulsion with warmed sterile saline containing 0.5% oxytetracycline or gentamicin, after applying a local anesthetic to the bladder. The solution is instilled via a No 1 atraumatic Rüsch catheter into the bladder. This method can be also used to expel pseudomembranes. Larger calculi (4-6 mm) can be extracted using sterile micro-Halsted mosquito forceps, preferably under ultrasound guidance or using an adapted endoscope (the author uses the ultrasound technique). Uroliths larger than 8 mm should not be approached per vias naturales, because of the risk of urethra damage. Sludge present in the distal urethral diverticulum (Figure 4) can be removed using local anesthetics and lubricants; no incision is needed.
Urethrotomy
In male animals, urethrotomy is a salvage procedure when the calculus obstructs the urethra distally from the pelvic girdle. The obstruction should be located as accurately as possible (radiography and ultrasonography). The distal flexure obstructions (close to os penis) can be removed by externalizing the penis, injecting 0.1-0.2 ml of the local anesthetic solution (see previous section) into the ventral midline of the penis, and making a longitudinal incision in the ventral midline at the position of the stone (in this way there will be practically no blood loss). After removing the stone from the penile urethra, the surgery site is flushed. The incision is sutured (continuous pattern) with an absorbable 4/0 monofilament; the recovery is usually uneventful.
Because of the anatomy, accessing the urethra through perineal urethrostomy is associated with massive tissue damage and a poor recovery rate. Therefore, proximal (pelvic) obstructions should be removed by anterograde propulsion (pushing back to the bladder) followed by routine cystotomy.
Cystotomy
Cystotomy is the most common procedure. The linea alba (midline) laparotomy is performed. The incision should be made only after confirming the exact location of the stone; it should not be longer than 2 cm and should never extend cranially to the navel. The bladder is externalized by gentle traction and fixed by applying the stay suture (Figure 7a). Care should be taken not to externalize the intestines, because this will increase the risk of post-operative complications. Urine may be aspirated (23G needle) in order to avoid contamination of the abdominal cavity. A longitudinal incision in the bladder should be made in the middle 2/3 of its ventral midline. Incising the bladder neck should be avoided, because it will damage the internal urethral sphincter and render the animal incontinent. After incision, the bladder is lavaged with 0.5% oxytetracycline in sterile saline. Lavaging causes the calculi to float, so that they can be easily localized and seized with micro-Halsted mosquito forceps. The bladder wall is closed with a full thickness continuous suture pattern, followed by an inverting (Cushing) suture (Figure 7b), using a resorbable 6/0 monofilament. This step is of crucial importance. Failing to close the bladder properly results in multiple adhesions and painful micturition for the rest of the animal’s life. The abdominal wall is closed in three layers: the peritoneum and muscles, the subcutis and the skin. The simple continuous pattern with a good apposition of the wound edges provides the best outcome.
Ureterotomy
Only large calculi (> 4 mm) should be treated surgically. The procedure is like the one described above, but a slightly larger incision (3 cm) in the body midline is necessary to access the posterior (trigonum) region. The calculi might be difficult to localize because ureters are embedded in fat tissue. If the stones are close to the ureter opening, one may attempt to milk them into the bladder and perform standard cystotomy. If this is unsuccessful, a longitudinal incision in the ureter should be made. The simple continuous pattern with a resorbable 8/0 or a non-resorbable 9/0 or 10/0 suture is applied to close the incision (a surgical microscope is required). A flap consisting of periureteral fat should be secured to cover the incision site, to assure a good support to the ureter and to prevent any leakage. The procedure is generally very well tolerated (Figure 8) and no stenoses have resulted in the author’s experience. Another method of removing ureteral obstructions is by nephrocentesis followed by retrograde hydropropulsion.21
Post-operative care
Most guinea pigs respond well to the urinary tract surgery: they are awake within less n under 5 minutes, and they eat and defecate within less than 30 minutes. These patients are discharged from the hospital on the same day. Post-operatively they are given antibiotics (enrofloxacin and nitrofurantoin) and pain medications (e.g., phenazopyridine and NSAIDs). A few animals may require additional analgesia (see PHARMACOTHERAPY); these animals should be preferably hospitalized. To avoid recurrent urolithiasis, the diet is drastically revised and sometimes hydrochlorothiazide (see PHARMACOTHERAPY) is given lifelong.
Figure 7. Suturing the bladder. A. a stay suture is placed; B. after closure of mucosa/muscularis (running), serosa is closed (Cushing); C. no mucosa/muscularis is exposed.
Figure 8. Six large ureter calculi, successfully removed surgically. The guinea pig remains healthy to date.
ETIOLOGY AND PATHOGENESIS
The ubiquity of LUTD in guinea pigs is baffling and so are the typical anamneses. The patients are initially presented in a very good body condition, are often overweight and described by their owners as “spoiled” or “picky eaters”. In the colony of one client, cystitis persisted in 24 in out of 25 animals. In another case, a boar required 4 surgeries for urolithiasis in less than 6 months (euthanized when he developed the fifth stone). The onset of the disease can be very early – even before the age of six months. The owners appear very motivated, and they report feeding their pets only the “tastiest treats” such as ad libitum luscious greens (all year round) and pelleted chow. Ascorbic acid is copiously supplemented in the form of 50 or 80 mg candies; some animals receive multiple servings daily. Many owners cope with LUTD for many years, and often admit feeding a “low-calcium diet” consisting of timothy hay, low-calcium bottled mineral water (but the animals usually ignore it) and vegetables low in calcium to prevent urolithiasis. For an unknown reason, some owners supplement vitamin D at doses considered high even for humans.
On the other hand, the author has housed and observed more than 150 guinea male and female guinea pigs of various ages. The author feeds a rather restricted diet consisting of ad libitum hay, carrots and cabbage. In season fruit, fresh grass, eggplants, tomatoes and cucumbers are included, but greenhouse vegetables are avoided. The vegetables are selected for their low organic and inorganic nitrogen content. Not more than 20 g pelleted chow per animal per day is consumed. Ascorbic acid is supplemented moderately as top dressing on the pellets, maximally 3 times in a week. Water is offered in bowls rather than drinking bottles, and the average daily water consumption is 20-30 ml per animal, despite ad libitum fresh vegetables. The incidence of LUTD in rhe author’s cases has been only 3% (4 cases) in two years: two sows with uncomplicated bacterial cystitis (recovered), one sow with IC (died of chronic renal failure at 6.5 yr) and one boar with recurrent urolithiasis (died at 7 yr). With these observations, the author suspects that some owners may unintentionally expose their animals to certain nutritional risk factors.
Renal calcium leak
Cystitis and urolithiasis (and also chronic kidney failure) are different manifestations of the same pathology, and it is plausible to search for their common cause. Urinary sludge appears to be the irritating agent that causes inflammation (cystitis) and formation of uroliths. Bacterial infection seems to be opportunistic and secondary to tissue damage. Both sludge and uroliths consist solely of calcium salts22, which points at the likely culprit: spontaneous or induced imbalances in calcium homeostasis.
Guinea pigs absorb dietary calcium via two mechanisms: the active transcellular dependent on vitamin D (more precisely, calcitriol) and the passive paracellular driven by the concentration gradient.23 This implies that a guinea pig can absorb large amounts of calcium depending on the supply. The excess is excreted in urine and may contribute to the pathology. The dietary calcium input can be high, especially when the animal is fed alfalfa-based pelleted chow. However, because of the continuous feeding pattern of guinea pigs, even in extreme situations (e.g., 50 g pelleted feed with 0.6% calcium per day) the eventual calcium concentration in ingesta would be below the typical serum values (10-12 mg/dl1). Thus, if no calcium boli are administered, gradient-driven absorption is not very likely to occur. Besides, most guinea pigs with LUTD are already on a calcium-restricting diet.
There are a few peculiarities concerning the guinea pig urine. The strictly herbivorous diet results in a strongly alkaline urine; the normal pH range is 8-9 and it can be lower than 7 only in pathological situations such as (metabolic) acidosis and shock. This alkaline environment facilitates precipitation of calcium carbonate (but not oxalate). In fact, guinea pig urine is always supersaturated with respect to calcium (the solubility at pH 9 is below 0.5 mmol/l, 2 mg/dl); crystallization of CaCO3 is to some extent prevented by urinary calcification inhibitors.24
Guinea pigs produce about 100 ml/kg urine per day.1 The urine has a very low specific gravity: typical values recorded using refractometry are 1.005-1.015 g/cm3. It is usually turbid due to the presence of mucus and there is significant “physiological” proteinuria. More than 0.5 g/dl (+++) protein can be detected using test strips, also in apparently healthy animals, and in absence of cystitis. Recently the author has recorded several urinary parameters using a SkylaVB1 Chemistry Analyzer in 20 well-fed and asymptomatic animals.
The results, together with reference data provided by Cernochova et al.25 are summarized in Table I. Urinary albumin and sodium concentrations are close to their serum levels and urinary calcium is much higher than in serum. Creatinine is very low, indicating that the kidneys fail to concentrate the urine. In humans, such results would be indicative of renal failure. Examined guinea pigs may still have functional kidneys, but such drastic loss of protein and electrolytes must have pathological consequences. For comparison, the author’s own guinea pigs display only moderate proteinuria (<0.3 g/l, +) and electrolytes are well below serum levels.
Thus, a naturally arising question is: “what causes such a calcium loss in urine?” The way kidneys process calcium provides the answer: proteinuria and natriuria are the most likely causes.1 Concisely, calcium is excreted into the ultrafiltrate and reabsorbed mainly in the proximal tubules. The reabsorption is passive and strongly dependent on the osmotic pressure exerted by other solutes in the ultrafiltrate. When the osmotic pressure is high due to the presence of proteins and sodium, calcium will not be reabsorbed. Thus, all factors that increase protein excretion and inhibit sodium reabsorption, lead to increased urinary calcium excretion. In extreme situations (e.g. renal or nutritional hyperparathyroidism), renal calcium loss can even lead to a metabolic bone disease and frequent dental problems.1
These facts also demonstrate that low-calcium diets are counterproductive. Urinary calcium concentration will be always high because it is linked to urinary proteins and sodium.1 If urinary calcium losses cannot be compensated by an adequate dietary intake, calcium (and phosphate) will be released from the bone. Subsequently, calcium phosphate will be excreted in urine, in agreement with the experimental observations. Vitamin D intoxication only worsens the pathology.
Persistent or recurrent bacterial infection may be another factor aggravating the disease. Prolonged antigen stimulation can lead to hypersensitivity; in fact, the histopathological presentation of guinea pig cystitis (Figure 2) resembles the corresponding human pathology, which is thought to be immune-mediated.26 Excessive supplementation of ascorbic acid is known to exacerbate the symptoms.27
The ubiquitous nitrogen species
The question should be now rephrased to: “what causes such a protein and sodium loss?” Its ubiquity, the fact that it can occur in very young animals and the lack of evidence of familial predisposition, does not support a hypothesis of a “mysterious” kidney disease. Conversely, there are numerous indications of apparent nutritional causes.
The diet of all guinea pigs with LUTD in the author’s practice, is very rich in inorganic and organic nitrogen species. Besides prominent proteinuria, all these animals have relatively high concentrations of nitrate in the urine (more than 400 mg/l, measured by an ion membrane based SOEKS nitrate detector) and test positively for nitrite in saliva (Combur nitrite test strips). The author’s own animals test negatively for salivary nitrite, and the urinary nitrate still substantial, but below 200 mg/l.
Standard pelleted chow contains 16-18% protein; animals fed ad libitum can easily consume 8-9 g protein daily. But also in absence of pellets, nitrogen species are copiously supplied with leafy vegetables. Nitrogen species are precursors of proteins, which are synthetized by the commensal caecum flora and ingested by coprophagy.
Commercial table vegetables are cultivated using large amounts of nitrate-based artificial fertilizers. Nitrate1 content in vegetables such as endives (a guinea pig favorite), spinach, parsley and lettuce can be as high as 5.5 g/kg in fresh mass.28 The author has found an average of 3.0-3.5 g/kg in endives using the SOEKS nitrate meter. A guinea pig can easily consume 200 g of endives (0.6 g nitrate) daily. Pelleted chow is also a significant source (alfalfa-based pellets: 2-3 g/kg, author’s measurement). Moderate intake of nitrates is associated with health benefits,29,30 but advised safe levels lie the mg/kg body weight range.31
Dietary nitrogen species serve as substrates for protein synthesis. Nitrates are readily reduced to nitrites by the commensal bacterial flora and further to nitric oxide by cellular enzymes.24 The latter step is augmented by ascorbic acid.32 Nitric oxide has a natriuretic effect by inhibiting tubular resorption of sodium, specifically by blocking the luminal sodium-proton antiporter and the basolateral Na+/K+-ATPase.30 Administration of sub-milligram amounts of nitrite results not only in an increase of sodium excretion (25%), but also in a decrease of free water clearance by 60%.33 This implies that affected individuals will have a lower need for water. In this sense, encouraging guinea pigs with LUTD to drink more water will fail, because the animals will refuse it as long as they receive the nitrogen-rich feed. Besides, guinea pig urine already has a low specific gravity and its volume is determined by the osmotic pressure of proteins and sodium. There is no physiological mechanism that can dilute it any further. The only feasible method to control urinary sludge excretion seems to be the restriction of dietary nitrogen species. Needless to mention, no “low-calcium” diets should be attempted: the dietary calcium to phosphate ratio should be close to 3:2 in order to avoid secondary hyperparathyroidism.1
Conclusion
In light of the above, LUTD has all the features of a disease of nutritional excess. It appears that most pet guinea pigs are “sub-clinically” intoxicated with nitrogen species originating from the guinea pig’s favorite feed. Treatment of the clinical disease is challenging and not always successful, but prevention is possible. Even though nitrogen may be a global environmental problem due to intensive farming, there are still enough plants low in nitrogen species that can be safely fed to guinea pigs. Awareness should arise among the owners, for the sake of their pets’ health.
Table 1. Average concentrations and concentration ranges of proteins, cations, nitrate and creatinine in urine of apparently healthy guinea pigs. Blood values are provided by a local analytical laboratory.
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