Crystalline-matrix plugs are a common cause of urethral obstruction in male cats.[1-3] Urethral plugs in cats are soft and paste-like with a classic cylindrical shape. They are composed of matrix (mucoprotein, composed of mucus and inflammatory debris) and varying amounts of mineral.[1, 2] In greater than 80% of urethral plugs from cats, the mineral content is struvite (aka magnesium ammonium phosphate). The etiology of this disease is not well understood. Over the past several years, we have observed a similar phenomenon of urethral plugs in male dogs. To our knowledge, this disease has not been previously described in dogs. The objective of this study was to report features of urethral plugs in dogs. This was achieved through 3 methods. First, we reported the composition of urethral plugs from dogs submitted to the Minnesota Urolith Center (MUC) during a 6-year period and provided signalment information on dogs diagnosed with this condition. Second, we performed statistical analyses to identify breeds that are overrepresented for urethral plugs; struvite breed data are provided as well to serve for comparison. Third, we described clinical data for a subset of cases that were evaluated at the Veterinary Medical Center, University of Minnesota (VMC UMN).
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- Materials and Methods
Review of the medical records from 9 affected dogs with struvite plugs that had been evaluated at the VMC UMN revealed several features that contrast starkly with the typical presentation of struvite urolithiasis in dogs. First, in urethral plugs, struvite was interspersed in a deformable matrix of cellular and proteinaceous material rather than as discrete uroliths. Of 42 plug samples from dogs analyzed by the MUC over a 6-year period, 83% had a struvite mineral component. One theoretical contributing factor in the development of urethral plugs in cats is that the bladder mucosal cells secrete excessive mucus in response to irritation or inflammation. The plug-forming dogs in this study could have had an underlying bladder disorder that was responsible for the production of the cellular and proteinaceous component of the plugs, but bladder mucosal biopsies were not available for evaluation. Three of the UMN VMC plug dogs had accompanying small uroliths. The presence of uroliths and secondary inflammation might have contributed to the formation of urethral plugs in these dogs.
A 2nd unique feature was that at least 4/9 VMC UMN dogs formed sterile struvite plugs. These 4 dogs had a negative urine culture and no history of antimicrobial therapy within the previous month. Two of these dogs also had concurrent struvite cystoliths. Bacterial culture results from 3 additional dogs were also negative. However, these dogs had received antimicrobials within the previous month. Although 2 dogs were only given a single dose, recent antibacterial therapy could have interfered with our ability to document concomitant bacterial infection. Bacteriuria was not observed for the 2 dogs in which urine cultures were not performed, but these data are insufficient to rule out the presence of a bacterial infection. Urine culture data were not available for the 33 other MUC plug submissions, and infection might have contributed to plug formation in these dogs.
Alkaluria favors dissociation of monobasic phosphate (H2PO4−) and dibasic phosphate (HPO42−) to trivalent phosphate ions (PO43−). Increasing the concentrations of the trivalent form of phosphate is a risk factor for struvite precipitation. In the absence of a urinary tract infection with urease producing microbes, other risk factors promoting alkaline urine must be considered. Diseases resulting in chronic respiratory alkalosis or chronic metabolic alkalosis would contribute to persistent alkaluria. Three of the breeds (Pug, Boxer, and Shih Tzu) with MUC plug submissions are brachycephalic and have been reported to develop brachycephalic obstructive airway syndrome. Dogs affected with this syndrome typically display excessive panting and hyperventilation. Hyperventilation can result in decreased partial pressure of carbon dioxide and subsequent respiratory alkalosis. To mitigate increasing blood pH, bicarbonate is excreted in the urine. However, in 1 study, arterial partial pressure of carbon dioxide was significantly higher in brachycephalic dogs (n = 11) when compared to nonbrachycephalic controls (n = 11); urine pH was not measured. Venous blood gases from 3 VMC UMN Pugs in our study did not support respiratory alkalosis as a contributing factor for struvite formation, but we cannot definitively rule out an underlying acid base disorder as a contributing factor to struvite plug formation.
Sterile struvite formation has been reported in 2 dogs suspected to have renal tubular acidosis.[7, 8] Distal renal tubular acidosis is characterized by a decrease in net H+ secretion in the collecting tubules. This condition should be suspected in dogs with hyperchloremic metabolic acidosis with a urine pH of >6.0. In the 3 VMC UMN dogs in this study with blood gas analysis and electrolytes, laboratory findings were not supportive of renal tubular acidosis. Three additional dogs had normal serum concentrations of bicarbonate or TCO2 at presentation, ruling out primary metabolic acidosis. None of the dogs had hyperchloremia.
In vitro studies with sterile human urine revealed that the addition of magnesium, ammonium, or phosphate with a pH range of 5.0–9.6 resulted in formation of struvite crystals. They determined that if the concentrations of these solutes were high enough, struvite crystallization would occur in acidic urine. In our study, struvite precursors were not measured in the urine from dogs with plugs. Therefore, we were unable to determine if the concentrations of magnesium, ammonium, or phosphate were sufficiently elevated to promote struvite precipitation irrespective of urine pH. We did not observe conditions associated with phosphaturia (hyperparathyroidism, hypophosphatemic rickets, or Fanconi syndrome) or magnesuria (excessive dietary magnesium, renal tubular disorders, or medications containing magnesium) in the VMC UMN plug cases. Liver insufficiency is a potential cause of hyperammonemia and subsequent hyperammonuria. Ammonia will hydrolyze with available carbon dioxide and form ammonium and bicarbonate, resulting in alkaline urine and dissociation of phosphate ions. Ammonium binding with magnesium and phosphate ions would result in precipitation of magnesium ammonium phosphate. Although several of the breeds (Pug, Yorkshire Terrier, Miniature Schnauzer, Shih Tzu, Great Dane) in the MUC plug submission group are reported to be at risk for hepatic portovascular anomalies,[10, 11] struvite uroliths are not typically associated with hepatic insufficiency. Three of the VMC UMN dogs in this study were evaluated for hepatic dysfunction with bile acids and fasting ammonia levels. Though only a subset of dogs was screened, liver disease was considered an unlikely cause of struvite plugs in dogs.
All of the plugs were from male dogs, whereas struvite urolithiasis is more common in females. The female predisposition for struvite is generally attributed to an increased risk for urinary tract infections. If urethral plugs in dogs are a microbiologically sterile disease, female dogs would no longer be expected to be at increased risk. In fact, because plugs are an obstructive disease, the male predisposition is logical. Male dogs have longer, narrower urethras, which place them at increased risk for urethral obstruction.
One of the most impressive features of the urethral plugs was their breed-specific nature. The majority of the MUC plugs were from Pugs. Odds ratios were calculated for the MUC population using a VMC UMN plug-free control group. The only breed found to be overrepresented for plug formation was the Pug with a significant OR of 179. A limitation of this calculation is that the MUC case population did not have the same geographical distribution as the VMC UMN control population, and there might be differences in breed popularity between these 2 sampled populations. A control population better matched to the MUC case submissions would provide more accurate estimates of breeds at risk for urethral plugs. All of the VMC UMN plug cases were Pugs, and this prohibited us from calculating breed-specific ORs for this subset of dogs.
Because most plugs from dogs had a struvite component, we also calculated breed ORs for a VMC UMN struvite (combined plug and urolith) case population. We found that Pugs were significantly overrepresented for precipitation of struvite in general (OR = 14.3). One other study evaluating urolith submissions from 1981 through 2001 also found that male Pugs had an increased risk (OR: 2.09; CI: 1.03–4.25) for struvite urolithiasis.
Breed predispositions are often an indication of a genetic or familial disorder. Sterile struvite urolithiasis has been reported in 3 related Cocker Spaniels. These dogs had normal urine acidification after ammonium chloride administration, ruling out renal tubular acidosis. Because of the retrospective nature in this case series, pedigrees from Pugs were not available to assess for familial tendencies beyond recognition of the breed. It is of interest that Pugs are also commonly affected by congenital vertebral abnormalities. Abnormalities of the lumbosacral vertebra could potentially affect innervation to the bladder, resulting in urine retention, urinary incontinence, and increased risk for urinary tract infections, and subsequently influence struvite crystal formation and retention. On abdominal radiographs, 2 dogs were noted to have 6 lumbar vertebrae and 1 dog had a transitional L7 vertebra. The only clinical sign or physical exam abnormality to suggest spinal cord disease in these 3 dogs was infrequent voiding (once daily) in a single dog, suggesting urine retention. Three other dogs had neurologic deficits on physical examination. The 7 dogs that had a urine culture were negative for aerobic bacterial growth: however, 3 had recently received antibiotics. Advanced imaging, such as spinal CT or myelogram, was not performed in these 9 dogs. Therefore, compressive lesions of the spinal cord cannot be ruled out.