Ferrets (Mustela putorius furo) are becoming increasingly popular as household pets.1–3 As the population of pet ferrets increases, uroliths are being recognized with increased frequency. The number of ferret cystine urolith submissions to the Minnesota Urolith Center progressively increased from 4 in the period 1992 to 1997, to 19 in the period 1998 to 2003, to 47 in the period 2004 to 2009.
As the frequency of detection of ferrets’ uroliths increases, knowledge of their mineral types and associated risk factors for formation is needed to develop effective diagnostic, management, and prevention strategies. The purpose of the study reported here was to determine the prevalence of naturally occurring cystine uroliths submitted to the Minnesota Urolith Center from ferrets and determine whether age, breed, sex, reproductive status, anatomic location within the urinary tract, and season of detection were risk factors associated with cystine urolith formation.
Materials and Methods
Cases—Medical records of ferret urolith submissions to the Minnesota Urolith Center between January 1, 1992, and December 31, 2009, were retrieved for review. During that period, 435 ferret uroliths, of which 70 were cystine uroliths, were received from veterinarians in the United States. To minimize the potential for confounding the results by the inclusion of ferrets with a history of recurrent urolithiasis, uroliths retrieved from ferrets were counted only once during the course of the cross-sectional study. Because preliminary evaluation indicated that cystine uroliths were not detected in ferrets < 6 months of age, ferrets of this age were excluded from the study.
Controls—Controls consisted of 6,426 ferrets without urinary tract disorders admitted to veterinary teaching hospitals in the United States between January 1, 1992, and December 31, 2009. They were identified by searching the records of the Veterinary Medical Database, which is responsible for compiling patients’ encounter data from nearly all North American veterinary medical colleges. Because preliminary evaluation indicated that cystine uroliths were not detected in ferrets < 6 months of age, control ferrets of this age were excluded from the study.
Urolith analysis—The mineral composition of the uroliths was determined by optical crystallography and, when necessary, by infrared spectroscopy.4 Uroliths containing at least 70% of a single mineral with lesser quantities of other minerals were classified as that mineral type. Uroliths containing nuclei and shells of at least 70% of 2 or more mineral types were classified as compound. Uroliths containing < 70% of a single mineral component and without a nucleus or shell were classified as mixed.
History—Information about age, sex, reproductive status, location of the uroliths within the urinary tract, season of detection, and geographic location obtained for each ferret was obtained from the submission forms (urolith analysis request form). Ferrets are not classified according to breed but are commonly differentiated by their coat colors,5 although all are considered domestic ferrets; therefore, evaluation of possible associations with breed were not possible.
Anatomic location of cystine uroliths—Anatomic location of the uroliths was divided into 2 categories. Nephroliths and ureteroliths were classified as uroliths of the upper portion of the urinary tract. Uroliths that were retrieved from the urinary bladder or urethra and uroliths that were voided were classified as uroliths of the lower portion of the urinary tract. Uroliths retrieved from upper and lower portions of the urinary tract were classified as both. When the location of the uroliths was not provided, the location was classified as unknown.
Statistical analysis—Standard statistical software6,7,a was used to determine descriptive statistics (mean, median, and SDs) of age (ie, 6 months to < 1 year, 1 to < 2 years, 2 to < 3 years, 4 to > 7 years, ≥ 4 years, and < 4 vs ≥ 4 years), sex, reproductive status, anatomic location of the uroliths, and the seasons of urolith submissions. Crude and adjusted ORs calculated at 95% CIs were used to assess whether, age, sex (male or female), reproductive status (neutered or sexually intact), season (fall, spring, winter, or summer), and anatomic location (lower portion of the urinary tract or upper portion of the urinary tract) were associated with the occurrence of cystine uroliths. Prevalence of each urolith mineral type was expressed as the relative frequency compared with all the uroliths submitted for analysis to the Minnesota Urolith Center. Relative frequencies also were used to describe the age, sex, reproductive status, and anatomic location. Reference groups for statistical analysis were arbitrarily chosen as follows: ferrets ≥ 6 months to < 1 year old, ferrets ≥ 4 years old, female, sexually intact, urolith in upper portion of the urinary tract, and spring season. The 18-year study was arbitrarily grouped into 4 intervals (1992 to 1996, 1997 to 2001, 2002 to 2006, and 2007 to 2009) to determine whether risk or protective factors changed over time. The Breslow-Day statistic was computed to determine whether ORs were homogeneous over the 4 time intervals.8 The Mantel-Haenszel summary of OR was computed when the results of the Breslow-Day test were not significant.
Because of the absence of continuous variables, OR values were computed via hierarchic well-formulated modeling to find the best risk model for age group, sex, reproductive status, and season. After adjusting for confounding factors and interactions, risk factors associated with urolith formation were determined from the best model.
Odds ratio estimates were considered to be significantly different from 1 if the 95% CI did not encompass 1.0.9 On the basis of recommendations by Lilienfeld and Stolley,10 we classified significant ORs between 1.1 and 1.9 and ORs between 0.5 and 0.9 as weak associations. Likewise, we interpreted significant ORs > 2 (ie, risk) and ORs < 0.5 (ie, protective) as clinically (biologically) important. All analyses were performed with standard software.6,7,9,a Results were considered significant at values of P < 0.05.
Results
Urolith analysis—Of the 435 ferret uroliths, 70 (16%) were cystine uroliths (Table 1). All ferrets with cystine uroliths resided in the United States. Among all uroliths, sterile struvite (magnesium ammonium phosphate 6H2O) uroliths were the most common by mineral type (277 [64%]). Calcium oxalate was identified as the primary component in 11% of the uroliths.
Mineral composition of 435 ferret (Mustela putorius furo) uroliths evaluated from 1992 to 2009.
| Mineral composition* | No. (%) of uroliths |
|---|---|
| Magnesium ammonium phosphate 6H2O | 277 (64) |
| Magnesium hydrogen phosphate trihydrate | 1 (< 1) |
| Cystine | 70 (16) |
| Calcium oxalate monohydrate and dihydrate | 50 (11) |
| Calcium phosphate | 3 (1) |
| Calcium carbonate | 1 (< 1) |
| Ammonium urate | 8 (1.8) |
| Miscellaneous material | 6 (1.4) |
| Mixed† | 8 (< 1.8) |
| Compound‡ | 6 (< 1.4) |
| Silica | 1 (< 1) |
| Other | 4 (< 1) |
| Total | 435 (100) |
Analyzed by polarizing light microscopy or infrared spectroscopy.
Uroliths contained < 70% of a single mineral component; no nucleus or shell detected.
Uroliths contained an identifiable nucleus and 1 or more surrounding layers of a different mineral type.
Age—The minimum age of ferrets at the time cystine uroliths were retrieved was 6 months (the arbitrary lower limit) and the maximum was 9 years. Mean ± SD age of ferrets with cystine uroliths was 4.1 ± 1.5 years, and the median age was 4 years. Cystine uroliths were found most commonly in the 2 to < 4 years age group (51%) followed by the 4 to < 7 years age group (21%). Taking ≥ 6 months to < 1 year as the baseline control age group for comparison, 1 to < 2-year-old ferrets were 3.9 times as likely to develop cystine uroliths as were ferrets in the control group (Table 2). Ferrets 2 to < 3 years old were 4 times as likely to develop cystine uroliths as were ferrets ≥ 6 months to < 1 year old. Likewise, 4- to < 7-year-old ferrets were 3 times as likely to develop cystine uroliths as were ferrets in the control group.
Crude and adjusted ORs and logistic regression analysis of variables associated with cystine uroliths in 70 ferrets.
| Variable | Description | Crude OR | 95% CI | Adjusted OR | 95% CI | P value |
|---|---|---|---|---|---|---|
| Age | (1 y–< 2 y) vs (≥ 6 mo–< 1 y) | 4.1 | 3.1–12.6 | 3.9 | 2.7–14.4 | < 0.001 |
| (2 y –< 3 y) vs (≥ 6 mo–1 y) | 4.8 | 4.6–11.2 | 4.1 | 3.2–11.1 | < 0.001 | |
| (4 y–< 7 y) vs (≥ 6 mo–1 y) | 3.9 | 2.8– 4.6 | 3.2 | 2.7–4.8 | < 0.001 | |
| ≥ 4 y vs (≥ 6 mo–1 y) | 1.2 | 1.1–2.3 | 1.1 | 0.02–2.9 | 0.80 | |
| < 4 y vs ≥ 4 y | 5.2 | 4.6–15.3 | 4.7 | 4.5–18.9 | < 0.001 | |
| Sex | Male vs female | 2.7 | 2.3– 12.6 | 2.5 | 2.3–15.2 | < 0.001 |
| Reproductive status | Neutered vs sexually intact | 3.6 | 3.2–8.6 | 3.1 | 2.4–9.2 | < 0.001 |
| Anatomic location | Lower vs upper portion of the urinary tract | 5.3 | 4.8–12.5 | 5.4 | 4.6–16.4 | < 0.001 |
| Season | Fall vs spring | 1.1 | 0.9–3.3 | 0.9 | 0.2–2.8 | 0.78 |
| Summer vs spring | 1.3 | 1.2–4.6 | 0.8 | 0.2–4.6 | 0.73 | |
| Winter vs spring | 1.0 | 0.3–2.3 | 0.9 | 0.2–11.3 | 0.74 |
For the Breslow-Day test, it was necessary to allocate ferrets into 2 age groups: those < 4 years old and those that were ≥ 4 years old. Ferrets ≥ 4 years old were 4.7 times as likely to develop cystine uroliths as were ferrets < 4 years old. Age was therefore a significant factor in the occurrence of cystine uroliths in ferrets.
Sex—Cystine uroliths in ferrets occurred more frequently in males (n = 54 [77%]) than in females (16 [23%]). Of the 70 ferrets with cystine uroliths for which sex was recorded, males were 2.5 times as likely to develop cystine uroliths as were females (Table 2).
Reproductive status—Sixty-five (93%) of the ferrets with cystine uroliths were neutered, whereas 5 (7%) were sexually intact. Of the 70 ferrets with cystine uroliths for which the reproductive status was recorded at the time of collection, neutered ferrets were 3.1 times as likely to develop cystine uroliths as were sexually intact ferrets (Table 2).
Anatomic location—Of the 70 cystine uroliths, 67 were retrieved from the lower portion of the urinary tract, 56 (84%) came from the urethra, and 11 (16%) came from the bladder. Three (4%) of the 70 uroliths were voided; therefore, their original anatomic locations were not known. The cystine uroliths were 5.4 times as likely to be retrieved from the lower portion of the urinary tract (Table 2).
Seasonal distribution—Of the 69 cystine uroliths for which the season of collection was recorded at the time they were retrieved, 17 (24%) were recorded in the fall, 12 (17%) in the spring, 22 (31%) in the summer, and 18 (26%) in the winter. Season of collection was not recorded for 1 urolith. With spring used as a reference season, probability values observed for fall (P = 0.78), winter (P = 0.73), and summer (P = 0.74) were not significant (Table 2).
Geographic distribution and submission rate—Of 56 ferrets with cystine urolithiasis for which the geographic locations in the United States were recorded, 10 (18%) were from the Northeast, 5 (9%) were from the West, 1 (2%) was from Southwest, 27 (48%) were from Southeast, and 13 (23%) were from Midwest. Fourteen cases were excluded on the basis of incomplete recording of location. The number of ferret cystine urolith submissions progressively increased from 4 in the period 1992 to 1997, to 19 in the period 1998 to 2003, to 47 in the period 2004 to 2009.
Between January 2010 and September 2012, uroliths from an additional 69 ferrets were submitted to the Minnesota Urolith Center for analysis. Of these 69 uroliths, 44 (64%) were cystine uroliths, 12 (17%) were struvite uroliths, and 6 (9%) were calcium oxalate uroliths, and 3 (4%) were ammonium nitrate uroliths. In addition, there was 1 urolith of mixed composition, 1 compound urolith, 1 urolith composed of miscellaneous material, and 1 urolith composed of inspissated blood.
Of 41 ferrets with cystine uroliths and with reproductive status recorded, 36 of 41 (88%) were neutered males and 5 of 41 (12%) were neutered females. For 44 of the ferrets for which age was available, mean ± SD age was 2.99 ± 1.5 years (range, 9.5 months to 6 years), with 8 (18%) < 2 years old, 25 (57%) 2 to < 4 years, and 11 (25%) ≥ 4 years old.
Cystine urolith composition—Quantitative analysis of the 70 cystine uroliths revealed that all were composed of 100% cystine. The uroliths were ovoid and smooth, light yellow to tan, and ranged from 0.5 mm to several centimeters in diameter (Figure 1). The number of uroliths in each ferret varied from 1 to > 100.
Photograph of typical cystine uroliths from the urinary bladder of a neutered, 6-year-old male ferret (Mustela putorius furo). Scale indicates centimeters.
Citation: Journal of the American Veterinary Medical Association 242, 8; 10.2460/javma.242.8.1099
Photograph of typical cystine uroliths from the urinary bladder of a neutered, 6-year-old male ferret (Mustela putorius furo). Scale indicates centimeters.
Citation: Journal of the American Veterinary Medical Association 242, 8; 10.2460/javma.242.8.1099
Photograph of typical cystine uroliths from the urinary bladder of a neutered, 6-year-old male ferret (Mustela putorius furo). Scale indicates centimeters.
Citation: Journal of the American Veterinary Medical Association 242, 8; 10.2460/javma.242.8.1099
Discussion
Cystine (also termed dicysteine) is a nonessential sulfur-containing amino acid that is normally present in low concentration in plasma. In healthy humans and dogs, cystine is freely filtered by glomeruli.11 Almost all the filtered cystine is then actively reabsorbed by the proximal tubules. Cystinuria in humans and dogs is typically characterized by impaired renal tubular reabsorption of cystine and occasionally other amino acids.13,14 Cystine is the least soluble of the 4 dibasic amino acids (cystine, ornithine, lysine, and arginine) commonly found in urine of cystinuric patients and is an important risk factor for urolithiasis. The solubility of cystine is pH dependent; it is less soluble in acidic than in alkaline urine. Concentrated urine and acidic urine pH increase the insolubility of cystine, whereas alkaline urine increases the solubility of cystine.12 Because studies in humans13 and dogs12 suggest a familial pattern of inheritance of this disease caused by genetic defects, it is likely that ferret cystinuria is also associated with genetic defects. However, further studies are needed to confirm this possibility.
In the present study, the mean age of ferrets at the time of detection of cystine uroliths was approximately 4 years. This was surprising, as one might expect an earlier onset of clinical manifestations of a probable genetic disorder, with the life span of ferrets being reported as 5 to 11 years.14
Cystine uroliths were submitted from male ferrets more often (77%) than from females (23%). Unlike in cats, in which cystine uroliths occur in males and females with equal frequency, male ferrets were approximately 2.5 times as likely to develop cystine uroliths as were female ferrets (Table 2). This difference is likely related to the unique J-shaped anatomy of the distal portion of the urethra of male ferrets, which is also smaller in diameter than the proximal portion of the urethra.14,15 This likely predisposes male ferrets to partial or total obstruction of the urethral lumen with uroliths.
It was observed that a higher proportion of neutered male and female ferrets (85%) had cystine uroliths, compared with sexually intact ferrets (15%). Neutered ferrets were approximately 3.1 times as likely to develop cystine uroliths as were sexually intact ferrets (Table 2). However, we do not think that there was an association between reproductive status and development of cystine uroliths because the control population had a similar sex distribution. Also, results of the study did not suggest that cystine uroliths may be influenced by season of submission because no significant differences were observed among different seasons. The number of ferret cystine urolith submissions progressively increased from 4 in the period 1992 to 1997, to 19 in the period 1998 to 2003, to 47 in the period 2004 to 2009, but the study was not designed to determine a cause for this increase in submission rate.
Cystine was the second most prevalent type of urolith in ferrets of this case series. The genetics, biological behavior, and treatment of cystine urolithiasis have been extensively reported in dogs and humans.12,13 Other investigators have reported that cystine uroliths rarely occur in ferrets.16–18 However, cystine uroliths were observed in 70 of 435 (16%) ferret uroliths submitted during the 18-year period of the present study. In contrast, cystine uroliths were found in 102 of 114,935 (0.09%) cat uroliths submitted to the Minnesota Urolith Center and 4,310 of 429,471 (1%) dog uroliths submitted to the Minnesota Urolith Center between 1992 and 2009.19
Apparently, the biological behavior of cystine urolithiasis in ferrets has not been studied, as we could only find empirical accounts of it in the literature. The biological behavior of cystine uroliths in 3 cats has been reported.19 The uroliths were detected when the cats were < 1 year of age. The cats died of complications associated with chronic progressive renal failure when they were 5 to 7 years of age.
Although a familial basis for cystine urolithiasis has been well documented in dogs and humans, a genetic predisposition has not yet been proven in ferrets.12,13 The observation that cystine uroliths are associated with a familial cause in other species and the relatively large percentage of cystine uroliths observed in ferrets, compared with the percentage in other species, suggests that the parent stock of the ferrets in the present study may have been inbred. The observations regarding the uroliths submitted between January 2010 and September 2012 provide further support to the suggestion that there is a familial predisposition for cystine urolithiasis in domestic ferrets and that domestic ferrets in the United States may be highly inbred. Additional studies are needed to evaluate these hypotheses.
ABBREVIATION
| CI | Confidence interval |
R, version 2, R Foundation for Statistical Computing, Vienna, Austria. Available at: www.r-project.org/. Accessed Dec 23, 2011.
References
1. Gehrke BC. Results of the AVMA survey of US pet-owning households on companion animal ownership. J Am Vet Med Assoc 1997 211 169–170.
2. Boyce SWZingg BMLightfoot TL. Behavior of Mustela putorius furo. Vet Clin North Am Small Anim Pract 2001 4 697–713.
3. Jurek RM. A review of national and Californian population estimates of pet ferrets Sacramento: California Department Fish and Game Wildlife Management Division, Bird and Mammal Conservation, 1998. Available at: www.dfg.ca.gov/wildlife/nongame/nuis_exo/ferret/ferret.html. Accessed Dec 23, 2011.
4. Ulrich KLBird KAKoehler LAet al. Uroliths analysis: submission, method, and interpretation. Vet Clin North Am Small Anim Pract 1996 26 393–400.
5. Schilling K. Ferrets for dummies 2nd ed. Indianapolis: Wiley Publishing Inc, 2009 29–38.
6. SAS/STAT user's guide, version 6 4th ed. Cary, NC: SAS Institute Inc, 1994.
7. Schlesselman JJ. Basic methods in cancer analysis. In: Schlesselman JJ, ed. Case-control studies: design, conduct, analysis New York: Oxford University Press, 1982 171–226.
8. Breslow NEDay NE. Statistical methods in cancer research. In: The analysis of case-control studies 1 Lyon, France: International Agency for Research on Cancer, 1980 142.
9. Fletcher RHFletcher SWWagner EH. Clinical epidemiology: the essentials 3rd ed. Baltimore: Williams & Wilkins, 1996 186–207.
10. Lilienfeld DEStolley PP. Foundations of epidemiology 3rd ed. Oxford, England: Oxford University Press, 1994 198–225.
11. Osborne CA. How would you manage cystine urocystoliths in a female Siamese cat? DVM Newsmagazine 2003 1–4.
12. Bannasch DHenthorn PS. Changing paradigms in diagnosis of inherited defects associated with urolithiasis. Vet Clin North Am Small Anim Pract 2009 39 111–125.
13. Schmidt CVester UWagner CAet al. Significant contribution of genomic rearrangements in SLC3A1 and SLC7A9 to the etiology of cystinuria Kidney Int 2003 64:1564-1572.
14. Brown SA. The basic anatomy, physiology and husbandry of ferrets. In: Hillyer EVQuesenberry KE, eds. Ferrets, rabbits and rodents-clinical medicine and surgery Philadelphia: WB Saunders Co, 1997 3–13.
15. Marini RPEsteves MIFox JG. A technique for catherization of the urinary bladder in the ferret. Lab Anim 1994 28 155–157.
16. Nguyen HTMoreland AFShield RPet al. Urolithiasis in ferrets (Mustela putorius furo. Lab Anim Sci 1979 29 243–245.
17. Lafeber Co Urolithiasis in ferrets, rabbits and rodents.
18. Oglesbee BL. Ferrets and rabbits. In: Oglesbee BL, ed. The 5-minute veterinary consult: ferret and rabbit Oxford, England: Blackwell Publishing Ltd, 2006 166–169.
19. Osborne CALulich JPKruger JMet al. Analysis of 451,891 canine uroliths, feline uroliths, and feline urethral plugs from 1981 to 2007: perspectives from the Minnesota Urolith Center. Vet Clin North Am Small Anim Pract 2009 39 183–197.
