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Cystic Renal Disease in the Domestic Ferret
Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA
*Corresponding author. Email: jgfox@MIT.edu
link: www.ncbi.nlm.nih.gov/pmc/articles/PMC2703171/
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Abstract.
Cystic renal diseases in domestic ferrets are a common anecdotal finding but have received scant systematic assessment. We performed a 17-y, case-control retrospective analysis of the medical records of 97 ferrets housed at our institution between 1987 and 2004, to determine the prevalence and morphotypes of cystic renal diseases in this species. Histologic sections stained with hematoxylin and eosin, Masson trichrome, or periodic acid–Schiff were evaluated by a comparative pathologist, and statistical analysis of hematologic and serum chemistry values was correlated with morphologic diagnosis. Of the 97 available records, 43 were eliminated due to lack of accompanying tissues. Of the 54 remaining cases, 37 (69% prevalence) had documented renal cysts, and 14 of the 54 ferrets (26%) had primary polycystic disease consisting of either polycystic kidney disease affecting renal tubules or, more commonly, glomerulocystic kidney disease. Secondary polycystic lesions were identified in 11 ferrets (20%), and 12 ferrets (22%) exhibited focal or isolated tubular cysts only as an incidental necropsy finding. Ferrets with secondary renal cysts associated with other developmental anomalies, mesangial glomerulopathy, or end-stage kidney disease had hyperphosphatemia and elevated BUN in comparison with those with primary cystic disease and elevated BUN compared with those without renal lesions. Although reflecting institutional bias, these results implicate primary and secondary cystic renal diseases as highly prevalent and underreported in the domestic ferret. In addition to the clinical implications for ferrets as research subjects and pets, these findings suggest a potential value for ferrets as a model of human cystic renal diseases.
Abbreviations: GCKD, glomerulocystic kidney disease; PKD, polycystic kidney disease
The domestic ferret (Mustela putorius furo) is a popular pet and remains an important experimental animal in biomedical research. In research, their use spans a spectrum of disciplines, including gastroenterology, cardiac physiology, infectious diseases, and neuroscience.17,37 Ferret medicine and physiology continues to be studied and defined as a consequence of their use in research and popularity as pets.17,29 Characterization of renal disease, however, has been limited in comparison to other domestic species. Renal diseases described in ferrets include renal cysts, acquired hydronephrosis, pyelonephritis, renal calculi, chronic interstitial nephritis, toxic nephropathy, immune complex glomerulonephritis and neoplasia.16,29 Renal cysts are frequent findings at necropsy or incidental findings during routine physical examination.17,29,33 Approximately 10% to 15% of ferrets had renal cysts in 2 separate studies.2,16 In 1 study in 1994, 22 of 27 ferret cases studied were affected by some type of renal disorder including membranoproliferative glomerulonephropathy and cortical cysts.14 There are 2 separate case reports of polycystic kidney disease in ferrets: 1 of polycystic kidney disease and bilateral perinephric pseudocysts in a 3-y-old ferret presented for abdominal distention and seizures,30 and another of a 3-y-old ferret with seizures, weakness, and ataxia.13
Here we present a comprehensive retrospective analysis of cystic renal disease in the ferret. Using archival records accumulated between 1987 and 2004, we characterize hematologic, serum chemical, and histologic features of these diseases.
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Materials and Methods.
Animal sources and husbandry.
Ferrets in this study were acquired from multiple sources comprising private owners and commercial vendors including Marshall Farms (North Rose, NY), Triple Farms (Sayre, PA), and The Massachusetts Institute of Technology (Cambridge, MA). Many had no experimental manipulations performed and were personal pets or retired breeders submitted for diagnostic evaluations. Use of both purpose-bred research ferrets and privately owned animals was approved by the Institutional Animal Care and Use Committee. Animals were assigned identification numbers on arrival at the Massachusetts Institute of Technology and a separate Division of Comparative Medicine diagnostic accession number at the time of necropsy. At the Institute, animals were maintained in an AAALAC-accredited facility. They were housed in rabbit cages (24 × 24 × 24 in.) with perforated plastic or stainless steel grid floors; flooring and drop pans were covered daily with cageboard. Rooms were maintained at 20 to 24 °C and 30% to 70% relative humidity; light cycles differed from 12:12 to 14:10 depending on the life-cycle stage and experimental use of the ferret. There were 10 to 15 complete air changes hourly. Food (Purina Ferret Chow, Brentwood, MO; Marshall Farm Ferret Chow, Wolcott, NY, with various commercial cat food supplements) and water were available ad libitum. Various experimental manipulations were performed on the ferrets including: jugular catheterization, gastrojejunostomy, pyloroplasty, Helicobacter mustelae or Brugia malayi inoculation, and routine gastric biopsy. Signalment, clinical signs, and results of select hematology and serum chemistry evaluation were documented from pathology, diagnostic laboratory, experimental, and clinical records.
Case selection and pathologic review.
Records from 1987 to 2004 in the archives of the Massachusetts Institute of Technology, Division of Comparative Medicine, Comparative Pathology Laboratory were reviewed. Included in this study were animals that had kidney lesions meeting the criteria of polycystic kidney disease (PKD), membranous glomerulonephritis, or glomerulocystic kidney disease (GCKD) or other noteworthy cystic kidney lesions. Animals without kidney lesions were used as controls. Determinations of hematocrit and total protein, necropsies, and microscopic reviews had been performed at the Massachusetts Institute of Technology;1,21 sera was out-sourced to commercial veterinary reference laboratories for chemical analysis. Renal size, weight, and the preparation method and orientation of renal section were not recorded. Kidney sections stained with hematoxylin and eosin were evaluated by a comparative pathologist without knowledge of case histories; in general, only 1 histologic section per kidney was evaluated. On the basis of this histopathologic review, cases were assigned to 1 of 4 groups: (1) no significant renal lesions (controls); (2) simple cysts; (3) renal lesions consistent with primary polycystic kidney disease; and (4) nephropathies with secondary polycystic lesions. Additional stains (Masson trichrome, periodic acid-Schiff) were used to further characterize tissue sections.
Statistical analysis.
Statistical analysis of ferret serum chemistry values between groups was performed by 1-way analysis of variance and Student 2-tailed t test. Analysis of gender and age by group was performed using the Fisher Exact test. All analyses were performed by using GraphPad Prism software (GraphPad, San Diego, CA). A P value of less than 0.05 was considered significant.
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Results.
Clinical presentation.
A total of 97 ferret records dating between 1987 and 2004 were evaluated; 43 cases were eliminated due to lack of histopathologic information, leaving a total of 54 records for review. The prevalence of cystic renal diseases was 69% (Table 1). No age or gender influences on disease categorization were detected. In some cases, age and gender were not recorded (Table 1). Clinical signs were variable, and their association with renal disease was obfuscated by concurrent disease or experimental use. Recorded signs among ferrets with primary polycystic disease included weight loss (n = 1), decreased appetite (n = 2), lethargy/weakness (n = 8), polyuria–polydipsia (n = 1), dysphagia (n = 1), diarrhea (n = 3), melena (n = 1), vomiting (n = 1), ptyalism (n = 1), seizure (n = 1) and trembling (n = 1). Recorded signs among ferrets with secondary polycystic disease included alopecia (n = 2), weight loss (n = 7), trembling (n = 1), decreased appetite (n = 1), dysphagia (n = 1), lethargy or weakness (n = 1), and diarrhea (n = 2). Recorded signs among ferrets with simple cysts included diarrhea (n = 2), poor reproductive performance (n = 1), decreased appetite (n = 1), and weakness or lethargy (n = 1). Two animals with primary polycystic disease, 5 with simple cysts, and 5 without renal disease either had no clinical history or lacked recorded clinical signs.
Table 1.
Summary of signalment data in ferrets grouped by morphologic diagnosis
Ferret histopathology.
The polygenic nature of ferret renal disease was manifest by the diverse pattern of lesions observed at gross necropsy and by histopathology (Figure 1 A through L). Six ferrets had kidneys without gross abnormalities. Kidneys later identified as having primary polycystic disease had a spectrum of gross lesions including cysts of various sizes (diameter, 1 to 25 mm; n = 6), pitted surface, wedge-shaped area of discoloration, foci of cortical pallor, and renal congestion. Kidneys later identified as having secondary polycystic disease had a variety of tinctorial changes from pallor to tan or gray coloration (n = 6). Gross cysts (diameter, 2 to 10 mm) were noted in kidneys of 4 animals. Discrepancy in renal size was noted in 1 ferret; no gross lesions were present in 2 others. Kidneys later identified as having simple cysts had 1 to several cysts that were 1 to 7 mm in diameter (n = 5); 4 ferrets had kidneys in which no gross lesions were noted. Only kidneys containing 1 or more cysts or microcysts greater than 1 mm in diameter and derived from glomeruli, tubules, or both met our inclusion criteria for renal disease. On the basis of renal histopathology, we divided this cohort into 3 groups: simple cysts, primary polycystic diseases, and secondary polycystic diseases. Simple cysts were of tubular origin, never exceeded a total of 3 within a single kidney section, and were surrounded by otherwise normal renal tissue. Primary polycystic diseases were subdivided into either polycystic kidney disease (PKD; tubular origin) or GCKD. Because only 1 ferret met our criteria for PKD, this ferret was combined with the GCKD cohort to form a single, primary polycystic kidney disease cohort for statistical analysis. PKD was characterized by numerous large cysts of presumptive tubular origin associated with destruction of surrounding kidney structures and absence of evidence for an underlying renal disease in the remaining functional nephrons (Figure 1 C through E). This animal also had small, multiloculated, adrenocortical cysts. GCKD was manifest as cystic dilation of Bowman capsules, with shrinkage or complete loss of the glomerular tuft. GCKD invariably affected many but not all glomeruli. An important feature distinguishing primary GCKD from secondary glomerular cysts was the absence of basement membrane thickening or fibrosis of intact glomeruli.
Figure 1.
Histopathology of cystic renal diseases in the ferret. (A) Normal kidney. (B) Large simple cyst of tubular origin surrounded by otherwise normal tissue. (C) Multicystic disease with destruction of preexisting renal tissue, consistent with primary polycystic ...
Renal cysts were defined as secondary if they were clearly associated with a predisposing condition (Figure 1 G through I). Kidney diseases predisposing to secondary cyst formation were heterogeneous in presentation, but they generally fell into one of 2 categories: developmental or chronic–end-stage kidney. Developmental nephropathies were usually segmental and defined by 3 histopathologic criteria: (1) cystic or microcystic dilatation of glomeruli, tubules, or both; (2) loose expansion of interstitial matrix associated with loss of preexisting glomeruli and tubules; and (3) thickening or splitting of glomerular and tubular basement membranes. This histologic presentation closely resembled canine familial nephropathies and polycystic kidney syndrome of New Zealand White rabbits, both presumed to be heritable conditions.7,18,24 Cystic renal dysplasia displayed elements of developmental nephropathy as well as retention of primitive ciliated metanephric-type ducts (Figure 1 J through L). Foci of cartilagenous or osseous metaplasia as noted in human renal dysplasia were not identified;38 however, intramedullary squamous metaplasia was evident in 1 specimen (Figure 1 K). Chronic renal failure with end-stage kidney disease was manifest by pitting of the renal capsule associated with segmental loss of underlying parenchyma, multifocal glomerular and tubular fibrosis with dilatation and atrophy, frequent protein and waxy tubular casts, and multifocal interstitial fibrosis. Cysts associated with end-stage kidney disease rarely exceeded 1 mm in diameter. The most common underlying lesion associated with end-stage kidney was membranous glomerulonephropathy characterized by basement membrane thickening and fibrosis of hypocellular glomerular corpuscles (Figure 1 G).
Hematology and serum chemistry.
Ferrets with primary polycystic lesions showed a trend toward lower hematocrit (34%), hypocalcemia (7.8 mg/dl), and hypoalbuminemia (2.2 g/dl) when compared with published normal values and all other groups (Table 2). However, these differences failed to achieve statistical significance. Two serum chemistry values typically elevated in renal disease, BUN and phosphorus, were the only analytes that differed statistically (P < 0.05) between groups. Azotemia and hyperphosphatemia were significantly associated with secondary polycystic but not primary polycystic diseases. High BUN alone was significantly (P < 0.05) elevated in ferrets with secondary polycystic diseases when compared with those without renal lesions.
Table 2.
Hematology and clinical pathology data
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Discussion.
This study was initiated to characterize renal cystic disease histologically in ferrets, to establish potential hematology and clinical pathology correlates, and to determine the usefulness of the ferret as an animal model of human disease. We demonstrate the common occurrence of primary polycystic diseases (GCKD), cystic kidney diseases due to secondary etiologies (membranous glomerulonephritis),10 and chronic end-stage renal disease and uncomplicated (simple) renal cysts. In addition to the ferret, cystic renal disease has been described in sheep, zebra fish, cats, dogs, rabbits, swine and cattle.16,18,22,24,26
Cystic renal disease in humans may be hereditary, nonhereditary developmental or acquired disorders. The term ‘cystic kidneys’ is used to describe a heterogeneous group of genetic and nongenetic conditions characterized either by single or multiple cysts, which include, polycystic kidney disease, glomerulocystic kidney disease, membranous glomerulonephritis and simple renal cysts among others.12 Overviews of such renal diseases have been published previously.6,12 Renal cystic disorders are relatively common in the human population and lead to chronic renal failure or disease, affecting approximately 25 million people in the United States alone. In humans, PKD is one of the most common genetically inherited diseases and is seen in approximately 1 of 400 to 1000 live births; PKD accounts for approximately 10% of chronic renal failure.
PKD is genetically heterogeneous in humans and can be associated with mutations of either the PKD1, PKD2, or, rarely, PKD3 gene.6,8,20,25,35 Because the genes responsible for PKD are expressed broadly among diverse tissues, the mutations may affect extrarenal tissues, including the liver, pancreas and choroid plexus.15 There are 3 forms, the most common of which is autosomal dominant PKD. Autosomal recessive PKD is a rare form, is usually seen at infancy, and has an incidence of 1 in 20,000 live births.22,37 The third type of PKD is acquired, has no genetic predisposition and tends to develop as a result of long-term kidney disease or dialysis use.
Several murine models of PKD have been used to study developmental, therapeutic, cellular, and molecular aspects of this disease.36 These models have recently been tabulated and include spontaneously occurring disease models (for example, the cpk knockout mouse and Han:SPRD-cy rat) and acquired disease models (for example, models induced by administration of chemicals or genetic manipulation).36 Factors manipulated to generate models of acquired disease include aging; exposure to hormones (hydrocortisone, triiodothyronine, diethylstilbesterol); overexpression of a gene or protein (for example, polycystin 1, β-catenin, activated epidermal growth factor receptor); and inactivation, knockout, or mutation of a gene or protein (for example, the apoptosis inhibitors bcl2 and activating protein 2B).36 These models have collectively provided critical insights into the etiopathogenesis of this collection of disorders and may ultimately lead to the development of strategies for intervention.
In autosomal dominant PKD in humans, male gender is associated with enhanced disease progression and severity. This association has also been demonstrated in several murine models of PKD, including the Crj:CD/SD-pck and Han:SPRD-cy rat models and the C57BL/6J juvenile cystic kidney (jck) mouse model.19,34 In the Han:SPRD-cy rat and C57BL/6J-jck mouse, gonadectomy and subsequent testosterone supplementation demonstrated a renotropic exacerbatory role for testosterone and a protective role for estrogen.11,34 Diminished disease progression and disease aggressiveness in females has also been correlated with a protective effect of soy protein when compared with casein in CD1 pcy/pcy mice3 and with oxidative stress in C57BL/6J cpk mice and Han:SPRD-cy rats.23 In the present study, gender associations were impossible to make due to the paucity of classical PKD in the primary cystic disease group and the effect of colony composition on gender distribution.
The best characterized nonmurine analog of PKD is the polycystic kidney disease of Persian and Persian-type cats. Feline PKD affects approximately 38% of animals in these breeds, is inherited as an autosomal dominant trait, and has recently been shown to involve a nucleotide transversion resulting in a stop codon in the feline PKD1 gene.5,22 The stop codon truncates the encoded protein and presumably makes it inoperable. The product of PKD1 in humans is polycystin 1, a protein that is involved in the regulation and coordination of cellular responses controlling kidney morphogenesis.36 Concordant with the disease in humans, hepatic and pancreatic cysts also can be seen in cats with PKD. As cats age, additional renal (chronic tubulointerstitial nephritis) and hepatic lesions (hepatic fibrosis) occur. Renal failure in these cats has an average age of onset of 7 y and is associated with azotemia, hyperphosphatemia, isosthenuria, nonregenerative anemia, and metabolic acidosis.5
Primary polycystic lesions in the study reported here included PDK and GCKD. PKD, 1 of the more commonly inherited kidney disorders in both men and women,9 was found in only 1 ferret.32 The paucity of cases in the present retrospective study agrees with the existing literature concerning PKD in ferrets.29 In contrast to the relative prevalences of PKD and GCKD in humans, GCKD accounted for most (92%) of the ferret cases determined to have primary polycystic lesions. In humans, GCKD is a rare, sporadic or familial related disease characterized by its histological features and can be divided into 3 major categories: (1) nonsyndromal heritable and sporadic forms of severely cystic kidneys in children and adults; (2) glomerulocystic kidneys in inheritable malformation syndromes; and (3) dysplastic kidneys with glomerular cysts which may be sporadic or syndromal.4 Our frequent identification of GCKD suggests that it is underreported in the ferret.
Renal pathology in the primary polycystic disease group was not correlated with azotemia or hyperphosphatemia. Ferrets from this group that contributed to serum chemistry values were both pets and experimental animals. All were euthanized due to disparate extrarenal diseases including lymphoma, adrenal-associated endocrinopathy, insulinoma, and cholangiohepatitis. Had they not succumbed to these conditions, these ferrets likely would eventually have expressed the characteristic hallmarks of renal failure. Palliative treatment (especially fluid therapy) contemporaneous with presentation might also have normalized serum chemistry abnormalities in this group.
Many cystic lesions were placed into the secondary polycystic lesion category; many of these were cases of membranous glomerulonephritis. Lesions of membranous glomerulonephritis were similar to human cases and a common cause of end-stage kidney disease. Islands of cartilage can be present in human cases but were not seen in the ferrets studied here. The contribution of Aleutian disease virus infection, a cause of membranous glomerulonephritis in the ferret, to secondary polycystic lesions described in this study was not determined.
Renal dysplasia refers to kidneys with foci of disorganized parenchyma or immature or anomalous structures resulting from abnormal differentiation.18 This abnormality occurs in many species including horses, dogs, ruminants, swine, and mice.18,26,28,31 Although morphologic criteria for renal dysplasia in veterinary medicine differ from those for humans, the cystic renal dysplasia demonstrated in the present study (that is, characterized by multiple cysts lined by flattened columnar to cuboidal epithelial cells) was concordant with lesions seen in humans. Renal dysplasia has an autosomal recessive mode of inheritance in certain breeds of dog (for example, Shih Tzu) and the Japanese Black breed of cattle.18,26 Partial anorexia, failure to thrive, weight loss, polyuria–polydipsia, and renal secondary hyperparathyroidism are potential signs; onset of signs typically occurs by 2 y of age. Characteristic clinical pathology findings include azotemia, isosthenuria, hyperphosphatemia, normocytic normochromic anemia, and metabolic acidosis.18 The use of genetically engineered mice also has generated considerable insights into the molecular basis of normal and anomalous renal differentiation.28 Lesions of renal dysplasia documented in the present study include squamous metaplasia and primitive metanephric-type renal duct.
Renal disease in ferrets, including cystic disease, can be clinically silent and remain undetected until necropsy. Due to intercurrent disease and the nature of use of the animals described here, a relationship between lesions and clinical signs could not be generally or unequivocally established, although clinical pathology correlates of disease were identified. Three ferrets with secondary cystic disease had clinical signs, clinical pathology, and histopathology findings highly suggestive of renal failure as a primary etiology. All 3 ferrets had decreased appetite and weight loss of 1 to 5 wk duration; 1 presented with dehydration. Two of the 3 were anemic; all had azotemia and hyperphosphatemia. Urinalysis was available from only 1 animal and demonstrated isosthenuria, moderate proteinuria, and mild hematuria. Treatment consisted of subcutaneously administered lactated Ringer's solution, antibiotics (trimethoprim–sulfadiazine), and, in 1 animal, administration of B complex vitamins and an anabolic steroid. Dietary modification and therapies commonly used in renal failure in companion animals (such as administration of phosphate binding agents, agents to correct acidosis, and gastroprotectants) were not used. Novel therapies evaluated in murine models of PKD include renin–angiotensin system blockade, tyrosine kinase receptor inhibition, matrix metalloproteinase inhibition, modulation of c-myc expression, and taxane, antiinflammatory agent, and lovastatin administration. These novel therapies have recently been reviewed19 but have not been documented in the ferret.
Although statistical significance was not achieved, all of the ferrets with cystic renal disorders had hypoalbuminemia, presumably the result of enhanced renal loss or inappetance. When compared with published normal values, hypoalbuminemia also existed in those ferrets without renal lesions. Importantly, this group controlled only the existence of renal lesions and not intercurrent, extrarenal conditions, or experimental use. The use of a naïve ‘control’ population might have resulted in statistically significant findings in more of the variables evaluated.
In contrast to the difference in BUN concentrations, the difference in mean concentrations of creatinine between the secondary and primary cystic disease groups approached (P = 0.0502), but did not achieve, significance, presumably because of limitations in numbers available for statistical comparison. Alternatively, creatinine elevation during renal disease in ferrets may be more modest than that seen in other species, and elevations in BUN in the ferret may not be accompanied by increases in serum creatinine that are commensurate with those observed in other domestic animals14,27. For example, 1 ferret with secondary cystic disease in our study population had a BUN concentration of 135 mg/dl and a creatinine concentration of 1.5 mg/dl. Creatinine concentrations in the ferret have a lower mean and narrower range than do those in other carnivores, for example, the dog or cat.14 This difference could be misleading to clinicians accustomed to normal creatinine concentrations over 1 mg/dl. Renal tubular excretion or enhanced enteric degradation of creatinine are potential mechanisms for its low, normal concentration in the ferret. Despite the use of different reference laboratories for evaluation of the concentration of serum chemistry analytes, laboratory methodologies for all analytes except calcium were identical. Other differences among laboratories in sample processing, the reagent source, and instrumentation used may have contributed to unquantifiable variation in the concentrations of these analytes.
Renal pathology is a common finding in ferrets. To our knowledge, the present study is the most systematic of cystic renal disease in ferrets to date, expands our earlier investigations into renal disease and function in this species, and augments the existing literature. The use of ferrets in renal function or other studies in which renal performance is pertinent should be preceded by ultrasonography or evaluation of serum chemistry. The relative contribution of genetic and environmental influences on ferret cystic renal disease has not been established. If these diseases are genetically determined, animals carrying the pertinent genes should be removed from breeding colonies. Finally, although PKD appears to be an uncommon form of cystic renal disease in the ferret, the prevalence and spectrum of other cystic diseases in this species, especially GCKD, may lend insight into similar lesions in humans.
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Acknowledgments.
We thank Kathleen Cormier and the Division of Comparative Medicine Histology Laboratory for assistance with tissue preparations and Bobi Young for administrative assistance. This work was supported in part by NIH grant T32 RR07036
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Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA
*Corresponding author. Email: jgfox@MIT.edu
link: www.ncbi.nlm.nih.gov/pmc/articles/PMC2703171/
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Abstract.
Cystic renal diseases in domestic ferrets are a common anecdotal finding but have received scant systematic assessment. We performed a 17-y, case-control retrospective analysis of the medical records of 97 ferrets housed at our institution between 1987 and 2004, to determine the prevalence and morphotypes of cystic renal diseases in this species. Histologic sections stained with hematoxylin and eosin, Masson trichrome, or periodic acid–Schiff were evaluated by a comparative pathologist, and statistical analysis of hematologic and serum chemistry values was correlated with morphologic diagnosis. Of the 97 available records, 43 were eliminated due to lack of accompanying tissues. Of the 54 remaining cases, 37 (69% prevalence) had documented renal cysts, and 14 of the 54 ferrets (26%) had primary polycystic disease consisting of either polycystic kidney disease affecting renal tubules or, more commonly, glomerulocystic kidney disease. Secondary polycystic lesions were identified in 11 ferrets (20%), and 12 ferrets (22%) exhibited focal or isolated tubular cysts only as an incidental necropsy finding. Ferrets with secondary renal cysts associated with other developmental anomalies, mesangial glomerulopathy, or end-stage kidney disease had hyperphosphatemia and elevated BUN in comparison with those with primary cystic disease and elevated BUN compared with those without renal lesions. Although reflecting institutional bias, these results implicate primary and secondary cystic renal diseases as highly prevalent and underreported in the domestic ferret. In addition to the clinical implications for ferrets as research subjects and pets, these findings suggest a potential value for ferrets as a model of human cystic renal diseases.
Abbreviations: GCKD, glomerulocystic kidney disease; PKD, polycystic kidney disease
The domestic ferret (Mustela putorius furo) is a popular pet and remains an important experimental animal in biomedical research. In research, their use spans a spectrum of disciplines, including gastroenterology, cardiac physiology, infectious diseases, and neuroscience.17,37 Ferret medicine and physiology continues to be studied and defined as a consequence of their use in research and popularity as pets.17,29 Characterization of renal disease, however, has been limited in comparison to other domestic species. Renal diseases described in ferrets include renal cysts, acquired hydronephrosis, pyelonephritis, renal calculi, chronic interstitial nephritis, toxic nephropathy, immune complex glomerulonephritis and neoplasia.16,29 Renal cysts are frequent findings at necropsy or incidental findings during routine physical examination.17,29,33 Approximately 10% to 15% of ferrets had renal cysts in 2 separate studies.2,16 In 1 study in 1994, 22 of 27 ferret cases studied were affected by some type of renal disorder including membranoproliferative glomerulonephropathy and cortical cysts.14 There are 2 separate case reports of polycystic kidney disease in ferrets: 1 of polycystic kidney disease and bilateral perinephric pseudocysts in a 3-y-old ferret presented for abdominal distention and seizures,30 and another of a 3-y-old ferret with seizures, weakness, and ataxia.13
Here we present a comprehensive retrospective analysis of cystic renal disease in the ferret. Using archival records accumulated between 1987 and 2004, we characterize hematologic, serum chemical, and histologic features of these diseases.
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Materials and Methods.
Animal sources and husbandry.
Ferrets in this study were acquired from multiple sources comprising private owners and commercial vendors including Marshall Farms (North Rose, NY), Triple Farms (Sayre, PA), and The Massachusetts Institute of Technology (Cambridge, MA). Many had no experimental manipulations performed and were personal pets or retired breeders submitted for diagnostic evaluations. Use of both purpose-bred research ferrets and privately owned animals was approved by the Institutional Animal Care and Use Committee. Animals were assigned identification numbers on arrival at the Massachusetts Institute of Technology and a separate Division of Comparative Medicine diagnostic accession number at the time of necropsy. At the Institute, animals were maintained in an AAALAC-accredited facility. They were housed in rabbit cages (24 × 24 × 24 in.) with perforated plastic or stainless steel grid floors; flooring and drop pans were covered daily with cageboard. Rooms were maintained at 20 to 24 °C and 30% to 70% relative humidity; light cycles differed from 12:12 to 14:10 depending on the life-cycle stage and experimental use of the ferret. There were 10 to 15 complete air changes hourly. Food (Purina Ferret Chow, Brentwood, MO; Marshall Farm Ferret Chow, Wolcott, NY, with various commercial cat food supplements) and water were available ad libitum. Various experimental manipulations were performed on the ferrets including: jugular catheterization, gastrojejunostomy, pyloroplasty, Helicobacter mustelae or Brugia malayi inoculation, and routine gastric biopsy. Signalment, clinical signs, and results of select hematology and serum chemistry evaluation were documented from pathology, diagnostic laboratory, experimental, and clinical records.
Case selection and pathologic review.
Records from 1987 to 2004 in the archives of the Massachusetts Institute of Technology, Division of Comparative Medicine, Comparative Pathology Laboratory were reviewed. Included in this study were animals that had kidney lesions meeting the criteria of polycystic kidney disease (PKD), membranous glomerulonephritis, or glomerulocystic kidney disease (GCKD) or other noteworthy cystic kidney lesions. Animals without kidney lesions were used as controls. Determinations of hematocrit and total protein, necropsies, and microscopic reviews had been performed at the Massachusetts Institute of Technology;1,21 sera was out-sourced to commercial veterinary reference laboratories for chemical analysis. Renal size, weight, and the preparation method and orientation of renal section were not recorded. Kidney sections stained with hematoxylin and eosin were evaluated by a comparative pathologist without knowledge of case histories; in general, only 1 histologic section per kidney was evaluated. On the basis of this histopathologic review, cases were assigned to 1 of 4 groups: (1) no significant renal lesions (controls); (2) simple cysts; (3) renal lesions consistent with primary polycystic kidney disease; and (4) nephropathies with secondary polycystic lesions. Additional stains (Masson trichrome, periodic acid-Schiff) were used to further characterize tissue sections.
Statistical analysis.
Statistical analysis of ferret serum chemistry values between groups was performed by 1-way analysis of variance and Student 2-tailed t test. Analysis of gender and age by group was performed using the Fisher Exact test. All analyses were performed by using GraphPad Prism software (GraphPad, San Diego, CA). A P value of less than 0.05 was considered significant.
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Results.
Clinical presentation.
A total of 97 ferret records dating between 1987 and 2004 were evaluated; 43 cases were eliminated due to lack of histopathologic information, leaving a total of 54 records for review. The prevalence of cystic renal diseases was 69% (Table 1). No age or gender influences on disease categorization were detected. In some cases, age and gender were not recorded (Table 1). Clinical signs were variable, and their association with renal disease was obfuscated by concurrent disease or experimental use. Recorded signs among ferrets with primary polycystic disease included weight loss (n = 1), decreased appetite (n = 2), lethargy/weakness (n = 8), polyuria–polydipsia (n = 1), dysphagia (n = 1), diarrhea (n = 3), melena (n = 1), vomiting (n = 1), ptyalism (n = 1), seizure (n = 1) and trembling (n = 1). Recorded signs among ferrets with secondary polycystic disease included alopecia (n = 2), weight loss (n = 7), trembling (n = 1), decreased appetite (n = 1), dysphagia (n = 1), lethargy or weakness (n = 1), and diarrhea (n = 2). Recorded signs among ferrets with simple cysts included diarrhea (n = 2), poor reproductive performance (n = 1), decreased appetite (n = 1), and weakness or lethargy (n = 1). Two animals with primary polycystic disease, 5 with simple cysts, and 5 without renal disease either had no clinical history or lacked recorded clinical signs.
Table 1.
Summary of signalment data in ferrets grouped by morphologic diagnosis
Ferret histopathology.
The polygenic nature of ferret renal disease was manifest by the diverse pattern of lesions observed at gross necropsy and by histopathology (Figure 1 A through L). Six ferrets had kidneys without gross abnormalities. Kidneys later identified as having primary polycystic disease had a spectrum of gross lesions including cysts of various sizes (diameter, 1 to 25 mm; n = 6), pitted surface, wedge-shaped area of discoloration, foci of cortical pallor, and renal congestion. Kidneys later identified as having secondary polycystic disease had a variety of tinctorial changes from pallor to tan or gray coloration (n = 6). Gross cysts (diameter, 2 to 10 mm) were noted in kidneys of 4 animals. Discrepancy in renal size was noted in 1 ferret; no gross lesions were present in 2 others. Kidneys later identified as having simple cysts had 1 to several cysts that were 1 to 7 mm in diameter (n = 5); 4 ferrets had kidneys in which no gross lesions were noted. Only kidneys containing 1 or more cysts or microcysts greater than 1 mm in diameter and derived from glomeruli, tubules, or both met our inclusion criteria for renal disease. On the basis of renal histopathology, we divided this cohort into 3 groups: simple cysts, primary polycystic diseases, and secondary polycystic diseases. Simple cysts were of tubular origin, never exceeded a total of 3 within a single kidney section, and were surrounded by otherwise normal renal tissue. Primary polycystic diseases were subdivided into either polycystic kidney disease (PKD; tubular origin) or GCKD. Because only 1 ferret met our criteria for PKD, this ferret was combined with the GCKD cohort to form a single, primary polycystic kidney disease cohort for statistical analysis. PKD was characterized by numerous large cysts of presumptive tubular origin associated with destruction of surrounding kidney structures and absence of evidence for an underlying renal disease in the remaining functional nephrons (Figure 1 C through E). This animal also had small, multiloculated, adrenocortical cysts. GCKD was manifest as cystic dilation of Bowman capsules, with shrinkage or complete loss of the glomerular tuft. GCKD invariably affected many but not all glomeruli. An important feature distinguishing primary GCKD from secondary glomerular cysts was the absence of basement membrane thickening or fibrosis of intact glomeruli.
Figure 1.
Histopathology of cystic renal diseases in the ferret. (A) Normal kidney. (B) Large simple cyst of tubular origin surrounded by otherwise normal tissue. (C) Multicystic disease with destruction of preexisting renal tissue, consistent with primary polycystic ...
Renal cysts were defined as secondary if they were clearly associated with a predisposing condition (Figure 1 G through I). Kidney diseases predisposing to secondary cyst formation were heterogeneous in presentation, but they generally fell into one of 2 categories: developmental or chronic–end-stage kidney. Developmental nephropathies were usually segmental and defined by 3 histopathologic criteria: (1) cystic or microcystic dilatation of glomeruli, tubules, or both; (2) loose expansion of interstitial matrix associated with loss of preexisting glomeruli and tubules; and (3) thickening or splitting of glomerular and tubular basement membranes. This histologic presentation closely resembled canine familial nephropathies and polycystic kidney syndrome of New Zealand White rabbits, both presumed to be heritable conditions.7,18,24 Cystic renal dysplasia displayed elements of developmental nephropathy as well as retention of primitive ciliated metanephric-type ducts (Figure 1 J through L). Foci of cartilagenous or osseous metaplasia as noted in human renal dysplasia were not identified;38 however, intramedullary squamous metaplasia was evident in 1 specimen (Figure 1 K). Chronic renal failure with end-stage kidney disease was manifest by pitting of the renal capsule associated with segmental loss of underlying parenchyma, multifocal glomerular and tubular fibrosis with dilatation and atrophy, frequent protein and waxy tubular casts, and multifocal interstitial fibrosis. Cysts associated with end-stage kidney disease rarely exceeded 1 mm in diameter. The most common underlying lesion associated with end-stage kidney was membranous glomerulonephropathy characterized by basement membrane thickening and fibrosis of hypocellular glomerular corpuscles (Figure 1 G).
Hematology and serum chemistry.
Ferrets with primary polycystic lesions showed a trend toward lower hematocrit (34%), hypocalcemia (7.8 mg/dl), and hypoalbuminemia (2.2 g/dl) when compared with published normal values and all other groups (Table 2). However, these differences failed to achieve statistical significance. Two serum chemistry values typically elevated in renal disease, BUN and phosphorus, were the only analytes that differed statistically (P < 0.05) between groups. Azotemia and hyperphosphatemia were significantly associated with secondary polycystic but not primary polycystic diseases. High BUN alone was significantly (P < 0.05) elevated in ferrets with secondary polycystic diseases when compared with those without renal lesions.
Table 2.
Hematology and clinical pathology data
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Discussion.
This study was initiated to characterize renal cystic disease histologically in ferrets, to establish potential hematology and clinical pathology correlates, and to determine the usefulness of the ferret as an animal model of human disease. We demonstrate the common occurrence of primary polycystic diseases (GCKD), cystic kidney diseases due to secondary etiologies (membranous glomerulonephritis),10 and chronic end-stage renal disease and uncomplicated (simple) renal cysts. In addition to the ferret, cystic renal disease has been described in sheep, zebra fish, cats, dogs, rabbits, swine and cattle.16,18,22,24,26
Cystic renal disease in humans may be hereditary, nonhereditary developmental or acquired disorders. The term ‘cystic kidneys’ is used to describe a heterogeneous group of genetic and nongenetic conditions characterized either by single or multiple cysts, which include, polycystic kidney disease, glomerulocystic kidney disease, membranous glomerulonephritis and simple renal cysts among others.12 Overviews of such renal diseases have been published previously.6,12 Renal cystic disorders are relatively common in the human population and lead to chronic renal failure or disease, affecting approximately 25 million people in the United States alone. In humans, PKD is one of the most common genetically inherited diseases and is seen in approximately 1 of 400 to 1000 live births; PKD accounts for approximately 10% of chronic renal failure.
PKD is genetically heterogeneous in humans and can be associated with mutations of either the PKD1, PKD2, or, rarely, PKD3 gene.6,8,20,25,35 Because the genes responsible for PKD are expressed broadly among diverse tissues, the mutations may affect extrarenal tissues, including the liver, pancreas and choroid plexus.15 There are 3 forms, the most common of which is autosomal dominant PKD. Autosomal recessive PKD is a rare form, is usually seen at infancy, and has an incidence of 1 in 20,000 live births.22,37 The third type of PKD is acquired, has no genetic predisposition and tends to develop as a result of long-term kidney disease or dialysis use.
Several murine models of PKD have been used to study developmental, therapeutic, cellular, and molecular aspects of this disease.36 These models have recently been tabulated and include spontaneously occurring disease models (for example, the cpk knockout mouse and Han:SPRD-cy rat) and acquired disease models (for example, models induced by administration of chemicals or genetic manipulation).36 Factors manipulated to generate models of acquired disease include aging; exposure to hormones (hydrocortisone, triiodothyronine, diethylstilbesterol); overexpression of a gene or protein (for example, polycystin 1, β-catenin, activated epidermal growth factor receptor); and inactivation, knockout, or mutation of a gene or protein (for example, the apoptosis inhibitors bcl2 and activating protein 2B).36 These models have collectively provided critical insights into the etiopathogenesis of this collection of disorders and may ultimately lead to the development of strategies for intervention.
In autosomal dominant PKD in humans, male gender is associated with enhanced disease progression and severity. This association has also been demonstrated in several murine models of PKD, including the Crj:CD/SD-pck and Han:SPRD-cy rat models and the C57BL/6J juvenile cystic kidney (jck) mouse model.19,34 In the Han:SPRD-cy rat and C57BL/6J-jck mouse, gonadectomy and subsequent testosterone supplementation demonstrated a renotropic exacerbatory role for testosterone and a protective role for estrogen.11,34 Diminished disease progression and disease aggressiveness in females has also been correlated with a protective effect of soy protein when compared with casein in CD1 pcy/pcy mice3 and with oxidative stress in C57BL/6J cpk mice and Han:SPRD-cy rats.23 In the present study, gender associations were impossible to make due to the paucity of classical PKD in the primary cystic disease group and the effect of colony composition on gender distribution.
The best characterized nonmurine analog of PKD is the polycystic kidney disease of Persian and Persian-type cats. Feline PKD affects approximately 38% of animals in these breeds, is inherited as an autosomal dominant trait, and has recently been shown to involve a nucleotide transversion resulting in a stop codon in the feline PKD1 gene.5,22 The stop codon truncates the encoded protein and presumably makes it inoperable. The product of PKD1 in humans is polycystin 1, a protein that is involved in the regulation and coordination of cellular responses controlling kidney morphogenesis.36 Concordant with the disease in humans, hepatic and pancreatic cysts also can be seen in cats with PKD. As cats age, additional renal (chronic tubulointerstitial nephritis) and hepatic lesions (hepatic fibrosis) occur. Renal failure in these cats has an average age of onset of 7 y and is associated with azotemia, hyperphosphatemia, isosthenuria, nonregenerative anemia, and metabolic acidosis.5
Primary polycystic lesions in the study reported here included PDK and GCKD. PKD, 1 of the more commonly inherited kidney disorders in both men and women,9 was found in only 1 ferret.32 The paucity of cases in the present retrospective study agrees with the existing literature concerning PKD in ferrets.29 In contrast to the relative prevalences of PKD and GCKD in humans, GCKD accounted for most (92%) of the ferret cases determined to have primary polycystic lesions. In humans, GCKD is a rare, sporadic or familial related disease characterized by its histological features and can be divided into 3 major categories: (1) nonsyndromal heritable and sporadic forms of severely cystic kidneys in children and adults; (2) glomerulocystic kidneys in inheritable malformation syndromes; and (3) dysplastic kidneys with glomerular cysts which may be sporadic or syndromal.4 Our frequent identification of GCKD suggests that it is underreported in the ferret.
Renal pathology in the primary polycystic disease group was not correlated with azotemia or hyperphosphatemia. Ferrets from this group that contributed to serum chemistry values were both pets and experimental animals. All were euthanized due to disparate extrarenal diseases including lymphoma, adrenal-associated endocrinopathy, insulinoma, and cholangiohepatitis. Had they not succumbed to these conditions, these ferrets likely would eventually have expressed the characteristic hallmarks of renal failure. Palliative treatment (especially fluid therapy) contemporaneous with presentation might also have normalized serum chemistry abnormalities in this group.
Many cystic lesions were placed into the secondary polycystic lesion category; many of these were cases of membranous glomerulonephritis. Lesions of membranous glomerulonephritis were similar to human cases and a common cause of end-stage kidney disease. Islands of cartilage can be present in human cases but were not seen in the ferrets studied here. The contribution of Aleutian disease virus infection, a cause of membranous glomerulonephritis in the ferret, to secondary polycystic lesions described in this study was not determined.
Renal dysplasia refers to kidneys with foci of disorganized parenchyma or immature or anomalous structures resulting from abnormal differentiation.18 This abnormality occurs in many species including horses, dogs, ruminants, swine, and mice.18,26,28,31 Although morphologic criteria for renal dysplasia in veterinary medicine differ from those for humans, the cystic renal dysplasia demonstrated in the present study (that is, characterized by multiple cysts lined by flattened columnar to cuboidal epithelial cells) was concordant with lesions seen in humans. Renal dysplasia has an autosomal recessive mode of inheritance in certain breeds of dog (for example, Shih Tzu) and the Japanese Black breed of cattle.18,26 Partial anorexia, failure to thrive, weight loss, polyuria–polydipsia, and renal secondary hyperparathyroidism are potential signs; onset of signs typically occurs by 2 y of age. Characteristic clinical pathology findings include azotemia, isosthenuria, hyperphosphatemia, normocytic normochromic anemia, and metabolic acidosis.18 The use of genetically engineered mice also has generated considerable insights into the molecular basis of normal and anomalous renal differentiation.28 Lesions of renal dysplasia documented in the present study include squamous metaplasia and primitive metanephric-type renal duct.
Renal disease in ferrets, including cystic disease, can be clinically silent and remain undetected until necropsy. Due to intercurrent disease and the nature of use of the animals described here, a relationship between lesions and clinical signs could not be generally or unequivocally established, although clinical pathology correlates of disease were identified. Three ferrets with secondary cystic disease had clinical signs, clinical pathology, and histopathology findings highly suggestive of renal failure as a primary etiology. All 3 ferrets had decreased appetite and weight loss of 1 to 5 wk duration; 1 presented with dehydration. Two of the 3 were anemic; all had azotemia and hyperphosphatemia. Urinalysis was available from only 1 animal and demonstrated isosthenuria, moderate proteinuria, and mild hematuria. Treatment consisted of subcutaneously administered lactated Ringer's solution, antibiotics (trimethoprim–sulfadiazine), and, in 1 animal, administration of B complex vitamins and an anabolic steroid. Dietary modification and therapies commonly used in renal failure in companion animals (such as administration of phosphate binding agents, agents to correct acidosis, and gastroprotectants) were not used. Novel therapies evaluated in murine models of PKD include renin–angiotensin system blockade, tyrosine kinase receptor inhibition, matrix metalloproteinase inhibition, modulation of c-myc expression, and taxane, antiinflammatory agent, and lovastatin administration. These novel therapies have recently been reviewed19 but have not been documented in the ferret.
Although statistical significance was not achieved, all of the ferrets with cystic renal disorders had hypoalbuminemia, presumably the result of enhanced renal loss or inappetance. When compared with published normal values, hypoalbuminemia also existed in those ferrets without renal lesions. Importantly, this group controlled only the existence of renal lesions and not intercurrent, extrarenal conditions, or experimental use. The use of a naïve ‘control’ population might have resulted in statistically significant findings in more of the variables evaluated.
In contrast to the difference in BUN concentrations, the difference in mean concentrations of creatinine between the secondary and primary cystic disease groups approached (P = 0.0502), but did not achieve, significance, presumably because of limitations in numbers available for statistical comparison. Alternatively, creatinine elevation during renal disease in ferrets may be more modest than that seen in other species, and elevations in BUN in the ferret may not be accompanied by increases in serum creatinine that are commensurate with those observed in other domestic animals14,27. For example, 1 ferret with secondary cystic disease in our study population had a BUN concentration of 135 mg/dl and a creatinine concentration of 1.5 mg/dl. Creatinine concentrations in the ferret have a lower mean and narrower range than do those in other carnivores, for example, the dog or cat.14 This difference could be misleading to clinicians accustomed to normal creatinine concentrations over 1 mg/dl. Renal tubular excretion or enhanced enteric degradation of creatinine are potential mechanisms for its low, normal concentration in the ferret. Despite the use of different reference laboratories for evaluation of the concentration of serum chemistry analytes, laboratory methodologies for all analytes except calcium were identical. Other differences among laboratories in sample processing, the reagent source, and instrumentation used may have contributed to unquantifiable variation in the concentrations of these analytes.
Renal pathology is a common finding in ferrets. To our knowledge, the present study is the most systematic of cystic renal disease in ferrets to date, expands our earlier investigations into renal disease and function in this species, and augments the existing literature. The use of ferrets in renal function or other studies in which renal performance is pertinent should be preceded by ultrasonography or evaluation of serum chemistry. The relative contribution of genetic and environmental influences on ferret cystic renal disease has not been established. If these diseases are genetically determined, animals carrying the pertinent genes should be removed from breeding colonies. Finally, although PKD appears to be an uncommon form of cystic renal disease in the ferret, the prevalence and spectrum of other cystic diseases in this species, especially GCKD, may lend insight into similar lesions in humans.
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Acknowledgments.
We thank Kathleen Cormier and the Division of Comparative Medicine Histology Laboratory for assistance with tissue preparations and Bobi Young for administrative assistance. This work was supported in part by NIH grant T32 RR07036
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