Familial Glomerulonephropathy in the Bullmastiff

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Vet PathoI41:3l9-325
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Familial
Glomerulonephropathy
in the Bullmastiff
M. L. CASAL, D. M. DAMBACH,T. MEISTER, P. E JEZYK, D. E PATTERSON.AND P. S. HENTHORN
Sections of Medical Genetics (MLC, PFJ, DFp, PSH) and Pathology (DMD), and School of Veterinary Medicine (TM),
University of Pennsylvania, Philadelphia, PA
Abstract.
Glomerular disease was diagnosed by histopathologic examination in II related Bullmastiff dogs,
and clinical and laboratory data were collected retrospectively. Four female and seven male dogs between the
ages of 2.5 and II years were affected. Clinical signs, including lethargy and anorexia, were nonspecific and
occurred shortly before death or euthanasia. In five affected dogs serial blood samples were obtained, and
dramatically elevated blood urea nitrogen and creatinine levels were demonstrated up to 2.75 years before death.
Protein-creatinine ratios were elevated in six of six dogs and were above normal 3.5 years before death in one
dog. The kidneys appeared grossly normal to slightly smaller than normal ~t necropsy. Histologic abnormalities
of the kidneys were consistent with chronic glomerulonephropathy with sclerosis. Examination of the pedigrees
of related affected dogs yielded evidence supporting an autosomal recessive mode of inheritance.
..
Key words:
Bullmastiffs; dogs; glomerulopathy;
glomerulosclerosis;
Inherited glomerulopathies have been described in
the Bull Terrier,12 Cocker Spaniel,lo.16.2?Samoyed,'.2
Shih Tzu.13 Soft Coated Wheaten Terrier,24 and Bernese MoUl;ltain Dog.22.26A hereditary basis for glomerulopathy is also highly likely in the Doberman Pinscher4.30and the Newfoundland dog.2OThe age of onset
of clinical signs in familial glomerulopathies ranges
from a few weeks to several years of age. Clinical
signs include anorexia, lethargy, weight loss, polyuria,
polydipsia. and vomiting. Although proteinuria is the
hallmark of these glomerulopathies, laboratory findings have varied considerably and can include isosthenuria, aminoaciduria, glucosuria, increased proteincreatinine ratios, nonregenerative anemia. increased
blood urea nitrogen (BUN) concentrations, increased
creatinine levels, hypoalbuminemia, hyperphosphatemia, and hypercholesterolemia.
In this report we describt: and discuss the range of
clinical, laboratory, and histologic findings in 11 related Bullmastiffs. along with pedigree relationships
and family data supporting an autosomal recessive
mode of inheritance.
Materials and Methods
histology; kidney; pathology.
eral closely related clinically healthy Bullmastiffs. Dogs older than 6 years of age with normal serum biochemistry values and normal urine protein-creatinine ratios (UPCs) or
with no histologic evidence of renal disease were considered
normal.
Tissues obtained through case submissions to the Surgical
Pathology (dog Nos. I and 2) and Necropsy (dog Nos. 3 and
4) Services of the University of Pennsylvania, School of
Veterinary Medicine, were fixed in 10% neutral buffered formalin, processed routinely, embedded in paraffin, and sectioned at 3 J.Lmfor light microscopy. Blocks of paraffinembedded renal tissue from three additional cases (dog Nos.
5-7) were obtained from two other diagnostic pathology laboratories. Serial sections of kidney were stained with hematoxylin and eosin, Masson's trichrome for collagen, Congo red for amyloid, periodic acid-Schiff (PAS) for matrix
deposition, Jones' methenamine silver for basement membranes, and alcian blue (pH 2.7) for acid mucopolysaccharides. Additional 3-J.Lm sections of renal tissue from dog
Nos. 1-3 were evaluated immunohistochemically with rabbit
anti-canine IgG, IgA, IgM, and C3 portion of complement
(Dako Corp., Carpinteria, CA), using the streptavidin-biotin
technique and the chromogen substrate diaminobenzidine
(Sigma Chemical Co., St. Louis, MO) as previously described.? Tissues were not available for four dogs (Nos. 811) diagnosed at other pathology laboratories; therefore,
only the information contained in pathology reports was
available for review.
Medical information from four related Bullmastiffs with
end-stage renal disease (dog Nos. I through 4) was obtained
from either patient records from the Veterinary Hospital or
Results
Surgical Pathology records at the University of Pennsylvania, School of Veterinary Medicine. Owners, local veteri- Clinical findings
narians, and breeders provided additional information, clinAjrbut one of the affected Bullmastiffs (Nos. 1-10)
ical observations, complete blood cell counts, serum chemappeared
to be healthy until shortly before death. at
istry profiles, and urinalyses (dog Nos. 5 through 16).
which
time
clinical signs that were reported in each
Pedigree information was obtained from the clinically afdog
included
lethargy, weakness, anorexia and weight
fected (dog Nos. 1-11), suspect (dog Nos. 12-16), and sev'110
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Table
Casal, Dambach, Meisler, Jezyk, Pauerson, and Henthorn
Vel PatboI4J :4, 2004
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List of Bullmastiffs affected with glomerulonephritis (dog Nos. 1-11) and Bullmastiffs suspected of having
the same renal disease (dog Nos. 12-16), including renal panels where available..
I~~".
Dog No. .
(age al dealh
in years)
Sex
1 (5.75)
F
2 (3)
3 (5)
F
M
~~1f.
f5
M
M
4 (11)
5 (5)
6 (5)
F
7 (7.75)
M
(3.5)
(6)
(2.5)
(6)
(3)
(3)
F
M
M
M
F
M
14 (1.9)
15 (6.5)
16 (1.3)
M
F
M
8
9
10
11
12
13
.
nl
= normal
Age al
Analysis
(years)
BUN
(mg/dl)
(nl: 6.8-19.1)
(nl: 0.5-1.2)
3
5.75
78
105
1.7
6.4
2
3.5
4
4.5
5
11
1.75
3.25
4.5
4.75
1.5
5
6.5
7.5
7.75
3.5
6
12
1.2
12
41
47
114
15
24
51
62
19
149
16
27
55
50
1.3
1.8
2.6
7
1.0
1.1
2.3
2.2
1.3
5.8
1.16
1.6
2
3
1.1
2.5
1.75
6.5
1.3
Crea.linine
(mg/dl)
'
UPC ratio
(nl: < 0.5)
0.84
1.9
1.57
2.6
2.29
4.9
0.88
3
2.3
25
22
1.87
1.3
12
100
91
1.1
3
1.54
1.8
2.7
2.7
value.
loss, and polyuria/polydypsia. Occasional episodes of
vomiting were noted in dog No.4, which was also
diagnosed with hemangiosarcoma and was subsequently euthanatized. Dog No. 11 was presented to the
local veterinarian with sudden onset of severe dyspnea,
lethargy, and weakness. During the examination the
dog went into cardiac arrest and died before a complete clinical examination could be done. The age of
death or euthanasia for all affected dogs ranged from
2.5 to II years (mean 5.2 :t 2.5 years; Table 1). Anorexia, weakness, lethargy, weight loss, and polyuriaJ
polydypsia were also reported shortly before .death or
euthanasia in five dogs suspected of having the same
renal disease (dog Nos. 12-16). In this group of two
female and three male dogs, the age of death or euthanasia ranged from 1.9 to 6.5 years of age (mean 3.6
:t 2.0 years).
Laboratory tests
Some laboratory test data were available for eight
of the 11 affected dogs (Nos. I and 3-9). Complete
'"'"
blood cell counts were normal, except for lymphocytosis and anemia in one dog with concurreJ;1themangiosarcoma (dog No.4). Elevated BUN and creatinine
levels were present in all affected dogs for which data
were available (Table 1). Examination of the serial serum chemistries for five affected dogs (Nos. 1, 3, 57) revealed mild elevations as early as 1.5 years of age
and up to 3.5 years before death. Severe proteinuria
(4+) occurred in all 11 dogs (Nos. 1-11). UPCs were
determined for six affected dogs (Nos. 3, 5-9). All six
affected dogs had elevated ratios (Table 1). Serial
UPCs were obtained for two of the affected dogs (Nos.
3 and 6) and were elevated 3.5 years before death
(UPC = 2.29 at age 1.5 years; normal UPC < 0.5).
UPCs were determined in 12 related, clinically healthy
dogs (seven female and five male dogs) aged between
6 months and 8 years (mean 2.9 :t 2.5 years). The
ratios\ranged between 0.03 and 0.26 (mean 0.098 :t
0.074), which is lower than is considered normal (UPC
< 0.5) by the Clinical Pathology Laboratory at the
Veterinary Hospital of the University of Pennsylvania.
Bullmastiff Nephropathy
4
5
13 14
7
6
Fig. 1. Composite pedigree of Bullmastiffs affected by
glomerulonephropathy.
Male dogs are represented by
squares and female dogs. circles. The parents of all affected
dogs have a common ancestor (dog No. 17), shown at the
top of the pedigree. Filled-in symbols represent affected
dogs (dog Nos. I-II), diagonally hatched symbols represent
dogs suspected of being affected (dog Nos. 12-16), symbols
shaded in gray represent clinically healthy dogs, and empty
symbols represent dogs for which no further medical history
was available.
Five related Bullmastiffs (Nos. 12-16) were suspected of having the same renal disease described here,
based on similar clinical signs and severe proteinuria
(4+). Elevated serum BUN, creatinine, or UPCs were
demonstrated in some of these dogs (Table I). Dog
No. 13 was euthanatized after lymphosarcoma was diagnosed, and dog No. 14 was euthanatized because of
behavioral problems. In all. five suspects no original
postmortem results were available. However, glomerulonephritis was noted as the final diagnosis in the
records of dog Nos. 13, 15, and 16 provided by the
local veterinarians.
Pedigree
A composite pedigree, shown in Fig. I, contains the
11 Bullmastiffs with glomerulonephropathy (dog Nos.
I-H) and the five dogs suspected to have the same
renal disease (dog Nos. 12-16). All dogs confinned as
well as suspected to be affected have male dog No. 17
as a common ancestor to both their sire and their dam.
Two of the affected Bullmastiffs (Nos. 4 and 7, both
male) were born to clinically normal parents, mitigating against dominant inheritance. Five dogs (Nos. 2,
l
--------
321
female; 3, male; 5, male; 6, female; and II, male) were
born to matings between one affected and one clinically nonnal parent (Fig. 1). There were no matings
between dogs that were proven to be affected based
on histologic findings. However, male dog No.9
(proven to be affected) was bred to female dog No.
IS, which was suspected to be affected based on the
information from the local veterinarian and the breeder. This mating produced two offspring, both affected
(dog Nos. 8, female, and 10, male). There was no medical information available for the parents of dog No.
I (female), who was proven to be affected based on
the histologic findings. Affected male dogs (proven
and suspected) outnumbered affected female dogs by
10 to 6, but this ratio does not differ significantly from
a 1: I ratio. The,one mating between an affected male
dog (No.9) anq an affected female dog (No. 15) produced two offspring, a male and a female dog, both
affected. However, it is not known whether there were
other liuermates. These observations are consistent
with a simple autosomal recessive mode of inheritance
of glomerulopathy in Bullmastiffs. Fully penetrant Xlinked dominant inheritance is excluded by the occurrence of unaffected female dogs in matings between
male dog No. 10, which was continned to be affected,
and an unaffected female dog (Fig. I). Although not
ruled out definitively by the pedigree data in Fig. 1,
X-linked recessive inheritance is less likely, with dog
No. I (female) producing three nonnal male offspring.
However, the sample size was small, a diagnosis was
not confinned in every dog, and infonnation on all
liuennates of affected dogs was not available to allow
an accurate estimation of segregation ratios. Consequently, an autosomal recessive mode of inheritance
should be taken as a working hypothesis, with a more
complex mode of inheritance also possible.Pathology
Renal biopsy specimens without other pathology
data were available for dog Nos. I and 2. Postmortem
examinations were perfonned in dog Nos. 3 and 4 at
the University of Pennsylvania and on dog No. 11 by
the local veterinarian. Gross descriptions of the kidneys from the other eight cases were not available (dog
Nos. 1, 2, 5-10). Both kidneys of dog No.3 were
smaller than nonnal, with three to four linear depressions in the cortical surfaces, which extended toward
the medullae. This dog was diagnosed with glomerulonephritis, which was the only significant disease process responsible for the dog's death.
The. kidneys from dog No.4 were grossly nonnal
except' for a focal tan area in the corticomedullary region, 'which corresponded to a regional infarct histologically. Although the significant cause of death in
this case was splenic hemangiosarcoma and secondary
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Casal, Dambach, Meister, Jezyk, Patterson, and Henthorn
Vet P8IboI41:4,
2004
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Table 2; Sununary of histological findings of renal tissues from Bullmastiffs affected with glomerulonephropathy.
Reports were available only for dog Nos. 8-11. Conunents included "like Elkhound disease" (dog Nos. 8 and 9), "chronic
glomerular disease" (dog No. 10), and "end-stage kidney disease" (dog No. 11).*
Y
Y
Y
Y
Y
Y
Y
N
N
Periglomerular sclerosis
Thickened Bowman's capsule
Glomerulopathy
Thbular atrophy
Interstitial inflammation
Interstitial fibrosis
Dilated tubules
Dilated Bowman's capsule
Shrunken glomeruli
. N = not present, Y =
2
3
4
5
Dog No.
6
7
8
9
10
II
N
Y
y
y
y
y
Y
Y
y
N
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
N
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
Y
Y
?
Y
?
?
?
?
?
?
?
?
Y
Y
Y
Y
?
?
?
?
'l
Y
'!
Y
Y
?
?
?
?
?
Y
Y
?
?
?
?
Y
present, ? = unknown.
hemoperitoneum, there was also biochemical evidence
of glomerular disease (Table I).
Dog No. 11 died unexpectedly of heart failure at 3
years of age. On necropsy the local veterinarian found
large thrombi in the pulmonary vasculature, with the
largest occluding the main pulmonary vein, and the
heart appeared mildly enlarged. The kidneys, however,
appeared grossly normal.
Glomerular changes predominated and were similar
in the seven affected kidneys examined histologically
(Table 2). The predominant glomerular change was
segmental expansion of the mesangial matrix and an
increase in the number of cells in the tufts in the expanded areas (Fig. 2). As such, the glomerular changes
were typically diagnosed as either membranoproliferative or membranous glomerulonephritis. Occasional
glomeruli had foci of active necrosis, infiltrates of neutrophils or rare plasma cell infiltrates. Although all glo-
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meruli were affected, the expansion of the tuft was
typically segmental and often in the hilar region or
associated with adhesions to Bowman's capsule. Masson's trichrome and PAS stains revealed that the expanded eosi,nophilic mesangial material was predominantly collagen (sclerosis) with mildly increased matrix deposition. Less frequently, there was evidence of
capillary loop membrane expansion by PAS-positive
matrix. In several glomeruli in each case, there were
mesangial segments, which were greatly expanded by
hyaline material, forming nodular foci within the tufts
(Fig. 3). The nodular, hyaline areas were consistent
with hyalinosis (PAS positive; red with trichrome and
negative with Jone's methenamine silver; not shown).
Congo red staining of the kidneys was uniformly negative in all cases, which indicates the absence of amyloid.
Another striking change associated with the glo-
'.""".Y.,
Fig. 2. Glomerulus; Bullmastiffwith glomerulonephropathy, dqg No.5.
and increased cellularity. PAS-methenamine silver. Bar = 20 ~m.
Segmental expansion of the mesangial matrix
Fig. 3. Glomeruli; Bullmastiff with glomerulonephropathy, dog No.5. Segmental. nodular hyalinosis with adhesions to
Bowman's capsule. HE. Bar = 30 ~m.
Bullmasliff Nephropathy
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meruli in four cases (dog Nos. 2, 3, 5, and 6) was
marked dilatation of Bowman's capsule, accentuating
the urinary space with only irregular remnants of glomerular tufts remaining (cystic glomerular atrophy).
The majority of these irregularly shaped tufts were
separated into two distinct lobules that were collapsed
and sclerotic with segmental adhesions to Bowman's
capsule; however, there were occasional tufts that had
remarkably normal components remaining. Also noted
in all but five cases were multifocal shrunken glomeruli (approximately 6 per 100) with collapsed and fibrotic, eosinophilic tuft remnants (obsolescent glomeruli).
Thickening of Bowman's capsule by collagen and
PAS-positive basement membrane material was present in all seven cases examined by the authors. Periglomerular sclerosis was multifocal and noted histologically or reported in only six cases.
Mild to moderate multifocal .interstitial fibrosis was
present or reported in nine cases. The fibrosis involved
both the medulla and the cortex. It was more diffuse
in the medulla, whereas in the cortex the fibrotic areas
tended to form radial bands toward the capsular surface. Tubular atrophy was associated with these fibrotic areas in nine cases. There was mild to moderate
tubular dilatation present in the seven cases examined
histologically, with luminal protein casts evident multifocally. Multifocal tubular epithelial hypertrophy was
noted occasionally in three cases. Proliferation of medullary tubular epithelium (metanephric ductlike) was
noted in dog Nos. 3 and 5. Lymphoplasmacytic interstitial inflammation was mild to moderate in nine cases
and was predominantly associated with the areas of
fibrosis and around glomeruli. The findings from all
cases are summarized in Table 2.
Immunohistochemical evaluation of the glomeruli
of dog Nos. 1-3 revealed minimal segmental deposition of IgM in the capillary loops and mesangium multifocally. Limited deposits of IgG and C3 were detected segmentally along occasional capillary loops in
two of th~three cases examined. IgA was not detected
in any case.
Extrarenal lesions in the suspect and affected Bullmastiffs included splenic hemangiosarcoma (dog No.
4), thromboembolic disease (dog No. 11), and lymphosarcoma (dog No. 13).
Discussion
Familial. renal disease of dogs can be separated into
three maj~ categories based on histologic patterns:
dysplasia, primary glomerular disease, and primary tubular disease. Those renal diseases characterized as
dysplastic: have features suggesting abnormal maturation of th~ nephron and its supporting interstitium,
with asynchronous glomerular development including
323
retention of fetal glomeruli, primitive tubules with retained metanephric ducts, and retention of primitive
mesenchyme. Those diseases characterized as glomerular have clinical evidence of glomerular disease and
diffuse involvement of glomeruli with secondary tubular and interstitial changes. Thbular diseases are
principally recognized as functional disturbances with
subtle to no characterizing histologic features. DiBartola8 has recently summarized familial renal diseases of the dog in this manner.
The clinical findings in the affected Bullmastiffs described here were nonspecific. Only anorexia, lethargy,
weight loss, and occasionally polyuria/polydipsia were
noticed shortly before death. This is typical of chronic
glomerulonephritis, whereas polyuria, polydipsia, and .
vomiting are more commonly found in dogs with renal
dysplasia.8 Th6 slow and insidious onset of the disease
process was characterized by increased BUN and creatinine, and proteinuria early in the course of disease,
well before clinical signs were present. An increased
UPC was found up to 3.5 years before the onset of
clinical signs in one of the affected dogs. Death occurred between 2.5 and 11 years of age.
GlomeruJopathics in the dog are transmitted as an
autosomal dominant trait in the Bull Terrier;12 as autosomal recessive traits in the Bernese Mountain
Dog,26 Cocker Spaniel,1O Shih Tzu,13 and Soft Coated
Wheaten Terrier;21.24or as an X-linked dominant trait
in the Samoyed.'5 In the present study in Bullmastiffs,
both sexes were affected with about equal frequency,
and clinically normal parents produced male and female dogs with glomerular disease. These findings are
consistent with an autosomal recessive mode of inheritance. However, additional family studies and breeding studies will be needed to verify this.
All tissues of the affected dogs had. histologic
changes characteristic of a chronic glomerulopathy.
The changes were advanced, with segmental glomerular sclerosis as the typical feature: In three of 11 samples, IgM immunoglobulin deposition was minor, was
present only in occasional glomeruli, and is most likely a secondary, nonspecific trapping of the components
in glomeruli damaged by the primary process. The
morphologic appearance of the glomerular changes
and the immunohistochemical findings are not suggestive of an infectious or primary immune-mediated process but more closely resemble the familial diseases of
breeds such as the Samoyed,I.15,29 Doberman Pinscher,4.2S.30
Rottweiler,6 Bull Terrier,J7 older Soft Coated
Wheaten Terrier,8.21and Newfoundland dog.20 This resemblance suggests the possibility of a biochemical or
struC\~ral def@ctin the glomerular basement membrane
as an underlying etiology, as proven in the Sarnoyed29.31and suspected in the Doberman Pinscher2S disease. An o-collagen-5 defect has been recognized in
.....
Casal, Dambach, Meister, Jezyk, Paucrson, and Henthorn
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the Samoyed glomerulopathy, which is inherited as an
X-linked dominant trait. Interestingly, both affected
male and female hcterozygotes develop proteinuria at
2-3 months of age, but only affected male dogs had a
decreased glomerular filtration rate. Focal multilaminar splitting of the glomerular capillary basement
membranes was found on ultrastructural examination.
Female dogs showed no signs of renal failure by 30
months of age, whereas affected male Samoyeds had
usuaHy died by 15 months of age.14 A dominant mode
of inheritance (such as X-linked dominant) is consistent with this concept of an inherited structural defect.
The presence of dilated Bowman's capsules in association with remnants of glomerular tufts, seen in
some of the affected dogs, has been termed cystic glomerular atrophy, which is also present in the familial
renal diseases of the Doberman Pinscher, standard
Poodle, RottweiJer, and BuH Terrier breeds. It is
thought to be a secondary change, perhaps related to
nephron blockage from fibrosis more distally.8
The underlying molecular abnormality responsible
for the development of the inherited glomerular disease in BulJmastiffs described here is unknown. The
materials available for this study were limited to tissues coHected terminally in the disease. Clinically,
there is evidence that proteinuria develops at a younger
age before clinical signs are apparent. The glomerulosclerosis-type changes seen here are commonly
caused by immunologic diseases, with associated amyloidosis or deposition of immune complexes in both
cats and dogs.8 However, there was no histologic evidence suggesting immune-mediated renal damage. Interestingly, glomerulosclerosis is quite prevalent (80%) among captive cheetahs both in South Africa and
in the United States of America.23 However, the form
of glomerulosclerosis described in the cheetah more
closely resembles diabetic nephropathy of humans.
Thus, it was suggested that chronic stress led to hyperglycemia through hyperadrenocorticism, which in
turn led to the nephropathy.3-Alternatively, the changes
also resembled those in the rat. Chronic progressive
rat nephropathy is characterized by late-onset renal
failure and is more common and more severe in male
than in female dogs. A familial basis has been proposed because the disease is common in a variety of
albino rat strains. However, high-protein diets have
also been suggested as a cause of rat nephropathy'"
The histologic findings described in the Bullmastiffs
resemble focal segmental glomerulosclerosis (FSGS)
in humans, which is seen in several renal disorders, all
of which are characterized by proteinuria and chronic,
progressive loss of renal functiOn. Familial forms have
been described,s.9.28and both autosomal recessive and
autosomal dominant modes of inheritance have been
suggested.s In humans and mice, mutations of cd2apl'J
Vel P8&boI4t:4, 2004
and acln418 have been shown to cause FSGS. Both
genes code for structural proteins, and ACTN4 is expressed at high levels in the glomerular podocyte. III
Elucidation of' the mechanisms of the renal disease
described here will require a prospective analysis,
which could include serial evaluation of biochemical
values, renal histology and electron microscopy, and
immunohistochemistry in dogs produced from affected
parents. Determination of the actual onset of the disease will require serum chemistry and urinalysis at an
early age, with continued evaluation at reasonable time
intervals.
Acknowledgements
.
This wock~was supported in pact by National Institutes of
Health grant RR02512. We thank the referring veterinarians
for submitting b~opsymaterial and the BuUmastiff breeders
for supplying pedigree and health information.
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of splitting glomerular capillary basement membranes.
Am J Pathol 125:536-545, 1986
16 Johnson ME, Denhart JD, Graber ER: Renal cortical hypoplasia in a litter of Cocker Spaniels. J Am Anim Hosp
Assoc 8:268-274, 1972
17 Jones BR, Gething MA, Badcoe LM, Pauli JV, Davies
E: Familial progressive nephropathy in young bull terriers. N Z Vet J 37:79-82, 1989
18 Kaplan JM, Kim SH, North KN, Rennke H, Correia LA,
Tong H-Q, Mathis BJ, Rodriguez-Perez J-C, Allen PG,
Beggs AH, Pollak MR: Mutations in ACTN4, encoding
alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Gcnet 24:251-256, 2000
19 KimJM, Wu H, Green G, Winkler CA, Kopp lB, Miner
JH, Unanue ER, Shaw AS: CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility. Science 300: 1298-1300, 2003
20 Koeman Jp, Biewenga WJ, Gruys E: Proteinuria associated with glomerulosclerosis and glomerular collagen
formation in three Ncwfoundland dog littermates. Vet
Pathol 31:188-193, 1994
21 Littman Mp, Dambach DM, Vaden SL, Giger U: Familial
protein-losing enteropathy and protein-losing nephropathy in Soft Coated Wheaten Terriers: 222 cases (19831997). J Vet Int Med 14:68-80, 2000
22 Minkus G, Breuer W, Wanke R, Reusch C, Leuterer G,
Brem G, Hermanns W: Familial nephropathy in Bemese
mountain dogs. Vet Pathol 31:421-428, 1994
23 Munson L, Nesbit JW, Meltzer DGA, Colly Lp, Bolton
L, Krick, NPJ: Diseases of captive cheetahs (Acinonyx
jubatus jubatus) in South Africa: a 20-year retrospective
survey. J Zoo Wildl Med 30:342-347, 1999
24 Nash AS, Kelly DF, Gaskell CJ: Progressive renal disease in Soft-Coated Wheaten Terrier: possible familial
nephropathy. J Small Anim Pract 25:479-487, 1984
25 Picut CA, Lewis RM: Juvenile renal disease in the Doberman Pinscher: ultrastructural changes in the glomerular
basement membrane. J Comp Pathol 97:587-596, 1987
26 Reusch C, Hoerauf A, Lechner J, Kirsch M, Leuterer G,
Minkus G, Brem G: A new familial glomerulonephropathy in Bemese mountain dogs. Vet Rec 134:411-415,
1994
27 Steward Ap, McDougall DF: Familial nephropathy in the
Cocker SpaQ~e1.J Small Anim Pract 25:15-24, 1984
28 Tejani A, Nicastri A, Phadke K, Sen D, Adamson 0,
Dunn I, ,Calderon P: Familial focal segmental glomerulosclerosis. Inl J Pediatr Nephrol 4:231-234, 1983
29 Thorner P, Jansen B, Baumal R, Valli V, Goldberger A:
Samoyed hereditary glomerulopathy: immunohistochemical staining of the basement membranes of kidney for
laminin, collagen type IV, fibronectin, and Goodpasture
antigen, and correlation with electron microscopy of glomerular capillary basement membranes. Lab Invest 56:
435-443, 1987
30 Wilcock Bp, Patterson JM: Familial glomerulonephritis
in Doberman Pinschers, Can Vet J 20:244-249, 1979
31 Zheng K, Thorner PS, Marrano P, Baumal R, McInnes
RR: Canine X chromosome-linked hereditary nephritis:
a genetic model for human X-linked hereditary nephritis
resulting from iI single base mutation in the gene encoding the u5 chain of collagen type IV. Proc Natl Acad Sci
USA 91:39H9-3993, 1994
,
..",
,
Requests reprinls from Dr. M. L. Casal, Section of Medical Genetics, Veterinary Hospital of the University of Pennsylvania,
3900 Delancey Street, Philadelphia, PA 19104-6010 (USA). E-mail: casalml(g>vel.upenn.edu.
....
,
Vel PoIhol41:4.
2004
325
Bullmastiff Nephropathy
13 Hoppe A, Swenson L, JOnsson L, Hedhammar A: Progressive nephropathy due to renal dysplasia in Shih Tzu
dogs in Sweden: a clinical pathological and genetic
study. J Small Anim Pract 31:83-91, 1990
14 Jansen B, Valli VEO, Thorner P, Baumal R, Lumsden
JH: Samoyed hereditary glomcrulopathy: serial, clinical
and laboratory (urine, serum biochemistry and hematology) studies. Am J Vet Rcs 51:387-393, 1987
15 Jansen BJ, Thorner P, Baumal R, Valli V, Maxia MG,
Singh A: Samoyed hereditary glomerulopathy: evolution
of splitting glomerular capillary basement membranes.
Am J Pathol 125:536--545, 1986
16 Johnson ME, Denhart JD, Graber ER: Renal cortical hypoplasia in a litter of Cocker Spaniels. J Am Anim Hosp
Assoc 8:268-274, 1972
17 Jones BR, Gething MA, Badcoe LM, Pauli JV, Davies
E: Familial progressive nephropathy in young bull terriers. N Z Vet J 37:79-82, 1989
18 Kaplan JM, Kim SH, North KN, Rennke H, Correia LA,
Tong H-Q, Mathis BJ, Rodriguez-Perez J-C, Allen PG,
Beggs AH, Pollak MR: Mutations in ACTN4, encoding
alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Gcnet 24:25 1-256, 2000
19 KimJM, Wu H, Green G, Winkler CA, Kopp JR, Miner
JH, Unanue ER, Shaw AS: CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility. Science 300: 1298-1300, 2003
20 Koeman Jp, Biewenga WJ, Gruys E: Proteinuria associated with glomerulosclerosis and glomerular collagen
formation in three Newfoundland dog littermates. Vet
Pathol 31:188-193, 1994
21 Littman Mp, Dambach DM, Vaden SL, Giger U: Familial
protein-losing enteropathy and protein-losing nephropathy in Soft Coated Wheaten Terriers: 222 cases (19831997). J Vet Int Med 14:68-80, 2000
22 Minkus G, Breuer W, Wanke R, Reusch C, Leuterer G,
Brem G, Hermanns W: Familial nephropathy in Bemese
mountain dogs. Vet Pathol 31:421-428, 1994
23 Munson L, Nesbit JW, Meltzer DGA, Colly Lp, Bolton
L, Krick, NPJ: Diseases of captive cheetahs (Acinonyx
jubatus jubatus) in South Africa: a 20-year retrospective
survey. J Zoo Wildl Med 30:342-347, 1999
24 Nash AS, Kelly DF, Gaskell CJ: Progressive renal disease in Soft-Coated Wheaten Terrier: possible familial
nephropathy. J Small Anim Pract 25:479-487, 1984
25 Picut CA, Lewis RM: Juvenile renal disease in the Doberman Pinscher: ultrastructural changes in the glomerular
basement membrane. J Comp Pathol 97:587-596, 1987
26 Reusch C, Hoerauf A, Lechner J, Kirsch M, Leuterer G,
Minkus G, Brem G: A new familial glomerulonephropathy in Bemese mountain dogs. Yet Rec 134:411-415,
1994
27 Steward Ap, McDougall DF: Familial nephropathy in the
Cocker SpaQ~el. J Small Anim Pract 25:15-24, 1984
28 Tejani A, Nicastri A, Phadke K, Sen D, Adamson 0,
Dunn I, ,Calderon P: Familial focal segmental glomerulosclerosis. Inl J Pediatr Nephrol 4:231-234, 1983
29 Thorner P, Jansen B, Baumal R, Valli V, Goldberger A:
Samoyed hereditary glomerulopathy: immunohistochemical staining of the basement membranes of kidney for
laminin, collagen type IV, fibronectin, and Goodpasture
antigen, and correlation with electron microscopy of glomerular capillary basement membranes. Lab Invest 56:
435-443, 1987
30 Wilcock Bp, Patterson JM: Familial glomerulonephritis
in Doberman Pinschers. Can Vet J 20:244-249, 1979
31 Zheng K, Thorner PS, Marrano P, Baumal R, McInnes
RR: Canine X chromosome-linked hereditary nephritis:
a genetic model for human X-linked hereditary nephritis
resulting from.. single base mutation in the gene encoding the u5 chain of collagen type IY. Proc Natl Acad Sci
USA 91:39~9-3993, 1994
,
..",
,
Requests reprinls from Dr. M. L. Casal, Section of Medical Genetics, Veterinary Hospital of the University of Pennsylvania,
3900 Delancey Street, Philadelphia, PA 19104-6010 (USA). E-mail: casalml(g>veLupenn.edu.
...