Familial Glomerulonephropathy in the Bullmastiff
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Vet Pathol 41:319–325 (2004)
Familial Glomerulonephropathy in the Bullmastiff
M. L. CASAL, D. M. DAMBACH, T. MEISTER, P. F. JEZYK, D. F. 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 11 related Bullmastiff dogs,
and clinical and laboratory data were collected retrospectively. Four female and seven male dogs between the
ages of 2.5 and 11 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 at 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; histology; kidney; pathology.
Inherited glomerulopathies have been described in eral closely related clinically healthy Bullmastiffs. Dogs old-
the Bull Terrier,12 Cocker Spaniel,10,16,27 Samoyed,1,2 er than 6 years of age with normal serum biochemistry val-
Shih Tzu,13 Soft Coated Wheaten Terrier,24 and Ber- ues and normal urine protein-creatinine ratios (UPCs) or
nese Mountain Dog.22,26 A hereditary basis for glo- with no histologic evidence of renal disease were considered
normal.
merulopathy is also highly likely in the Doberman Pin-
Tissues obtained through case submissions to the Surgical
scher4,30 and the Newfoundland dog.20 The age of onset Pathology (dog Nos. 1 and 2) and Necropsy (dog Nos. 3 and
of clinical signs in familial glomerulopathies ranges 4) Services of the University of Pennsylvania, School of
from a few weeks to several years of age. Clinical Veterinary Medicine, were fixed in 10% neutral buffered for-
signs include anorexia, lethargy, weight loss, polyuria, malin, processed routinely, embedded in paraffin, and sec-
polydipsia, and vomiting. Although proteinuria is the tioned at 3 m for light microscopy. Blocks of paraffin-
hallmark of these glomerulopathies, laboratory find- embedded renal tissue from three additional cases (dog Nos.
ings have varied considerably and can include isosthe- 5–7) were obtained from two other diagnostic pathology lab-
nuria, aminoaciduria, glucosuria, increased protein- oratories. Serial sections of kidney were stained with he-
creatinine ratios, nonregenerative anemia, increased matoxylin and eosin, Masson’s trichrome for collagen, Con-
blood urea nitrogen (BUN) concentrations, increased go red for amyloid, periodic acid–Schiff (PAS) for matrix
deposition, Jones’ methenamine silver for basement mem-
creatinine levels, hypoalbuminemia, hyperphosphate-
branes, and alcian blue (pH 2.7) for acid mucopolysaccha-
mia, and hypercholesterolemia. rides. Additional 3-m sections of renal tissue from dog
In this report we describe and discuss the range of Nos. 1–3 were evaluated immunohistochemically with rabbit
clinical, laboratory, and histologic findings in 11 re- anti-canine IgG, IgA, IgM, and C3 portion of complement
lated Bullmastiffs, along with pedigree relationships (Dako Corp., Carpinteria, CA), using the streptavidin–biotin
and family data supporting an autosomal recessive technique and the chromogen substrate diaminobenzidine
mode of inheritance. (Sigma Chemical Co., St. Louis, MO) as previously de-
scribed.7 Tissues were not available for four dogs (Nos. 8–
Materials and Methods 11) diagnosed at other pathology laboratories; therefore,
Medical information from four related Bullmastiffs with only the information contained in pathology reports was
end-stage renal disease (dog Nos. 1 through 4) was obtained available for review.
from either patient records from the Veterinary Hospital or
Surgical Pathology records at the University of Pennsylva- Results
nia, School of Veterinary Medicine. Owners, local veteri- Clinical findings
narians, and breeders provided additional information, clin-
ical observations, complete blood cell counts, serum chem- All but one of the affected Bullmastiffs (Nos. 1–10)
istry profiles, and urinalyses (dog Nos. 5 through 16). appeared to be healthy until shortly before death, at
Pedigree information was obtained from the clinically af- which time clinical signs that were reported in each
fected (dog Nos. 1–11), suspect (dog Nos. 12–16), and sev- dog included lethargy, weakness, anorexia and weight
319
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Table 1. 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.*
Dog No. Age at BUN Creatinine
(age at death Analysis (mg/dl) (mg/dl) UPC ratio
in years) Sex (years) (nl: 6.8–19.1) (nl: 0.5–1.2) (nl: ⬍ 0.5)
1 (5.75) F 3 78 1.7
5.75 105 6.4
2 (3) F
3 (5) M 2 12 1.2 0.84
3.5 1.9
4 12 1.3 1.57
4.5 41 1.8
5 47 2.6
4 (11) M 11 114 7
5 (5) M 1.75 15 1.0
3.25 24 1.1
4.5 51 2.3 2.6
4.75 62 2.2
6 (5) F 1.5 19 1.3 2.29
5 149 5.8 4.9
7 (7.75) M 6.5 16 1.16 0.88
7.5 27 1.6
7.75 55 2
8 (3.5) F 3.5 50 3
9 (6) M 6 2.3
10 (2.5) M
11 (6) M
12 (3) F 3 25 1.87 3
13 (3) M 1.1 22 1.3
2.5 1.54
14 (1.9) M 1.75 12 1.1 1.8
15 (6.5) F 6.5 100 2.7
16 (1.3) M 1.3 91 2.7
* nl ⫽ normal value.
loss, and polyuria/polydypsia. Occasional episodes of blood cell counts were normal, except for lymphocy-
vomiting were noted in dog No. 4, which was also tosis and anemia in one dog with concurrent heman-
diagnosed with hemangiosarcoma and was subse- giosarcoma (dog No. 4). Elevated BUN and creatinine
quently euthanatized. Dog No. 11 was presented to the levels were present in all affected dogs for which data
local veterinarian with sudden onset of severe dyspnea, were available (Table 1). Examination of the serial se-
lethargy, and weakness. During the examination the rum chemistries for five affected dogs (Nos. 1, 3, 5–
dog went into cardiac arrest and died before a com- 7) revealed mild elevations as early as 1.5 years of age
plete clinical examination could be done. The age of and up to 3.5 years before death. Severe proteinuria
death or euthanasia for all affected dogs ranged from (4⫹) occurred in all 11 dogs (Nos. 1–11). UPCs were
2.5 to 11 years (mean 5.2 ⫾ 2.5 years; Table 1). An- determined for six affected dogs (Nos. 3, 5–9). All six
orexia, weakness, lethargy, weight loss, and polyuria/ affected dogs had elevated ratios (Table 1). Serial
polydypsia were also reported shortly before death or UPCs were obtained for two of the affected dogs (Nos.
euthanasia in five dogs suspected of having the same 3 and 6) and were elevated 3.5 years before death
renal disease (dog Nos. 12–16). In this group of two (UPC ⫽ 2.29 at age 1.5 years; normal UPC ⬍ 0.5).
female and three male dogs, the age of death or eu- UPCs were determined in 12 related, clinically healthy
thanasia ranged from 1.9 to 6.5 years of age (mean 3.6 dogs (seven female and five male dogs) aged between
⫾ 2.0 years). 6 months and 8 years (mean 2.9 ⫾ 2.5 years). The
ratios ranged between 0.03 and 0.26 (mean 0.098 ⫾
Laboratory tests 0.074), which is lower than is considered normal (UPC
Some laboratory test data were available for eight ⬍ 0.5) by the Clinical Pathology Laboratory at the
of the 11 affected dogs (Nos. 1 and 3–9). Complete Veterinary Hospital of the University of Pennsylvania.
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female; 3, male; 5, male; 6, female; and 11, male) were
born to matings between one affected and one clini-
cally normal 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.
15, which was suspected to be affected based on the
information from the local veterinarian and the breed-
er. This mating produced two offspring, both affected
(dog Nos. 8, female, and 10, male). There was no med-
ical information available for the parents of dog No.
1 (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 : 1 ratio. The one mating between an affected male
dog (No. 9) and an affected female dog (No. 15) pro-
duced two offspring, a male and a female dog, both
affected. However, it is not known whether there were
other littermates. These observations are consistent
with a simple autosomal recessive mode of inheritance
Fig. 1. Composite pedigree of Bullmastiffs affected by of glomerulopathy in Bullmastiffs. Fully penetrant X-
glomerulonephropathy. Male dogs are represented by linked dominant inheritance is excluded by the occur-
squares and female dogs, circles. The parents of all affected rence of unaffected female dogs in matings between
dogs have a common ancestor (dog No. 17), shown at the male dog No. 10, which was confirmed to be affected,
top of the pedigree. Filled-in symbols represent affected
and an unaffected female dog (Fig. 1). Although not
dogs (dog Nos. 1–11), diagonally hatched symbols represent
dogs suspected of being affected (dog Nos. 12–16), symbols
ruled out definitively by the pedigree data in Fig. 1,
shaded in gray represent clinically healthy dogs, and empty X-linked recessive inheritance is less likely, with dog
symbols represent dogs for which no further medical history No. 1 (female) producing three normal male offspring.
was available. However, the sample size was small, a diagnosis was
not confirmed in every dog, and information on all
littermates of affected dogs was not available to allow
Five related Bullmastiffs (Nos. 12–16) were sus- an accurate estimation of segregation ratios. Conse-
pected of having the same renal disease described here, quently, an autosomal recessive mode of inheritance
based on similar clinical signs and severe proteinuria should be taken as a working hypothesis, with a more
(4⫹). Elevated serum BUN, creatinine, or UPCs were complex mode of inheritance also possible.
demonstrated in some of these dogs (Table 1). Dog
No. 13 was euthanatized after lymphosarcoma was di- Pathology
agnosed, and dog No. 14 was euthanatized because of Renal biopsy specimens without other pathology
behavioral problems. In all five suspects no original data were available for dog Nos. 1 and 2. Postmortem
postmortem results were available. However, glomer- examinations were performed in dog Nos. 3 and 4 at
ulonephritis was noted as the final diagnosis in the the University of Pennsylvania and on dog No. 11 by
records of dog Nos. 13, 15, and 16 provided by the the local veterinarian. Gross descriptions of the kid-
local veterinarians. neys from the other eight cases were not available (dog
Nos. 1, 2, 5–10). Both kidneys of dog No. 3 were
Pedigree smaller than normal, with three to four linear depres-
A composite pedigree, shown in Fig. 1, contains the sions in the cortical surfaces, which extended toward
11 Bullmastiffs with glomerulonephropathy (dog Nos. the medullae. This dog was diagnosed with glomeru-
1–11) and the five dogs suspected to have the same lonephritis, which was the only significant disease pro-
renal disease (dog Nos. 12–16). All dogs confirmed as cess responsible for the dog’s death.
well as suspected to be affected have male dog No. 17 The kidneys from dog No. 4 were grossly normal
as a common ancestor to both their sire and their dam. except for a focal tan area in the corticomedullary re-
Two of the affected Bullmastiffs (Nos. 4 and 7, both gion, which corresponded to a regional infarct histo-
male) were born to clinically normal parents, mitigat- logically. Although the significant cause of death in
ing against dominant inheritance. Five dogs (Nos. 2, this case was splenic hemangiosarcoma and secondary
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Table 2. Summary of histological findings of renal tissues from Bullmastiffs affected with glomerulonephropathy.
Reports were available only for dog Nos. 8–11. Comments included ‘‘like Elkhound disease’’ (dog Nos. 8 and 9), ‘‘chronic
glomerular disease’’ (dog No. 10), and ‘‘end-stage kidney disease’’ (dog No. 11).*
Dog No.
1 2 3 4 5 6 7 8 9 10 11
Periglomerular sclerosis Y N N Y Y Y Y Y ? ? ?
Thickened Bowman’s capsule Y Y Y Y Y Y Y ? ? ? ?
Glomerulopathy Y Y Y Y Y Y Y Y Y Y Y
Tubular atrophy Y Y Y Y Y Y Y ? Y ? Y
Interstitial inflammation Y Y Y Y Y Y Y ? Y Y ?
Interstitial fibrosis Y Y Y Y Y Y Y ? Y Y ?
Dilated tubules Y Y Y Y Y Y Y ? ? ? ?
Dilated Bowman’s capsule N Y Y N Y Y N ? ? ? ?
Shrunken glomeruli N Y Y N Y Y Y ? ? ? Y
* N ⫽ not present, Y ⫽ present, ? ⫽ unknown.
hemoperitoneum, there was also biochemical evidence meruli were affected, the expansion of the tuft was
of glomerular disease (Table 1). typically segmental and often in the hilar region or
Dog No. 11 died unexpectedly of heart failure at 3 associated with adhesions to Bowman’s capsule. Mas-
years of age. On necropsy the local veterinarian found son’s trichrome and PAS stains revealed that the ex-
large thrombi in the pulmonary vasculature, with the panded eosinophilic mesangial material was predomi-
largest occluding the main pulmonary vein, and the nantly collagen (sclerosis) with mildly increased ma-
heart appeared mildly enlarged. The kidneys, however, trix deposition. Less frequently, there was evidence of
appeared grossly normal. capillary loop membrane expansion by PAS-positive
Glomerular changes predominated and were similar matrix. In several glomeruli in each case, there were
in the seven affected kidneys examined histologically mesangial segments, which were greatly expanded by
(Table 2). The predominant glomerular change was hyaline material, forming nodular foci within the tufts
segmental expansion of the mesangial matrix and an (Fig. 3). The nodular, hyaline areas were consistent
increase in the number of cells in the tufts in the ex- with hyalinosis (PAS positive; red with trichrome and
panded areas (Fig. 2). As such, the glomerular changes negative with Jone’s methenamine silver; not shown).
were typically diagnosed as either membranoprolifer- Congo red staining of the kidneys was uniformly neg-
ative or membranous glomerulonephritis. Occasional ative in all cases, which indicates the absence of am-
glomeruli had foci of active necrosis, infiltrates of neu- yloid.
trophils or rare plasma cell infiltrates. Although all glo- Another striking change associated with the glo-
Fig. 2. Glomerulus; Bullmastiff with glomerulonephropathy, dog No. 5. Segmental expansion of the mesangial matrix
and increased cellularity. PAS-methenamine silver. Bar ⫽ 20 m.
Fig. 3. Glomeruli; Bullmastiff with glomerulonephropathy, dog No. 5. Segmental, nodular hyalinosis with adhesions to
Bowman’s capsule. HE. Bar ⫽ 30 m.
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meruli in four cases (dog Nos. 2, 3, 5, and 6) was retention of fetal glomeruli, primitive tubules with re-
marked dilatation of Bowman’s capsule, accentuating tained metanephric ducts, and retention of primitive
the urinary space with only irregular remnants of glo- mesenchyme. Those diseases characterized as glomer-
merular tufts remaining (cystic glomerular atrophy). ular have clinical evidence of glomerular disease and
The majority of these irregularly shaped tufts were diffuse involvement of glomeruli with secondary tu-
separated into two distinct lobules that were collapsed bular and interstitial changes. Tubular diseases are
and sclerotic with segmental adhesions to Bowman’s principally recognized as functional disturbances with
capsule; however, there were occasional tufts that had subtle to no characterizing histologic features. Di-
remarkably normal components remaining. Also noted Bartola8 has recently summarized familial renal dis-
in all but five cases were multifocal shrunken glomer- eases of the dog in this manner.
uli (approximately 6 per 100) with collapsed and fi- The clinical findings in the affected Bullmastiffs de-
brotic, eosinophilic tuft remnants (obsolescent glomer- scribed here were nonspecific. Only anorexia, lethargy,
uli). weight loss, and occasionally polyuria/polydipsia were
Thickening of Bowman’s capsule by collagen and noticed shortly before death. This is typical of chronic
PAS-positive basement membrane material was pre- glomerulonephritis, whereas polyuria, polydipsia, and
sent in all seven cases examined by the authors. Per- vomiting are more commonly found in dogs with renal
iglomerular sclerosis was multifocal and noted histo- dysplasia.8 The slow and insidious onset of the disease
logically or reported in only six cases. process was characterized by increased BUN and cre-
Mild to moderate multifocal interstitial fibrosis was atinine, and proteinuria early in the course of disease,
present or reported in nine cases. The fibrosis involved well before clinical signs were present. An increased
both the medulla and the cortex. It was more diffuse UPC was found up to 3.5 years before the onset of
in the medulla, whereas in the cortex the fibrotic areas clinical signs in one of the affected dogs. Death oc-
tended to form radial bands toward the capsular sur- curred between 2.5 and 11 years of age.
face. Tubular atrophy was associated with these fi- Glomerulopathies in the dog are transmitted as an
brotic areas in nine cases. There was mild to moderate autosomal dominant trait in the Bull Terrier;12 as au-
tubular dilatation present in the seven cases examined tosomal recessive traits in the Bernese Mountain
histologically, with luminal protein casts evident mul- Dog,26 Cocker Spaniel,10 Shih Tzu,13 and Soft Coated
tifocally. Multifocal tubular epithelial hypertrophy was Wheaten Terrier;21,24 or as an X-linked dominant trait
noted occasionally in three cases. Proliferation of med- in the Samoyed.15 In the present study in Bullmastiffs,
ullary tubular epithelium (metanephric ductlike) was both sexes were affected with about equal frequency,
noted in dog Nos. 3 and 5. Lymphoplasmacytic inter- and clinically normal parents produced male and fe-
stitial inflammation was mild to moderate in nine cases male dogs with glomerular disease. These findings are
and was predominantly associated with the areas of consistent with an autosomal recessive mode of inher-
fibrosis and around glomeruli. The findings from all itance. However, additional family studies and breed-
cases are summarized in Table 2. ing studies will be needed to verify this.
Immunohistochemical evaluation of the glomeruli All tissues of the affected dogs had histologic
of dog Nos. 1–3 revealed minimal segmental deposi- changes characteristic of a chronic glomerulopathy.
tion of IgM in the capillary loops and mesangium mul- The changes were advanced, with segmental glomer-
tifocally. Limited deposits of IgG and C3 were de- ular sclerosis as the typical feature. In three of 11 sam-
tected segmentally along occasional capillary loops in ples, IgM immunoglobulin deposition was minor, was
two of the three cases examined. IgA was not detected present only in occasional glomeruli, and is most like-
in any case. ly a secondary, nonspecific trapping of the components
Extrarenal lesions in the suspect and affected Bull- in glomeruli damaged by the primary process. The
mastiffs included splenic hemangiosarcoma (dog No. morphologic appearance of the glomerular changes
4), thromboembolic disease (dog No. 11), and lym- and the immunohistochemical findings are not sugges-
phosarcoma (dog No. 13). tive of an infectious or primary immune-mediated pro-
cess but more closely resemble the familial diseases of
Discussion breeds such as the Samoyed,1,15,29 Doberman Pin-
Familial renal disease of dogs can be separated into scher,4,25,30 Rottweiler,6 Bull Terrier,17 older Soft Coated
three major categories based on histologic patterns: Wheaten Terrier,8,21 and Newfoundland dog.20 This re-
dysplasia, primary glomerular disease, and primary tu- semblance suggests the possibility of a biochemical or
bular disease. Those renal diseases characterized as structural defect in the glomerular basement membrane
dysplastic have features suggesting abnormal matura- as an underlying etiology, as proven in the Samo-
tion of the nephron and its supporting interstitium, yed29,31 and suspected in the Doberman Pinscher25 dis-
with asynchronous glomerular development including ease. An ␣-collagen-5 defect has been recognized in
Downloaded from vet.sagepub.com by guest on May 20, 2015324 Casal, Dambach, Meister, Jezyk, Patterson, and Henthorn Vet Pathol 41:4, 2004
the Samoyed glomerulopathy, which is inherited as an and actn418 have been shown to cause FSGS. Both
X-linked dominant trait. Interestingly, both affected genes code for structural proteins, and ACTN4 is ex-
male and female heterozygotes develop proteinuria at pressed at high levels in the glomerular podocyte.18
2–3 months of age, but only affected male dogs had a Elucidation of the mechanisms of the renal disease
decreased glomerular filtration rate. Focal multilami- described here will require a prospective analysis,
nar splitting of the glomerular capillary basement which could include serial evaluation of biochemical
membranes was found on ultrastructural examination. values, renal histology and electron microscopy, and
Female dogs showed no signs of renal failure by 30 immunohistochemistry in dogs produced from affected
months of age, whereas affected male Samoyeds had parents. Determination of the actual onset of the dis-
usually died by 15 months of age.14 A dominant mode ease will require serum chemistry and urinalysis at an
of inheritance (such as X-linked dominant) is consis- early age, with continued evaluation at reasonable time
tent with this concept of an inherited structural defect. intervals.
The presence of dilated Bowman’s capsules in as-
sociation with remnants of glomerular tufts, seen in Acknowledgements
some of the affected dogs, has been termed cystic glo- This work was supported in part by National Institutes of
merular atrophy, which is also present in the familial Health grant RR02512. We thank the referring veterinarians
renal diseases of the Doberman Pinscher, standard for submitting biopsy material and the Bullmastiff breeders
Poodle, Rottweiler, and Bull Terrier breeds. It is for supplying pedigree and health information.
thought to be a secondary change, perhaps related to
nephron blockage from fibrosis more distally.8 References
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Requests reprints 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@vet.upenn.edu.
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