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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 theages of 2.5 and II years were affected. Clinical signs, including lethargy and anorexia, were nonspecific andoccurred shortly before death or euthanasia. In five affected dogs serial blood samples were obtained, anddramatically 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 onedog. The kidneys appeared grossly normal to slightly smaller than normal ~t necropsy. Histologic abnormalitiesof the kidneys were consistent with chronic glomerulonephropathy with sclerosis. Examination of the pedigreesof related affected dogs yielded evidence supporting an autosomal recessive mode of inheritance.

Key words: Bullmastiffs; dogs; glomerulopathy; glomerulosclerosis; histology; kidney; pathology.

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Inherited glomerulopathies have been described inthe Bull Terrier,12 Cocker Spaniel,lo.16.2?Samoyed,'.2Shih Tzu.13 Soft Coated Wheaten Terrier,24 and Ber-nese MoUl;ltain Dog.22.26A hereditary basis for glo-merulopathy is also highly likely in the Doberman Pin-scher4.30and the Newfoundland dog.2OThe age of onsetof clinical signs in familial glomerulopathies rangesfrom a few weeks to several years of age. Clinicalsigns include anorexia, lethargy, weight loss, polyuria,polydipsia. and vomiting. Although proteinuria is thehallmark of these glomerulopathies, laboratory find-ings have varied considerably and can include isosthe-nuria, aminoaciduria, glucosuria, increased protein-creatinine ratios, nonregenerative anemia. increasedblood urea nitrogen (BUN) concentrations, increasedcreatinine levels, hypoalbuminemia, hyperphosphate-mia, and hypercholesterolemia.

In this report we describt: and discuss the range ofclinical, laboratory, and histologic findings in 11 re-lated Bullmastiffs. along with pedigree relationshipsand family data supporting an autosomal recessivemode of inheritance.

Materials and Methods

Medical information from four related Bullmastiffs withend-stage renal disease (dog Nos. I through 4) was obtainedfrom either patient records from the Veterinary Hospital orSurgical Pathology records at the University of Pennsylva-nia, School of Veterinary Medicine. Owners, local veteri-narians, and breeders provided additional information, clin-ical observations, complete blood cell counts, serum chem-istry profiles, and urinalyses (dog Nos. 5 through 16).

Pedigree information was obtained from the clinically af-fected (dog Nos. 1-11), suspect (dog Nos. 12-16), and sev-

eral closely related clinically healthy Bullmastiffs. Dogs old-er than 6 years of age with normal serum biochemistry val-ues and normal urine protein-creatinine ratios (UPCs) orwith no histologic evidence of renal disease were considerednormal.

Tissues obtained through case submissions to the SurgicalPathology (dog Nos. I and 2) and Necropsy (dog Nos. 3 and4) Services of the University of Pennsylvania, School ofVeterinary Medicine, were fixed in 10% neutral buffered for-malin, processed routinely, embedded in paraffin, and sec-tioned at 3 J.Lmfor light microscopy. Blocks of paraffin-embedded renal tissue from three additional cases (dog Nos.5-7) were obtained from two other diagnostic pathology lab-oratories. Serial sections of kidney were stained with he-matoxylin and eosin, Masson's trichrome for collagen, Con-go red for amyloid, periodic acid-Schiff (PAS) for matrixdeposition, Jones' methenamine silver for basement mem-branes, and alcian blue (pH 2.7) for acid mucopolysaccha-rides. Additional 3-J.Lm sections of renal tissue from dogNos. 1-3 were evaluated immunohistochemically with rabbitanti-canine IgG, IgA, IgM, and C3 portion of complement(Dako Corp., Carpinteria, CA), using the streptavidin-biotintechnique and the chromogen substrate diaminobenzidine(Sigma Chemical Co., St. Louis, MO) as previously de-scribed.? Tissues were not available for four dogs (Nos. 8-11) diagnosed at other pathology laboratories; therefore,only the information contained in pathology reports wasavailable for review.

Results

Clinical findings

Ajrbut one of the affected Bullmastiffs (Nos. 1-10)appeared to be healthy until shortly before death. atwhich time clinical signs that were reported in eachdog included lethargy, weakness, anorexia and weight

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loss, and polyuria/polydypsia. Occasional episodes ofvomiting were noted in dog No.4, which was alsodiagnosed with hemangiosarcoma and was subse-quently euthanatized. Dog No. 11 was presented to thelocal veterinarian with sudden onset of severe dyspnea,lethargy, and weakness. During the examination thedog went into cardiac arrest and died before a com-plete clinical examination could be done. The age ofdeath or euthanasia for all affected dogs ranged from2.5 to II years (mean 5.2 :t 2.5 years; Table 1). An-orexia, weakness, lethargy, weight loss, and polyuriaJpolydypsia were also reported shortly before .death oreuthanasia in five dogs suspected of having the samerenal disease (dog Nos. 12-16). In this group of twofemale and three male dogs, the age of death or eu-thanasia 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 eightof the 11 affected dogs (Nos. I and 3-9). Complete

blood cell counts were normal, except for lymphocy-tosis and anemia in one dog with concurreJ;1theman-giosarcoma (dog No.4). Elevated BUN and creatininelevels were present in all affected dogs for which datawere available (Table 1). Examination of the serial se-rum chemistries for five affected dogs (Nos. 1, 3, 5-7) revealed mild elevations as early as 1.5 years of ageand up to 3.5 years before death. Severe proteinuria(4+) occurred in all 11 dogs (Nos. 1-11). UPCs weredetermined for six affected dogs (Nos. 3, 5-9). All sixaffected dogs had elevated ratios (Table 1). SerialUPCs 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 healthydogs (seven female and five male dogs) aged between6 months and 8 years (mean 2.9 :t 2.5 years). Theratios\ranged between 0.03 and 0.26 (mean 0.098 :t0.074), which is lower than is considered normal (UPC< 0.5) by the Clinical Pathology Laboratory at theVeterinary Hospital of the University of Pennsylvania.

Casal, Dambach, Meisler, Jezyk, Pauerson, and Henthorn Vel PatboI4J :4, 2004

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 al BUN Crea.linine(age al dealh 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 6.42 (3) F3 (5) M 2 12 1.2 0.84

3.5 1.94 12 1.3 1.574.5 41 1.85 47 2.6

4 (11) M 11 114 75 (5) M 1.75 15 1.0

3.25 24 1.14.5 51 2.3 2.6

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4.75 2.26 (5) F 1.5 19 1.3 2.29

5 149 5.8 4.97 (7.75) M 6.5 16 1.16 0.88

7.5 27 1.67.75 55 2

8 (3.5) F 3.5 50 39 (6) M 6 2.3

10 (2.5) M11 (6) M12 (3) F 3 25 1.87 3 '-13 (3) M 1.1 22 1.3 "'"

2.5 1.5414 (1.9) M 1.75 12 1.1 1.815 (6.5) F 6.5 100 2.716 (1.3) M 1.3 91 2.7.nl = normal value.

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Bullmastiff Nephropathy

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5 13 14 6

Fig. 1. Composite pedigree of Bullmastiffs affected byglomerulonephropathy. Male dogs are represented bysquares and female dogs. circles. The parents of all affecteddogs have a common ancestor (dog No. 17), shown at thetop of the pedigree. Filled-in symbols represent affecteddogs (dog Nos. I-II), diagonally hatched symbols representdogs suspected of being affected (dog Nos. 12-16), symbolsshaded in gray represent clinically healthy dogs, and emptysymbols represent dogs for which no further medical historywas available.

Five related Bullmastiffs (Nos. 12-16) were sus-pected of having the same renal disease described here,based on similar clinical signs and severe proteinuria(4+). Elevated serum BUN, creatinine, or UPCs weredemonstrated in some of these dogs (Table I). DogNo. 13 was euthanatized after lymphosarcoma was di-agnosed, and dog No. 14 was euthanatized because ofbehavioral problems. In all. five suspects no originalpostmortem results were available. However, glomer-ulonephritis was noted as the final diagnosis in therecords of dog Nos. 13, 15, and 16 provided by thelocal veterinarians.

Pedigree

A composite pedigree, shown in Fig. I, contains the11 Bullmastiffs with glomerulonephropathy (dog Nos.I-H) and the five dogs suspected to have the samerenal disease (dog Nos. 12-16). All dogs confinned aswell as suspected to be affected have male dog No. 17as a common ancestor to both their sire and their dam.Two of the affected Bullmastiffs (Nos. 4 and 7, bothmale) were born to clinically normal parents, mitigat-ing against dominant inheritance. Five dogs (Nos. 2,

321

female; 3, male; 5, male; 6, female; and II, male) wereborn to matings between one affected and one clini-cally nonnal parent (Fig. 1). There were no matingsbetween dogs that were proven to be affected basedon 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 theinformation 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.I (female), who was proven to be affected based onthe histologic findings. Affected male dogs (provenand suspected) outnumbered affected female dogs by10 to 6, but this ratio does not differ significantly froma 1: I ratio. The,one mating between an affected maledog (No.9) anq an affected female dog (No. 15) pro-duced two offspring, a male and a female dog, bothaffected. However, it is not known whether there wereother liuermates. These observations are consistentwith a simple autosomal recessive mode of inheritanceof glomerulopathy in Bullmastiffs. Fully penetrant X-linked dominant inheritance is excluded by the occur-rence of unaffected female dogs in matings betweenmale dog No. 10, which was continned to be affected,and an unaffected female dog (Fig. I). Although notruled out definitively by the pedigree data in Fig. 1,X-linked recessive inheritance is less likely, with dogNo. I (female) producing three nonnal male offspring.However, the sample size was small, a diagnosis wasnot confinned in every dog, and infonnation on allliuennates of affected dogs was not available to allowan accurate estimation of segregation ratios. Conse-quently, an autosomal recessive mode of inheritanceshould be taken as a working hypothesis, with a morecomplex mode of inheritance also possible.-

Pathology

Renal biopsy specimens without other pathologydata were available for dog Nos. I and 2. Postmortemexaminations were perfonned in dog Nos. 3 and 4 atthe University of Pennsylvania and on dog No. 11 bythe local veterinarian. Gross descriptions of the kid-neys from the other eight cases were not available (dogNos. 1, 2, 5-10). Both kidneys of dog No.3 weresmaller than nonnal, with three to four linear depres-sions in the cortical surfaces, which extended towardthe medullae. This dog was diagnosed with glomeru-lonephritis, which was the only significant disease pro-cess responsible for the dog's death.

The. kidneys from dog No.4 were grossly nonnalexcept' for a focal tan area in the corticomedullary re-gion, 'which corresponded to a regional infarct histo-logically. Although the significant cause of death inthis 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), "chronicglomerular disease" (dog No. 10), and "end-stage kidney disease" (dog No. 11).*

. N = not present, Y = present, ? = unknown.

hemoperitoneum, there was also biochemical evidenceof glomerular disease (Table I).

Dog No. 11 died unexpectedly of heart failure at 3years of age. On necropsy the local veterinarian foundlarge thrombi in the pulmonary vasculature, with thelargest occluding the main pulmonary vein, and theheart appeared mildly enlarged. The kidneys, however,appeared grossly normal.

Glomerular changes predominated and were similarin the seven affected kidneys examined histologically(Table 2). The predominant glomerular change wassegmental expansion of the mesangial matrix and anincrease in the number of cells in the tufts in the ex-

panded areas (Fig. 2). As such, the glomerular changeswere typically diagnosed as either membranoprolifer-ative or membranous glomerulonephritis. Occasionalglomeruli had foci of active necrosis, infiltrates of neu-trophils or rare plasma cell infiltrates. Although all glo-

meruli were affected, the expansion of the tuft wastypically segmental and often in the hilar region orassociated with adhesions to Bowman's capsule. Mas-son's trichrome and PAS stains revealed that the ex-panded eosi,nophilic mesangial material was predomi-nantly collagen (sclerosis) with mildly increased ma-trix deposition. Less frequently, there was evidence ofcapillary loop membrane expansion by PAS-positivematrix. In several glomeruli in each case, there weremesangial segments, which were greatly expanded byhyaline material, forming nodular foci within the tufts(Fig. 3). The nodular, hyaline areas were consistentwith hyalinosis (PAS positive; red with trichrome andnegative with Jone's methenamine silver; not shown).Congo red staining of the kidneys was uniformly neg-ative in all cases, which indicates the absence of am-yloid.

Another striking change associated with the glo-

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Fig. 2. Glomerulus; Bullmastiffwith glomerulonephropathy, dqg No.5. Segmental expansion of the mesangial matrixand increased cellularity. PAS-methenamine silver. Bar = 20 ~m.

Fig. 3. Glomeruli; Bullmastiff with glomerulonephropathy, dog No.5. Segmental. nodular hyalinosis with adhesions toBowman's capsule. HE. Bar = 30 ~m.

2 3 4

Periglomerular sclerosis Y N N YThickened Bowman's capsule Y Y Y YGlomerulopathy Y y Y YThbular atrophy Y y Y YInterstitial inflammation Y y Y YInterstitial fibrosis Y y Y YDilated tubules Y Y Y YDilated Bowman's capsule N Y Y NShrunken glomeruli N y Y N

Dog No.5 6 7 8 9 10 II

Y Y Y Y ? ? ?Y Y Y ? ? 'l ?Y Y Y Y Y Y YY Y Y ? Y '! YY Y Y ? Y Y ?Y Y Y ? Y Y ?Y Y Y ? ? ? ?Y Y N ? ? ? ?Y Y Y ? ? ? Y

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meruli in four cases (dog Nos. 2, 3, 5, and 6) wasmarked dilatation of Bowman's capsule, accentuatingthe urinary space with only irregular remnants of glo-merular tufts remaining (cystic glomerular atrophy).The majority of these irregularly shaped tufts wereseparated into two distinct lobules that were collapsedand sclerotic with segmental adhesions to Bowman'scapsule; however, there were occasional tufts that hadremarkably normal components remaining. Also notedin all but five cases were multifocal shrunken glomer-uli (approximately 6 per 100) with collapsed and fi-brotic, eosinophilic tuft remnants (obsolescent glomer-uli).

Thickening of Bowman's capsule by collagen andPAS-positive basement membrane material was pre-sent in all seven cases examined by the authors. Per-iglomerular sclerosis was multifocal and noted histo-logically or reported in only six cases.

Mild to moderate multifocal .interstitial fibrosis waspresent or reported in nine cases. The fibrosis involvedboth the medulla and the cortex. It was more diffusein the medulla, whereas in the cortex the fibrotic areastended to form radial bands toward the capsular sur-face. Tubular atrophy was associated with these fi-brotic areas in nine cases. There was mild to moderatetubular dilatation present in the seven cases examinedhistologically, with luminal protein casts evident mul-tifocally. Multifocal tubular epithelial hypertrophy wasnoted occasionally in three cases. Proliferation of med-ullary tubular epithelium (metanephric ductlike) wasnoted in dog Nos. 3 and 5. Lymphoplasmacytic inter-stitial inflammation was mild to moderate in nine cases

and was predominantly associated with the areas offibrosis and around glomeruli. The findings from allcases are summarized in Table 2.

Immunohistochemical evaluation of the glomeruliof dog Nos. 1-3 revealed minimal segmental deposi-tion of IgM in the capillary loops and mesangium mul-tifocally. Limited deposits of IgG and C3 were de-tected segmentally along occasional capillary loops intwo of th~three cases examined. IgA was not detectedin any case.

Extrarenal lesions in the suspect and affected Bull-mastiffs included splenic hemangiosarcoma (dog No.4), thromboembolic disease (dog No. 11), and lym-phosarcoma (dog No. 13).

Discussion

Familial. renal disease of dogs can be separated intothree maj~ categories based on histologic patterns:dysplasia, primary glomerular disease, and primary tu-bular disease. Those renal diseases characterized asdysplastic: have features suggesting abnormal matura-tion of th~ nephron and its supporting interstitium,with asynchronous glomerular development including

323

retention of fetal glomeruli, primitive tubules with re-tained metanephric ducts, and retention of primitivemesenchyme. Those diseases characterized as glomer-ular have clinical evidence of glomerular disease anddiffuse involvement of glomeruli with secondary tu-bular and interstitial changes. Thbular diseases areprincipally recognized as functional disturbances withsubtle to no characterizing histologic features. Di-Bartola8 has recently summarized familial renal dis-eases of the dog in this manner.

The clinical findings in the affected Bullmastiffs de-scribed here were nonspecific. Only anorexia, lethargy,weight loss, and occasionally polyuria/polydipsia werenoticed shortly before death. This is typical of chronicglomerulonephritis, whereas polyuria, polydipsia, and .vomiting are more commonly found in dogs with renaldysplasia.8 Th6 slow and insidious onset of the diseaseprocess was characterized by increased BUN and cre-atinine, and proteinuria early in the course of disease,well before clinical signs were present. An increasedUPC was found up to 3.5 years before the onset ofclinical signs in one of the affected dogs. Death oc-curred between 2.5 and 11 years of age.

GlomeruJopathics in the dog are transmitted as anautosomal dominant trait in the Bull Terrier;12 as au-tosomal recessive traits in the Bernese MountainDog,26 Cocker Spaniel,1O Shih Tzu,13 and Soft CoatedWheaten Terrier;21.24or as an X-linked dominant traitin the Samoyed.'5 In the present study in Bullmastiffs,both sexes were affected with about equal frequency,and clinically normal parents produced male and fe-male dogs with glomerular disease. These findings areconsistent with an autosomal recessive mode of inher-

itance. However, additional family studies and breed-ing studies will be needed to verify this.

All tissues of the affected dogs had. histologicchanges characteristic of a chronic glomerulopathy.The changes were advanced, with segmental glomer-ular sclerosis as the typical feature: In three of 11 sam-ples, IgM immunoglobulin deposition was minor, waspresent only in occasional glomeruli, and is most like-ly a secondary, nonspecific trapping of the componentsin glomeruli damaged by the primary process. Themorphologic appearance of the glomerular changesand the immunohistochemical findings are not sugges-tive of an infectious or primary immune-mediated pro-cess but more closely resemble the familial diseases ofbreeds such as the Samoyed,I.15,29 Doberman Pin-scher,4.2S.30Rottweiler,6 Bull Terrier,J7 older Soft CoatedWheaten Terrier,8.21and Newfoundland dog.20 This re-semblance suggests the possibility of a biochemical orstruC\~ral def@ctin the glomerular basement membraneas an underlying etiology, as proven in the Sarno-yed29.31and suspected in the Doberman Pinscher2S dis-ease. An o-collagen-5 defect has been recognized in

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Casal, Dambach, Meister, Jezyk, Paucrson, and Henthorn

the Samoyed glomerulopathy, which is inherited as anX-linked dominant trait. Interestingly, both affectedmale and female hcterozygotes develop proteinuria at2-3 months of age, but only affected male dogs had adecreased glomerular filtration rate. Focal multilami-nar splitting of the glomerular capillary basementmembranes was found on ultrastructural examination.Female dogs showed no signs of renal failure by 30months of age, whereas affected male Samoyeds hadusuaHy died by 15 months of age.14 A dominant modeof inheritance (such as X-linked dominant) is consis-tent with this concept of an inherited structural defect.

The presence of dilated Bowman's capsules in as-sociation with remnants of glomerular tufts, seen insome of the affected dogs, has been termed cystic glo-merular atrophy, which is also present in the familialrenal diseases of the Doberman Pinscher, standardPoodle, RottweiJer, and BuH Terrier breeds. It isthought to be a secondary change, perhaps related tonephron blockage from fibrosis more distally.8

The underlying molecular abnormality responsiblefor the development of the inherited glomerular dis-ease in BulJmastiffs described here is unknown. Thematerials available for this study were limited to tis-sues coHected terminally in the disease. Clinically,there is evidence that proteinuria develops at a youngerage before clinical signs are apparent. The glomeru-losclerosis-type changes seen here are commonlycaused by immunologic diseases, with associated am-yloidosis or deposition of immune complexes in bothcats and dogs.8 However, there was no histologic ev-idence suggesting immune-mediated renal damage. In-terestingly, glomerulosclerosis is quite prevalent (-80%) among captive cheetahs both in South Africa andin the United States of America.23 However, the formof glomerulosclerosis described in the cheetah moreclosely resembles diabetic nephropathy of humans.Thus, it was suggested that chronic stress led to hy-perglycemia through hyperadrenocorticism, which inturn led to the nephropathy.3-Alternatively, the changesalso resembled those in the rat. Chronic progressiverat nephropathy is characterized by late-onset renalfailure and is more common and more severe in male

than in female dogs. A familial basis has been pro-posed because the disease is common in a variety ofalbino rat strains. However, high-protein diets havealso been suggested as a cause of rat nephropathy'"

The histologic findings described in the Bullmastiffsresemble focal segmental glomerulosclerosis (FSGS)in humans, which is seen in several renal disorders, allof which are characterized by proteinuria and chronic,progressive loss of renal functiOn. Familial forms havebeen described,s.9.28and both autosomal recessive andautosomal dominant modes of inheritance have beensuggested.s In humans and mice, mutations of cd2apl'J

Vel P8&boI4t:4, 2004

and acln418 have been shown to cause FSGS. Bothgenes code for structural proteins, and ACTN4 is ex-pressed 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 biochemicalvalues, renal histology and electron microscopy, andimmunohistochemistry in dogs produced from affectedparents. Determination of the actual onset of the dis-ease will require serum chemistry and urinalysis at anearly age, with continued evaluation at reasonable timeintervals.

Acknowledgements

. This wock~was supported in pact by National Institutes ofHealth grant RR02512. We thank the referring veterinariansfor submitting b~opsymaterial and the BuUmastiff breedersfor supplying pedigree and health information.

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29 Thorner P, Jansen B, Baumal R, Valli V, Goldberger A:Samoyed hereditary glomerulopathy: immunohistochem-ical staining of the basement membranes of kidney forlaminin, collagen type IV, fibronectin, and Goodpastureantigen, and correlation with electron microscopy of glo-merular capillary basement membranes. Lab Invest 56:435-443, 1987

30 Wilcock Bp, Patterson JM: Familial glomerulonephritisin Doberman Pinschers, Can Vet J 20:244-249, 1979

31 Zheng K, Thorner PS, Marrano P, Baumal R, McInnesRR: Canine X chromosome-linked hereditary nephritis:a genetic model for human X-linked hereditary nephritisresulting from iI single base mutation in the gene encod-ing the u5 chain of collagen type IV. Proc Natl Acad SciUSA 91:39H9-3993, 1994

....

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..",,

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.

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15 Jansen BJ, Thorner P, Baumal R, Valli V, Maxia MG,Singh A: Samoyed hereditary glomerulopathy: evolutionof splitting glomerular capillary basement membranes.Am J Pathol 125:536--545, 1986

16 Johnson ME, Denhart JD, Graber ER: Renal cortical hy-poplasia in a litter of Cocker Spaniels. J Am Anim HospAssoc 8:268-274, 1972

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19 KimJM, Wu H, Green G, Winkler CA, Kopp JR, MinerJH, Unanue ER, Shaw AS: CD2-associated protein hap-loinsufficiency is linked to glomerular disease suscepti-bility. Science 300: 1298-1300, 2003

20 Koeman Jp, Biewenga WJ, Gruys E: Proteinuria associ-ated with glomerulosclerosis and glomerular collagenformation in three Newfoundland dog littermates. VetPathol 31:188-193, 1994

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22 Minkus G, Breuer W, Wanke R, Reusch C, Leuterer G,

Brem G, Hermanns W: Familial nephropathy in Bemesemountain dogs. Vet Pathol 31:421-428, 1994

23 Munson L, Nesbit JW, Meltzer DGA, Colly Lp, BoltonL, Krick, NPJ: Diseases of captive cheetahs (Acinonyxjubatus jubatus) in South Africa: a 20-year retrospectivesurvey. J Zoo Wildl Med 30:342-347, 1999

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erman Pinscher: ultrastructural changes in the glomerularbasement 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 glomerulonephro-pathy in Bemese mountain dogs. Yet Rec 134:411-415,1994

27 Steward Ap, McDougall DF: Familial nephropathy in theCocker 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 glomeru-losclerosis. Inl J Pediatr Nephrol 4:231-234, 1983

29 Thorner P, Jansen B, Baumal R, Valli V, Goldberger A:Samoyed hereditary glomerulopathy: immunohistochem-ical staining of the basement membranes of kidney forlaminin, collagen type IV, fibronectin, and Goodpastureantigen, and correlation with electron microscopy of glo-merular capillary basement membranes. Lab Invest 56:435-443, 1987

30 Wilcock Bp, Patterson JM: Familial glomerulonephritisin Doberman Pinschers. Can Vet J 20:244-249, 1979

31 Zheng K, Thorner PS, Marrano P, Baumal R, McInnesRR: Canine X chromosome-linked hereditary nephritis:a genetic model for human X-linked hereditary nephritisresulting from.. single base mutation in the gene encod-ing the u5 chain of collagen type IY. Proc Natl Acad SciUSA 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.