Inheritance of Polycystic Kidney Disease inPersian CatsD. S. Biller, S. P. DiBartola, K. A. Eaton, S. Pflueger, M. L. Wellman, andM. J. Radin

From the Department of Veterinary Clinical Sciences(Biller and DiBartola) and Department of Veterinary Bi-osciences (Eaton, Wellman, and Radin), College of Vet-erinary Medicine, Ohio State University, Columbus,Ohio, and Cytogenetics Laboratory, Baystate MedicalCenter, Springfield, Massachusetts (Pflueger). Dr. Bil-ler's present address is Department of Clinical Sci-ences, College of Veterinary Medicine, Kansas StateUniversity, Manhattan, Kansas. This research was sup-ported by grants from the University of Wisconsin-Madison, Ohio State University, Polycystic Kidney Re-search Foundation, and National Kidney Foundation.Address reprint requests to Dr. Stephen P. DiBartola,Department of Veterinary Clinical Sciences, College ofVeterinary Medicine, Ohio State University, 601 VernonL Tharp St., Columbus, OH 43210.

Journal of Heredity 1996;87:l-5; 0022-1503/96/S5.00

Polycystic kidney disease in Persian cats culminates in chronic renal failure aftera variable clinical course. An affected 6-year-old Persian cat was used to establisha colony of cats with polycystic kidney disease. In affected cats, cysts could bedetected by ultrasonography as early as 7 weeks of age. Absence of cysts onultrasound examination at 6 months of age was correlated with absence of poly-cystic kidney disease at necropsy. Both males and females were affected and, ofprogeny from affected x unaffected crosses, 42% were affected and 58% wereunaffected. In affected x affected crosses, 73% of progeny were affected and 27%were unaffected. These results are compatible with autosomal dominant inheri-tance of this trait. Polycystic kidney disease in Persian cats resembles autosomaldominant polycystic kidney disease (ADPKD) in human beings, and represents avaluable animal model of the human disease.

Autosomal dominant polycystic kidneydisease (ADPKD) is the most common ge-netic disorder of human beings, occurringin 1 in 200 to 1 in 1,000 people (Kimberlinget al. 1991; Welling and Grantham 1991).The disease occurs in all races, affectingas many as 5 million people worldwide. Itis one of the most common causes of end-stage renal disease in the United States,and accounts for approximately 10% of pa-tients on dialysis (Welling and Grantham1991).

Polycystic kidney disease has been de-scribed in adult male and female long-haired, Persian-type cats (Battershell andGarcia 1969; Lulich et al. 1988; Northing-ton and Juliana 1977; Stebbins 1989), anda family of affected Persian cats has beendescribed (Biller et al. 1990). In affectedcats, the kidneys are enlarged and irregu-lar, and renal failure develops after a vari-able number of years. Azotemia, hyper-phosphatemia, isosthenuria, nonregenera-tive anemia, and metabolic acidosis arepresent in affected cats with renal failure.The renal cysts are smooth, round, and an-echoic on ultrasonography. At necropsy,there are multiple cysts of varying size inthe cortex and medulla of both kidneys,and lymphoplasmacytic inflammation andinterstitial fibrosis also may be present.The purpose of this study was to deter-mine the mode of inheritance of polycys-tic kidney disease in Persian cats.

Materials and Methods

Description of Propositus andEstablishment of Breeding ColonyThe propositus was a 6-year-old femalePersian cat referred to the Ohio State Uni-versity Veterinary Teaching Hospital in1987 for evaluation of polyuria and poly-dipsia (Biller et al. 1990). The cat was thinand both kidneys were enlarged. Azotemia[creatinine 2.6 mg/dL (normal, 0.8-1.8 mg/dL), BUN 69 mg/dL (normal, 15-35 mg/dL)] and decreased renal concentratingcapacity [urine specific gravity 1.012 (nor-mal, > 1.045)] were present. Abdominal ra-diographs showed bilateral renomegaly,and multiple well-circumscribed, roundfilling defects caused distortion of the re-nal pelvis on excretory urography. Multi-ple cysts were observed in both kidneyson ultrasonography. At necropsy, the cor-tex and medulla of both kidneys containedmany epithelial-lined cysts that rangedfrom 5 mm to 10 mm in diameter. Cystswere not observed in other organs.

Offspring from two litters born to thisaffected queen and an unaffected malePersian cat were used to establish a colo-ny of cats with polycystic kidney disease(Figure 1). The sire used in these breed-ings was determined to be unaffected byrenal ultrasonography. One litter was com-prised of one affected male (#473) and oneaffected female (#475). The affected male(#473) served as sire for nine breedings.

PersianPropositus

Persian •

Persian I475

Persian!476 O

Persian473

DSH296

DSH464 V 708 709 71

a c b bDSH045 666 667 668 669 670 671 785 786 787 788 612

b b b b c b c c b c c

DSHn127 V 594 595 596 597 641 642 782 783 7L

b b c a c c c c b

DSH,038

56957057157257361661761861c c c c b a c b c

802C 604 605 606 607 608 644 645 646 647 648 911 912 913 914 915 601

b b c b b b b c a c b a b b b c

803 804 805 806 807 808c b b b b b

|| 741 742 743 744 745 858 859 860 861 862 863c b b c c c c c c c c

| 864 865 866 867 868 773 774 775 776 777 778c c c c a b b c b b c

il853 854 855 856 857C C C C C

606-1c

Persian I474 Q

4646662 663 664 665c a a a

Persian472

DSH224

582 677 678 679 680 789 7§0 791 622 653 624 65c c c c b b b c c c c b

I6

791-1 791-2C b

TTT6071 607TTTT 4 4607-1 607-2 607-3 607-4

b C b b

778-2 778-1C C

Figure 1. Pedigree of a colony of cats with polycystic kidney disease at Ohio State University. Squares = males; circles = females; filled symbols = affected; open symbols= unaffected; DSH = domestic shorthaired. Symbols: a = renal histopathology; b = ultrasonography; c = renal histopathology and ultrasonography. All cats not labeled asPersian or DSH are crosses (DSH x Persian).

The affected female (#475) from this litterwas euthanatized due to renal failure at 10years of age. The second litter was com-prised of one affected male (#472) and twounaffected females (#474, #476). The af-fected male (#472) served as sire for threebreedings and one unaffected female(#474) served as queen for one breeding.The remaining unaffected female (#476) inthe second litter was lost to follow up.The affected male (#472) died of renalfailure at 8 years of age. The domesticshorthaired cats (#038, #045, #127, #224,#296, #340, #464) used in this study wereunrelated individuals donated from amultiple cat household by a private indi-vidual. These domestic shorthaired cats,and cats in the F, generation (#472-#476)were not included in the data analyzedfor the present study.

Of the remaining 115 cats in Figure 1, 75

had renal histopathology (N = 54) or com-plete necropsy (yv = 21) performed, 11 re-main in the colony, 17 were provided asresearch animals to other investigators,and 12 were adopted as pets and lost tofollow up. The colony is being maintained,and blood and tissue samples are avail-able for collaborative research.

UltrasonographyUltrasonography was used to establish oreliminate a diagnosis of polycystic kidneydisease in 102 of 115 cats in this study.These 102 cats included 62 of those withrenal histopathology or necropsy data, all11 cats remaining in the colony, all 17 catsprovided as research animals to other in-vestigators, and all 12 cats adopted aspets. In the remaining 13 cats, ultrasonog-raphy was not performed, and the diag-nosis was confirmed or eliminated by

gross and microscopic pathology. Renalultrasonography was performed using a7.5 MHz transducer and an ATL UltraMark4 high-resolution real-time ultrasonogra-phy unit with videotape and multiformatcamera for hard copy backup. Cats werescanned in dorsal recumbency in theawake state or sedated with ketamine (10mg/kg) administered intramuscularly. Lon-gitudinal and transverse plane images ofthe kidney were examined.

Cysts were identified as anechoic, spher-ical structures with smooth, sharply mar-ginated walls and through-transmission(acoustic enhancement posterior to andconsistent with the size of the lesion). Ul-trasonography was performed on catsranging in age from 7 weeks to 12 months,and ultrasound examinations were repeat-ed two to five times over several months.

2 The Journal of Heredity 1996:87(1)

In 62 cats, both ultrasonography and renalhistopathology were performed.

PathologyRenal histopathology (N = 54) or com-plete necropsy (N = 21) were performedin 75 cats at ages ranging from 1 day (neo-natal deaths) to 6 years. The light micro-scopic, electron microscopic, and immu-nohistochemical findings in the 21 catsthat had complete necropsies performedand in one cat from the F, generation(#472) have been reported elsewhere (Ea-ton et al., in press). In the remaining 54cats, renal tissue was examined by lightmicroscopy, but complete necropsy ex-aminations were not performed. For his-tologic examination, selected tissue sam-ples collected at necropsy were fixed inneutral buffered 10% formalin, embeddedin paraffin, cut in 6 (Jim sections, andstained with hematoxylin and eosin.

StatisticsAffected cats were identified by renal ul-trasonography, gross and microscopic pa-thology, or both as described above. Re-sults of breeding trials were subjected tostandard chi-square analysis. A P value ofless than .050 was considered significant.

Results

Breeding StudiesBreeding studies were carried out inwhich affected cats were bred to affectedand unaffected cats. From these breed-ings, 115 kittens were born of which 71(62%) were males and 44 (38%) were fe-males (x2 = 2.755, P = .097). Of the 115kittens, 52 (45%) were affected and 63(55%) were unaffected. Of the 52 affectedcats, 29 (56%) were male and 23 (44%)were female (x2 = 0.154, P = .694). Of the63 unaffected cats, 42 (67%) were maleand 21 (33%) were female (x2 = 2.947, P =.086).

There were 11 offspring from breedingsof affected cats to affected cats. In all in-stances, these breedings were backcross-es in which affected Persian cats werebred to affected mixed breed cats. The af-fected mixed breed cats were offspring ofoutcrosses of affected Persian cats to un-affected domestic shorthaired cats. Ofthese 11 cats, 8 (73%; 5 male, 3 female)were affected and 3 (27%; 1 male, 2 fe-males) were unaffected. The observed sexratios did not differ significantly from theexpected ratios when all offspring (x2 =0.046, P = .831), affected offspring (x2 =0.000, P = 1.000), or unaffected offspring

(X2 = 0.171, P = .679) were considered.Chi-square analysis of the results for thepolycystic kidney disease phenotype wasperformed using a null hypothesis of dom-inant inheritance and the assumption oflethality for the homozygous genotype.This analysis yielded x2 = 0.024 (P =.877). The same data were subjected tochi-square analysis using a null hypothe-sis of dominant inheritance and the as-sumption of nonlethality for the homozy-gous genotype. This analysis yielded x2 =0.132 (P = .716).

There were 104 offspring from breedingsof affected to unaffected cats. Of these 104cats, 44 (42%; 24 males, 20 females) wereaffected and 60 (58%; 41 males, 19 fe-males) were unaffected. The observed sexratios did not differ significantly from theexpected ratios when all offspring (x2 =2.813, P = .093), affected offspring (x2 =0.046, P = .831), or unaffected offspring (x2

= 3.449, P = .063) were considered. Chi-square analysis of the results for the po-lycystic kidney disease phenotype using anull hypothesis of dominant inheritanceyielded x2 = 0.948 (P = .330). The off-spring in this group were derived fromoutcrosses of affected Persian cats or af-fected mixed breed cats to unaffected do-mestic shorthaired cats. Of 61 offspringproduced by breedings between affectedPersian cats and unaffected domesticshorthaired cats, 29 (48%) were affectedand 32 (52%) were unaffected. Chi squareanalysis of this data using a null hypoth-esis of dominant inheritance yielded x2 =

0.008 (P = .928).

In affected x unaffected crosses, therewere 65 offspring (31 affected, 34 unaffect-ed) from breedings in which the male par-ent was affected and 39 offspring (13 af-fected, 26 unaffected) from breedings inwhich the female parent was affected. Onchi-square analysis, the proportions of af-fected offspring in these different types ofcrosses did not differ significantly (x2 =1.513, P = .219).

Imaging StudiesThe earliest age at which cysts could bedetected by ultrasound examination was 7weeks. In seven cats, ultrasound exami-nations initially were negative, but a diag-nosis of polycystic disease was made at alater age by repeated ultrasound exami-nation or by gross and microscopic pa-thology. One cat (#744) was negative onultrasound examination at 10, 17, and 27weeks of age, but was determined to havepolycystic disease at necropsy performedat 44 weeks of age. Another cat (#791) was

negative on ultrasound examination at 7and 22 weeks of age but was positive whenultrasound examination was performed at35 weeks of age. This cat was confirmedas affected when necropsied at 5 years ofage. Two cats (#782 and #786) were neg-ative on ultrasound examination at 7 and8 weeks of age but had gross and micro-scopic evidence of polycystic kidney dis-ease when necropsied at 10 and 11 weeksof age, respectively. In the remaining threecats (#789, #803, and #806), ultrasound ex-amination for cysts was negative at 7 to 8weeks of age, but positive when repeatedat 17 to 22 weeks of age. Cat #789 is stillin the colony, cat #803 was confirmed tobe affected at necropsy performed at 3years of age, and cat #806 was studied byanother investigator and confirmed to beaffected at the time of euthanasia.

Both ultrasonography and renal histo-pathology were performed in 62 of the 115cats in Figure 1 that comprise the presentstudy. The sensitivity and specificity of ul-trasonography for the diagnosis of poly-cystic kidney disease were calculated us-ing data from these 62 cats. Sensitivitywas defined as the number of affected catspositive on ultrasound at or younger thana specified age divided by the total num-ber of cats positive for polycystic kidneydisease on renal histopathology. Specifici-ty was defined as the number of unaffect-ed cats negative on ultrasonography divid-ed by the total number of cats negative forpolycystic kidney disease on renal histo-pathology. Using these definitions, ultra-sonography had a sensitivity of 75% (15/20) and a specificity of 100% (21/21) whenperformed at £16 weeks of age and a sen-sitivity of 91% (29/32) and a specificity of100% (30/30) when performed at s36weeks of age.

Pathologic FindingsAt necropsy, polycystic kidney diseasewas diagnosed by the presence of renalcysts ranging in size from <1 mm to ap-proximately 20 mm and in number from 20to >200 per kidney (Figure 2) (Eaton etal., in press). Cysts were present in the re-nal cortex and medulla of both kidneys,and their number, size, and appearancevaried markedly among cats. In spite ofmarked individual variation in cyst size,cysts tended to be larger in older cats. His-tologic lesions were confined to the kid-neys and liver. Renal cysts were lined byepithelium which varied from cuboidal tosquamous. Some cysts were surroundedby interstitial fibrosis or lymphoplasma-cytic inflammation, and some cysts com-

Biller et al • Polycystic Kidney Disease in Persian Cats 3

Figure 2. Gross pathologic appearance of kidneyfrom a 3-year-old cat with polycystic kidney disease.

pressed adjacent renal parenchyma. Manycysts, however, were not accompanied bylesions in the adjacent parenchyma. In ad-dition to renal cysts, mild to severe wide-spread multifocal chronic tubulointersti-tial nephritis was present in affected cats,and was more common in older cats.Chronic tubulointerstitial nephritis wascharacterized by lymphoplasmacytic in-terstitial infiltration, interstitial fibrosis,and associated tubular epithelial atrophyand regeneration. Small hepatobiliarycysts were observed in the livers of 2 cats,and mild to marked, widespread biliaryhyperplasia and fibrosis were observed inthe livers of 10 affected cats.

Discussion

Animal models of polycystic kidney dis-ease include chemically induced andspontaneously occurring genetic forms ofthe disease in mice and rats (Gattone andGrantham 1991). Chemically induced mod-els include those produced by administra-tion of diphenylthiazole, nordihydro-guaiaretic acid, and corticosteroids. Cpkand pcy strains of mice develop polycystickidney disease that is inherited as an au-tosomal recessive trait. A form of autoso-mal dominant polycystic kidney diseasehas been described in the Han:SPRD rat(Cowley et al. 1993; Kaspareit-Rittinghau-sen et al. 1989; Schafer et al. 1994). Thisdisease leads to massive renal enlarge-ment, uremia, and death by 2 to 3 weeksof age in affected homozygotes. Heterozy-gous males develop renal cysts, progres-sive interstitial fibrosis, and azotemia by 6months of age whereas heterozygous fe-males develop stable renal disease with-out azotemia (Cowley et al. 1993).

The gene responsible for the most com-mon form of ADPKD in human beings has

been localized to the short arm of chro-mosome 16 in the region of the a-hemo-globin and phosphoglycolate phosphatasegenes (ADPKD1) (Reeders et al. 1985,1986). Genetic heterogeneity for ADPKDwas soon recognized (Kimberling et al.1988) and a second ADPKD gene (ADPKD2)was assigned to chromosome 4 (Kimber-ling et al. 1993; Peters et al. 1993). Othergenetic forms of polycystic kidney alsomay exist (Daoust et al. 1993). Recently,the complete structure of the ADPKD 1gene and its protein product have been re-ported (Consortium 1994, 1995). The ami-no acid sequence predicted by theADPKD1 gene does not show homologywith known proteins. Carriers of theADPKD1 gene are thought to account forapproximately 85% of ADPKD in humanbeings, with most of the remaining casesbeing associated with ADPKD2 (Petersand Sandkuijl 1992).

Several adult cats with polycystic kid-ney disease have been reported in the vet-erinary literature in the past 30 years (Bat-tershell and Garcia 1969; Caputo 1980; Lu-lich et al. 1988; Northington and Juliana1977; Rendano and Parker 1976; Stebbins1989). Speculation that polycystic kidneydisease in Persian cats is an inherited traitwas based on its common occurrence inlonghaired or Persian-type cats and iden-tification of the disease in a family of re-lated Persian cats (Biller et al. 1990). Untilnow, however, the mode of inheritancewas unknown.

Results of the present study support theconclusion that polycystic kidney diseasein Persian cats is inherited as an autoso-mal dominant trait. Chi-square analysis in-dicated that the observed distribution ofoffspring in affected X unaffected crosseswas not significantly different from the50% predicted by the assumption of dom-inant inheritance. The percentage of af-fected offspring did not differ significantlywhether the affected parent was male orfemale. The distribution of offspring in af-fected x affected crosses also was consis-tent with autosomal dominant inheritance.On chi-square analysis, these results werenot significantly different from the 75% ofoffspring expected to be affected with sim-ple dominant inheritance or from the 67%of offspring expected to be affected withdominant inheritance and lethality of thehomozygous genotype. The occurrence ofunaffected cats in these breedings effec-tively eliminated the possibility of auto-somal recessive inheritance. In addition,the breeding experiments in this studydemonstrated male-to-male, male-to-fe-

male, female-to-male, and female-to-femaletransmission, effectively eliminating X-linked inheritance. Finally, the trait of po-lycystic kidney disease has been main-tained in the colony for four generationsand all affected kittens have had at leastone affected parent.

In the Han:SPRD rat, homozygotes areeasily recognized because their kidneysenlarge rapidly and constitute 25%-30% ofbody weight by 3 weeks of age (Cowley etal. 1993). In human beings with ADPKD,the homozygous state has not yet beenrecognized despite the fact that ADPKD isa relatively common disease. In Persiancats with ADPKD, individual cats with ex-tremely rapid disease progression (i.e., de-velopment of renal failure by 1 year of age)have not been observed, and the homo-zygous genotype has not yet been identi-fied. Of six cats with polycystic kidney dis-ease previously reported in the veterinaryliterature, four were longhaired or Persian-type (Battershell and Garcia 1969; Lulichet al. 1988; Northington and Juliana 1977;Stebbins 1989) and two were shorthairedcats (Caputo 1980; Rendano and Parker1976). Polycystic kidney disease also hasbeen reported in a shorthaired cat with re-nal lymphosarcoma (Podell et al. 1992).These observations still are compatiblewith dominant inheritance of this trait inPersian cats. Many cats in the colony de-scribed in this report have short hair andlack the typical brachycephalic facial con-formation of Persian cats. Presumably,long hair coat and brachycephalic facialconformation do not segregate with poly-cystic kidney disease in the cat.

The variable number and size of renalcysts in the Persian cats of this study re-semble what is observed in human beingswith ADPKD, and the rate of progressionof renal disease is highly variable in bothspecies. Hepatic cysts commonly compli-cate ADPKD in human patients, especiallywomen (Gabow 1993; Kaehny and Everson1991), but were uncommon in Persian catsof either sex (Eaton et al., in press). He-patobiliary fibrosis was a common lesionin affected cats, but its presence was notcorrelated with the severity of the renallesions. Both hepatic fibrosis and chronictubulointerstitial nephritis were morecommon in older cats. Hepatic fibrosis isuncommon, but has been reported in hu-man patients with ADPKD (Cobben et al.1990; Ramos et al. 1990). The occurrenceof extrarenal lesions in Persian cats withADPKD further supports its validity as ananimal model of the human disease.

The penetrance (i.e., presence or ab-

4 The Journal of Heredity 1996:87(1)

sence of cysts) and expression (i.e., sever-ity of the disease) of ADPKD are age de-pendent in human patients (Kimberling etal. 1991). In ADPKD1, approximately 90%of presumed gene carriers will have cyststhat can be identified by ultrasound byage 20 (Bear et al. 1992). In most affectedcats subjected to ultrasound at <16 weeksof age, the renal parenchyma appearednormal except for the presence of small(1-2 mm) cysts. Only two cats that werenegative on ultrasound examination at 6months of age were later found to haveADPKD at subsequent ultrasound exami-nation or at necropsy. This suggests thatabsence of renal cysts in young adulthoodis associated with a low risk of later de-velopment of ADPKD both in human pa-tients and cats.

Approximately 45% of human patientswith ADPKD will develop renal failure byage 60, but the age of onset ranges from 2to 80 years (Gabow 1993). In adult patientswith renal cysts on ultrasonography, therisk of developing renal failure was esti-mated to be 2% by age 40, 23% by age 50,and 48% by age 73 (Churchill et al. 1984).The age at which renal failure develops inPersian cats with ADPKD also is variable.The average age of onset of renal failurein affected cats is 7 years, with a range of3 to 10 years.

There are several possible explanationsfor variability in the clinical progression ofADPKD. Environmental factors may play arole. Hypertension, multiple pregnancies,and urinary tract infections were somefactors potentially influenced by environ-ment that were associated with more rap-id progression in one study of affected hu-man patients (Gabow et al. 1992). Geneticfactors also may contribute to variabilityin expression of ADPKD. Different geneticloci for ADPKD can result in variations inclinical course. For example, the age of on-set of renal failure is later in patients withnon-ADPKDl genotypes (Parfrey et al.1990). Interactions with other genes or dif-ferent alleles at a single ADPKD locus alsomay occur (Kimberling et al. 1991). Evenwithin ADPKD1 families, there may bemarked variation in the severity of the dis-ease and the age of onset of renal failure(Milutinovic et al. 1992). One possible ex-planation for such variation within fami-lies is unstable DNA with varying numbersof triplet repeat sequences within the gene(Fick et al. 1994).

In summary, polycystic kidney disease

in Persian cats closely resembles ADPKDin human beings. Both diseases are inher-ited as autosomal dominant traits. Bothdiseases are characterized by develop-ment and enlargement of cysts in the renalcortex and medulla resulting in progres-sive renomegaly. Finally, both diseasesusually are accompanied by onset of renalfailure late in life, although, in both spe-cies, there is marked variability in the clin-ical course of the disease.

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Received February 2, 1995Accepted July 18, 1995

Corresponding Editor: Stephen J. O'Brien

Biller et al • Polycystic Kidney Disease in Persian Cats 5