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Diagnosis of Autosomal-DominantPolycystic Kidney Disease:An Integrated Approach

Moumita Barua, MD, FRCPC, and York Pei, MD, FRCPC, FACP, FASN

Summary: Autosomal-dominant polycystic kidney disease (ADPKD) is the most commonMendelian disorder of the kidney and accounts for approximately 5% of end-stage renaldisease in developed countries. It is characterized by focal and sporadic development of renalcysts that increase in number and size with age. Mutations of 2 genes (ie, PKD1 and PKD2)account for most of the cases. Although the clinical manifestations of both gene types overlapcompletely, PKD1 is associated with more severe disease than PKD2, with bigger kidneys andearlier onset of end-stage renal disease. In general, the diagnosis of ADPKD is commonly madeby renal ultrasonography. Age-dependent ultrasound criteria have been established for bothdiagnosis and disease exclusion in subjects at risk of PKD1. However, the utility of thesecriteria in the clinic setting is unclear because their performance characteristics have notbeen defined for the milder PKD2 and the gene type for most test subjects is unknown.Recently, highly predictive ultrasound diagnostic criteria have been derived for at-risk sub-jects of unknown gene type. In addition, molecular genetic testing is now available for thediagnosis of ADPKD, especially in subjects with equivocal imaging results, with a negative orindeterminate family history, or in younger at-risk individuals with a negative ultrasound studybeing evaluated as potential living-related kidney donor. Here, we review the clinical utilitiesand limitations of these imaging- and molecular-based diagnostic tests, and outline ourapproach for the evaluation of individuals suspected to have ADPKD.Semin Nephrol 30:356-365 © 2010 Elsevier Inc. All rights reserved.Keywords: Diagnosis, screening, ADPKD

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utosomal-dominant polycystic kidneydisease (ADPKD) is the most commonMendelian disorder of the kidney that

ffects all racial groups worldwide with a prev-lence of 1 in 500 to 1,000.1-4 It is characterizedy focal and sporadic development of renalysts that increase in number and size with age.ypically, only a few renal cysts are detected byonventional imaging before age 30, but hun-reds to thousands of cysts are present in mostatients by the fifth decade. Kidney enlarge-ent commonly is associated with pain, hema-

uria, hypertension, and renal insufficiency.

ivisions of Nephrology and Genomic Medicine, University Health Networkand University of Toronto, Toronto, Ontario, Canada.

ddress reprint requests to York Pei, MD, FRCPC, FASN, Divisions ofNephrology and Genomic Medicine, University of Toronto, 8N838, 585University Ave, Toronto, Ontario, Canada M5G 2N2. E-mail: york.pei@uhn.on.ca

270-9295/ - see front matter

m2010 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2010.06.002

Semina56

verall, ADPKD accounts for approximately 5%f the cases of end-stage renal disease (ESRD) ineveloped countries.5 It also is associated withxtrarenal complications including hepaticysts, valvular cardiac defects, colonic divertic-losis, inguinal hernias, and intracranial arterialneurysms.

ADPKD is genetically heterogeneous, withutations of 2 genes (PKD1 and PKD2) respon-

ible for most cases (Fig. 1). The clinical mani-estations of these 2 gene types overlap com-letely. PKD1 has been reported to account for5% and PKD2 for 15% of linkage-characterizeduropean families from studies performed inhe late 1980s.6,7 Two recent population-basedtudies, however, have reported a higher pro-ortion of PKD2, ranging from 26% to 36%.8,9

he latter studies suggest a possible selectionias in the earlier studies for PKD1, which is

ore severe than PKD2 (see later). These more

rs in Nephrology, Vol 30, No 4, July 2010, pp 356-365

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Integrated approach to ADPKD 357

ecent findings have implications in the diagno-is and screening of ADPKD.

A strong genetic locus effect is well docu-ented in ADPKD (Fig. 2), with larger kidneys

nd earlier age of onset of ESRD in age-matchedatients with PKD1 compared with PKD2. Spe-ifically, patients with PKD1 develop ESRD ap-roximately 20 years earlier than patients withKD2, with a median age of onset of ESRD at

Figure 1. The genomic

igure 2. Hypothetical distributions of age at ESRDllustrating the interplay of genetic and environmentaleterminants on renal disease variability in ADPKD. Theean difference between PKD1 and PKD2 is owing to

he genetic locus effect whereas the variability withinach gene locus largely reflects the effects of modifiers

trom genetic and environmental factors.

4.3 years and 74.0 years, respectively.10 Aeak allele effect (depending on the 5’ versus

’ location of the germline mutations) may beresent for PKD1 but not PKD2.11 Within eachene type, however, there is significant within-amily variability for the age of onset of ESRD,uggesting a modifier effect (Fig. 2).9,11-13 Threeecent studies have quantified this modifier ef-ect and suggest that both genetic and environ-ental factors contribute to the renal disease

ariability.13-15 For PKD2 but not PKD1, a gen-er effect favoring milder renal disease inomen also is observed.10-12 At the level of

ndividual patients, therefore, it is not reliableo predict the underlying gene type on the basisf renal disease severity.PKD1 is a large and complex gene on chro-

osome 16p13.3 spanning 13 kilobytes andonsisting of 46 exons, 33 of which are dupli-ated elsewhere on the chromosome. PKD2esides on chromosome 4q21, spans 3 kilo-ytes, and is a single-copy gene. Polycystin-1nd -2 are transmembrane proteins encoded byKD1 and PKD2, respectively, and are compo-ents of a novel signaling pathway.16-20 Polycys-in-1 is an integral membrane protein of un-nown function with a large extracellulartructure composed of multiple domains anday function as a receptor or adhesion mole-

ule. By contrast, polycystin-2 is a member of

ure of PKD1 and PKD2.

he family of transient receptor potential pro-

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358 M. Barua and Y. Pei

eins and functions as a nonselective cationhannel.16,18 Polycystin-1 and -2 interact physi-ally to form a complex that regulates intracel-ular levels of calcium and are located in therimary cilia of renal tubular cells. Recent stud-

es suggest that the polycystin complex in therimary cilia of renal tubular cells serves as aechanosensor for urine flow and that disrup-

ion of this mechanosensory mechanism by mu-ations in ADPKD result in aberrant cellularroliferation and cystogenesis.17,18 Details onhe disease genes and their predicted proteintructures, molecular and genetic mechanismsf cystogenesis, and promising novel therapies

n ADPKD can be found in several recent re-iews.17-21

IAGNOSIS OF ADPKD

he diagnosis of overt ADPKD generally istraightforward and relies on sonographic fea-ures of the disease in the setting of a positiveamily history consistent with autosomal-domi-ant inheritance. Additional clinical findingshat are helpful for the diagnosis include thebsence of symptoms and signs suggestive ofther syndromic forms of renal cystic diseaseTable 1) and the presence of extrarenal mani-estations of ADPKD.

ifferential Diagnosis

enal cysts can be a manifestation of both syn-romic and acquired disorders other thanDPKD (Table 1).22 A careful review of theistory, clinical, and radiologic investigationsay reveal clinical features of these disorders

hat are atypical of ADPKD. von Hippel-Lindauyndrome, for example, is characterized by theresence of retinal and central nervous systememangioblastomas, renal cell carcinomas,heochromocytoma, papillary cystadenomasf the epididymis, or multiple pancreaticysts. Other syndromic causes include tuber-us sclerosis (TSC), glomerulocystic disease,edullary cystic disease, medullary sponge

idney, and orofaciodigital syndrome. TSC isharacterized by skin lesions and the coexist-nce of renal cysts with angiomyolipomas. Itarely can be associated with a contiguous

ene syndrome involving deletion of PKD1 d

nd TSC2, both lie in close proximity on chro-osome 16p13.3.23,24 Patients with this syn-

rome typically present with bilaterally en-arged polycystic kidneys during infancy, withrogression to ESRD by their teenage years. A

amily history of renal cystic disorder may note evident in this syndrome because the af-ected parents are sometimes somatic mosaicshereas other cases represent de novo muta-

ions. Clinical features suggestive of TSC, how-ver, may be absent in approximately 30% ofases, therefore leading to a misdiagnosis of thisyndrome as ADPKD. Another condition thatay mimic ADPKD arises from mutations in theepatocyte nuclear factor-1-�, which can leado glomerulocystic disease or renal cysts amongther heterogeneous renal phenotypes.25,26

hese include renal dysplasia, hyperechogenic,r enlarged cystic kidneys that can be detectedn ultrasonography in the fetus, renal hypopla-ia, and slowly progressive renal insufficiency.hese renal abnormalities are associated withaturity-onset diabetes of the young type 5,ancreatic atrophy, and genital tract abnormal-

ties.27

Acquired disorders also should be consid-red in the differential diagnosis and includeultiple benign simple cysts, localized cystic

isease, and acquired renal cystic disease ofhronic renal failure/ESRD (Table 1).22 Multipleenign simple cysts are relatively common and

ncrease in number with age. The prevalence ofne or more simple renal cysts has been esti-ated to be 0% to 0.2% in individuals who are

ounger than age 30, approximately 2% in indi-iduals who are between ages 30 and 49, 11.5%n those who are between ages 50 and 70, and2% in those who are older than age 70.28,29

owever, the use of stringent criteria for ultra-ound diagnosis of ADPKD makes it unlikelyhat simple cysts are confused as ADPKD.30-32

ocalized cystic disease of the kidney is an un-ommon benign condition, with multiple cystsf various sizes separated by normal or atrophicarenchyma involving one kidney.33,34 Ac-uired renal cystic disease of chronic renal fail-re or ESRD is associated with the developmentf multiple and bilateral small cysts. It usually is

istinguished easily from ADPKD because there

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Integrated approach to ADPKD 359

s no family history of ADPKD and the kidneysre small to normal in size.35

Occasionally, ADPKD will present very early,ithin the first years of life, and may be con-

Table 1. Differential Diagnosis of ADPKD

Cystic Disorder Prevalence

Syndromicvon Hippel-Lindau

syndrome�1:50,000 Autosoma

Central necysts; pcystade

Tuberous sclerosis �1:10,000 AutosomaSkin lesion

hypomehamartosubepenrhabdomangiom

ContiguoupolycysESRD ty

Glomerulocysticdisease

Rare AutosomaMutations

factor-1Ultrasono

hypoplacysts, o

Other mayoung acysts, a

Medullary cysticdisease

Rare AutosomaSmall rena

progreshyperur

Medullary spongekidney

�1:5,000 Familial clMedullary

appearaOrofaciodigital

syndromeVery rare X-linked d

Lethal in acleft tonanomaland ma

NonsyndromicSimple renal cysts Common Rare in pa

with agesmooth

Acquired renal cysticdisease

Common Chronic reassociat

used with autosomal-recessive polycystic kid- m

ey disease and renal cystic dysplasia.22,36 Thenheritance pattern may help to distinguish be-ween ADPKD and autosomal-recessive poly-ystic kidney disease whereas the presence of

Clinical Features

inants system/retinal hemangioblastoma; pancreaticromocytoma; renal cell carcinoma;of epididymisinantial angiofibromas, periungual fibroma,ic macules, Shagreen patch); retinalseizures; mental retardation; cortical tuber;

al giant cell astrocytoma; cardiaca; lymphangioleiomyomatosis; renalma

etion of PKD1/TSC2 may result in severeney disease in infancy or early childhood withy occurring in the first 2 decades of lifeinantF2, the gene encoding for hepatocyte nuclear

, lead to heterogeneous renal phenotypesy may show hyperechogenic kidneys, renalysplasia, oligomeganephronia, multiple renal

erulocystic diseaseations include maturity-onset diabetes of theenital tract abnormalities such as epididymalof vas deferens, and bicornuate uterusinants in the corticomedullary junction; slowlyenal failure; small to normal size kidneys;a; goutng reportedrocalcinosis; usually benign; paintbrushf renal papillae on intravenous pyelogramantd males; oral anomalies (hyperplastic frenula,cleft palate or lip, and malposed teeth); facial

road nasal root with hypoplasia of nasal alaenes), and digital anomalies

younger than age 30 but increases in numbermal renal function; normal-sized kidneys withursufficiency or ESRD with multiple renal cysts

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elp to differentiate renal cystic dysplasia fromDPKD (Table 1).

amily History

he presence of a family history that is consis-ent with autosomal-dominant inheritance isseful for confirming the diagnosis of ADPKDlinically. However, a detailed family historylso can aid in determining the underlying geneype (PKD1 or PKD2), as illustrated by a recenttudy by our group.9 In this study, we examinehe renal function of 481 affected membersrom 90 families with known underlying geneype (PKD1, 67 families; PKD2, 23 families). Weound that the presence of at least one affectedamily member who developed ESRD at age 55r younger was highly predictive of PKD1, withpositive predictive value of 100% and a sensi-

ivity of 72%. By contrast, the presence of ateast one affected family member who re-

ained renal sufficient or developed ESRD atge 70 or later was highly predictive of PKD2,ith a positive predictive value (PPV) of 100%

nd a sensitivity (SEN) of 74%. None of theriteria had a negative predictive value of 100%nd, thus, the absence of the criteria could notxclude a specific gene type. These simplelinical predictors will provide the cliniciansith an evidence-based approach to evaluate

enal prognostication of individual patients

Table 2. Ultrasound Criteria for Diagnosis of A

Age, y PKD1

15-30 �3 cysts*PPV, 100%SEN, 94.3%

30-39 �3 cysts*PPV, 100%SEN, 96.6%

40-59 �2 cysts in each kidneyPPV, 100%SEN, 92.6%

NOTE. All values presented are mean estimates. For 95% coReprinted with permission.31

*Unilateral or bilateral.

ith ADPKD. s

A family history of ADPKD, however, may bebsent in 20% to 40% of study patients in whomhe diagnosis of ADPKD first is suspected frommaging studies that are performed to evaluatetherwise unexplained hematuria, abdominalasses, flank pain, or renal insufficiency.1,2 In

hese cases, the finding of ADPKD can be owingo a de novo mutation or, more likely, ascertain-ent of a small PKD2 family with mild renal

isease, which often is underdiagnosed.10,37 In theatter instance, ultrasound screening of the parents

ay show multiple renal cysts in one parent. If oner both parents are deceased, review of autopsyeports, if available, also may be helpful.

maging-Based Diagnosis of ADPKD

enal ultrasound commonly is used for diagnos-ic screening of at-risk subjects from families withDPKD. Age-specific ultrasound diagnostic crite-ia for disease confirmation or exclusion haveeen established for PKD1 and, more recently,efined and extended to at-risk subjects from fam-lies of unknown gene type (Table 2). The highiagnostic accuracy of ultrasonography in mostt-risk subjects older than age 30, as well as itsafety, accessibility, and comparatively low costs,ill ensure its ongoing use in ADPKD.In 1994, Ravine et al30 published a set of

ge-specific ultrasonographic diagnostic criteriaor PKD1 based on their study of 128 at-risk

D

PKD2Unknown

ADPKD Gene Type

PPV, 100%SEN, 69.5%

PPV, 100%SEN, 81.7%

PPV, 100%SEN, 94.9%

PPV, 100%SEN, 95.5%

PPV, 100%SEN, 88.8% PPV, 100%

SEN, 90%intervals, please refer to the text.

DPK

nfident

ubjects from 18 PKD1-linked families. Among

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Integrated approach to ADPKD 361

ndividuals between 15 and 30 years of age, theresence of “at least two unilateral or bilateralysts” is deemed sufficient for the diagnosis ofisease (PPV, �99%; SEN, 96.2%). Because ofhe increased prevalence of simple cysts withge, which can mimic ADPKD, the presence ofat least two cysts in each kidney” in individuals0 to 59 years of age (PPV, 100%; SEN, 100%)nd “four or more cysts in each kidney” amongndividuals 60 years or older (PPV, 100%; SEN,00%) are required for diagnosis. By contrast,he finding of “fewer than two unilateral orilateral renal cysts” is sufficient for diseasexclusion in at-risk individuals 30 years of ager older (negative predictive value [NPV],00%), although the false-negative rate in thisge group is approximately 4%.30

Although the earlier-described diagnostic cri-eria are useful in assessing subjects at risk forKD1, its utility in the usual clinical setting isncertain because the gene type of most fami-

ies seldom is known. Also, these same criteriaay not perform well in patients with theilder PKD2. To re-examine these issues, we

ecently completed a multicenter study of 577ndividuals from 58 PKD1 families and 371 in-ividuals from 39 PKD2 families who under-ent ultrasound screening.31 The gene type of

ach family and the disease status of each studyubject were determined by either DNA linkager mutation-based analysis. The performanceharacteristics of various criteria were also re-xamined for individuals at risk for PKD1 andKD2 (Table 2). For subjects age 15 to 29 at riskf PKD1, the traditional criteria of “two or moreysts unilaterally or bilaterally” had a PPV of8.7% and a SEN of 98.1%.30 In the same ageroup at-risk of PKD1, a more stringent crite-ion of “three or more cysts unilaterally or bi-aterally” increased the PPV to 100% but re-uced the SEN to 94.3%. By contrast, we foundhe Ravine diagnostic criteria did not performell when applied to the milder PKD2, primar-

ly because of higher false-negative results,hich reduced the test sensitivity. The criteriaf “three or more cysts unilaterally or bilater-lly” among individuals ages 15 to 29 who are atisk of PKD2 was found to have a PPV of 100%ut a SEN of only 69.5%. The same criterion in

ndividuals who were ages 30 to 39 had a PPV m

f 100% for both gene types and a SEN of 96.6%nd 64.9% for PKD1 and PKD2, respectively.or at-risk subjects ages 40 to 59, the presencef “2 or more cysts in each kidney” was associ-ted with a PPV of 100% for both gene typesnd a SEN of 92.6% and 88.8% for PKD1 andKD2, respectively. For at-risk subjects 60 yearsnd older, the criterion of “four cysts or more inach kidney” provided both a PPV and SEN of00% for both gene types.30

The same study also examined the perfor-ance characteristics of different ultrasound

riteria applied to at-risk individuals with un-nown genotype using a statistical resamplingethod termed bootstrapping to ensure the

KD1 and PKD2 case mix (ie, PKD1:PKD2 �5:15) expected in practice was taken into ac-ount (Table 2). For those individuals ages 15 to9, the presence of “three or more unilateral orilateral renal cysts” had a PPV of 100%, but aEN of 81.7% and 95.5% for the age 15 to 29nd age 30 to 39 groups, respectively. Amongndividuals who are age 40 to 59, the presencef “at least two cysts in each kidney” was asso-iated with a PPV of 100% and a SEN of 90%.inally, among individuals age 60 and older, theresence of “at least four cysts in each kidney”ad a PPV and SEN of 100% for both gene types.We also examined ultrasound diagnostic cri-

eria for disease exclusion, an issue of greatmportance for evaluating potential living-re-ated kidney donors who are at risk for ADPKDTable 3). Among subjects younger than age 30ho are at risk of PKD2 or of unknown gene

ype, ultrasound is limited in its ability to ex-lude the disease. Specifically, the NPV associ-ted with no renal cyst is 83.5% and 90.8%,espectively. However, the NPV for subjectsrom the same age group who are at risk ofKD1 is 99.1%. Thus, the absence of renal cyst

n this latter setting provides almost certaintyor disease exclusion. For subjects at risk ofKD2 or of unknown gene type who are age 30o 39, the NPV increases to 96.8% and 98.3%,espectively. However, the absence of renalyst does not exclude ADPKD in these subjectst risk of PKD2 or of unknown gene type untilge 40.

In the circumstance of equivocal or indeter-

inate ultrasound results, more sensitive imag-

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362 M. Barua and Y. Pei

ng modalities such as computed tomographyCT) and magnetic resonance imaging (MRI) areromising alternatives to consider, although no

ormal studies have compared these techniquesith ultrasound to date. For example, in sub-

ects younger than age 30 who are at risk ofKD1 or between ages 30 and 39 with un-nown gene type, a negative CT or MRI scanould provide further assurance that they likelyre unaffected, bearing in mind that this ap-roach has not been validated by any system-tic study. However, it would be inappropriateo extrapolate the same ultrasound criteria toT or MRI because more simple cysts may beetected by the latter modalities as a result ofheir enhanced detection sensitivity. Futuretudies are needed to validate the use of theseore sensitive imaging modalities in the

ounger subjects at risk of ADPKD.

olecular Genetic Testing in ADPKD

olecular testing has the potential to provideefinitive diagnosis of ADPKD and can be per-ormed by either direct sequencing of the PKDenes or by linkage analysis.38 Direct sequenc-ng of all the exons and splice junctions of bothKD1 and PKD2 using DNA as templates isow feasible and offers the advantage of need-

ng a blood sample from a single patient. Toate, more than 333 and 95 truncating muta-ions have been reported in PKD1 and PKD2,espectively (http://pkdb.mayo.edu). Most of

Table 3. Ultrasound Criteria for Exclusion of A

Age, y PKD1

15-30 �1 cystNPV, 99.1%SPEC, 97.6%

30-39 �1 cystNPV, 100%SPEC, 96%

40-59 �1 cystNPV, 100%SPEC, 93.9%

NOTE. All values presented are mean estimates. For 95% coReprinted with permission.31

hese mutations do not recur in multiple fami- m

ies and are scattered throughout both genes. Inddition, a large number of missense variantslso are found mostly in PKD1. By using directequencing, definitive mutations can be foundn approximately 42% to 63% of cases and likelyisease-associated mutations in an additional6% to 37% of cases.39,40 The latter category ofutations comprise mostly nonsynonymousissense variants resulting in single amino acid

lterations predicted to be damaging to the en-oded protein. However, in the absence of aalid functional assay the clinical utility of thisategory of mutations is uncertain at this time.he moderate detection rate also can be attrib-ted to the technical challenges of sequencinghe large and complicated structure of PKD1. Inddition, up to 4% patients may have a grossearrangement of PKD1, which would not beetected by a sequencing-based approach. In-tead, multiplex ligation-dependent probe am-lification provides an efficient and high-hroughput screen for this type of mutations.41

inally, direct sequencing is costly, rangingrom $3,650 to $4,880 (US dollars) per sampley commercially available testing (offered bythena Diagnostics, Worcester, MA).DNA-linkage analysis using flanking and intra-

enic polymorphic (typically microsatellite)arkers for PKD1 and PKD2 is an alternate test

hat tracks a disease haplotype and its segrega-ion within the family.38 The major advantage ofhis approach is that when a large family with

D

PKD2Unknown

ADPKD Gene Type

V, 83.5%EC, 96.6%

NPV, 90.8%SPEC, 97.1%

V, 96.8%EC, 93.8%

NPV, 98.3%SPEC, 94.8%

V, 100%EC, 93.7%

NPV, 100%SPEC, 93.9%

intervals, please refer to the text.

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NPSP

NPSP

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Integrated approach to ADPKD 363

vailable, it is almost always possible to deter-ine if the at-risk subject is an obligate carrierithout the need to identify the pathogenicutation. It is less expensive than direct se-

uencing and costs approximately $2,500 (USollars) regardless of the number of samplesent. However, the technique requires the ac-urate clinical diagnosis in an adequate numberf known family members who provide DNAamples. Notwithstanding its limitations, theres a role for molecular genetic testing, especiallyn patients with equivocal imaging results, inhose with a negative or indeterminate familyistory, and in younger at-risk individuals with aegative ultrasound study who are being evalu-ted as a potential living-related kidney donor.he most up-to-date information about which

aboratories are providing commercial assaysan be obtained from Gene Tests (www-genetests.org).

DIAGNOSTIC ALGORITHM FOR ADPKD

igure 3 illustrates our approach in the evalua-ion of a patient suspected to have ADPKD. Asndicated in this algorithm, obtaining a detailedamily history is a key step in the diagnosis notnly to confirm the autosomal-dominant pat-ern of inheritance but also to aid in determin-

igure 3. Diagnostic algorithm for the evaluation of an

ng underlying gene type. The knowledge of c

ene type helps in the selection of appropriateltrasound criteria, especially for the purposef disease exclusion. In general, the presence ofthree unilateral or bilateral renal cysts” in at-isk subjects ages 15 to 39 or “two cysts in eachidney” in at-risk subjects ages 40 to 59 can beonsidered sufficient for the diagnosis of AD-KD regardless of their underlying gene typePPV, 100%) (Table 2). For older at-risk subjectsges 60 and older, the presence of “at least fourysts in each kidney” is sufficient for a diagnosisf ADPKD regardless of the gene type. Theensitivity (ie, proportion of the affected sub-ects with the positive test result) of these cri-eria, however, will differ between the differentene types. On the other hand, individuals withn affected relative who developed ESRD at age5 or younger are at risk of PKD1 and thereforeKD1-specific ultrasound criteria should be ap-lied for earlier disease exclusion. In this case,he absence of any renal cyst by 30 years of agerovides almost complete certainty for diseasexclusion. By contrast, in the absence of such aamily history indicative of PKD1, the ultra-ound criteria for unknown genotype can besed and ADPKD cannot be excluded until 40ears of age.

Other renal (eg, angiomyolipomas, renal cell

idual suspected to have ADPKD. See text for details.

arcinomas) and extrarenal (eg, facial and peri-

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ngual fibromas, pancreatic cysts) clinical find-ngs also are important in providing clues todentifying syndromic disorders that mimic AD-KD (Table 1). The presence of early and se-ere disease should raise the suspicion ofKD1-TSC2 deletion syndrome.23,24 Individualsith findings atypical for ADPKD should un-ergo further evaluation, including additional

maging and referral for medical genetics con-ultation and molecular testing. On the otherand, the finding of small kidneys bilaterallyhould alert the physician to the possibility ofcquired cystic disease. When no family historyf ADPKD is apparent, screening parents oreview of their autopsy results if available mayncover occult disease, especially in small fam-

lies with milder PKD2. Molecular genetic test-ng, however, is indicated in the evaluation oft-risk individuals with equivocal imaging re-ults, younger at-risk individuals being evalu-ted for living kidney donation, and individualsith atypical or de novo renal cystic disease. In

he not too distant future, the role of molecularenetic testing may expand if the ADPKD geneype influences the choice of effective disease-odifying treatments that currently are being

ested.17

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kidney. 7th ed. Philadelphia: Elsevier Saunders; 2004.3. Iglesias C, Torres V, Offord K, Holley K, Beard C,

Kurland L. Epidemiology of adult polycystic kidneydisease, Olmsted County, Minnesota: 1935-1980. Am JKidney Dis. 1983;2:630-9.

4. Davies F, Coles G, Harper P, Williams A, Evans C,Cochlin D. Polycystic kidney disease re-evaluated: apopulation-based study. QJM. 1991;79:477-85.

5. US Renal Data System. Excerpts from the USRDS 2004annual data report. Am J Kidney Dis. 2005;45 Suppl:S1-280

6. Peters D, Sandkkuijl L. Genetic heterogeneity of poly-cystic kidney disease in Europe. Contrib Nephrol.1992;97:128-39.

7. Dobin A, Kimberling W, Pettinger W, Bailey-WilsonJE, Shugart YY, Gabow P. Segregation analysis ofautosomal dominant polycystic kidney disease. GenetEpidemiol. 1993;10:189-200.

8. Rossetti S, Adeva M, Kubly V, Consugar MB, Torres VE,Harris PC. An Olmsted County population-based studyindicates that PKD2 is more common than previously

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