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Renal Ultrasonographic Evaluation in Children at Risk of AutosomalDominant Polycystic Kidney Disease

Berenice Reed, PhD,1 Ehsan Nobakht, MD,1 Sherry Dadgar, MS,1 Mir Reza Bekheirnia, MD,1

Amirali Masoumi, MD,1 Frank Belibi, MD,1 Xiang Dong Yan, MS,1

Melissa Cadnapaphornchai, MD,2 and Robert W. Schrier, MD1

Background: To date, there are no criteria for diagnosing autosomal dominant polycystic kidneydisease (ADPKD) in at-risk children 15 years or younger.

Study Design: Longitudinal (retrospective cohort study).Setting & Participants: 420 children (mean age, 8.3 � 4.2 years) with a family history of ADPKD

were studied.Measurements: Renal ultrasonography was performed for cyst detection. Urine protein was mea-

sured using two 24-hour urine collections. Glomerular filtration rate was calculated using the Schwartzformula. Blood pressure measurements were performed in the arm with the highest blood pressure,using an appropriate cuff size. Standard 2-dimensional and Doppler echocardiography was performedfor measuring left ventricular mass index.

Predictors: None.Outcome: Presence of renal cysts.Results: Renal cysts were detected in 193 children and no cysts were detected in 227 children. In

children with renal cysts, 150 had bilateral and 43 had unilateral cysts. Children with bilateral cysts hadlarger kidneys and more hypertension than children with unilateral or no cysts. Follow-up in 77 children15 years or younger showed bilateral cysts in 14 and unilateral cysts in 4 of the children who had nodetectable renal cysts using ultrasonography at baseline. Similar follow-up of 26 children 15 years oryounger with unilateral cysts detected at baseline showed bilateral cysts in 17 children using ultrasonog-raphy. By 15 years of age, 181 patients in the total group of 420 showed bilateral cysts. Overall, 193 of304 children (63.4%) who had follow-up at any age developed bilateral cysts detected using ultrasonog-raphy.

Limitations: Follow-up unavailable for all participants.Conclusion: The present results in 420 at-risk children with ADPKD 15 years or younger detected

bilateral renal cysts using ultrasonography in 181 of the children who had a family history of this geneticdisease.Am J Kidney Dis 56:50-56. © 2010 by the National Kidney Foundation, Inc.

INDEX WORDS: Autosomal dominant polycystic kidney disease (ADPKD); diagnosis; ultrasound.

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utosomal dominant polycystic kidney dis-ease (ADPKD) is the most common heredi-

ary kidney disease, occurring in 1 in 400 to 1 in,000 live births.1 ADPKD is more common thanuntington disease, hemophilia, sickle cell dis-

ase, Down syndrome, cystic fibrosis, and myo-

From the 1Division of Renal Diseases and Hypertensionnd 2Department of Pediatrics, School of Medicine, Univer-ity of Colorado Denver, CO.

Received July 11, 2009. Accepted in revised form Febru-ry 25, 2010. Originally published online as doi:10.1053/j.jkd.2010.02.349 on May 10, 2010.Address correspondence to Robert W. Schrier, MD, Uni-

ersity of Colorado Denver, Division of Renal Diseasesnd Hypertension, Box C281, 12700 E 19th Ave, Research, Rm 7001, Aurora, CO 80045. E-mail: robert.schrier@cdenver.edu© 2010 by the National Kidney Foundation, Inc.0272-6386/10/5601-0010$36.00/0

sdoi:10.1053/j.ajkd.2010.02.349

American Journ0

onic dystrophy combined.2 ADPKD accountsor 4%-10% of end-stage renal disease and is theourth leading cause of end-stage renal disease inhe United States.3,4

Although previously considered a disease ofdults, it now is clear that ADPKD can be diag-osed as early as in utero, with significant clini-al manifestations affecting some patients inarly childhood or adolescence.5,6 Affected chil-ren show enlarged kidneys and increased fre-uency of hypertension compared with unaf-ected children.7 Children with ADPKD andypertension (blood pressure [BP] �95th percen-ile for their age, sex, and height) are at particularisk of increased kidney volume and left ventric-lar mass index (LVMi) and decreased kidneyunction over time compared with ADPKD chil-ren with BP less than the 75th percentile.8,9

hildren with ADPKD with borderline hyperten-

ion, defined as BP between the 75th and 95th

al of Kidney Diseases, Vol 56, No 1 (July), 2010: pp 50-56

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Diagnosis of ADPKD in Children 51

ercentiles, also have increased LVMi comparedith affected children with lower BPs.8 Impor-

antly, in ADPKD children with borderline hyper-ension, monotherapy with an angiotensin-con-erting enzyme inhibitor to control BP to lesshan the 50th percentile has been shown to ame-iorate the decrease in kidney function and in-rease in LVMi observed in these children overime.9

Thus, early diagnosis during childhood anddolescence is critical to allow for optimal inter-ention(s) to slow the progression of kidney andardiac disease in patients with ADPKD. Diag-ostic criteria for ADPKD using renal ultrasonog-aphy recently have been updated, but did notrovide guidelines for children younger than 15ears with a known family history of ADPKD.10

he present study therefore was undertaken tovaluate the presence or absence of renal cystsetected using ultrasonography in 420 children5 years or younger with a family history ofDPKD.

METHODSChildren with a family history of ADPKD who partici-

ated in a longitudinal study of the natural history ofDPKD or other clinical studies in 1985-2008 were admit-

ed to the Pediatric Clinical Translational Research Center athe Children’s Hospital in Denver, CO. Standard historyas reviewed, and physical examination, BP monitoring,

outine blood and urine laboratory studies, and abdominalltrasonography were performed. Informed consent/assentas obtained from all parents and/or participants.BP measurements were obtained in the arm with the highest

P, using an appropriate cuff for the size of the participant’srm according to guidelines set forth by the National Highlood Pressure Education Program after 5 minutes of quiet

itting.11-13 Hypertension was defined as systolic and/oriastolic BP at the 95th or higher percentile for sex, age, andeight based on 3 or more measurements. Urine proteinxcretion and creatinine clearance were assessed using two4-hour urine collections. Glomerular filtration rate (GFR)as calculated using the Schwartz formula.14

Kidney volume was measured using standard abdominalltrasonography. Kidney volume was calculated as the vol-me of a modified ellipse for each kidney using the follow-ng formula: volume � �/6 � length � width � depth.ength, width, and depth were measured in centimeters.ength and width were obtained from longitudinal imagescquired in planes ranging from sagittal to coronal, whereasepth was obtained from transverse images of the midkidneycquired in the plane perpendicular to the longitudinal plane.otal kidney volume was measured by summing the vol-mes of both kidneys. Based on ultrasound results, partici-ants were grouped into 1 of 3 categories: unilateral cysts,

ilateral cysts, or no cysts present. s

Standard 2-dimensional and Doppler echocardiographyas performed with the participant in a supine positionsing an Acuson 128 XP/5 ultrasound Acuson Corporationwww.Acuson.com). Left ventricular mass (LVM) was deter-ined using the formula LVM � 0.80 [1.04 (LVDd � PWTIVSd)3 � (LVDd)3] � 0.6, where LVDd is left ventricular

iameter in diastole, PWT is posterior wall thickness iniastole, and IVSd is ventricular septal thickness in diastole.VM was then corrected by body surface area and reporteds LVMi in grams per meter squared.

Participants 15 years or younger returned for a secondlinical examination and renal ultrasonography after thenitial visit, as described.

Statistical analysis was performed to compare kidneyunction, kidney volume, cyst numbers, LVMi, urine proteinxcretion, and hypertension status in children who hadnilateral, bilateral, or no cysts at the first visit and at aollow-up visit performed by age 15 years. Analysis ofariance was used to compare all quantitative measures, and2 test was used for comparative frequency analysis (inci-ence of hypertension between studied groups). All statisti-al analyses were performed using SAS, version 9.2 (www.as.com), with P � 0.05 considered significant.

RESULTS

aselineRenalUltrasound

Four hundred twenty children 15 years orounger, predominantly white (89%), who had aocumented family history of ADPKD were stud-ed. Of these children, 401 were studied before000 and 19 children were studied between 2000nd 2008. At a mean age of 8.6 � 4.2 years at theaseline visit, 193 (46%) children showed renalysts. Of these, 150 (78%) had bilateral and 4322%) had unilateral renal cysts, as shown in Fig 1.t the baseline visit, 227 (54%) of 420 childrenith a mean age of 8.0 � 4.1 years had no cystsetected using renal ultrasonography. The distri-ution of renal cysts by age is shown in Fig 2. Inhe 13- to 15-year-old age group, 50% ofatients had no cysts, 8% had unilateral cysts,nd 42% had bilateral cysts. The proportion ofhildren with bilateral cysts was lower in theounger age groups and the correspondingroportion of children with either no or unilat-ral cysts was higher.

aselinePatient Characteristics

Baseline characteristics for patients are listedn Table 1. Age, sex, kidney function, urinaryrotein excretion, and LVMi were similar inarticipants with bilateral, unilateral, or noysts at baseline. The incidence of hyperten-

ion was significantly higher (P � 0.008) in

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Reed et al52

articipants with bilateral cysts compared withhose with unilateral or no cysts, as listed inable 1. Mean kidney volume corrected byeight and cyst count also was significantlyigher in participants with bilateral cysts com-ared with those with unilateral or no cysts ataseline (Table 1).

ollow-upRenalUltrasonography

Of 43 children with unilateral renal cysts, 26eturned for a follow-up study at 15 years orounger. Of 26 ADPKD children with unilateralysts, 17 (65%) had developed bilateral cysts,hereas no cysts were detected in 3 patients inhom unilateral cysts were detected at the base-

ine ultrasonographic examination. Of 227 chil-ren without renal cysts using ultrasonographyn the baseline visit, 77 children 15 years orounger were seen for follow-up, with 14 chil-ren (18%) 15 years or younger showing bilat-ral renal cysts and 4 children (5%) showingnilateral cysts by ultrasound. A total of 11628%) of the 420 patients initially seen at base-ine had no follow-up ultrasonographic examina-ion. These results are shown in Fig 1. Of 43atients with unilateral cysts detected using ultra-onography at baseline, 8 patients were older

Figure 1. Flow diagram of ultrasound findings of 420idney disease (ADPKD) at initial and follow-up ultrasononilateral cyst(s) at baseline who had follow-up ultrasonogrf 43 children with no cyst at baseline who had follow-upetected in 10 and unilateral cysts were detected in 3.

han 15 years at the time of the follow-up study s

mean time between baseline and follow-up ex-mination, 9.8 years); of these, 2 patients hadeveloped bilateral renal cysts detected usingltrasonography. Likewise, of 227 with no cystetected at baseline ultrasonographic examina-ion, 43 patients were older than 15 years at theollow-up study (mean time between baselinend follow-up examination, 9.9 years); of these,0 patients had developed bilateral cysts and 3ad developed unilateral cysts. The mean inter-al between baseline and follow-up ultrasono-raphic examinations was significantly longer inatients with bilateral cysts on follow-up study,s listed in Table 2. Of 420 children at risk ofDPKD, 167 either had no follow-up ultrasono-raphic examination or were older than 15 yearst the time of examination. Bilateral renal cystsere detected using ultrasonography in 181

71.5%) of the remaining 253 children by age 15ears. Overall, of 420 children at risk of ADPKD,04 children had a follow-up renal ultrasono-raphic examination at any age, and of thosehildren, 193 of 304 (63.4%) eventually formedilateral renal cysts.

atient Characteristics at the Follow-upVisit

There were no significant differences in age,

n with a family history of autosomal dominant polycysticc evaluations at 15 years or younger. Of 8 children witht age older than 15 years, 2 had developed bilateral cysts.nography at age older than 15 years, bilateral cysts were

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ex, hypertension, GFR, LVMi, or urinary pro-

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Diagnosis of ADPKD in Children 53

ein excretion between patients with no, unilat-ral, or bilateral cysts at the follow-up ultrasono-raphic examination at 15 years or younger (Table). Mean serum creatinine level, kidney volumeorrected by height, and cyst number were signifi-antly higher in patients with bilateral cystsompared with those with unilateral or no cysts,s listed in Table 2.

Figure 2. Distribution of renal cysts by age in 420hildren at risk of autosomal dominant polycystic kidneyisease (ADPKD) at the time of the initial ultrasonographicxamination. Numbers within each age group are as fol-

ows: age 0-4 years: 59 with no cysts, 9 with unilateralysts, 33 with bilateral cysts; age 5-8 years: 68 with noysts, 15 with unilateral cysts, 37 with bilateral cysts; age-13 years: 67 with no cysts, 14 with unilateral cysts, 52ith bilateral cysts; and age 13-15 years: 33 with no cysts,with unilateral cysts, 28 with bilateral cysts.

Table 1. Characteristics of 420 Children With

Bilate(n

ge (y) 8.8 �ale (%) 43.ypertension (%) 2Cr (mg/dL) 0.6 �FR (mL/min/1.73 m2) 134 �rinary protein excretion (mg/kg/24 h) 3.92 �ean kidney volume corrected by height (cm2) 0.97 �ean no. of cysts 13 �VMi (g/m2) 110 �

Note: Values expressed as mean � standard deviationFR in mL/min/1.73 m2 to mL/s/1.73 m2, �0.01667; SCr inAbbreviations: ADPKD, autosomal dominant polycyst

entricular mass index; SCr, serum creatinine.

DISCUSSION

The present study analyzed 420 children, meange of 8.3 � 4.2 years, who had a family historyf ADPKD. Renal ultrasonography was used toiagnose ADPKD in these children. Althoughenal ultrasonography has been used to establishhe Ravine criteria for the diagnosis of adultDPKD, it must be emphasized that in theresent era, identification of the causative muta-ion must be considered the gold standard. Thus,lthough the present results provide observa-ional data that support the early diagnosis ofDPKD in children 15 years and younger using

enal ultrasonography, the future identification ofhe specific mutations must be considered theptimal diagnostic standard.The possibility of false-negative and false-

ositive renal ultrasounds in the present studylso must be considered. The sensitivity of renalltrasonography has improved with time; there-ore, in the earlier years, a false-negative renalltrasound result in a child with ADPKD wasore likely. However, during the entire study

eriod, renal cysts were found by age 15 years in9% (208) of 420 at-risk children with thisutosomal dominant disease. However, false-ositive renal ultrasound results also must beonsidered in this study, such as might occur inistaking a medullary pyramid for a cyst. It

hould be noted that in 3 patients with unilateralysts detected at their first ultrasonographic ex-mination, no cysts were found on follow-upltrasonography by age 15 years.

D at Baseline Ultrasonographic Examination

ts Unilateral Cysts(n � 43)

No Cysts(n � 227) P

0) 8.1 � 4.1 (43) 8.0 � 4.1 (227) 0.246.5 (43) 45.0 (227) 0.9

10 (10) 6 (71) 0.0084) 0.6 � 0.2 (34) 0.6 � 0.2 (185) 0.9) 134 � 38 (30) 126 � 35 (171) 0.1112) 2.31 � 1.44 (21) 2.45 � 3.90 (113) 0.335) 0.65 � 0.22 (27) 0.58 � 0.21 (141) �0.001) 2 � 1 (31) 0 (227) �0.001

99 � 21 (7) 94 � 26 (29) 0.5

er) or percentage (number). Conversion factors for units:to mol/L, �88.4.ey disease; GFR, glomerular filtration rate; LVMi, left

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4.2 (153 (150)5 (57)0.3 (1436 (14010.39 (0.59 (111 (11460 (8)

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On the initial ultrasound screen, 46% (n �93) showed at least 1 renal cyst, whereas 54%n � 227) did not show renal cysts using ultra-onography. Of the 193 children showing renalysts, they were bilateral in 150 (78%) childrennd unilateral in 43 (22%). Moreover, the distri-ution of cysts appears to be age dependent, withilateral cysts detected most frequently in chil-ren aged 13-15 years, as shown in Fig 2. Demo-raphic characteristics of the children in these 3roups, namely, bilateral, unilateral, or no detect-ble renal cysts, were similar. The children inhese separate groups at baseline could not beistinguished by age, sex, serum creatinine level,FR, or LVMi (Table 1). However, total kidneyolumes were significantly greater in childrenith bilateral cysts than those with either unilat-

ral or no cysts. The mean total number ofetectable cysts was significantly higher in chil-ren with bilateral versus unilateral cysts. BPsreater than the 95th percentile occurred in 25%f children with bilateral renal cysts and only0% of children with unilateral cysts. Urinarylbumin excretion also was greater in childrenith bilateral cysts, although this difference didot reach significance.Analysis of these 3 groups, namely, bilateral,

nilateral, and no cysts, raised some criticaluestions. Specifically, on follow-up, would pa-ients with unilateral cysts become bilateral and

Table 2. Follow-up Characteristics of Children With EitheWho Had Follow-u

Bilate(n

ean time between baseline and follow-up (y) 6.9ge (y) 11.9 �ale (%)ypertension 18.Cr (mg/dL) 0.7 �FR (mL/min/1.73 m2) 141 �rinary protein excretion (mg/kg/24 h) 3.22 �ean kidney volume corrected by height (cm2) 0.87 �ean no. of cysts 12 �

Note: Values expressed as mean � standard deviationass index is not presented because only 7 patients had da

o mL/s/1.73 m2, �0.01667; SCr in mg/dL to mol/L, �88.4.Abbreviations: GFR, glomerular filtration rate; SCr, serumaThree patients with initial unilateral cysts and no cysts abPatients in whom bilateral cysts were detected had a l

xamination.

ould any children with no detectable cysts e

evelop cysts on follow-up? In 43 children withnilateral cysts, 26 had a follow-up visit whiletill 15 years or younger. Of these 26 children, 17eveloped bilateral renal cysts while 15 years orounger. In 227 children without cysts, 77 chil-ren 15 years or younger had a follow-up visit.ighteen patients developed renal cysts while 15ears or younger. At follow-up, children withilateral, unilateral, or no cysts could not beistinguished by age, sex, GFR, or LVMi (Table). Similar to baseline, children with bilateralysts had larger kidneys and a higher cyst countompared with children in the other groups.

Because ADPKD has an autosomal dominantode of transmission, in a large group of at-risk

hildren, 50% would be expected to have ADPKDnd 50% would be expected not to have ADPKD.n the present group of 420 children with a familyistory of ADPKD, by age 15 years, 208 children49%) showed either unilateral or bilateral renalysts, including 190 at baseline (after removing 3hildren with baseline unilateral cysts in whomo cyst was detected at follow-up) and 18 whoad follow-up at 15 years or younger. Also ofnterest, 65% (17 of 26) of children who origi-ally had only unilateral cysts developed bilat-ral cysts on follow-up by age 15 years. Whenatients with unilateral cysts who had follow-upfter age 15 are included, 19 (55.9%) patients

r Unilateral Cysts at Initial Ultrasonographic ExaminationYears or Younger

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10 (10) 5 (59) 0.10) 0.6 � 0.1 (10) 0.6 � 0.1 (57) 0.03) 165 � 54 (7) 139 � 27 (54) 0.128) 2.18 � 0.71 (5) 2.58 � 1.85 (45) 0.431) 0.64 � 0.13 (7) 0.62 � 0.2 (62) �0.001

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r) or percentage (number). Information for left ventricularlable. Conversion factors for units: GFR in mL/min/1.73 m2

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Diagnosis of ADPKD in Children 55

ients who had follow-up ultrasonographic exami-ation at any age.The recent criteria for diagnosing ADPKD

sing ultrasonography for both PKD1 (average,5% of patients) and PKD2 (average, 15% ofatients) between the ages of 15 and 39 years haseen proposed to be 3 or more renal cysts by theost up-to-date Ravine criteria.10 In the present

arge study, 181 of 253 (71.5%) at-risk childrenho had follow-up evaluations had detectableilateral renal cysts (mean total cyst count, 12)y 15 years of age using renal ultrasonography.verall, the total number of patients with bilat-

ral cysts was only slightly higher: 193 of 30463%) when patients who had a follow-up ultra-onographic examination at any age were in-luded. Therefore, considering detection of bilat-ral renal cysts in at-risk children 15 years orounger as diagnostic of ADPKD seems reason-ble from the present data.

Children with unilateral cysts are of interestor several reasons. The present data showed that5% (17 of 26) of children with unilateral cystst baseline progressed to develop bilateral cystsy age 15 years, indicating that in some children,nilateral cysts may be an early presentation ofDPKD. Studies have shown magnetic reso-ance imaging in adults with ADPKD to be moreensitive than renal ultrasonography.15 Thus, chil-ren with unilateral cysts might be shown toave bilateral cysts using magnetic resonancemaging. However, magnetic resonance imagings more expensive and sedation may be neces-ary for children with claustrophobia.16 More-ver, results of the present study indicate thatenal ultrasonography appears to be sensitive iniagnosing ADPKD in children 15 years andounger based on detection of bilateral renalysts.

Acknowledging that ADPKD in young chil-ren younger than 15 years may begin with unilat-ral and progress to bilateral renal cysts has impli-ations for the differential diagnosis of ADPKDrom the entity termed “unilateral renal cystic dis-ase.” The latter cystic disease is not hereditary,emains unilateral, and loss of kidney functionoes not occur.17-21 In 1 report of 13 patientsith a diagnosis of unilateral renal cystic dis-

ase, 9 underwent nephrectomy (3 were chil-ren), presumably to exclude a cystic renal neo-

lasm.22 In patients with ADPKD in whom c

nilateral cysts progress to bilateral renal cysts andidney function is progressively lost, an unneces-ary unilateral nephrectomy would shorten the timeo end-stage renal disease. On gross and histologicnspection, unilateral renal cystic disease has beeneported not to differ from cysts in ADPKD.19 Theuestion thus arises whether some of the re-orted cases of unilateral renal cystic disease inhildren may have been early manifestation ofDPKD with unilateral cysts. In this regard, a

amily history on questioning is absent in one-hird of patients with ADPKD.23 However, ifenal ultrasonography is performed on both par-nts, family inheritance is supported in �90% ofases.

In summary, the present study of 420 children5 years or younger with a family history ofDPKD showed bilateral renal cysts using ultra-

onography in 71.5% (181 of 253) of childrenho had repeated evaluations before age 15ears. Differences in age, sex, kidney function,r LVMi did not distinguish between childrenith renal cysts. However, children with bilat-

ral renal cysts had larger renal volumes andore hypertension. The issues of potential false-

ositive or false-negative findings using ultra-onography have been discussed, as has the fu-ure importance of mutation identification as theiagnostic gold standard.

ACKNOWLEDGEMENTSSupport: This research study was supported by grantsO1RR00051 and MO1 RR00069 (General Research Cen-

ers Program, National Center for Research Resources, Na-ional Institutes of Health), grant DK34039 from the Na-ional Institute of Diabetes, Digestive, and Kidney Diseases,nd the Zell Family Foundation.

Financial Disclosure: The authors declare that they haveo relevant financial interests.

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Reed et al56

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