Phenotypic Heterogeneity in Pediatric Autosomal Dominant Polycystic Kidney Disease at First Presentation: A Single-Center, 20-Year Review

James B. Tee, MD, Philip D. Acott, MD, D. Heather McLellan, RN, and John F.S. Crocker, MD
Background: The presentation of autosomal dominant polycystic kidney disease (ADPKD) in childhood provides an insight into comorbidities and potential areas for interventions and investigation. Methods: Phenotypic heterogeneity at the time of rst presentation was studied with respect to age of diagnosis, mode of presentation, parental inheritance pattern, renal function, associated hypertension, and hyperlipidemia. Fifty-ve children (median age of presentation, 8.7 years; 27% < 1 year) with ADPKD from 44 families followed up between March 1983 and March 2003 were reviewed. The diagnosis was based on family history and ultrasound conrmation of cysts. Progression of renal disease was followed over the study period (mean duration of follow-up, 4.9 years). Results: A family history of ADPKD was known at presentation in 89%, which precipitated the screening diagnostic imaging in 59% of these children. Maternal inheritance was displayed in 51%, whereas 5% had no known family history of ADPKD. Bilateral renal ndings were present in 78%. Hypertension (>95th percentile for age) was present in 22%, and hyperlipidemia was present in 54%. Renal function was not signicantly diminished in 98% of patients with creatinine clearance >3rd percentile for age, and 7% had persistent proteinuria (>150 mg/d). No subjects had hepatic, splenic, or pancreatic cysts on ultrasound scan. A subpopulation of 10 patients had features of ADPKD dating back to prenatal ultrasound scans. All prenatal cases were characterized by bilateral renal ndings, 90% had a known family history of ADPKD at the time of presentation, and 89% of these patients displayed maternal inheritance. Follow-up studies showed a persistence of hyperlipidemia despite pharmacotherapeutic treatment of hypertension, infrequent proteinuria, and sustained renal function in most patients. Conclusion: The results of this study show that many children at the time of rst presentation have a signicant prevalence of modiable risk factors: hypertension, proteinuria, and hyperlipidemia, in the face of normal renal function. The results also show a unique presentation existing in prenatal subjects. Am J Kidney Dis 43:296-303. 2004 by the National Kidney Foundation, Inc. INDEX WORDS: Autosomal dominant polycystic kidney disease (ADPKD); polycystic kidney disease (PKD); presentation; risk factors; pediatric.

UTOSOMAL DOMINANT polycystic kidney disease (ADPKD) is a common hereditary renal disorder occurring in 1 in every 400 to 2,500 live births.1,2 It is being identied with increasing frequency in the pediatric population. This is in part because of advances in perinatal ultrasound imaging3,4 as well as a growing recognition of the childhood origins of what is classically thought of as an adult disease. Exhibited intrafamilial phenotypic variability
From the Division of Pediatric Nephrology, Department of Pediatrics, Izaak Walton Killam Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada. Received May 1, 2003; accepted in revised form October 20, 2003. The study methodology requiring out-patient chart reviews and the proposed ndings were approved by the institutions divisional research Internal Review Board for publication on September 3, 2002. Address reprint requests to James Tee, MD, Division of Pediatric Nephrology, IWK Health Centre, 5850 University Ave, Halifax, Nova Scotia, Canada B3J 3G9. E-mail: james.tee@utoronto.ca 2004 by the National Kidney Foundation, Inc. 0272-6386/04/4302-0006$30.00/0 doi:10.1053/j.ajkd.2003.10.017
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has led researchers to study potential contributors to this heterogeneous disease expression.5 The few studies looking at the natural history of ADPKD in children have found risk factors for disease progression that include a younger age and the existence of hypertension.6,7 Our study instead focuses on reviewing the phenotypic characteristics at the time of rst presentation. Examining such a previously undiagnosed pediatric population with respect to modiable risk factors such as hypertension, proteinuria, and hyperlipidemia may provide clues of contribution to a condition that accompanies the clinical presentation of ADPKD.
METHODS
We reviewed every child that was directly referred to our nephrology practice and subsequently had ADPKD diagnosed between March 1983 and March 2003. First presentation was dened as the rst clinical visit when a phenotypic diagnosis of ADPKD was conrmed. As such, the rst presentation of a child who did not satisfy phenotypic criteria for ADPKD but was previously followed up because of a signicant family history, would be the rst visit in which the diagnosis of ADPKD could be made. Phenotypic diagnosis of ADPKD required the presence of at least 1 renal

American Journal of Kidney Diseases, Vol 43, No 2 (February), 2004: pp 296-303

PEDIATRIC ADPKD PHENOTYPE AT PRESENTATION

297 Table 1. Characteristics at Diagnostic Presentation (n 55)

Patients (%)

cyst on ultrasound scan.7-9 Where a supportive family history was absent, and autosomal recessive polycystic kidney disease was questioned, a liver biopsy was performed to rule out the characteristic hepatic changes. Individuals with renal cysts in association with a known malformative syndrome were excluded from the study. Examples of such excluded disorders include Laurence-Moon-Bardet-Biedl syndrome and von Hippel-Lindau disease. Individuals with tuberous sclerosis were excluded from the study because renal cysts can exist in isolated tuberous sclerosis, and it would not be possible to determine genetic involvement of the adjacent ADPKD locus based on phenotypic criteria. All children at presentation underwent ultrasound imaging looking for accompanying hepatic, splenic, biliary, and pancreatic cysts. Age and mode of presentation were assessed as was the presence of a known family history. All children underwent a standard history and physical examination. Blood pressure was assessed at the time of presentation, or, in the case of neonates with a prenatal suggestion of ADPKD, after birth. Measurements were taken manually using a mercury sphygmomanometer or, when necessary in infants, by an automated cuff device with systolic conrmation by a Doppler device. Signicant hypertension was dened as systolic and/or diastolic blood pressures above the 95th percentile for age10; elevated blood pressures were conrmed by readings taken on 3 separate occasions. Lipid proles included a fasting serum cholesterol and triglyceride level. Lipid levels were deemed elevated when greater than the 95th percentile for age and sex.11 Glomerular ltration rate (GFR) was estimated by an adequate 24-hour urine collection for creatinine clearance (CrCl) analyzed on a Johnson & Johnson Vitros 250 chemistry system (Ortho-Clinical Diagnostics, Rochester, NY). Where a timed urine collection was impractical (such as in infants), GFR was calculated from serum creatinine levels and length measurements using the formula: GFR (K length/serum creatinine) where K is a constant determined by age and sex.12,13 Where serum creatinine was used, levels were taken after 48 hours of life in newborns so as not to reect maternal contribution. A GFR less than the third percentile for age was deemed signicantly decreased.14 Urine protein excretion was evaluated by 24-hour urine collection or, where unavailable, by urinalysis. Proteinuria was considered signicant if greater than 150 mg/d. All patients were followed up regularly from the point of presentation to the maximum end of the study period on March 1, 2003, or until emigration or transfer to adult services.

Age at presentation Prenatal 0 to 11 mo 1 to 9 y 10 to 18 y Mode precipitating rst presentation Positive family history Antenatal ultrasound scan Urinary tract infection Abdominal pain or mass Urinary frequency/dysuria with negative cultures Gross hematuria Miscellaneous Ultrasound ndings at presentation Bilateral renal cysts Unilateral renal cyst/s-right kidney Unilateral renal cyst/s-left kidney Hepatic, splenic, or pancreatic cysts Renal function and other modiable risk factors GFR 3rd percentile for age Urinary protein 150 mg/d Blood pressure 95th percentile for age Fasting serum lipids 95th percentile for age and sex (n 37): Elevated cholesterol only Elevated triglyceride only Elevated cholesterol and triglyceride

18 9 35 38 53 18 13 5 4 2 5 78 15 7 0 2 7 22

8 35 11

RESULTS

Clinical Manifestations at Presentation Fifty-ve children from 44 families presented to our pediatric institution between March 1983 and March 2003 and were found to have ADPKD. Two boys with known tuberous sclerosis of paternal inheritance with bilateral renal cystic involvement were excluded from the study. Median age at diagnosis was

8.7 years. A total of 47% were boys; 53% were girls. Eighty-nine percent of these individuals had a known family history of ADPKD at the time of presentation. An additional 5% were later discovered to have a family history via familial screening. Known inheritance of ADPKD was paternal in 46% and maternal in 54%. One of the 3 patients without a known family history was a result of adoption with no available history. The primary reasons precipitating the diagnostic imaging on rst presentation are summarized in Table 1. Antenatal ultrasound scans were performed from 4 to 7 months gestational age. Individuals in the miscellaneous subheading, where a renal ultrasound was incidentally diagnostic, included 1 individual who was being investigated for short stature, 1 during follow-up for post streptococcal glomerulonephritis, and 1 for persistent hepatosplenomegaly postvaricella infection.

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Ultrasound Findings at Presentation Table 1 illustrates the renal cystic involvement at presentation on ultrasound scan, as well as results of screening for associated hepatic, splenic, or pancreatic cysts. Of note, extrarenal ultrasound scan detected ovarian cysts in 2 postmenarcheal adolescents. These were excluded from discussion because functional ovarian cysts are common in postmenarcheal girls. One neonate with a prenatal diagnosis had a computed tomography of his head, the result of which was negative for cerebral aneurysms. Only 1 child had persistent headaches warranting magnetic resonance angiography; this result was also negative for cerebral aneurysms. Renal Function and Modiable Risk Factors at Presentation Table 1 reviews the state of renal function at time of presentation, as well as any associated proteinuria, hypertension, or hyperlipidemia. Table 2 details the lipid and urinary protein data. All cases of signicant proteinuria were conrmed via a 24-hour urine collection. The single individual with a signicantly decreased GFR was a full-term boy with renal cysts detected at 24 weeks gestational age. He was a notably large baby, with height and weight greater than the 95th percentile for age and persistently enlarged kidneys for age. Persistent hypertension, isolated hypertriglyceridemia, and high-normal proteinuria were noted at birth. Inheritance of the disease was from his biological mother. The donating biological father had no radiologic evidence of polycystic kidney disease, and biopsy ndings of the transplant kidney were clear of cysts. There was no history of consanguinity, and this infants workup included a liver biopsy that was negative for changes that would be characteristic of autosomal recessive polycystic kidney disease. Abdominal ultrasound scan was negative for hepatic, splenic, or pancreatic cysts. A computed tomography of the head was negative for cerebral aneurysms. Fifteen patients, all under 1 year of age, were eliminated in the lipid analysis because their age and nutritional needs precluded the ability to meet the 12-hour fasting requirement. Three other individuals who all presented before 1989 did not have lipid levels done at the time of presenta-

tion because this was not a part of the routine screening protocol at that time. Subgroup: Prenatal Detection Ten individuals making up 18% of the study population had radiologic evidence of ADPKD on prenatal ultrasound scan. The median age of antenatal diagnosis was 28 weeks gestational age. Table 3 summarizes the clinical characteristics of this subpopulation. Follow-Up Data: Progression of Renal Disease and Evolution of Risk Factors The mean follow-up period for the patient population was 4.9 years. Of the 29 patients who ended their follow-up period before the end of the study, 34% were the result of emigration away from the referral area, and 66% were the result of graduation to the adult nephrology service. These included 6 patients who were seen only once at presentation with no further follow-up (2 because of emigration and 4 transferred to adult nephrology). During the period of follow-up after presentation, a further 2 patients had new-onset hypertension, and 3 other patients had new-onset proteinuria. The mainstay of treatment for all cases of persistent hypertension or proteinuria was early initiation of an angiotension-converting enzyme (ACE) inhibitor. No patients encountered side effects that would necessitate discontinuation of the drug. The involvement of hyperlipidemia over the course of follow-up was noted in 29 patients. This included 17 of the 20 individuals who had hyperlipidemia at rst presentation and were available for follow-up beyond their rst visit, and 12 patients with new-onset hyperlipidemia after rst presentation. Of these latter 12 patients, 10 were infants who, during the course of follow-up, reached 1 year of age permitting the necessary 12-hour fasting for accurate serum lipid assessment. The 29 hyperlipidemic patients are categorized with respect to the presence of proteinuria and the concurrent use of ACE inhibitors in Table 4. As previously described, only 1 patient was noted to have decreased renal function at the time of rst presentation. This prenatally detected infant had persistent hypertension and proteinuria requiring increasing ACE inhibition.

PEDIATRIC ADPKD PHENOTYPE AT PRESENTATION Table 2. Raw Data for Modiable Risk Factors at Presentation
12 h Fasting Serum Cholesterol/Triglyceride (mg/dL)

299

Patient No.

Age (y), Sex

Urinary Protein (mg/d)

95th Percentile Cholesterol/Triglyceride for Age and Sex (mg/dL)*

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55

Prenatal, M Prenatal, M Prenatal, M Prenatal, M Prenatal, M Prenatal, F Prenatal, F Prenatal, F Prenatal, F Prenatal, F 0, M 0, F 0.2, F 0.5, M 0.9, M 3, M 3, F 3, F 4, M 4, M 5, F 5, F 6, M 6, F 7, M 7, M 7, F 8, M 9, M 9, M 9, F 9, F 9, F 9, F 10, M 10, M 11, M 11, M 11, F 11, F 11, F 12, F 12, F 13, M 13, M 13, M 13, F 14, M 14, F 15, F 15, F 16, M 16, F 16, F 18, M

50 0 0 140 30 30 0 50 0 0 40 0 0 50 0 60 20 350 0 30 30 80 0 0 0 90 30 20 30 70 70 100 50 160 50 50 80 30 100 180 30 50 40 90 20 50 0 50 0 550 60 60 0 70 0

139/70 132/61 128/139 178/96 115/70 146/136 127/62 205/174 178/101 175/82 161/60 161/98 199/136 195/100 192/172 215/108 123/120 128/177 149/76 141/59 115/95 228/210 136/60 174/117 116/194 124/181 162/90 183/419 155/135 131/160 158/76 N/A 118/91 N/A 158/203 237/108 119/109 167/134 172/.143 N/A

182/86 182/99 182/99 189/86 189/86 189/99 189/99 191/108 209/114 191/108 191/108 209/114 191/108 191/108 191/108 209/114 209/114 209/114 209/114 204/108 204/108 204/108 204/108 217/114 217/114 217/114 217/138 217/138 204/138 204/138 204/138 217/138 204/138 217/138 212/138 212/138 198/163 212/128 212/128 198/163

NOTE. To convert cholesterol in mg/dL to mmol/L, multiply by 0.02586: triglyceride in mg/dL to mmol/L, multiply by 0.01129. *Behrman RE, Kleigman RM, Jenson HB: Nelson Textbook of Pediatrics (ed 16). Philadelphia, PA, Saunders, 2000, pp 21922210 (Chap 726). Unable to meet 12-hour fasting requirement.

300 Table 3. Subgroup at Presentation and on Follow-Up: Prenatally Detected (n 10)

Patients (%)

TEE ET AL

At presentation Bilateral renal cysts Known family history of ADPKD Inheritance (n 9)maternal Inheritance (n 9)paternal GFR 3rd percentile for age Urinary protein 150 mg/d Blood pressure 95th percentile for age By end of follow-up period GFR 3rd percentile for age Urinary protein 150 mg/d Blood pressure 95th percentile for age Fasting serum lipids 95th percentile for age and sex (n 9)* persistence (n 7) regression to normal levels (n 7)

90 90 89 11 10 0 20

10 0 30 78 71 29

*Included only patients reaching 1 year of age on follow-up to permit 12-hour fasting for lipid levels.

typic linkage analysis is neither widely available nor possible in decient pedigrees. Our study population taken as a whole reects the results of an autosomally transmitted disease, with nearly equal boys and girls, as well as balanced paternal and maternal inheritance. We show that nearly 9 of every 10 patients had a known family history of ADPKD at the time of presentation, which was the principal precipitant for the diagnostic evaluation in more than half of these individuals. When all patients were analyzed, 3 of every 4 patients had bilateral renal involvement, whereas the remainder had a 2:1 predilection for the right kidney. None of our patients had evidence of related extrarenal abdominal cystic involvement, in sharp contrast to studies in adults in which up to 2 of every 3 patients have hepatic cysts.15,16 Neither of the 2 patients who were assessed radiographically for cerebral aneurysms had any evidence of cranial involvement. All but 1 patient had adequate renal function at presentation. Modiable Risk Factor: Hypertension Hypertension was noted at presentation in 1 of every 5 of our patients. This is consistent with studies that have found an early trend for increased blood pressure in children with ADPKD.7,17 The fact that hypertension is seen as early as the rst visit in the presence of normal renal function, however, points to the importance of regular blood pressure checks in the asymptomatic at-risk pediatric population. It also highlights a potential for early treatment of what has been shown to be a risk factor for disease progression in eventual chronic renal insufciency.18 The current literature suggests possible contributors to hypertension in individuals with ADPKD. Several studies on adult hypertension in ADPKD have suggested activation of the renin angiotensin system by cystic compression on renal arterioles and synthesis of renin by tubulocystic epithelium.19,20 More specic genetic studies on adults include studies suggesting that a deletion/ deletion (DD) haplotype of the ACE may contrib-

The isolated hypertriglyceridemia at presentation resolved. This infant was the sole patient whose disease progressed to end-stage renal disease, necessitating renal transplantation at 6 years of age. Only 1 other patient during the period of follow-up had signicantly impaired renal function. This latter patient, originally presenting at 6 months of age, was noted by 12 years of age to have decreased renal function and new onset of proteinuria despite treatment with ACE inhibitors for existing hypertension. This patient also had a history of persistent hypercholesterolemia and hypertriglyceridemia despite dietary counseling.
DISCUSSION

This is the rst study to focus specically on the characteristics of rst presentation in a large population with ADPKD diagnosed phenotypically. Diagnosis based on phenotype remains an important area of investigation because genoTable 4.

Progression of Hyperlipidemia During Follow-Up (n 29)

Use of ACE Inhibitor and History of Proteinuria (no.) Use of ACE Inhibitor and No Proteinuria (no.) Total Patients

Status of Hyperlipidemia

No Use of ACE Inhibitor (no.)

Persistence Regression to normal levels

6 7

2 3

7 4

15 14

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301

ute to hypertension and greater disease severity in ADPKD21,22 as well as studies supporting the role of a specic endothelial nitric oxide synthase (ENOS) gene polymorphism in the occurrence of hypertension.23 Modiable Risk Factor: Hyperlipidemia Hypertriglyceridemia was noted in just less than half of our fasting patients, and hypercholesterolemia was noted in nearly one fth of the study group. The predominant presentation was an isolated elevation in serum triglyceride. No previous study to date has looked at the lipid status of children with ADPKD. Minimal data exist in the adult population, complicated by a higher incidence of nonrenal-related hyperlipidemia. Although abnormalities in lipid metabolism are frequent in chronic renal failure, it is surprising to see such a high prevalence of hyperlipidemia in a young population presenting with normal renal function. Longitudinal studies are required to view the contribution of hyperlipidemia to pediatric ADPKD disease progression before treatment can be proposed. Subgroup: Prenatal Detection The widespread use of fetal ultrasonography has resulted in more cases detected in utero. Nearly 1 of every 5 of our presenting patients had radiologic evidence of ADPKD on prenatal ultrasound scan. Analysis of this subgroup reveals several striking ndings. Similar to the parent study group is the predilection for bilateral renal cystic involvement as well as a known family history of ADPKD at presentation. Of note is that 8 of 9 neonates had maternal inheritance. A predominance of transmitting mothers in the prenatal ADPKD population was observed in 3 of 4 families of a previous study in which clinically asymptomatic individuals were excluded from the study group.24 In another study that excluded individuals with no known family history, both cases diagnosed on prenatal ultrasound were of maternal inheritance.7 No publication to date has veried a denite genetic imprinting effect for early manifesting ADPKD. The potential for an inherited maternal genome to play an unbalanced role in fetal renal development predisposing to earlier or more progressive cystogenesis remains to be studied. Although disease progression past the point of

presentation was not the focus of our study, we note that the single individual with signicantly decreased renal function presented with prenatal ultrasound ndings and had a rapidly deteriorating course progressing to chronic renal failure and requiring renal transplantation at 6 years of age. Presentation was complicated by concurrent hypertension and hyperlipidemia. An increase in disease severity appears to be associated with bilineal inheritance of ADPKD resulting in a child homozygous for the dominant disease allele; however, only 1 parent was affected by the condition in this case, and there was no history of consanguinity.25 The other patient who had a borderline low GFR also presented on prenatal ultrasound scan and had a severe postnatal course involving hypercalcemia and supraventricular tachycardia. As such, prenatal presentation of ADPKD, which we propose is associated with maternal inheritance, may predispose to a more severe progression of disease. Bear et al26 noted that the age of adult-onset end stage renal disease was also earlier in persons inheriting the disease from their mothers. Of corollary note is that no individuals in our study presenting past the neonatal age had rapid progression of disease. The only individual out of the entire study population progressing to end-stage renal failure by the end of the follow-up period was the aforementioned patient. Similar to the parent study group, 1 in 5 of the prenatal subgroup had hypertension in the face of predominantly normal renal function. The existence of this potentially modiable risk factor at birth suggests a contributory prenatal genetic event given the minimal exposure to extrauterine environmental inuences. Progression of Renal Disease and Evolution of Risk Factors New-onset hypertension or proteinuria developed in 5 additional patients. Although this suggests evidence of a progressive renal cystic disease, the signicance of this is complicated by early treatment with ACE inhibitors, which likely masked or prevented their evolution in other patients. This may have, in turn, been a contributor to the low incidence of end-stage renal disease over the study period in our population. Hyperlipidemia persisted in just more than half of the affected patient population despite

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dietary counseling. The concurrent exposure to ACE inhibitors did not appear to alter the progression of hyperlipidemia, because a similar number of patients had either persistence or regression of their hyperlipidemia regardless of whether they were on ACE inhibitors or had never used them. This may have been associated with the nonmaximal dosing of ACE inhibitor together with the infrequency of proteinuria, both of which may complicate assessment of evolving hyperlipidemia during the course of follow-up.27 Analysis of the subgroup of 9 patients in whom ADPKD was detected prenatally and reached 1 year of age on follow-up to permit fasting lipid studies showed that approximately 3 of every 4 had hyperlipidemia, which persisted in most. Study Limitations The importance of utilizing a phenotypic diagnosis for ADPKD, as was previously outlined, may have also lent to a population bias. Although the optimal denition of a positive radiologic screening test is uncertain in children, the choice of a threshold of 1 cyst was based on age-specic research. One such study indicated that ultrasound scan may have a false-negative rate of up to 19% to 38% for age-specic groups in ADPKD with the PKD1 gene mutation.9 Therefore, our study may have been biased toward a more clinically symptomatic group, because individuals with a known PKD gene mutation without cysts may have been excluded, based on the assumption that the patients with a positive ADPKD genotype without the ADPKD phenotype may have a decreased incidence of risk factors such as hyperlipidemias or hypertension. However, this is potentially lessened by the observation that renal function was not signicantly decreased in most patients, and that nearly two thirds of our study population were clinically asymptomatic at the time of diagnosis, having presented owing to a known family history or prenatal imaging. The same study showed an overall 2% false-positive rate, although our exclusion of individuals with tuberous sclerosis as well as our phenotypic inclusion of non-PKD1 gene mutations may account for some of this. Other factors also lent to a study population bias. The size of our prenatally diagnosed subgroup limited our ability to draw absolute conclu-

sions from analysis, although clearly signicant results in maternal inheritance, prevalence of hypertension, and hyperlipidemias permit us to suggest areas for further study. Some limits were imposed on quantiable laboratory values. The nutritional needs of our infant study group population would only permit a 4-hour fast rather than the necessary protocol-12 hour fasting desired for triglyceride levels. As a result, these data were not included in the initial presentation but were incorporated into the follow-up analysis as they reached 1 year of age. Of note, the cutoff values used for signicant declines in GFR in neonates were based on the limited information available on normal ranges of GFR in this subpopulation. A referral bias is inherent in ADPKD as with other autosomally inherited conditions in which otherwise asymptomatic siblings are diagnosed and included on presentation of the proband. However, the effect of this is lessened in our study because nearly 4 of every 5 patients originated from a unique family. Although our study highlights early-onset modiable risk factors with an implied potential benet for subsequent early treatment, the screening of asymptomatic family members, in particular with genetic markers, also carries risks and remains debatable. There exists potential psychologic and social consequences, such as being labeled with a disease that may otherwise remain clinically dormant and future qualication for health insurance. All of our presenting families were counseled on the potential benets and risks of sibling screening, which may have limited the number of siblings in our study population.
CONCLUSIONS

The results of this study show that many children at the time of rst presentation have a signicant prevalence of modiable risk factors: hypertension, proteinuria, and hyperlipidemia, in the face of normal renal function. Signicant involvement in subjects with a prenatal diagnosis highlights the early phenotypic expression of ADPKD as well as the potential importance of early screening. Further study is required to validate a potential maternal inheritance effect on earlier and more rapidly progressive disease. Further longitudinal studies as well as correla-

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tion with genotype will aid in our ability to advise early treatment for these factors.
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14. Postlethwaite: Clinical Pediatric Nephrology (ed 2). Oxford, Butterworth-Heinemann Ltd, 1994, p 91 15. Segal AJ, Spataro RF, Barbaric ZL: Adult polycystic kidney disease: A review of 100 cases. J Urol 118:711-713, 1977 16. Nicolau C, Torra R, Bianchi L, et al: Abdominal sonographic study of autosomal dominant polycystic kidney disease. J Clin Ultrasound 28:277-282, 2000 17. Seeman T, Sikut M, Konrad M, Vondrichova H, Janda J, Scharer K: Blood pressure and renal function in autosomal dominant polycystic kidney disease. Pediatr Nephrol 11:592596, 1997 18. Marcelli D, Locatelli F, Alberti D, et al: Hypertension as a factor in chronic renal insufciency progression in polycystic kidney disease. The Northern Italian Cooperative Study Group. Nephrol Dial Transplant 10:15-17, 1995 (suppl 6) 19. Ecder T, Schrier RW: Hypertension in autosomaldominant polycystic kidney disease: Early occurrence and unique aspects. J Am Soc Nephrol 12:194-200, 2001 20. Torres VE, Donovan KA, Scicli G, et al: Synthesis of renin by tubulocystic epithelium in autosomal-dominant polycystic kidney disease. Kidney Int 42:364-373, 1992 21. Rossetti S, Burton S, Strmecki L, et al: The position of the polycystic kidney disease 1 (PKD1) gene mutation correlates with the severity of renal disease. J Am Soc Nephrol 13:1230-1237, 2002 22. Perez-Oller L, Torra R, Badenas C, Mila M, Darnell A: Inuence of the ACE gene polymorphism in the progression of renal failure in autosomal dominant polycystic kidney disease. Am J Kidney Dis 34:273-278, 1999 23. Walker D, Consugar M, Slezak J, Rossetti S, Torres VE, Winearls CG: The ENOS polymorphism is not associated with severity of renal disease in polycystic kidney disease 1. Am J Kidney Dis 41:90-94, 2003 24. Zerres K, Rudnik-Schoneborn S, Deget F: Childhood onset autosomal dominant polycystic kidney disease in sibs: Clinical picture and recurrence risk. German Working Group on Paediatric Nephrology (Arbeitsgemeinschaft fur Padiatrische Nephrologie). J Med Genet 30:583-588, 1993 25. Paterson AD, Wang KR, Lupea D, St George-Hyslop P, Pei Y: Recurrent fetal loss associated with bilineal inheritance of type 1 autosomal dominant polycystic kidney disease. Am J Kidney Dis 40:16-20, 2002 26. Bear JC, Parfrey PS, Morgan JM, Martin CJ, Cramer BC: Autosomal dominant polycystic kidney disease: New information for genetic counselling. Am J Med Genet 43:548553, 1992 27. Ruggenenti P, Mise N, Pisoni R, et al: Diverse effects of increasing lisinopril doses on lipid abnormalities in chronic nephropathies. Circulation 107:586-592, 2003