Kidney International Vol. 46 (1994), pp. 951—964

PERSPECTIVES IN CLINICAL NEPHROLOGY

Hereditary and acquired cystic disease of the kidney

As a nephrologist thinks about the renal cystic diseases, severalobservations emerge: first, the disorders are numerous and vari-able in etiology; second, they span a wide range of both age ofpresentation and severity of the renal disease; third, many of themare systemic disorders; fourth, despite diverse etiologies, many ofthem share similar processes of cyst formation. Additionally, onecannot help but be impressed with the new information which hasemerged about the genetics, pathogenesis, clinical presentationand management of these disorders in the last decade.

Renal cystic diseases have been classified in a variety of ways,but from a clinical perspective it is perhaps most useful toseparate them into genetic and non-genetic (Table 1) disorderssince this approach guides evaluation and management. It isworth remembering that not all genetic disorders are congenital(onset at birth), and conversely not all congenital disorders areheritable. Many of the congenital renal cystic disorders are part ofrecognized syndromes, including chromosomal aberrations, suchas trisomy 9 and 18, and other rare autosomal recessive orX-linked syndromes such as oro-facio-digital syndrome type 1;these as well as congenital multicystic kidneys are reviewed indetail elsewhere and are not discussed here [1, 2]. The geneticdisorders display both autosomal dominant and autosomal reces-sive inheritance; the former include the most common geneticdisease in this country, autosomal dominant polycystic kidneydisease (ADPKD), while the recessive diseases are all uncommon.The genetic diseases are often systemic disorders, perhaps reflect-ing the fact that the protein abnormalities resulting from the genedefects in these disorders likely influence the development andfunction of more than one organ. Also in the genetic disorders,the availability of gene linkage techniques have permitted identi-fication of the chromosomes which carry the putative genes and insome instances even the gene itself. This provided additionaldiagnostic techniques (Fig. 1) and identified that some of thedisorders can actually be caused by different gene defects, such asADPKD which was thought to be a single entity, but can becaused by defects on different chromosomes.

The non-genetic disorders encompass both developmental ab-errancies and acquired disorders (Table 1), many of which arecommon disorders.

The pathobiology of cystogenesisThe fact that renal cysts occur in so many disorders suggests

that there is not likely to be a single pathogenetic mechanism forcystogenesis; rather, multiple heritable or acquired defects couldmediate cyst formation. Indeed, experimental data and clinicalobservations suggest that there are at least three components of

Received for publication February 1, 1994and in revised form April 29, 1994Accepted for publication May 3, 1994

© 1994 by the International Society of Nephrology

cystogenesis: cell proliferation, fluid secretion, and extracellularmatrix abnormalities.

Increased renal epithelial proliferation is manifested in multi-ple ways in the cystic disorders. In ADPKD hyperplasia includespolyps of the cyst-lining epithelium [3], microscopic renal adeno-mas [4] and increased proliferation and responsiveness of culturedADPKD cyst epithelia to mitogens such as EGF [5]. Similarly, intuberous sclerosis (TS), renal cysts demonstrate hyperplasticepithelia with nodular extensions into the lumen and angiomyo-lipomas [6]. The renal cystic epithelia in Von-Hippel-Lindau(VHL) disease display a histopathologic continuum from normalto hyperplastic to malignant epithelia [7]. Moreover, in VHL andTS the responsible genes are mutated tumor suppressor genes [8,9], confirming the hypothesis that increased cell proliferation canlead to cyst formation. This concept is supported by the observa-tion that renal cysts occur in transgenic animal models in whichc-myc or HrasT24 is in the transgene [10, 11]. The question of aninterrelationship of such oncogenes with genes regulating celldeath has also been raised by recent experimental studies [12].

Increased cell proliferation alone would be expected to resultonly in the solid tumors seen in these disorders. It is apparent thatfluid secretion is also necessary to form a fluid-filled cyst. Directevidence comes from in vitro studies of MDCK cells suspended incollagen matrix [13]. In defined medium alone, these cells do notproliferate or form cysts. If EGF is added, dense, solid balls ofcells form. If a cAMP-agonist is added, which stimulates both cellproliferation and fluid secretion, cysts are formed [13]. This fluidsecretion by cyst epithelia is demonstrated by studies on intactcysts excised from human ADPKD kidneys which vigorouslysecrete fluid when they remain filled with the original cyst fluid orwhen stimulated with a cAMP agonist [14]. The secretory andcystogenic capacity of ADPKD cyst fluid is also demonstratedboth by its ability to stimulate fluid secretion by monolayers ofMDCK and human kidney cortex cells in cell culture and toinduce cyst formation in both these cell types in collagen matrix[13].

Clinically this secretory capacity of cyst epithelia is seen whencysts are punctured and drained; they will rapidly reaccumulatefluid if the epithelium is not altered with alcohol sclerosis [15, 16].The critical role of fluid secretion in cystogenesis offers a potentialfor ultimate treatment of these disorders with agents which inhibitepithelial fluid secretion.

Alterations of the extracellular matrix in the cystic disorders aresuggested by the splitting, duplication and lamination of tubularbasement membranes (BM) seen in early stages of ADPKD [17];the thickened BM of cyst-lining epithelia at later stages ofADPKD [18]; the thickened tubular BM in a drug-induced ratmodel of PKD [19], and extremely thin, attenuated tubular BMadjacent to thickened and laminated areas in patients withjuvenile medullary cystic disease [20]. In cell culture ADPKDepithelia elaborate a grossly abnormal-appearing extracellularmatrix [18]. Some studies have shown reduced de novo synthesis of

951

952 Fick and Gabow: Cystic disease

Table 1. Genetic and non-genetic renal cystic disorders

GeneticAutosomal dominant

Autosomal-dominant polycystic kidney diseaseTuberous sclerosisVon-Hippel-Lindau diseaseAdult-onset form of medullary cystic disease

Autosomal recessiveAutosomal-recessive polycystic kidney diseaseJuvenile nephronophthisis

Cysts associated with multiple malformation syndromesChromosome disordersAutosomal recessive syndromesX-linked syndromes

Non-geneticDevelopmental disorders

Multicystic dysplasiaMedullary sponge kidney

Acquired disordersSimple renal cystsMultilocular cystic nephromaHypokalemic cystic diseaseAcquired renal cystic kidney disease

(in chronic renal failure patients)

proteoglycans by human ADPKD cyst-derived epithelia and analtered composition of various proteoglycan fractions [21]. Fi-nally, the array of systemic disorders present in a disease likeADPKD is compatible with a matrix disorder.

One possible explanation for these alterations in proliferation,secretion and matrix in cystic epithelia is that cyst epithelium iseither incompletely differentiated or partly dedifferentiated. Inhereditary or developmental disorders, a block in the normaltubular development could lead to continued cell growth withoutterminal differentiation, whereas an insult to mature kidneyscould cause dedifferentiation [22]. This concept is supported bythe observation of an immature phenotype of cyst-lining epithelia,the abnormal expression of developmentally regulated genes incpk mice [23], the overexpression of differentiation antigens andgrowth-related genes in human ADPKD cells [24], reduced distaltubular EGF expression with consequent lack of collecting ductmaturation in cpk [25] and pcy mice [26], and persistence of fetalproteins in human ADPKD and ARPKD epithelia [27, 28].Abnormal responsiveness to growth factors [5, 18] and themislocation of Na-K-ATPase to apical plasma membranes ob-served in human ADPKD kidneys [29] are compatible with animmature state [27]. The presence of Na-K-ATPase on apicalmembranes of collecting tubules has also been shown in develop-ing cpk mice [30]. Likewise, the abnormal basement membranecomposition has been viewed as reflecting an undifferentiatedstage of renal tubules [21, 23].

The observation which is most intriguing for the clinician is thereversibility of cystic lesions, This has been shown to occur indrug-induced animal models with removal of the cystogene [31],in bypokalemic-induced renal cysts with reversal of the hyperal-dosterone state [32], and in acquired cystic disease with removalof the uremic environment [33]. Thus, there might also bepotential for reversal of the other polycystic lesions once theputative stimuli are identified in other disorders. Moreover,availability of drugs which interfere with proliferation and secre-tion could also impact disease progression.

Renal cystic disorders

Autosomal-dominant polycystic kidney disease

Epidemiology and genetics. ADPKD has a world-wide distribu-tion and an estimated prevalence of 1:200 to 1:1000. ADPKDdemonstrates genetic heterogeneity with two and possibly threecausative genes. About 90% of white families of European originhave the gene located on the short arm of chromosome 16(ADPKD1) [34]. A second gene locus is on chromosome 4(ADPKD2) [35, 36]. There is a recent preliminary report of afamily whose ADPKD gene is not linked to either chromosome 16or 4, suggesting yet a third gene [37]. Recently, the ADPKD1 genehas been identified; but the function of the protein has not beendetermined (note added in proof, A).

There are phenotypic differences between ADPKD1 and AD-PKD2, with ADPKD2 individuals developing hypertension andESRD at an older age than ADPKD1 individuals (mean age atESRD 69.4 1.7 vs. 56.7 1.9 years) [38]. However, even withinADPKD1 families there is considerable variability both in theoccurrence of extrarenal manifestations and in the severity of therenal disease [39, 40]. For example, within a family, some mem-bers may reach ESRD more than 30 years earlier than others [40].In addition, some families have one or more offspring who arediagnosed in utero or in the first year of life from a mother withtypical adult onset disease [41]. This phenotypic variability withinfamilies has both clinical and scientific implications. Clinically itmeans that when counselling ADPKD families one cannot assumethe disease will have a similar course in a given family. From amore scientific perspective, this variability is of interest because ofits similarities with diseases such as fragile-X syndrome, myotonicdystrophy, and Huntington's disease [42—44]. The underlyingmolecular mechanism in these diseases is unstable DNA, withvarying numbers of triplet repeats within the gene in differentfamily members relating to different age of onset and diseaseseverity [45—47]. Whether a similar mechanism is operative inADPKD or whether this intrafamilial variability is due to theinteraction of the ADPKD genes with other modifying genes orenvironmental factors is not yet clear. However, the identificationof the ADPKD1 gene will permit this question to be answered inADPKD1 families. The unstable DNA would also explain theapparent high spontaneous mutation rate and the variability inextrarenal manifestations. This question of etiology of phenotypicvariability is of interest not only in ADPKD but also in the othersystemic renal cystic diseases, particularly TS, which shows manyof the same features of differing age of onset, variable phenotypicexpression and severity of disease.

Diagnosis, clinical manifestations, and management consider-ations. The mainstay for diagnosing ADPKD is ultrasonography.Its only limitation is that it relies on the presence of renal cysts todefine the gene carrier state. In ADPKD1 families 64% ofaffected children under the age of 10 years and about 90% ofteenagers between 10 and 19 years who are presumed genecarriers have detectable renal cysts [48]. The reliability of ultra-sonography for ADPKD2 patients has not yet been defined, Genelinkage analysis can be used to determine the status of an at-riskindividual who does not yet have detectable renal cysts. Even withthe cloning of the ADPKD1 gene, gene linkage analysis remainsthe only method available in ADPKD2 families and may still needto be used in ADPKD1 families until specific gene testing iscommercially available. An example of an application for this

Fick and Gabow: Cystic disease 953

12C2 C202 Dl

2 3

6(40)

C2 ClDl 03

Table 2. Frequency of renal manifestations of autosomal-dominantpolycystic kidney disease in adults

4 5

•TLIII ó 6(37) (40) (34) (30) (28)

C2 C3 Cl Cl C2 C3 C2 Cl C2 ClDl D2 D2 03 D2 02 02 D3 D2 03

?(18) (20)

Cl C3 C2 C2D3 D2 D3 D3

Manifestation Frequency

AnatomicalRenal cysts 100%Renal adenomas 21%Cyst calcification Common

FunctionalDecreased renal concentrating Affects potentially all adults

abilityDecreased urinary citrate 67% (10/15 subjects)

excretionImpaired renal acidification Unknown

Hormonal alterationsIncreased renin production Probably affects all hypertensive

adultsPreserved erythropoietin Probably affects all ESRD

production patientsComplications

Hypertension Affects 60—75% of adultsHematuria and/or hemorrhage 50%Acute and chronic pain 60%Urinary tract infection: Common

bladder, interstitium, cystsNephrolithiasis 20%Nephromegaly 100% of adultsRenal failure Affects 50% of patients by age

60

Ill

Fig. 1. Pedigree of a kindred with ADPKD1. Circles denote female familymembers, squares male family members, and solid symbols affectedmembers. Ages are shown in parentheses. Subject Ill-i wished to knowher status before her marriage. Ultrasonography was negative. Two typesof chromosome l6p markers were used (C and D). The three possiblealleles are indicated (1, 2 and 3). Markers C and D are assumed to flankthe ADPKD1 gene locus. These types are depicted below each symbol. Inthis family the haplotype C3, D2 is transmitted with the ADPKD1 gene.Therefore, Subject Ill-i has an approximately 99% chance of being a genecarrier. This type of linkage analysis can be performed in hereditarydisorders for which the chromosome location of the gene has beendetermined. (With permission of GABOW PA: Autosomal dominantpolycystic kidney disease. N Engi J Med 329:332—342, 1993)

technique is shown in Figure 1. An 18-year-old woman who hadno cysts by ultrasonography had approximately a 10% chance ofcarrying the gene (if she was in an ADPKD1 family). She wisheda more precise answer regarding her gene status. This could onlybe obtained with gene linkage; this could be performed in herbecause she had 2 other affected family members which werenecessary to identify the marker haplotype travelling with theADPKD gene in this family.

Before performing gene linkage or before any screening isdone, patients must be competently informed about the potentialpsychological and insurance implications of a positive diagnosis.These are issues of particular concern in screening children [49].Because of the expense of gene linkage techniques, the need toinvolve other family members and the reliability of ultrasonogra-phy, gene linkage will likely be limited to circumstances in whichfamily planning would be altered, or for potential kidney donorswhen ultrasound findings are nondiagnostic [49, 50]. Although theneed to involve other family members will not be requiredeventually for the ADPKD1 gene, the other advantages of ultra-sonography will still remain.

ADPKD is a systemic disease with both renal and extrarenalmanifestations (Tables 2 and 3). The anatomic renal manifesta-tion is diffuse renal cystic disease; the cysts are distributedthroughout the cortex and medulla (Fig. 2). The common clinicalrenal manifestations are chronic flank and/or back pain, hematu-na, infection, nephrolithiasis and hypertension [51]. Pain, hema-tuna and hypertension occur more often in patients with largerkidneys [52—54]. The relationship between renal and/or cyst sizeand pain is demonstrated by the long-term relief achieved inpatients with disabling pain who undergo cyst decompression [55,56].

Adapted from GABOW PA: Autosomal dominant polycystic kidneydisease. N Engi J Med 329:332—342, 1993. Used with permission.

Both microscopic and gross hematuria occur in ADPKD; acuteepisodes of macroscopic hematuria can be caused by cyst hemor-rhage, infection or nephrolithiasis. Cyst hemorrhages are bestmanaged conservatively, with bed rest and mild analgesics [57]. Ifa particular activity reproducibly provokes hematuria, this activityshould be discouraged since repeated episodes of gross hematuriahave been associated with decreased renal function [53].

Nephrolithiasis occurs in 20 to 36% of ADPKD patients [58,59]. This high frequency may be related to both urinary stasissecondary to cyst compression of tubules and metabolic factorssuch as hypocitraturia, hyperoxaluria and hyperuricemia whichhave been found to occur in ADPKD patients with nephrolithiasisand normal renal function [58].

Infection can occur as lower urinary tract infection, renalinterstitial infection (pyelonephritis), renal cyst infection or pen-nephric abscess. Although lower UTI and pyelonephritis aremanaged as in the general population, renal cyst infection re-quires the administration of lipid-soluble antibiotics such astrimethoprim-sulfamethoxazole, chloramphenicol or ciprofloxa-cm which can penetrate cyst walls [57].

Hypertension is an early and common manifestation ofADPKD. Sixteen percent of children under the age of 18 yearshave blood pressures above the 95th percentile for age- andgender-matched children [601 and 60 to 75% of adults arehypertensive before impairment of renal function [51]. Moreover,in one study ADPKD adults between 15 and 25 years of age hadsignificantly elevated left ventricular mass compared to controls,attesting to the biologic significance of the blood pressure eleva-tion early in the course of the disease [611. Numerous studies haveshown that the renin-angiotensin system is activated in patientswith ADPKD [62—66], presumably via disruption of the renal

954 Fick and Gabow: Cystic disease

Table 3. Extrarenal manifestations of the hereditary cystic diseases

Autosomal-dominant polycystic kidney diseaseGastrointestinal

Hepatic cystsCongenital hepatic fibrosis (rare)Pancreatic cysts (uncommon)Diverticuli

CardiovascularCardiac valve abnormalitiesIntracranial aneurysms

MusculoskeletalHernias

Extrarenal cystsOvariesTesticles (rare)ArachnoidSpleen

Tuberous sclerosisSkin

Adenoma sebaceumHypomelanotic maeulesUngual fibroma

Central nervous systemCortical tubersGlial nodulesGiant cell and retinal astrocytomas

CardiovascularRhabdomyomas

GastrointestinalHepatic angiolipoma

PulmonaryMalignant lymphangiomyomatosis

Von-Hippel-Landau diseaseCentral nervous system

Brain hemangioblastomaRetinal angiomasSpinal hemangioblastomas

EndocrinePheochromocytomaPancreatic islet cell tumors

Miscellaneous cystsPancreaticEpididymal

Autosomal-reeessive polyeystic kidney diseaseGastrointestinal

Congenital hepatic fibrosisJuvenile nephronophthisis

GastrointestinalCongenital hepatic fibrosis

OcularTapetoretinal degeneration

BoneCone shaped epiphyses

vasculature by cysts and the subsequent development of intrarenalischemia.

ESRD does not occur in every ADPKD patient. In fact, severalstudies have shown that by age 60 only about 50% of patients havereached ESRD [67, 68]. Factors which have been reported tocontribute to a faster rate of progression are the ADPKD1genotype, male gender, younger age at diagnosis, hypertension,increased left ventricular mass, hepatic cysts in women, three ormore pregnancies, multiple episodes of gross hematuria, urinarytract infections in men, and increased renal volume [38, 52, 68,691. Some of these factors such as hypertension, infection andpregnancies are amenable to intervention and their modificationmay improve the renal outcome of ADPKD patients. Once ESRD

has been reached, ADPKD patients are good candidates forhemo- or peritoneal dialysis and renal transplantation [70].

The most common extrarenal manifestation is hepatie cystswhich are rarely seen in children but increase with age, decliningrenal function, and parity in women. Seventy-seven percent ofpatients over the age of 60 have hepatic cysts [71]. Massive hepaticcystic disease occurs predominantly in women [72, 73]. Thisobservation and the relationship of disease severity to paritysuggest a pathogenetic role for female steroid hormones inhepatic cystogenesis [72]. Liver function is normal unless acomplication such as infection or malignancy is present [73, 74].For the rare patient with a grossly enlarged liver and disablingpain, surgical resection and decompression is a therapeutic option[75]. Although congenital hepatic fibrosis is generally associatedwith ARPKD, some cases have been described in association withADPKD [76—78], and even Caroli's disease coexisting with con-genital hepatic fibrosis and polycystic liver and kidney disease inthe same patient has been reported [79].

The other common gastrointestinal tract manifestation is co-Ionic diverticula and associated complications which occur moreoften in ADPKD-ESRD patients compared to ESRD patientswith other diseases and to the general population [51, 80]. Herniasalso occur more often than in the general population [51]. Themost devastating extrarenal manifestation is a ruptured intracra-nial aneurysm (ICA). Three recent prospective studies haveshown a frequency of ICA in asymptomatic ADPKD patientsbetween 5 and 11% [81—83]. There may be family clustering ofruptured ICA [83—86], and rupture of an ICA in ADPKD seemsto occur at a younger age and with smaller aneurysms than in thegeneral population [82, 83, 87]. Screening for ICA by noninvasivemethods such as dynamic CT or magnetic resonance angiographycurrently is recommended only for patients with a family history ofruptured ICA, patients with a previous ruptured ICA, thoseengaged in an activity where loss of consciousness would placethem or others at extreme risk, or those who are undergoing asurgical intervention likely to be associated with hemodynamicinstability with hypertension [87—90], A flow chart of our currentrecommendations is displayed in Figure 3.

Cardiac valvular abnormalities are also common in ADPKD.Mitral valve prolapse has been shown in two prospective echocar-diographic studies to occur in about 25% of ADPKD patients,compared to only 2% of controls [91, 92]. This is often associatedwith atypical chest pain or palpitations [91, 92]. The naturalhistory of these cardiac valvular lesions is uncertain, but someADPKD patients have required valve replacements [93]. Ingeneral, an assessment for extrarenal manifestations should occuronly when clinically indicated.

Tuberous sclerosis

Epidemiology and genetics. Tuberous sclerosis (TS) is character-ized by multiple hamartomas, which are benign congenital tumorscomposed of abnormally arranged and differentiated tissues inbrain, retina, skin, heart, kidneys, liver, lung and bone. It is muchmore common than previously thought with recent prevalenceestimates of 1:5800 to 1:10000 [94—96]. Inheritance is autosomaldominant with genetic heterogeneity. Linkage to chromosome 9has been established for about one-third of families [97]; linkagehas also been reported to markers on chromosomes 11, 12 and 16[98—100], but recent evidence has questioned the existence of TS

Fick and Gabow: Cystic disease 955

Fig. 2. (A) ADPKD kidney with visible cysts on the kidney's surface. (B) Cutsection of the ADPKD kidney showing cortical and medullary cysts ofvarying size.

genes on chromosomes 11 and 12 [9]. In most, if not all multi-generation families the disease appears to be caused by a muta-tion either on chromosome 9 or 16 [9]. Recently the TS genelocated on chromosome 16 (TSC2) has been identified, andinterestingly lies in the same region as the ADPKD1gene [9]. Theprotein product, tuberin, has homology with proteins involved incell proliferation and differentation [9].

About two-thirds of cases seem to be new mutations in that theyhave a negative family history [94, 95, 99, 101], but as in ADPKD,a negative family history could reflect minimal disease in parentswho remain undiagnosed rather than a true new mutation. TS ischaracterized by extreme variability of phenotypic expression,with some members of a family having fatal disease complicationsand others being normal on routine clinical examination [101,102].

Diagnosis, clinical manifestations and management consider-ations. The diagnosis of TS is usually made by a typical constel-lation of clinical findings [95, 103]. These include skin lesions such

as facial angiofibromas (adenoma sebaceum), hypomelanoticmacules, and ungual fibromas. Central nervous system manifesta-tions, some of which are considered pathognomonic and are bestdiagnosed by CT or MRI of the brain, include multiple corticaltubers, subependymal glial nodules, giant cell astrocytoma, andretinal astrocytomas [95]. Seizures can occur in up to 80% ofpatients [94, 95, 102], and about 50—60% of patients are mentallyretarded [94, 95, 102]. The heart may be affected by benignrhabdomyomas, the liver by angiomyolipomas, and the lung bymalignant lymphangiomyomatosis.

Renal manifestations occur in 50 to 100% of patients, mostoften as multiple and bilateral angiomyolipoma, with or withoutcysts, and rarely as renal cell carcinoma [6]. TS mimickingADPKD has repeatedly been described in adults and children[104—107]. Tuberous sclerosis should be entertained as an alter-native diagnosis in patients with presumed ADPKD when thepatient appears to be a spontaneous mutation, is older withoutliver cysts, has radiologically detectable solid masses as well ascysts, and of course when any pathognomonic findings of TS arepresent. The cysts in TS have a unique lining with eosinophilic andnodular hyperplastic epithelium [6]. Renal failure can result fromextensive involvement of both angiomyolipoma and cysts but ismore common with polycystic kidneys [6, 105]. In one study, renaldisease was the most common cause of death occurring in patientsolder than 10 years and increased in frequency with advancing age[108].

Management recommendations are to periodically monitor TSpatients with MRI of the brain, renal ultrasonography, renalfunction studies, and chest X-ray, because most causes of deathresult from potentially treatable causes [102]. In patients present-ing predominantly as polycystic kidney disease, screening forother clinical features of TS is important to verif' the diagnosis.

Von-Hippel-Lindau disease

Epidemiology and genetics. Von-Hippel-Lindau disease (VHL)is a rare (about 1:36000 live births) autosomal dominant disease

956 Fick and Gabow: Cystic disease

characterized by multiple tumors, most often retinal angiomas,CNS and spinal haemangioblastomas, renal cell carcinomas andpheochromocytomas. Cysts in kidneys, pancreas and epididymisare also frequent findings [109]. Penetrance is more than 90% byage 60 years [109]. Linkage of the VHL disease gene to markerson the short arm of chromosome 3 was reported in 1988, andsubsequently linkage analysis was shown to accurately predictgene carrier status in 88% of asymptotnatic members of diseasefamilies [1101. There is no evidence for genetic heterogeneity[110], and new mutations seem to be uncommon (less than 10%)[109]. Recently, the VHL gene itself, a tumor suppressor gene,was identified [8]. Interestingly, renal cell carcinoma cell linesobtained from patients with sporadic renal cell carcinoma showedmutations in the same tumor suppressor gene [8].

Diagnosis, clinical manifestations and management consider-ations. The diagnosis in a family member is made when one ormore disease manifestations are present [110]. When there is nofamily history, two or more hemangioblastomas or one heman-gioblastoma and one visceral manifestation are required fordiagnosis [1091. The mean age at onset in one study was 26.3years, with retinal angioma as the first manifestation in 43% ofpatients, cerebellar hemangioblastoma in 39%, and renal cellcarcinoma in 10% [109]. Renal cysts occur in up to 76% ofpatients and may be detected in the second decade, whereas renalcarcinomas usually occur at a mean age of 44 years [109]. Renalcell carcinomas can be present in patients who also have cysts [7].The carcinomas are often multiple and bilateral and occur at

younger ages than tumors in the general population. Renalcarcinoma was the leading cause of death in one study, accountingfor 47% of all deaths [109].

Some VHL families have a high incidence of pheochromocy-toma. Conversely when unselected patients with pheochromocy-toma were screened, 19% were found to be carriers of VHL [11 1],Pancreatic and epididymal cysts appear to be common, althoughtheir exact incidence is not known [109].

Gadolinium-enhanced MRI of the brain, ophthalmoscopy, andCT of the abdomen are considered the best screening proceduresfor family members who may be gene carriers [111, 112]. Themanagement of renal cystic disease is not clear because of thepossibility of coexisting carcinoma even in benign-appearing cysts.Bilateral nephrectomy versus a conservative approach with regu-lar screening and tumor enucleation have both been advocated.

Autosomal-recessive polycystic kidney disease

Epidemiology and genetics. ARPKD is a rare genetic disorderwith reported incidence from 1:6000 to 1:55,000 in various studies[113, 114]. Given the autosomal recessive inheritance, the parentsare always unaffected and each offspring has a one in four chanceof inheriting the defective gene from each carrier parent andhence the disease. A gene for ARPKD has been located onchromosome 6 (note added in proof, B). Therefore, linkagestudies for diagnosis are now available. No genetic heterogeneitywas found in the first 16 families studied (note added in proof, B).Since the disease can present from perinatal life to early adult-hood, four distinct genetic entities had been proposed in the past,based on the age at presentation: perinatal, neonatal, infantile andjuvenile [115]. However, the observation of different ages ofpresentation in siblings from the same family led to the view thatthere is one causative gene [116—118]. Linkage analysis in morefamilies will provide further information on this. All affectedchildren have both renal and hepatic abnormalities, but youngerchildren have a predominance of the renal disease and olderchildren and adolescents manifest more significant hepatic disease[114, 117—119].

Diagnosis, clinical manifestations and management consider-ations. The diagnosis is usually made by imaging studies of thechild. Characteristic ultrasonographic findings prenatally and inyoung children are enlarged, hyperechoic kidneys with poordifferentiation between cortex and medulla. However, these signsare not specific since they can also be seen prenatally or in infantswith ADPKD [114, 117, 120]. Older children with ARPKD candevelop macrocysts, and the appearance of the kidneys on US canresemble ADPKD. Other less common entities can also have asimilar radiographic appearance to ADPKD [119]. The differen-tiation between ARPKD and ADPKD depends heavily upon theultrasonographic findings in the parents. Providing non-paternityhas been excluded, the finding of a normal ultrasonogram in bothparents, particularly if they are over thirty years of age, supportsthe diagnosis of ARPKD. When parents are not available forstudy or have equivocal findings, biopsy of the patient's kidneys orliver may be required to establish the diagnosis of ARPKD [119].Although ultrasonographic similarities exist between ARPKD andADPKD, pathologically the disorders are distinct both in thekidneys and the liver. The kidneys in ARPKD display numeroussmall fusiform cysts, generally 1 to 8 mm in size, in the medullaand cortex (Fig. 4). These cysts arise from dilated distal tubulesand collecting tubules and are aligned in a radial distribution (Fig.

ADPKD PATIENTS

SYMPTOMATIC FOR ICA ASYMPTOMATIC FOR ICA

ARTERIOGRAPHY POSITIVE FAMILYHISTORY FOR ICA,

PREVIOUS RUPTURE,OR HIGH-RISK ACTIVITY

v' 'GOODRENAL

FUNCTION

RENALFAILURE

STOPCT SCAN/MRI ANGlO

NEGATIVE FAMILYHISTORY FOR ICA,

NO RUPTURE,NO HIGH-RISK

ACTIVITY.1.

STOP

ANEURYSM7 mm OR GREATER

1.

PROPHYLACTICSURGERY, IF

POSSIBLE

NEGATIVE

STOP

NEGATIVE

REP EAT

STUDY IN

5 YEARS

SUSPICIOUSOR POSITIVE

1.

ARTERlOG RAPHY

POSITIVE

ANEURYSMLESS THAN

7 mm

TREATHYPERTENSION

AND REPEATSTUDY IN

3—5 YEARS

Fig. 3. Current recommendations for screening for intracranial aneu,ysms inADPKD patients. (With permission of Fick GM, Gabow PA: The urgentcomplications of autosomal dominant polycystic kidney disease. J CritIllness 7:1905—1920, 1992)

ee..

C],1It

I.It

Fick and Gabow: Cystic disease 957

Fig. 4. (A) ARPKD kidney showing little distortion of the external surface.(B) Cut section of the ARPKD kidney demonstrating fusiform cysts witha radial distribution.

4). The liver displays a varying severity of congenital hepaticfibrosis with proliferation of bile ducts, periportal fibrosis, ascarcity of portal vein branches and an absence of inflammatorychanges. Because congenital hepatic fibrosis is very rare inADPKD, these findings together with the specific renal histologyestablish a diagnosis of ARPKD.

Although prenatal diagnosis by US has been possible as early asthe 14th week of gestation [121], often renal abnormalitiesbecome apparent only in the third trimester [114, 121], and bothfalse negative and false positive prenatal ultrasound diagnoseshave been reported [121, 122], the latter particularly if there is noprior family history [123]. Moreover, even severe prenatal abnor-malities do not necessarily predict a fatal outcome [124]. For aclinician it is most important to remember that not all renal cysticdisease presenting in utero, infancy or childhood is ARPKD.

Most patients present at birth or in early infancy, most com-monly with abdominal masses due to the enlarged kidneys [114,118, 1251. Some of these severely affected children still die in thefirst month of life of respiratory failure due to pulmonary hyp-oplasia [114, 118, 119]. Children who survive the neonatal periodoften have adequate renal function for many years [118, 119, 126],although they always have decreased urinary concentrating capac-ity. Hypertension is common and often severe, requiring therapyin early childhood [114, 118, 119, 126]. In older children andadolescents signs of liver involvement with hepatosplenomegaly,portal hypertension and bleeding esophageal varices predominateover the renal disease; liver function tests, however, are alwaysnormal [117, 119], unless cholangitis supervenes.

Management is directed at the renal and hepatic complicationsand includes treatment of hypertension and urinary tract infec-tions and renal replacement therapy with dialysis and transplan-tation. The complications of portal hypertension may requireesophageal scierotherapy or portacaval shunting. With moderntreatment modalities the prognosis is not as grim as previouslyreported. In one study the life-table survival rate was 46% at 15years for all children and 79% at 15 years for those who hadsurvived the first year of life [125].

Juvenile nephronophthisis—Medullaiy cystic disease

Epidemiology and genetics. Two different terms, juvenile neph-ronophthisis (JN) and medullary cystic disease (MCD), have beenused for diseases with similar renal morphology but different typesof inheritance, ages of onset, and associated abnormalities. Bothdisorders are characterized by slowly progressive renal insuffi-ciency with shrunken kidneys, and histologically by prominent,diffuse interstitial lesions [127]. It is probable that different genesare responsible for the two entities. JN shows an autosomalrecessive inheritance, presents in childhood, and progresses toESRD before the age of 25, whereas MCD shows an autosomaldominant inheritance and presents later in life, up to the fourth orfifth decade [127—129]. Recent linkage studies have mapped thegene for JN to chromosome 2p, whereas linkage for Senior-Lokensyndrome, which is nephronophthisis with retinal degeneration,was not linked to this site [130, 131]. Another phenotypic form has

958 Fick and Gabow: Cystic disease

Table 4. Approach to a patient with renal cystic disease

Obtain family histoty including autopsy dataConstruct pedigreeDetermine if consanguinity is presentMay need ultrasonography of parentsCareful physical examination

Blood pressureAssessment for extrarenal manifestations

Skin, eyes, heart, lungs, liver, musculoskeletal system, centralnervous system

Assessment of renal size, structure and calcificationUS and CIBiopsy occasionally

Assessment of renal functionBUN/creatinineConcentrating abilityUrinalysis

been described in infants presenting within the first months of lifeand progressing to ESRD before the age of two years; this may bea variant of JN or a distinct genetic entity [132]. The prevalence ofJN is unkifown. Although some reports demonstrate that itaccounts for 10 to 32% of ESRD in children [127], it appears thatin large populations it accounts for 2.4% of childhood ESRD[133], The autosomal dominant form of medullary cystic diseaseseems to be very rare [127].

Diagnosis, clinical manifestations and management consider-ations. Children with this disease have an early urinary concen-trating defect leading to polydipsia and polyuria and slowlyprogressive renal failure accompanied by growth retardation,anemia and hypertension in advanced stages. Heavy proteinuriaand hematuria are usually absent. Prominent salt wasting has beenreported in some cases [127, 134]. Diagnosis is difficult becausemost findings are nonspecific; ultrasonography shows kidneys ofnormal or reduced size, loss of corticomedullary differentiation,and sometimes medullary cysts; however, usually these are foundonly in advanced stages [127]. Abdominal CT was shown in onecase report to be diagnostic, revealing multiple cysts up to 5 mmin diameter throughout the medulla of both kidneys, whereas UShad been nonspecific [135]. Percutaneous biopsy usually shows atubulointerstitial nephropathy with atrophic tubules with seg-ments of markedly thickened basement membrane as well assegments of thinned basement membranes [20]; the cysts are oftenmissed with biopsy.

Extrarenal manifestations have been reported in associationwith JN, including congenital hepatic fibrosis [136—141], tape-toretinal degeneration, mental retardation, cerebellar dysfunctionand skeletal abnormalities [127], but these may represent othergenetic disorders. None of these associations have been found inthe dominant form of medullary cystic disease [1271. Since thereis no specific therapy, management is directed at avoiding andtreating complications of progressive renal insufficiency. Renaltransplantation is the treatment of choice for children with ESRDdue to JN; recurrence has never been observed.

Medullaty sponge kidney

Medullary sponge kidney (MSK) is characterized by nonpro-gressive dilatation of collecting ducts and tubules, sometimesassociated with multiple small cysts, in one or more renal papillae.Although autosomal dominant inheritance has been reported in a

minority of cases, the disorder is more often seen sporadically.The pathogenesis is thought to be due to a developmentalabnormality [142], and other associated developmental and ge-netic disorders including congenital hemihypertrophy, Ehiers-Danlos and Marfan's syndrome, Caroli's disease and ADPKDhave been described in patients with MSK [142, 143]. Thediagnosis is made by excretory urography which shows typicalbrush-like linear striations or spherical cystic lesions of the renalpapillae; difficulties in diagnosing MSK arise when only one ortwo papillae are involved or when the urogram is not of highquality [142]. The prevalence in unselected patients undergoingexcretory urography is 0.5 to 1% [142, 144]; both sexes appear tobe equally affected.

Although MSK is often asymptomatic, clinical manifestationscan include hematuria, infections and nephrolithiasis. The latter isa particularly interesting association. The prevalence of MSKamong stone patients has been reported between 12% [144] and21% [142]. The pathogenetic factors responsible for the associa-tion with nephrolithiasis and nephrocalcinosis are not entirelyclear. One study found metabolic disorders accounting for thenephrolithiasis in 93% of stone patients without MSK but in only60% of stone patients with MSK, concluding that MSKper se is acause for nephrolithiasis [144]. In another study the compositionof stones was found to be similar in patients with or without MSK[145]. Urinary stagnation in the dilated collecting ducts, subtleacidification defects, hypercalciuria and hyperoxaluria all havebeen implicated as contributing to stone formation in patientswith MSK [1421. Some authors have reported an association ofprimary hyperparathyroidism with MSK [146], but others viewevidence for a direct association as still insufficient [142].

Management of urolithiasis and nephrocalcinosis in MSK pa-tients does not differ from that of stone patients of the generalpopulation. ESWL has been used in MSK patients with goodsuccess and without major complications [147, 148]; thiazidesprevent new calcium stone formation in normocalciuric as well ashypercalciuric patients. If infections and nephrolithiasis aretreated appropriately, MSK does not lead to renal insufficiency.

Acquired renal cystic diseaseSeveral types of renal cysts are acquired. The most common

type is simple renal cysts which are rare in children but increase infrequency with age. In a recent study unilateral cysts occurred in1.7% of normal patients 30 to 49 years old, in 11.5% of those 50to 70 years old and in 22% of those over seventy [149]. Bilateralcysts were observed in 1, 4, and 9% of these age groups,respectively [149]. Usually they are asymptomatic and are de-tected as an incidental finding on an ultrasound study where theyshow smooth walls and no intracystic echoes. Occasionally theycan bleed causing flank pain and/or hematuria. CT scanning isrecommended in such cases to exclude malignancy.

Another form of acquired renal cysts is associated with hypo-kalemia. Patients with primary hyperaldosteronism were found byCT scanning to have bilateral renal cysts, predominantly in themedulla, more often than age-matched control patients withessential hypertension [32]. Moreover, the cysts regressed afterresection of an adrenal adenoma [32]. The pathogenesis is notclear, but hypokalemia may stimulate tubular cells to proliferate[150].

The term acquired cystic kidney disease (ACKD) usually refersto the development of cysts in the kidneys of chronic renal failure

Fick and Gabow: Cystic disease 959

Table 5. Comparison of various cystic renal disorders

SimpleFeature ADPKD TS VHL ARPKD JN/MCD MSK ACKD cysts

Inheritance AD, '10% newmutations

AD, 66%newmutations

AD, <10% newmutations

AR AR/AD none none none

Linkage to 16, 4 9, 16 3 6 2 NA NA NAchromosome gene on

chromosome16 identified

gene onchromosome16 identified

gene identified

Prevalence 1:200-1:1,000 1:10,000 1:36,000 rare rare common up to 90% oflong term(>10 years)dialysispatients

11.5% age50—70

years

Age of clinical usually adults children and usually adults children, rarely children/ usually children and adultsonset adults young adults adults adults adults

Method of US, linkage US, brain CT US, brain CT or MRI, US, occasionally none IVP CT/US USdiagnosis

Presenting pain, hematuria,

or MRI,linkage

seizures, renal

linkage

retinal, brain or renal

liver or renalbiopsy

abdominal mass,

reliable

polyuria, renal calculi, hematuria, incidentalsymptom infection,

familyscreening

bleeding,cardiacarrhythmias,skin lesions,mentalretardation

tumors,phaeochromocytoma

HTN, ESRD,portal HTN

anemia,ESRD

infection pain,malignancy,screeningUS

findingon US

Hypertension 60—75% ofadults

occurs patients withphaeochromocytoma

common late inthecourse

no dependent onunderlyingdisease

no

Gross 42% of adults occurs patients with renal occurs rare common occurs rarehematuria carcinoma

Nephrolithiasis 20—36% ofadults

no no no no common no no

Renal size normal early,later enlarged

normal orenlarged

enlarged if tumorous enlarged reduced normal reduced,normal orenlarged

normal

Extrarenal commona common" commonc congenital occur in no no nomanifestations hepatic

fibrosisJN

Renal rare occurs very common not reported rare no common raremalignancy

Abbreviations are: AD, autosomal dominant; AR, autosomal recessive; NA, not applicable; US, ultrasound; CT, computed tomography; MRI,magnetic resonance imaging; IVP, intravenous pyelography; HTN, hypertension; ESRD, end-stage renal disease.

ae.g. liver cysts, heart valve abnormalities, intracranial aneurysms, diverticula

"skin, brain, heart, retinaretina, brain, phaeochromocytoma

patients with underlying non-cystic renal disorders. Other organsare not affected.

Epidemiology of ACKD. Acquired renal cysts can be found in 7to 22% of chronic renal failure patients before the start of dialysistherapy, but their frequency increases with increasing duration ofdialysis [151]. About 44% of patients treated for less than threeyears, 80% of those treated for more than four years and 90% ofthose on dialysis for more than 10 years develop ACKD, withsimilar incidence for hemodialysis and peritoneal dialysis patients[151, 152]. Children with long standing renal failure or onlong-term dialysis can also develop ACKD [151—153]. The severityof ACKD manifests as increasing cyst numbers and renal volumeswith increased duration of dialysis treatment [154]. After success-ful transplantation ACKD regresses in some but not lI patients.In one study, 18% of renal allograft recipients had an increase incyst numbers in their native kidneys despite long-standing goodtransplant function [155], and another study found an increasedprevalence of ACKD among transplant recipients treated with

cyclosporin A [156]. Some but not all studies have demonstratedan increased frequency of ACKD in males than in females [151,152, 157]. An overrepresentation of black ESRD patients withACKD has been reported [1521.

Diagnosis, clinical manifestations and management consider-ations. Diagnosis can be made by renal ultrasonography; however,since the kidneys and cysts are often small, CT scanning may bemore sensitive [152, 154]. Usually ACKD is asymptomatic, butpainful cyst hemorrhage, retroperitoneal hemorrhages, and infec-tion can occur. Rarely, kidneys with ACKD can enlarge signifi-cantly, particularly when a previous unilateral nephrectomy hasbeen performed, and thus mimic ADPKD with symptoms ofheaviness and pain [158], The most serious complication is renalcell carcinoma (RCC), which is best diagnosed by contrast-enhanced CT-scanning. Two prospective studies examining theincidence of RCC have been reported. One from Japan found 2RCC among 57 patients over a 10 year period [159]; the otherfrom the USA also found 2 RCC among 30 patients over 7 years

960 Pick and Gabow: Cystic disease

[154]. Therefore, the annual incidence of RCC in dialysis patientsis about 3 to 6 times greater as compared with an age-matchedgeneral population [160]. The incidence of RCC increases withduration of dialysis and with increasing severity of ACKD, andmales are 4 to 7 times more often affected than females [151, 152,1601. In up to 86% of cases RCC are asymptomatic, and thereforeannual screening of dialysis patients by CT has been recom-mended by some authors [151]. On the other hand, RCC is arelatively rare cause of death in dialysis patients, and their lifeexpectancy if often reduced by concomitant, particularly cardio-vascular, diseases; moreover, often these patients are poor candi-dates for major surgery if RCC is detected by screening. There-fore, it has been questioned whether regular screening of allpatients would have a significant impact on patient survival [160].This needs to be considered in light of the substantial cost.Probably it is best to screen selected patients who are young, ingeneral good condition and have risk factors for RCC such as longduration of dialysis, significant ACKD and large kidneys, partic-ularly if they are male [160].

Approach to the patient with cystic disease. This array of cysticdisease may seem like a maze, but it is a maze with many clues todirect the physician to the correct diagnosis in a given patient(Tables 4 and 5). The family history including autopsy data,questions about consanguinity and construction of a pedigree areimportant first steps; often ultrasonographic information on thefamily is needed. This information serves to determine if there isa familial aspect to the disorder and if transmission is compatiblewith autosomal dominant inheritance. Consanguinity increasesthe likelihood of a recessive disorder. The patient's age, bloodpressure, renal size and function and the extrarenal manifesta-tions point the way to the correct diagnosis. Utilizing the infor-mation supplied in Table 5 one can see which of these manifes-tations are compatible with the various cystic diseases. Thus, notall entities would be entertained in a specific patient. For example,in a patient with a strong family history of cystic renal disease,ACKD and MSK are not likely to be the disorders, In a patientwith large kidneys, the medullasy cystic diseases and simple cystswould be excluded; similarly in patients with renal failure simplecysts, VHL, and medullary sponge kidney would be extremelyunlikely candidates. In contrast, certain entities should always beconsidered together. In a child with large kidneys, particularly ifother family members are affected, ADPKD, ARPKD and TSshould all be considered. In some patients diagnosis remainsdifficult. For example, the 22 year old patient in an ADPKDfamily with a single cyst as her sole abnormality who wishes todonate her kidney to an affected brother and who has no otherliving affected family members cannot be definitively diagnosed ashaving ADPKD or a simple cyst. The answers to these dilemmasawait the evolution of the disease and/or the evolution of ourunderstanding and diagnostic armamentarium.

GODELA M. FIcK AND PATRIcIA A. GABOwDenver, Colorado, USA

Acknowledgments

This research was supported by Grant 5 P01 DK34039, Human Poly-cystic Kidney Disease, awarded by the Department ot Health and HumanServices, Public Health Service, NIDDK, and Grants MOl RR00069 andMOl RR00051 from the General Clinical Research Centers Program,National Center for Research Resources, National Institutes of Health.G.M. Fick is supported by a grant from the DAAD (Deutscher Akade-

mischer Austauschdienst), by a special program to support studies inepidemiology. The authors thank Dr. William Hammond, Denver Veter-ans Administration Hospital for the photomicrographs of ADPKD andARPKD kidneys.

Notes added in proof

A. THE EUROPEAN P0LYcY5TIc KIDNEY DISEAsE C0N50RnJM: Thepolycystic kidney disease 1 gene encodes a 14 kb transcript and lies withina duplicated region on chromosome 16. Cell 77:881—894, 1994

B. ZERRES K, MUcHER G, BACHNER L, DE5cHENNES G, EGGERMANN T,KAARIAINEN H, KNAPP M, LENNERT M, MlssELwrrz J, voN MCJHLENDAHLKB, NEUMANN HPH, PIR50N Y, RUDNIK-SCHONEBORN 5, STEINBICKER V,WIRTH B, SCHARER K: Mapping of the gene for autosomal recessivepolycystic kidney disease (ADPKD) to chromosome 6p21-cen. NatureGenet 7:429—432, 1994

Reprint requests to Patricia A. Gabow, M.D., Box C283, 4200 East NinthAvenue, Denver, Colorado 80262, USA.

References

1. GILBERT-BARNE5S BE, OPITZ JM, BARNE55 LA: Heritable malforma-tions of the kidney and urinary tract, in Inheritance of Kidney andUrinary Tract Diseases, edited by A SPITZER, ED AvNER, Boston,Kluwer Academic Publishers, 1990, pp. 327—400

2. T0RRE5 VE: Genetics of renal cystic diseases, in Inheritance ofKidney and Urinary Tract Diseases, edited by A SPITZER, ED AvNER,Boston, Kluwer Academic Publishers, 1990, pp. 177—219

3. GRANTHAM JJ, GIusEs JL, EvAN AP: Cyst formation and growth inautosomal dominant polycystic kidney disease. Kidney mt 31:1145—1152, 1987

4. GREGOIRE JR, TORRES VE, HOLLEY KB, FARROw GM: Renalepithelial hyperplastic and neoplastic proliferation in autosomaldominant polycystic kidney disease. Am J Kidney Dis 9:27—38, 1987

5. Wmsor'i PD: Aberrant epithelial cell growth in autosomal dominantpolycystic kidney disease. Am J Kidney Dis 17:634—637, 1991

6. STILLwELL TJ, GOMEZ MR, KELALIS PP: Renal lesions in tuberoussclerosis. J Urol 138:477—481, 1987

7. SoLoMoN D, SCHWARTZ A: Renal pathology in von Hippel-Lindaudisease. Hum Pathol 19:1072—1079, 1988

8. LATIF F, TORY K, GNARRA J, YAO M, DUH F-M, ORCUTr ML,STAcscHoUsa T, KUZMIN I, Mom W, GaIL L, SCHMIDT L, ZHOU F, LIH, WEI MH, CHEN F, GLENN G, CHOYKE P. WALTHER MM, WENGY, DUAN D-SR, DEAN M, GLAvAC D, RICHARDs FM, CROSSEY PA,FERGUSON-SMITH MA, PASLIER DL, CHUMAKOv I, COHEN D, Cm-NAULT AC, MAHER ER, LINEHAN WM, ZBAR B, LERMAN MI:Identification of the von Hippcl-Lindau disease tumor suppressorgene. Science 260:1317—1320, 1993

9. THE EUROPEAN CHROMOSOME 16 TUBEROUS SCLEROSIS CONsoR-TIUM: Identification and characterization of the tuberous sclerosisgene on chromosome 16. Cell 75:1305—1315, 1993

10. TRUDEL M, D'AGA'rs V, C05TANTINI F: c-myc as an inducer ofpolycystic kidney disease in transgenic mice. Kidney mt 39:665—671,1991

11. SCHAFPNER DL, BARR5OS R, MASSEY C, BASEZ El, OU C-N,RAJAGOPALAN 5, AGUILAR-CORDOvA B, LEB0vITz RM, OvERBEEKPA, LIEBERMAN MW: Targeting of the rasT24 oncogene to theproximal convoluted tubules in transgenic mice results in hyperplasiaand polycystic kidneys. Am J Pathol 142:1051—1060, 1993

12. VEIS DJ, SORENSON CM, SmJrrER JR, KORSMEYER SJ: Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystickidneys, and hypopigemented hair. Cell 75:229—240, 1993

13. YE M, GRANT M, SHARMA M, ELZINGA L, SWAN 5, TORRES VE,GRANTHAM JJ: Cyst fluid from human autosomal dominant polycys-tic kidneys promotes cyst formation and expansion by renal epithelialcells in vitro. JAm Soc Nephrol 3:984—994, 1992

14. YE M, GRANTHAM JJ: The secretion of fluid by renal cysts frompatients with autosomal dominant polycystic kidney disease. N EngIJMed 329:310—313, 1993

15. BENNETr WM, ELZINGA L, GOLPER TA, BARRY JM: Reduction ofcyst volume for symptomatic management of autosomal dominantpolycystic kidney disease. J Urol 137:620—622, 1987

Fick and Gabow: Cystic disease 961

16. OZGUR S, CETIN S, ILKER Y: Percutaneous renal cyst aspiration andtreatment with alcohol. mt Urol Nephrol 20:481—484, 1988

17. M1LuT1N0vIc J, AGODOA LY: Potential causes and pathogenesis inautosomal dominant polycystic kidney disease. Nephron 33:139—144,1983

18. WILsoN PD, HRENIUK D, GABOW PA: Abnormal extraclluIar matrixand excessive growth of human adult polycystic kidney diseaseepithelia. J Cell Physiol 150:360—369, 1992

19. CARONE FA, NAKAMURA S, PUNYARIT P, KANWAR YS, NELSON WJ:Sequential tubular cell and basement membrane changes in polycys-tic kidney disease. JAm Soc Nephrol 3:244—253, 1992

20. COHEN AH, HOYER JR: Nephronophthisis: A primary tpbular base-ment membrane defect. Lab Invest 55:564—572, 1986

21. Liv ZZ, CARONE FA, NAKUMARA S, KANWAR YS: Altered synthesisof proteoglycans by cyst-derived cells from autosomal-dominantpolycystic kidneys. Am J Physiol 263:F697—F704, 1992

22. GRANTHAM JJ: Fluid secretion, cellular proliferation, and the patho-genesis of renal epithelial cysts. JAm Soc Nephrol 3:1843—1857, 1993

23. CALVET JP: Polycystic kidney disease: Primary extracellular matrixabnormality or defective cellular differentiation? Kidney mt 43:101—108, 1993

24. KLINGEL R, DIPPOLD W, STORKEL S, MEYER ZUM BtJSCHENFELDEK-H, KOHLER H: Expression of differentiation antigens and growth-related genes in normal kidney, autosomal dominant polycystickidney disease, and renal cell carcinoma. Am J Kidney Dis 19:22—30,1992

25. GAl-cONE VH II, CALVET JP: Murine infantile polycystic kidneydisease: A role for reduced renal epidermal growth factor. Am JKidney Dis 17:606—607, 1991

26. NAKAMURA T, EBH-IARA I, NAGAOKA I, TOMINO Y, NAGAO 5,TAKAHASHI H, KOIDE H: Growth factor gene expression in kidney ofmurine polycystic kidney disease. JAm Soc Nephrol 3:1378—1386,1993

27. FALKENSTEIN D, BURROW CR, GATFI L, HARTZ P, WILSON PD:Expression of fetal proteins in human polycystic kidney diseaseepithelia. (abstract) JAm Soc Nephrol 4:813, 1993

28. BACALLAO R, NAKAMURA 5, CARONE FA: Intermediate filamentexpression suggests a block in the differentiation pathway of ADPKDepithelial cells. (abstract) JAm Soc Nephrol 4:811, 1993

29. WILSON PD, SHERWOOD AC, K, Dv J, WATSON R, NORMANJT: Reversed polarity of Na-K-ATPase: Mislocation to apicalplasma membranes in polycystic kidney disease epithelia. Am JPhysiol 260:F420—F430, 1991

30. AVNER ED, SWEENEY WE JR, NELSON WJ: Abnormal sodium pumpdistribution during renal tubulogenesis in congenital murine polycys-tic kidney disease. Proc NatI Acad Sci USA 89:7447—745 1, 1992

31. KANWAR YS, CARONE FA: Reversible changes of tubular cell andbasement membrane in drug-induced renal cystic disease. Kidney mt26:35—43, 1984

32. TORRES yE, YOUNG WF JR, OFFORD KP, HATrERY RR: Associationof hypokalemia, aldosteronism, and renal cysts. N Engi J Med322:345—351, 1990

33. ISI-JIKAWA I, Yuiu T, KITADA H, SHINODA A: Regression of acquiredcystic disease of the kidney after successful renal transplantation. AmJ Nephrol 3:310—314, 1983

34. PiEKE SA, KIMBERLING WJ, KENYON JB, GABow P: Genetic heter-ogeneity of polycystic kidney disease: An estimate of the proportionof families unlinked to chromosome 16. (abstract) Am J Hum Genet45(Suppl):A58, 1989

35. KIMBERLING WJ, KUMAR S, GABow PA, KENYON JB, CONNOLLY CJ,S0ML0 S: Autosomal dominant polycystic kidney disease: Localiza-tion of the second gene to chromosome 4q13-q23. Genomics 18:467—472, 1993

36. PETERS DJM, SPRUIT L, SARIS JJ, RAVINE D, SANDKUIJL LA,FOSSDAL R, BOERSMA J, VAN EIJK R, NORBY S, CONSTANTINOU-DELTAS CD, PIERIDES A, BRISSENDEN JE, Fiwrrs RR, VAN OMMENG-JB, BREUNING MH: Chromosome 4 localization of a second genefor autosomal dominant polycystic kidney disease. Nature Genet5:359—362, 1993

37. DAOUST MC, BICHET DG, SOML0 5: A French-Canadian family withautosomal dominant polycystic kidney disease unlinked to ADPKD1and ADPKD2. (abstract) JAm Soc Nephrol 4:262, 1993

38. PARFREY PS, BEAR JC, MORGAN J, CRAMER BC, MCMANAMON PJ,

GAULT MH, CHURCHILL DN, SINGH M, HEWn-c R, SOMLO 5,REEDERS ST: The diagnosis and prognosis of autosomal dominantpolycystic kidney disease. N Engi J Med 323:1085—1090, 1990

39. MILUTINOVIC J, RUST PF, FIALKOW PJ, AGODOA LY, PHILLIPS LA,RUDD TG, SUTHERLAND S: Intrafamilial phenotypic expression ofautosomal dominant polycystic kidney disease. Am J Kidney Dis19:465—472, 1992

40. FICK GM, JOHNSON AM, GABow PA: Is there evidence for anticipa-tion in autosomal dominant polycystic kidney disease? Kidney Int45:1153—1162, 1994

41. FIcK GM, JOHNSON AM, SrRAlN JD, KIMBERLING Wi, KUMAR S,MANCO-JOHNSON ML, DULEY IT, GAISOW PA: Characteristics of veryearly onset autosomal dominant polycystic kidney disease. JAm SocNephrol 3:1863—1870, 1993

42. SHERMAN SL, JACOBS PA, MORTON NE, FROSTER-ISKENIUS U,HOWARD-PEEBLES PN, NIELSEN KB, PARTINGTON MW, SUTHERLANDGR, TURNER G, WATSON M: Further segregation analysis of thefragile X syndrome with special reference to transmitting males.Hum Genet 69:289—299, 1985

43. HOWELER CJ, BUSCH HFM, GERAEDTS JPM, NIERMEIJER MF,STAAL A: Anticipation in myotonic dystrophy: Fact or fiction? Brain112:779—797, 1989

44. RIDLEY RM, FRITH CD, CROW TJ, CONNEALLY PM: Anticipation inHuntington's disease is inherited through the male line but mayoriginate in the female. J Med Genet 25:589—595, 1988

45. Yv S, MULLEY J, LOESCH D, TURNER G, DONNELLY A, GEDEON A,HILLEN D, KREMER E, LYNCH M, PRITCHARD M, SUTHERLAND GR,RICHARDS RI: Fragile-X syndrome: Unique genetics of the heritableunstable element. Am J Hum Genet 50:968—980, 1992

46. BROOK D, MCCURRACH ME, HARLEY HG, BUCKLER AJ, CHURCH D,ABURATANI H, HUNTER K, STANTON VP, THIRION J-P, HUDSON T,SOHN R, ZEMELMAN B, SNELL RG, RUNDLE SA, CROW 5, DAVIES J,SHELBOURNE P, BUXTON J, JONES C, JUVONEN V, JOHNSON K,HARPER PS, SHAW DJ, HOUStvIAN DE: Molecular basis of myotonicdystrophy: Expansion of a trinucleotide (CTG) repeat at the 3' endof a transcript encoding a protein kinase family member. Cell68:799—808, 1992

47. THE HUNTINGTON'S DISRA5E COLLABORATIVE RESEARCH GROUP: Anovel gene containing a trinucleotide repeat that is expanded andunstable on Huntington's disease chromosomes. Cell 72:971—983,1993

48. BEAR JC, PARFREY PS, MORGAN JM, MAKTIN Ci, CRAMER BC:Autosomal dominant polycystic kidney disease: New information forgenetic counselling. Am J Med Genet 43:548—553, 1992

49. GABOW PA, GRANTHAM JJ, BENNETF W, CHILDRESS JF, COLE B,CONNEALLY PM, GARDNER K, KIMBERLING WJ, MARSH F, REEDERSS: Gene testing in autosomal dominant polycystic kidney disease:Results of National Kidney Foundation workshop. Am J Kidney Dis13:85—87, 1989

50. HANNIG VL, HOPKINS JR, JOHNSON HK, PHILLIPS JA III, REEDER5ST: Presymptomatic testing for adult onset polycystic kidney diseasein at-risk kidney transplant donors. Am J Med Genet 40:425—428,1991

51. GABOW PA: Autosomal dominant polycystic kidney disease—Morethan a renal disease. (review) Am J Kidney Dis 16:403—413, 1990

52. MILUTINOVIC J, FIALKOW PJ, AGODOA LY, PHILLIPS LA, RUDD TG,BRYANT JI: Autosomal dominant polycystic kidney disease: Symp-toms and clinical findings. Q J Med 53:511—522, 1984

53. GABOW PA, DULEY I, JOHNSON AM: Clinical profiles of grosshematuria in autosomal dominant polycystic kidney disease. Am JKidney Dis 20:140—143, 1992

54. GAB0W PA, CHAPMAN AB, JOHNSON AM, TANGEL DJ, DULEY IT,KAEHNY WD, MANCO-JOHNSON M, SCHRIER RW: Renal structureand hypertension in autosomal dominant polycystic kidney disease.Kidney mnt 38:1177—1180, 1990

55. Fiw'i D, CZVALINGA I, POLYAK L: A new approach to the treatmentof polycystic kidneys. Int Urol Nephrol 20:13—21, 1988

56. ELZINGA LW, BARRY JM, TORRES yE, ZLNCKE H, WAHNER HW,SWAN S, BENNETT WM: Cyst decompression surgery for autosomaldominant polycystic kidney disease. JAm Soc Nephrol 2:1219—1226,1992

57. GABOW PA, BENNETT WM: Renal manifestations: Complication

962 Fick and Gabow: Cystic disease

management and long-term outcome of autosomal dominant poiy-cystic kidney disease. Semin Nephrol 11:643—652, 1991

58. TORRES yE, WwsoN DM, HATFERY RR, SEGURA JW: Renal stonedisease in autosomal dominant polycystic kidney disease. Am JKidney Dis 22:513—519, 1993

59. LEVINE E, GRANTHAM JJ: Calcified renal stones and cyst calcifica-tions in autosomal dominant polycystic and kidney disease: Clinicaland CT study in 84 patients. AJR 159:77—81, 1992

60. FICK GM, DULEY IT, JOHNSON AM, STRAIN JD, MANCO-JOHNSONML, GABOW PA: The spectrum of autosomal dominant polycystickidney disease in children. JAm Soc Nephrol 4:1654—1660, 1994

61. ZEIER M, GEBERTH S, SCHMIDT KG, MANDELBAUM A, RITZ E:Elevated blood pressure profile and left ventricular mass in childrenand young adults with autosomal dominant polycystic kidney disease.JAm Soc Nephrol 3:1451—1457, 1993

62. CHAPMAN AB, JOHNSON A, GABOW PA, SCHRIER RW: The renin-angiotensin-aldosterone system and autosomal dominant polycystickidney disease. N Engi J Med 323:1091—1096, 1990

63. GRAHAM PC, LINDOP GBM: The anatomy of the renin-secreting cellin adult polycystic kidney disease. Kidney mt 33:1084—1090, 1988

64. 1-IARRAP SB, DAVIES DL, MACNICOL AM, DOMINICZAK AF, FRASERR, WRIGHT AF, WATSONML, BRIOGS JD: Renal, cardiovascular andhormonal characteristics of young adults with autosomal dominantpolycystic kidney disease. Kidney mt 40:501—508, 1991

65. WATSON ML, MACNICOL AM, ALLAN PL, WRIGHT AF: Effects ofangiotensin converting enzyme inhibition in adult polycystic kidneydisease. Kidney mt 41:206—210, 1992

66. TORRES yE, WILSON DM, BURNETT JC JR, JOHNSON CM, OFFORDKP: Effect of inhibition of converting enzyme on renal hemodynam-ics and sodium mangement in polycystic kidney disease. Mayo ClinProc 66:1010—1017, 1991

67. CHURCHILL DN, BEAR JC, MORGAN J, PAYNE RH, MCMANAMON PJ,GAULT MH: Prognosis of adult onset polycystic kidney diseasere-evaluated. Kidney mt 26:190—193, 1984

68. GABOW PA, JOHNSON AM, KAEHNY WD, KIMBERLING WJ, LEzorrEDC, DULEY IT, JONES RH: Factors affecting the progression of renaldisease in autosomal-dominant polycystic kidney disease. Kidney mt41:1311—1319, 1992

69. GRETZ N, ZELER M, GEBERTH 5, STRAUCH M, RITZ E: Is gender adeterminant for evolution of renal failure? A study in autosomaldominant polycystic kidney disease. Am J Kidney Dis 14:178—183,1989

70. FITZPATRICK PM, TORRES YE, CHARBONEAU JW, OFFORD KP,HOLLEY KE, ZINcRE H: Long-term outcome of renal transplantationin autosomal dominant polycystic kidney disease. Am J Kidney Dis15:535—543, 1990

71. MILUTINOVIC J, FIALKOW PJ, RUDD TG, AGODOA LY, PI-IIWPS LA,BRYANT JI: Liver cysts in patients with autosomal dominant polycys-tic kidney disease. Am J Med 68:741—744, 1980

72. GABOW PA, JOHNSON AM, KAEHNY WD, MANCO-JOHNSON ML,DULEY IT, EVERSON GT: Risk factors for the development of hepaticcysts in autosomal dominant polycystic kidney disease. Hepatology11:1033—1037, 1990

73. EVERSON GT, SCI-IERZINGER A, BERGER-LEFF N, REICHEN J,LEZOTFE D, MANCO-JOHNSON M, GABOW P: Polycystic liver disease:Quantitation of parenchymal and cyst volumes from computedtomography images and clinical correlates of hepatic cysts. Heparol-ogy 8:1627—1634, 1988

74. LEVINE E, COOK LT, GRANTHAM JJ: Liver cysts in autosomaldominant polycystic disease: Clinical and computed tomographicstudy. AJR 145:229—233, 1985

75. NEWMAN KD, TORRES YE, RAKELA J, NAGORNEY DM: Treatment ofhighly symptomatic polycystic liver disease: Preliminary experiencewith a combined hepatic resection-fenestration procedure. Ann Surg212:30—37, 1990

76. COBBEN JM, BREUNING MH, ScHoom C, TEN KATE LP, ZERRES K:Congenital hepatic fibrosis in autosomal-dominant polycystic kidneydisease. Kidney mt 38:880—885, 1990

77. MATSUDA 0, IDEURA T, SHINODA T, SHIIGAI T, TAKEUCHI H,WEI-CHIA C, MIYAKE S: Polycystic kidney of autosomal dominantinheritance, polycystic liver and congenital hepatic fibrosis in a singlekindred. Am J Nephrol 10:237—24 1, 1990

78. GRUNFELD JP, ALBOUZE G, JUNGERS P, LANDAI5 P, DANA A, DROZ

D, MOYNOT A, LAFFORGUE B, BOURSZTYN E, FRANCO D: Liverchanges and complications in adult polycystic kidney disease. AdvNephro/ 14:1—20, 1985

79. JORDON D, HARPAZ N, THUNG SN: Caroli's disease and adultpolycystic kidney disease: A rarely recognized association. Liver9:30—35, 1989

80. SCHEFF RT, ZUCKERMAN G, HARTER H, DELMEZ J, KOEHLER R:Diverticular disease in patients with chronic renal failure due topolycystic kidney disease. Ann Intern Med 92:202—204, 1980

81. CHAPMAN AB, RUBINSTEIN D, HUGHES R, STEARS JC, EARNEST MP,JOHNSON AM, GABOW PA, KAEHNY WD: Intracranial aneurysms inautosomal dominant polycystic kidney disease. N Engi J Med 327:916—920, 1992

82. ScHIEvmn WI, TORRES yE, PIEPGRAS DG, WIEBERS DO: Saccularintracranial aneurysms in autosomal dominant polycystic kidneydisease. JAm Soc Nephrol 3:88—95, 1992

83. HUSTON J III, TORRES yE, SULIVAN PP, OFFORD KP, WIEBERS DO:Value of magnetic resonance angiography for the detection ofintracranial aneurysms in autosomal dominant polycystic kidneydisease. JAm Soc Nephro/ 3:1871—1877, 1993

84. KAEHNY W, BELL P, EARNEST M, STEARS J, GABOW P: Familyclustering of intracranial aneurysms in autosomal dominant polycys-tic kidney disease. (abstract) Kidney mt 31:204, 1987

85. SAIFUDDIN A, DATHAN JRE: Adult polycystic kidney disease andintracranial aneurysms. Br Med J 295:526, 1987

86. FEHLINGS MG, GENTILI F: The association between polycystic kidneydisease and cerebral aneurysms. Can J Neurol Sci 18:505—509, 1991

87. CHAPMAN AB, JOHNSON AM, GABOW PA: Intracranial aneurysms inpatients with autosomal dominant polycystic kidney disease: How todiagnose and who to screen. Am J Kidney Dis 22:526—531, 1993

88. TORRES YE, WIEBERS DO, FORBES GS: Cranial computed tomogra-phy and magnetic resonance imaging in autosomal dominant poly-cystic kidney disease. JAm Soc Nephrol 1:84—90, 1990

89. LEVEY AS: Screening for occult intracranial aneurysms in polycystickidney disease: Interim guidelines. (editorial) J Am Soc Nephro/1:9—12, 1990

90. FICK GM, GABOW PA: The urgent complications of autosomaldominant polycystic kidney disease. J Crit mi/ness 7:1905—1920, 1992

91. HOSSACK KF, LEDDY CL, JOHNSON AM, SCHRIER RW, GABOW PA:

Echocardiographic findings in autosomal dominant polycystic kidneydisease. NEnglJMed 319:907—912, 1988

92. TIMI0 M, MONARCA C, PEDE 5, GENTILI 5, VERDURA C, LOLLI 5: Thespectrum of cardiovascular abnormalities in autosomal dominantpolycystic kidney disease: A 10-year follow-up in a five-generationkindred. C/in Nephroi 37:245—251, 1992

93. LELER CV, BAKER PB, KILMAN JW, WOOLEY CF: Cardiovascularabnormalities associated with adult polycystic kidney disease. AnnIntern Med 100:683—688, 1984

94. OSBORNE JP, FRYER A, WEBB D: Epidemiology of tuberous sclerosis.Ann N YAcad Sci 615:125—127, 1991

95. ROACH ES: Neurocutaneous syndromes. Pediatr C/in NAm 39:591—620, 1992

96. WEBB DW, OSBORNE JP: New research in tuberous sclerosis. Br MedJ 304:1647—1648, 1992

97. HAINES JL, SHORT MP, KWIATEOWSKI DJ, JEWELL A, ANDERMANNE, BEJJANI B, YANG C-H, GUSELLA JF, AMOS JA: Localization of onegene for tuberous sclerosis within 9q32-9q34, and further evidencefor heterogeneity. Am J Hum Genet 49:764—772, 1991

98. SMITH M, SMALLEY S. CANTOR R, PANDOLFO M, GOMEZ MI,BAUMANN R, FLODMAN P, YOSHIYAMA K, NAKAMURA Y, JULIER C,DUMARS K, HAINES J, TROFATTER J, SPENCE MA, WEEKS D,CONNEALLY M: Mapping of a gene determining tuberous sclerosis tohuman chromosome 11q14-11q23. Genomics 6:105—114, 1990

99. FAHSOLD R, Rorr H-D, LORENZ P: A third gene locus for tuberoussclerosis is closely linked to the phenylalanine hydroxylase genelocus. Hum Genet 88:85—90, 1991

100. KANDT RS, HAINES JL, SMITH M, NORTHRUP H, GARDNER RJM,SHORT MP, DUMARS K, ROACH ES, STEINGOLD 5, WALL 5, BLANTONSH, FLODMON P, KWIATKOWSKI DJ, JEWELL A, WEBER JL, ROSESAD, PERICAK-VANCE MA: Linkage of important gene locus fortuberous sclerosis to a chromosome 16 marker for polycystic kidneydisease. Nature Genet 2:37—41, 1992

Fick and Gabow: Cystic disease 963

101. NORTHRUP H: Tuberous sclerosis complex: Genetic aspects. J Der-matol 19:914—919, 1992

102. STEFANSSON K: Tuberous sclerosis. (editorial) Mayo Clin Proc 66:868—872, 1991

103. Dermatology In General Medicine (3rd ed, vol 2). Edited by TBFITZPATRICK, AZ EISEN, K Wow, IM FREEDBERG, KF AUSTEN, St.Louis, McGraw-Hill Book Company, 1987

104. DURHAM DS: Tuberous sclerosis mimicking adult polycystic kidneydisease. Aust NZ J Med 17:71—73, 1987

105. Yu DT, SHETH KJ: Cystic renal involvement in tuberous sclerosis.Clin Pediatr 24:36—39, 1985

106. SAGUEM MH, LAARIF M,REMADI S, BOZAKOURA C, Cox JN: Diffusebilateral glomerulocystic disease of the kidneys and multiple cardiacrhabdomyomas in a newborn. Path Res Pract 188:367—373, 1992

107. WENZL JE, LAGOS JC, ALBERS DD: Tuberous sclerosis presenting aspolycystic kidneys and seizures in an infant. J Pediatr 77:673—675,1970

108. SHEPHERD CW, GOMEZ MR, LIE iT, CRowsoN CS: Causes of deathin patients with tuberous sclerosis. Mayo Clin Proc 66:792—796, 1991

109. MAHER ER, YATES JRW, HARRIES R, BENJAMIN C, HARRIS R,MOORE AT, FERGUSON-SMITH MA: Clinical features and naturalhistory of von Hippel-Lindau disease. Quart J Med 77:1151—1163,1990

110. GLENN GM, LINEHAN WM, H0S0E S, LATIF F, YAO M, CHOYKE P,G0RIN MB, CHEW E, OLDFIELD E, MANOLATOS C, ORCUTI ML,WALTHER MM, WEISS GH, TORY K, JENSSON 0, LERMAN MI, ZBARB: Screening for von Hippel-Lindau disease by DNA polymorphismanalysis. .JAMA 267:1226—1231, 1992

111. NEUMANN HPH, BERGER DP, SIGMUND G, BLUM U, SCHMIDT D,PARMER RJ, yOLK B, KIRSTE G: Pheochromocytomas, multipleendocrine neoplasia type 2, and von Hippel-Lindau disease. N EngIJ Med 329:1531—1538, 1993

112. FILLING-KATZ MR, CHOYKE PL, OLDFIELD E, CHARNAS L, PATRO-NAS NJ, GLENN GM, GORIN MB, MORGAN JK, LINEHAN WM,SEIZINGER BR, ZBAR B: Central nervous system involvement in vonHippel-Lindau disease. Neurology 41:41—46, 1991

113. COLE BR: Autosomal recessive polycystic kidney disease, in TheCystic Kidney, edited by KD GARDNER JR, J BERNSTEIN, Boston,Kluwer Academic Publishers, 1990, pp. 327—350

114. ZERRES K: Autosomal recessive polycystic kidney disease. Clin Invest70:794—801, 1992

115. BLYTH H, OCKENDEN BG: Polycystic disease of kidneys and liverpresenting in childhood. J Med Genet 8:257—284, 1971

116. KAPLAN BS, KAPLAN P, DE CHADAREVIAN J-P, JEQUIER 5, O'REGAN5, RUSSO P: Variable expression of autosomal recessive polycystickidney disease and congenital hepatic fibrosis within a family. Am JMed Genet 29:639—647, 1988

117. MCDONALD RA, AVNER EA: Inherited polycystic kidney disease inchildren. Semin Nephrol 11:632—642, 1991

118. KAARIAINEN H, KOSKIMIES 0, NORIO R: Dominant and recessivepolycystic kidney disease in children: Evaluation of clinical featuresand laboratory data. Pediatr Nephrol 2:296—302, 1988

119. KAPLAN BS, KAPLAN P, ROSENBERG HK, LAMOTHE E, ROSENBLATITDS: Polycystic kidney diseases in childhood. J Pediatr 115:867—880,1989

120. PRETORIUS DH, LEE ME, MANCO-JOHNSON ML, WEINGAST GR,SEDMAN AB, GABOW PA: Diagnosis of autosomal dominant polycys-tic disease in utero and in the young infant. J Ultrasound Med6:249—255, 1987

121. BRONSHTEIN M, BAR-HAVA I, BLUMENFELD Z: Clues and pitfalls inthe early prenatal diagnosis of 'late onset' infantile polycystic kidney.PrenatDiagn 12:293—298, 1992

122. LUTHY DA, HIRSCH JH: Infantile polycystic kidney disease: Obser-vations from attempts at prenatal diagnosis. Am J Med Genet20:505—517, 1985

123. LILFORD RJ, IRvING HC, ALLIBONE EB: A tale of two priorprobabilities—avoiding the false positive antenatal diagnosis ofautosomal recessive polycystic kidney disease. Br J Obstet Gynaecol99:216—219, 1992

124. BARTH RA, GUILLOT AP, CAPELESS EL, CLEMMONS JJW: Prenataldiagnosis of autosomal recessive polycystic kidney disease: Variableoutcome within one family. Am J Obstet Gynecol 166:560—567, 1992

125. KAPLAN BS, FAY J, Su4.H V, DILLION MJ, BARRATr TM: Autosomalrecessive polycystic kidney disease. Pediatr Nephrol 3:43—49, 1989

126. COLE BR, CONLEY SB, STAPLETON FB: Polycystic kidney disease inthe first year of life. J Pediatr 111:693—699, 1987

127. KLEINKNECHT C, HABIB R: Nephronophthisis, in Oxford Textbook ofClinical Nephrology, edited by S CAMERON, AM DAVISON, JP SEIN-FEW, D KERR, E RITZ, New York, Oxford University Press, 1992, pp.2188—2197

128. GARDNER K.EI JR: Evolution of clinical signs in adult-onset cysticdisease of the renal medulla. Ann Intern Med 74:47—54, 1971

129. CHAMBERLIN BC, HAGGE WW, STICKLER GB: Juvenile nephronoph-thisis and medullary cystic disease. Mayo Clin Proc 52:485—491, 1977

130. ANTIGNAC C, ARDUY CH, BECKMANN JS, BENESSY F, GRos F,MEDHIOUB M, HILDEBRANDT F, DUFIER J-L, KLEINKNECHT C,BROYER M, WEISSENBACI-! J, HABIB R, COHEN D: A gene for familial

juvenile nephronophthisis (recessive medullary cystic kidney disease)maps to chromosome 2p. Nature Genet 3:342—345, 1993

131. HILDEBRANDT F, SCHNIEDERS B, SINGH-SAWHNEY I, WAGNER M,EMSCHERMANN M, WEBER JL, BRANDIS M: A gene for familialjuvenile nephronophthisis (recessive medullary cystic disease) mapsto chromosome 2q11.1-q21.1. (abstract) J Am Soc Nephrol 4:814,1993

132. GAGNADOUX MF, BACRI JL, BROYER M, HABIB R: Infantile chronictubulointerstitial nephritis with cortical microcysts: Variant ofnephronophthisis or new disease entity? Pediatr Nephrol 3:50—55,1989

133. ALEXANDER SR, SULLIVAN EK, HARMON WE, STABLEIN DM, TEJANIA, FOR THE NORTH AMERICAN PEDIATRIC RENAL TRANSPLANTCOOPERATIVE STUDY (NAPRTCS): MAintenance dialysis in NorthAmerican children and adolescents: A preliminary report. Kidney mt44:S104—S109, 1993

134. CHAGNAC A, ZEVIN D, WEINSTEIN T, HIRSH J, LEVI J: Combinedtubular dysfunction in medullary cystic disease. Arch Intern Med146:1007—1009, 1986

135. MCGREGOR AR, BAILEY RR: Nephronophthisis-cystic renal medullacomplex: Diagnosis by computerized tomography. Nephron 53:70—72, 1989

136. B0ICHIS H, PASSWELL J, DAVID R, MILLER H: Congenital hepaticfibrosis and nephronophthisis. Q JMed 42:221—233, 1973

137. PROESMANS W, VAN DAMME B, MACKEN J: Nephronophthisis andtapetoretinal degeneration associated with liver fibrosis. Clin Nephrol3:160—164, 1975

138. ROBINS DG, FRENCH TA, CI-IAKERA TMH: Juvenile nephronophthi-sis associated with skeletal abnormalities and hepatic fibrosis. ArchDis Child 51:799—801, 1976

139. DELANEY V, MULLANEY J, BOURKE E: Juvenile nephronophthisis,congenital hepatic fibrosis and retinal hypoplasia in twins. Q J Med47:281—290, 1978

140. DIETERICH E, STRAUB E: Familial juvenile nephronophthisis withhepatic fibrosis and neurocutaneous dysplasia. Helv Paediat Acta35:261—267, 1980

141. WITZLEBEN CL, SRF AR: Nephronophthisis-congenital hepaticfibrosis: An additional hepatorenal disorder. Hum Pathol 13:728—733, 1982

142. YENDT ER: Medullary sponge kidney, in Diseases of the Kidney (5thed), edited by RW SCI-IRIER, CW GOTFSCHALK, Boston, Little, Brownand Company, 1993, pp. 525—533

143. ABREO K, STEELE TH: Simultaneous medullary sponge and adultpolycystic kidney disease: The need for accurate diagnosis. ArchIntern Med 142:163—165, 1982

144. GINALSKI JM, PORTMANN L, JAEGER PH: Does medullaly spongekidney cause nephrolithiasis? AJR 155:299—302, 1990

145. SAGE MR, LAWSON AD, MARSHALL VR, RYALL RL: Medullarysponge kidney and urolithiasis. C/in Radiol 33:435—438, 1982

146. MASCHIO G, TESSITORE N, D'ANGELO A, FABRI5 A, CORGNATI A,OLDRIZZI L, LOSCHIAVO C, LUPO A, VALVO E, GAMMARO L, RUGIU

C: Medullaiy sponge kidney and hyperparathyroidism—A puzzlingassociation. Am J Nephrol 2:77—84, 1982

147. CHEN W-C, LEE Y-H, HUANG J-K, CHEN M-T, CHANG LS: Experi-ence using extracorporeal shock-wave lithotripsy to treat urinarycalculi in problem kidneys. Urol mt 5 1:32—38, 1993

148. NAKADA SY, ERTURK E, MONAGHAN J, COCKETF ATK: Role of

964 Fick and Gabow: Cystic disease

extracorporeal shock-wave lithotripsy in treatment of urolithiasis inpatients with medullary sponge kidney. Urology 41:331—333, 1993

149. RAVINE D, GIBSON RN, DONLAN J, SHEFFIELD U: An ultrasoundrenal cyst prevalence survey: Specificity data for inherited renal cysticdiseases. Am J Kidney Dis 22:803—807, 1993

150. ALPERN RJ, Taco RD: Hypokalemie nephropathy—A clue to cysto-genesis? (editorial) N Eng! J Med 322:398—399, 1990

151. ISHIKAWA I: Acquired cystic disease: Mechanisms and manifesta-tions. Semin Nephrol 11:671—684, 1991

152. MATSON MA, COHEN EP: Acquired cystic kidney disease: Occur-rence, prevalence, and renal cancers. Medicine 69:217—226, 1990

153. Hooo Ri: Acquired renal cystic disease in children prior to the startof dialysis. Pediatr Nephrol 6:176—178, 1992

154. LEVINE F, SLU5HER SL, GIw'rmAM ii, WETZEL LH: Natural historyof acquired renal cystic disease in dialysis patients: A prospectivelongitudinal CT study. AJR 156:501—506, 1991

155. I5HIKAwA I, SHIKURA N, SHINODA A: Cystic transformation in native

kidneys in renal allograft recipients with long-standing good func-tion.AmJNephrol 11:217—223, 1991

156. LIEN Y-HH, HUNT KR, SI5MND MS, ZUKOSKJ C: Association ofcyclosporin A with acquired cystic kidney disease of the nativekidneys in renal transplant recipients. Kidney In! 44:613—616, 1993

157. CoNcoLNo 0, Lualw4o C, OMBRES M, SANTONATI A, FLAMMIA GP,DI SILVERIO F: Acquired cystic kidney disease: The hormonalhypothesis. Urology 41:170—175, 1993

158. KESSLER M, TESTEVUIDE P, AYMARD B, Huu TC: Acquired renalcystic disease mimicking adult polycystic kidney disease in a patientundergoing long-term hemodialysis. Am J Nephrol 11:513—517, 1991

159. ISHIKAwA I, SAITO Y, SHIKURA N, KITADA H, SHINODA A, SUzUIu 5:Ten-year prospective study on the development of renal cell carci-noma in dialysis patients. Am I Kidney Dis 16:452—458, 1990

160. LEVINE F: Renal cell carcinoma in uremic acquired renal cysticdisease: Incidence, detection, and management. Urol Radio! 13:203—210, 1992