*Dept. of Obstetrics and Gynecology, Clinical Center Novi Sad, Yugoslavia

Synonyms: Autosomal dominant polycystic kidney disease, adult hepatorenal polycystic disease

Definition:     Autosomal dominant polycystic kidney disease is a common autosomal dominant disorder that frequently results in renal failure due to progressive cyst development. Autosomal dominant polycystic kidney disease is characterized by replacement of renal parenchyma with multiple cysts of different size as a result of dilatation of the collecting tubules and other tubular segments of the nephrons.

Etiology:       Unknown, it is inherited as an autosomal dominant trait and the recurrence risk is 50%. The major locus, PKD1, maps to 16p13.31.

Incidence:     Autosomal dominant polycystic kidney disease is the most widespread genetic nephropathy. Only twenty-five per cent of patients are symptomatic[2]. One in 1,000 people carry the autosomal dominant polycystic kidney disease mutant gene. Autosomal dominant polycystic kidney disease is usually asymptomatic until the third or fourth decade of life, and although histological evidence of the disease is likely to be present from intrauterine life the age of onset of gross morphological changes that are potentially detectable by ultrasonography is uncertain. Rarely, however, kidneys that are anatomically similar may cause death in infancy or early childhood and the condition has been designated as "adult variety occurring in infancy”[3].

Autosomal dominant polycystic kidney disease is one of the most common genetic disorders and the third most prevalent cause of chronic renal failure[4]. The penetrance of the gene is virtually 100%, but the expressivity of the gene may vary ranging from severe forms that result in neonatal death to asymptomatic forms detected at post mortem examinations^,[6].

In order to prevent the disease it is important to do early screening by ultrasonography that shows a typical picture only in adults. Familial history is determinant for diagnosis in intrauterine age, in newborns and in infants2.

Pathogenesis and pathology: Autosomal dominant polycystic kidney disease is one of the entities that can produce Potter's type III polycystic kidney. In Potter's type III kidneys, the defect seems to be at the level of the ampulla (distal end of the ureter bud), similar to that found in type II. However, the involvement is not universal and some ampullae are normal. The result is the presence of cysts coexisting with normal renal tissue. The cysts correspond to both dilated collecting ducts and other tubular portions of the nephron1.

Potter type III renal dysplasia is characterized by markedly enlarged irregular kidneys with innumerable cysts of variable sizes interspersed among normal or compressed renal parenchyma. Some cysts may reach several centimeters[7]. Cysts are visible in nephrons and in collecting tubules, and there is a mixture of normal and abnormal elements.

It is the common morphological expression of autosomal dominant kidney disease, but also of other Mendelian disorders such as tuberous sclerosis, Jeune syndrome, Sturge-Weber syndrome, Zellweger syndrome, Lawrence-Moon-Biedl syndrome, von Hippel-Lindau syndrome and Meckel-Gruber syndrome. Macroscopically, the kidneys are almost always bilaterally affected and often enlarged1. Both kidneys are generally equally enlarged and only rarely is one involved so slightly that it remains of normal size. Unilateral involvement may be the first manifestation of the disease5.

There is considerable variation in the degree of renal involvement in patients of the same age, suggesting variability in the expressivity of the gene.

The cases of autosomal dominant polycystic kidney disease in fetus in the literature show that:

• Expression of autosomal dominant polycystic kidney disease during fetal life is variable,

• All fetal kidneys that have been histologically studied have shown cystic dilatations

• A majority of these fetuses had ultrasonographic manifestations of the disease and/or had sibs with an early-onset form of it;

• The cysts can be found in newly formed nephrons, predominantly in the more mature nephrons of the deep cortex, or more sparsely distributed in the cortex - these different patterns may reflect different rates of progression of the disease

• In contrast to the histological findings in adult kidneys, glomeruli seem to be predominantly affected in fetal form;

• Severe fetal expression of autosomal dominant polycystic kidney disease seems to cluster in some families; and so far, all DNA analyses performed in families with subjects presenting during the fetal or neonatal period have been consistent with linkage to the PKD1 locus

Genetics: It was suggested that the different forms of autosomal dominant polycystic kidney disease, autosomal dominant polycystic kidney disease 1 and autosomal dominant polycystic kidney disease 2, and perhaps a third form result from defects in interactive factors involved in a common pathway (OMIM).

Roughly 86% of affected European families have their renal disorder on the basis of a mutation on 16p. When autosomal dominant polycystic kidney disease is not linked to chromosome 16, the life expectancy is longer, there is lower risk of progressing to renal failure, the patients are less likely to have hypertension, they are diagnosed at an older age, and had fewer renal cysts at the time of diagnosis ("less aggressive phenotype")[11]^{,[12],[13],[14]}. The locus suggested in these cases is 4q^10,[15]. Mochizuki et al. reported the isolation and characterization of a candidate gene for PKD2 on chromosome 4[16].

Ultrasonographic diagnosis in adults: Diagnosis of autosomal dominant adult polycystic kidney disease is possible by ultrasonographic scanning or by using DNA markers linked to the PKD1 locus. Ultrasonography is complicated by the age-dependent penetrance of the gene and linkage studies are subject to recombination errors owing to meiotic crossing over and locus heterogeneity. In families large enough for linkage analysis, most people who were at 50% prior risk can be given a final risk below 5% or above 95%, by using combined ultrasound and DNA studies[17]. In adults, currently used criteria (bilateral cysts with at least two in one kidney) provide good sensitivity (88.5% at age 15-29 years and 100% at 30 years and above) but performance could be improved by less stringent criteria in subjects aged 15-29 years and more stringent criteria in older family members, in whom simple renal cysts are frequent. The presence of at least two renal cysts (unilateral or bilateral) in individuals at risk and younger than 30 years may be regarded as sufficient to establish a diagnosis; among those aged 30-59 years, the presence of at least two cysts in each kidney may be required, and among those aged 60 years and above, at least four cysts in each kidney should be required[18]. The sensitivity of US in individuals younger than 30 years who are at risk is 95% for autosomal dominant adult polycystic kidney disease type 1 but only 67% for autosomal dominant adult polycystic kidney disease type 2. The sensitivity of US for either autosomal dominant adult polycystic kidney disease type 1 or autosomal dominant adult polycystic kidney disease type 2 in individuals aged 30 years or older who were at risk was 100%. The overall sensitivity in individuals younger than 30 years was 93%. For both autosomal dominant adult polycystic kidney disease types 1 and 2 in all patients, ultrasound demonstrated a sensitivity of 97%, a specificity of 100%, and an accuracy of 98%. Ultrasound is the first-line imaging technique that should be used in the diagnosis of autosomal dominant adult polycystic kidney disease. The sensitivity in individuals aged 30 years or older is 100%, but if there is a clinical suspicion of autosomal dominant adult polycystic kidney disease type 2 in individuals younger than 30 years, linkage analysis should also be considered[19].

Prenatal ultrasonography: Prenatal diagnosis by ultrasonography is confined to a few case reports and the kidneys have been described as enlarged and hyper-echogenic with or without multiple cysts3.  Unlike infantile polycystic kidneys, where there is a loss of the cortico-medullary junction, in autosomal dominant polycystic kidney disease there is accentuation of this junction. The amniotic fluid volume is either normal or reduced. The kidney size is usually smaller than the infant polycystic kidneys3.  Autosomal dominant polycystic kidney disease in the fetus should be suspected when cystic enlarged kidneys are detected in association with a normal amount of amniotic fluid1.  The anomaly can be found as late as the third trimester, with normally looking kidneys in midtrimester[20], which can be used as an argument for introduction of a routine third trimester scan[21].  The diagnosis of intrauterine or neonatal autosomal dominant polycystic kidney disease should prompt investigation of both parents. Molecular analysis of autosomal-dominant polycystic kidney disease allows presymptomatic diagnosis in individuals younger than age 30, and helps in establishing prognosis[22].

Case #1 (Dr. Luis Flavio Goncalves)

This 3rd trimester fetus has brightly echogenic kidneys with accentuation of the cortico-medullary junction and a small bladder with decreased fluid.

Case #2 (Philippe Jeanty)

This patient was scanned for routine exam. The fetal kidneys are brightly echogenic. On further anamnestic interrogation it appeared that the patient"s grandmother, father, aunt and her 2 sisters had adult polycystic kidneys disease. Two other daughters were present and had apparently normal kidneys. The mother (28-year-old) has a single cyst in the right kidney. There is also a 3.7 MB video-clip..

The fetus (#1 in the drawing). Note the echogenic kidneys but normal bladder and amniotic fluid.

The 8-month-old sister  (#2 in above drawing)

The 3-year-old sister  (#3 in above drawing)

The mother"s right kidney (#4 in above drawing)

Differential diagnosis

• Multicystic dysplastic kidneys: in cases of multicystic dysplastic kidneys the cysts are grouped at the periphery, and in autosomal dominant polycystic kidney disease they are randomly distributed

• Meckel-Gruber syndrome: the cysts are all the same size, relatively small. Associated polydactily and cephalocele

• Infantile polycystic kidney disease: (see also 1 and 2) no cysts visible, kidney hyperechoic, greatly enlarged. Often similar ultrasonographic picture to autosomal dominant polycystic kidney disease, though in autosomal dominant polycystic kidney disease more often cysts are seen. In infantile polycystic kidneys reduced amniotic fluid volume is found more often

• Trisomy 13 kidneys: kidney enlarged, hyperechogenic, randomly dispersed small cysts

Associated anomalies: The anomalies mentioned in connection with autosomal dominant polycystic kidney disease are anencephaly9, multiple skeletal and limb defects, including polydactily, syndactily, bilateral agenesis of the tibia, and clubfoot[23].

One third of the cases have cysts in the liver, pancreas, spleen, ovary or lungs and one fifth are found to have cerebral aneurysms^3,24. Involvement of the liver is less prominent than in infantile form of the polycystic kidney disease1.

Asymptomatic hepatic cysts are found in about 30% of patients with autosomal dominant polycystic kidney disease and in these patients renal involvement is usually minimal. The frequency of hepatic involvement in patients with an early onset of autosomal dominant polycystic kidney disease in the fetal or neonatal period is unknown1.

Prognosis:   Autosomal dominant polycystic kidney disease is a chronic disease that may become symptomatic over a wide range of ages from the newborn period to adulthood and it can be severe or completely asymptomatic. The mean age of onset of symptoms is 35 years and of diagnosis 43 years[25]. The symptoms are loin pain, renal enlargement, renal insufficiency and uremia, and hypertension is observed in majority of patients1. Since berry aneurisms can be found in one fifth of the patients3, the rupture of the aneurysm can be a cause of death in patients with autosomal dominant polycystic kidney disease.

In counseling parents affected with autosomal dominant polycystic kidney disease, it should be emphasized that the prenatal demonstration of sonographically normal kidneys does not necessarily exclude the possibility of developing polycystic kidneys in adult life3.

Median age at death or onset of end-stage renal disease is 53.0 years in individuals with polycystic kidney disease 1, 69.1 years in those with polycystic kidney disease 2. Women with polycystic kidney disease 2 have a significantly longer median survival than men (71.0 vs. 67.3 years), but no sex influence was apparent in polycystic kidney disease 1. Age at presentation with kidney failure is later in polycystic kidney disease 2 than in polycystic kidney disease 1, polycystic kidney disease 2 patients were less likely to have hypertension, a history of urinary-tract infection, or hematuria (0.59 [0.35-0.98]). So, although polycystic kidney disease 2 is clinically milder than polycystic kidney disease 1, it has a deleterious impact on overall life expectancy and cannot be regarded as a benign disorder[26].

Obstetrical management:  Parents at risk should be counseled about the possibility of first trimester prenatal diagnosis. Prenatal diagnosis is possible, by chorionic villous sampling, using a DNA probe linked to the locus of the mutant gene8.

If the diagnosis is made before viability, the option of pregnancy termination should be offered to the parents. After viability, the diagnosis of autosomal dominant polycystic kidney disease probably should not alter standard obstetrical management. Any time enlarged hyperechogenic kidneys are diagnosed in a fetus, members of the family should be screened with renal sonography. There are no data in which to base the management of fetuses with evidence of in utero renal failure1.

Postnatal ultrasound and treatment: Although for decades autosomal dominant polycystic kidney disease was considered a disease of adults, recent longitudinal studies on children from autosomal dominant polycystic kidney disease families have shown that the disease is evident by ultrasound imaging in approximately 75% of children who are carriers of the autosomal dominant polycystic kidney disease 1 gene, the most common form of autosomal dominant polycystic kidney disease. In contrast to adults, the disease appears to be unilateral initially in approximately 17% of children. Asymmetric enlargement of the kidneys is also frequently observed. This renal asymmetry can be extreme and lead to diagnostic confusion27.

A carefully obtained family history and examination of both parents with ultrasound can help to avoid unnecessary invasive procedures. If pain is a prominent symptom, it can be treated by cyst aspiration if there are only a few cysts or a single dominant cyst. The molecular mechanism for extremely asymmetric renal disease remains to be elucidated.

Genetic diagnosis: A prenatal diagnosis of adult polycystic kidney disease by DNA testing is possible. Evidence showing a linkage between the disease and the DNA markers on chromosome 16 can be obtained in the affected family by linkage analysis and homogeneity testing with families of the linked type. Prenatal diagnosis is performed either by polymerase chain reaction (PCR) of GGG1 fragment either by Southern blotting analysis of the others chromosome 16 markers. Diagnostic results are available by PCR analysis in a few hours and then confirmed by Southern blotting of the others probes[28].

Flanking DNA markers can be linked to the PKD1 gene on chromosome 16p, and for a polymorphism close to a second putative disease gene (PKD2) on chromosome 2[29].

References:

[1] Romero R, Pilu G, Jeanty P, Ghidini A, Hobbins JC, Eds. Prenatal Diagnosis of Congenital Anomalies. Appleton and Lange, Norwalk/San Mateo, 1988; pp 268-270.

[2] Serbelloni P; Conte F; Garavaglia G; Spattini A; Sessa A .Echographic screening for autosomal dominant polycystic kidney disease from intrauterine life to adult life. Arch Ital Urol Nefrol Androl 1991 Jun;63 Suppl 2:89-92.

[3] Pilu G, Nicolaides KH. Diagnosis of fetal abnormalities – The 18-23 week scan. Diploma in Fetal Medicine Series/ The Parthenon Publishing Group, New York/London 1999; pp 80-81.

[4] Milutinovic J, Fialkow PJ, Phillips LA. Autosomal dominant polycycstic disease: Early diagnosis and data for genetic counselling. Lancet 1980; 1:1203.

[5] Spence HM, Baird SS, Ware EW. Cystic disorders of the kidney: Classification, diagnosis, treatment. JAMA 1957; 163:1466.

[6] Dalgaard OZ. Bilateral polycycstic disease of the kidney: A follow-up of two-hundred eighty four patients and their families. Acta Med Scand (Suppl) 1957; 328.

[7] Madewell JE, Hartman DS, Lichtenstein JE. Radiologic pathologic correlations in cystic disease of the kidney. Radiol Clin North Am 1979; 17:261.

[8] Reeders ST, Zerres K, Ga IA. Prenatal diagnosis of autosomal dominant polycystic kidney disease with a DNA probe. Lancet 1986; 2:6.

[9] Michaud J; Russo P; Grignon A; Dallaire L; Bichet D; Rosenblatt D; Lamothe E.. Autosomal dominant polycystic kidney disease in the fetus. Am J Med Genet 1994 Jul 1;51(3):240-6.

[10] Peters, D. J. M.; Spruit, L.; Saris, J. J.; Ravine, D.; Sandkuijl, L. A.; Fossdal, R.; Boersma, J.; van Eijk, R.; Norby, S.; Constantinou-Deltas, C. D.; Pierides, A.; Brissenden, J. E.; Frants, R. R.; van Ommen, G.-J. B.; Breuning, M. H. : Chromosome 4 localization of a second gene for autosomal dominant polycystic kidney disease. Nature Genet. 5: 359-362, 1993.

[11] Ravine, D.; Walker, R. G.; Gibson, R. N.; Forrest, S. M.; Richards, R. I.; Friend, K.; Sheffield, L. J.; Kincaid-Smith, P.; Danks, D. M. : Phenotype and genotype heterogeneity in autosomal dominant polycystic kidney disease. Lancet 340: 1330-1333, 1992.

[12] Jeffery, S.; Saggar-Malik, A. K.; Morgan, S.; MacGregor, G. A. :A family with autosomal dominant polycystic kidney disease not linked to chromosome 16p13.3. Clin. Genet. 44: 173-176, 1993.

[13] Bear, J. C.; Parfrey, P. S.; Morgan, J. M.; Martin, C. J.; Cramer, B. C. : Autosomal dominant polycystic kidney disease: new information for genetic counselling. Am. J. Med. Genet. 43: 548-553, 1992.

[14] Hateboer, N.; van Dijk, M. A.; Bogdanova, N.; Coto, E.; Saggar-Malik, A. K.; San Millan, J. L.; Torra, R.; Breuning, M.; Ravine, D. : Comparison of phenotypes of polycystic kidney disease types 1 and 2. Lancet 353: 103-107, 1999.

[15] Fossdal, R.; Boovarsson, M.; Asmundsson, P.; Ragnarsson, J.; Peters, D.; Breuning, M. H.; Jensson, O. :

Icelandic families with autosomal dominant polycystic kidney disease: families unlinked to chromosome 16p13.3 revealed by linkage analysis. Hum. Genet. 91: 609-613, 1993.

[16] Mochizuki, T.; Wu, G.; Hayashi, T.; Xenophontos, S. L.; Veldhuisen, B.; Saris, J. J.; Reynolds, D. M.; Cai, Y.; Gabow, P. A.; Pierides, A.; Kimberling, W. J.; Breuning, M. H.; Constantinou Deltas, C.; Peters, D. J. M.; Somlo, S.: PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272: 1339-1342, 1996.

[17] Elles RG; Hodgkinson KA; Mallick NP; O"Donoghue DJ; Read AP; Rimmer S; Watters EA; Harris R. Diagnosis of adult polycystic kidney disease by genetic markers and ultrasonographic imaging in a voluntary family register. J Med Genet 1994 Feb;31(2):115-20

[18] Ravine D; Gibson RN; Walker RG; Sheffield LJ; Kincaid-Smith P; Danks DM. Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1. Lancet 1994 Apr 2;343(8901):824-7.

[19] Nicolau C; Torra R; Badenas C; Vilana R; Bianchi L; Gilabert R; Darnell A; Bru C. Autosomal dominant polycystic kidney disease types 1 and 2: assessment of US sensitivity for diagnosis. Radiology 1999 Oct;213(1):273-6.

[20] Main D, Mennuti MT, Cornfeld D. Prenatal diagnosis of adult polcystic kidney disease. Lancet 1983;2:337.

[21] Fugelseth D; Lindemann R; Sande HA; Refsum S; Nordshus T . Prenatal diagnosis of urinary tract anomalies. The value of two ultrasound examinations. Acta Obstet Gynecol Scand 1994 Apr;73(4):290-3.

[22] Torra R; Badenas C; Darnell A; Nicolau C; Volpini V; Revert L; Estivill X. Linkage, clinical features, and prognosis of autosomal dominant polycystic kidney disease types 1 and 2. J Am Soc Nephrol 1996 Oct;7(10):2142-51.

[23] Turco AE; Padovani EM; Chiaffoni GP; Peissel B; Rossetti S; Marcolongo A; Gammaro L; Maschio G; Pignatti PF. Molecular genetic diagnosis of autosomal dominant polycystic kidney disease in a newborn with bilateral cystic kidneys detected prenatally and multiple skeletal malformations. J Med Genet 1993 May;30(5):419-22.

[24] Hartnett M, Bennett W. Extrarenal manifestations of cystic kidney disease. In: Gardner KD Jr (Ed): Cystic Diseases of the Kidney. New York, Wiey, 1976, pp 201-219.

[25] Zerres K, Volpel MC, Weiss H. Cystic kidneys. Geneics, pathologic anatomy, clinical picture and prenatal diagnosis. Hum Genet 1984; 68:104.

[26] Hateboer N; v Dijk MA; Bogdanova N; Coto E; Saggar-Malik AK; San Millan JL; Torra R; Breuning M; Ravine D. Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group. Lancet 1999 Jan 9;353(9147):103-7.

[27] Fick-Brosnahan G; Johnson AM; Strain JD; Gabow PA, Renal asymmetry in children with autosomal dominant polycystic kidney disease.Am J Kidney Dis 1999 Oct;34(4):639-45

[28] Bellone E; Mandich P; Costa P; Dalerba L; Ajmar F. Adult polycystic kidney disease: prenatal diagnosis with DNA polymorphic markers.