Current convention restricts the use of the term “polycystic kidney disease” (PKD) to two genetically distinct conditions: autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).1 Patients with PKD have bilateral enlarged cystic kidneys (i.e. both kidneys are larger than normal due to the presence of cysts).
There are several syndromic conditions associated with cysts in the kidneys which are differentiated from the inherited forms of PKD by the presence of associated extra-renal abnormalities, for example Tuberous Sclerosis and Von Hippel Lindau syndrome.2
Multicystic dysplasia (MCD,) on the other hand, is a much more common condition than PKD. It is often incorrectly labelled a “polycystic kidney”. It is a sporadic developmental disorder of the kidney, usually occurring unilaterally (on one side only).3 A multicystic kidney is not functional. This implies that bilateral multicystic dysplastic kidney disease is invariably a fatal condition.
Autosomal recessive polycystic kidney disease (ARPKD)
The overall frequency of ARPKD is one in 20 000 live births. In South Africa it is well known that ARPKD occurs more commonly in the white Afrikaner population, due to a founder effect.4
ARPKD is caused by mutations of a single gene, Polycystic Kidney and Hepatic Disease I (PKHD1) located on chromosome 65,which encodes a multi-domain membrane protein, called fibrocystin or polyductin.6
The majority of children with ARPKD are identified in utero, thanks to the routine use of ultrasound during pregnancy.7 Affected foetuses have decreased urine production, resulting in decreased amniotic fluid volume (oligohydramnios) and poor foetal lung development. Ultrasound investigation in the mid trimester of pregnancy reveals bilateral enlarged echogenic kidneys and oligohydramnios.
At birth newborn infants have respiratory distress due to poor lung development, very large palpable flank masses (large kidneys) and impaired renal function. About 25-30% of babies die at or shortly after birth due to respiratory insufficiency.8 Death from renal insufficiency at this stage is uncommon. There is usually a transient improvement in renal function, due to some degree of normal renal maturation that occurs during the first 18 months of life. Thereafter a progressive but variable decrease of renal function occurs.
Nearly 50% of affected infants surviving the neonatal period progress to end-stage renal failure within the first 10 years of life. Early reports stated that all children with ARPKD died, but more recent studies have shown that the 10 year survival of children who survive the first year is estimated to be 82% and the 15 year survival is projected to be 67-79%.2
ARPKD in infancy and childhood
Children who survive the neonatal period have considerable variability in the degree of involvement of the kidneys and liver.
The majority of children have significant hypertension, requiring treatment with different antihypertensive drugs to control their blood pressure.9 ARPKD is associated with poor renal concentrating ability, causing children to have polyuria and polydipsia.10 (They pass large volumes of urine and drink a lot of fluid). Poor growth is a common feature and is in part caused by the polydipsia. Progressive renal failure develops over time, with most children requiring dialysis and or renal transplantation during late childhood or early puberty.
Liver disease (hepatic fibrosis) is invariably present in all patients with ARPKD, but usually only becomes symptomatic later in childhood.10 A subset of patients may present, as congenital hepatic fibrosis and associated renal disease in older infants are only then discovered coincidently. The main hallmarks of liver disease are intra-hepatic bile duct dilatation and portal fibrosis. (The bile ducts in the liver are dilated and have abnormal features, a condition which is called Caroli disease).7
Hepatic fibrosis manifests with splenomegaly (enlargement of the spleen), hypersplenism (increased consumption of red blood cells, white blood cells and platelets by the spleen) and gastro-oesophageal varices with the risk of bleeding. Infants who present with predominantly liver disease (Caroli disease) may develop recurring ascending cholangitis (bacterial infection in the bile ducts, originating from gram negative bacteria in the gastro-intestinal tract).7
Early diagnosis of ARPKD, e.g. in an infant born to parents with a previously affected child affords the opportunity for maximal anticipatory care, including management of hypertension and conservative treatment of the complications of chronic renal failure. In such patients pre-emptive hepato-renal or renal transplantation may be done before dialysis becomes necessary.
Diagnostic criteria for ARPKD9
Ultrasound features typical of ARPKD, including large echogenic kidneys and one or more of the following:
- Absence of renal cysts in the parents
- Clinical, laboratory or radiographic evidence of hepatic fibrosis
- Liver biopsy: histology demonstrating hepatic fibrosis
- Previous affected sibling with ARPKD
- Parental consanguinity suggestive of autosomal recessive inheritance
Molecular diagnostic testing is available for ARPKD which can be used to establish a diagnosis with 85% certainty.11-13 In South Africa the diagnosis of ARPKD usually relies on imaging studies, a complete family history, clinical findings, and rarely biopsy findings. Genetic testing has been available in South Africa for more than a decade and should be offered to parents and their first affected child. Further details on the molecular diagnosis of ARPKD can be found at GeneClinics: Clinical Genetic Information Research (database online) at http://www.geneclinics.org14
Autosomal dominant (ADPKD)
ADPKD is a systemic disease which usually only becomes symptomatic in the 3rd to 4th decades of life. It is characterised by bilateral progressively enlarging cysts in the kidney with variable extrarenal manifestations.
It is an autosomal dominant disorder with 100% penetrance. It is caused by mutations in 2 genes, PKD1 (85%) and PKD2 (15%), located on chromosomes 16 and 4 respectively. PKD1 gene encodes a large complex glycoprotein (polycystin-1), which is an integral membrane protein.PKD2 encodes polycystin-2, which is a calcium permeable, non-selective cation channel that increases membrane permeability to calcium and plays an essential role in polycystin-1 localization and function.15,16
Mutations of PKD1 are associated with more severe disease and earlier onset of end stage renal failure.17
ADPKD occurs in 1 in 1000 adults, making it one of the most common causes of end stage renal failure in adults. It occurs in all races and both sexes, but the renal disease appears to be more severe in males.
The main characteristic of ADPKD is bilateral renal cysts in progressively enlarging kidneys. Despite the presence of numerous cysts in the kidney, renal function usually remains preserved until the age of 30-40 years where after renal function rapidly declines.
Although the disease usually only manifests in adulthood, a spectrum of presentationsis possible throughout childhood.18 ADPKD may be diagnosed, following the coincidental finding of renal cysts noted on an ultrasound scan in an asymptomatic child, or present with a severe neonatal or early childhood form of the disease, in which case it may be indistinguishable from ARPKD. In most such cases a careful history and positive kidney sonar in a parent helps to confirm the diagnosis of ADPKD. In some cases a family with ADPKD is only identified following the investigation of a child presenting with a unilateral large kidney, hypertension or renal impairment.
Early manifestation of ADPKD is defined as a symptomatic disease occurring before the age of 15 years. Families with offspring who present at a young age have a high recurrence risk, which means that subsequent siblings will follow a similar early manifesting course.
Renal manifestations of ADPKD include:
- Hypertension occurring at an earlier age compared to the general population.19, 20
- Hypertension developing in 50-70% of patients, even before they have any decline in renal function.
- Hypertension associated with a rapid progression to end stage renal failure and increased risk of cardiovascular complications.21
- Other renal manifestations: microscopic or macroscopic haematuria, flank pain, pyelonephritis (infection in the kidneys). nephrolithiasis (renal stones) and chronic renal failure.
Extra-renal manifestations 22
Cysts can also occur in other organs (in the liver, pancreas, spleen and lung), but do not affect the function of the organ.
ADPKD is associated with several vascular abnormalities, including cerebral aneurysms, mitral valve prolapse and dilatation of the aortic root. Intracerebral aneurysms (ICA) occur in 8% of patients with ADPKD. Screening for ICA in patients diagnosed with ADPKD is recommended at the age of 20 years in patients with a family history of ruptured ICA.
Imaging and diagnosis
- There are no specific clinical diagnostic criteria for children with suspected ADPKD.
- The most useful examination in the assessment of a child with early onset renal cystic disease of unknown cause is ultrasound of the parents.
- In a family with PKD the presence of a single renal cyst is considered diagnostic.23
Age dependant ultrasound criteria for the diagnosis of PKD in families of unknown genotype were proposed but were found to be insensitive. Ultrasound cannot be used to exclude the diagnosis of PKD in asymptomatic patients under 40 year of age.
Molecular genetic testing for ADPKD is available. Log onto www.genetests.org for more information.
It can be used to establish a diagnosis with >90% certainty. 24.25 In most cases in South Africa the diagnosis still relies on a complete family history, clinical findings and imaging studies.
There are currently no specific or curative treatments for PKD.
Complications specific to ARPKD and ADPKD as described above should be managed. The most important aspect in the management is control of hypertension as it slows the rate of deterioration of kidney function and decreases the cardiovascular complications. Treatments which have been shown not to be of benefit include drainage of the cysts and dietary protein restriction.
Nephrotoxic drugs and other drugs which have been shown to have deleterious effect on renal function (caffeine, theophylline-like drugs, estrogens, calcium-channel blocking drugs) should be avoided.
Patients with PKD should be followed up in a specific nephrology clinic to plan initiation of renal replacement therapy (dialysis) or pre-emptive renal transplantation.
Reviewed by Prof Ida van Biljon, MMed(Paed)Pret, FCP(Paed)SA, Paediatric Nephrologist, Department of Paediatrics, University of Pretoria, July 2011
1. Sweeney WE, Avner ED. Diagnosis and management of childhood polycystic kidney disease. Pediatr Nephrol 2011; 26: 675-692.
2. Dell KM, Sweeney WE, Avner ED. Polycystic kidney disease. 2009. In Avner ED, Harmon WE, Niadet P, Yoshikawa N (eds) Pediatric Nephrology. Vol 1. Springer, Berlin, Heidelberg, pp 849-887.
3. Simple Multicystic Dysplastic Kidney disease: end points for sub-speciality follow up. Weinstein A, Goodman TR, Iragorri S Pediatr Nephrol. 2008;23:111-116.
4. Autosomal recessive polycystic kidney disease. Evidence for high frequency of the gene in the Afrikaans-speaking population. EH Lombard, JGR Kromberg, PD Thomson. LS Milner, G van Biljon, J Jenkins. SAMJ. 7 Oct 1989; Vol 76:321-24.
5. Guay-Woodford LM, Muecher G, Hopkins SD, Avner ED, Germino GG, Guillot AP, Herrin J, Holleman R, Irons DA, Primack W, Thompson PD, Waldo FB, Lunt PW, Zerres K. The severe perinatal form of autosomal recessive polycystic kidney disease maps to chromosome 6 p21.1-p12: Implications for genetic counseling. Am J Hum Genet 1995; 56:1101–1107.
6. Onuchic LF, Furu L, Nagasawa Y, Hou X, Eggermann T, Ren Z, Bergmann C, Senderek J, Esquivel E, Zeltner R, Rudnik-Schoneborn S, Mrug M, Sweeney W, Avner ED, Zerres K, Guay-Woodford LM, Somlo S, Germino GG (2002) PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexintranscription- factor domains and parallel beta-helix 1 repeats. Am J Hum Genet 70:1305–1317.
7. Guay-Woodford LM, Desmond RA. Autosomal recessivepolycystic kidney disease: the clinical experience in North America. Pediatrics 2003; 111:1072–1080.
8. Roy S, Dillon MJ, Trompeter RS, Barratt TM. Autosomal recessive polycystic kidney disease: long-term outcome of neonatal survivors. Pediatr Nephrol 1997; 11:302–306.
9. Zerres K, Rudnik-Schoneborn S, Deget F, Holtkamp U, Brodehl J, Geisert J, Scharer K Autosomal recessive polycystic kidney disease in 115 children: clinical presentation, course and influence of gender. Arbeitsgemeinschaft für Pädiatrische,Nephrologie. Acta Paediatr 1996; 85:437–445.
10. Kaplan BS, Kaplan P, Rosenberg HK, Lamothe E, Rosenblatt DS. (1989) Polycystic kidney diseases in childhood. J Pediatr 115:867–880.
11. Sharp AM, Messiaen LM, Page G, Antignac C, Gubler MC, Onuchic LF, Somlo S, Germino GG, Guay-Woodford LM. Comprehensive genomic analysis of PKHD1 mutations in ARPKD cohorts. J Med Genet 2005; 42:336–349.
12. Bergmann C, Kupper F, Dornia C, Schneider F, Senderek J, Zerres K. Algorithm for efficient PKHD1 mutation screening in autosomal recessive polycystic kidney disease (ARPKD). Hum Mutat 2005; 25:225–231.
13. Rossetti S, Torra R, Coto E, Consugar M, Kubly V, Malaga S, Navarro M, El-Youssef M, Torres VE, Harris PC (2003) A complete mutation screen of PKHD1 in autosomal-recessive polycystic kidney disease (ARPKD) pedigrees. Kidney Int 64:391–403.
14. Dell KM, Avner ED Autosomal recessive polycystic kidney disease. In: GeneClinics: Clinical Genetic Information Resource (database online). Copyright, University of Washington, Seattle 2008. Available at http://www.geneclinics.org. Initial posting July 2001, updated August 2008.
15. Ong AC, Harris PC. Molecular pathogenesis of ADPKD: the polycystin complex gets complex. Kidney Int 2005; 67:1234–1247.
16. Gabow PA. Autosomal dominant polycystic kidney disease. N Engl J Med 1993; 329:332–342.
17. Barua M, Cil O, Paterson AD, Wang K, He N, Dicks E, Parfrey P, Pei Y. Family history of renal disease severitypredicts the mutated gene in ADPKD. J Am Soc Nephrol 2009; 20:1833–1838.
18. Sedman A, Bell P, Manco-Johnson M, Schrier R, Warady BA, Heard ED, Butler-Simon N, Gabow P Autosomal dominant polycystic kidney disease in childhood: a longitudinal study. Kidney Int 1987;31:1000–1005.
19. Kelleher CL, McFann KK, Johnson AM, Schrier RW. Characteristics of hypertension in young adults with autosomal dominant polycystic kidney disease compared with the general U.S. population. Am J Hypertens 2004; 17:1029–1034.
20. Schrier RW, Johnson AM, McFann K, Chapman AB. The role of parental hypertension in the frequency and age of diagnosis of hypertension in offspring with autosomal dominant polycystic kidney disease. Kidney Int 2003; 64:1792–1799.
21. Gabow PA, Johnson AM, Kaehny WD, Kimberling WJ, Lezotte DC, Duley IT, Jones RH. Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease. Kidney Int 1992; 41:1311–1319.
22. Harris PC, Torres VE. Polycystic kidney disease. Annu Rev Med 2009; 60:321–337.
23. Gabow PA, Kimberling WJ, Strain JD, Manco-Johnson ML, Johnson AM. Utility of ultrasonography in the diagnosis of autosomal dominant polycystic kidney disease in children. J Am Soc Nephrol 1997; 8:105–110.
24. Harris PC, Rossetti S. Determinants of renal disease variability in ADPKD. Adv Chronic Kidney Dis 2010; 17:131–139.
25. Harris PC, Rossetti S Molecular diagnostics for autosomal dominant polycystic kidney disease. Nat Rev Nephrol 2010; 6:197–206.