Polycystic kidney diseases (PKD) are severe systemic disorders that predominantly affect the kidneys and the liver [1
]. The two main forms of PKD are autosomal recessive PKD (ARPKD; OPRHA:731) and autosomal dominant PKD (ADPKD, OPRHA:730).
ARPKD is usually diagnosed prenatally or in the first year of life. The disease is characterized by bilateral fibrocystic changes of the kidneys typically presenting with massive organ enlargement due to ubiquitous microcysts mainly developing from the collecting duct. Impairment of kidney function is variable. Antenatal decline of kidney function is associated with oligo-/anhydramnios which subsequently results in pulmonary hypoplasia. Early pulmonary disease in ARPKD is still associated with substantial mortality even in very advanced medical centers. In addition, hepatic involvement due to a developmental defect of bile ducts is an obligatory finding in ARPKD, which may clinically result in hepatic fibrosis with portal hypertension and bile duct dilatations with an increased risk of cholangitis [1
ADPKD is a more slowly developing disease with clinical symptoms typically becoming prominent in adulthood, even though cyst development starts in childhood or even in utero
]. The disease is characterized by progressive development of macrocysts in the kidney developing from all parts of the tubule. Kidney volume increases with cyst volume. Fibrotic changes in the kidney develop during the course of the disease. Extrarenal manifestations include - amongst others - the development of hepatic cysts, diverticula and hernia, cardiovascular anomalies, and pain (Table 1
Comparison of typical clinical features of ARPKD and ADPKD
Main clinical kidney manifestations
Prenatal enlarged kidneys, cystic kidneys, oligo-/anhydramnios
Chronic kidney disease
Increased TKV, cystic kidneys
Chronic kidney disease
Increased echogenicity of kidney parenchyma. „Salt-and-pepper“-pattern. Small, sometimes invisible cysts (<2mm).
More ADPKD-like pattern with advancing age
Cysts of different sizes in cortex and medulla.
Usually several large cysts.
Usually bilateral cysts
Mandatory: Ductal plate malformation/congenital hepatic fibrosis with hyperplastic biliary ducts and portal fibrosis
Dilated bile ducts (Caroli syndrome)
Increased risk of cholangitis
Occasionally ductal plate malformation/congenital hepatic fibrosis
Liver cysts: Common in adults, rare in children.
Neonatal respiratory distress/failure due to pulmonary hypoplasia
Rarely pancreatic cysts.
Single case reports of intracranial aneurysms.
Pancreatic cysts and/or cysts in other epithelial organs
Colon diverticula and hernia
Cardiovascular anomalies, and familiarly clustered intracranial aneurysms, abdominal Aorta aneurysms
The genes mainly affected in ARPKD and ADPKD are well-known (PKHD1
(ADPKD)), but the pronounced and poorly understood clinical variability cannot be fully explained by underlying genotypes. Variants in additional genes and first modifier genes have been identified [1
]. Overlapping phenotypes between ARPKD and rapidly progressing ADPKD, and patients with coincidental variants in multiple PKD genes that show aggravated phenotypes have been described [6
]. Biallelic hypomorphic PKD1
variants have been identified as a common cause of early-onset PKD [7
]. In addition to genetic aspects, unknown environmental factors may influence the phenotype.
In this manuscript we focus on kidney involvement in the two main forms of PKD. ARPKD and ADPKD are major contributors to chronic kidney disease (CKD) with ARPKD being an important cause of CKD specially in very young children and ADPKD being the by far most common genetic cause for chronic kidney failure (CKF) in adults. Despite important work by multiple groups [8
], there has been a knowledge gap on longitudinal courses of ARPKD and pediatric ADPKD and prognostic markers. Clinically, there is limited published data on severe and rapidly-progressing early-onset ADPKD. For typical ADPKD that progresses to kidney failure at a mean age of 58.1 years for PKD1
patients and at 79.9 years for PKD2
patients first risk scores have been developed in adult patients [12
]. Yet, these scores cannot be fully applied in pediatric and young adult patients as they include age-dependent variables. Height-adjusted total kidney volume (HtTKV) has been associated with hypertension of ADPKD already in children [14
], but data on in-depth longitudinal clinical characterization of children suffering from ADPKD remains sparse.
There is a clear need for evidence-based and targeted treatment in both forms of PKD during childhood and adolescence. ARPKD is a very severe disorder of early childhood. In ADPKD on the other hand cystogenesis starts early in life and kidney function mainly declines once structural changes in the kidney parenchyma are pronounced. It has therefore been suggested that young ADPKD patients could highly profit from early interventions that would retard the development of structural changes in the kidney with subsequent positive long-term effects.
Clinical research on ARPKD and pediatric ADPKD has for a long time been hampered by the lack of well-defined primary end points for trials. Most of the current treatment approaches for pediatric PKD therefore remain symptomatic and opinion-based. The current treatment of severely affected children with ADPKD is based on strict antihypertensive therapy [4
For treatment of adult ADPKD patients multiple clinical trials are ongoing. The vasopressin V2-receptor antagonist Tolvaptan has been shown to retard cyst growth and the loss of kidney function in large cohorts of adult ADPKD patients [1
]. A clinical trial on the use of Tolvaptan in children with ADPKD is currently ongoing (EudraCT 2016-000187-42). While tolvaptan has shown a clinical benefit for adult patients with ADPKD, it is associated with relevant side effects including polydipsia and polyuria. Adult patients produce 4-8 liters of urine a day and rare but severe hepatic side effects have been described [1
Data from preclinical studies show that common molecular and cellular mechanisms in ARPKD and ADPKD contribute to the pathogenesis of the different subtypes of PKD [1
]. Thus, a transfer of knowledge from ADPKD to ARPKD seems plausible. However, given the current difficulties to predict disease courses and to identify children at special risk of very rapid disease progression in both forms of PKD, novel targeted therapies could either be withheld or expose individuals to potential side effects without providing any benefit. A deeper understanding of the natural disease history and rapid, accurate and prognostic diagnostic measures are therefore urgently required to guide counseling, the timing of diagnosis and monitoring, and to work towards personalized therapeutic approaches. A combination of longitudinal clinical phenotyping and the survey of international cohorts together with a translational research approach to identify underlying molecular disease mechanisms and biomarkers appears ideal to identify diagnostic criteria that can be applied early in life.
Over the last years we have established the international registry studies ARegPKD (www.ARegPKD.org
) and ADPedKD (www.ADPedKD.org
]. In brief, we aim to follow patients with the clinical diagnosis of ARPKD or pediatric ADPKD to describe the longitudinal clinical courses. By End of May 2021 more than 680 patients have been included in ARegPKD and more than 1200 patients have been registered for the more recently launched global ADPedKD network.
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