Polycystic kidney disease


Polycystic kidney disease (PKD) is a rare genetic disorder characterized by the development of cysts in the kidneys. Cysts are fluid-filled sacs that can vary in number and size. Their formation can damage the filtering ability of the kidneys which over time can evolve into chronic kidney failure. Often the cysts can also develop in other organs, first of all the liver. Although the clinical manifestation is highly variable from individual to individual, the main symptoms associated with this condition, in addition to enlargement of the kidneys (nephromegaly), are hypertension, abdominal pain, hematuria, kidney stones and susceptibility to urinary tract infections. Patients also have an increased risk of developing brain aneurysms. There are two main forms of polycystic kidney disease: one more frequent, with autosomal dominant transmission, with onset in adulthood, while the other rarer, with recessive transmission, with onset in early childhood. Diagnosis is made on the basis of imaging techniques (ultrasounds, MRI) and supported by genetic testing.

Detailed clinical description

Autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is a rare, multisystemic and progressive genetic disease characterized mainly by the development of cysts, fluid-filled sacs, in the kidneys. ADPKD is the leading cause of kidney failure in the adult population. Although patients are born with this condition, it is often not diagnosed before the age of 30-50, when the first symptoms begin to appear. ADPKD is characterized by a high degree of phenotypic variability, both inter and intra familiar.

ADPKD key sign is the formation of cysts in the kidneys, which have a variable number and which tend to enlarge over time. The formation of cysts leads to an enlargement of the kidneys and their impairment. Other symptoms are hypertension, hematuria, abdominal pain, nephrolithiasis and susceptibility to urinary tract infections. Renal function worsens over time, up to chronic kidney disease (in 50% of patients by the age of 65).

Among the extrarenal manifestations, the most common is the development of cysts also in other parts of the body, particularly in the liver. Hepatic cysts are very rare in children, but their prevalence increases with age, reaching 94% in the age group between 35 and 46 years. Polycystic liver disease usually remains asymptomatic, but in rare cases it can lead to dyspnea, abdominal pain and, cystic bleeding and infections. Other organs that can be affected by cyst formation are the pancreas, seminal vesicles and the arachnoid membrane. Cardiac and vascular abnormalities may also be present, such as intracranial aneurysms (present in approximately 10% of cases) and heart valve abnormalities.

The penetrance of the disease is incomplete, often dependent on the genotype and age.

Autosomal recessive polycystic kidney disease

As ADPKD, autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disorder belonging to the class of fibrocystic congenital hepatorenal syndromes. The onset, however, occurs in the first months/years of life (neonatal), and in some cases the disease may already manifest in the uterus.

The main clinical sign is the presence of renal cysts. Prenatally, fetuses may have enlarged kidneys (nephromegaly) and, in severe cases, a Potter-like phenotype with low amniotic fluid and underdeveloped lungs. Renal function progressively worsens, up to chronic renal failure (in 50% of cases within 10 years of life). Hypertension is a frequent sign. The second most affected organ is the liver: patients often have congenital hepatic fibrosis, which may be associated with non-obstructive dilation of the intrahepatic bile ducts (Caroli syndrome) and hepatosplenomegaly. One of the main complications, which often causes early death, is pulmonary hypoplasia resulting from oligohydramnios. Other problems include feeding difficulties, poor growth, and rarely aneurysms.

ARPKD penetrance is complete, but intra- and inter-familial phenotypic variability is often observed.

The diagnosis relies on imaging methods, primarily ultrasound, thanks to its low cost and high safety. In-depth analyzes can be performed with CT or MRI, which are more sensitive and in particular MRI allows to measure the size of cysts and kidneys. The genetic test is not classically part of the standard diagnostic practice, mainly because of the difficulty of analyzing PKD1, which has high sequence homology with 6 pseudogenes. However, genetic testing is recommended on potential living liver/kidney donors, in very early onset cases (neonatal), especially due to the risk of recurrence in subsequent pregnancies, and in patients with atypical manifestation and negative family history. However, genetic testing remains useful in distinguishing some forms of PKD from disorders of the differential diagnosis.

Prevalence and/or incidence

ADPKD has an incidence of about 1: 1000, without differences either by sex or by geographical origin.

ARPKD is much rarer and has an incidence of 1: 10,000-1: 40,000, although it may be underestimated due to the difficulty in diagnosing the rare forms with onset in late childhood or adolescence.

Molecular genetics

ADPKD is caused by heterozygous mutations in the PKD1, PKD2, GANAB and DNAJB11 genes.

PKD1 is the most frequently mutated gene (approximately 78% of AD cases), and causes a more severe phenotype than that of PKD2, with earlier onset and earlier renal failure. Mutations are mainly sequence variants (missense, nonsense, frameshift, splicing), but large/deletions duplications are present in about 3% of cases.

Mutations in PKD2 account for about 15% of ADPKD patients and are predominantly sequence variations. Large deletions/duplications were described in about 3% of cases. The phenotype is usually less severe than that of PKD1, and more than 50% of patients still have normal kidney function after the age of 70.

Mutations in the GANAB and DNAJB11 genes have also recently been reported in ADPKD patients. In all of these cases, the mutations described are sequence variants. These genes are mutated in 0.3% and 0.1% of ADPKD cases, respectively. It is also important to underline that in about 7% of patients no mutation is identified, supporting the existence of other genes not yet known.

About 95% of ADPKD cases have an affected parent or family member, while only a small percentage is due to de novo mutations. The risk of transmission to offspring is 50%.

ARPKD is associated with bi-allelic mutations in the PKHD1 and DZIP1L genes. Mutations in PKHD1 are for about 73% sequence variations such as missense, nonsense, frameshift, splicing and in 1-2% of cases they are large deletions/duplications. DZIP1L has only recently been associated with ARPKD and no large deletions/duplications have been reported to date.

In the case of ARPKD, if two parents are healthy carriers, the reproductive risk is 25%.

Differential diagnosis

The differential diagnosis of ADPKD includes, in addition to the acquired form of the disease, those disorders that include the presence of renal cysts among the main signs. Among these we find:

Renal cysts and diabetes syndrome It is an autosomal dominant multisystem disorder due to heterozygous mutations in the HNF1B gene. It is characterized by heterogeneous cystic kidney disease and early-onset diabetes.

Polycystic liver disease It includes a heterogeneous group of diseases characterized by a predominantly hepatic phenotype, which occasionally can also be associated with the appearance of renal cysts. The genes associated with this condition are ALG8, GANAB, LRP5, PRKCSH, SEC63 and SEC61B.

Von Hippel Lindau disease It is an autosomal dominant disease caused by mutations in the VHL gene. It is characterized by uncontrolled growth of blood vessels in some parts of the body and increased susceptibility to tumors (including kidneys). Multiple kidney cysts and pancreatic cysts are also often present.

Autosomal dominant tubulointerstitial nephropathy It is a progressive disease characterized by the development of cysts in the deepest kidney region. The genes involved are UMOD, SEC61A1 and MUC1. Renal function worsens over time until it reaches chronic renal failure.

Tuberous sclerosis It is a multisystem disorder characterized by the formation of hamartomas in various organs including the brain, kidneys, heart, lungs and skin. Kidney cysts may be present. It is due to heterozygous mutations in the TSC1 and TSC2 genes.

The differential diagnosis of ARPKD includes, in addition to the dominant form of PKD, also all those syndromic and non-syndromic disorders, which have renal cysts among the signs. These include Bardet-Biedl syndrome, Meckel syndrome, Joubert syndrome, Senior-Loken syndrome, nephronophthisis and oro-facio-digital syndrome.

Recommended genetic strategy

The analysis of a Next generation sequencing including DNAJB11, DZIP1L, GANAB, HNF1B, LRP5, MUC1, PAX2, PKD1, PKD2, PKHD1, PRKCSH, SEC61A1, SEC63, TSC1, TSC2, UMOD and VHL genes is certainly the most suitable choice for pursuing genetic confirmation of polycystic kidney disease and its differential diagnosis. In the event of negative results, it is possible to test large deletions/duplications in the genes of the panel. Panel analysis can be performed successfully on the basis of whole exome or whole genome sequencing, which can pave the way for the identification of mutations in genes not yet associated with the disease. Solutions based on whole genome sequencing also allow for the screening of copy number variations (CNVs), i.e. large deletions and large duplications on the entire genome.

Panel testing recommended at Breda Genetics for this condition:

Pan29 – Polycystic kidney disease and differential diagnosis, extended (DNAJB11, DZIP1L, GANAB, HNF1B, LRP5, MUC1, PAX2, PKD1, PKD2, PKHD1, PRKCSH, SEC61A1, SEC63, TSC1, TSC2, UMOD, VHL)


OMIM Phenotypic series Polycystic kidney disease – PS173900

OMIM Phenotypic series Polycystic liver disease – PS174050

Oh YK, Park HC, Ryu H, Kim YC, Oh KH. Clinical and genetic characteristics of Korean autosomal dominant polycystic kidney disease patients. Korean J Intern Med. 2021 Jul;36(4):767-779. doi: 10.3904/kjim.2021.176. Epub 2021 Jul 1. PMID: 34237823

Wicher D, Obrycki Ł, Jankowska I. Autosomal Recessive Polycystic Kidney Disease-The Clinical Aspects and Diagnostic Challenges. J Pediatr Genet. 2021 Mar;10(1):1-8. doi: 10.1055/s-0040-1714701. Epub 2020 Jul 29. PMID: 33552631;

Saini AK, Saini R, Singh S. Autosomal dominant polycystic kidney disease and pioglitazone for its therapy: a comprehensive review with an emphasis on the molecular pathogenesis and pharmacological aspects. Mol Med. 2020 Dec 11;26(1):128. doi: 10.1186/s10020-020-00246-3. PMID: 33308138

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