Description of the evidence collection method

The literature review of scientific articles in this guideline was held in the databases Medline, Cochrane and SciELO. The search for evidence came from actual clinical scenarios and used keywords (MeSH terms) grouped in the following syntax: adult dominant polycystic kidney disease; adult recessive polycystic kidney disease; PKD mutation; PKDH1 mutation; renal cystic disease; polycystin; renal ultrassonography; renal transplantation; fibrocystin; congenital hepatic fibrosis; biliary dysgenesis; liver cystic disease; end-stage renal disease; linkage analysis.

Degree of recommendation and strength of evidence

A: Experimental or observational studies of higher consistency.

B: Experimental or observational studies of lower consistency.

C: Case reports (non-controlled studies).

D: Opinions without critical evaluation, based on consensus, physiological studies, or animal models.

Objectives: to present the main scientific information linked to acquired clinical experience and related to diagnosis and genetic counseling in polycystic kidney disease (hereditary).

Introduction

The hereditary polycystic kidney disease is defined as autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (Adpkd). These two diseases must be distinguished from other hereditary or non-hereditary conditions presenting renal cysts. The hereditary polycystic kidney disease is important because it is relatively common. Adpkd is one of the most common monogenic diseases, with an incidence of 1 in 700 individuals and accounts for 5% of patients requiring hemodialysis or kidney transplantation (B).² AR-PKD is rarer, with an incidence of 1 in 20,000 individuals (B).²

In prenatal and neonatal context, ultrasonography is sufficient to confirm the clinical diagnosis of arpkd in a patient?

In ARPKD, renal ultrasound abnormalities are detectable from the 20^(th) week of pregnancy, or perhaps from the 13^(th) week of pregnancy when there is an established diagnosis in an affected sibling. However, this applies to 40% of the affected patients that have a more severe form of the disease. In this subgroup, the ultrasound reveals en larged bilateral hyperechogenic kidneys, with or without cysts associated with oligohydramnios (B).²

Before focusing on this nephropathy, renal tract abnormalities (obstructive cystic dysplasia and multicystic dysplastic kidney) should be excluded. Other hereditary nephropathies (e.g., Bardet-Biedl syndrome) leading to this clinical picture are associated with other anomalies, which set them apart (C).³ The most important differential diagnosis is an early presentation of Adpkd. For this reason, it is essential that both parents undergo renal ultrasounds to diagnose the disease. A pregnant woman with fetus affected by Adpkd usually has a normal amniotic fluid volume. Patients in this subgroup (40%) develop Potter sequence and die of respiratory failure shortly after birth. Other patients affected with milder ARPKD (60%) do not show conclusive ultrasound signs and can survive for more than three decades.

In prenatal and neonatal context, if the result of the ultrasound is inconclusive, does histopathology allow to reach a definitive conclusion?

Pathological examinations performed during autopsy in patients affected with severe nephropathy (subgroup of 40%) confirmed the diagnosis of ARPKD (C) (D).^4,5Dilation and hyperplasia of collecting duct are observed, which may appear cystic, without involvement of the nephron.

ARPKD invariably occurs with biliary dysgenesis (B) (D).^5,6 The intrahepatic bile ducts dilate and increase in number with subsequent development of periportal fibrosis. This clinical picture, called congenital hepatic fibrosis, is essential for the diagnosis of ARPKD, even though it is not a pathognomonic sign. Portal hypertension is a common sequel, which evidence can be obtained through ultrasonography.

In patients affected with milder ARPKD (the subgroup of 60%), the clinical course is variable and signs of portal hypertension may prevail. Liver biopsy should therefore be considered in these cases (C).^7,8

In the context of a young adult, the ultrasound examination is sufficient to confirm the clinical diagnosis of arpkd in a patient?

Patients affected with ARPKD who survive to (and throughout) adolescence tend to develop primarily liver and biliary impairment with less renal involvement. Hepatosplenomegaly, portal hypertension and Caroli disease, in the presence of systemic hypertension and renal failure, serve to confirm the diagnosis (C).⁹ In these cases, the kidney may be reduced in size (C).¹⁰

In the context of an adult, if the result of the ultrasound examination is inconclusive, does the molecular test allow to reach a definitive conclusion?

Molecular tests can be direct (such as gene sequencing PKHD1) or indirect, using linkage analysis (C),¹¹ which depends on the possibility of analyzing a minimum number of family members known to be affected and unaffected - which is not always feasible. Direct molecular genetic tests cannot detect all mutations causing ARPKD, so that the detection rate is around 80% or less when the disease is milder (C).^12,13 Occasionally, the patient may inherit two low penetrance mutations (hypomorphic) in both copies of the PKD1 (or PKD2) gene, thus showing a phenotype that is very similar to neonatal ARPKD, which makes the molecular test even more necessary (C).¹⁴

What is the role of molecular testing for genetic counseling of a couple or a family transmitting arpkd?

Molecular tests are the only ones able to provide predictive information about ARPKD in individuals before the clinical signs and symptoms develop. In some families, the disease has a different progression among affected siblings and molecular test can determine if a brother with mild signs is affected or not (C).^8,15 Since a high percentage of individuals affected with ARPKD survive until (and throughout) adolescence, molecular tests allow to identify them prior to onset of symptoms. In these individuals, the verification of the effects of hypertension and portal hypertension enables treatment, prolonging life (C).¹⁶

Is ultrasound examination used to confirm the clinical Diagnosis of adpkd?

There are consensual criteria for establishing the diagnosis in patients suspected of Adpkd. The greatest difficulty is to make the diagnosis in patients younger than 30 years and without a family history of the disease, since the formation of renal cysts depends on the age, and the disease may be caused by new mutations in up to 15% of cases (C).¹⁷

In patients suspected of Adpkd, the presence of renal cysts on ultrasonography allows the diagnosis, depending on the age (B), of:(¹⁸,¹⁹)

The criteria are different when the goal is to exclude potential kidney donors, in transplants, as described below.

Does magnetic resonance imaging add information to the ultrasound examination to improve the clinical diagnosis of a patient with adpkd?

When the result of the ultrasound is inconclusive, MRI, being more sensitive, can provide additional information. However, MRI also detects small simple cysts (without consequence), which have their number and size increase with age, and its role in this context has not been formally evaluated (C).²⁰

Which ultrasound and MRI test results indicate subsequent use of molecular tests to indicate adpkd?

Individuals under 30 years old and at risk of being affected with Adpkd, with less than 3 renal cysts on ultrasound, can be carriers of a mutated gene. Furthermore, up to 15% of affected individuals have no family history of the disease, and may or may not show abnormalities on imaging studies (C).¹⁷ Mutations in the PKD1 gene cause a more severe disease with early development of renal failure and less survival than mutations in the PKD2 gene (mean age 53 years for PKD1 versus 69.1 for PKD2 versus 78 years for controls) (B).²¹ However, the molecular tests are capable of identifying close to 85% of all disease-causing mutations (in both genes, PKD1 [85% of cases] and PKD2 [15% of cases]), and several molecular variants found are still difficult to categorize as pathogenic or nonpathogenic (B) (C).^22-24

What are the advantages and disadvantages of indirect approaches (linkage analysis) versus direct approaches in molecular testing for adpkd?

Genetic linkage analysis with polymorphic markers within and/or near genes and which define haplotypes, complements the direct tests, and gene sequencing is the most direct of them (C).²⁴ The haplotype analysis is quick, simple and low cost, but depends on the possibility of analyzing a minimum number of relatives knowingly affected and unaffected within a family, which is not always possible.

Even so, occasionally, the markers are not sufficiently informative in some families. Direct studies can be made in a single patient, but are costly, time consuming and expensive, and not always provide definitive information (D).²⁶ Few centers are able to conduct the full direct studies.

What is the role of molecular testing for genetic counseling of a couple or a family transmitting adpkd?

Molecular tests are the only ones able to provide predictive information about Adpkd in individuals before the clinical signs and symptoms develop. In some families, the disease develops differently among affected siblings and molecular tests can define whether a sibling with different signs is affected or not (B) (C).^27,28 The type and position of mutations in the genes provide information on disease prognosis (C).^28-30 The characteristics of the clinical course of the disease in the family allow to predict which of the genes, PKD1 or PKD2, is probably the cause of the disease (C).³¹ Gene rearrangements make up around 4% of the molecular lesions, which, together with the occurrence of mosaicism, complicates the molecular analysis (B) (C).^32,33

Does a close relative of an affected patient with adpkd (who is clinically normal and a candidate for kidney donation) have to perform molecular examination in a pretransplant context?

For donors under 30 years of age, imaging studies are not adequate to exclude the presence of disease, and the same applies if these tests are inconclusive; in these cases, molecular tests are indicated (B).¹⁹ If the donor is part of a family well studied in relation to Adpkd, linkage studies are likely to be sufficient to conclude whether he or she has PKD1 or PKD2 mutated. Otherwise, direct studies will be needed, with exceptions already presented.