Arpkd Q61.1

In 1934 Marquardt differentiated for the first time between 2 different modes of inheritance in renal cysts. A comprehensive monograph on clinic and genetics was published by Dalgaard in 1957.

In 1971, Blyth and Ockenden comprehensively described the clinical variability of autosomal recessive in form until adolescence (Ganten 2013).

Caroli syndrome (and Caroli disease) were first described by Caroli in 1958 and subsequently named after him (Krombach 2015).

Autosomal recessive polycystic nephropathy (ARPKD) is a disease of the kidneys in which cystic dilatation of the collecting tubes occurs.

ARPKD is always bilateral and is always combined with congenital hepatic fibrosis, in which cysts and possibly portal hypertension may develop (Risler 2008).

Liver involvement is more severe the later the disease becomes symptomatic (Manski 2019).

According to Potter, the cystic kidney diseases were divided into (Michels 2010):

• Type I: infantile polycystic kidney disease
• Type II: congenital renal dysplasia
• Type III: adult polycystic kidney disease
• Type IV: congenital polycystic dysplasia

This historical classification is now no longer in use (Manski 2019).

Nowadays, cystic nephropathies are differentiated between:

• Dysplastic kidney disease
• Cystic kidney disease with classical inheritance (which includes ARPKD).

ARPKD is additionally differentiated between various forms of progression, which are age-dependent (Hofmann 2005):

• neonatal form
• infantile form
• juvenile form
• adult form

The incidence is 1: 20,000 live births (Herold 2021), the carrier frequency is 1: 70 (Kasper 2015). There is no gender preference.

ARPKD is an autosomal recessive disease in which a mutation of the PKHD1 gene occurs in chromosome 6 (Hegele 2015) with varying degrees of multiple allelicity (Ganten 2013).

The mutation leads to a defect in the protein fibrocystin, which plays a role both in tubulogenesis and in maintaining the architecture of the lumen in the area of the collecting tube (Hegele 2015).

Should the disease already result in reduced urine production prenatally, lung hypoplasia will develop as a result (Kasper 2015).

ARPKD usually manifests in the perinatal period or early childhood, less commonly in adolescence or adulthood (Kuhlmann 2015).

In ARPKD, both kidneys and liver are affected and sometimes also the lungs.

Kidneys: The formation of cysts is always bilateral and primarily originates from the collecting tubes (Haumann 2018).

At the beginning of the disease, the kidneys are conspicuously large due to minute cysts, but macroscopically no cysts are visible. The size of the kidneys decreases in relative and absolute terms during the course of the disease due to the progression of renal insufficiency. This causes atrophy of the renal tubules and inhibits the formation of new cysts (Hofmann 2005).

Liver: Liver fibrosis increases during childhood and adolescence and may lead to portal hypertension with possibly life-threatening esophageal variceal hemorrhage (Hofmann 2005).

Lung: pulmonary hypoplasia (Kasper 2015).

Failure to thrive: These occur in particular due to respiratory exhaustion, uremic nausea and / or hepatic gastropathy due to portal hypertension (Haumann 2018).

Arterial hypertension: In 80% of children, arterial hypertension is already present in the early months of life, and hyponatremia is also frequently detectable (Haumann 2018).

In classical ARPKD, the diagnosis is often already made in utero, since an oligohydramnios occurs due to a reduction in fetal urine production (Kasper 2015).

A liver biopsy should only be performed in unclear cases. It is not necessary for the diagnosis (Manski 2019).

Sonography

Kidneys: In ARPKD - in contrast to ADPKD - no cysts are visible macroscopically, the kidneys can rather be depicted symmetrically, but enlarged (Ganten 2013).

Otherwise, the parenchymal echo structure is heterogeneous, also known as the "pepper and salt pattern". This is caused by the multiple tiny cysts.

Sometimes sonographically normal sized kidneys with hyperechogenicity are found in the area of the medulla or the cysts appear as macrophages of different number, localization and size (Kemper 2020).

Neonatally, there is often exclusively hepatic fibrosis with no apparent renal involvement.

Liver: The liver is obligatorily altered in ARPKD, even if it is sometimes (still) unremarkable sonographically.

Typical changes are:

• increased liver echogenicity
• rounded liver contour
• caliber increase of the V. portae
• periportal fibrosis
• portal bypass collaterals
• tortuosity of the splenic vein
• dilated cystic intrahepatic bile ducts

In some cases fibrotic changes of the liver are evident, in other patients dilated bile ducts are detectable (Kemper 2020). The latter is also known as the "Caroli syndrome". In this case, cystic changes of the bile ducts are found around the V. portae centrally emphasized, extending into the periphery, which is also called "intraluminal portal vein" (Hofmann 2005). Particular attention should be paid to indications of portal hypertension, as this has been underdiagnosed overall to date (Kemper 2020).

Transaminases: The transaminases are usually inconspicuous or only changed very late in the course of the disease, as the hepatocellular function remains intact (Haumann 2018).

Sodium: Hyponatremia often already exists in the neonatal period (Kemper 2020).

Inflammatory signs: Laboratory chemical evidence of inflammation may indicate cholangitis (Kemper 2020).

Kidney: The kidneys are classically interspersed with microcysts < 3 mm in diameter below the renal capsule. A flattened epithelium is found in the area of the collecting tubes.

In older patients these cysts may reach a maximum size of 1 cm. In addition, signs of interstitial fibrosis are found (Risler 2008).

Liver: The portal fields are histologically enlarged due to periportal fibrosis and proliferation of bile ducts. The hepatocytes are unremarkable (Risler 2008).

• ADPKD (Haumann 2018).

• Hyponatremia in the neonatal period (Kemper 2020)
• recurrent cholangitis in Caroli syndrome (Hofmann 2005)
• portal hypertension (Kemper 2020)
• Esophageal varices in 15%-37% (about 33% experience variceal hemorrhage [Haumann 2018])

There is no specific treatment (Kasper 2015).

Respiratory insufficiency: In the first days of life, the treatment of respiratory insufficiency is the first priority (Manski 2019).

Hyponatremia: Hyponatremia, which is particularly prevalent neonatally, should be treated primarily with water restriction rather than sodium supplementation (Kemper 2020).

Arterial hypertension, hepatic and renal insufficiency can only be treated symptomatically (Manski 2019).

Terminal renalfailure: If terminal renal failure occurs, renal replacement therapy or renal transplantation is required (Manski 2019).

Portalhypertension: If portal hypertension occurs, a splenorenal shunt is useful. However, sometimes transplantation becomes necessary (Manski 2019).

Gastrostomy: In order to optimally promote age-appropriate growth, the early creation of a gastrostomy is sometimes unavoidable (Haumann 2018).

Nephrectomy: There are individual case reports in which neonates underwent nephrectomy due to massively enlarged kidneys in order to improve the nutritional situation, ventilation and arterial hypertension (Kemper 2020).

Recurrent cholangitis: In recurrent cholangitis with unilateral involvement, hemihepatectomy may be indicated (Hofmann 2005).

Transplantation: Both renal insufficiency and liver involvement may require transplantation (Kemper 2020).

In ARPKD, 50 % die in the neonatal period due to respiratory complications. Causes of death are predominantly respiratory distress syndrome or pulmonary hypoplasia (Herold 2021). The earlier the disease manifests, the more pronounced are renal involvement, respiratory insufficiency and the worse is the life expectancy.

If the onset of the disease is immediately postpartum, a lethal course within months due to respiratory insufficiency and renal failure is found in up to 30 % - 50 %.

If disease onset occurs after 6 months of age, terminal renal failure and portal hypertension occur in childhood or sometimes as a young adult (Manski 2019).

In the 1st study of long-term outcomes of ARPKD by Bergmann (2005) showed:

• Initiation of dialysis / kidney transplant / death from kidney disease 86 % after 5 years.
• 75 % developed systemic hypertension
• 44 % developed consequences of congenital liver fibrosis and portal hypertension

The diagnosis of ARPKD can be made in utero in severe cases as early as after the 24th week of gestation (Kasper 2015).

If there is a prenatal suspicion of ARPKD, the pregnant woman should be offered prompt interdisciplinary counselling (consisting of a prenatal physician, neonatologist, paediatric nephrologist, human geneticist) (Kemper 2020).

It is recommended that affected children present to a gastroenterologist at least 1 x per year for evaluation of the hepatocholangiopathic phenotype (Kemper 2020).

Siblings have a 25% risk of also developing the disease (Manski 2019).

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