Nephronophthisis

In 1951 Fanconi et al. described the term nephronophthisis (NPH / NPHP) for the first time, which literally means "shrinkage of the kidney" (from the Greek "Phthisis" [Keller 2010]) (Schärer 2002 / Titieni 2018). With the further development of molecular genetics, Antignac et al. were the first to describe the gene locus on chromosome 2q in 1993, see NPHP gene below (Schärer 2002).

The term "nephronophthisis" refers to a group of genetic tubulointerstitial nephropathies (renal ciliopathy), including Senior Loken syndrome and Joubert syndrome (Herold 2020). NPH belongs to the bilateral microcystic kidney diseases (Speer 2009) and can hardly be distinguished clinically-pathologically from ADTKD (Zalewski 2005).

NPH is divided into 3 clinical subtypes, which are characterized by the age of onset of ESRD:

• infantile
• juveniler
• adolescent (Herold 2020)

NPH is - all in all - very rare. In Europe, however, it is more common than in the USA, where one in seven vs. one in 42 children is required to undergo dialysis for this reason.

There is no gender specificity (Keller 2010).

In about 20 % of children and adolescents with chronic renal insufficiency - the cause of which is still unclear - an NPH is found to be the cause (Kuhlmann 2015).

NPH is a genetic disease with autosomal recessive inheritance. So far, at least 7 genes are known to cause NPH.

The most common is a deletion of the NPHP1 gene on chromosome 2q12-q13, which is called "juvenile form" (Herold 2020).

In the infantile form there is a mutation in the NPHP2 gene. (Kasper 2015)

Pathophysiologically it is a dysfunction of the primary cilia. These represent the sensors of the urinary flow. Defects of the primary cilia lead to polycystic changes of the kidney (Titieni 2018 / Welsch 2018).

NPH leads to terminal renal failure at the end of the 2nd decade of life (Keller 2010), the infantile form already in infancy (Kasper 2015).

NPH can occur in isolation, but in about 10 % - 15 % there are other organ manifestations, the most common of which are localized in the area of the CNS and eyes (Herold 2020). As a multi-organ syndrome can occur, for example:

• neurological disorders
• Bone alterations
• Liver changes
• Retinitis pigmentosa (then referred to as the so-called Senior-Loken syndrome)
• multiple neurological findings (then called Joubert syndrome) such as
  • Hypoplasia of the cerebellar worm (Kasper 2015)

The renal phenotype NPH can also be part of various syndromal clinical pictures, which are summarized under the term "NPH- related ciliopathies = NPH- RC" (Titieni 2018).

Already in the 1st year of life the children can sometimes become conspicuous by e.g.:

• Growth inhibition
• Polyuria (basement 2015)

In the further course of time, the following may occur:

• Polydipsia
• arterial hypertension (especially at the beginning due to the tubulointerstitial remodelling processes)
• arterial hypotension (is found in the further course due to renal salt losses) (Kuhlmann 2015)
• Osteopathy

The symptoms are often only discrete. In about 15 % of those affected, the diagnosis can only be made at the stage of terminal renal failure (Schärer 2002).

The diagnosis is made by family history, physical, apparatus and laboratory chemical examinations (Kuhlmann 2015). The so-called renal concentration test is only performed in cases of doubt (Schärer 2002).

Sonographically, the kidneys appear predominantly small and with poor differentiation between medulla and cortex (Schuster 1996).

The typical medullary cysts at the marrow-bark border are found in about 75% of the patients. They can theoretically be visualized by ultrasound, CT or MRT (Keller 2010).

However, since the cysts are very small, sonographic imaging is often not successful. The highest detection of cysts is found in the MRI (Kuhlmann 2015).

In the 1st year of life the sediment is usually still largely inconspicuous.

With increasing functional impairment, a slight proteinuria can occur in the further course of the disease (Kasper 2015) and a strongly reduced osmolality of the morning urine can exist (Schärer 2002).

If the salt supply is insufficient, laboratory chemical reactions will result in a:

• hyponatremia
• Hypovolemia (Keller 2015)

Genetic diagnosis is possible, but is difficult because of the multiple genes that may be responsible for NPH (Kasper 2015). Even today, approximately 40% of NPH patients remain genetically unclarified (Titieni 2018).

In children with chronic renal insufficiency and concomitant blank urinalysis, differential diagnosis should consider the following diseases:

• chronic pyelonephritis
• obstructive uropathy
• polycystic kidney disease (Keller 2010)

Further differential diagnoses can be e.g.:

• diabetes insipidus centralis
• Diabetes insipidus renalis
• renal hypoplasia
• urogenital malformations
• glomerulocystic kidney disease (Schärer 2002)

A causal therapy is not known. The increasing renal insufficiency ultimately makes renal replacement treatment or a kidney transplant necessary (Herold 2020).

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