Nephronophthisis Type 1 (Deletion 2q13) [Medical Review]

Pathogenesis of nephronophthisis

The mechanism of urine production

Nephronophthisis (NPH) is often described as a representative disease in which cysts form in the renal medulla. So, what exactly is the function of the renal medulla in the kidney?

The kidney consists of the outer cortex, the inner medulla, and the innermost renal pelvis. The cortex contains many glomeruli that filter blood and produce urine, and the medulla contains tubules that reabsorb the primary urine produced in the glomeruli, which is then sent to the renal pelvis. It is said that 170 liters of primary urine is filtered by the glomerulus per day, but the concentration and volume of urine is adjusted by the renal tubules in the medulla reabsorbing water and electrolytes such as sodium into the capillaries, ultimately resulting in an amount of about 1-2 liters of urine being produced per day.

Impaired urine reabsorption in nephronophthisis

On the other hand, in kidneys with nephronophthisis, which I will explain in detail later, there is an abnormality in the NPHP gene, which plays an important role in the function of epithelial cells in the renal tubules, and reabsorption in the renal tubules is impaired by the formation of small cysts in the renal tubules and their atrophy. As a result, urine is not concentrated and polyuria occurs, and large amounts of sodium are excreted in the urine, causing a decrease in blood sodium and leading to hyponatremia and hyperkalemia.

Clinical manifestations of nephronophthisis

The main symptoms of nephronophthisis include polyuria as explained above, the associated polydipsia and enuresis (peeing oneself), and growth and development disorders associated with chronic renal failure.
Electrolyte abnormalities such as hyponatremia and hyperkalemia are observed due to impaired renal tubular resorption, but in the early stages, renal symptoms such as edema, hematuria, and proteinuria are not observed, and blood pressure is normal. As the atrophy of the renal tubules progresses, renal function declines, eventually leading to renal failure. It is only when the decline in renal function progresses that the amount of urine decreases, and sodium retention and the associated high blood pressure and anemia appear.

Since the responsible gene, NPHP , is present in other organs, including the brain and nerves, in addition to the kidneys, symptoms other than those of the kidneys may be observed in 10-20% of cases. Representative symptoms include retinitis pigmentosa (Senior-Loken syndrome), ocular ataxia (Cogan syndrome), cerebellar ataxia (Jourbert syndrome), liver fibrosis, skeletal and facial abnormalities, and mental retardation.

Clinical forms of nephronophthisis

Nephronophthisis is clinically classified into three disease types depending on the time it takes to develop end-stage renal failure. Type 1 develops during childhood to school age, progressing to end-stage renal failure at an average age of 13 to 14 years old, and is also called juvenile nephronophthisis. Type 2 is also called infantile nephronophthisis, and develops renal failure by the age of 3 to 5 years old. Type 3 develops end-stage renal failure at an average age of around 19 years old, and is called adolescent nephronophthisis. As we will discuss later, these three disease types are known to be caused by different gene mutations.

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The gene responsible for nephronophthisis type 1

Nephrocystin-1

The gene responsible for the onset of nephronophthisis is called NPHP , and to date, as many as 20 genes have been reported to be involved. The proteins encoded by these genes play an important role in the normal functioning of renal tubular epithelial cells, and in nephronophthisis, genetic mutations cause renal tubule dysfunction, which leads to poor urine reabsorption and symptoms centered on the kidneys.

Among these, nephronophthisis type 1 is caused by a mutation in the NPHP1 gene, which encodes a protein called nephrocystin-1 present in the primary cilia of renal tubular epithelial cells, and it has been reported that there are extensive gene deletions and point mutations. NPHP1 is present on chromosome 2q13 and is approximately 11,000 base pairs in length, and nephrocystin-1, which is translated and synthesized from the NPHP1 gene, consists of 677 amino acids.

Nephrocystin-1 is thought to be an important protein in adhesion and signal transmission between cells and between cells and the extracellular matrix. Abnormalities in this molecule cause major disruptions to cell adhesion, cilia function, and intracellular and extracellular signal transmission, which is thought to lead to structural and functional disorders of the renal tubular epithelium, such as cyst formation in the renal tubules and impaired urine reabsorption.

Other NPHP gene mutations

The responsible gene for nephronophthisis type 2 is NPHP2 , located on chromosome 9q31 , and is known to code for a protein called inversin. The responsible gene for nephronophthisis type 3 is NPHP3 , located on chromosome 3q22 , and codes for a protein called nephrocystin-3. Both proteins are thought to play important roles in renal tubular epithelial cells, just like nephrocystin-1 in nephronophthisis type 1, and gene mutations significantly reduce kidney function.

Recessive disorders

Nephronophthisis, including type 1, is known to be primarily a recessive genetic disease. In other words, parents (either affected or carriers) with a recessive gene with a mutation in the same part can have a child with two mutations. If both parents are carriers, there are cases where the child will develop the disease even if the parents are healthy.
In addition to recessive genetic diseases, sporadic cases due to mutations have also been reported, although this is rare.

Epidemiology of nephronophthisis

No detailed epidemiological surveys have been conducted in Japan regarding the incidence of nephronophthisis, but overseas, it has been reported that the incidence rate is about 1 in every tens to hundreds of thousands of people. The number of patients in Japan is said to be about 500 to 600. Nephronophthisis is also said to account for 5 to 10% of the causes of end-stage renal failure in children.
Of the three clinical disease types, nephronophthisis type 1, which is juvenile nephronophthisis, is the most frequent, and it has been reported that NPHP1 mutations are found in 20 to 40% of all nephronophthisis cases.

Diagnosis of Nephronophthisis Type 1

To diagnose nephronophthisis type 1, the disease is suspected based on symptoms and clinical findings, and a comprehensive diagnosis is made by combining histological and genetic tests. Recently, the research group “Establishment of diagnostic criteria and treatment guidelines for rare intractable diseases of the kidney and urinary system” has created diagnostic criteria for nephronophthisis.

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Clinical Findings

As mentioned before, this disease is suspected based on clinical symptoms and test results such as polydipsia, polyuria, decreased urine concentration ability, and decreased renal function in children. The frequency of low specific gravity urine (dilute urine) due to impaired renal tubular reabsorption is high, and when such findings are observed, nephronophthisis must be considered when proceeding with the diagnosis.
Detection of urinary protein is a commonly used test method for screening for kidney disorders, but proteinuria in nephronophthisis is mainly low molecular weight proteinuria such as β2-microgloblin, and is difficult to detect with test strip methods that mainly detect albumin, a large molecule, so it may be overlooked in mass screening including school checkups, so caution is required. In addition to low molecular weight proteins, urinary glucose may also be observed. According to the diagnostic criteria, low specific gravity urine and low molecular weight proteinuria are necessary findings for a definitive diagnosis.
Other characteristic findings in ultrasound examinations include increased kidney brightness, disappearance of the border between the cortex and medulla, and small cysts in the renal parenchyma.

Kidney Tissue Findings

Kidney tissue is mainly collected by renal biopsy, which is performed using a needle outside the body. Therefore, it is a more invasive test than urine tests or ultrasound tests. The
histological characteristic of nephronophthisis is the presence of numerous cysts at the boundary between the cortex and medulla. As the disease progresses, atrophy of the renal tubules and thickening and atrophy of the tubular basement membrane are also observed, and in the terminal stage, fibrosis around the glomerulus and sclerotic glomeruli appear. The diagnostic criteria require cystic dilation of the renal tubules and irregular changes in the tubular basement membrane for a definitive diagnosis.

Genetic Testing

As mentioned above, the diagnosis of nephronophthisis can be narrowed down to a certain extent based on clinical symptoms and histological findings, and the identification rate of gene mutations in nephronophthisis is not very high at about 30%, so it is not an essential test for diagnosis. However, if mutations can be identified by genetic testing, there are advantages such as being able to diagnose the disease without invasive renal biopsy and being able to identify complications characteristic of mutated genes early.
Considering the age at which end-stage renal failure is reached, gene mutations in NPHP1 (the gene responsible for juvenile nephronophthisis) or NPHP2 (the gene responsible for infantile nephronophthisis) are searched for. If mutations in these genes are not found, other NPHP gene mutations will be searched for , referring to the presence or absence of non-renal symptoms such as retinal pigmentary lesions (common in NPHP5 and NPHP6 mutations) .

In recent years, whole-exome analysis, a method for comprehensively analyzing the exon sequences of the entire genome that are translated into proteins, has become available, and the number of reports of responsible gene mutations has increased, with reports indicating that more than 60% of genetic abnormalities can be detected.

Treatment of Nephronophthisis Type 1

Unfortunately, there is currently no established cure for nephronophthisis, including type 1. Symptomatic treatments such as dietary therapy, ion adsorption resin, and administration of bicarbonate are used to treat hyponatremia, hyperkalemia, and metabolic acidosis caused by impaired renal tubular resorption. If the disease progresses to end-stage renal failure, treatments such as artificial dialysis are used, and ultimately kidney transplantation may be selected. Growth hormone therapy is also indicated for cases of short stature caused by renal failure. In addition to treatment of
the disease, it is also important to consider the psychological burden on the family and the impact on relatives in hereditary diseases such as this disease, so it is also important to provide psychological and social support to the patient and their family through genetic counseling and counseling.

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Future challenges

As mentioned before, nephronophthisis rarely shows abnormal findings in urine in the early stages of onset, and is often overlooked in mass screening tests such as school urinalysis. Therefore, by the time proteinuria is detected, patients often already have end-stage renal failure, and the development of a screening method for early detection is awaited.
Recently, a Japanese research group reported that human iPS cells were established from a nephronophthisis type 1 patient with a deletion mutation in the NPHP1 gene. It is expected that pathological iPS cells will be useful in further elucidating the pathogenesis of nephronophthisis type 1 and developing a fundamental treatment method.

Nephronophthisis and Hiro Clinic NIPT (New Prenatal Test)

Nephronophthisis cannot be detected by testing for chromosomal aneuploidies such as Down syndrome (trisomy 21) . Hiro Clinic NIPT also performs full-region chromosomal testing to check for partial deletions and duplications of all autosomal regions, including nephronophthisis.

Knowing the condition before birth allows families to prepare for their baby. We recommend that you also consider full-region chromosome testing, which can test for all autosomal partial deletions and duplications.