Understanding Nephronophthisis : Causes, Symptoms and Diagnosis - Dr Anil Kumar BT

Nephronophthisis (NPHP) is an genetic cystic kidney disease. It is the most common monogenic cause of Chronic Kidney Disease in children or adolescents.

History

It was first described in in 1945 by Smith and Graham, they termed it Medullary cystic kidney disease and 6 years later in 1951 Fanconi et al described this disease as “familial juvenile nephronophthisis”.

The term “Nephronophthisis” is derived from a Greek word meaning “degeneration of the kidney” because there is decreasing function and size of the kidneys during disease course.

Nephronophthisis is found in populations worldwide. It occurs in an estimated 1 in 50,000 new-borns in Canada, 1 in 100,000 in Finland, and 1 in 922,000 in the United States. Its incidence in other populations is unknown. It is termed as a rare disease. However it is one of the most important causes of chronic kidney failure in childhood

Inheritance

This condition is inherited as autosomal recessive, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

At least 13 different genes NPHP 1-13 are identified. Among the known genes causing NPHP, a large deletion of NPHP1 is the most common, accounting for approximately one fifth of NPHP cases

Clinical Features

The patients affected typically present with symptoms of passing large volume of urine (polyurea), excessive fluid intake(polydipsia), and after several months to years they reach “end stage kidney disease” a condition necessitating either dialysis or kidney transplantation in order to survive.

About 85 percent of all cases of nephronophthisis are isolated, which means they occur without other signs and symptoms. Some people with nephronophthisis have additional features, so-called "extra-renal symptoms" which can include eye problems (Retinitis pigmentosa) causing blindness, Cardiac defects, liver problems, skeletal problems, polydactyly(multiple fingers), obesity and neurological defects

Nephronophthisis can occur as part of separate syndromes that affect other areas of the body; these are often referred to as nephronophthisis-associated ciliopathies.

like Bardet Biedel syndrome, Cogan syndrome, Senior-Lekon syndrome and Joubert syndrome.

Different Variants

There are three variants of the disease depending the time these patients reach end stage renal disease (ESRD)

1. Juvenile Nephronophthisis: ESRD around the thirteenth year of age.

2. Infantile Nephronophthisis: ESRD before the fourth year of age

3. Adolescent Nephronophthisis: ESRD around the nineteenth year of age

In juvenile NPHP, renal failure develops within the first three decades of life.In contrast, infantile NPHP, which is characterized by mutations in NPHP2/inversin, leads to renal failure between birth and age 3 yr.

Diagnosis

In order to establish a clinical diagnosis of NPHP, a detailed history, clinical examination, including looking for extrarenal associations (abnormal eye movements, retinopathy, ataxia, polydactyly, and cardiac malformations) is required.

We need to see if any other family members are affected with similar problems. Other useful tools for diagnosis are kidney Ultrasound and a kidney biopsy. The biopsy shows features of atrophic tubules, tubular fibrosis and corticomedullary cysts. Furthermore to confirm the diagnosis genetic studies are useful.

Management

There is no specific treatment for these patients. In the early phase of the disease we need to correct the electrolyte imbalances. In the later phase of the disease when they reach end stage renal disease Kidney transplantation is the option. However with a growing understanding of the pathophysiology of NPHP, the future is more hopeful.

In recent years various drugs including vasopressin receptor antagonists , mTOR inhibitors (mammalian target of rapamycin), triptolide and roscovitine (cyclin-dependent kinase inhibitor)have been shown to be effective in reducing renal cysts in animal models of NPHP

There is no risk of recurrence after kidney transplantation however extra-renal symptoms progress irrespective of kidney transplantation.

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