Nephronophthisis (NPHP) is a rare genetic kidney disease that affects children and young adults. It is a form of medullary cystic kidney disease and the most frequent genetic cause of kidney failure in this demographic. The condition is a ciliopathy, stemming from the improper function of cilia—microscopic, antenna-like structures on cell surfaces involved in signaling. The disease leads to end-stage renal disease, and its name, derived from Greek, means “wasting of the nephrons,” describing the gradual scarring and deterioration of the kidney’s filtering units.
Genetic Origins and Inheritance
Nephronophthisis is a monogenic disorder caused by mutations in specific genes, called NPHP genes. Scientists have identified more than 20 different genes whose mutations can cause this condition. These genes provide instructions for making proteins, known as nephrocystins, which are found in the primary cilia of kidney cells. A defect in these genes disrupts the normal function of cilia, which play a part in kidney development and tissue maintenance.
The condition is almost always inherited in an autosomal recessive pattern. This means an individual must inherit two mutated copies of an NPHP gene—one from each parent—to develop the disease. The parents, who each carry only one copy of the mutated gene, are known as carriers. They do not show any signs or symptoms of the condition themselves because their single normal copy of the gene is sufficient for proper function. When both parents are carriers, there is a 25% chance with each pregnancy that the child will inherit both mutated genes and develop NPHP.
Recognizing the Symptoms
Initial symptoms of nephronophthisis are often subtle, beginning around age six. One of the earliest and most common signs is a defect in the kidney’s ability to concentrate urine. This leads to polyuria, the production of an unusually large volume of urine, and polydipsia, which is excessive thirst to compensate for the fluid loss. This can also manifest as secondary enuresis, or bed-wetting, in school-aged children.
As kidney function declines, other symptoms emerge. Anemia, or a low red blood cell count, is common and contributes to feelings of fatigue and general weakness. Poor growth is another frequent finding in children with NPHP. Unlike many other kidney diseases, high blood pressure is absent in the early stages due to the body’s tendency to lose salt.
In about 10-20% of cases, NPHP is accompanied by symptoms outside of the kidneys, known as extrarenal manifestations. The most frequent of these involves retinal degeneration, which can lead to vision loss and, in some cases, blindness. When NPHP occurs with severe retinal disease, it is known as Senior-Løken syndrome. Other less common extrarenal findings can include liver fibrosis, skeletal abnormalities, and developmental issues with the brain, such as those seen in Joubert syndrome.
The Diagnostic Process
Diagnosing nephronophthisis involves a combination of clinical evaluation, laboratory tests, and imaging studies. Blood tests are used to assess kidney function by measuring levels of waste products like creatinine and calculating the glomerular filtration rate, which indicates how well the kidneys are filtering blood. Urine tests are also performed to check for a bland urinalysis, meaning the absence of significant protein or blood, and to confirm the urine is not properly concentrated.
A renal ultrasound is the primary imaging tool used. In the early stages of NPHP, the kidneys may appear normal in size or slightly small, but they will show increased echogenicity, which means they appear brighter on the ultrasound. A characteristic is the loss of clear distinction between the kidney’s outer layer (cortex) and inner part (medulla). Small cysts may be visible at this corticomedullary junction in many, but not all, patients.
The definitive diagnosis is made through molecular genetic testing. This testing analyzes an individual’s DNA to identify mutations in the known NPHP genes. Confirming a specific genetic mutation establishes the diagnosis without the need for an invasive kidney biopsy and allows for genetic counseling for the family. A biopsy, if performed, would show tubulointerstitial fibrosis (scarring), tubular atrophy, and the characteristic cysts.
Managing Kidney Function
There is no cure for nephronophthisis, so treatment is supportive and focuses on managing symptoms and slowing the decline in kidney function. This supportive care is tailored to each individual and includes strategies to maintain the body’s fluid and electrolyte balance, which is often disrupted by the kidneys’ inability to conserve water and salt. Anemia is managed with iron supplements or erythropoietin-stimulating agents, which are hormones that encourage the production of red blood cells. Nutritional support and growth hormone therapy may also be used for children experiencing growth delays.
Eventually, renal replacement therapy becomes necessary. The two main options for this are dialysis and kidney transplantation. Dialysis is a procedure that artificially filters waste products from the blood, and it can be done through hemodialysis or peritoneal dialysis. A kidney transplant is considered the best long-term treatment for the kidney failure caused by NPHP.
A transplant can come from either a living or deceased donor and effectively resolves the renal aspects of the disease. Post-transplant outcomes for patients with NPHP are excellent, and the disease does not recur in the new kidney. While a transplant addresses the kidney failure, it does not cure any of the extrarenal manifestations, such as retinal degeneration, which will continue to require separate management.