Nephronophthisis

Clinical characteristics.

The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recognized: infantile, juvenile, and adolescent/adult.

• Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia, and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years.
• Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size.
• Adolescent/adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype, inter- and intrafamilial variability in rate of progression to ESRD is considerable.

Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).

Diagnosis/testing.

Establishing the diagnosis of the NPH phenotype relies on presence of characteristic clinical findings and imaging findings on renal ultrasound examination. Establishing the genetic cause of the NPH phenotype is possible in approximately 30%-40% of individuals by identification of homozygous or compound heterozygous deletions of NPHP1 or biallelic pathogenic variants in one of the 19 known NPH-related genes.

Genetic counseling.

Isolated and syndromic nephronophthisis are both inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Once the NPH-related pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Management.

Treatment of manifestations: Note: Treatment discussed in this GeneReview is limited to management of the NPH phenotype and does not include management of other findings observed in syndromic NPH. Treatment (based on international clinical practice) includes correction of water and electrolyte imbalances; treatment of anemia, hypertension, and proteinuria if present; growth hormone treatment in children who meet criteria for treatment; dialysis or renal transplantation for ESRD.

Prevention of secondary complications: Annual influenza vaccination for those with CKD; other vaccinations (e.g., pneumococcal vaccine and hepatitis B) according to local practice guidelines; standard measures to prevent secondary cardiovascular complications.

Surveillance: Monitoring of the following is recommended at least annually (and more frequently as needed for individuals with advanced CKD or at increased risk for disease progression and for therapeutic decision making): blood pressure, growth parameters, and psychomotor development; renal function; liver function; urinalysis (for evidence of proteinuria); abdominal ultrasound examination (for progression of renal disease and possible involvement of the liver, bile duct, spleen, and pancreas); and evaluations for extrarenal manifestations of syndromic NPH that can appear with time, especially retinal dystrophy.

Agents/circumstances to avoid: Nephrotoxic agents including nonsteroidal anti-inflammatory drugs (NSAIDS), aminoglycosides, and radiocontrast studies. For those with liver involvement: hepatotoxic medications.

Evaluation of relatives at risk: Presymptomatic diagnosis helps identify those who would benefit from prompt initiation of treatment and surveillance.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with nephronophthisis, the following evaluations are recommended [Parisi et al 2007, Simms et al 2011, KDIGO 2013]:

• Detailed family history and physical examination including blood pressure, growth parameters, developmental assessment, and dysmorphology examination to evaluate for extrarenal manifestations (Table 3a)
• Tests to evaluate the kidneys:
  • Tests of renal function including serum creatinine concentration, estimated glomerular filtration rate (eGFR), urea or blood urea nitrogen (BUN), and electrolytes
  • Complete blood count (CBC) to evaluate for anemia
  • Tests to evaluate for the metabolic bone disease of chronic kidney disease (CKD) including serum calcium, phosphate, parathyroid hormone (PTH), and alkaline phosphatase activity
  • Urinalysis from first-morning void for specific gravity to test concentrating ability (if feasible), proteinuria
• Tests of liver function including serum concentrations of transaminases, albumin, bilirubin, and prothrombin time
• Abdominal ultrasound examination to evaluate renal findings consistent with nephronophthisis and to evaluate for additional anomalies in liver, bile duct, spleen, and/or pancreas (including situs inversus)
• Referral as needed for evaluation of extrarenal manifestations, including:
  • Ophthalmologic examination
  • Brain MRI
  • Skeletal radiographs
  • Assessment of psychomotor development and/or behavior
  • Neurologic assessment
  • Endocrine assessment
  • Cardiac ultrasound examination
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

This section discusses only the management of the phenotype of nephronophthisis. Management of other findings associated with syndromic NPH (Table 3a) are beyond the scope of this GeneReview.

Currently no cure for nephronophthisis exists. Treatment is aimed at slowing the progression of CKD and its complications, according to international clinical practice guidelines for chronic renal failure (Kidney Disease – Improving Global Outcomes [KDIGO] 2012 Clinical Practice Guideline (CPG) for Evaluation and Management of Chronic Kidney Disease [KDIGO 2013] (full text):

• Correction of water and electrolyte imbalances, especially during intercurrent illness
• Treatment of anemia, hypertension, and proteinuria if present. Preferred therapy may differ between adult and pediatric patients [KDIGO 2013].
• Growth hormone treatment for children who have severe growth retardation as a result of chronic renal insufficiency and meet criteria for treatment [Wilson et al 2003]
• Dialysis or renal transplantation when patients reach ESRD. Renal transplantation is the preferred treatment as disease does not recur in the transplanted kidney [Pistor et al 1985].

Prevention of Secondary Complications

Annual influenza vaccination is indicated for patients with CKD. Other vaccinations (e.g., pneumococcal vaccine and hepatitis B) should follow local practice guidelines [KDIGO 2013].

For measures to prevent secondary cardiovascular complications, see KDIGO Clinical Practice Guideline for Evaluation and Management of Chronic Kidney Disease [KDIGO 2013] (full text).

Surveillance

Evaluations are recommended at least annually. More frequent monitoring is recommended for individuals with advanced-stage CKD, individuals at higher risk of disease progression, or when assessment will affect therapeutic decision making [KDIGO 2013].

• Monitoring of blood pressure, growth parameters, and development
• Renal function including serum creatinine concentration and estimated glomerular filtration rate (eGFR), urea or BUN, electrolytes, CBC, CKD metabolic bone disease including serum calcium, phosphate, PTH, and alkaline phosphatase activity
• Liver function including serum concentrations of transaminases, albumin, bilirubin, and prothrombin time
• Urinalysis to monitor proteinuria
• Abdominal ultrasound examination to evaluate progression of renal disease and possible liver, bile duct, spleen, or pancreas anomalies
• Routine evaluations for extrarenal manifestations of syndromic NPH that can appear with time, especially ophthalmologic examination for visual acuity, visual field examination, and evidence of retinal dystrophy

Agents/Circumstances to Avoid

Nephrotoxic agents – e.g., nonsteroidal anti-inflammatory drugs (NSAIDS), aminoglycosides, and radiocontrast studies – should be avoided.

Individuals with liver function impairment should avoid hepatotoxic medication.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband with NPH in order to identify as early as possible those who would benefit from initiation of treatment and surveillance measures.

Evaluations can include:

• Molecular genetic testing if the NPH-related pathogenic variants in the family are known;
• Monitoring of renal function and blood pressure if the pathogenic variants in the family are not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

For reviews of management of CKD in pregnancy see Smyth et al [2013] and Piccoli et al [2015].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.