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Nephronophthisis and Medullary Cystic Kidney Disease Complex

(Autosomal Dominant Tubulointerstitial Kidney Disease [ADTKD])

By Navin Jaipaul, MD, MHS

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Nephronophthisis and medullary cystic kidney disease are inherited disorders that cause cysts restricted to the renal medulla or corticomedullary border and, eventually, end-stage renal disease.

Nephronophthisis and medullary cystic kidney disease are grouped together because they share many features. Pathologically, they cause cysts restricted to the renal medulla or corticomedullary border, as well as a triad of tubular atrophy, tubular basement membrane disintegration, and interstitial fibrosis. They probably share similar mechanisms, although these are not well characterized. Features of both disorders include the following:

  • A vasopressin (ADH)-resistant urine-concentrating defect that leads to polyuria and polydipsia

  • Na wasting severe enough to require supplementation

  • Anemia

  • A tendency toward mild proteinuria and a benign urinary sediment

  • Eventually, end-stage renal disease (ESRD)

Key differences between nephronophthisis and medullary cystic kidney disease include inheritance patterns and age at onset of chronic kidney disease.


Inheritance is autosomal recessive. Nephronophthisis accounts for up to 15% of chronic kidney disease with renal failure in children and young adults (< 20 yr). There are 3 types:

  • Infantile, median age at onset 1 yr

  • Juvenile, median age at onset 13 yr

  • Adolescent, median age at onset 19 yr

Nine gene mutations have been identified in patients with nephronophthisis. Mutations of the NPHP1 gene are the most common, identified in about 30 to 60% of patients. About 10% of patients with nephronophthisis also have other manifestations, including retinitis pigmentosa, hepatic fibrosis, intellectual disability, and other neurologic abnormalities.

ESRD often develops during childhood and causes growth restriction and bone disease. However, in many patients, these problems develop slowly over years and are so well compensated for that they are not recognized as abnormal until significant uremic symptoms appear. Hypertension sometimes develops.


  • Imaging, genetic testing, or both

The diagnosis should be suspected in children with the following, particularly if the urinary sediment is benign:

  • Polydipsia and polyuria

  • Progressively decreasing renal function, particularly without hypertension

  • Associated extrarenal findings

  • Anemia out of proportion to the degree of renal failure

Proteinuria is usually absent. Diagnosis is confirmed by imaging, but cysts often occur only late in disease. Ultrasonography, CT, or MRI may show smooth renal outlines with normal-sized or small kidneys, loss of corticomedullary differentiation, and multiple cysts at the corticomedullary junction. Hydronephrosis is typically absent. Genetic testing is available.


  • Supportive care

In early disease, treatment involves management of hypertension, electrolyte and acid-base disorders, and anemia. Children with growth restriction may respond to nutritional supplements and growth hormone therapy. Ultimately, all patients develop renal failure and require dialysis or transplantation.

Medullary cystic kidney disease

Inheritance is autosomal dominant. The disease affects people in their 30s through 70s. There are 2 types, which differ by median age at onset and by genetic mutation:

  • Type 1: Median age at onset is 62 yr. Localized to chromosome 1.

  • Type 2 (familial juvenile hyperuricemic nephropathy): Median age at onset is 32 yr. Localized to the uromodulin gene on chromosome 16

About 15% of patients have no family history, suggesting a sporadic new mutation. Hypertension is common. Hyperuricemia and gout are the only extrarenal manifestations; they tend to develop early in type 2 and late in type 1. ESRD typically develops at age 30 to 50.

Medullary cystic kidney disease should be suspected in patients with the following, particularly if the urinary sediment is benign:

  • Polydipsia and polyuria

  • Gout at a young age

  • Family history of gout and chronic kidney disease

Mild proteinuria is possible. Results of imaging studies have many similarities to that of nephronophthisis; however, renal medullary cysts are only sometimes visible. Genetic testing can confirm the diagnosis of type 2. Kidney biopsy may be necessary for diagnosis of type 1.

Treatment is generally similar to that of nephronophthisis. Allopurinol can help control gout.

Key Points

  • Nephronophthisis and medullary cystic kidney disease cause inability to concentrate urine (with polydipsia and polyuria), Na wasting, anemia, and ESRD.

  • Nephronophthisis is autosomal recessive and causes ESRD during childhood, whereas medullary cystic kidney disease is autosomal dominant and causes ESRD at age 30 to 50.

  • Obtain renal imaging and, when available, genetic testing.

  • Treat associated disorders and treat kidney disease supportively.

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