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Nephronophthisis and Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)

By Navin Jaipaul, MD, MHS

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Nephronophthisis and autosomal dominant tubulointerstitial kidney disease (ADTKD) are inherited disorders that cause cysts restricted to the renal medulla or corticomedullary border and, eventually, end-stage renal disease.

Nephronophthisis and autosomal dominant tubulointerstitial kidney disease (ADTKD) are grouped together because they share many features. Pathologically, they can 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. Cysts may or may not be present and are a result of tubular dilation. 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

  • Sodium 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

Eleven 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.

Autosomal dominant tubulointerstitial kidney disease (ADTKD)

Autosomal dominant tubulointerstitial kidney disease (previously known as medullary cystic kidney disease) is a group of uncommon genetic disorders. A consensus report (1) from Kidney Disease Improving Global Outcomes (KDIGO) has proposed classifying these disorders based on the causative gene, of which 4 are currently known (see Table: Autosomal Dominant Tubulointerstitial Kidney Disease: Gene-based Classification).

Autosomal Dominant Tubulointerstitial Kidney Disease: Gene-based Classification

Causal gene

Previous terminology


Uromodulin ( UMOD )

Uromodulin kidney disease (UKD)

Uromodulin-associated kidney disease (UAKD)

Familial juvenile hyperuricemic nephropathy (FJHN)

Medullary cystic kidney disease type 2 (CKD2)

Rarely presents in childhood

Early gout with hyperuricemia

Mucin-1 ( MUC1 )

Mucin-1 kidney disease (MKD)

Medullary cystic kidney disease type 1 (MCKD1 )

No childhood presentation

Renin ( REN )

Familial juvenile hyperuricemic nephropathy type 2 (FJHN2)

Frequent childhood presentation

Mild hypotension

Risk for acute kidney injury

Risk for anemia, hyperuricemia, and hyperkalemia

Hepatocyte nuclear factor-1 beta ( HNF1B )

Maturity-onset diabetes mellitus of the Young type 5 (MODY5)

Renal cyst and diabetes syndrome (RCAD)

Frequent childhood presentation

Prenatal ultrasound findings

Genital abnormalities

Pancreatic atrophy

Hypomagnesemia, hypokalemia

Liver enzyme test abnormalities

Histopathologic changes common to these disorders include

  • Interstitial fibrosis

  • Tubular atrophy

  • Thickening of tubular basement membranes

  • Possible cyst formation as a result of tubular dilation

  • Absence of complement and immunoglobulin staining on immunofluorescence

Autosomal dominant tubulointerstitial kidney disease affects people in their 30s through 70s. About 15% of patients have no family history, suggesting a sporadic new mutation. Hypertension is common but usually only modest and typically does not precede the onset of kidney dysfunction. Hyperuricemia and gout is common and can precede the onset of significant renal insufficiency. ESRD typically develops at age 30 to 50. ADTKD should be suspected in patients with the following, particularly if the urinary sediment is benign:

Proteinuria is absent to mild. 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. Kidney biopsy may be necessary in at least one affected family member.

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


Key Points

  • Nephronophthisis and autosomal dominant tubulointerstitial kidney disease cause inability to concentrate urine (with polydipsia and polyuria), sodium wasting, anemia, and ESRD.

  • Nephronophthisis is autosomal recessive and causes ESRD during childhood, whereas ADTKD 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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