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Nephronophthisis and Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)

By

Enrica Fung

, MD, MPH, Loma Linda University School of Medicine

Last full review/revision Apr 2021| Content last modified Apr 2021
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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)

Nephronophthisis

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

  • Infantile, median age at onset 1 year

  • Juvenile, median age at onset 13 years

  • Adolescent, median age at onset 19 years

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 Hepatic Fibrosis Hepatic fibrosis is overly exuberant wound healing in which excessive connective tissue builds up in the liver. The extracellular matrix is overproduced, degraded deficiently, or both. The trigger... read more , intellectual disability, and other neurologic abnormalities.

Diagnosis of Nephronophthisis

  • 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.

Treatment of Nephronophthisis

  • Supportive care

In early disease, treatment involves management of hypertension Hypertension Hypertension is sustained elevation of resting systolic blood pressure (≥ 130 mm Hg), diastolic blood pressure (≥ 80 mm Hg), or both. Hypertension with no known cause (primary; formerly, essential... read more Hypertension , electrolyte abnormalities and acid-base disorders Acid-Base Disorders Acid-base disorders are pathologic changes in carbon dioxide partial pressure (Pco2) or serum bicarbonate (HCO3−) that typically produce abnormal arterial pH values. Acidemia is serum pH 7... read more , and anemia Overview of Decreased Erythropoiesis Anemia, a decrease in the number of red blood cells (RBCs), hemoglobin (Hb) content, or hematocrit (Hct), can result from decreased RBC production (erythropoiesis), increased RBC destruction... read more . Children with growth restriction may respond to nutritional supplements and growth hormone therapy. Ultimately, all patients develop chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more Chronic Kidney Disease and require dialysis Hemodialysis In hemodialysis, a patient’s blood is pumped into a dialyzer containing 2 fluid compartments configured as bundles of hollow fiber capillary tubes or as parallel, sandwiched sheets of semipermeable... read more or transplantation Kidney Transplantation Kidney transplantation is the most common type of solid organ transplantation. (See also Overview of Transplantation.) The primary indication for kidney transplantation is End-stage renal failure... read more .

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 Treatment reference Nephronophthisis and autosomal dominant tubulointerstitial kidney disease (ADTKD) are inherited disorders that cause cysts restricted to the renal medulla or corticomedullary border and, eventually... read more ) 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 ).

Table
icon

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 Hypertension Hypertension is sustained elevation of resting systolic blood pressure (≥ 130 mm Hg), diastolic blood pressure (≥ 80 mm Hg), or both. Hypertension with no known cause (primary; formerly, essential... read more 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 Renal biopsy Biopsy of the urinary tract requires a trained specialist (nephrologist, urologist, or interventional radiologist). Indications for diagnostic biopsy include unexplained nephritic or nephrotic... read more may be necessary in at least one affected family member.

Treatment reference

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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