Medullary Cystic Disease

Updated: Mar 16, 2020
  • Author: Prasad Devarajan, MD, FAAP; Chief Editor: Craig B Langman, MD  more...
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Practice Essentials

Medullary cystic kidney disease (MCKD) and nephronophthisis (NPH) are inherited diseases with similar renal morphology that share many clinical and histopathologic features. Contrast-enhanced thin-section computed tomography (CT) scanning typically reveals multiple cysts in the medulla and corticomedullary region of the kidneys. In all variants of NPH and MCKD, end-stage renal disease (ESRD) develops, and no specific therapy is available. Treatment is directed at preventing and managing the complications of progressive renal insufficiency. [1]

Signs and symptoms

Common findings in both NPH and MCKD include the following clinical features:

Extrarenal associations of NPH include the following:

  • Cogan syndrome: Oculomotor apraxia
  • Senior-Loken syndrome: Retinitis pigmentosa
  • Mainzer-Saldino syndrome: Liver fibrosis and bone dysplasia
  • Joubert syndrome: Coloboma or retinal degeneration, nystagmus, ptosis, aplasia of cerebellar vermis with ataxia and psychomotor retardation, polydactyly, and neonatal tachypnea or dyspnea
  • Sensenbrenner syndrome: Cranioectodermal dysplasia and electroretinal abnormalities

Extrarenal associations of MCKD are limited to hyperuricemia and gout.

See Presentation for more detail.


Laboratory studies

Urinalysis results may be helpful. A low specific gravity in the first morning voiding sample is a characteristic feature; the concentrating ability rarely exceeds 800 mOsm/kg of water. Significant proteinuria develops late in the course of the disease, reflecting secondary glomerular sclerosis.

Metabolic acidosis, elevated serum blood urea nitrogen (BUN) and creatinine concentrations, hypocalcemia, and hyperphosphatemia are indicators of renal failure.

The complete blood cell (CBC) count frequently reveals profound normocytic normochromic anemia. Low erythropoietin (EPO) levels have been found in patients with NPH.

Hyperuricemia with hypouricosuria is characteristic of MCKD patients with UMOD or REN gene mutations. The fractional excretion of uric acid is often below 4% (normal values, 8-13%).

Imaging studies

Contrast-enhanced thin-section computed tomography (CT) scanning is the imaging modality of choice. Multiple cysts are usually evident in the medulla and corticomedullary region of the kidneys.

Renal ultrasonography may be helpful in assessing NPH-MCKD. The kidneys are of normal or moderately reduced size, with a smooth outline. Typically, corticomedullary differentiation is lost, and echogenicity is increased.

Hepatic ultrasonography is used to detect congenital hepatic fibrosis, and skeletal radiography is used to identify dysplastic lesions.

Other tests

Ophthalmoscopy and electroretinography are used to determine the presence of tapetoretinal degeneration.

Molecular genetic analysis is the only test with which the diagnosis of NPH or MCKD can be confirmed with certainty.

See Workup for more detail.


ESRD develops in all patients with NPH or MCKD. Management is symptomatic and is aimed at preventing and treating the complications of progressive renal insufficiency, such as the correction of electrolyte, acid-base, and water-balance disturbances.

Anemia may be treated with erythropoietin. Growth retardation is responsive to recombinant growth hormone.

All patients eventually require renal replacement therapy, including peritoneal dialysis or hemodialysis or preemptive kidney transplantation. The treatment of choice for patients who have NPH or MCKD and ESRD is kidney transplantation.

See Treatment and Medication for more detail.



Medullary cystic kidney disease (MCKD) and nephronophthisis (NPH) refer to 2 inherited diseases with similar renal morphology characterized by bilateral small corticomedullary cysts in kidneys of normal or reduced size and tubulointerstitial sclerosis leading to end-stage renal disease (ESRD). These disorders have traditionally been considered as parts of a complex (the NPH complex) because they share many clinical and histopathologic features. The major differences are in the modes of inheritance, the age of onset of ESRD, and the extrarenal manifestations. In this article, the 2 diseases are discussed as a single clinicopathologic entity of NPH-MCKD to reflect recommendations for the classification of renal cystic diseases. [2]


NPH was first described by Smith et al in 1945, and then by Fanconi et al in 1951, as a familial disorder leading to progressive renal damage and death in late childhood. NPH has an autosomal recessive inheritance pattern. Positional cloning and candidate gene approaches have led to the identification of more than 20 causative genes, which appear to encode for proteins expressed in the primary cilia of renal epithelial cells; hence, these disorders are now referred to as ciliopathies. [2, 3, 4, 5, 6, 7, 8]

NPH presents in childhood or adolescence with progressive renal insufficiency and is frequently associated with extrarenal organ involvement such as retinitis pigmentosa, hepatic fibrosis, skeletal defects, and cerebellar aplasia. Three clinical variants have been described, based on the age of onset of ESRD.

The juvenile form is the most common, in which ESRD usually occurs in the second decade of life (mean age, 13 years). It is characterized by the presence of small medullary cysts, extensive tubular atrophy, thickened tubular basement membranes, and prominent interstitial fibrosis. Advances in molecular genetics have identified mutations in 9 distinct genes (designated as NPHP1, NPHP4, NPHP5, NPHP6, NPHP7, NPHP8,NPHP9, NPH11, and NPH1L) that are associated with defects in distinct proteins that lead to heterogeneity in clinical manifestations.

The adolescent form is characterized by the development of ESRD at about age 20 years. It is associated with defects in the NPHP3 gene but with histologic features similar to the juvenile form. The genotype-phenotype correlations are not always clear-cut, and some patients with an NPHP3 mutation can progress to ESRD before age 10 years.

The infantile form is characterized by progression to ESRD before age 4 years. It is associated with defects in the NPHP2 gene. Histopathology reveals cystic dilatations of the collecting ducts, but the typical tubular basement changes seen in juvenile NPH are usually absent. In contrast with the other 2 forms, these children usually demonstrate severe hypertension and moderately enlarged kidneys on ultrasonography.

Aside from NPH, a number of conditions have now been recognized and considered to also represent ciliopathies. [2, 3, 4, 5, 6, 7] These conditions include autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, Bardet-Biedl syndrome, Meckel-Gruber syndrome, oral-facial-digital syndrome, Jeune asphyxiating thoracic dystrophy, and the tuberous sclerosis complex. All these conditions are associated with renal cysts and abnormalities in the cilium, but each has additional features that distinguish them from NPH.

Medullary cystic kidney disease

MCKD is inherited in an autosomal dominant pattern and usually presents with adult-onset renal failure and no extrarenal involvement. MCKD has also been referred to as autosomal dominant interstitial kidney disease (ADIKD), to highlight the most distinctive features, namely the autosomal dominant inheritance and slowly progressive kidney disease due to progressive interstitial fibrosis. It should be noted that medullary cysts may not be detected in many patients with MCKD/ADIKD, and the presence of medullary cysts is not required for the diagnosis. The following clinical variants have been described:

  • MCKD type 1 has a median onset of ESRD at age 62 years and is caused by defects in the MUC1 gene that encodes mucin 1. [9]

  • MCKD type 2 has an earlier onset of ESRD (mean age, 32 years) and is the result of defects in the UMOD gene that encodes uromodulin/Tamm-Horsfall mucoprotein. [10, 11, 12]

  • MCKD type 2 is also referred to as uromodulin-associated kidney disease (UAKD) and as familial juvenile hyperuricemic nephropathy (FJHN) because of the frequent association with hyperuricemia.

  • Dominant mutations in the REN gene, which encodes renin, have been described in families with hyperuricemia, anemia, progressive kidney failure, and progressive interstitial fibrosis. [13] These patients may also be considered to fall under the umbrella of MCKD or ADIKD.



Advances in molecular genetics have led to the identification of the gene defects underlying several forms of NPH-MCKD. [3, 4, 5, 6, 14] Characterization of the encoded proteins reveals novel pathogenetic mechanisms. Many have been shown to localize to primary cilia, which are highly conserved structures that sense and process various extracellular signals. An important role of normal cilia in renal tubular cells is mechanosensation, whereby flow-mediated bending of primary cilia elicits signal transduction pathways that regulate the cell cycle, cell proliferation, and cell death. Defects in these cellular functions may contribute to cystogenesis. Because cilia are present in almost all cells and tissues, ciliary dysfunction may also account for the extrarenal manifestations encountered in some forms of NPH.

Pathophysiology of nephronophthisis

NPH type 1 is characterized by mutations in the NPHP1 gene, which encodes the protein nephrocystin-1. Nephrocystin-1 interacts with the products of other NPHP genes as well as components of cell-cell and cell-matrix signaling. Nephrocystin-1 and its interacting partners are localized to the cell-cell junction (adherens junction) and cell-matrix interface (focal adhesion), suggesting important roles in maintaining the integrity of the tubular epithelium. Thus, cystogenesis in NPH type 1 may result from defects in tubular cell-cell and cell-substratum contacts. Nephrocystin-1 and other NPHP gene products are also prominently localized to the primary cilia in the apical (luminal) membranes of renal tubular epithelial cells. Patients develop ESRD at a median age of 13 years and may also display extrarenal manifestations, including retinitis pigmentosa and oculomotor apraxia.

In NPH type 2, the mutated gene NPHP2/INVS encodes for inversin, which interacts with nephrocystin-1 and β-tubulin and localizes to primary cilia in renal tubular cells. β-Tubulin constitutes the microtubule axoneme of primary cilia. Hence, defects in these interactions may impair ciliary function and thereby contribute to cyst development. The age of onset of ESRD is much earlier (younger than age 5 years), and patients often display cardiac abnormalities such as situs inversus and ventricular septal defects.

Mutations in the NPHP3 gene (which encodes nephrocystin-3, another nephrocystin-1 and inversin–interacting protein) result in a variety of human phenotypes, including infantile and adolescent ESRD. Mutations in the other nephrocystin genes account for a minority of patients with NPH. All encode for proteins that similarly interact with other proteins that localize to different portions of primary cilia, basal bodies, centrosomes, or the mitotic spindle of cilia, providing ample evidence for the ciliopathy hypothesis.

Pathophysiology of medullary cystic kidney disease

MCKD type 2 is due to mutations in the UMOD gene, which encodes uromodulin (Tamm-Horsfall mucoprotein). [10, 11, 12] Uromodulin is produced in the thick ascending limb of the loop of Henle, where it is thought to maintain the water-tight integrity of that nephron segment. Uromodulin also plays a role in the regulation of the Na-K-2Cl furosemide-sensitive transporter as well as the ROMK potassium channel on the apical surface of the thick ascending loop epithelial cells.

In MCKD type 2, the mutant uromodulin proteins cannot exit the endoplasmic reticulum, leading to intracellular accumulation of abnormal uromodulin protein, with resultant tubular cell death and chronic kidney disease. However, one of the hallmarks of patients with MCKD type 2 is that the hyperuricemia is disproportional to the degree of renal insufficiency. [15, 16] Hyperuricemia results largely from impaired uric acid excretion, although the mechanism remains unclear.

MCKD type 1 is caused by mutations in the MUC1 gene, which encodes mucin 1. [9] The abnormal mucin 1 protein accumulates intracellularly in the distal nephron segments. How this accumulation of protein leads to the MDCK phenotype is unclear.

Bleyer et al analyzed the clinical characteristics of families and individuals with the MUC1 mutation that leads to MCKD type 1. The investigators concluded that the MUC1 mutation results in progressive chronic kidney failure with a bland urinary sediment. They also observed that the age of onset of ESRD is highly variable; this finding suggests that gene-gene or gene-environment interactions contribute to phenotypic variability. [17]



All of the disease variants of the nephronophthisis–medullary cystic kidney disease complex are caused by defects in different genes at distinct chromosomal loci.

Table. Molecular Genetic Features of the Nephronophthisis–Medullary Cystic Kidney Disease Complex (Open Table in a new window)





Gene, Protein

Genetic Defect


Autosomal recessive



NPHP1, nephrocystin-1

Homozygous deletion, heterozygous deletion


Autosomal recessive



NPHP2/INV, inversin

Recessive mutations


Autosomal recessive



NPHP3, nephrocystin-3

Recessive mutations


Autosomal recessive



NPHP4, nephroretinin

Point mutations


Autosomal recessive



NPHP5, nephrocystin-5



Autosomal recessive



NPHP6, nephrocystin-6



Autosomal recessive



NPHP7, nephrocystin-7



Autosomal recessive



NPHP8, nephrocystin-8

Truncations, missense


Autosomal recessive



NPHP9, nephrocystin-9



Autosomal recessive



NPHP11, nephrocystin-11



Autosomal recessive






Autosomal dominant







Autosomal dominant



UMOD, Uromodulin


*Co-localizes with familial juvenile hyperuricemic nephropathy.



United States data

The incidence of juvenile NPH is 9 cases per 8.3 million population. NPH is the most common genetic cause of ESRD in the first 2 decades of life, accounting for 5-15% of cases of ESRD. [18]

MCKD is rare and has been primarily reported in the United States. Approximately 200 families with MCKD type 2 have been reported, each having several affected individuals. This figure most likely represents an underestimation, owing to difficulties associated with making an accurate diagnosis. [17]

International data

The incidence of NPH is higher in Europe, where it accounts for 15-25% of cases of childhood ESRD. [19]

Race-, sex-, and age-related demographics

No racial predilection is noted, and both sexes are equally affected.

NPH occurs during childhood and progresses to renal failure before age 20 years. The median age of onset of ESRD is 13 years in juvenile NPH, 1-3 years in infantile NPH, and 19 years in adolescent NPH. [18] If ESRD has not developed by age 25 years, the diagnosis of recessive NPH is unlikely, and autosomal dominant MCKD should be considered.

ESRD typically develops when patients with MCKS are aged 25-50 years. Median onset of ESRD is age 62 years for MCKD type 1 and age 32 years for MCKD type 2. [9, 10, 11, 12]




ESRD develops in all patients with NPH-MCKD, although the rate of progression is faster in the recessive form of the disease than in the dominant form. Mortality is related to the complications of renal failure.

NPH-MCKD does not recur in transplanted kidneys.


The complications of NPH-MCKD are those of progressive renal failure.