Medullary Cystic Disease 

Updated: Nov 16, 2015
Author: Prasad Devarajan, MD, FAAP; Chief Editor: Craig B Langman, MD 

Overview

Background

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 of the clinical and histopathological 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 current recommendations for the classification of renal cystic diseases.[1]

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 11 causative genes to date, all of which appear to encode for proteins expressed in the primary cilia of renal epithelial cells; hence, these disorders are now referred to as ciliopathies.[1, 2, 3, 4, 5, 6]

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 y). It is characterized by the presence of small medullary cysts, extensive tubular atrophy, thickened tubular basement membranes, and prominent interstitial fibrosis. Recent 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 ESRD developing around 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.[1, 2, 3, 4, 5, 6] 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.

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.[7]

  • MCKD type 2 has an earlier onset of ESRD (mean age, 32 y) and is the result of defects in the UMOD gene that encodes uromodulin/Tamm-Horsfall mucoprotein.[8, 9, 10]

  • 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 recently been described in families with hyperuricemia, anemia, progressive kidney failure, and progressive interstitial fibrosis.[11] These patients may also be considered to fall under the umbrella of MCKD or ADIKD.

Pathophysiology

Advances in molecular genetics have led to the identification of the gene defects underlying several forms of NPH-MCKD.[2, 3, 4, 5, 12] Characterization of the encoded proteins is revealing 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.

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 the 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 b-tubulin and localizes to primary cilia in renal tubular cells. B-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 (< 5 y), 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.

MCKD type 2 is due to mutations in the UMOD gene, which encodes uromodulin (Tamm-Horsfall mucoprotein).[8, 9, 10] 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.[13, 14] 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.[7] The abnormal mucin 1 protein accumulates intracellularly in the distal nephron segments. How this leads to the MDCK phenotype is unclear.

A study by Bleyer et al analyzed the clinical characteristics of families and individuals with the MUC1 mutation leading to MCKD type 1. The study concluded that MUC1 mutation results in progressive chronic kidney failure with a bland urinary sediment. The authors also added that the age of onset of end stage kidney disease is highly variable, suggesting that gene-gene or gene-environment interactions contribute to phenotypic variability.[15]

Epidemiology

Frequency

United States

The incidence of juvenile NPH is 9 cases per 8.3 million population. Nephronophthisis is the most common genetic cause of ESRD in the first 2 decades of life, accounting for 5-15% of cases of ESRD. Medullary cystic kidney disease 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 most likely represents an underestimation, owing to difficulties associated with making an accurate diagnosis.

International

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

Mortality/Morbidity

ESRD develops in all patients, 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.

Race

No racial predilection is noted.

Sex

Both sexes are equally affected.

Age

NPH occurs during childhood and progresses to renal failure before the 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. 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.

 

Presentation

History

A family history of consanguinity, early death, or renal disease is present in 67% of patients with nephronophthisis (NPH).

In juvenile nephronophthisis (the most common form), the first symptoms usually develop around age 5 years and consist of polyuria and polydipsia. These symptoms are related to a reduced urinary concentrating capacity and loss of sodium conservation and occur early in the course of the disease, well before a reduction in glomerular filtration rate. Typically, the urine osmolarity is less than 400 mosm/kg in the first morning sample.

Children exhibit decreased growth velocity, initially related to chronic dehydration and subsequently confounded by renal insufficiency.

Features that distinguish nephronophthisis from medullary cystic kidney disease (MCKD) include the following:

  • The inheritance pattern is autosomal recessive.

  • The median age of onset of end-stage renal disease (ESRD) is 13 years in juvenile nephronophthisis, 1-3 years in infantile nephronophthisis, and 19 years in adolescent nephronophthisis.

Extrarenal associations of nephronophthisis include the following:

  • Cogan syndrome - Oculomotor apraxia

  • Senior-Loken syndrome - Retinitis pigmentosa

  • Mainzer-Saldino syndrome - Liver fibrosis, 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

Distinguishing features of medullary cystic kidney disease include the following:

  • The inheritance pattern is autosomal dominant.

  • The median onset of ESRD for medullary cystic disease type 1 is age 62 years and for medullary cystic kidney disease type 2 is age 32 years.

  • Extrarenal associations are restricted to hyperuricemia and gout.

The following conditions have renal histologic features similar to those of nephronophthisis:

  • Jeune syndrome or asphyxiating thoracic dysplasia - Small thorax, short limbs, and hypoplastic Iliac wings

  • Ellis-van Creveld syndrome - Chondroectodermal dysplasia

  • PHYNS syndrome - Retinitis pigmentosa, hypopituitarism, nephronophthisis, and skeletal dysplasia

  • Laurence-Moon-Bardet-Biedl syndrome - Retinitis pigmentosa, obesity, polydactyly, and mental retardation

In the case of MCKD, there is usually a family history of hyperuricemia and progressive kidney disease. Patients with MCKD type 2 (the more common form) present as adolescents or young adults with gout and chronic kidney disease, with a relatively bland urinalysis. Patients with MUC1 mutations typically present with slowly progressive chronic kidney disease and usually develop hyperuricemia later in life. Patients with REN mutations present with features similar to those with UMOD mutations, but additionally have manifestations of low renin and angiotensin (anemia out of proportion to the kidney disease, low blood pressure, hyperkalemia, and increased risk of volume depletion).

Physical

The clinical findings are related to tubular injury that leads to a reduction in urinary concentrating capacity, renal sodium loss, and insidious but inevitable progression to renal failure. The tubular defects precede the decline in renal function and may be present in asymptomatic siblings with the disease.

Nephronophthisis and medullary cystic kidney disease share several clinical features. In most patients, the signs associated with decreased urinary concentration capacity are present by age 5 years. The signs include polyuria, polydipsia, enuresis, and dehydration. Common findings include a failure to thrive and weakness. Anorexia, nausea, pruritus, bone pain, and neurologic symptoms herald ESRD. Because of salt wasting, hypertension is rare, except in the infantile form of nephronophthisis.

Pallor is another characteristic finding. In contrast to other renal diseases in which the degree of anemia depends on the stage of renal insufficiency, in nephronophthisis, the severity of the anemia exceeds the degree of renal insufficiency. Anemia may occur before renal insufficiency develops. This normocytic and normochromic anemia is more severe than that of other chronic renal diseases and does not result from iron deficiency or hemolysis.

Studies have shown that, in patients with nephronophthisis, the serum erythropoietin (EPO) concentration is lower than that of patients with other progressive renal diseases. EPO is a glycoprotein hormone that controls the differentiation of erythroid progenitor cells in the bone marrow and the production of erythrocytes. After birth, EPO is produced mainly in the kidneys, specifically in the peritubular fibroblasts. In patients with nephronophthisis, the synthesis of EPO is decreased.

Causes

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)

Disease

Inheritance

 

Chromosome

Gene, Protein

Genetic Defect

NPH1

Autosomal recessive

 

2q13

NPHP1, nephrocystin-1

Homozygous deletion, heterozygous deletion

NPH2

Autosomal recessive

 

9q31

NPHP2/INV, inversin

Recessive mutations

NPH3

Autosomal recessive

 

3q22

NPHP3, nephrocystin-3

Recessive mutations

NPH4

Autosomal recessive

 

1p36

NPHP4, nephroretinin

Point mutations

NPH5

Autosomal recessive

 

3q21

NPHP5, nephrocystin-5

Truncations

NPH6

Autosomal recessive

 

12q21

NPHP6, nephrocystin-6

Truncations

NPH7

Autosomal recessive

 

16p

NPHP7, nephrocystin-7

Unknown

NPH8

Autosomal recessive

 

16p

NPHP8, nephrocystin-8

Truncations, missense

NPH9

Autosomal recessive

 

17q11

NPHP9, nephrocystin-9

Missense

NPH11

Autosomal recessive

 

8q22.1

NPHP11, nephrocystin-11

Missense

NPH1L

Autosomal recessive

 

22q13

Nephrocystin-1L

Deletion

MCKD1

Autosomal dominant

 

1q21

MUC1,

mucin1

Missense

MCKD2

Autosomal dominant

 

16p12*

UMOD, Uromodulin

Missense

*Co-localizes with familial juvenile hyperuricemic nephropathy

 

DDx

 

Workup

Laboratory Studies

Urinalysis may be helpful in patients with nephronophthisis (NPH)–medullary cystic kidney disease (MCKD) complex. A low specific gravity in the first morning voiding sample, which should be concentrated, is a characteristic feature of this disease. The concentrating ability rarely exceeds 800 mOsm/kg of water. Hematuria, proteinuria, and bacteriuria are uncommon. Proteinuria, if present, is mild and of tubular origin. Significant proteinuria develops late in the course of the disease, reflecting secondary glomerular sclerosis.

Metabolic acidosis, elevated serum BUN and creatinine concentrations, hypocalcemia, and hyperphosphatemia are indicators of renal failure.

The CBC count frequently reveals profound normocytic normochromic anemia. Approximately one third of patients develop anemia before renal insufficiency occurs. Low erythropoietin (EPO) levels have been found in patients with nephronophthisis.

Liver function tests are used to detect congenital hepatic fibrosis.

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 CT scanning is the modality of choice. The kidneys are imaged with 1-mm to 2-mm-thick sections. Multiple cysts are typically seen in the medulla and corticomedullary region. The cysts range from smaller than 0.5 mm to 2 cm in diameter.

Renal ultrasonography may be helpful in assessing nephronophthisis–medullary cystic kidney disease. The kidneys are of normal or moderately reduced size, with a smooth outline. Typically, corticomedullary differentiation is lost, and echogenicity is increased. Cysts may or may not be present at the corticomedullary border. These findings are distinct from those of autosomal dominant or autosomal recessive polycystic kidney disease (PKD), in which the kidneys are enlarged and the cysts are uniformly distributed throughout the entire kidney. Patients with end-stage renal disease (ESRD) have multiple small and large cysts that can be seen in the corticomedullary area. No cysts are located in organs other than the kidney. The absence of cysts on the sonogram does not exclude the diagnosis of nephronophthisis–medullary cystic kidney disease. Patients with UMOD mutations frequently do no exhibit renal cysts that are detectable byultrasound.

Hepatic ultrasonography is used to detect congenital hepatic fibrosis.

Skeletal radiography is used to identify dysplastic lesions.

Other Tests

See the list below:

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

  • Molecular genetic analysis is the only diagnostic procedure with which the diagnosis of nephronophthisis or MCKD can be confirmed with certainty. Details are available at Renal Genes.

    • Before genetic counseling is given, a thorough pedigree analysis should be performed to distinguish recessive (early-onset) disease from dominant (late-onset) disease, and extrarenal involvement should be excluded.

    • Blood may be obtained from a patient with clinical and renal ultrasonographic findings suggestive of nephronophthisis–medullary cystic kidney disease complex or from an affected parent. DNA is extracted from this blood and amplified by using the polymerase chain reaction (PCR) to detect the homozygous deletion in the NPH1 gene.

    • Approximately 66% of children with nephronophthisis type 1 have this large homozygous deletion.

    • However, because of the additional loci for nephronophthisis, the disease cannot be excluded if mutations in the NPH1 gene are not detected.

Histologic Findings

See the list below:

  • On renal biopsy findings, the characteristic histologic triad is identical in the findings in childhood and adult forms of nephronophthisis. First, tubular basement membrane disintegration with irregular thickening is present with membrane attenuation. In later stages, biopsy findings include distal tubular atrophy and cystic formation predominantly at the corticomedullary junction. Second, the interstitium shows round cell infiltration and fibrosis. Third, periglomerular fibrosis is observed. These histologic changes are characteristic but not pathognomonic for the disease complex. Nephronophthisis type 3 should be considered if the histologic features are consistent with nephronophthisis in the absence of molecular defects in nephronophthisis type 1.

  • Early histologic findings reveal peritubular lymphohistiocytic infiltrations. As renal failure progresses, diffuse tubulointerstitial fibrosis occurs, with tubular atrophy and dilatation. Light microscopy and electron microscopy reveal periglomerular and peritubular basement membrane thickening and splitting.

  • The renal architecture is characterized by a uniformly thinned cortex and a segmental distribution of variably sized cysts in the medulla and corticomedullary junction. Cysts can be barely visible to several centimeters in size, and they vary in number from fewer than 5 to more than 50 in a segmental distribution. The cysts do not communicate with nephrons. The presence of cysts is not a diagnostic requirement because it is a late finding, and cysts may not be detected at biopsy.

 

Treatment

Medical Care

See the list below:

  • In all variants of nephronophthisis (NPH)–medullary cystic kidney disease (MCKD), end-stage renal disease (ESRD) insidiously ensues within characteristic age ranges, and no specific therapy is available. Management is symptomatic and directed at preventing and treating 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.

Surgical Care

See the list below:

  • Access for hemodialysis or peritoneal dialysis should be secured before ESRD develops.

  • Kidney transplantation is the treatment of choice for patients who have nephronophthisis–medullary cystic kidney disease and ESRD.

    • ESRD does not recur in the transplanted kidney.

    • Living, related donors should be thoroughly screened for the disease prior to the transplantation procedures.

Consultations

See the list below:

  • All children with polyuria, polydipsia, or a failure to thrive must be evaluated by a pediatric nephrologist. Children found to have nephronophthisis–medullary cystic kidney disease should be referred for an ophthalmologic examination and closely followed up by the nephrologist.

  • Offer genetic counseling to the family.

    • A carefully constructed pedigree may help in distinguishing between the recessive and dominant forms of the disease.

    • Because of the genetic locus heterogeneity among diseases in the nephronophthisis–medullary cystic kidney disease complex, prenatal diagnosis can be performed only by means of direct genetic testing. This testing requires a setting in which a specific deletion or mutation of the NPH1 gene has already been characterized in an affected sibling. The urinary concentrating ability of asymptomatic siblings should be tested at yearly intervals.

Diet

See the list below:

  • In children with nephronophthisis, their nutrition should be appropriate for their age.

  • Adequate hydration is important to replace urinary water losses and sodium loss in patients with salt-wasting.

  • As renal insufficiency progresses, foods high in phosphorus and potassium should be limited.

Activity

See the list below:

  • Activities may be pursued as tolerated.

  • Strenuous exercise and prolonged heat exposure should be avoided because children with NPH-MCKD are prone to dehydration.

 

Medication

Medication Summary

Pharmacotherapy in patients with nephronophthisis (NPH)–medullary cystic kidney disease (MCKD) is symptomatic and directed at preventing and treating complications of progressive renal insufficiency.

Erythropoietin

Class Summary

This is a glycoprotein normally produced in the kidneys that is responsible for the stimulation of red blood cell production. Anemia occurs because of deficient erythropoietin production during renal failure.

Epoetin alfa (Epogen, Procrit)

Indicated for the treatment of anemia associated with chronic renal failure. Stimulates division and differentiation of committed erythroid progenitor cells; induces release of reticulocytes from bone marrow into bloodstream.

 

Follow-up

Transfer

See the list below:

  • Transfer to a pediatric dialysis unit is required when the child with nephronophthisis (NPH)–medullary cystic kidney disease (MCKD) develops end-stage renal disease (ESRD).

Complications

See the list below:

  • Complications are those of progressive renal failure.

Prognosis

See the list below:

  • ESRD develops in all patients.

  • The disease does not recur in transplanted kidneys.

Patient Education

See the list below:

  • As ESRD develops, appropriate nutritional and medical education should be made available.