Autosomal Dominant Tubulointerstitial Kidney Disease, MUC1-Related
Synonyms: ADTKD-MUC1, MCKD1, Medullary Cystic Kidney Disease Type 1
Anthony J Bleyer, MD, MS and Stanislav Kmoch, PhD.
Author InformationInitial Posting: August 15, 2013; Last Update: June 30, 2016.
Summary
Clinical characteristics.
Autosomal dominant tubulointerstitial kidney disease, MUC1-related (ADTKD-MUC1) was previously known as medullary cystic kidney disease type 1. It is characterized by slowly progressive tubulointerstitial disease that leads to end-stage renal disease (ESRD) and the need for dialysis or kidney transplantation. ESRD typically occurs in adulthood but is extremely variable, occurring at any age between 20 and 70 years. There are no other systemic manifestations.
Diagnosis/testing.
Diagnosis of ADTKD-MUC1 is suspected in individuals with an elevated serum creatinine, bland urinary sediment (i.e., little blood or protein), and a family history of kidney disease inherited in an autosomal dominant manner. Renal ultrasound examination may reveal normal or small kidneys. Renal biopsy findings are nonspecific (and, hence, not diagnostic). Identification of a heterozygous MUC1 pathogenic variant on molecular genetic testing confirms the diagnosis.
Management.
Treatment of manifestations: Treatment follows standard guidelines for chronic kidney disease (CKD) and its sequelae, which can include hypertension, anemia, and gout. Affected individuals are encouraged to prepare for kidney transplantation, the definitive treatment of ADTKD-MUC1, by staying in optimal health (e.g., by exercising, avoiding obesity and tobacco usage, and maintaining strict control of hypertension, dyslipidemia, and other cardiovascular risk factors). Transplantation is curative, and the outcome from kidney transplantation in this group of patients is excellent.
Surveillance: Measurement of hemoglobin, serum concentrations of uric acid and creatinine and blood pressure annually prior to entering CKD Stage 3. Thereafter, follow up is determined by the treating nephrologist.
Agents/circumstances to avoid: Drugs or agents known to be nephrotoxic such as nonsteroidal anti-inflammatory drugs, especially when dehydrated.
Evaluation of relatives at risk: If the MUC1 pathogenic variant has been identified in an affected family member, predictive molecular genetic testing of at-risk relatives allows early diagnosis and treatment of renal disease and its sequelae. Additionally, all related potential kidney donors should be tested for the family-specific MUC1 pathogenic variant, as only those without the pathogenic variant should be assessed as eligible kidney donors.
Genetic counseling.
ADTKD-MUC1 is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant. Once the pathogenic variant has been identified in an affected family member, molecular genetic testing can clarify the genetic status of at-risk family members. While prenatal testing is theoretically possible, the complexities of molecular genetic testing make it difficult.
Diagnosis
Suggestive Findings
Autosomal dominant tubulointerstitial kidney disease, MUC1-related (ADTKD-MUC1) should be suspected in individuals with the following findings.
Clinical Signs
Tubulointerstitial kidney disease. Urinalysis of affected individuals reveals few or no red cells or white cells and less than 500 mg of urinary protein.
Slowly progressive chronic kidney disease. Affected individuals usually develop asymptomatic elevations in their serum creatinine concentration or reduced estimated glomerular filtration rate (eGFR), which may initially appear in the late teens or early twenties. ESRD typically occurs in adulthood but is extremely variable, occurring at any age between 20 and 70 years.
Autosomal dominant inheritance. The presence of chronic kidney disease (elevated serum creatinine) or end-stage renal disease inherited in an autosomal dominant manner is another important clue to this disorder.
No other systemic findings are present.
Testing
The majority of patients with ADTKD-MUC1 have the following lab test abnormalities.
Serum creatinine (eGFR). As individuals with ADTKD-MUC1 age, kidney function worsens, and the serum creatinine rises.
The serum creatinine is an indirect measure of glomerular filtration rate, and there are formulas that calculate the eGFR from the serum creatinine.
On most laboratory reports, the eGFR is included. However, calculators are available online for this purpose (e.g.,
MDRD GFR Equation).
A reduced eGFR (<90 mL/min/1.73 m2) is a sensitive indicator of ADTKD-MUC1 in adults, but it is not specific, as many individuals in the general population have mildly decreased eGFR measurements.
Urinalysis. Hematuria is not present, and excretion of protein is <500 mg/24 hours until kidney failure is advanced.
Kidney imaging and histology
Renal ultrasound examination is usually normal or shows small kidneys. As with other patients with chronic kidney disease, occasional cysts may be seen.
Kidney biopsy reveals focal tubular atrophy, secondary glomerular scarring, and interstitial fibrosis. Biopsy findings are nonspecific and usually do NOT lead to the diagnosis of ADTKD-MUC1.
Establishing the Diagnosis
The diagnosis of ADTKD-MUC1
is established in a proband with the above suggestive findings and identification of a heterozygous MUC1 pathogenic variant on molecular genetic testing (see ).
The only molecular genetic testing approach used to date is targeted analysis for the duplicated C or inserted A nucleotide within the coding variable-number tandem repeat (VNTR) in MUC1 [Kirby et al 2013]
Note: The pathogenic variant cannot be detected with routine single-gene sequencing or deletion/duplication testing techniques. Likewise, existing multi-gene panels and genomic testing (i.e., exome and genome sequencing) will not identify the causative pathogenic variants in MUC1.
Currently, genetic testing for ADTKD-MUC1 is available on a limited basis; see Author Notes.
To date, no individual with a de novo
MUC1 pathogenic variant has been identified [Author, personal observation]: individuals with no family history of the disorder are unlikely to have ADTKD-MUC1.
Table 1.
Molecular Genetic Testing Used in Autosomal Dominant Tubulointerstitial Kidney Disease, MUC1-Related
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| Gene 1 | Test Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by This Method |
|---|
| MUC1 | Targeted analysis for pathogenic variants 3 | 21/24 families tested 4 |
Clinical Characteristics
Clinical Description
Autosomal dominant tubulointerstitial kidney disease, MUC1-related (ADTKD-MUC1) is characterized by slowly progressive tubulointerstitial disease that leads to end-stage renal disease (ESRD).
Onset. ADTKD-MUC1 rarely manifests in childhood. Abnormal serum creatinine concentration or reduced eGFR may initially appear in the late teens or early twenties. As the overlap between a normal serum creatinine value and a mildly abnormal value is considerable, ADTKD-MUC1 may be difficult to diagnose in the early stages.
Progression. With time, kidney function slowly worsens and serum creatinine concentration slowly rises from the normal range to the high normal range, and then to above normal. In adults the eGFR (calculated using the serum creatinine concentration, age, gender, and race) will show a progressive reduction over time.
As kidney function worsens, manifestations of chronic kidney disease (CKD) develop, including high blood pressure, gout, and anemia. Kidney function progressively worsens until dialysis or kidney transplantation is required.
Post-transplantation. ADTKD-MUC1 does not recur in the transplanted kidney.
Penetrance
CKD occurs in all affected individuals; however, the age of onset of ESRD ranges from age 20 years to older than 70 years.
Nomenclature
Medullary cystic kidney disease type 1 is the name that has historically been given to this disorder. The name is a misnomer in that cysts in the renal medulla are not a common clinical characteristic, and the presence of medullary cysts is not a good predictor of the presence of ADTKD-MUC1.
According to the nomenclature from 2015 [Eckardt et al 2015], the term "autosomal dominant tubulointerstitial kidney disease" (ADTKD) refers to the following disorders characterized by: (1) autosomal dominant inheritance; (2) slowly progressive chronic tubulointerstitial kidney disease resulting in ESRD in the third through seventh decade of life; (3) urinalysis revealing a bland urinary sediment (i.e., little blood or protein); and (4) renal ultrasound examination that is normal early in the disease course [Bleyer et al 2010]. Subtypes include the following:
Note: (1) The term "nephronophthisis/medullary cystic kidney disease (NPH/MCKD) complex" was used in the past to refer to both autosomal recessive and autosomal dominant forms of hereditary chronic tubulointerstitial disease [Hildebrandt et al 1992]. Nephronophthisis is now used to refer to a group of conditions with autosomal recessive inheritance that present in childhood with chronic kidney failure. These conditions are caused by pathogenic variants in at least 12 different genes, denoted as nephrocystins (NPHP1-NPHP11, NPHP1L) [Wolf & Hildebrandt 2011]. Clinical characteristics include polyuria, anemia, and slowly progressive kidney failure. (2) Medullary sponge kidney (MSK), associated with calcifications of the medulla of the kidney, hypercalciuria, hematuria, and tubular acidification defects [Gambaro et al 2006], is not in any way related to medullary cystic kidney disease. See Nephronopthisis.
Prevalence
ADTKD-MUC1 is estimated to affect about 100 families in the United States and about 1000 families worldwide. This is likely to be an underestimate and will increase with accurate molecular diagnostics.
Differential Diagnosis
, a diagnostic algorithm for inherited kidney disease, recommends the following.
Testing strategy for inherited kidney disease – 2015 update
Urinalysis. If blood and protein are present, consider evaluation for inherited glomerulonephritis. If the urine sediment is bland (trace or no blood and protein <1 gm/24 h), obtain a family history to determine the likely inheritance pattern. If autosomal recessive (i.e., only sibs are affected), consider autosomal recessive polycystic kidney disease or the group of disorders termed "nephronophthisis."
Renal imaging. Renal imaging should always be performed. Ultrasound examination is typically performed first. If numerous cortical and medullary cysts and enlarged kidneys are present, consider autosomal dominant polycystic kidney disease (ADPKD).
If the number of cysts is fewer than required for a diagnosis of ADPKD, the family history suggests autosomal dominant inheritance, the urine is bland, the kidneys are normal or reduced in size with or without medullary cysts, and renal histology (if performed) has shown interstitial fibrosis, consider screening for pathogenic variants in UMOD, REN, or MUC1.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with ADTKD-MUC1, the following evaluations are recommended:
Measurement of hemoglobin concentration and serum concentration of uric acid and creatinine
Measurement of blood pressure
Referral to a nephrologist for further evaluation
Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Care by a nephrologist is recommended.
Treatment follows standard guidelines for chronic kidney disease – based on the level of the serum creatinine and estimated glomerular filtration rate (eGFR) – and its sequelae, which can include hypertension, anemia, and gout. Affected individuals are encouraged to prepare for kidney transplantation, the definitive treatment of ADTKD-MUC1, by staying in optimal health (e.g., by exercising, avoiding obesity and tobacco usage, and maintaining strict control of hypertension, dyslipidemia, and other cardiovascular risk factors).
Transplantation is curative, and the outcome from kidney transplantation in this group of patients is excellent.
Surveillance
Annually, starting at the time of diagnosis and continuing until chronic kidney disease (CKD) Stage 3:
After CKD Stage 3, follow up as determined by the treating nephrologist is appropriate.
Agents/Circumstances to Avoid
Avoid use of nonsteroidal anti-inflammatory drugs (NSAIDs), especially when dehydrated, as NSAIDs can further impair kidney function in individuals with CKD. Avoid all nephrotoxic drugs or use with caution depending on the clinical indication.
Evaluation of Relatives at Risk
For the purpose of early diagnosis and treatment. If the pathogenic variant has been identified in an affected family member, molecular genetic testing can be used to clarify the genetic status of at-risk relatives (parents, sibs, and offspring). Relatives found to have a pathogenic variant can be monitored with serum creatinine measurements to allow early diagnosis and treatment (see Related Genetic Counseling Issues for discussion of testing of children.)
For the purpose of kidney donation. If an MUC1 pathogenic variant is known to be present in an affected family member, any relative who is a potential kidney donor should undergo molecular genetic testing to clarify his/her genetic status so that only those without the pathogenic variant are evaluated further. Several individuals with what appeared to be clinically normal kidney function have donated kidneys and later been found to have ADTKD, MUC1.Thus, it is important to test even those family members with normal kidney function to be certain that they do not have a pathogenic variant.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members. This section is not meant to address all personal, cultural, or
ethical issues that individuals may face or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
Autosomal dominant tubulointerstitial kidney disease, MUC1-related (ADTKD-MUC1) is inherited in an autosomal dominant manner.
Risk to Family Members
Parents of a proband
Most individuals diagnosed with ADTKD
-MUC1 have an
affected parent.
A
proband with ADTKD
-MUC1 may have the disorder as the result of a
de novo pathogenic variant. Because
simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if the pathogenic variant was
de novo, the proportion of ADTKD
-MUC1 caused by a
de novo pathogenic variant is unknown.
If the
pathogenic variant found in the
proband cannot be detected in leukocyte DNA of either parent, possible explanations include a
de novo pathogenic variant in the proband or
germline mosaicism in a parent (although no instances of germline mosaicism have been reported, it remains a possibility).
Recommendations for the evaluation of parents of a
proband with an apparent
de novo pathogenic variant include
molecular genetic testing of the parents. Evaluation of parents may determine that one is
affected but has escaped previous diagnosis because of a milder
phenotype. Therefore, an apparently negative family history can be confirmed only after appropriate evaluations have been performed.
Although most individuals diagnosed with ADTKD
-MUC1 have an
affected parent, the family history may appear to be negative because of early death of the parent before the onset of symptoms or late onset of the disease in the affected parent.
Sibs of a proband
The risk to the sibs of the
proband depends on the genetic status of the proband's parents: if a parent of the proband is
affected or has an
MUC1 pathogenic variant, the risk to the sibs is 50%.
When the parents are clinically unaffected, the risk to the sibs of a
proband appears to be low. However, such individuals are still at increased risk for ADTKD
-MUC1 because of the possibility later onset in a parent.
If the
MUC1 pathogenic variant found in the
proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of parental
germline mosaicism.
Offspring of a proband. Each child of an individual with ADTKD-MUC1 has a 50% chance of inheriting the MUC1 pathogenic variant.
Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected or has an MUC1 pathogenic variant, his or her family members may be at risk.
Prenatal Testing and Premplantation Genetic Diagnosis
Even if the MUC1 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for ADTKD-MUC1 are currently unavailable at this time due to the complexity of the genetic testing in this disorder.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.
MUC1-Related Kidney Disease Registry
Dr. Anthony Bleyer has established a registry of individuals with MUC1 pathogenic variants. Please contact him (ableyer@wakehealth.edu) if interested in participation. A pamphlet for living with ADTKD-MUC1 is available as well.
Email: ableyer@wakehealth.edu
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
Autosomal Dominant Tubulointerstitial Kidney Disease, MUC1-Related: Genes and Databases
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Gene structure.
MUC1 consists of seven exons. Alternative splicing events yield at least ten transcript variants of MUC1 [Reference sequence NM_002456.5]. MUC1 contains a 60-mer variable-number tandem repeat (VNTR) within the coding region. The normal VNTR copy number ranges from 20 to 125. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. The only molecular mechanism of disease identified to date is a heterozygous duplication of one cytosine in a heptanucleotide cytosine tract within one copy of the VNTR. The specific VNTR involved varies by family but is consistent within a family. Repeat expansion is not a mechanism of disease.
Several other pathogenic variants (including an A insertion instead of a C insertion) that result in the creation of a frameshift causing the transcription of the same neopeptide as that formed with the C insertion have been identified [S Kmoch, personal communication].
Normal gene product. Mucin-1 is a membrane-anchored mucoprotein found in breast, respiratory tract, sebaceous gland, salivary gland, and renal tubules. Mucin-1 provides (among other functions) a protective barrier that prevents pathogens from accessing the cell surface. Of note, with the exception of the kidney, no evidence of clinical abnormality is found in persons with an MUC1 pathogenic variant.
Abnormal gene product. The abnormal gene product is a neopeptide that has the same signal peptide as wild type mucin-1. The neopeptide is deposited in the cytoplasm of the renal tubular cells and is thought to accelerate apoptosis in the renal tubular cells, leading to nephron dropout resulting in slowly progressive chronic kidney disease [Kirby et al 2013].
References
Literature Cited
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Chapter Notes
Author Notes
Dr Stanislav Kmoch (zc.inuc.1fl@hcomks) and Dr Anthony Bleyer (ude.cmbufw@reyelba) are actively involved in clinical research regarding individuals with MUC1 mutations and other forms of inherited kidney disease and would be happy to communicate with individuals who have any questions regarding diagnosis or other considerations.
Related website: www.wfubmc.edu
Molecular genetic testing for medullary cystic kidney disease type 1 is currently not commercially available. Contact Dr Bleyer (ude.htlaehekaw@reyelba) to inquire about testing.
Revision History
30 June 2016 (ha) Comprehensive update posted live
15 August 2013 (me) Review posted live
30 April 2013 (ab) Original submission
