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UMOD-Associated Kidney Disease

Synonyms: Familial Juvenile Hyperuricemic Nephropathy 1, Medullary Cystic Kidney Disease 2, Uromodulin Storage Disease

, MD, MS and , PhD.

Author Information
, MD, MS
Section on Nephrology
Wake Forest University School of Medicine
Winston-Salem, North Carolina
, PhD
Office of the Clinical Director
National Human Genome Research Institute
National Institutes of Health
Bethesda, Maryland

Initial Posting: ; Last Update: September 12, 2013.

Summary

Disease characteristics. UMOD-associated kidney disease (uromodulin-associated kidney disease) is also known as familial juvenile hyperuricemic nephropathy type 1 (FJHN1) and medullary cystic kidney disease type 2 (MCKD2). Clinical findings typically include hyperuricemia and gout (resulting from reduced kidney excretion of uric acid) that usually occur as early as the teenage years. Slowly progressive interstitial kidney disease begins early in life. Elevations in serum creatinine usually occur between ages five and 40 years, leading to end-stage kidney disease (ESRD) usually between the fourth and seventh decade. The age at ESRD varies both between and within families.

Diagnosis/testing. UMOD-associated kidney disease is defined by the presence of a mutation in UMOD, the gene encoding uromodulin (also known as Tamm Horsfall protein). Elevated serum uric acid concentration and reduced fractional excretion of urate are often, but not always, found. Renal ultrasound examination usually shows normal or small-sized kidneys. Of note, medullary cysts (i.e., in the medulla or at the corticomedullary junction) are a late finding and may not be seen on imaging studies because of their small size.

Management. Treatment of manifestations: Allopurinol or probenecid for treatment of gout; referral to a nephrologist (to monitor kidney function, evaluate for manifestations of chronic kidney disease, prepare for renal replacement therapy). Hemodialysis and peritoneal dialysis can replace renal function; kidney transplantation is curative.

Prevention of primary manifestations: Treatment of hyperuricemia with allopurinol or febuxostat can prevent development of gout.

Surveillance: Measurement of serum concentration of creatinine and uric acid at least annually.

Agents/circumstances to avoid: Drugs known to be nephrotoxic; volume depletion and dehydration; high meat and seafood intake (may exacerbate hyperuricemia/gout).

Evaluation of relatives at risk: If the UMOD mutation has been identified in an affected family member, offer molecular genetic testing to at-risk relatives particularly: (1) adolescents because of the benefit of allopurinol treatment for hyperuricemia/gout; (2) those who are potential kidney donors; (3) those in whom measurements of serum uric acid and serum creatinine are equivocal.

Pregnancy management: Allopurinol should probably be discontinued in women who are pregnant or who may become pregnant. Women taking an angiotensin-converting enzyme inhibitor and who are pregnant or may become pregnant should transition to another antihypertensive medication. Ideally women should not be taking either allopurinol or an ACE inhibitor during pregnancy.

Genetic counseling. UMOD-associated kidney disease is inherited in an autosomal dominant manner. Most individuals diagnosed with UMOD-associated kidney disease have an affected parent. Each child of an affected individual has a 50% chance of inheriting the mutation. Prenatal testing is possible for pregnancies at increased risk in families in which the disease-causing mutation has been identified. Requests for prenatal testing for conditions which (like UMOD-associated kidney disease) do not affect intellect and have treatment available are not common.

Diagnosis

Clinical Diagnosis

UMOD-associated kidney disease (uromodulin associated kidney disease) is defined by the presence of a mutation in UMOD, the gene encoding uromodulin, the most abundant urinary protein [Hart et al 2002, Turner et al 2003].

UMOD-associated kidney disease is also known as familial juvenile hyperuricemic nephropathy type 1 (FJHN1) and medullary cystic kidney disease type 2 (MCKD2) [Bleyer et al 2010].

Clinical findings include the following:

  • Hyperuricemia and gout, found in most (not all) affected individuals. The first manifestation in almost all individuals is an elevated serum (blood) uric acid concentration (see Testing). Elevated serum uric acid concentrations frequently result in gout in the teen years, especially in young men, though it also can occur in women [Bleyer et al 2003].
  • Slowly progressive chronic tubulo-interstitial kidney disease. Affected individuals usually develop asymptomatic elevations in their serum creatinine concentration between ages ten and 40 years, although asymptomatic elevations may occur at a younger age [Schäffer et al 2010]. End-stage renal disease (ESRD) usually develops in the fourth to seventh decades of life [Bleyer et al 2003].
  • Autosomal dominant inheritance. The presence of gout prior to onset of kidney failure and/or ESRD in a number of family members suggests this condition.

Testing

Serum concentration of uric acid. Hyperuricemia (serum uric acid concentration >6 mg/dL) is present in the vast majority of individuals with UMOD-associated kidney disease, even prior to the development of kidney failure.

Usually, hyperuricemia in an individual with normal kidney function corresponds to a serum concentration of uric acid more than 1 SD above the normal value for age and sex.

Note: It is important to compare the serum uric acid concentration with age- and gender-specific normal values (see Table 1) [Wilcox 1996].

Table 1. Serum Uric Acid Concentration in Individuals with Normal Renal Function

AgeSerum Concentration (mg/dL)
MalesFemales
<5 years3.6±0.9
5-10 years4.1±1.0
12 years4.4±1.14.5±0.9
15 years5.6±1.14.5±0.9
>18 years6.2±0.84.0±0.7

Fractional excretion of urinary uric acid is usually decreased in UMOD-associated kidney disease [Moro et al 1991].

The fractional excretion of urinary uric acid can be calculated as shown:

Urinary uric acid concentration x serum creatinine concentration ÷ serum uric acid concentration x urine creatinine concentration

In UMOD-associated kidney disease, the fractional excretion of uric acid is usually less than 5% in adult men and less than 6% in adult women. The reduction of urate excretion is an early event since it can be detected in affected children with preserved renal function [Moro et al 1991, McBride et al 1998].

Note: (1) The fractional excretion of urinary uric acid can be measured from a spot urine sample; however, a 24-hour urine collection is preferable. (2) Aspirin, diuretics, and nonsteroidal agents should be avoided during the collection. (3) Because the fractional excretion of uric acid rises above 5% as renal function worsens, this test is not sensitive in individuals with UMOD-associated kidney disease who have an estimated glomerular filtration rate less than 70 mL/min. (4) Because of limited experience in children younger than age three years, the level of fractional excretion of urate is not known, but is likely to be low.

Table 2 provides the reference ranges by age in individuals with normal kidney function. A fractional excretion of urate more than 1 SD below the mean suggests reduced urate excretion.

Table 2. Fractional Excretion of Urinary Uric Acid in Individuals with Normal Renal Function

Age (Gender)Mean (%) Standard Deviation
0-6 weeks29.111.7
6 weeks - 1 year23.910.4
1-3 years15.26.2
3-13 years12.25.5
>13 years (male)8.03.7
>13 years (female)10.34.2

Kidney function and findings

  • Urinalysis. Usually the urinary sediment is bland (i.e., little blood or protein). Usually hematuria is not present, and excretion of protein is less than 1 g/24 hours except when kidney failure is advanced. A recent report noted increased urinary protein in two individuals with a UMOD mutation and advanced kidney disease; thus the presence of proteinuria cannot completely exclude UMOD-associated kidney disease [Gbadegesin, personal communication].
  • Renal ultrasound examination usually reveals normal kidneys. With more advanced disease, small kidneys may be seen. Cysts in the medulla of the kidney may be seen in advanced disease.
  • Kidney biopsy
    • Histologic examination shows chronic interstitial nephritis, with focal tubular atrophy and interstitial fibrosis, occasionally accompanied by lymphocytic infiltration. The main lesions include tubular basement membrane disintegration (thickening and attenuation) and medullary cyst formation in distal tubules and collecting ducts [Simmonds et al 1980, Richmond et al 1981, Gagnadoux et al 1989, Puig et al 1993, Dahan et al 2001].

      Note: Biopsy interpretation may be misleading: many pathologists focus on glomerular changes (which are secondary) and may make the incorrect diagnosis of focal glomerulosclerosis [Bleyer et al 2005].
    • Immunostaining. Normally uromodulin (also known as the Tamm-Horsfall protein [THP]), is distributed primarily in the tubular cells lining the thick ascending limbs of the loops of Henle and early distal convoluted tubules with a staining pattern characteristic of apical membrane reactivity [Sikri et al 1981]. Significant modification in the expression and immunostaining pattern for THP is detected in the kidneys of persons with a UMOD mutation, in particular intense staining limited to a number of tubule profiles that sometimes are enlarged or even cystic. At higher magnification, the THP immunostaining is diffusely intracellular, with intratubular heterogeneity [Dahan et al 2003].

      Note: Immunostaining for THP is not routinely performed by clinical laboratories and may only be available at centers pursuing research in this area.
  • Uromodulin excretion in the urine is low in individuals with UMOD-associated kidney disease at a very young age prior to the decline in kidney function [Bleyer et al 2004]. Because decreased urinary uromodulin is associated with other forms of chronic kidney disease, its measurement in a person with early chronic kidney disease is nonspecific and nondiagnostic [Bleyer et al 2004].

Molecular Genetic Testing

Gene. UMOD, encoding uromodulin (Tamm-Horsfall glycoprotein, or THP), the most abundant urinary protein [Hart et al 2002], is the only gene in which mutations cause UMOD-associated kidney disease [Wolf et al 2003a].

Clinical testing

Table 3. Summary of Molecular Genetic Testing Used in UMOD-Associated Kidney Disease

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
UMODSequence analysisSequence variants 4>95% 5
Sequence analysis of exons 3, 4, 5, 7 6, 7Sequence variants 4>95% 5
Duplication/deletion analysis 8(Multi)exonic or whole-gene deletion/duplicationUnknown; none reported 9

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Mutations in UMOD have been identified in exons 3, 4, 5, and 7 [Williams et al 2009]. Most mutations are identified in exons 3 and 4. It is important to determine whether a diagnostic laboratory sequences all UMOD coding exons or only select exons, which may miss mutations in other exons.

6. Specific exons sequenced may vary by laboratory.

7. Note: See Molecular Genetic Pathogenesis regarding exon numbering of UMOD.

8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

9. No exonic or whole-gene deletions or duplications have been reported as a cause of UMOD-associated kidney disease. This type of mutation would be an unlikely cause of this condition; thus, the clinically utility of such testing is unknown.

Interpretation of test results. A mutation identified in exon 3, 4, 5, or 7 of UMOD is highly likely to be causative of UMOD-associated kidney disease. The following characteristics point to a mutation being causative:

  • All mutations identified thus far have been in exons 3, 4, 5, 6, 7, and 8. [Moskowitz et al 2013]. It is highly likely that disease-causing mutations may be found in the future in other exons as well [Author, personal observation].
  • Approximately two thirds of mutations result in an amino acid change that either creates or replaces a cysteine residue. All such mutations have been found to cause UMOD-associated kidney disease.
  • Mutations involving more than one amino acid change have all been associated with disease [Bleyer et al 2003].
  • Mutations that result in a significant change in the size or polarity of the amino acid residue are more likely to result in disease.

Testing Strategy

To confirm/establish the diagnosis in a proband. Figure 1 summarizes the diagnostic algorithm for inherited kidney disease.

Figure 1

Figure

Figure 1. Testing strategy for inherited kidney disease

  • Urinalysis to evaluate for presence or absence of hematuria or proteinuria. If the urinary sediment is bland (little proteinuria and no hematuria), the individual has a form of inherited interstitial kidney disease. If blood or protein is present in the urine, consider inherited glomerulonephritis (e.g., Alport syndrome).
  • Renal ultrasound examination to evaluate for the presence or absence of cysts. Presence of multiple cysts suggests polycystic kidney disease. See Differential Diagnosis.
  • Family history to determine if the kidney disease is inherited in an autosomal dominant manner. If the disease is inherited in an autosomal recessive manner other conditions, such as nephronophthisis, should be considered (see Differential Diagnosis).
  • Molecular genetic testing. In individuals with autosomal dominant inheritance of progressive chronic kidney disease with inactive urinary sediment molecular genetic testing of UMOD, MUC1 (the gene associated with medullary cystic kidney disease type 1) or REN (associated with Familial juvenile hyperuricemic nephropathy type 2) (see Differential Diagnosis section) should be considered. Testing may be considered sequentially or simultaneously.
    • Consider molecular genetic testing of UMOD first if there is a strong family history of gout and no history of childhood anemia.
      • Mutations in UMOD are the most common. Hyperuricemia and gout is more common in individuals with mutations in UMOD compared to individuals with mutations in REN or MUC1.
    • Consider molecular testing for MUC1 in families with a similar history of chronic kidney disease, bland urinary sediment, and autosomal dominant inheritance, but without early-onset gout, childhood anemia, mild hyperkalemia, and mild hypotension.
    • Consider molecular genetic testing of REN first if there is a family of anemia in childhood, mild hyperkalemia, and mild hypotension.
  • If no mutation is identified in UMOD, MUC1, or REN, consider referral to a center studying inherited kidney disease.

Note: Kidney biopsy should not be performed to establish a diagnosis of UMOD-associated kidney disease because it is an invasive procedure with some risk; and pathologic findings are too nonspecific to reliably identify the causative disorder. Molecular genetic testing, the gold standard for diagnosis, is safer and less expensive than kidney biopsy. However, some affected individuals (or their relatives) may have undergone kidney biopsy prior to consideration of UMOD- or REN-associated kidney disease as a diagnostic possibility.

Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Initial symptoms of UMOD-associated kidney disease (uromodulin-associated kidney disease) are relatively mild. The impaired ability to maximally concentrate urine may give rise to polyuria. For this reason, the prevalence of enuresis is somewhat increased by age ten years [Hart et al 2002].

Hyperuricemia or gout. The usual presenting feature is hyperuricemia or gout. However, hyperuricemia is not a constant finding: some women over age 16 years who have a UMOD mutation have been found to have a normal serum uric acid concentration [Bleyer & Hart 2003, Dahan et al 2003]. Furthermore, a history of gout is recorded in only 45% of individuals with a UMOD mutation, with onset ranging from ages eight to 38 years [Dahan et al 2003].

Gout characteristically involves the big toe, other areas of the feet, the ankle, or the knees. Onset is acute with severe tenderness and redness of the affected joint. While not all affected individuals have gout, virtually all families have a number of family members who have gout.

In those with a strong family history of UMOD-associated kidney disease, diagnosis of gout is usually made by the affected individual or a parent. As renal function worsens, gout worsens and the frequency of attacks increases. Without treatment, tophi (large subcutaneous depositions of uric acid) and crippling arthritis can develop.

Slowly progressive chronic tubulo-interstitial kidney disease. Mild chronic renal insufficiency may occur in childhood and is usually incidentally noted on laboratory testing for other reasons or when screening is performed in children of an affected individual.

The chronic tubulo-interstitial kidney disease of UMOD-associated kidney disease usually leads to end-stage renal disease (ESRD) in the fourth through seventh decade of life, although renal disease can progress to ESRD before age 30 years [Simmonds et al 1980, Richmond et al 1981, Cameron et al 1993, Puig et al 1993]. Symptoms of ESRD include loss of appetite, nausea, cold intolerance, and fatigue. The age at ESRD varies both between families and among affected individuals in the same family. For example, three affected individuals in one family had ESRD between age 46 and 50 years, whereas two others did not need renal replacement therapy at ages 56 and 63 years [Puig et al 1993].

Early in the disease course hypertension is not a prominent finding.

Other. No other systemic manifestations of disease are present.

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known at the present time.

Penetrance

Penetrance appears to be complete, although some individuals (especially females) may not develop ESRD until the sixth or seventh decade.

The penetrance of hyperuricemia has been estimated at 92% in people with UMOD-associated kidney disease of all ages [Bleyer et al 2003].

Anticipation

It is unknown if anticipation occurs. Gout may be more prevalent in younger generations because of the increase in worldwide consumption of meat.

Nomenclature

The nomenclature for UMOD-associated kidney disease and related conditions is very confusing.

The term "autosomal dominant tubulo-interstitial kidney disease" refers to disorders characterized by: (1) autosomal dominant inheritance; (2) slowly progressive chronic tubulo-interstitial 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:

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 tubulo-interstitial 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 mutations 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.

Prevalence

UMOD-associated kidney disease is rare, accounting for less than 1% of ESRD. However, UMOD-associated kidney disease has been chronically underdiagnosed and prevalence rates may be somewhat higher.

Differential Diagnosis

Polycystic kidney disease. In persons with kidney disease inherited in an autosomal dominant manner, one must first exclude autosomal dominant polycystic kidney disease (ADPKD), in which a large number of cysts are seen on renal ultrasound examination in affected individuals older than age 25 years. In an individual who is at 50% risk for ADPKD the following findings on renal ultrasound examination are diagnostic for ADPKD:

  • The presence of three or more (unilateral or bilateral) renal cysts in an individual aged 15-39 years
  • The presence of two or more cysts in each kidney in an individual aged 40-59 years

If the urinary sediment is bland (i.e., with little blood or protein) and the individual does not have ADPKD, the two other forms of autosomal dominant tubulo-interstitial kidney disease to consider are:

Another condition to be considered is any form of hereditary glomerulonephritis. Affected individuals invariably have significant proteinuria (>3 g/24 hour urine) and/or hematuria. Rarely, individuals with UMOD-associated kidney disease have been found to have proteinuria; however, this is uncharacteristic.

Fabry disease, an X-linked disorder, results from deficient activity of the enzyme α-galactosidase (α-Gal) A and progressive lysosomal deposition of globotriaosylceramide (GL-3) in cells throughout the body. The classic form, occurring in males with less than 1% α-Gal A activity, usually has its onset in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesias), the appearance of vascular cutaneous lesions (angiokeratomas), hypohidrosis, characteristic corneal and lenticular opacities, and proteinuria (which usually exceeds that seen in UMOD-associated kidney disease). Gradual deterioration of renal function to end-stage renal disease (ESRD) usually occurs in the third to fifth decade. Males with greater than 1% α-Gal A activity have a cardiac or renal variant phenotype. Rarely, heterozygous carrier females may have symptoms as severe as those observed in males with the classic phenotype.

Gout may lead to the suspicion of chronic lead poisoning.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with UMOD-associated kidney disease, the following evaluations are recommended:

  • Determination of kidney function (measurement of serum creatinine concentration)
  • Measurement of serum uric acid concentration
  • Referral to a nephrologist due to the possibility of progression to chronic kidney disease
  • Medical genetics consultation

Treatment of Manifestations

Hyperuricemia/gout. Gout typically responds well to prednisone, nonsteroidal anti-inflammatory drugs (NSAIDs), or colchicine.

Treatment with allopurinol or probenecid should be considered in individuals with gout. With allopurinol treatment, serum uric acid concentration returns to normal and gout attacks can be entirely prevented. Lifelong therapy with allopurinol may be required. In individuals with allergies or intolerance to allopurinol, febuxostat may be considered; however, no data on the use of this medication in UMOD-associated kidney disease are available at present.

Renal disease. Referral to a nephrologist is indicated to monitor kidney function, evaluate for manifestations of chronic kidney disease, and prepare for renal replacement therapy when renal insufficiency occurs.

Renal replacement therapies such as hemodialysis and peritoneal dialysis replace renal function but are associated with potential complications.

Kidney transplantation cures UMOD-associated kidney disease. The transplanted kidney does not develop the disease.

The following studies suggest that it is possible that treatment with allopurinol or benzbromarone slows progression of medullary cystic kidney disease (most of which is likely UMOD-associated kidney disease) [Fairbanks et al 2002, Bleyer & Hart 2003]; however, it is important to note that progression of UMOD-associated kidney disease is slow in younger individuals and controlled trials have not been performed.

  • Pirson et al [2000] reviewed the results of allopurinol administered to 20 individuals for at least four years. In 13 who were treated for seven to 23 years, deterioration of renal function continued; in the other seven, renal function remained stable or tended to improve. Of note, in the latter group, four persons had had the disease for less than 20 years when they started treatment; in three individuals, follow up was for at least five years.
  • Fairbanks et al [2002] showed that 21 of 27 individuals from eight families maintained stable renal function during allopurinol treatment given for a mean of 14.5 years (mean age: 34 years).
  • In the majority of individuals studied by the authors, renal disease has progressed despite the use of allopurinol [Author, personal observation].

Prevention of Primary Manifestations

Treatment of hyperuricemia with allopurinol or febuxostat can prevent development of gout.

Kidney transplantation cures UMOD-associated kidney disease. The transplanted kidney does not develop the disease.

Surveillance

Appropriate surveillance includes the following:

  • Measurement of serum creatinine concentration at least annually in affected individuals, and more frequently in those with severe disease
  • Measurement of serum uric acid concentration at least annually

Agents/Circumstances to Avoid

Volume depletion and dehydration may worsen hyperuricemia and lead to more frequent attacks of gout.

High meat and seafood intake could exacerbate gout.

Drugs known to be nephrotoxic (e.g., NSAIDs) should be avoided.

Evaluation of Relatives at Risk

If the UMOD mutation has been identified in an affected family member, it is appropriate to offer molecular genetic testing of at-risk relatives, particularly:

  • Adolescents because of their increased risk for gout, which can be prevented with allopurinol treatment;
  • Relatives interested in donating a kidney to an affected family member.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

There are no pregnancy issues that are particular to UMOD-associated kidney disease. However, in general, chronic kidney disease, depending on the stage, can affect pregnancy through increased hypertension and increased fetal loss.

Women of childbearing age who are taking medications such as allopurinol or an angiotensin-converting enzyme (ACE) inhibitor should discuss their medication regimen with their physician prior to conception.

  • A recent study has suggested that allopurinol usage during pregnancy may be associated with fetal malformations. While the study included women who were on many other medications when they became pregnant, allopurinol should probably be discontinued in women who are pregnant or who may become pregnant [Hoeltzenbein et al 2013].
  • Similarly, the use of ACE inhibitors during the second and third trimesters of pregnancy can result in fetal damage and death. Women who are taking ACE inhibitors prior to pregnancy or at the time of conception should be transitioned to another antihypertensive medication.

Ideally women should not be taking either allopurinol or an ACE inhibitor during pregnancy.

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

UMOD-associated kidney disease (uromodulin-associated kidney disease) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with UMOD-associated kidney disease have an affected parent.
  • A proband with UMOD-associated kidney disease may have the disorder as the result of a new gene mutation.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include UMOD molecular genetic testing and measurement of serum concentrations of uric acid and creatinine. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: Although most individuals diagnosed with UMOD-associated kidney disease have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, 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 and/or has a UMOD mutation, 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.
  • Parental germline mosaicism has not been reported.

Offspring of a proband. Each child of an individual with UMOD-associated kidney disease has a 50% chance of inheriting the mutation.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for UMOD-associated kidney disease is possible using the techniques described in Molecular Genetic Testing. Such testing is helpful in predicting the future development of chronic kidney disease. When testing at-risk individuals for UMOD-associated kidney disease, an affected family member should be tested first to confirm the molecular diagnosis in the family.

Testing for the disease-causing mutation in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow up and evaluations.

Testing of at-risk asymptomatic individuals younger than age 18 years. Because of the increased risk for gout, which can be prevented with allopurinol treatment in adolescents who have a UMOD mutation, testing at-risk family members during adolescence may be appropriate. In addition, individuals younger than age 18 years who are symptomatic usually benefit from having a specific diagnosis established.

See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like UMOD-associated kidney disease) do not affect intellect and have treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Individuals who have UMOD-associated kidney disease will not be affected with kidney disease for 30 to 40 years. It is anticipated that rapid advances in treatment, renal replacement therapy, and transplantation will result in marked improvements in care for individuals with this disease.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

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.

  • Medline Plus
  • UMOD-Related Kidney Disease Registry
    Wake Forest University School of Medicine is keeping a registry of families with UMOD mutations. Please contact ableyer@wfubmc.edu if interested in participating.
    Email: ableyer@wfubmc.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. UMOD-Associated Kidney Disease: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
UMOD16p12​.3UromodulinUMOD homepage - Mendelian genesUMOD

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for UMOD-Associated Kidney Disease (View All in OMIM)

162000HYPERURICEMIC NEPHROPATHY, FAMILIAL JUVENILE, 1; HNFJ1
191845UROMODULIN; UMOD
603860MEDULLARY CYSTIC KIDNEY DISEASE 2; MCKD2
609886GLOMERULOCYSTIC KIDNEY DISEASE WITH HYPERURICEMIA AND ISOSTHENURIA

Molecular Genetic Pathogenesis

UMOD-associated kidney disease (uromodulin-associated kidney disease) is an endoplasmic reticulum storage disease resulting in chronic renal failure from deposition of abnormal uromodulin over time [Rampoldi et al 2003, Bleyer et al 2004].

Normal allelic variants. The gene comprises 11 exons. Exon 1 is noncoding. Note: Exon numbering may vary in the literature; this GeneReview uses that of Williams et al [2009].

Pathologic allelic variants. More than 40 mutations have been found in families with UMOD-associated kidney disease [Hart et al 2002, Dahan et al 2003, Rampoldi et al 2003, Turner et al 2003, Wolf et al 2003b, Kudo et al 2004, Lens et al 2005, Puig et al 2006]. Mutations are almost exclusively missense changes.

Normal gene product. Uromodulin is a large glycoprotein with a large number of cysteine residues [Serafini-Cessi et al 2003] (reference sequence NP_001008390.1). Uromodulin is produced only in the thick ascending limb of Henle's loop of the renal tubule; therefore, disease is limited to the kidney. While uromodulin is the most common protein found in normal human urine, its function is uncertain. Uromodulin is likely responsible for maintaining the integrity of the thick ascending limb of Henle's loop, the kidney region in which the water permeability is remarkably low and salts are efficiently absorbed. Although it has been postulated that uromodulin is important in preventing urinary tract infections, individuals with abnormal uromodulin do not have an increased incidence of urinary tract infections or kidney stones.

Abnormal gene product. A majority of the mutations causing UMOD-associated kidney disease involve an addition or deletion of a cysteine residue or highly conserved polar residue that are likely to alter either disulfide bond formation, thereby disrupting the correct protein folding [Whiteman & Handford 2003], or hydrophobicity distribution responsible for protein spatial flexibility [Xu et al 1997].

Increasing evidence supports the fact that intracellular accumulation of mutant uromodulin leads to increased apoptosis and likely is an important contributor to the pathogenesis of this disorder [Williams et al 2009]. Abnormal uromodulin may also prevent the proper function of ion channels in the thick ascending limb, resulting in mild natriuresis leading to proximal tubular reabsorption of urate and hyperuricemia [Renigunta et al 2011].

Histochemical studies have shown abnormal uromodulin deposition in the endoplasmic reticulum of cells of the thick ascending limb of Henle's loop. In heterozygotes, urinary excretion of uromodulin is much less than half the expected amount, likely resulting from a dominant-negative effect (e.g., interference with synthesis of the normal uromodulin by abnormal uromodulin). Accordingly, the abnormal expression of the mutated uromodulin in the thick ascending limb of Henle's loop of the renal tubule decreases NaCl reabsorption and subsequently induces a state of volume contraction known to promote the proximal reabsorption of urate [Renigunta et al 2011].

References

Literature Cited

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Suggested Reading

  1. Bisceglia M, Galliani CA, Senger C, Stallone C, Sessa A. Renal cystic diseases: a review. Adv Anat Pathol. 2006;13:26–56. [PubMed: 16462154]
  2. Bleyer AJ, Hart TC. Genetic factors associated with gout and hyperuricemia. Adv Chronic Kidney Dis. 2006;13:124–30. [PubMed: 16580613]
  3. Gbadegesin R, Lavin PJ, Homstad A, Wu G, Byrd A, Eckel JJ, Winn MP. Novel insertion-deletion mutation in uromodulin in a large kindred with familial CKD and nephrotic range proteinuria. Denver, CO: American Society of Nephrology Annual Meeting; 2010.

Chapter Notes

Author Notes

Dr. Bleyer pursues active clinical research in the area of MCKD. He is forming a registry of individuals with UMOD mutations. In addition, he is most interested in identifying families with the MCKD phenotype who have a mutational analysis that is negative. Please call with any questions about MCKD (336-716-4513).

Wake Forest University School of Medicine, Section on Nephrology

Author History

Anthony J Bleyer, MD, MS (2006-present)
Karn Gupta, MD; Wake Forest University School of Medicine (2006-2011)
P Suzanne Hart, PhD (2011-present)

Revision History

  • 12 September 2013 (me) Comprehensive update posted live
  • 15 March 2011 (me) Comprehensive update posted live
  • 26 September 2007 (cd) Revision: prenatal diagnosis available
  • 12 January 2007 (me) Review posted to live Web site
  • 3 August 2006 (ajb) Original submission
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