Clinical characteristics.

Autosomal dominant tubulointerstitial kidney disease caused by UMOD pathogenic variants (ADTKD-UMOD) was previously known as familial juvenile hyperuricemic nephropathy type 1 (FJHN1), medullary cystic kidney disease type 2 (MCKD2), and UMOD-associated kidney disease (or uromodulin-associated kidney disease). Typical clinical findings:

• Urinalysis revealing minimal protein and no blood
• Slowly progressive chronic kidney failure, usually first noted in the teen years and progressing to end-stage renal disease (ESRD) between the fourth and seventh decades (Age at ESRD varies among and within families.)
• Hyperuricemia and gout (resulting from reduced kidney excretion of uric acid) that occurs as early as the teenage years

Diagnosis/testing.

ADTKD-UMOD is defined by the presence of a heterozygous pathogenic variant in UMOD, the gene encoding uromodulin. The majority of persons with ADTKD-UMOD have the following laboratory test abnormalities: elevated serum creatinine (decreased estimated glomerular filtration rate), bland urinary sediment, elevated serum urate level, and reduced fractional excretion of uric acid. In children with the disorder, serum creatinine levels may be normal but elevated serum urate levels are usually present.

Management.

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

Prevention of primary manifestations: Allopurinol, febuxostat, or probenecid lowers high serum urate levels effectively and will 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 causative UMOD pathogenic variant 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 administration for the prevention of gout; (2) potential kidney donors.

Pregnancy management: Allopurinol should 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.

ADTKD-UMOD is inherited in an autosomal dominant manner. Most individuals diagnosed with ADTKD-UMOD have an affected parent. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant. Prenatal testing is possible for pregnancies at increased risk in families in which the pathogenic variant has been identified.

Suggestive Findings

Autosomal dominant tubulointerstitial kidney disease, UMOD-related (ADTKD-UMOD) should be suspected in individuals with the following findings:

Clinical

• Tubulointerstitial kidney disease. Urinalysis of affected individuals reveals few or no red cells or white cells, and <500 mg of urinary protein.
• Slowly progressive chronic 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 decade of life [Bleyer et al 2003].
• Hyperuricemia and gout, found in most (not all) affected individuals. Elevated serum uric acid concentrations are usually present in childhood and often result in gout in the teen years, especially in young men, though it also can occur in women [Bleyer et al 2003]. Some families have milder forms of disease, and in these families, gout may be uncommon or absent in family members [Smith et al 2011].
• Autosomal dominant inheritance. The presence of chronic kidney disease (elevated serum creatinine) or ESRD inherited in an autosomal dominant manner is another important clue to this disorder.

Establishing the Diagnosis

The diagnosis of ADTKD-UMOD is established in a proband by identification of a heterozygous pathogenic variant in UMOD by molecular genetic testing (see Table 3).

Molecular testing approaches can include single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing:

• Single-gene testing. Full sequence analysis of UMOD has identified all causative pathogenic variants in ADTKD-UMOD. Since ADTKD-UMOD occurs through a gain-of-function mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant.
• A multi-gene panel that includes UMOD and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multi-gene panel that includes UMOD) fails to confirm a diagnosis in an individual with features of ADTKD-UMOD. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

The initial presenting feature is either chronic tubulointerstial kidney disease (elevated serum creatinine) or gout.

Slowly progressive chronic tubulointerstitial kidney disease. Most commonly, the presenting sign is an elevated serum creatinine in a patient with a family history of kidney disease. A mild elevation in serum creatinine 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 tubulointerstitial kidney disease of ADTKD-UMOD usually leads to end-stage renal disease (ESRD) between the fourth and seventh decades 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]. The age at ESRD varies both between and within families.
• Symptoms of ESRD include loss of appetite, nausea, cold intolerance, and fatigue. The age at ESRD varies both among and within families. 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].
• Unlike most other kidney diseases, hypertension frequently does not occur in ADTKD-UMOD.

Gout. A history of gout is recorded in only 45% of individuals with a UMOD pathogenic variant, 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 ADTKD-UMOD, 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.
• Hyperuricemia is not a constant finding: some women older than age 16 years who have a UMOD pathogenic variant have been found to have a normal serum uric acid concentration [Bleyer & Hart 2003, Dahan et al 2003].

Genotype-Phenotype Correlations

The pathogenic variant p.Val93_Gly97del/insAASC is associated with less frequent gout and possibly a later age of onset of ESRD [Smith et al 2011].

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 ADTKD-UMOD [Bleyer et al 2003].

Nomenclature

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]:

• Autosomal dominant tubulointerstitial kidney disease – MUC1-related (ADTKD-MUC1) (previously medullary cystic kidney disease type 1). Autosomal dominant interstitial kidney disease that is associated with a pathogenic variant in MUC1 [Kirby et al 2013]
• Autosomal dominant tubulointerstitial kidney disease – UMOD-related (ADTKD-UMOD) (previously UMOD-associated kidney disease). Familial juvenile hyperuricemic nephropathy type 1, medullary cystic kidney disease type 2 [MCKD2], and uromodulin storage disease
• Autosomal dominant tubulointerstitial kidney disease – REN-related (ADTKD-REN) (previously familial juvenile hyperuricemic nephropathy type 2). Also known as REN-associated kidney disease [Zivná et al 2009]

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. See Nephronophthisis. (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

ADTKD-UMOD is rare, accounting for <1% of ESRD. However, ADTKD-UMOD has been chronically underdiagnosed and prevalence rates may be somewhat higher.

Evaluations Following Initial Diagnosis

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

• Determination of kidney function (measurement of serum creatinine concentration)
• Measurement of serum uric acid concentration
• Referral to a nephrologist because of the possibility of progression to chronic kidney disease
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Hyperuricemia/gout

• Acute gout typically responds well to prednisone, short-term nonsteroidal anti-inflammatory drugs (NSAIDs), or colchicine.
• Gout prevention with allopurinol or probenecid should be considered.
  • 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.

Kidney 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 ADTKD-UMOD. The transplanted kidney does not develop the disease.
• Allopurinol may slow the progression of kidney disease, although reliable data are not available [Pirson et al 2000, Fairbanks et al 2002].

Prevention of Primary Manifestations

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

Kidney transplantation cures ADTKD-UMOD. 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 should be avoided. NSAIDs are appropriate for short-term administration for treatment of gout or similar painful conditions. However, patients should avoid chronic daily use.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic relatives of an affected individual by molecular genetic testing for the familial UMOD pathogenic variant in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. Particularly important are:

• 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

No pregnancy issues are particular to ADTKD-UMOD. 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 use 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 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.

Mode of Inheritance

Autosomal dominant tubulointerstitial kidney disease, UMOD-related (ADTKD-UMOD) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with ADTKD-UMOD have an affected parent.
• A proband with ADTKD-UMOD may have the disorder as the result of a de novo UMOD pathogenic variant.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include UMOD molecular genetic testing and measurement of serum concentrations of uric acid and creatinine.
• 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.)
• An apparently negative family history cannot be confirmed without molecular genetic testing for the familial UMOD pathogenic variant. 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, a milder phenotypic presentation, early death of the parent before the onset of symptoms, and/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 pathogenic variant, the risk to the sibs of inheriting the variant 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 ADTKD-UMOD has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the UMOD pathogenic variant, his or her family members may be 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 pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the pathogenic variant is de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and 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.

Molecular genetic testing of at-risk asymptomatic relatives of individuals with ADTKD-UMOD is possible after molecular genetic testing has identified the specific pathogenic variant in the family. Such testing is helpful in predicting the future development of chronic kidney disease and should be performed if the family member is considering becoming a kidney donor.

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 pathogenic variant, testing of at-risk family members during adolescence may be appropriate.

Symptomatic individuals younger than age 18 years usually benefit from having a specific diagnosis established.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the UMOD pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for ADTKD-UMOD are possible.

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 ADTKD-UMOD 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.

Molecular Genetic Pathogenesis

Autosomal dominant tubulointerstitial kidney disease, UMOD-related (ADTKD-UMOD) 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].

Gene structure. The gene comprises 11 exons. Exon 1 is non-coding. Note: Exon numbering may vary in the literature; this GeneReview uses that of Williams et al [2009]. See Table A for a detailed summary of gene and protein information.

Pathogenic variants. More than 40 pathogenic variants have been found in families with ADTKD-UMOD [Hart et al 2002, Dahan et al 2003, Rampoldi et al 2003, Turner et al 2003, Wolf et al 2003, Kudo et al 2004, Lens et al 2005, Puig et al 2006]. Pathogenic variants are almost exclusively missense variants.

The majority of the pathogenic variants causing ADTKD-UMOD involve an addition or deletion of a cysteine residue or highly conserved polar residue that is 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].

Pathogenic variants have been identified in exons 3, 4, 5, and 7 of UMOD.

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. Increasing evidence suggests that intracellular accumulation of abnormal uromodulin leads to increased apoptosis and is likely 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].

Published Guidelines/Consensus Statements

• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 2-14-17. [PubMed: 23428972]
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2017. Accessed 2-14-17.

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• Whiteman P, Handford PA. Defective secretion of recombinant fragments of fibrillin-1: implications of protein misfolding for the pathogenesis of Marfan syndrome and related disorders. Hum Mol Genet. 2003;12:727–37. [PubMed: 12651868]
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• Williams SE, Reed AAC, Galvanovskis J, Antignac C, Goodship T, Karet FE, Kotanko P, Lhotta K, Moriniere V, Williams P, Wong W, Rorsman P, Thakker RV. Uromodulin mutations causing familial juvenile hyperuricaemic nephropathy lead to protein maturation defects and retention in the endoplasmic reticulum. Hum Mol Genet. 2009;18:2963–74. [PMC free article: PMC2714724] [PubMed: 19465746]
• Wolf MT, Hildebrandt F. Nephronophthisis. Pediatr Nephrol. 2011;26:181–94. [PMC free article: PMC4160028] [PubMed: 20652329]
• Wolf MT, Mucha BE, Attanasio M, Zalewski I, Karle SM, Neumann HP, Rahman N, Bader B, Baldamus CA, Otto E, Witzgall R, Fuchshuber A, Hildebrandt F. Mutations of the Uromodulin gene in MCKD type 2 patients cluster in exon 4, which encodes three EGF-like domains. Kidney Int. 2003;64:1580–7. [PubMed: 14531790]
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Suggested Reading

• Bisceglia M, Galliani CA, Senger C, Stallone C, Sessa A. Renal cystic diseases: a review. Adv Anat Pathol. 2006;13:26–56. [PubMed: 16462154]
• Bleyer AJ, Hart TC. Genetic factors associated with gout and hyperuricemia. Adv Chronic Kidney Dis. 2006;13:124–30. [PubMed: 16580613]
• 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.

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)
Stanislav Kmoch, PhD (2016-present)

Revision History

• 30 June 2016 (ha) Comprehensive update posted live
• 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