Autosomal Dominant Tubulointerstitial Kidney Disease, Umod-Related

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2021-01-18

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Genes

UMOD, GLI2, KCNJ1, MUC1, HNF1B

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Summary

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.

Diagnosis

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.

Testing

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.

Serum creatinine (eGFR). As individuals with ADTKD-UMOD 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 estimated glomerular filtration rate from the serum creatinine.
Note: On most laboratory reports, the estimated glomerular filtration rate is included. However, calculators for this purpose are available online (see, e.g., www.mdcalc.com).
A reduced eGFR (<90 mL/min/1.73 m²) is a sensitive indicator of ADTKD-UMOD in adults, but it is not specific, as many individuals in the general population have mildly decreased eGFR measurements.
The lower the eGFR in an affected family member, the more likely it is to indicate ADTKD-UMOD: very few individuals in the general population have an eGFR <60 mL/min/1.73 m².

Urinalysis. In almost all individuals with ADTKD-UMOD, the urinary sediment is bland, with <3 red blood cells/high power field and urinary protein on dipstick negative or 1+.

A 24-hour urinary collection yields <500 grams protein/24 hours.
A spot urinary protein:creatinine ratio will be <500 mg protein/g creatinine.
Rarely, in advanced kidney disease, the urinary protein may be increased.

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

In children, hyperuricemia is more likely to be present than an elevated serum creatinine concentration.
Usually, hyperuricemia in an individual with normal kidney function corresponds to a serum concentration of uric acid >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

Age	Serum Concentration (mg/dL)
Age	Males	Females
<5 years	3.6±0.9
5-10 years	4.1±1.0
12 years	4.4±1.1	4.5±0.9
15 years	5.6±1.1	4.5±0.9
>18 years	6.2±0.8	4.0±0.7

: Mikkelsen et al [1965], Harkness & Nicol [1969], Wilcox [1996]

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

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

Urinary uric acid c. x serum creatinine c. ÷ serum uric acid c. x urine creatinine c.

: c. = concentration

In ADTKD-UMOD, the fractional excretion of uric acid is usually <5% in adult men and <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 ADTKD-UMOD who have an estimated glomerular filtration rate <70 mL/min.

Table 2 provides the reference ranges by age in individuals with normal kidney function. A fractional excretion of urate >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 weeks	29.1	11.7
6 weeks - 1 year	23.9	10.4
1-3 years	15.2	6.2
3-13 years	12.2	5.5
>13 years (male)	8.0	3.7
>13 years (female)	10.3	4.2

: Stibůrková et al [2006]

Kidney imaging and histology

Renal ultrasound examination usually reveals normal kidneys. With more advanced disease, small kidneys may be seen. The ultrasound is not helpful in making the diagnosis of ADTKD-UMOD, except for ruling out polycystic kidney disease or other conditions as a cause of kidney failure.
Kidney biopsy. Histologic examination shows chronic interstitial fibrosis, 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: (1) 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]. (2) Kidney biopsy should not be performed to establish a diagnosis of ADTKD-UMOD because it is an invasive procedure with some risk; and pathologic findings are too nonspecific to reliably identify the causative 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 multigene 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 multigene panel that includes UMOD and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
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 multigene 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.

Table 3.

Molecular Genetic Testing Used in ADTKD-UMOD

Gene ¹	Test Method	Proportion of Probands with a Pathogenic Variant ² Detectable by This Method
UMOD	Sequence analysis ³	>95% ⁴
UMOD	Gene-targeted deletion/duplication analysis ⁵	Unknown; none reported ⁶

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Pathogenic variants in UMOD have been identified in exons 3, 4, 5, and 7 [Williams et al 2009]. Most variants 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 pathogenic variants in other exons. See Molecular Pathogenesis regarding exon numbering of UMOD.
5.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
6.: No exon or whole-gene deletions or duplications have been reported as a cause of ADTKD-UMOD. This type of pathogenic variant would be an unlikely cause of this condition; thus, the clinical utility of such testing is unknown.

Clinical Characteristics

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.

Differential Diagnosis

See Figure 1 for a diagnostic algorithm for inherited kidney disease.

Figure 1.

Testing strategy for inherited kidney disease – 2015 update

Hereditary glomerulonephritis. Affected individuals usually have proteinuria and/or hematuria. If blood or protein is present in the urine, consider inherited glomerulonephritis (e.g., Alport syndrome). Rarely, individuals with UMOD-associated kidney disease have been found to have proteinuria; however, this is uncharacteristic.

Polycystic kidney disease. If the urinary sediment is bland (i.e., with little blood or protein) in persons with kidney disease inherited in an autosomal dominant manner, one must 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.

Other forms of ADTKD. If the individual does not have ADPKD and the urinary sediment is bland, consider the following forms of autosomal dominant tubulointerstitial kidney disease:

ADTKD-MUC1 is associated with pathogenic variants in MUC1. Affected individuals have slowly progressive chronic kidney disease and minimal proteinuria. An important differentiating factor is that in ADTKD-MUC1 gout usually only occurs in the setting of Stage III or later chronic kidney disease. Affected individuals do not suffer from anemia or other manifestations in childhood.
ADTKD-REN is associated with pathogenic variants in REN [Zivná et al 2009]. Like ADTKD-UMOD, this condition is associated with early-onset gout and slowly progressive chronic kidney disease. Persons with a REN pathogenic variant also manifest hypoproliferative anemia in childhood.

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 <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 ADTKD-UMOD). Gradual deterioration of renal function to ESRD usually occurs in the third to fifth decade. Males with >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.

Management

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 take either allopurinol or an ACE inhibitor during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.