Clinical characteristics.

Autosomal dominant tubulointerstitial kidney disease – UMOD (ADTKD-UMOD) is characterized by normal urinalysis and slowly progressive chronic kidney disease (CKD), usually first noted in the teen years and progressing to end-stage renal disease (ESRD) between the third and seventh decades. Hyperuricemia is often present from an early age, and gout (resulting from reduced kidney excretion of uric acid) occurs in the teenage years in about 8% of affected individuals and develops in 55% of affected individuals over time.

Diagnosis/testing.

The diagnosis of ADTKD-UMOD is established in a proband with suggestive findings and a heterozygous pathogenic variant in UMOD identified by molecular genetic testing.

Management.

Treatment of manifestations: With allopurinol treatment, serum uric acid concentration returns to normal and gout attacks can be entirely prevented. Lifelong therapy with allopurinol is required for future gout prevention. Referral to a nephrologist to monitor kidney function; evaluate for manifestations of CKD, and prepare for renal replacement therapy when ESRD occurs. Renal replacement therapies such as hemodialysis and peritoneal dialysis replace kidney function but are associated with potential complications; kidney transplantation is curative.

Surveillance: 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: Drugs known to be nephrotoxic; volume depletion and dehydration. Nonsteroidal anti-inflammatory drugs are generally discouraged but could be used for short-term administration for treatment of gout or similar painful conditions in early CKD (prior to Stage 3 CKD). Chronic daily use should be avoided.

Evaluation of relatives at risk: Asymptomatic at-risk relatives younger than age 18 years from a family with ADTKD-UMOD with an early age of onset of gout may benefit from testing for the familial UMOD pathogenic variant so that those with the variant can initiate treatment that would prevent gout.

It is appropriate to clarify the genetic status of apparently asymptomatic at-risk adult relatives in order to identify those with the familial UMOD pathogenic variant (and thus, at risk for CKD) who would be benefit from routine surveillance and awareness of agents/circumstances to avoid.

Any relative who is a potential kidney donor should be tested for the familial UMOD pathogenic variant so that only those without the variant are evaluated further for kidney donation.

Pregnancy management: The use of angiotensin-converting enzyme inhibitors even in early pregnancy can result in fetal damage and death. Use of allopurinol during pregnancy should be avoided.

Genetic counseling.

ADTKD-UMOD is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% chance of inheriting the UMOD pathogenic variant. Once the UMOD pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at risk and preimplantation genetic testing are possible.

Suggestive Findings

ADTKD-UMOD should be suspected in individuals with the following findings and family history.

Autosomal dominant inheritance is a key finding in this disease with few distinctive clinical features. One should consider this diagnosis when both the patient and a parent have kidney disease, even if the parent's kidney disease is suspected of having another cause.

Slowly progressive chronic kidney disease (CKD) is often present from childhood, as manifested with an estimated glomerular filtration rate (eGFR) < 90 ml/min/1.73m² [Kidd et al 2020].

Bland urinary sediment without blood or protein is present in almost all individuals. Urinary protein is <250 mg/24 hours except when CKD is advanced (e.g., eGFR <40 mL/min/1.73m²).

Hyperuricemia results from decreased renal excretion of uric acid and is found in almost all affected individuals. The fractional excretion of urate is <5% in most individuals with this disorder, but such a value can also be seen in healthy individuals [Stibůrková & Bleyer 2012]. In children with the disorder, serum creatinine levels may be normal but elevated serum urate levels are usually present.

Usually, hyperuricemia in an individual with normal kidney function corresponds to a serum concentration of uric acid >1 SD of the normal value for age and sex. It is important to use age-related norms for serum urate [Wilcox 1996] (see Table 1).

Gout due to hyperuricemia occurs in 55% of affected individuals [Kidd et al 2020]; 8% of affected children develop gout before age 18 years [Bleyer et al 2021].

Establishing the Diagnosis

NOTE: Kidney biopsy should NOT be performed because it is an invasive procedure with some risk, and pathologic findings are too nonspecific to reliably identify the causative disorder (see Clinical Description). Molecular genetic testing, the gold standard for diagnosis, is safer and less expensive than kidney biopsy.

The diagnosis of ADTKD-UMOD is established in a proband with suggestive findings and a heterozygous pathogenic variant in UMOD identified by molecular genetic testing (see Table 2).

Note: Identification of a heterozygous UMOD variant of uncertain significance does not by itself establish or rule out the diagnosis of this disorder. The authors of this chapter have offered to review with clinicians UMOD variants of uncertain significance; see Molecular Pathogenesis, UMOD-specific laboratory technical considerations, and Chapter Notes.

Molecular genetic testing approaches can include gene-targeted testing (multigene panel) (Option 1) or comprehensive genomic testing (exome sequencing, genome sequencing) (Option 2).

Clinical Description

Autosomal dominant tubulointerstitial kidney disease – UMOD (ADTKD-UMOD) is characterized by a normal urinalysis and slowly progressive chronic kidney disease (CKD), usually first noted in the teen years and progressing to end-stage renal disease (ESRD) between the third and seventh decades [Kidd et al 2020]. Hyperuricemia is often present from an early age, and gout (resulting from reduced kidney excretion of uric acid) occurs in the teenage years in about 8% of affected individuals and develops in 55% of affected individuals over time [Hart et al 2002, Bleyer et al 2021].

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] (see Table 5).

Penetrance

Penetrance appears to be complete, but age related. Some individuals (especially females) may not develop ESRD until the sixth or seventh decade.

Nomenclature

According to the 2015 nomenclature [Eckardt et al 2015], the term "autosomal dominant tubulointerstitial kidney disease" (ADTKD) refers to disorders characterized by the following:

• Autosomal dominant inheritance
• Slowly progressive chronic tubulointerstitial kidney disease resulting in ESRD in the third through seventh decade of life
• Urinalysis revealing a bland urinary sediment (i.e., little blood or protein)
• Renal ultrasound examination that is normal early in the disease course [Bleyer et al 2010]

Terms previously used to refer to ADTKD-UMOD that are no longer in use:

• Familial juvenile hyperuricemic nephropathy 1
• Medullary cystic kidney disease 2 (MCKD2)
• UMOD-associated kidney disease

Prevalence

ADTKD-UMOD accounts for approximately 0.2% of individuals with ESRD [Cormican et al 2019, Groopman et al 2019]. The prevalence is expected to be similar in all populations. Approximately 2,000 individuals have been identified with this disorder; however, these numbers are expected to increase significantly due to better recognition and genetic testing for this condition [Bleyer et al 2020].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ADTKD-UMOD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Care by a nephrologist is recommended.

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

Avoid use of the following:

• Nonsteroidal anti-inflammatory drugs. NSAIDs are generally discouraged except for short-term treatment of gout or similar painful conditions in early CKD (prior to Stage 3 CKD). Chronic daily use should be avoided.
• Drugs known to be nephrotoxic
• The low sodium diet, which is typically prescribed in the treatment of CKD
• Volume depletion, dehydration, and physical exertion under extreme conditions (e.g., in hot weather), as these may worsen hyperuricemia, leading to more frequent attacks of gout

Evaluation of Relatives at Risk

For early diagnosis and treatment

• Asymptomatic at-risk relatives younger than age 18 years. Many experts believe that testing of asymptomatic children for genetic disorders for which there are no specific treatments is inadvisable and violates the child's autonomy. However, genetic testing of a child from a family with ADTKD-UMOD may be considered for the purpose of early diagnosis to initiate treatment that would prevent gout (a secondary manifestation of ADTKD-UMOD). For example, a child may belong to a family with an early age of onset of ESRD and the occurrence of gout in the teenage years. If the child is an athlete or dancer, testing could be considered in order to provide preventive therapy for gout and thus avoid the inopportune occurrence of gout prior to an important sporting event or performance. In contrast, testing of asymptomatic individuals younger than age 18 years should likely be avoided in families with a late age of onset of ESRD and no history of gout in childhood.
  If performed, testing should only be done after a full discussion with the child and after obtaining the child's assent and the parents'/guardians' consent.
• Asymptomatic at-risk adult relatives. It is appropriate to clarify the genetic status of apparently asymptomatic * at-risk adult relatives (by molecular genetic testing for the familial UMOD pathogenic variant) in order to identify those individuals who would benefit from surveillance and awareness of agents/circumstances to avoid.
  * Chronic kidney disease, one of the primary manifestations of this disorder, is often asymptomatic.

For kidney donation. Any relative who is a potential kidney donor should undergo molecular genetic testing to clarify his/her genetic status so that only those who do not have the UMOD pathogenic variant are evaluated further.

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

Pregnancy Management

Pregnancy in women with ADTKD-UMOD is associated with fetal outcomes comparable to the general population. There is an increased risk of hospitalization for high blood pressure [Author, personal observation]. Acceleration of loss of kidney function can be seen in some kidney diseases during pregnancy; data specifically for ADTKD-UMOD are not available.

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

ACE inhibitors. The use of ACE inhibitors even in early 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.

Allopurinol. Published data on the fetal risk associated with use of allopurinol during pregnancy is limited. While a number of pregnancies in which allopurinol was used resulted in the birth of healthy infants, the rare occurrence of a pattern of malformations similar to what is observed in women who use mycophenolate mofetil during pregnancy was reported in two infants born to women who took allopurinol throughout pregnancy [Kozenko et al 2011, Hoeltzenbein et al 2013].

This finding is concerning because the mechanism of action of allopurinol (inhibiting purine degradation) is similar to the mechanism of action of mycophenolate mofetil (inhibition of de novo purine biosynthesis).

Prednisone. Use of prednisone during pregnancy has been associated with fetal growth restriction. Use in the first trimester of pregnancy is associated with a slightly increased risk of orofacial clefting [Carmichael et al 2007].

Colchicine. Chronic use of colchicine that includes the immediate preconception and conception period has been associated with an increased risk of fetal chromosome abnormalities [Berkenstadt et al 2005]. However, the risk of adverse fetal outcome for short courses of colchicine during pregnancy outside of the periconeptional period is low.

See MotherToBaby for further information on medication use 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.

Mode of Inheritance

By definition, autosomal dominant tubulointerstitial kidney disease – UMOD (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.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the UMOD pathogenic variant identified in the proband. 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 a proband depends on the genetic status of the proband's parents:

• If a parent of the proband has the UMOD pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• The rate of chronic kidney disease progression and age of onset of end-stage renal disease (ESRD) can vary significantly between heterozygous sibs and does not correlate well with the age of ESRD in the affected parent.
• If the proband has a known UMOD pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the UMOD pathogenic variant but are clinically asymptomatic, sibs are still presumed to be at increased risk for ADTKD-UMOD because of the possibility of later onset in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with ADTKD-UMOD has a 50% chance of inheriting the UMOD 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.

Predictive testing for at-risk asymptomatic family members requires prior identification of the UMOD 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 in families in which gout occurs at a younger age. In contrast, testing of asymptomatic individuals younger than age 18 years should likely be avoided in families with a late age of onset of ESRD and no history of gout in childhood.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Autosomal dominant tubulointerstitial kidney disease – UMOD (ADTKD-UMOD) is an endoplasmic reticulum storage disease resulting in chronic kidney disease from deposition of abnormal uromodulin over time [Rampoldi et al 2003, Bleyer et al 2004, Williams et al 2009]. 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, in which the water permeability is remarkably low and salts are efficiently absorbed.

UMOD pathogenic variants are mostly missense variants [Kidd et al 2020]. The majority involve the 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].

Mechanism of disease causation. 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].

UMOD-specific laboratory technical considerations. UMOD comprises 11 exons. Exon 1 is noncoding. Note: Exon numbering may vary in the literature; this GeneReview uses that of Williams et al [2009].

Pathogenic variants in UMOD have been identified in exons 3, 4, 5, and 7 [Williams et al 2009]. Most variants are in exons 3 and 4.

For interpretation of variants of uncertain significance:

• An updated list of more than 200 clinically significant UMOD variants maintained by the authors is available here.
• Variants that affect cysteine residues are highly likely to be pathogenic.
• Other testing can include in vitro testing [Kidd et al 2020] and/or immunohistochemical examination of kidney biopsy tissue, if obtained.

Author Notes

Dr Bleyer pursues clinical and genetic research of autosomal dominant tubulointerstitial kidney disease (ADTKD).

Regarding ADTKD-UMOD:

• He and his colleagues (who have diagnosed more than 200 families with ADTKD-UMOD) are committed to using their laboratory and genetic expertise in the interpretation of UMOD variants of uncertain significance.
• He is developing a registry of individuals with benign and pathogenic UMOD variants.

In addition:

• He is most interested in hearing about families with ADTKD in whom no causative variant has been identified on molecular genetic testing of the genes known to cause ADTKD.
• Single-gene testing for MUC1 pathogenic variants can be provided free of charge.

Please contact Dr Bleyer (ableyer@wakehealth.edu) with any questions about ADTKD.

Related website: www.wakehealth.edu

Author History

Anthony J Bleyer, MD, MS (2007-present)
Karn Gupta, MD; Wake Forest University School of Medicine (2007-2011)
P Suzanne Hart, PhD; National Human Genome Research Institute (2011-2021)
Kendrah Kidd, MS (2021-present)
Stanislav Kmoch, PhD (2016-present)
Martina Živná, PhD (2021-present)

Revision History

• 23 December 2021 (sw) Revision: nomenclature corrections (Table 5)
• 8 April 2021 (bp) Comprehensive update posted live
• 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 live
• 3 August 2006 (ajb) Original submission

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 12-21-21.
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 12-21-21.

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