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Autosomal Dominant Tubulointerstitial Kidney Disease, REN-Related (ADTKD-REN)

Synonyms: Familial Juvenile Hyperuricemic Nephropathy Type 2; Early-Onset Hyperuricemia, Anemia, and Progressive Tubulointerstitial Nephropathy; FJHN2

, PhD, , PhD, and , MD, MS.

Author Information
, PhD
Institute for Inherited Metabolic Disorders
Prague, Czech Republic
, PhD
Institute for Inherited Metabolic Disorders
Prague, Czech Republic
, MD, MS
Wake Forest University School of Medicine
Winston-Salem, North Carolina

Initial Posting: ; Last Update: December 29, 2015.

Summary

Clinical characteristics.

Autosomal dominant tubulointerstitial kidney disease, REN-related (ADTKD-REN) (previously familial juvenile hyperuricemic nephropathy type 2 [FJHN2]) is characterized by: hypoproliferative anemia with low hemoglobin concentrations, found in most affected children by age one year; hyperuricemia and gout, found in most (not all) affected individuals; and slowly progressive chronic tubulointerstitial kidney disease. Some affected children have polyuria (excessive urine production leading to frequent urination) and enuresis. Mildly elevated serum creatinine concentration and reduced estimated glomerular filtration rate in an asymptomatic child often progresses to end-stage renal disease (ESRD) in the fourth to sixth decades of life. Of note, information on only fourteen families with this condition has been published; better understanding of the disease is likely to emerge when more families are described.

Diagnosis/testing.

Diagnosis is based on findings of hypoproliferative anemia (low reticulocyte count relative to hemoglobin concentration and low erythropoietin concentration), hyperuricemia (serum uric acid concentration >6 mg/dL), decreased fractional excretion of urinary uric acid, bland urinary sediment, and low plasma renin activity. Kidney size is normal or small with no evidence of cyst formation. REN (encoding renin) is the only gene in which mutation is known to cause ADTKD-REN.

Management.

Treatment of manifestations: Anemia may be reversed by erythropoietin; acute gout typically responds well to prednisone or colchicine. Treatment of low plasma renin activity/low plasma concentration of aldosterone may be indicated prior to the development of stage III chronic kidney disease. If hyperkalemia is present, treatment with fludrocortisone or potassium restriction may be indicated. When end-stage kidney disease develops, kidney transplantation can be performed. ADTKD-REN does not recur in the transplanted kidney, which produces renin in a normal manner.

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

Surveillance: Measurement of hemoglobin concentration and serum concentration of uric acid and creatinine annually starting at the time of diagnosis.

Agents/circumstances to avoid: Nonsteroidal anti-inflammatory medications, especially in persons who are dehydrated. Angiotensin-converting enzyme inhibitors could aggravate the underlying relative renin deficit. Volume depletion and dehydration as well as high meat and seafood intake could exacerbate gout. Patients should not be on the low sodium diet that is typically used in chronic kidney disease.

Evaluation of relatives at risk: If the REN pathogenic variant has been identified in an affected family member, molecular genetic testing of at-risk relatives may be considered, particularly in: children because of their increased risk for anemia; adolescents because of their increased risk for gout, which can be prevented with appropriate treatment; and relatives considering kidney donation.

Genetic counseling.

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

Diagnosis

Suggestive Findings

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

  • Hypoproliferative anemia with low hemoglobin concentrations, found in most affected children by age one year as a result of low erythropoietin production
    • Hemoglobin concentrations can be low (usually 9-11 g/dL).
    • Reticulocyte count is low relative to the hemoglobin concentration.
    • Erythropoietin concentration is low.
    • All other hematologic aspects are normal.
  • Hyperuricemia and gout, found in most (not all) affected individuals as a result of decreased renal excretion of uric acid
    • Hyperuricemia (serum uric acid concentration >6 mg/dL) is present in 80% of affected individuals beginning in childhood.
    • 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 (see Table 1) [Wilcox 1996].
    • Fractional excretion of urinary uric acid is decreased in the vast majority of individuals with ADTKD-REN (see Table 2).
  • Slowly progressive chronic tubulointerstitial kidney disease
    • Urinalysis reveals a bland urinary sediment (i.e., little blood or protein). Hematuria is generally not present, and excretion of protein is <1 g/24h except when kidney failure is advanced.
    • Plasma renin is low.
    • Plasma aldosterone is low.
    • Serum potassium is mildly elevated.
    • Renal ultrasound shows normal to small kidney size without cysts.
    • Kidney biopsy (see Note):

      Histologic examination reveals focal tubular atrophy, secondary glomerular scarring, and interstitial fibrosis [Zivná et al 2009].

      Immunostaining for renin and prorenin is markedly decreased compared to control tissues in the granular cells of the juxtaglomerular apparatus and undetectable in the tubular epithelium early in the course of the disease. In advanced stages, neither the granular cells of the juxtaglomerular apparatus or the tubular epithelium stain for renin or prorenin.

      Note: Kidney biopsy should NOT be performed to establish a diagnosis of ADTKD-REN because it is an invasive procedure with some risk and pathologic findings are too nonspecific to reliably identify the causative disorder. Molecular genetic testing (see Establishing the Diagnosis), 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 ADTKD-REN as a diagnostic possibility.
  • Autosomal dominant inheritance

Table 1.

Serum Uric Acid Concentration in Individuals with Normal Renal Function

AgeSerum Concentration (mg/dL)
MalesFemales
<5 years3.6±0.93.6±0.9
5-10 years4.1±1.04.1±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

Table 2.

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

AgeMeanStandard Deviation 1
0-6 weeks29.1%11.7
6 weeks - 1 year23.9%10.4
1-3 years15.2%6.2
3-13 years12.2%5.5
>13 yearsFemale8.0%3.7
Male10.3%4.2

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

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

1.

A fractional excretion of urate >1 SD below the mean suggests reduced urate excretion.

Establishing the Diagnosis

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

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

  • Single-gene testing. Sequence analysis of REN is performed.
    Note: Only pathogenic missense variants and/or small insertions/deletions affecting renin biosynthesis and trafficking are expected to cause ADTKD-REN, therefore, deletion/duplication testing is not indicated.
  • A multi-gene panel that includes REN and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and sensitivity of multi-gene panels vary by laboratory and over time.
  • Genomic testing may be considered if serial single-gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of ADTKD-REN. Such testing may include whole-exome sequencing (WES), whole-genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq).

    For issues to consider in interpretation of genomic test results, click here.

Table 3.

Summary of Molecular Genetic Testing Used in Autosomal Dominant Tubulointerstitial Kidney Disease, REN-Related (ADTKD-REN)

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
RENSequence analysis 314/14 families 4
1.
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.

Clinical Characteristics

Clinical Description

Fourteen families have been identified with autosomal dominant tubulointerstitial kidney disease, REN-related (ADTKD-REN); therefore, the spectrum of clinical manifestations may not yet be fully appreciated.

First decade of life. Children with ADTKD-REN may first be identified at age one year when a low hemoglobin concentration is identified during routine well child care. Although the children are asymptomatic, mild kidney failure may be evident on tests of renal function at that time.

Affected but as-yet undiagnosed children placed on a nonsteroidal anti-inflammatory drug (NSAID) during a febrile illness may develop acute kidney failure due to the combination of low plasma renin activity, volume depletion, and prostaglandin inhibition [Bleyer et al 2010a]. Acute kidney failure usually resolves if treated appropriately, but chronic kidney failure and anemia may first be noted at that time.

Hyperuricemia with a low fractional excretion of uric acid is present in childhood but is usually asymptomatic.

Second decade of life. As the child enters adolescence, the anemia resolves, and the hemoglobin concentration rises into the normal range.

Elevated uric acid concentrations may result in gout. Gout is associated with the acute onset of pain and erythema in the big toe, forefoot, heel, knee, or other joints. The diagnosis of gout is often missed in this condition because the gout may occur in children or young women, whereas traditional gout occurs in middle-aged men. Gout should be treated acutely with prednisone or colchicine. Gout can be prevented with long-term administration of allopurinol.

Some, but not all, affected individuals have:

  • Polyuria and excessive urine output due to decreased urinary concentrating ability [Bleyer et al 2010a]. Polyuria present in childhood persists into adulthood.
  • Mildly low blood pressure;
  • Mildly elevated serum potassium concentration.

Adulthood. Renal function slowly worsens over time. A mildly elevated serum creatinine concentration and reduced estimated glomerular filtration rate in an asymptomatic child often progresses to end-stage renal disease (ESRD) in the fourth to sixth decades of life. Renal replacement therapy may be necessary in the fourth through seventh decades of life. Kidney transplantation cures the condition.

Genotype-Phenotype Correlations

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

Penetrance

All affected individuals who have undergone genetic testing have been found to have anemia in childhood, hyperuricemia, and chronic kidney disease.

Chronic kidney disease occurs in all affected individuals, although progression may be very slow, with ESRD occurring as late as the seventh decade in some individuals.

Nomenclature

According to the 2015 nomenclature [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 2010a]:

Note: (1) The term "nephronophthisis/medullary cystic kidney disease (NPH/MCKD) complex" was used in the past to refer to both autosomal recessive and autosomal dominant forms of hereditary chronic tubulointerstitial disease [Hildebrandt et al 1992]. Nephronophthisis is now used to refer to a group of conditions with autosomal recessive inheritance that present in childhood with chronic kidney failure. These conditions are caused by pathogenic variants in at least 12 different genes, denoted as nephrocystins (NPHP1- NPHP11, NPHP1L) [Wolf & Hildebrandt 2011]. Clinical characteristics include polyuria, anemia, and slowly progressive kidney failure. (2) Medullary sponge kidney (MSK), associated with calcifications of the medulla of the kidney, hypercalciuria, hematuria, and tubular acidification defects [Gambaro et al 2006], is not in any way related to medullary cystic kidney disease.

Prevalence

Autosomal dominant tubulointerstitial kidney disease, REN-related (ADTKD-REN) is extremely rare, with only approximately fourteen families having been identified world-wide. Several researchers who have studied inherited kidney disease in large numbers of families with inherited kidney disease have identified only a few families with this condition.

Differential Diagnosis

Figure 1 provides a flow diagram to aid in the differential diagnosis of inherited kidney disease.

Figure 1.

Figure 1.

Testing strategy for inherited kidney disease – update 2015

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). Although rare individuals with ADTKD-UMOD have been found to have proteinuria, this is uncharacteristic.

Autosomal dominant polycystic kidney disease (ADPKD). 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 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, the two other forms of autosomal dominant tubulointerstitial kidney disease to consider are the following:

  • 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-UMOD. Like ADTKD-REN, this condition is associated with slowly progressive chronic kidney disease. Persons with a UMOD-associated kidney disease do not have anemia in childhood and do not have the mild hyperkalemia often seen in ADTKD-REN.

Nephronophthisis (NPH; OMIM) is an autosomal recessive form of tubulointerstitial kidney disease. Like ADTKD-REN, it is often seen in childhood and can be associated with anemia and mild hypotension. The two conditions differ in three respects: (1) ADTKD-REN is usually associated with a family history of kidney disease, anemia, and gout. In nephronophthisis, a positive family history would not be expected because the disorder is inherited in an autosomal recessive manne. (2) Anemia in ADTKD-REN will be present from infancy, whereas anemia in nephronophthisis usually correlates with the level of kidney function. (3) The severity of kidney failure is usually much greater in nephronophthisis, with affected individuals usually requiring dialysis in their teens and early twenties. In contrast, individuals with ADTKD-REN usually have an eGFR >50 mL/min into early adulthood. NPH is associated with pathogenic variants in one of at least 19 known genes.

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 (usually exceeding that seen in ADTKD-UMOD). Gradual deterioration of renal function to end-stage renal disease (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 of an individual diagnosed with ADTKD-REN, the following evaluations are recommended:

  • Hemoglobin concentration to document the level of anemia
  • Serum uric acid concentration to identify persons at risk for gout
  • A 24-hour urine collection to quantify urine output and determine if polyuria is present (although this can usually determined by history). Clinical questioning regarding enuresis (bed-wetting) or frequent thirst or urination will help establish a diagnosis of polyuria.
  • A standard basic metabolic panel to determine if hyperkalemia is present
  • Consultation with a medical geneticist and/or genetic counselor

Treatment of Manifestations

Anemia may be reversed by treatment with erythropoietin [Zivná et al 2009], a medication that is given subcutaneously and managed by hematologists or pediatric nephrologists. Dose is based on response to therapy. There is no clear target at this time and it is left to the discretion of the hematologist or nephrologist. Many children have relatively mild anemia with hemoglobin levels of 10 to 11 g/dL, and can be safely followed off of erythropoietin.

Note: The dose of erythropoietin will need to be reduced as hemoglobin concentration increases during adolescence.

Hyperuricemia/gout. Gout typically responds well to prednisone or colchicine. One should not use of nonsteroidal agents in individuals with ADTKD-REN because the combination of nonsteroidal agents and the low renin state in patients with ADTKD-REN can lead to acute kidney injury; prednisone is the preferable alternative.

Prevention of future gout attacks 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 REN-associated kidney disease are available.

Hypotension and mild hyperkalemia may be present in children and young adults with this condition. As chronic kidney disease progresses to stage III chronic kidney disease, hypertension may develop, and hyperkalemia is due not to low plasma renin activity but rather to decreased elimination of potassium by the kidneys.

Therefore, treatment of low plasma renin activity/plasma concentration of aldosterone may be indicated prior to the development of stage III chronic kidney disease. Such treatment may include liberal sodium intake if the patient has mild hypotension and hyperkalemia but preserved kidney function. Dietary sodium intake of 3-4 g/day may prevent hypotension. Note: A low-sodium diet should not be used in persons with ADTKD-REN.

If hyperkalemia is present, treatment with fludrocortisone or potassium restriction may be indicated [Bleyer et al 2010b]. Fludrocortisone treatment (0.1 mg orally/day) of one affected child with low plasma renin activity resulted in a mild rise in blood pressure, correction of mild hyperkalemia, and a significant improvement in estimated glomerular filtration rate that may have been hemodynamically mediated [Bleyer at al 2010b]. The use of fludrocortisone may also prevent hypotension that could result from volume depletion such as that associated with viral syndromes or vigorous activities associated with excessive perspiration. Note: Fludrocortisone treatment in two adults with advanced kidney disease had no clinical effect [Author, personal observation].

Fludrocortisone could have the advantage of decreasing renin production (through negative feedback), and thus the production of the abnormal renin deposits. However, since blockade of the renin angiotensin system and aldosterone production has been a general treatment of chronic kidney disease, it is possible that increased serum concentration of aldosterone may increase progression of renal disease. Thus, while the use of fludrocortisone may potentially be beneficial in this condition, at present its use is at the discretion of the clinician.

Mineralocorticoid replacement. Recommendations regarding treatment are not evidence based due to the small number of individuals with this disorder and the limited experience treating affected individuals.

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 ADTKD-REN. The transplanted kidney does not develop the disease.

Prevention of Primary Manifestations

Treatment with erythropoietin can reverse anemia [Zivná et al 2009].

Treatment of hyperuricemia with allopurinol can prevent development of gout.

Prevention of Secondary Complications

Iron stores should be replenished as needed to treat iron deficiency (an unrelated condition) if it is present.

Surveillance

Measure hemoglobin concentration and serum concentration of uric acid and creatinine annually starting at the time of diagnosis.

Agents/Circumstances to Avoid

The use of nonsteroidal anti-inflammatory medications (NSAIDs) should be avoided, especially in persons who are dehydrated. The use of NSAIDs in a febrile child with ADTKD-REN precipitated acute renal failure [Bleyer et al 2010b]. The use of other analgesics/antipyretics should be considered.

It would appear that the use of an angiotensin-converting enzyme inhibitor may not be beneficial in the treatment of chronic kidney failure and could aggravate the underlying relative renin deficit.

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

High meat and seafood intake could exacerbate gout.

Exertion under extreme conditions (e.g., physical exertion when it is hot) should be avoided.

Evaluation of Relatives at Risk

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

  • Children because of their increased risk for anemia;
  • 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

Successful pregnancies have been documented in women with a REN pathogenic variant. The rate of miscarriages or other adverse outcomes was not increased.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with ADTKD-REN have an affected parent.
  • A proband with ADTKD-REN may have the disorder as the result of a de novo REN pathogenic variant. Because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if the pathogenic variant was de novo, the proportion of ADTKD-REN caused by de novo pathogenic variants is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo REN pathogenic variant include molecular genetic testing of the parents.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are 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 REN 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 disorder and/or a milder phenotypic presentation.
    • Parents will usually have suffered from anemia in childhood, but they may not recall this from their childhood and/or the diagnosis of anemia may have been missed at that time.

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 has the REN 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.
  • The sibs of a proband with apparently unaffected parents are still at increased risk for ADTKD-REN (see Penetrance).
  • If the REN pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with ADTKD-REN has a 50% chance of inheriting the REN 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 REN 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 has ADTKD-REN, the REN pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could 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.

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 REN pathogenic variant has been identified in an affected family member, prenatal testing or preimplantation genetic diagnosis for a pregnancy at increased risk for ADTKD-REN may be options that a couple may wish to consider.

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.

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.

  • REN-Related Kidney Disease Registry
    Dr. Anthony Bleyer has established a registry of individuals with REN mutations. Please contact him (ableyer@wfubmc.edu) if interested in participation.
    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.

Autosomal Dominant Tubulointerstitial Kidney Disease, REN-Related (ADTKD-REN): Genes and Databases

GeneChromosome LocusProteinLocus SpecificHGMD
REN1q32​.1ReninREN databaseREN

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

Table B.

OMIM Entries for Autosomal Dominant Tubulointerstitial Kidney Disease, REN-Related (ADTKD-REN) (View All in OMIM)

179820RENIN; REN
613092HYPERURICEMIC NEPHROPATHY, FAMILIAL JUVENILE, 2; HNFJ2

Molecular Genetic Pathogenesis

Renin is an aspartyl protease synthesized as preprorenin which contains a signal sequence that directs endoplasmic reticulum (ER) targeting, glycosylation, and proteolytic processing [Imai et al 1983]. Renin cleaves angiotensinogen to angiotensin, with the subsequent stimulation of aldosterone production. The renin angiotesin system (RAS) has been found to have widespread and diverse roles, including modulating vascular tone, renal sodium and potassium handling, erythropoiesis, thirst, cardiac hypertrophy, and functioning through local RAS systems in many organs [Paul et al 2006].

In vitro studies have shown that the presence of the mutated signal peptide affects renin targeting and cotranslational translocation of preprorenin into the ER and, thus, proper biosynthesis and intracellular trafficking of prorenin. This results in ER stress, cytosolic accumulation of abnormal non-glycosylated preprorenin, accelerated autophagocytosis, and reduced growth rate. In vivo this gradually reduces viability of renin-producing juxtaglomerular cells, and results – by as-yet undefined mechanism(s) – in tubular atrophy, nephron loss, and chronic kidney failure, similar to that observed in mice with ablated juxtaglomerular cells [Pentz et al 2004].

REN pathogenic variants also result in decreased renin production, a goal of therapy for many chronic kidney diseases. Thus, the disease becomes its own treatment.

Benign allelic variants. REN is located on chromosome 1 (genomic position chr1:204123944-204135465; according to GRCh37/hg19 [Feb 2009] assembly). The gene comprises ten exons, which are transcribed into a 1493-bp long transcript encoding for 406 amino-acid preprorenin (reference sequence NM_000537.3). No pathogenic variants in the C-terminal part of the protein have been associated with disease and are hypothesized to be benign [Villard et al 1994; Bleyer & Kmoch, unpublished data].

Pathogenic allelic variants. Only pathogenic missense variants and/or small insertions/deletions affecting renin biosynthesis and trafficking are expected to cause ADTKD-REN. Pathogenic variants in exons 1 and 2, the exons encoding the signal peptide and propeptide, are expected to account for most pathogenic variants that result in ADTKD-REN.

Normal gene product. Renin is normally produced by modified juxtaglomerular cells of the afferent arterioles in the macula densa of the kidney. Renin cleaves the N-terminal ten amino acids of angiotensinogen to produce angiotensin I, which is further converted to angiotensin II by angiotensin-converting enzyme. Angiotensin II stimulates aldosterone production. Through a number of mechanisms, renin and angiotensin help to maintain normal blood pressure and to lower serum potassium concentrations into the normal range.

Abnormal gene product. ADTKD-REN is caused by REN pathogenic variants predominantly in the signal sequence of the protein renin, affecting targeting and cotranslational translocation of preprorenin into the ER. This leads to reduced expression of renin and other components of the renin angiotensin system in kidney biopsy specimens of affected individuals. It is likely that expression of the mutated proteins has a dominant toxic effect gradually reducing the viability of renin-expressing cells. This alters the intrarenal renin-angiotensin system and the functionality of the juxtaglomerular apparatus, resulting in nephron dropout and progressive kidney failure.

References

Literature Cited

  1. Beck BB, Trachtman H, Gitman M, Miller I, Sayer JA, Pannes A, Baasner A, Hildebrandt F, Wolf MT. Autosomal dominant mutation in the signal peptide of renin in a kindred with anemia, hyperuricemia, and CKD. Am J Kidney Dis. 2011;58:821–5. [PMC free article: PMC3366501] [PubMed: 21903317]
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Chapter Notes

Author Notes

Dr Stanislav Kmoch (zc.inuc.1fl@hcomks) and Dr Anthony Bleyer (ude.cmbufw@reyelba) are actively involved in clinical research regarding individuals with renin mutations and other forms of inherited kidney disease and would be happy to communicate with individuals who have any questions regarding diagnosis or other considerations.

Related Web site: www.wakehealth.edu/Nephrology/Gout-Kidney-Disease.htm

Revision History

  • 29 December 2015 (me) Review posted live
  • 5 April 2011 (me) Review posted live
  • 21 December 2010 (ab) Original submission
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