Clinical characteristics.

The two clinical presentations observed in autosomal dominant tubulointerstitial kidney disease – REN (ADTKD-REN) correlate with the renin protein domains affected by the causative REN variants.

• Childhood/adolescent onset, the more common presentation (caused by REN variants encoding the signal peptide or prosegment domains), is characterized by decreased estimated glomerular filtration rate, acidosis, hyperkalemia, and anemia early in life, followed by slowly progressive chronic kidney disease (CKD) and gout.
• Adult onset, the less common presentation (caused by REN variants encoding the mature renin peptide), is characterized by gout or mild slowly progressive CKD, beginning in the third decade. Anemia, hyperkalemia, and acidemia do not occur.

Diagnosis/testing.

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

Management.

Treatment of manifestations: Care by a nephrologist as soon as ADTKD-REN is diagnosed. In persons with childhood/adolescent-onset disease, anemia may be treated with erythropoietin. Fludrocortisone (a pharmacologic analog of aldosterone) corrects aldosterone deficiency (and associated mild hypotension), hyperkalemia, and acidemia. Treatment with fludrocortisone prior to the development of Stage 3 CKD may be indicated.

In all persons with ADTKD-REN, lifelong treatment of hyperuricemia with allopurinol prevents gout. Renal replacement therapies (such as hemodialysis and peritoneal dialysis) can replace renal function, but are associated with potential complications. Kidney transplantation is curative, as the transplanted kidney does not develop the disease.

Surveillance: Childhood/adolescent-onset disease: measurement of hemoglobin concentration and serum concentration of uric acid, bicarbonate, and creatinine at least every six months starting at the time of diagnosis. Adult-onset disease: similar laboratory testing every six to 12 months, depending on the level of kidney function.

Agents/circumstances to avoid: Nonsteroidal anti-inflammatory drugs, 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 may worsen hyperuricemia and exacerbate gout. Affected individuals should not be on the low-sodium diet typically used in the treatment of CKD.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status (by molecular genetic testing for the familial REN pathogenic variant) of apparently asymptomatic at-risk relatives, as CKD – one of the primary manifestations of this disorder – is often asymptomatic. Diagnosis of an affected individual as early as possible allows prompt initiation of treatment and awareness of agents/circumstances to avoid. Particularly important are: (1) children and adolescents because of their increased risk for acute kidney injury, anemia, acidemia, and hyperuricemia and gout; and (2) relatives interested in donating a kidney to an affected family member.

Genetic counseling.

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

Suggestive Findings

ADTKD-REN should be suspected in individuals with the following clinical findings (grouped by age) and a family history consistent with autosomal dominant inheritance [Živná et al 2020].

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-REN is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in REN identified by molecular genetic testing (see Table 3).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous REN variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of ADTKD-REN has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

In the most comprehensive report of autosomal dominant tubulointerstitial kidney disease due to REN pathogenic variants (ADTKD-REN) to date, comprising 111 individuals from 30 families, Živná et al [2020] observed two clinical presentations, childhood/adolescent onset and adult onset, which correlate with the protein domains encoded by REN variants (see Table 4).

Childhood/adolescent onset, the more common presentation, is caused by REN variants encoding the signal peptide or prosegment domains. It is characterized by decreased estimated glomerular filtration rate (eGFR), acidosis, hyperkalemia, and anemia early in life, followed by slowly progressive chronic kidney disease and gout. Some children also experience polyuria.

Adult onset, the less common presentation, is caused by REN variants encoding the mature renin peptide. It is characterized by gout or mild, slowly progressive CKD, beginning in the third decade. Anemia, hyperkalemia, and acidemia do not occur.

Genotype-Phenotype Correlations

The following phenotype-genotype correlations have been identified based on the REN variants encoding the signal peptide and prosegment protein domains [Živná et al 2020, Table 4]. See Table 7 for details about specific REN pathogenic variants.

Childhood/adolescent-onset disease with a more severe disease course is associated with the following:

• REN variants involving nucleotides c.45-113 in exon 1, which encode the signal peptide domain (i.e., the first 23 amino acids of preprorenin)
• REN variants involving nucleotides c.114-242 in exon 1 and exon 2, which encode the prosegment protein domain (i.e., amino acids 24-66 of preprorenin)

Adult-onset and milder disease course is associated with REN variants involving nucleotides c.243-1262 in exons 2 to 10, which encode the mature renin peptide segment of preprorenin (i.e., amino acids 67-406).

Penetrance

Penetrance is age related. Thus, in individuals with childhood-onset disease, manifestations of ADTKD-REN, especially anemia, are evident early in life; and in individuals with adult-onset disease, manifestations (gout and chronic kidney disease) do not become evident until adulthood.

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 ESKD 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 2010a]

Prevalence

ADTKD-REN is extremely rare, with approximately 30 families reported worldwide [Živná et al 2020 and references therein].

The prevalence of disease is expected to be similar in all populations.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ADTKD-REN, the evaluations summarized in Table 6 (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

Childhood/adolescent-onset disease. Monitor blood pressure, serum potassium, bicarbonate, creatinine, and hemoglobin at least every six months.

Adult-onset disease. Monitor blood pressure, serum potassium, bicarbonate, creatinine, and hemoglobin every six to 12 months, depending on the level of kidney function.

Agents/Circumstances to Avoid

Avoid use of the following:

• NSAIDs, especially in a person who is dehydrated or in a febrile child, as they can precipitate acute renal failure [Bleyer et al 2010b]. The use of other analgesics/antipyretics should be considered.
• Angiotensin-converting enzyme inhibitors, which may not be beneficial in the treatment of CKD and could aggravate the underlying relative renin deficit
• Drugs known to be nephrotoxic
• The low-sodium diet typically prescribed in the treatment of CKD

Avoid the following, which may worsen hyperuricemia, leading to more frequent attacks of gout:

• Volume depletion, dehydration, and physical exertion under extreme conditions (e.g., when it is hot)
• High meat and seafood intake

Evaluation of Relatives at Risk

For early diagnosis and treatment. It is appropriate to clarify the genetic status of apparently asymptomatic* at-risk relatives (by molecular genetic testing for the familial REN pathogenic variant) to identify individuals with the familial REN variant as early as possible in order to monitor their serum creatinine levels, and promptly initiate treatment and awareness of agents/circumstances to avoid. Early evaluation of children and adolescents is particularly important because of their increased risk for acute kidney injury, anemia, acidemia, and hyperuricemia.

* 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 the relative's genetic status so that only those who do not have the REN pathogenic variant are evaluated further.

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 ADTKD-REN. The rate of miscarriages or other adverse outcomes was not increased.

Allopurinol. Published data on the fetal risk associated with use of allopurinol during pregnancy is limited. While a number of pregnancies in which allopurinol use resulted in the birth of healthy infants, the rare occurrence of a pattern of malformations similar to that observed in women who took 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).

In the authors' experience, in ADTKD-REN, most women complete pregnancy without developing gout while not on allopurinol; therefore, the authors recommend discontinuing use of allopurinol during pregnancy.

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 periconceptional period is low.

Erythropoietin use during pregnancy is unlikely to lead to congenital anomalies in the fetus [Cyganek et al 2011].

Fludrocortisone. Women who use high doses of fludrocortisone during pregnancy may be at increased risk of having an infant who has clinical hyperaldosteronism (see Prescribing Information).

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 due to pathogenic variants in REN (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; the proportion of probands who have a de novo pathogenic variant is unknown.
• 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.
• An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the REN 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 disorder and/or a milder phenotypic presentation.
  • Parents will usually have had anemia in childhood, but they may not recall this from their childhood, or the diagnosis of anemia may have been missed at that time.

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 REN pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. ADKTD-REN is associated with biochemical abnormalities from birth in all heterozygous individuals, although some individuals may be clinically asymptomatic.
• If the proband has a known REN 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 REN pathogenic variant but are clinically asymptomatic, sibs are still presumed to be at increased risk for ADTKD-REN because of the possibility of asymptomatic chronic kidney disease or age-related penetrance (see Penetrance) in a heterozygous parent or the theoretic possibility of parental 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, the parent's 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 REN 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.

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 REN pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for ADTKD-REN 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

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 angiotensin system (RAS) has been found to have widespread and diverse roles, including modulation of 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.

Mechanism of disease causation. Autosomal dominant tubulointerstitial kidney disease due to pathogenic variants in REN (ADTKD-REN) is caused by pathogenic variants in the REN signal peptide, prosegment, and mature renin peptide [Zivná et al 2009, Schaeffer et al 2019, Živná et al 2020].

• Mutated signal peptide cannot enter the ER for transcription. Mutated prosegment prevents proper folding of the renin peptide. In both instances, mutated renin is deposited within the cell, leading to cell stress, premature cell death, and subsequent tubular cell dropout, interstitial scarring, and chronic kidney disease. Individuals with childhood/adolescent-onset disease, caused by REN pathogenic variants encoding the signal peptide and prosegment, have more severe disease that presents in childhood.
• Mutated mature renin peptide is deposited in the endoplasmic reticulum. Individuals with adult-onset disease, caused by REN pathogenic variants encoding the mature renin peptide, have milder manifestations (presenting with gout in the third decade) and slower progression to end-stage kidney disease.

REN-specific laboratory technical considerations. Only pathogenic missense variants and/or small insertions/deletions affecting renin biosynthesis and trafficking are expected to cause ADTKD-REN.

REN pathogenic variants occur in exons 1, 2, 8, 9, and 10.

• 62% occur in exon 1 encoding the signal peptide of preprorenin, and 27% in the part encoding the prosegment of prorenin.
• 15% occur in exons 2, 8, 9, and 10 encoding the mature renin peptide.

Author Notes

Martina Živná, PhD (zc.inuc.1fl@anvizm) and Stanislav Kmoch, PhD (zc.inuc.1fl@hcomks) are actively involved in basic research on ADTKD-REN. Anthony Bleyer, MD (ude.htlaehekaw@reyelba) is actively involved in clinical research concerning individuals with REN pathogenic variants and other forms of inherited kidney disease; all the authors would be happy to communicate with individuals who have any questions regarding diagnosis or other considerations.

Related website: www.wakehealth.edu/condition/i/inherited-kidney-disease

Acknowledgements

The authors would like to acknowledge the many patients and their physicians who shared clinical and genetic information that formed the basis of our clinical and genetic characterization of ADTKD-REN.

Revision History

• 10 December 2020 (bp) Comprehensive update posted live
• 29 December 2015 (me) Comprehensive update posted live
• 5 April 2011 (me) Review posted live
• 21 December 2010 (ab) Original submission

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