Autosomal Dominant Tubulointerstitial Kidney Disease – Ren
Summary
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.
Diagnosis
Consensus clinical diagnostic criteria for autosomal dominant tubulointerstitial kidney disease due to REN pathogenic variants (ADTKD-REN) have been published [Eckardt et al 2015] (full text).
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].
Clinical Findings – Childhood/Adolescent-Onset Disease
Low renin production (low to low-normal plasma renin and aldosterone levels associated with the following in most, but not all, individuals) manifesting as:
- Blood pressure that is often borderline low, but usually asymptomatic
- Hyperkalemia (serum potassium levels >5 mEq/L, sometimes as high as 6.5 mEq/L) in about 50% of individuals, often present from birth
- Acidosis (serum bicarbonate levels between 15 and 24 mEq/L), often present from birth
Hypoproliferative anemia in most affected children by age one year characterized by:
- Low erythropoietin concentration
- Low hemoglobin concentrations (usually 9-11 g/dL)
- Low reticulocyte count relative to the hemoglobin concentration
- Otherwise normal hematologic findings
Hyperuricemia resulting from 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. It is important to use age-related norms for serum urate [Wilcox 1996] (see Table 1).
- Decreased fractional excretion of urinary uric acid in the vast majority of individuals with ADTKD-REN. See Table 2 for reference ranges by age in individuals with normal kidney function.The fractional excretion of uric acid is usually <5% in adult men and <6% in adult women. The reduction of urate excretion 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 who have an eGFR <70 mL/min.
Table 1.
Serum Uric Acid Concentration in Individuals with Normal Renal Function
| Age | Serum Concentration (mg/dL) | |
|---|---|---|
| Males | Females | |
| <5 yrs | 3.6±0.9 | 3.6±0.9 |
| 5-10 yrs | 4.1±1.0 | 4.1±1.0 |
| 12 yrs | 4.4±1.1 | 4.5±0.9 |
| 15 yrs | 5.6±1.1 | 4.5±0.9 |
| >18 yrs | 6.2±0.8 | 4.0±0.7 |
Mikkelsen et al [1965], Harkness & Nicol [1969], Wilcox [1996]
Table 2.
Fractional Excretion of Urinary Uric Acid in Individuals with Normal Renal Function
| Age | Mean | Standard Deviation 1 | |
|---|---|---|---|
| 0-6 wks | 29.1% | 11.7 | |
| 6 wks-1 yr | 23.9% | 10.4 | |
| 1-3 yrs | 15.2% | 6.2 | |
| 3-13 yrs | 12.2% | 5.5 | |
| >13 yrs | Female | 8.0% | 3.7 |
| Male | 10.3% | 4.2 | |
Stibůrková et al [2006]
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.
Gout (due to hyperuricemia) may first appear in the early teen years, but has been described in some younger children.
Kidney
- Estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 was seen at earliest clinical presentation in most children.
- Bland urinary sediment (i.e., little blood or protein). Hematuria is generally not present, and excretion of protein is <1 g per 24 hours except when CKD is advanced.
- Kidney ultrasound examination shows normal-to-small kidney size without cysts.
- Predisposition to acute, but reversible, kidney injury in the setting of dehydration or viral illness, especially if there has been concomitant treatment with a nonsteroidal anti-inflammatory drug [Bleyer et al 2010b]
Clinical Findings – Adult-Onset Disease (from 3rd decade)
Slowly progressive chronic tubulointerstitial kidney disease evident as a slowly rising serum creatinine in the absence of hematuria and proteinuria
Hyperuricemia (serum urate level >6 mg/dL in adults) and gout, resulting from decreased renal excretion of uric acid
Family History
Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.
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 variant in REN identified by molecular genetic testing (see Table 3).
Note: Identification of a heterozygous REN variant of uncertain significance does not establish or rule out the diagnosis of this disorder.
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).
Option 1
Single-gene testing. Sequence analysis of REN is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Typically, if no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications; however, to date such variants have not been identified as a cause of this disorder, and thus are unlikely to cause this disorder.
A kidney disease multigene panel that includes REN and other genes of interest (see Differential Diagnosis) 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. 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. (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.
Option 2
Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
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-REN
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| REN | Sequence analysis 3 | All variants reported to date 4 |
| Gene-targeted deletion/duplication analysis 5 | None reported |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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.
Živná et al [2020] and references therein
- 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.
Clinical Characteristics
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.
Table 4.
ADTKD-REN: Comparison of Phenotypes by Genotype and Select Features
| Features | Childhood/Adolescent Onset | Adult Onset | ||
|---|---|---|---|---|
| Signal peptide 1 | Prosegment 1 | Mature peptide 2 | ||
| # of families/persons | 21/69 | 4/27 | 5/15 | |
| Mean age at presentation ± SD | 19.7±15.7 yrs | 22.4±20.2 yrs | 37.0±12.4 yrs | |
| Age at presentation | <10 yrs | 39% | 61% | 0 |
| 10-20 yrs | 32% | 11% | 0 | |
| >20 yrs | 29% | 28% | 100% | |
| Presented with: | AKI | 10% | 0 | 0 |
| Anemia, acidosis, CKD | 13% | 0 | 0 | |
| Anemia | 31% | 50% | 0 | |
| CKD | 22% | 14% | 25% | |
| Gout | 25% | 36% | 75% | |
| Anemia as child | 91% | 69% | 0 | |
| Gout | 56% | 65% | 54% | |
| Age of first gout attack | 29.7±9.9 yrs | 25.7±8.2 yrs | 32.9±11.2 yrs | |
| Age of ESRD | 53.1±10.6 yrs | 50.8±17.6 yrs | 63.6±7.6 yrs | |
Adapted from Živná et al [2020]
AKI = acute kidney injury; CKD = chronic kidney disease; ESRD = end-stage renal disease
- 1.
Correlated with REN variants encoding the signal peptide and prosegment (See Genotype-Phenotype Correlations.)
- 2.
Correlated with REN variants encoding the mature peptide (See Genotype-Phenotype Correlations.)
Childhood/Adolescent Onset
Individuals often present between birth and age ten years with manifestations related to renin deficiency. As renin is important in prenatal kidney development, the eGFR is low (usually <60 mL/min/1.73 m2) from early in life. These individuals frequently have mildly low blood pressure, hyperkalemia, acidosis, and hyperkalemia. They often first come to medical attention with acute kidney injury during a viral infection [Bleyer et al 2010a]. Although acute kidney failure usually resolves if treated appropriately, chronic kidney disease remains, and the associated findings of hyperkalemia, anemia, and acidemia are first noted.
Chronic kidney disease may slowly worsen in the second decade; acidemia and hyperkalemia persist. Gout may develop at this time due to decreased renal excretion of uric acid.
Despite low eGFR at presentation, only one child required renal replacement therapy at age 15 years; others did not reach end-stage renal disease (ESRD) until after age 30 years (mean age ~52 years). For these individuals, kidney function continues to worsen very slowly over time, with a mean age of ESRD of 53 in the signal peptide group and 51 in the prosegment group (see Table 4).
Adult Onset
Individuals present in their twenties with gout and chronic kidney disease. Gout is easily controlled with allopurinol. The serum creatinine slowly rises with slow progression to ESRD at a mean age of 64 years [Živná et al 2020]. Although CKD occurs in all individuals with adult-onset disease, progression may be very slow, with ESRD occurring as late as the seventh decade in some individuals.
Kidney Biopsy
The following information is provided in the event that some affected individuals (or their relatives) may have undergone kidney biopsy prior to consideration of ADTKD-REN as a diagnostic possibility.
Histologic examination reveals focal tubular atrophy, secondary glomerular scarring, and interstitial fibrosis [Zivná et al 2009]. Early in the disease course 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. In advanced stages, neither the granular cells of the juxtaglomerular apparatus or the tubular epithelium stain for renin or prorenin.
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 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 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.
Differential Diagnosis
See Figure 1 for a diagnostic algorithm for inherited kidney disease.
Figure 1.
Testing strategy for inherited kidney disease
Table 5.
Monogenic Kidney Diseases in the Differential Diagnosis of ADTKD-REN
| Gene(s) | Disorder | MOI | Renal Phenotype | Distinguishing Features of Disorder |
|---|---|---|---|---|
| CEP290 INVS IQCB1 NPHP1 NPHP3 NPHP4 TMEM67 (19 genes 1) | Isolated nephronophthisis (NPH) | AR | Tubulointerstitial kidney disease; often seen in childhood & can be assoc w/anemia & mild hypotension |
|
| COL4A3 COL4A4 COL4A5 | Alport syndrome (& other types of hereditary glomerulonephritis) | XL AR AD | Microscopic hematuria (microhematuria), proteinuria, progression to ESRD |
|
| DNAJB11 GANAB PKD1 PKD2 | Autosomal dominant polycystic kidney disease (ADPKD) | AD | Bland urinary sediment 2; large # of cysts > age 25 yrs | Numerous cysts seen on kidney ultrasound |
| GLA | Fabry disease, classic form | XL | Proteinuria (usually ↑ than in ADTKD-UMOD); gradual deterioration of renal function to ESRD in ~3rd-5th decade 3 | Classic form (males w/<1% α-Gal A activity) usually has onset in childhood or adolescence w/periodic crises of severe pain in extremities (acroparesthesias); vascular cutaneous lesions (angiokeratomas), hypohidrosis, & characteristic corneal & lenticular opacities. |