Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)

A group of autosomal dominant monogenic nephropathies with slowly progressive tubulointerstitial fibrosis, bland urinary sediment and normal-sized or small kidneys, caused predominantly by variants in UMOD, MUC1 and REN and, less frequently, SEC61A1 and DNAJB11; the HNF1B-associated form is part of the differential diagnosis.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition and scope

Autosomal dominant tubulointerstitial kidney disease (ADTKD, autosomal dominant tubulointerstitial kidney disease) denotes a group of inherited nephropathies defined by four features: autosomal dominant transmission; slowly progressive chronic tubulointerstitial disease leading to end-stage kidney disease (ESKD) between the third and seventh decades; bland urinary sediment, with little or no haematuria and proteinuria; and normal renal ultrasound in early disease [1, 2]. The concept brings together diseases caused by genes with very different functions under a shared renal phenotype, whose distinction has practical consequences for laboratory diagnosis, treatment of extrarenal manifestations and family counselling. “Chronic kidney disease” (CKD) is used here in the sense of the KDIGO classification, with stages defined by estimated glomerular filtration rate (eGFR), in mL/min/1.73 m².

This article addresses the dominant forms associated with UMOD (uromodulin), MUC1 (mucin-1), REN (renin), SEC61A1 (endoplasmic reticulum translocon subunit) and DNAJB11 (endoplasmic reticulum co-chaperone), and includes in the differential diagnosis the forms associated with APOA4, BICC1, mitochondrial DNA (mtDNA) and karyomegalic tubulointerstitial nephropathy caused by biallelic FAN1 variants. HNF1B-associated ADTKD (renal cysts and diabetes syndrome) meets the definition but is a multisystemic disease with renal and genital tract malformations, MODY5 diabetes and liver abnormalities; it appears here only in the differential [26, 27].

1.2. Historical overview

Before 2000, ADTKD was an exclusively clinical diagnosis, described in fewer than 50 families under names reflecting the most visible trait in each lineage: familial juvenile hyperuricaemic nephropathy when hyperuricaemia and early gout predominated, or medullary cystic kidney disease when biopsy or imaging showed medullary cysts [2, 28]. The sources consulted do not describe the earliest published families in detail, so this article begins with the molecular era.

In 2002, Hart and colleagues mapped the disease to 16p11–p13 in two families with familial juvenile hyperuricaemic nephropathy and identified four novel UMOD variants segregating with disease in three families with that diagnosis and in one family with medullary cystic kidney disease type 2, demonstrating that the two entities were allelic [29]. In 2009, Živná and colleagues, using linkage analysis and candidate gene sequencing in three families with early anaemia, hyperuricaemia with low urate excretion and progressive kidney failure, identified the variants p.Leu16del and p.Leu16Arg (historical numbering, = NM_000537.4:c.46_48del p.(Leu16del) and NM_000537.4:c.47T>G p.(Leu16Arg)) in the renin signal peptide [30].

Identification of the MUC1-associated form proved elusive for more than a decade. Medullary cystic kidney disease type 1 had been mapped to a 2-Mb region of chromosome 1, but it was only in 2013, through cloning, capillary sequencing and de novo assembly, that Kirby and colleagues found, in six families, the insertion of a cytosine into one unit (different in each family) of a very long guanine- and cytosine-rich (GC) coding VNTR in MUC1, a sequence almost invisible to massively parallel sequencing; the authors presented the finding as a methodological warning for clinical genomics [31]. These discoveries were followed by SEC61A1 in 2016, in two families with ADTKD and congenital anaemia [23], and DNAJB11 in 2018, with a phenotype combining non-enlarged cystic kidneys with interstitial fibrosis and late progression to kidney failure [7]. Between 2024 and 2026, dominant forms associated with APOA4 and medullary amyloidosis [32] were described and, in preprints not yet peer reviewed, truncating BICC1 variants [33] and insertions in the mitochondrial LSP2 promoter in families with maternal transmission [34].

1.3. Nomenclature and reclassifications

In 2014, a KDIGO consensus conference held in Boston proposed the term ADTKD, singular for practical reasons, with subclassification by causal gene (ADTKD-UMOD, ADTKD-MUC1, ADTKD-REN, ADTKD-HNF1B) and the category ADTKD-NOS (not otherwise specified) for families without genetic testing or with inconclusive testing [2]. The report rejected type numbering to avoid a translation step between number and gene, and explicitly recommended abandoning the acronym MCKD (medullary cystic kidney disease) because cysts are not characteristic, are not predominantly medullary and appear at advanced stages, as in other forms of CKD [2]. The 2022 KDIGO conference on genetics in CKD retained the two-part nomenclature, permitting use of ADTKD alone or accompanied by the gene [35]. The terms “uromodulin-associated kidney disease” and “mucin-1-associated kidney disease” remain acceptable in communication with patients [2].

Historical designations persist in databases: OMIM numbers the forms as ADTKD1 (UMOD), ADTKD2 (MUC1), ADTKD4 (REN) and ADTKD5 (SEC61A1), and Orphanet marks the entry “familial juvenile hyperuricaemic nephropathy type 1” (ORPHA:209886) as obsolete [5, 6, 13]. Some clinical genetics reference works still describe the entity with incorrect spellings and place ESKD in the fourth–seventh decades, a narrower range than in GeneReviews [26].

1.4. Definition of each entity

ADTKD-UMOD is defined by a heterozygous pathogenic UMOD variant in a patient with tubulointerstitial CKD, hyperuricaemia due to low renal urate excretion and, in around half of cases, early gout [1]. ADTKD-MUC1 results from frameshift variants producing a unique abnormal protein, MUC1fs, and manifests only as slowly progressive CKD [4]. ADTKD-REN results from variants impairing renin biosynthesis and trafficking and has childhood-onset and adult-onset forms depending on the affected protein domain [5, 22]. ADTKD-SEC61A1 combines CKD with congenital anaemia, neutropenia or growth restriction [23]. DNAJB11-associated disease lies at the boundary between ADPKD and ADTKD [7, 19].

2. Molecular Genetics and Pathophysiology

2.1. Genetic architecture and shared mechanism

The main ADTKD forms share a mechanism of proteotoxicity: a mutant protein, produced in specific tubular cells, accumulates in the endoplasmic reticulum (ER) or ER–Golgi intermediate compartment (ERGIC), triggers ER stress and premature cell death, and leads to tubular atrophy, nephron loss and interstitial fibrosis [1, 4, 5]. The cellular localisation of expression explains phenotypic differences: uromodulin is produced only in the thick ascending limb of the loop of Henle (TAL), renin in juxtaglomerular cells and mucin-1 in several epithelia, although the clinical manifestations of MUC1fs are confined to the kidney [1, 4]. In referral cohorts with a presumptive ADTKD diagnosis, UMOD and MUC1 explain most resolved families; REN, SEC61A1 and DNAJB11 are much rarer [21, 36, 37]. ADTKD accounts for approximately 5% of monogenic diseases causing CKD, according to a review cited by GeneGuidance [6].

Table sources: [1, 4–6, 8, 11].

2.2. ADTKD-UMOD

The UMOD gene (16p12.3) has 11 exons, the first non-coding, and encodes uromodulin, a glycosylphosphatidylinositol-anchored glycoprotein that is the most abundant protein in normal urine [1, 29]. Uromodulin organises the TAL apical membrane, forms a gel influencing water and electrolyte handling, binds type 1-fimbriated Escherichia coli and other uropathogens and inhibits crystal formation; its precise function in the integrity of a segment with very low water permeability and intense salt reabsorption remains incompletely understood [1, 3].

Pathogenic variants are predominantly missense, cluster in exons 3 and 4 (93% of those described by 2015) and add or remove a cysteine or a highly conserved polar residue, altering disulphide bonds and protein folding [1, 2]. Mutant uromodulin accumulates in the TAL ER, making ADTKD-UMOD an ER storage disease; urinary uromodulin excretion in heterozygotes is much lower than half the expected amount, indicating a dominant-negative effect on the normal protein [1]. Defective trafficking inhibits NKCC2 cotransporter delivery to the luminal membrane, reduces sodium chloride reabsorption in the TAL and causes a concentrating defect with mild extracellular volume contraction; the proximal response to this contraction increases urate reabsorption, explaining early hyperuricaemia and its worsening with sodium restriction, diuretics and dehydration [1, 2].

Notable variants collected in GeneReviews, with the number of families and median age at ESKD from the 2020 international consortium, are shown in the following table; parenthesised associations are possible and require further evidence [1, 20].

GeneGuidance gives RefSeq NM_001008389 as the gene transcript, but current clinical numbering follows MANE Select NM_003361.4 used in GeneReviews and VariantValidator [3, 9]. Examples of cysteine variants in ClinVar are c.376T>C p.(Cys126Arg), pathogenic with criteria, and c.444T>G p.(Cys148Trp), pathogenic without criteria [40]. GeneReviews maintains a list of more than 200 clinically significant variants and considers those affecting cysteines very likely pathogenic [1].

The NM_003361.4:c.184A>C p.(Thr62Pro) variant illustrates an intermediate-effect allele: present in approximately 1 in 1000 Europeans, with incomplete penetrance, it was associated with kidney failure in the 100,000 Genomes project (odds ratio [OR] 3.99; 95% confidence interval [95% CI] 1.84–8.98) and in UK Biobank (OR 4.12; 95% CI 1.32–12.85), with slower progression and an intermediate reduction in urinary uromodulin; ClinVar records conflicting classifications [40, 41]. Eight missense variants described in ADTKD families are present in gnomAD at allele frequencies of 10⁻⁵ to 10⁻³, which requires caution in interpreting rare UMOD variants [41].

The 2020 international consortium also analysed the minor allele of the UMOD promoter polymorphism rs4293393, which reduces uromodulin production by approximately 50% and has a population frequency of 19%: it was present in only 11.6% of affected individuals, an imbalance preventing Mendelian randomisation analysis; an in vitro severity score for the mutant uromodulin trafficking defect proved a promising predictor of age at ESKD [20]. Common UMOD locus variants are associated, in genome-wide association studies, with renal function, CKD and arterial hypertension, linking monogenic disease to multifactorial CKD [2].

2.3. ADTKD-MUC1

The MUC1 gene (1q22) encodes mucin-1, a heavily glycosylated transmembrane glycoprotein expressed in the breast, respiratory tract, salivary and sebaceous glands, gastric mucosa and distal renal tubules [2, 4]. The protein is cleaved into an adhesive α subunit with a mucosal barrier function and a signalling β subunit; the serum markers KL-6 and CA15-3 correspond to epitopes of the same molecule [42]. The extracellular domain contains a coding VNTR of 60-nucleotide units, each with a seven-cytosine tract, with 20 to 125 repeats per allele [4]. The 2015 KDIGO report estimated 25–125 units (1.5–7.5 kb) with more than 80% GC, and the 2013 article described a length of approximately 1.5–5 kb; the range depends on the populations studied [2, 31].

In approximately 99% of patients, the causal variant lies in the VNTR and, in approximately 95% of these, is a cytosine insertion in the seven-cytosine tract of a unit whose position varies between families, according to observations by the GeneReviews authors in 196 families [4]. In single-molecule sequencing of 300 individuals, cytosine duplication, termed “59dupC” after its position within the 60-bp unit, accounted for approximately 90% of families, and the other eight frameshift types occurred at most twice; the same study identified 215 distinct VNTR alleles composed of 80 unit types, 46 of them new [43]. Other groups call the same insertion “27dupC”, following a different numbering convention within the unit [18].

All causal variants produce the same frameshift protein, MUC1fs, which loses its transmembrane anchor and accumulates in the ERGIC [4, 44]. MUC1fs activates the ATF6 branch of the unfolded protein response and is retained in vesicles containing the cargo receptor TMED9 [44]. Disease results from toxic gain of function: no patients with truncating or loss-of-function MUC1 variants are known [4]. Although MUC1fs exists in all tissues expressing MUC1, manifestations are confined to the kidney, through accelerated tubular cell apoptosis [4]. In a 2026 preprint, MUC1fs showed a much longer half-life than normal mucin-1 in primary tubular cells obtained from patients' urine [45]. A registry survey showed that patients produce approximately half the normal plasma mucin-1 [46].

Nomenclature of MUC1 variants

Because the number of VNTR units and the mutated unit vary between alleles, cytosine insertion has no unique HGVS (Human Genome Variation Society) description on the reference transcript; ClinVar records it as a genomic interval, NC_000001.10:g.(155160963_155162030)insC (GRCh37; VCV000055830, pathogenic without criteria) [9, 40]. Transcript NM_001371720.2 is the gene's RefSeq Select, without an assigned MANE Select; GeneReviews uses NM_002456.5 [4, 9].

Table 4 of the MUC1 GeneReviews contains an incongruous row: it assigns NM_002456.5:c.253C>T p.Gln85Ter to the “presence of an adenine in the seven-cytosine tract of a VNTR unit” [4]. In VariantValidator, NM_002456.6:c.253C>T corresponds to NP_002447.4:p.(Gln85Ter), NC_000001.11:g.155188192G>A, a nonsense substitution in the reference sequence rather than an insertion; ClinVar records this variant as VCV001301998, without classification [9, 40]. Adenine insertion in the cytosine tract, like cytosine insertion, is described by its position within the VNTR unit rather than c.253C>T, a designation that should not be used as a synonym.

2.4. ADTKD-REN

The REN gene (1q32.1) encodes 406-amino-acid preprorenin, comprising a signal peptide (amino acids 1–23), a prosegment (24–66) and mature renin (67–406) [22]. Renin is an aspartic protease that cleaves angiotensinogen to angiotensin I, the rate-limiting step of the renin–angiotensin–aldosterone system (RAAS), with roles in vascular tone, renal sodium and potassium handling, erythropoiesis, thirst and prenatal renal development [5, 17].

The mechanism depends on the affected domain [5, 22]. Signal peptide variants reduce its hydrophobicity, prevent cotranslational translocation into the ER and cause non-glycosylated preprorenin to accumulate in the cytoplasm; by blocking the translocon, they also affect synthesis from the normal allele, paralleling SEC61A1 and preproinsulin variants. Prosegment variants prevent correct folding and deposit prorenin and renin in the ERGIC. Mature renin variants deposit mutant protein in the ER, similarly to uromodulin, and cause milder forms [22]. All cases involve ER stress, progressive loss of juxtaglomerular cells, tubular atrophy and CKD, similar to that occurring in mice with ablation of these cells [5]. Aldosterone deficiency reduces distal potassium and hydrogen ion secretion (hyperkalaemia and acidosis), low angiotensin II explains borderline blood pressure and low eGFR, and low erythropoietin explains hypoproliferative anaemia [17]. Since renin reduction is a therapeutic goal in many CKDs, the GeneReviews authors note that, in this disease, deficiency acts as partial self-treatment [5].

The REN GeneReviews defines domains by the intervals “c.45–113” for the signal peptide, “c.114–242” for the prosegment and “c.243–1262” for mature renin, but these intervals are incompatible with the c. numbering of its listed variants: c.28T>C corresponds to codon 10 and is a valid HGVS description, NM_000537.4:c.28T>C p.(Trp10Arg), NC_000001.11:g.204166266A>G [5, 9]. The interval appears to follow old messenger RNA numbering including the 5' untranslated region, so this article defines domains by amino acids. The historical designation “p.delLeu16” corresponds, under the right-alignment rule, to NM_000537.4:c.46_48del p.(Leu16del), recorded in ClinVar as c.36GCT[3] (VCV000013125) [9, 40].

In the international cohort of 111 individuals from 30 families, 69 (62%) had signal peptide variants, 27 (24%) prosegment variants and 15 (14%) mature renin variants [22]. Only missense variants and small indels affecting biosynthesis or trafficking cause disease; no deletions or duplications have been described [5]. Notable variants, with the number of families relative to the domain total, are as follows.

GeneReviews uses transcript NM_000537.3; variants checked in VariantValidator (c.28T>C, c.47T>G, c.49T>C, c.58T>C) retain the same c. numbering in MANE Select NM_000537.4, and c.58T>C p.(Cys20Arg) is classified in ClinVar as pathogenic or likely pathogenic by multiple submitters without conflicts (VCV000974505) [9, 40]. In African Americans, p.Pro8Ala (allele frequency 0.007) had no functional effect, p.Arg33Trp (0.001) behaved like prosegment variants and may contribute to low renin and CKD, and p.Ser45Asn did not segregate with disease [22].

2.5. ADTKD-SEC61A1

The SEC61A1 gene (3q21.3) encodes the pore-forming subunit of the Sec61 translocon, mediating cotranslational and post-translational translocation of proteins with a signal peptide, transmembrane segment insertion and passive calcium efflux from the ER [6]. The two founding families had heterozygous missense variants c.200T>G p.(Val67Gly) and c.553A>G p.(Thr185Ala), described on transcript NM_013336, which mislocalise the protein to the Golgi, selectively impair renin transport and reduce SERCA2 calcium pump abundance; in zebrafish, orthologue knockdown caused pronephric tubule defects rescued by normal but not mutated human messenger RNA [6, 23]. The Swedish case described in section 10 had a de novo variant NM_013336.4:c.1372T>G p.(Phe458Val) in the last transmembrane domain [10]. An Omani series described c.554C>G p.(Thr185Ser) in an adolescent with CKD, hypomagnesaemia, microcephaly and epilepsy, the latter never previously associated with the gene [49]. Phenylbutyrate, a chemical chaperone, reversed defective renin transport and calcium homeostasis in cellular models with p.Val67Gly and p.Thr185Ala, without animal studies or clinical trials [6].

2.6. DNAJB11-associated disease

The DNAJB11 gene (3q27.3) encodes ERdj3, a BiP (HSPA5) co-chaperone required for polycystin-1 maturation and trafficking [11]. Heterozygous loss-of-function variants cause haploinsufficiency, with defective maturation of polycystin-1 and uromodulin; the mechanism converges with that of GANAB, ALG9 and ALG5 [7, 11]. The initial description assembled seven families with 23 affected individuals and the variants NM_016306.6:c.161C>G p.(Pro54Arg) and NM_016306.6:c.166_167insTT p.(Arg56LeufsTer40), and estimated that the gene explains approximately 7% of ADPKD families without a genetic diagnosis [7]; the 2020 series added 13 loss-of-function variants in 20 families [19].

2.7. Inheritance, penetrance and expressivity

All forms are autosomal dominant. UMOD penetrance is apparently complete but age-dependent, and some people, particularly women, reach ESKD only in the sixth or seventh decade [1]. MUC1 penetrance is complete, without known genotype–phenotype correlations in GeneReviews [4]; a 2025 preprint associated rapid progression with fewer repeat units on the normal allele and more on the mutated allele, a modest contribution explaining approximately 6% of variance [51]. In ADTKD-REN, all heterozygotes have biochemical abnormalities from birth, even when clinically asymptomatic [5]. The KDIGO report summarises penetrance as close to 100% if patients live long enough, with variable severity and age at onset within and between families [2]. Within the same family, one ADTKD-UMOD member may reach ESKD at 30 years and another only at 70 [1].

2.8. Allelic diseases

No other germline phenotypes associated with heterozygous UMOD or MUC1 variants are known [1, 4]. Homozygosity or compound heterozygosity for REN null variants causes autosomal recessive renal tubular dysgenesis (OMIM 267430), with macroscopically normal kidneys, loss of proximal tubular differentiation, fetal anuria, oligohydramnios with Potter sequence and perinatal death from pulmonary hypoplasia [5, 17]. Heterozygous SEC61A1 variants also cause common variable immunodeficiency 15 (OMIM 620670), described in 11 patients from two families with hypogammaglobulinaemia and severe respiratory infections due to blocked plasma cell differentiation (NM_013336.4:c.254T>A p.(Val85Asp)), and severe congenital neutropenia 11 (OMIM 620674), with a still provisional relationship [6]. Biallelic DNAJB11 variants cause a cystic kidney–liver–pancreas disease with hepatic ductal plate malformation (Ivemark II syndrome) [8].

3. Clinical Spectrum and Manifestations by System

3.1. Shared renal phenotype

The KDIGO report lists the usual ADTKD findings: autosomal dominant transmission; progressive renal function loss; bland urinary sediment; absent to mild albuminuria or proteinuria; absence of severe hypertension in early stages; no exposure to drugs causing tubulointerstitial nephritis; normal-sized or small kidneys on ultrasound; and childhood nocturia or enuresis due to loss of urinary concentrating ability [2]. Age at initiation of kidney replacement therapy (KRT) generally lies between 20 and 80 years, with most patients between 30 and 50 years, and the rate of eGFR decline is highly variable [2]. In a 2025 review, mean age at kidney failure was approximately 45 years [28]. Cysts of variable number and size may develop, generally not medullary, no more frequently than in other non-cystic CKDs, at advanced stages and without a causal role in eGFR decline; hypertension, when it develops, follows renal dysfunction and is generally moderate [2].

Histology shows interstitial fibrosis, tubular atrophy, thickening and lamellation of tubular basement membranes and sometimes microcystic tubular dilatation; immunofluorescence is negative for immunoglobulins and complement, glomeruli are normal or show secondary sclerosis, and electron microscopy adds little, although it may show mutant uromodulin retained in the TAL ER [2]. Proteinuria permitted by GeneReviews definitions varies by gene: below 250 mg/24 h in ADTKD-UMOD, below 500 mg/24 h in ADTKD-MUC1 and below 1 g/24 h in ADTKD-REN, except in advanced CKD [1, 4, 5].

Source: KDIGO report, Table 4, “possible but not mandatory findings” [2].

3.2. ADTKD-UMOD

The most common presentation is elevated creatinine in a person with a family history of kidney disease, sometimes detected incidentally in childhood or when screening the children of an affected parent [1]. CKD is often noted in adolescence, with eGFR below 90 mL/min/1.73 m² from childhood, and progresses slowly to ESKD between the third and seventh decades; childhood ESKD is rare [1, 39]. In the international consortium of 722 affected individuals from 249 families with 125 variants, median age at ESKD was 47 years, and men had a greater progression risk (hazard ratio [HR] 1.78; p<0.001) [20]. In European and US registries combined in 2020, median renal survival was 54 years in ADTKD-UMOD versus 46 years in ADTKD-MUC1 [21]. In natural history modelling from the Wake Forest registry (371 adults), eGFR decline followed a sigmoid curve, with a slow initial phase and rapid decline after an inflection point; men reached the characteristic age of kidney failure four years earlier than women, and older age at first consultation was associated with slower progression [52].

Hyperuricaemia is present in almost all patients, owing to low renal urate excretion, and precedes any renal function decline [1]. Gout occurs in 55% of affected individuals, with median onset at 28 years, and in 8% before 18 years [1, 20]. The KDIGO report gives gout onset ages between 3 and 51 years and ESKD between 25 and over 70 years [2]. In the 2020 registries, median gout-free survival was 30 years in ADTKD-UMOD and 67 years in ADTKD-MUC1 [21]. Not all affected individuals have gout, but almost all families have members with gout, often recognised by relatives themselves; attacks typically affect the great toe, other foot areas, ankles or knees, worsen and become more frequent as renal function is lost, may be triggered by sporting exertion in children and, untreated, progress to tophi and disabling arthritis [1]. The p.(Val93_Gly97delinsAlaAlaSerCys) variant is associated with less frequent gout [38].

3.3. ADTKD-MUC1

CKD is the only primary manifestation, and all other abnormalities are secondary to functional loss [4]. Patients are generally asymptomatic when laboratory abnormalities appear in late adolescence or the early 20s; approximately 50% of affected children have eGFR below 90 at 15 years, and rarely below 60 before 18 years [4, 53]. In other patients, eGFR falls only in adulthood: in a cohort of 311 people, 14% of patients aged 20–29 years and 1% aged 30–49 years retained eGFR above 90, according to unpublished observations by the GeneReviews authors [4]. Ultrasound shows normal or small kidneys, with occasional cysts [4].

Median age at ESKD is 46 years, ranging from 20 to 70 years, with rare cases before 20 years and some patients without ESKD after 70 [4, 21]. In Wake Forest modelling (233 adults), post-inflection decline was faster than in ADTKD-UMOD [52]. Gout relates only to loss of urate excretion: in six large Cypriot families, hyperuricaemia existed in approximately 50% of affected individuals with CKD and 81% of those with ESKD, and gout occurred in 5 of 75 affected individuals [54]. In systematic French exome screening, among 24 patients with complete descriptions, median age at kidney failure was 50 years, 38% had multiple bilateral renal cysts, 8% had early gout and 58% had hypertension [18].

In a 2021 registry survey, previous COVID-19 infection was more frequent in ADTKD-MUC1 (19 of 83, 23%) than ADTKD-UMOD (14 of 125, 11%), and COVID-19 deaths, including relatives, were 10 of 41 (24%) versus 1 of 30 (3%) (OR 9.21; 95% CI 1.22–69.32); in the three-year longitudinal registry, 19 of 360 ADTKD-MUC1 patients (5%) and 3 of 478 ADTKD-UMOD patients (0.6%; p=0.0007) died [46]. On regression, ADTKD-MUC1 (OR 8.4; 95% CI 2.9–29.5), kidney transplantation, body mass index and age were associated with risk, and preinfection plasma mucin-1 was lower in infected individuals (7.06 ± 4.12 versus 10.21 ± 4.02 U/mL) [46]. The study is observational, based on a survey with a low response rate, and does not establish causality.

3.4. ADTKD-REN

The two presentations correspond to the affected renin domains [5]. In the more frequent childhood- or adolescent-onset form, associated with signal peptide or prosegment variants, low renin production, with low or low-normal plasma renin and aldosterone in most patients, manifests as blood pressure at the lower limit, usually asymptomatic; hyperkalaemia above 5 mEq/L, sometimes up to 6.5 mEq/L, in approximately 50%, often from birth; acidosis with bicarbonate 15–24 mEq/L; and hypoproliferative anaemia by the first year of life in most children, with low erythropoietin, haemoglobin usually 9–11 g/dL, reticulocytes low for haemoglobin and an otherwise normal blood count [5]. Hyperuricaemia (urate above 6 mg/dL) exists in 80% of affected individuals from childhood, and gout may develop in early adolescence [5]. eGFR is below 60 mL/min/1.73 m² at first presentation in most children because renin is necessary for prenatal renal development; some children have polyuria, and the first encounter is often AKI during viral infection or dehydration, particularly with non-steroidal anti-inflammatory drugs (NSAIDs), resolving with treatment but leaving persistent CKD [5, 50].

Childhood anaemia resolves at puberty, which is attributed to increased testosterone, and may recur with loss of renal function [2]. In the international cohort, without erythropoietin, mean haemoglobin was 9.6 ± 1.04 g/dL below 10 years, 10.1 ± 1.1 g/dL from 10 to 15 years and 10.5 ± 1.2 g/dL from 15 to 20 years, with a minimum of 7.5 g/dL; girls had more childhood anaemia (97% versus 46%; p=0.005), and in men haemoglobin rose after 20 years, whereas in women it remained low [22]. Hyperkalaemia was frequent but rarely severe, bicarbonate was often below 24 mEq/L, urate without urate-lowering therapy was 9.4 ± 2.7 mg/dL in men and 7.7 ± 1.6 mg/dL in women (p=0.02), and random plasma renin activity (normal 2.9–24 ng/mL/h) was 0.5 ± 0.8, 0.5 ± 0.6 and 0.8 ± 0.7 ng/mL/h in the signal peptide, prosegment and mature renin groups [22]. Despite low eGFR at presentation, function remained stable in childhood and adolescence, for example with eGFR of approximately 30 between 2 and 16 years in a patient with NM_000537.4:c.58T>C p.(Cys20Arg); only one child, with NM_000537.4:c.116T>A p.(Met39Lys) and eGFR 19, required KRT, at 15 years [22].

In the adult-onset form, associated with mature renin variants, patients present in the third decade with gout and slowly progressive mild CKD, without anaemia, hyperkalaemia or acidaemia; gout is easily controlled with allopurinol, and ESKD occurs at a mean of 64 years, sometimes only in the seventh decade [5, 22].

Sources: GeneReviews, Table 4, adapted from the cohort of 111 individuals from 30 families, and the original article's full text; presentation analysis included 81 patients, excluding 14 without data and 16 identified by genetic screening; SD, standard deviation [5, 22]. The article gives discordant values for ESKD comparison between the mature renin group and the others (HR 0.367 in the abstract, 0.37 in the text and 0.237 in a figure legend), so the direction of effect is certain but its exact magnitude is not. Childhood anaemia was associated with earlier ESKD (HR 2.82; p=0.03), and sex was not associated [22].

3.5. ADTKD-SEC61A1

The two founding families had slowly progressive CKD, bland sediment, absent or mild albuminuria, small dysplastic kidneys with cysts, congenital anaemia and, in one family, intrauterine growth restriction and, in the other, neutropenia; histology showed interstitial fibrosis, tubular atrophy, tubular basement membrane thickening, microcystic dilatation and secondary glomerulosclerotic or glomerulocystic changes [6, 23]. Leucopenia with abscesses and intrauterine and postnatal growth restriction are clues distinguishing it from other forms, and anaemia should not be attributed solely to CKD [1, 6]. The 2024 Swedish case added hyporeninaemic hypoaldosteronism with severe hypotension, a presentation overlapping childhood ADTKD-REN [10].

3.6. DNAJB11-associated disease

The phenotype is consistent: small bilateral renal cysts, usually without kidney enlargement, progressing to fibrotic kidneys and renal failure with ADTKD features; occasional hepatic cysts [8]. In 77 patients from 27 families, 32 reached ESKD between 55 and 89 years (median 75), without a sex difference; cysts were inconsistently identified before 45 years, and four families had vascular phenotypes (intracranial aneurysms, thoracic aortic dilatation, carotid dissection) [19]. In the initial description, one family had recurrent gout [7].

3.7. Histology by gene

When biopsy was performed before the diagnosis was considered, ADTKD-UMOD shows interstitial fibrosis with focal tubular atrophy, sometimes a lymphocytic infiltrate, and mutant uromodulin accumulation visible with periodic acid–Schiff staining as disorganised polymorphic material [1]. ADTKD-MUC1 and ADTKD-REN show non-specific focal tubular atrophy, secondary glomerular scarring and interstitial fibrosis; in ADTKD-REN, renin and prorenin immunostaining is markedly reduced in juxtaglomerular granular cells in early stages and disappears in advanced stages [4, 5].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

Autosomal dominant transmission is the key finding in a disease with few distinguishing traits: ADTKD should be considered whenever the patient and one parent have kidney disease, even if the parent's disease was attributed to another cause such as hypertension or gout [1]. CKD combined with bland sediment, minimal proteinuria, normal-sized or small kidneys and no hypertension before renal function decline should prompt a three-generation family history [2]. Absence of a family history does not exclude diagnosis because of de novo variants, early parental death, a mild phenotype or late onset [4]. In French VNtyper screening, 6 of 33 ADTKD-MUC1 index cases had no family history and de novo origin was confirmed in 2; in the Chinese series, 50% of HNF1B variants were de novo [37, 55].

4.2. Emergency signs

Signs requiring immediate assessment are concentrated in ADTKD-REN and ADTKD-SEC61A1: hyperkalaemia above 6.5 mEq/L, marked metabolic acidosis, AKI during fever, vomiting or diarrhoea, and symptomatic hypotension with extreme fatigue [5, 10]. In a child with ADTKD-REN, NSAID administration during a febrile episode precipitated acute kidney failure [50]. In all forms, an acute gout attack requires prompt treatment, and a rash after starting allopurinol requires immediate discontinuation because of the risk of severe cutaneous reactions [2, 58].

4.3. Newborn screening

There is no newborn screening for any ADTKD form. In ADTKD-REN families, children of an affected parent may be assessed early with haemoglobin, potassium, bicarbonate, creatinine and urate, because anaemia, acidosis and hyperkalaemia are treatable [2, 5].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Consensus criteria

The 2015 KDIGO report distinguishes suspected and established diagnoses [2]. A family history compatible with autosomal dominant transmission requires at least one affected individual in at least two generations. Isolated cases without a family history should not be classified as suspected without histological evidence, to avoid overdiagnosis, and once diagnosis is established in a family, biopsy of other members is generally unnecessary [2].

Source: KDIGO report, Table 5 [2]. Criteria name four genes (UMOD, MUC1, REN, HNF1B) because they predate the description of SEC61A1 and DNAJB11; the 2022 KDIGO conference did not update them [6, 35].

5.2. Biomarkers

Serum urate should be interpreted using age- and sex-specific norms; hyperuricaemia with normal renal function is defined as a value more than 1 standard deviation above the mean [1]. In children, creatinine may be normal while urate is already elevated [1]. A metabolic disease reference work gives normal serum urate of approximately 300 μmol/L (5.0 mg/dL) in men, 240 μmol/L (4.0 mg/dL) in women and 180–240 μmol/L (3.0–4.0 mg/dL) in children, and considers a value above 360 μmol/L (6.0 mg/dL) always abnormal in children [59].

Source: serum urate with normal renal function, UMOD and REN GeneReviews, Table 1 [1, 5].

Fractional urate excretion (FEUA) is calculated as (urinary urate × serum creatinine) ÷ (serum urate × urinary creatinine) × 100; a value more than 1 standard deviation below the age-specific mean suggests reduced excretion [5]. In ADTKD-UMOD and ADTKD-REN, FEUA is usually below 5% in adult men and below 6% in adult women, and the reduction is detectable in children with preserved renal function; however, values below 5% also occur in healthy people [1, 5]. The test has three limitations: 24-hour urine is preferable to a spot sample; acetylsalicylic acid, diuretics and NSAIDs should be avoided during collection; and, because FEUA rises above 5% as renal function is lost, it ceases to be sensitive with eGFR below 70 mL/min [5]. Hyperuricaemia and low FEUA are not pathognomonic, overlapping those of CKD from other causes [2].

Source: FEUA with normal renal function, REN GeneReviews, Table 2 [5].

Urinary or serum uromodulin helps separate ADTKD-UMOD from other forms. In the 2020 registries, urinary uromodulin excretion and tubular distribution were normal in ADTKD-MUC1 and reduced in ADTKD-UMOD, and an algorithm combining a simple clinical score with urinary uromodulin identified UMOD variant carriers with 94.1% sensitivity, 74.3% specificity and 84.2% positive predictive value [21]. In the Chinese series of 70 patients, uromodulin distinguished ADTKD-UMOD with an area under the curve of 0.85 in plasma, 0.86 in urine and 0.93 combined [37]. In a Japanese series of 13 patients, serum uromodulin was 24.5 ± 13.9 ng/mL, significantly lower than in other renal diseases, and the authors considered it more reliable than urinary uromodulin because of its stability [60]. These values come from small series and do not define decision thresholds.

In ADTKD-REN, plasma renin and aldosterone are low to low-normal in most patients, but the KDIGO report considers them to have no diagnostic value; GeneReviews recommends measuring them in the childhood form with hypotension as part of assessment [2, 5].

5.3. Kidney biopsy

The authors of all three GeneReviews recommend against kidney biopsy for diagnosis: it is invasive, carries risks and produces non-specific findings, whereas molecular testing is the reference standard, safer and less expensive [1, 4, 5]. The KDIGO report accepts histology as a suspicion criterion in isolated cases and an established diagnosis criterion when combined with family history [2]. This divergence reflects the era: in 2015, MUC1 testing was not clinically available [2]. In practice, biopsy continues when disease is unsuspected: in the Japanese cohort, 55% of patients had undergone biopsy and pathological ADTKD confirmation was obtained in 41% [36]. When tissue is available, MUC1fs immunohistochemistry detects the protein independently of the variant and is useful in genetically unresolved cases, but is a specialised test available in research laboratories [43, 47]. In Irish families, MUC1fs was also detected in urinary cell smears [61].

5.4. Genetic testing: strategy

The testing indications listed by the KDIGO report are diagnostic confirmation in adults with suspected CKD, assessment of relatives with normal function who wish to donate a kidney, diagnosis of healthy at-risk adults, preimplantation genetic diagnosis and children with a suspected REN variant [2]. The 2022 KDIGO conference adds general indications: a clinical category with high monogenic prevalence, positive family history, early onset, syndromic features, consanguinity, potential for targeted treatment and an alternative to biopsy in high-risk patients; tubulointerstitial diseases have a higher diagnostic yield than diabetic nephropathy [35]. For a potential living donor from a family with a known variant, testing is mandatory [2]. The indications for genetic testing in adults with chronic kidney disease of undetermined cause and the technical limits of renal panels are common to the hereditary nephropathies.

For UMOD and REN, single-gene sequencing, a renal disease multigene panel or exome sequencing are appropriate [1, 5]. Sequencing detects more than 95% of pathogenic UMOD variants recorded in HGMD (Human Gene Mutation Database), and all REN variants described by 2020; this proportion measures the fraction of known variants accessible to the method rather than the test's clinical sensitivity in a patient with suspected ADTKD [1, 5]. No exonic or whole-gene deletions or duplications have been described as causal in either gene, and the utility of copy-number testing is unknown [1, 5]. In the US exome study of 3315 CKD patients, ADTKD-UMOD was diagnosed in 9 and the tubulointerstitial category had a 4.5% yield (11 of 244) [62].

5.5. The particular case of MUC1

The most frequent MUC1 variant is not detected by clinical panels, exomes or genomes analysed conventionally, or by Sanger sequencing, because of the VNTR's high GC content and repetitive nature; panels including MUC1 identify less than 1% of causal variants, those outside the VNTR [4, 31]. Short reads cover only the first VNTR units [63]. In the Danish genome sequencing study of 114 patients with kidney failure of undetermined cause by 50 years, all causes found were detectable by genome sequencing except MUC1 variants [64]. A letter by Bleyer, Kmoch and Greka about the 2019 US exome study recalled that it could not detect ADTKD-MUC1 [65]. A 2026 review from the Wake Forest group states that MUC1 testing is not performed in multigene panels or obtained through exome or genome sequencing [66], which is accurate for standard analysis; French, Danish, Czech and German groups showed between 2024 and 2026 that dedicated algorithms applied to the same short-read data detect the variant when VNTR coverage is sufficient.

GeneReviews proposes a three-step approach: a hereditary renal disease multigene panel with UMOD, REN and other genes; if negative, targeted MUC1 analysis, reliably detecting the cytosine duplication responsible for approximately 95% of cases but potentially missing rare variants; and, if negative, referral to an academic centre experienced in variants not detected by targeted analysis [4]. The 2026 German review proposes alignment-free short-read analysis as first line and VNTR-targeted long-read sequencing for confirmation [67]. MUC1 testing is available in several European commercial laboratories and, in the United States, free of charge at the Broad Institute and Wake Forest registry [4].

5.6. Algorithm

The GeneReviews algorithm starts with urinary sediment: with haematuria and proteinuria, suspicion points towards hereditary glomerulonephritis; with bland sediment (trace or no blood, proteinuria below 500 mg/24 h), family history is assessed, and transmission only among siblings suggests recessive disease such as autosomal recessive polycystic kidney disease or nephronophthisis [4]. Renal imaging, starting with ultrasound, is always performed: numerous cortical and medullary cysts with enlarged kidneys indicate ADPKD; when cysts are insufficient for ADPKD, inheritance is dominant, urine is bland and kidneys are normal or small, UMOD, REN and MUC1 are investigated [4]. The original algorithm figure was not consulted; the description follows the text.

Sources: [2, 4, 32, 34, 67].

5.7. Reporting, variants of uncertain significance and segregation

The report should state the gene, versioned transcript (NM_003361.4 for UMOD, NM_000537.4 for REN, NM_013336.4 for SEC61A1), HGVS description, zygosity and classification according to ACMG/AMP criteria (American College of Medical Genetics and Genomics/Association for Molecular Pathology); for MUC1, it should state the VNTR event type and method used, because no unique HGVS description exists [4, 9]. Pathogenic and likely pathogenic variants are clinically equivalent, and a variant of uncertain significance (VUS) neither establishes nor excludes diagnosis [4]. For UMOD VUS, an in vitro uromodulin trafficking functional assay and immunohistochemistry of a previous biopsy are available, and the GeneReviews authors offer to review variants with clinicians [1, 20]. Familial segregation is limited by age-dependent penetrance. A negative test in any gene does not exclude ADTKD [2].

5.8. Assessment after diagnosis

Sources: GeneReviews, Tables 4 (UMOD), 3 (MUC1) and 6 (REN) [1, 4, 5].

5.9. Prenatal and preimplantation diagnosis

With the familial variant identified, prenatal diagnosis and preimplantation genetic testing (PGT) are technically possible for UMOD and REN [1, 5]. In 2021, prenatal testing for MUC1 variants was unavailable in the United States, reflecting the VNTR's technical difficulty [4]. The sources consulted do not describe current availability of prenatal MUC1 diagnosis in Europe.

6. Differential Diagnosis

6.1. Differential diagnosis between ADTKD forms

The most frequent differential diagnosis of ADTKD-MUC1 is ADTKD-UMOD: gout occurs in approximately half of ADTKD-UMOD patients and precedes CKD, but many ADTKD-UMOD families without gout present identically [4]. In ADTKD-MUC1, gout usually develops only with CKD stage 3 or above, and there is no childhood anaemia or other manifestations [1]. Childhood anaemia and slightly elevated potassium in relatives point towards ADTKD-REN [4]. Adult-onset ADTKD-REN is indistinguishable from ADTKD-UMOD without genetic testing [5]. Normal urinary uromodulin favours MUC1 and low levels favour UMOD or REN [2, 21].

6.2. Monogenic differential diagnosis

Sources: UMOD (Table 3), MUC1 (Table 2) and REN (Table 5) GeneReviews and specific sources indicated in the text [1, 2, 4, 5, 32–34, 57, 70].

6.3. Main differential diagnoses

Juvenile nephronophthisis may mimic ADTKD in young adults, but is autosomal recessive, and only rare pseudodominant families cause confusion [2]. ADPKD, with bland sediment and dominant inheritance, is excluded by numerous cysts on ultrasound after 25 years [1]; DNAJB11-associated disease complicates this distinction because kidneys do not enlarge and cysts are inconsistent before 45 years; contrast-enhanced computed tomography detects small simple cysts in 39% of people aged 19–49 years and 63% of those aged 50–75 years in the general population, so cyst presence discriminates poorly [11, 19]. Classical Fabry disease in men with less than 1% α-galactosidase A activity begins in childhood or adolescence, with greater proteinuria than ADTKD-UMOD and ESKD in the third to fifth decade; men with more than 1% activity have cardiac or renal variants, and rare heterozygous women are as severely affected as men [1].

In APOA4-associated ADTKD, described in five families with the variants NM_000482.4:c.196C>G p.(Leu66Val) and NM_000482.4:c.97G>A p.(Asp33Asn) (hg19 coordinates chr11:116692578G>C and chr11:116693454C>T), 44 of 48 carriers had eGFR below 60, including all 25 with kidney failure, and 11 of 14 non-carriers had eGFR above 60; mass spectrometry identified mutant ApoA4 as the principal constituent of a medulla-limited amyloidosis [32]. In a 2026 preprint, heterozygous truncating BICC1 variants segregated with ADTKD in eight families, with a proposed dominant-negative or gain-of-function mechanism [33].

Mitochondrial tubulointerstitial disease is distinguished by exclusively maternal transmission. The NC_012920.1:m.547A>T variant was described with tubulointerstitial CKD without childhood anaemia, hyperkalaemia or acidaemia [57]. In a 2026 preprint, 18 of 33 unresolved families with maternal transmission (55%) had mtDNA variants, mainly recurrent homoplasmic insertions in the LSP2 promoter (9 families) and MT-TF variants (5 families); 54 of 60 children of affected mothers (90%) had below-normal GFR, versus 1 of 17 children of affected fathers (6%) [34]. Karyomegalic tubulointerstitial nephropathy due to biallelic FAN1 variants was characterised in 86 families from 22 countries: median presentation at 38.5 years, elevated liver tests in 46%, pulmonary complications in 39%, cancer in 6%, median kidney failure at 45 years (95% CI 38–56) and death in 27.1% (median at 55 years); the NM_014967.5:c.2120G>A p.(Trp707Ter) variant was associated with more pulmonary complications (adjusted OR 8.26) and lower survival (HR 3.24) [70].

6.4. Metabolic differential diagnosis of hyperuricaemia and juvenile gout

Hyperuricaemia in ADTKD-UMOD and ADTKD-REN results from urate underexcretion with normal renal function, which distinguishes it from overproduction hyperuricaemias [59, 71]. Phosphoribosylpyrophosphate synthetase 1 (PRPS1) overactivity causes gout or uric acid stones in young men, with possible renal failure, and partial hypoxanthine–guanine phosphoribosyltransferase (HPRT) deficiency causes isolated hyperuricaemia with urolithiasis; urinary urate excretion is high in both [71]. Glycogen storage disease type I, methylmalonic acidaemia (in which gout and hyperuricaemic nephropathy may be the presenting sign), other organic acidaemias, hyperlactataemias and HUPRA syndrome (SARS2) cause hyperuricaemia with low excretion through competition for tubular urate secretion [59]. Conversely, renal hypouricaemia type 1 (SLC22A12, URAT1, more common in Asia) and type 2 (SLC2A9, GLUT9) present with low urate, increased fractional excretion, nephrolithiasis and exercise-induced AKI [71]. Tubulointerstitial nephropathy also occurs in glycogen storage disease type I, methylmalonic acidaemia and respiratory chain disorders [59].

7. Treatments and Risk Management Strategies

7.1. General principles

No disease-modifying therapy is approved for any ADTKD form, and kidney transplantation is the only option for kidney failure [2, 72]. The only specific guideline is the 2015 KDIGO consensus report, whose recommendations, according to its own text, do not rest on high-level evidence because there are no randomised trials [2]. Treatment follows general CKD guidelines, adjusted by gene: control of progression risk factors (hypertension, diabetes, obesity, smoking), nephrology follow-up from diagnosis and timely KRT preparation [1, 2, 4]. In ADTKD-MUC1, GeneReviews recommends maintaining optimal health for transplantation, with exercise, avoidance of obesity and tobacco and strict control of hypertension, dyslipidaemia and other cardiovascular risk factors [4].

7.2. Hyperuricaemia and gout

The KDIGO report recommends, in ADTKD-UMOD, starting allopurinol or, if not tolerated, febuxostat after the first gout attack resolves, because recurrent attacks are likely [2]. GeneReviews adds that, on allopurinol, urate normalises and attacks may be completely prevented, that therapy is lifelong and that, in ADTKD-REN, lifelong allopurinol treatment of hyperuricaemia prevents gout in all patients [1, 5]. Evidence that allopurinol slows renal progression is insufficient: available studies are small, non-randomised, have short follow-up and predate genetic diagnosis [1, 2]. A strict low-purine diet has no known benefit, but the REN GeneReviews recommends avoiding high meat and seafood intake [2, 5]. Starting allopurinol may trigger an attack, which does not justify stopping it [2, 58].

Allopurinol (Zyloprim® in the United States; nationally authorised medicines in the European Union) is a xanthine oxidase inhibitor. The US label recommends, in adults with gout and normal renal function, starting at 100 mg orally once daily, with weekly 100 mg increases until urate is at or below 6 mg/dL, up to a maximum of 800 mg/day, and, in renal impairment, starting at 50 mg/day and increasing by 50 mg every 2–4 weeks [58]. Before initiation, urate, blood count, biochemistry, liver tests, creatinine and eGFR are assessed; attack prophylaxis with colchicine or an anti-inflammatory is maintained until urate normalisation and for several attack-free months [58]. The label does not define a maximum dose for each eGFR level and recommends monitoring renal function and reducing or discontinuing treatment with persistent deterioration [58]. The sources consulted do not include any Member State's summary of product characteristics (SmPC).

Source: FDA (Food and Drug Administration) label, Table 1, revised 3 September 2026; adults with gout and renal impairment; 50 mg/day increases every 2–4 weeks until target, with no maximum dose per eGFR level defined in the source [58].

Serious allopurinol adverse effects are Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), with a frequency of approximately 5 in 10,000 (0.05%); the drug should be permanently discontinued at the first rash [2, 58]. Carriers of HLA-B*58:01 have a greater hypersensitivity syndrome risk, use is not recommended in these carriers unless there is clear benefit, and screening should be considered in populations with high allele prevalence (African, Han Chinese, Korean, Thai, Hawaiian and Pacific Island ancestry) [58]. Other risks are nephrotoxicity, requiring lower doses in CKD, reversible hepatotoxicity, myelosuppression and somnolence [58]. In children, allopurinol safety and efficacy in gout are not established, and the label provides for paediatric use only in oncological hyperuricaemia; its use for gout in childhood ADTKD-UMOD or ADTKD-REN is therefore off-label [58].

Febuxostat (Uloric® in the United States, Adenuric® in the European Union) is a non-purine xanthine oxidase inhibitor. GeneReviews considers it an alternative in allopurinol allergy or intolerance, without ADTKD-specific data [1]. The US label includes a boxed warning about increased cardiovascular mortality versus allopurinol in patients with gout and established cardiovascular disease, restricts use to patients with an inadequate response to titrated allopurinol, intolerance or contraindication, and recommends 40 mg/day, increasing to 80 mg/day if urate remains at or above 6 mg/dL after two weeks, and a maximum of 40 mg/day in severe renal impairment [73]. The European SmPC specifies 80 mg/day, increasing to 120 mg/day if urate exceeds 6 mg/dL (357 μmol/L) after 2–4 weeks, no adjustment in mild or moderate renal impairment, efficacy and safety not fully assessed below creatinine clearance 30 mL/min, attack prophylaxis for at least six months and a cardiovascular warning in section 4.4 without a box [74]. The European SmPC does not recommend febuxostat in organ transplant recipients because of lack of experience, relevant to transplanted ADTKD patients [74]. Both labels contraindicate or discourage combination with azathioprine or mercaptopurine, and neither establishes paediatric use [73, 74].

In an acute attack, prednisone, short-course NSAIDs and colchicine are effective; NSAIDs should be avoided from CKD stage 3, and in ADTKD-REN prednisone is preferred to NSAIDs because combining NSAIDs with a low-renin state causes AKI [1, 5]. The sources consulted do not specify ADTKD-specific prednisone or colchicine doses, which follow general gout recommendations adjusted for renal function.

7.3. ADTKD-REN: fludrocortisone, erythropoiesis, acidosis and volume

Fludrocortisone, a synthetic aldosterone analogue, corrects aldosterone deficiency and mild hypotension and improves serum urate, potassium and bicarbonate [5]. Use in ADTKD is off-label: the US label limits the indication to partial replacement therapy in Addison disease (usual dose 0.1 mg/day, ranging from 0.1 mg three times weekly to 0.2 mg/day, reducing to 0.05 mg/day if transient hypertension develops) and salt-wasting adrenogenital syndrome (0.1–0.2 mg/day), with no maximum dose defined in the source and no paediatric dose, expressly discourages use in other conditions because of sodium retention, recommends monitoring blood pressure, oedema, weight and electrolytes, may require salt restriction and potassium supplementation and increases calcium excretion; paediatric safety and efficacy are not established [75].

The first treatment description, in a family with c.58T>C p.(Cys20Arg), used fludrocortisone acetate 0.1 mg orally once daily in a 10-year-old girl, with reduced potassium, increased blood pressure and a significant sustained eGFR increase after six weeks, without an effect on FEUA or polyuria; in two adults, including one with p.(Leu16del), a protocol of three days at 0.1 mg/day followed by four days at 0.2 mg/day had no haemodynamic or eGFR effect [50]. In the international cohort, two patients received continuous fludrocortisone (from 11 and 13 years) and seven short courses, without adverse effects, with lower potassium (4.37 ± 0.54 versus 4.77 ± 0.55 mEq/L; p<0.01) and higher bicarbonate (25.9 ± 2.3 versus 23.7 ± 3.5 mEq/L; p=0.003) on treatment, and a sustained eGFR increase in the patient starting at 11 years; the article does not state doses, and the small number limits conclusions [22]. In an ADTKD-SEC61A1 case, the dose was titrated from 0.025 mg/day at 8 years (22 kg) to 0.125 mg/day (28 kg) and 0.15 mg/day at 12 years (38.4 kg) [10].

GeneReviews suggests starting fludrocortisone before stage 3 (eGFR above 60 mL/min/1.73 m²), because at eGFR below 60 it may cause fluid retention and hypertension, according to the authors' observation, and values taking one 0.1 mg tablet over high sodium bicarbonate doses, often above 1300 mg/day, particularly in children, with no maximum dose defined in the source [5]. The KDIGO report allows fludrocortisone for symptomatic hypotension, weighs the theoretical risk of worsening interstitial fibrosis and stipulates that it should not be used with declining renal function, hypertension, hyperkalaemia or oedema [2]. The potential benefit invoked is feedback reduction of abnormal renin production, to be weighed against the harmful effects of aldosterone in CKD [50].

Anaemia may reverse with subcutaneous erythropoiesis-stimulating agents, managed by haematology or paediatric nephrology, with response-adjusted dosing and no established haemoglobin target; many children with haemoglobin 10–11 g/dL may be followed without treatment, the dose should be reduced when haemoglobin rises in adolescence, and iron deficiency, when present, is treated as an independent condition [2, 5]. In the international cohort, 14 never-treated children had mean haemoglobin 9.8 ± 1.2 g/dL [22].

Acidosis is treated with sodium bicarbonate tablets or liquid sodium citrate, dosed by body size and degree of acidaemia; correction is often suboptimal, and in the international cohort bicarbonate on alkali treatment frequently remained below 24 mEq/L, whereas with fludrocortisone it was more likely to exceed that value [5, 22]. Hypotension responds to sodium intake of 3–4 g/day, sodium bicarbonate or fludrocortisone, and hyperkalaemia to dietary potassium restriction and bicarbonate itself [5]. For fever and pain in children, analgesics and antipyretics other than NSAIDs should be preferred [5, 50].

7.4. Volume, sodium and agents to avoid

The low-sodium diet usually prescribed in CKD is not recommended in ADTKD-UMOD because it worsens hyperuricaemia, or in ADTKD-REN because it worsens volume depletion [1, 2]. Liberal fluid intake and caution with diuretics are recommended in all forms [2]. Dehydration, volume depletion and physical exertion in extreme heat should be avoided [1, 5].

7.5. Renal protection: RAAS blockade and SGLT2 inhibitors

There are no data on the effect of ACE inhibitors or angiotensin II receptor blockers (ARBs) on ADTKD progression; when used in a patient with hyperuricaemia, the KDIGO report suggests preferring losartan, the only agent lowering urate by increasing urinary excretion [2]. The REN GeneReviews advises against ACE inhibitors and does not comment on ARBs [5]. In an observational study not yet peer reviewed, 27 ADTKD patients received sodium–glucose cotransporter type 2 inhibitors (SGLT2 inhibitors); 12 stopped before one year because of concern about the expected acute creatinine rise, there were no adverse effects, and the eGFR slope was −2.61 ± 2.58 mL/min/1.73 m² per year after initiation versus −3.13 ± 5.39 before (p=0.71) and −2.25 ± 2.39 in 30 matched controls (p=0.83), without changes in haemoglobin or kidney injury molecule 1 (KIM-1), leading the authors to suggest these drugs may not be beneficial in this disease [76]. Sample size and observational design do not allow an effect to be excluded.

7.6. Kidney transplantation and living donors

Kidney transplantation is the treatment of choice for kidney failure, and disease does not recur in the graft [2]. ADTKD-UMOD and ADTKD-MUC1 patients are good candidates: slow progression allows time to find a living donor, and the absence of systemic manifestations apart from gout reduces comorbidity [1, 4]. The MUC1 GeneReviews recommends referral for transplant assessment when eGFR falls below 19 mL/min/1.73 m² [4]. In the Irish national registry, 31 ADTKD patients (28 with a definitive diagnosis, 23 with an identified variant) received 36 grafts, with graft and patient survival similar to 4633 non-ADTKD recipients and no evidence of recurrence in 25 graft biopsies; the small number limits precision [24].

Any relative being considered as a donor should undergo testing for the familial variant, and only non-carriers proceed with assessment [1, 2]. In DNAJB11-associated disease, a related donor with normal kidneys and few cysts may be mistakenly accepted without genetic testing [11]. In ADTKD-HNF1B with diabetes, the KDIGO report suggests considering kidney–pancreas transplantation [2].

7.7. Pregnancy and lactation

According to unpublished data from the MUC1 GeneReviews authors, pregnancies in women with ADTKD have better maternal and fetal outcomes than other nephropathies with similar renal function: approximately 20% develop hypertension in pregnancy, approximately 10% deliver before 38 weeks and the caesarean rate is not increased [4]. In ADTKD-UMOD, fetal outcomes are comparable to the general population, with a greater hospitalisation risk for hypertension according to the authors' observation, and there are no specific data on accelerated functional loss [1]. Successful pregnancies are documented in ADTKD-REN, without increased miscarriage or other adverse outcomes [5].

Women of reproductive age should review medication before conception. ACE inhibitors may cause fetal injury and death even in early pregnancy, so are replaced by another antihypertensive in women who are pregnant, planning pregnancy or not using effective contraception [1, 4]. Allopurinol should be stopped before pregnancy according to the KDIGO report because of its association with cleft palate and other facial abnormalities [2]. Human data are limited: approximately 50 published pregnancies included two major malformations; a 2011 case described multiple malformations and death on day eight; and in a prospective series of 31 first-trimester-exposed pregnancies, the overall malformation rate was as expected but one child had similar severe malformations [58, 77, 78]. The malformation pattern resembles mycophenolate, a parallel considered concerning by the GeneReviews authors because of the shared mechanism of interference with purine metabolism [1]. In the authors' experience, most women with ADTKD-REN complete pregnancy without gout and without allopurinol [5].

Prednisone is associated with fetal growth restriction and, in the first trimester, a slight increase in orofacial clefts; chronic periconceptional colchicine use was associated, in a familial Mediterranean fever cohort, with a greater risk of fetal chromosomal abnormalities, whereas short courses outside that period carry low risk [1]. Erythropoietin is unlikely to cause congenital abnormalities, based on pregnant kidney transplant recipients [5]. For fludrocortisone, the US label (category C) recommends observing neonates born to exposed mothers for signs of hypoadrenalism, and the REN GeneReviews, citing prescribing information, reports a risk of clinical neonatal hyperaldosteronism with high doses [5, 75]. Febuxostat should not be used in pregnancy or breastfeeding according to the European SmPC, and the US label considers data insufficient [73, 74]. The sources consulted do not describe breastfeeding safety for the other drugs; GeneReviews refers to the MotherToBaby service [1].

7.8. Perioperative care, intercurrent illness and transition

During surgery, febrile illness and vomiting or diarrhoea episodes, the principles are the same as chronic management: maintain circulating volume, avoid NSAIDs and nephrotoxins and monitor creatinine and potassium, particularly in ADTKD-REN, in which AKI with dehydration is characteristic [2, 5]. At transition to adult nephrology, ADTKD-REN requires attention to anaemia evolution, regressing at puberty and potentially recurring with functional loss, and reduction of erythropoiesis-stimulating agents when haemoglobin rises [2, 5]. The KDIGO report recommends referral of children at risk of ADTKD-REN and ADTKD-HNF1B to paediatric nephrology because they benefit from early management [2].

7.9. Regulatory status

No drug has an approved ADTKD indication; urate-lowering agents are used under the general indication of gout or hyperuricaemia, and fludrocortisone is used off-label.

Sources: [2, 58, 73–75]. The sources consulted do not include reimbursement or access data for Portugal or Brazil.

7.10. Clinical studies

There are no randomised trials of any ADTKD intervention, and the October 2026 ClinicalTrials.gov search found no registered interventional disease-modifying therapy trials or BRD4780 trial registration [79]. Available intervention evidence is observational or comes from data collection studies.

These studies do not allow treatment effects to be estimated with confidence intervals: they are small series without a randomised control group, selected by referral and, for SGLT2 inhibitors, a preprint. Observed differences on fludrocortisone are within-person biochemical variations rather than renal outcomes. The absence of an SGLT2 inhibitor effect in 27 patients is compatible with a small undetected effect. To prepare trials, the Wake Forest and University of Florida group published a publicly accessible clinical trial simulator in May 2026, based on natural history models, treating eGFR slope and final eGFR as surrogate outcomes and estimating statistical power by scenario [52, 72].

7.11. Developments and research

BRD4780 remains preclinical seven years after its description, and the 2021 GeneReviews text anticipating trials within two to five years had not materialised by October 2026 [4, 79]. Absence of registration does not prove no development is under way. In diagnosis, the last twelve months brought single-molecule VNTR sequencing in 300 individuals, long-read amplicon sequencing with VNTRtools, VNtyper 2 in preprint and descriptions of BICC1 and mitochondrial LSP2 promoter insertions, also in preprints [33, 34, 43, 67, 68]. Characterisation of FAN1 nephropathy in 86 families was published in 2026 [70].

7.12. Guideline recommendations and divergences

Sources: [1, 2, 4, 5]. ERKNet has not published an ADTKD-specific guideline in the sources consulted [25].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

All ADTKD forms described in this article are autosomal dominant, and most patients have an affected parent [1, 4, 5]. The proportion of de novo cases is not established for MUC1 and REN, because few simplex cases have been identified; in recent series, de novo MUC1 variants were confirmed in two French patients and a 32-year-old German patient, and the Swedish case's SEC61A1 variant was de novo [4, 10, 55, 67]. An Italian ADTKD-UMOD case without a family history, with deceased parents and a non-carrier sister, illustrates the difficulty distinguishing a de novo variant from an unrecognised family history [85].

An apparently negative family history is confirmed only by parental testing, because it may result from failure of recognition, a mild phenotype, early death or late onset [1]. In ADTKD-REN, affected parents will have had childhood anaemia, which may have been unnoticed or forgotten [5]. Progression rate and age at ESKD vary greatly between siblings and correlate poorly with the parent's [1].

8.2. Cascade and predictive testing

Predictive testing requires a known familial variant, is useful for predicting CKD and is mandatory for donor candidates [1, 2]. In asymptomatic at-risk adults, clarifying genetic status is appropriate because CKD is often asymptomatic and diagnosis permits renal function monitoring and avoidance of nephrotoxins; in ADTKD-MUC1, normal renal function in an at-risk relative does not exclude disease [1, 4]. Responsibility for informing relatives usually rests with the patient [2].

8.3. Counselling of minors

Testing children for adult-onset diseases without specific treatment is generally discouraged to preserve future autonomy, and the KDIGO report does not recommend routine testing, advising an individualised decision [2, 4]. The position varies by gene. In ADTKD-UMOD, testing may be considered to start gout prevention in a family with early ESKD and adolescent gout, or in a child athlete or dancer, and should be avoided in families with late ESKD and no childhood gout; testing requires discussion with the child, their assent and parental consent [1]. In ADTKD-MUC1, the alternative is annual blood pressure and creatinine measurement, with genetic testing if creatinine rises or relatives have early onset; in one series, seven people predictively tested in childhood reported high satisfaction [4]. In ADTKD-REN, early clarification is particularly important because of AKI, anaemia, acidaemia and gout risks, and symptomatic individuals should be tested at any age [4, 5].

8.4. Prenatal and preimplantation diagnosis and family planning

With the familial variant identified, prenatal diagnosis and PGT are possible for UMOD and REN, and the KDIGO report includes interest in preimplantation diagnosis among reasons for testing [1, 2, 5]. For MUC1, prenatal testing was unavailable in the United States in 2021 [4]. Views on using these tests for an adult-onset disease with effective replacement therapy differ between people and should be discussed non-directively [1]. For women with ADTKD-MUC1 considering pregnancy, GeneReviews suggests not delaying pregnancy, because eGFR declines during the reproductive years and earlier pregnancy occurs with better renal function and fewer complications [4]. Preconception medication review (allopurinol, ACE inhibitors) is described in section 7.7.

8.5. Counselling content

Counselling should be provided by genetics professionals and address dominant transmission, age-dependent penetrance and intrafamilial variability, the meaning of a negative test, particularly for MUC1, mandatory donor testing, avoidance of NSAIDs, dehydration and a low-sodium diet, and the good transplant prognosis [1, 2]. In families without an identified variant (ADTKD-NOS), annual renal function surveillance in at-risk relatives continues, and reanalysis with new methods for MUC1, APOA4, BICC1 and mtDNA may resolve old cases [2, 32, 43].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each number measures

ADTKD prevalence is not established, and the KDIGO report considered in 2015 that UMOD and MUC1 would be more frequent than HNF1B and REN [2]. Published estimates differ because they measure different fractions of different populations, and none is a validated national prevalence.

The values 0.2%, 1% and 2% do not conflict: the highest comes from a centre actively seeking family history, the intermediate from a review and the lowest from exomes in unselected CKD, which by design do not include ADTKD-MUC1. In the US exome study, disease was diagnosed in patients with widely varied clinical diagnoses, showing that many cases reach testing without ADTKD being suspected [62]. In France, among 4040 referrals without suspected ADTKD, the MUC1 detection rate was 0.05% in glomerular diseases, 1.2% in ciliopathies, 0.09% in congenital anomalies of the kidney and urinary tract (CAKUT) and 2.5% in CKD of unknown cause [55]. Approximately 2000 people with ADTKD-UMOD had been identified in 2020, a number expected to grow with recognition and testing [1]. A 2025 review describes ADTKD as the third most frequent monogenic cause of kidney failure, a statement by its authors [28].

9.2. Europe and the United States

According to GeneGuidance, Orphanet records ADTKD-UMOD at 1.7 per million in Austria and 9 per million in the United Kingdom, and ADTKD-MUC1 at 0.4 per 100,000 in Ireland and 0.07 per 100,000 in the United States, with worldwide prevalence unknown; ADTKD-REN belongs to the below-1-per-million class, with approximately 35 families [17, 42]. In European (Belgian, Swiss and European consortium) and US (Wake Forest) registries combined in 2020, 726 patients from 585 families with a presumptive diagnosis had UMOD variants in 216 of 562 families (38.4%) and MUC1 variants in 72 of 205 UMOD-negative families (35.1%); these proportions describe a referral cohort rather than prevalence [21]. In Ireland, 54 individuals from 16 families meeting clinical criteria had MUC1 in 3 families, UMOD in 5, HNF1B in 2 and MUC1fs in urinary smears in 3 [61]. In Lille, the authors suggest that MUC1 may be the leading ADTKD cause in their cohort [69]. In the Czech–US single-molecule sequencing study, half the families with suspected ADTKD-MUC1 had a frameshift [43].

In the United States, between 1996 and 2017, the Wake Forest programme received 665 referrals, 27% directly from families through the internet, with genetic positivity similar to professional referrals (24%, 27% and 25%); 25% of diagnosed families arrived through self-referral, and 99% of direct contacts were white people from higher-income areas, an access bias limiting the representativeness of US registries [87].

9.3. Founder populations and other regions

Six large Cypriot ADTKD-MUC1 families constituted one of the first clinical series [54]. The UMOD variant “C744G”, now c.744C>G p.(Cys248Trp), was associated with a possible founder effect, an attribution made by the article title [39]. REN c.1172C>G p.(Thr391Arg) was described in a Tunisian family [5]. In China, at a Beijing hospital between 2010 and 2024, 70 patients meeting KDIGO criteria had UMOD variants in 51%, HNF1B in 23%, MUC1 in 20% and REN in 6%, with age at diagnosis 32 ± 11 years and eGFR 46 ± 21 [37]. In Japan, among 1097 families tested for suspected CAKUT, nephronophthisis, cystic disease or ADTKD, 40 families had ADTKD (UMOD 18, MUC1 16, REN 5, SEC61A1 1), with median age at diagnosis 38.5 years and ESKD already present in 37% at diagnosis; 75% of MUC1 families were identified by long reads [36]. In another Japanese series, long reads detected MUC1 in 8 of 39 patients negative on short-read sequencing, with an overall detection rate of 18.8% and median age at ESKD 45 years [63]. In Oman, a paediatric series described three siblings with REN c.49T>C p.(Trp17Arg), two with significant hypomagnesaemia [49].

9.4. Portugal and Brazil

The sources consulted contain no prevalence estimates for Portugal or Brazil. Centres in Lisbon (Centro Hospitalar Universitário Lisboa Norte, GenoMed and Instituto de Medicina Molecular, NOVA Medical School) and Niterói (Universidade Federal Fluminense) participated in the 2020 international ADTKD-UMOD consortium, and Portuguese authors participated in the 2026 MUC1 single-molecule sequencing study [20, 43]. In Brazil, an observational Universidade Federal Fluminense study assessed familial kidney disease frequency in 1308 patients on KRT in the south-east between 2017 and 2020, without published registry results [79]. The absence of data in these sources does not demonstrate absence of published data.

9.5. Special populations

In children, ADTKD-REN and ADTKD-SEC61A1 are the forms with early manifestations, and age-specific urate and FEUA norms are indispensable [1, 5]. Men with ADTKD-UMOD progress faster, adolescent gout is more frequent in males, and some women reach ESKD only in the sixth or seventh decade [1, 2, 20]. In patients of African or Asian ancestry, HLA-B*58:01 screening before allopurinol merits consideration [58]. Transplanted ADTKD-MUC1 patients had a higher COVID-19 death risk in the registry survey [46]. Genetic testing is indispensable in all forms when selecting related living donors [2].

9.6. European networks and patient associations

ERKNet includes ADTKD in the autosomal dominant structural disease group; in October 2026, the ADTKD-Net registry contained 377 patients (42 paediatric and 335 adult), and the central ERKReg registry 6385 patients in that group; GeNepher combines a registry with a DNA biobank [25]. In the United Kingdom, the UK Kidney Association's RaDaR rare disease group has an ADTKD group, with a patient representative, patient days (London in 2018, Newcastle in 2024) and a link to the Purine Metabolic Patients Association (PUMPA); families are enrolled by the local team [88]. In the United States, the Wake Forest programme maintains UMOD, MUC1 and REN registries with educational materials, and the Rare Kidney Disease Foundation, a patient-led organisation, participated in the 2026 FDA webinar [1, 4, 84]. MedlinePlus provides patient information [1].

10. Illustrative Clinical Case

10.1. ADTKD-UMOD discovered on routine testing

A 42-year-old man in Italy had creatinine 1.6 mg/dL (eGFR 52.7 mL/min/1.73 m²) and urate 8 mg/dL on annual tests, with normal urine [85]. One month later, creatinine was 1.67 mg/dL, urate 8.3 mg/dL and proteinuria 150 mg/24 h; ultrasound showed normal-sized kidneys with a cyst at the right upper pole. He had no gout, took no medication and had no family history of kidney disease or gout: his father had type 2 diabetes and a brother hypertension [85]. At admission, blood pressure was 115/75 mmHg, creatinine 1.44 mg/dL (eGFR 59.5), urate 7.5 mg/dL, cystatin C 1.11 mg/L and proteinuria 75 mg/day, with normal autoimmunity tests and complement [85].

Kidney biopsy, with 12 glomeruli (1 globally sclerosed), showed focal Bowman capsule thickening, mild tubular atrophy and interstitial fibrosis (less than 10%) and cytoplasmic hyaline inclusions in some TAL profiles on Masson trichrome staining, with negative immunofluorescence (Figure 1 of the article) [85]. Clinical exome sequencing identified NM_003361.4:c.409T>C p.(Cys137Arg) in UMOD exon 3, confirmed by Sanger sequencing (Figure 2 of the article), absent from ClinVar and LOVD (Leiden Open Variation Database) and classified as likely pathogenic (criteria PM1, PM2, PP3 and PP4); his sister was not a carrier and had no signs of disease, and his parents were deceased, so de novo origin was considered possible but unproven [9, 85]. He was informed of the 50% offspring risk and discharged without drugs: no ACE inhibitor or ARB because blood pressure was normal and proteinuria minimal, and no urate-lowering agent, which he declined. One year later, creatinine was 1.5 mg/dL (eGFR 51), urate 7.6 mg/dL and haemoglobin 14 g/dL, without gout and with blood pressure approximately 120/75 mmHg [85].

The case shows three ADTKD-UMOD features: hyperuricaemia preceding asymptomatic CKD, minimal proteinuria and lack of family history as a barrier to recognition. Diagnostic management differed from GeneReviews recommendations advising against biopsy when the diagnosis is considered [1]; here disease was not suspected before biopsy, which guided testing. The authors stress that variant classification rests on computational and rarity criteria, without functional studies and with limited segregation [85]. However, cysteine substitution is the type of change considered very likely pathogenic by GeneReviews [1].

10.2. Hypoaldosteronism in a child with a de novo SEC61A1 variant

A Swedish girl presented at one year with growth failure, renal failure (GFR 18 mL/min/1.73 m²), hyperkalaemia and acidosis [10]. Biopsy at 18 months, with 24 glomeruli, showed neither glomerulosclerosis nor glomerulocystic changes, but focal immature podocytes and glomerular density suggestive of tubular dysgenesis, with renin in the juxtaglomerular apparatus in 3 of 14 glomeruli. At two years, blood pressure was 60/30 and 80/40 mmHg. She continuously received erythropoietin and iron, vitamin D and sodium bicarbonate. A tubular dysgenesis gene panel (REN, AGT, ACE, AGTR1) at 18 months identified only an AGT variant inherited from her unaffected mother, likely benign [10].

At 8 years she was admitted with extreme fatigue, mean 24-hour blood pressure 70/46 mmHg and nocturnal blood pressure 60/42 mmHg, and undetectable aldosterone [10]. She started fludrocortisone acetate at 22 kg at 0.025 mg/day, increased to 0.125 mg/day at 28 kg and 0.15 mg/day at 12 years (38.4 kg; body surface area 1.26 m²), with salt 4.2 mmol/kg/day and water via gastrostomy. Well-being improved markedly, blood pressure rose to 95/70 mmHg, potassium and acid–base balance normalised, and iohexol-measured GFR rose from 18 to 54 mL/min/1.73 m² at 12 years, without proteinuria or polyuria [10]. A second biopsy at 9 years showed global or near-global sclerosis in 10 of 16 glomeruli and mild tubulointerstitial fibrosis (Figure 1 of the article) [10]. Trio genome sequencing at 9 years identified the de novo SEC61A1 variant NM_013336.4:c.1372T>G p.(Phe458Val), in the last transmembrane domain, classified as likely pathogenic (PS2 and PM2); serum uromodulin was low (median 72 versus 168 ng/mL in controls) (Figure 2 of the article), as was angiotensin II [10].

The case illustrates overlap between ADTKD-SEC61A1 and childhood ADTKD-REN, explained by defective renin transport through the translocon, and an eight-year diagnostic delay with a targeted panel compared with genome sequencing [10, 23]. Fludrocortisone is off-label here, in a child, with weight-based titration that cannot be generalised; initiation at GFR approximately 18, far below the threshold of 60 suggested by GeneReviews for ADTKD-REN, and the favourable response show that this threshold derives from clinical observation rather than comparative studies [2, 5].

11. Prognosis and Long-Term Follow-Up

11.1. Renal prognosis

Prognosis is dominated by age at ESKD, varying by gene, variant and between members of the same family. In ADTKD-UMOD, median age at ESKD was 47 years in the international consortium, with greater risk in men (HR 1.78), and median renal survival was 54 years in the 2020 registries; some variants are associated with early ESKD, such as p.(Cys92Gly) with a median of 31.5 years, and others with late ESKD, such as p.(Cys248Trp) with 71 years [1, 20, 21]. In ADTKD-MUC1, median age at ESKD is 46 years (20–70) [4, 21], with faster decline than ADTKD-UMOD after the eGFR curve's inflection point [52]. In ADTKD-REN, mean age at ESKD was 53.1 years in the signal peptide group, 50.8 in the prosegment group and 63.6 in the mature renin group, and childhood anaemia was associated with earlier ESKD [22]. In DNAJB11-associated disease, ESKD occurs between 55 and 89 years, with a median of 75 [19]. In Wake Forest modelling, eGFR and age at first consultation explained part of progression variability, and older age at first consultation was associated with slower progression [52].

These data come from referral cohorts of families with manifest disease rather than population samples, and describe patients treated with general CKD care; comparable untreated natural history data do not exist. Kidney transplantation offers graft and patient survival similar to other recipients, without recurrence [24]. COVID-19 mortality was higher in ADTKD-MUC1 than ADTKD-UMOD in an observational study [46].

11.2. Surveillance

11.3. Signs changing management

Rising creatinine, worsening hyperkalaemia or acidosis, symptomatic hypotension, AKI during intercurrent illness, the first gout attack and planned pregnancy are the moments when treatment changes [2, 5]. eGFR falling below 19 mL/min/1.73 m² marks transplant referral in ADTKD-MUC1 [4]. In children with ADTKD-REN, rising haemoglobin in adolescence allows erythropoiesis-stimulating agents to be reduced, and at transition to adult nephrology, surveillance frequency is adjusted to renal function [5].

12. Summary and Final Considerations

ADTKD is a group of autosomal dominant nephropathies that share slowly progressive tubulointerstitial CKD, bland sediment, minimal proteinuria and normal-sized or small kidneys, and that lead to kidney failure between the third and seventh decades. The main genes are UMOD, MUC1 and REN, with SEC61A1 and DNAJB11 as rare causes and APOA4, BICC1 and mitochondrial DNA as recent entities in the differential diagnosis; the HNF1B-associated form is also part of the differential diagnosis. The shared mechanism is proteotoxicity of mutant proteins retained in the endoplasmic reticulum or intermediate compartment, with progressive loss of tubular cells.

Each form has its own clues. ADTKD-UMOD is associated with hyperuricaemia with low fractional urate excretion from childhood and gout in approximately half of patients, with median age at kidney failure 47 years. ADTKD-MUC1 has no sign apart from CKD, with median kidney failure at 46 years, and its most frequent variant, a VNTR cytosine insertion, escapes standard panel, exome and genome analysis, requiring targeted tests, long-read sequencing or algorithms such as VNtyper. ADTKD-REN manifests in childhood with hypoproliferative anaemia, hyperkalaemia, acidosis, low blood pressure and susceptibility to acute kidney injury, or in adulthood with gout and CKD indistinguishable from ADTKD-UMOD.

Diagnosis rests on family history and genetic testing, preferred to biopsy by GeneReviews; a negative test does not exclude disease, particularly when MUC1 has not been assessed by a targeted method. Frequency in end-stage kidney disease ranges from approximately 0.2% to 2% according to study denominators and selection, and none of these numbers is a national prevalence.

There is no disease-modifying therapy. Treatment follows general CKD guidelines, with allopurinol for gout, avoidance of NSAIDs, dehydration and a low-sodium diet, erythropoiesis-stimulating agents and alkalinisation in ADTKD-REN and, in this form, off-label fludrocortisone in selected cases with preserved function. The 2015 KDIGO consensus report remains the only specific guideline, and its indications on biopsy and MUC1 testing have been overtaken by technical progress. Kidney transplantation is the treatment of choice for kidney failure, without graft recurrence, and genetic testing is mandatory for related living donors. Therapies targeting TMED cargo receptors and mutant protein clearance remain preclinical.

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