Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease

Abstract

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a clinical entity defined by interstitial fibrosis with tubular damage, bland urinalysis and progressive kidney disease. Mutations in UMOD and MUC1 are the most common causes of ADTKD but other rarer (REN, SEC61A1), atypical (DNAJB11) or heterogeneous (HNF1B) subtypes have been described. Raised awareness, as well as the implementation of next-generation sequencing approaches, have led to a sharp increase in reported cases. ADTKD is now believed to be one of the most common monogenic forms of kidney disease and overall it probably accounts for ∼5% of all monogenic causes of chronic kidney disease. Through international efforts and systematic analyses of patient cohorts, critical insights into clinical and genetic spectra of ADTKD, genotype-phenotype correlations as well as innovative diagnostic approaches have been amassed during recent years. In addition, intense research efforts are addressed towards deciphering and rescuing the cellular pathways activated in ADTKD. A better understanding of these diseases and of possible commonalities with more common causes of kidney disease may be relevant to understand and target mechanisms leading to fibrotic kidney disease in general. Here we highlight recent advances in our understanding of the different subtypes of ADTKD with an emphasis on the molecular underpinnings and its clinical presentations.

Keywords: cohort studies; inherited kidney diseases; interstitial fibrosis; monogenic kidney disease; rare diseases.

FIGURE 1

Pathophysiology of ADTKD-UMOD and ADTKD-MUC1. (A) Left panel: UMOD expression is restricted to the thick ascending limb and the early DCT. Right panel: Cellular pathways activated by the expression of mutant UMOD (in cellular and murine studies as well as patient biopsies) and its toxic accumulation in the ER. (B) Left panel: Mucin 1 expression along the entire distal tubule. Right panel: Cellular pathways activated by the expression of mutant mucin 1 (in cellular and murine studies as well as patient biopsies) and its toxic accumulation in the ERGIC.

FIGURE 2

Diagnostic algorithm in ADTKD. ADTKD should be suspected based on a series of clinical findings (or the absence thereof) and typically a positive family history (in blue) [1]. A firm diagnosis in suspected cases can only be established by molecular genetics (in green). Diagnostic approaches are likely to change with evolving molecular methodologies. Targeted analysis should take into consideration typical extrarenal features where present and may also take into account clinical scores developed for the rational prioritization of genetic tests. NGS-based approaches will likely become the preferred technology for detecting ADTKD with the limitations that variants in MUC1 VNTR are not detectable by NGS and require tailored approaches. +, positive result; –, negative result; ARPKD, autosomal recessive polycystic kidney disease; CNV, copy number variation; MLPA, multiplex ligation-dependent probe amplification.;Adapted from Devuyst O, Olinger E, Weber S et al. Autosomal dominant tubulointerstitial kidney disease. Nat Rev Dis Primer 2019; 5: 60.

FIGURE 3

ADTKD in the UK. (A) Major UK centres (with family numbers) from which ADTKD families have been recruited into the RaDaR and Genomics England 100 000 Genomes Project. (B) UMOD mRNA (NM_003361) and exon structure with UTR in grey. Protein domains are shown in colour code. UMOD mutations detected in the recruited families are presented above the mRNA structure with respect to their location and with disc size reflecting family numbers. For five families, the exact UMOD mutations were not recorded.