Autosomal Dominant Tubulointerstitial Kidney Disease: An Emerging Cause of Genetic CKD

Abstract

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare inherited disorder characterized by progressive loss of kidney function, nonsignificant urinalysis and tubulointerstitial fibrosis. ADTKD progresses to end stage renal disease (ESRD) in adulthood. The classification of ADTKD is an evolving concept and the agreement is now that, due to the overlap in terms of phenotype characteristics, this should be based on the involved gene. The umbrella term ADTKD therefore includes different conditions as follows: ADTKD-UMOD, ADKTD-MUC1, ADTKD-REN, and ADTK-HNF1B, with ADTKD-SEC61A1 and ADTKD-DNAJB11 as a further rare and atypical diagnosis recently described. The employment of next-generation sequencing (NGS) as a diagnostic tool in patients with familial kidney disease has improved the diagnostic accuracy in this field with ADTKD now being considered the third genetic cause of renal disease worldwide after autosomal dominant polycystic kidney disease (ADPKD) and Alport syndrome. On average, the disease pathogenesis is similar across the different subtypes, With the exception of HNF1B, the different mutated genes give rise to misfolded proteins leading to cellular stress and cytotoxicity. Research is now focused in better defining the underlying mechanism of fibrosis to guide therapeutic interventions. The aim of this review is to discuss how the knowledge of ADTKD has evolved in the last decades, with emphasis on the clinical features, molecular diagnosis, and pathogenic aspects of the different diseases included under the ADTKD term.

Keywords: ADTKD; DNAJB11; HNF1B; MUC1; REN; UMOD.

Figure 1

Shared and hallmark clinical features of the different types of ADTKD. ADTKD, autosomal dominant tubulointerstitial kidney disease; CAKUT, congenital anomalies of the kidney and urinary tract; CKD, chronic kidney disease; ESRD, end stage renal disease; NDD, neurodevelopmental delay; yo, year.

Figure 2

Age at onset of renal and extrarenal manifestation in different types of ADTKD according to the mutated gene. ADTKD, autosomal dominant tubulointerstitial kidney disease; CAKUT, congenital anomalies of the kidney and urinary tract; CKD, chronic kidney disease; ESRD, end stage renal disease; RTI, respiratory tract infections; yo, year.

Figure 3

ADTKD-UMOD kidney biopsy. (a) Light microscopy shows lymphocytic infiltrate associated with interstitial fibrosis and tubular atrophy (hematoxylin and eosin stain). (b) Immunohistochemical examination with anti-UMOD antibody shows intracellular aggregates of mutant UMOD in tubular cells.

Figure 4

Common cellular pathway in ADTKD. SEC61A1, REN, UMOD, MUC1 disease-causing variants effect on the early secretory pathway, ranging from ER translocation defect (SEC61, REN), to retention of mutant protein in the ER (UMOD, REN) or ER-Golgi intermediate compartment (MUC1-fs, REN). ER stress and induction of the Unfolded Protein Response have been reported on expression of the mutated genes, with the exception of renin mutations in the prosegment for which no data are available yet. Intracellular accumulation of UMOD, REN and MUC1-fs lead to a subsequent decrease of their delivery to the apical plasma membrane (UMOD,MUC1-fs) and/or of their secretion (UMOD,REN). Of note, mutant uromodulin reaching the plasma membrane interferes with the polymerization of wild-type protein. HNF1B coordinates several transcriptional networks. It seems likely that the ADTKD-like phenotype due to HNF1B pathogenic variants can be explained by the absence of transcriptional activation of HNF1B target genes. ADTKD, autosomal dominant tubulointerstitial kidney disease; ER, endoplasmic reticulum; fs, frameshift.