Autosomal dominant tubulointerstitial kidney disease – from a diagnostic desert to a more nuanced landscape of roses and thorns

Abstract Autosomal dominant tubulointerstitial kidney disease (ADTKD) constitutes a spectrum of rare, but underdiagnosed renal disorders. ADTKD presents with a bland urinary sediment (no hematuria and little to no proteinuria), usually has no extrarenal manifestations (with the exception of HNF1B- associated disease), and results in a slowly progressive chronic kidney disease. Renal failure typically occurs in the fourth to fifth decade of life. Despite a uniform clinical picture, there is substantial interfamilial- and intrafamilial diversity in progression of CKD sometimes ranging from before the third to beyond the sixth decade of life. ADTKD shows modest genetic heterogeneity, with four main types ( UMOD , MUC1 , HNF1B , and REN ) accounting for the vast majority of cases. However, sometimes ADTKD is used as an umbrella term for a broader number of isolated or syndromal conditions that may present with an ADTKD phenotype. The two most common ADTKD types caused by pathogenic variants in the glycoproteins uromodulin ( UMOD ), mucin 1 ( MUC1 ), and the enzyme renin ( REN ) show striking similarities in their molecular pathophysiology and are considered toxic proteinopathies. From a spectrum of kidney disease virtually unknown to the public and to large parts of the medical community before the identification of UMOD as the first identified cause of ADTKD (then termed MCKD2) in 2002, ADTKD is increasingly recognized as a leading genetic cause of kidney disease in adults. The identification of MUC1 as the cause for the second main type has greatly stimulated research on all aspects of ADTKD and unveiled important molecular insights into its underlying pathophsiology. Our molecular knowledge on common ADTKD forms has passed the critical threshold required for developing targeted therapeutic strategies and personalized treatment approaches can be expected in the near future.