Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management—A KDIGO consensus report

Abstract

Rare autosomal dominant tubulointerstitial kidney disease is caused by mutations in the genes encoding uromodulin (UMOD), hepatocyte nuclear factor-1β (HNF1B), renin (REN), and mucin-1 (MUC1). Multiple names have been proposed for these disorders, including 'Medullary Cystic Kidney Disease (MCKD) type 2', 'Familial Juvenile Hyperuricemic Nephropathy (FJHN)', or 'Uromodulin-Associated Kidney Disease (UAKD)' for UMOD-related diseases and 'MCKD type 1' for the disease caused by MUC1 mutations. The multiplicity of these terms, and the fact that cysts are not pathognomonic, creates confusion. Kidney Disease: Improving Global Outcomes (KDIGO) proposes adoption of a new terminology for this group of diseases using the term 'Autosomal Dominant Tubulointerstitial Kidney Disease' (ADTKD) appended by a gene-based subclassification, and suggests diagnostic criteria. Implementation of these recommendations is anticipated to facilitate recognition and characterization of these monogenic diseases. A better understanding of these rare disorders may be relevant for the tubulointerstitial fibrosis component in many forms of chronic kidney disease.

Elevated urinary CRELD2 is associated with endoplasmic reticulum stress–mediated kidney disease

“…ADTKD is a monogenic condition in which ER stress is prominent and leads to tubulointerstitial fibrosis and progression of chronic kidney disease. ADTKD-UMOD is a phenotypically heterogeneous disorder manifested by variable age of disease onset, disease severity, and rate of disease progression among affected individuals within and between families, with patients reaching ESRD between the ages of 25 and 70 years or older (12). Human mature uromodulin, mainly localized at the apical plasma membrane of TAL cells (45), contains a signal peptide, 3 EGF-like domains, a central domain of unknown function, a zona pellucida domain, and a glycosylphosphatidylinositol-anchoring (GPI-anchoring) site (13).…”

Need to Reclassify Etiologies of ESRD on the CMS 2728 Medical Evidence Report

“…Identification of the apolipoprotein L1 gene (APOL1)-associated spectrum of nondiabetic nephropathy in patients with recent African ancestry supports the need to remove "hypertension" as the cause of ESRD in those with mild to moderately elevated BPs. Detection of genes underlying steroid-resistant nephrotic syndrome and autosomal dominant tubulointerstitial forms of nephropathy further supports the need to update the nomenclature, particularly after genetic testing becomes widely available (8,9).…”

Hepatocyte Nuclear Factor 1β–Associated Kidney Disease

“…These are diseases characterized by bland urinary sediment, tubular and interstitial fibrosis, and slowly progressive kidney disease. 50 Indeed, the phenotypes associated with HNF1B mutations partly overlap with mutations in REN, UMOD, and MUC1, which are also part of the spectrum of autosomal dominant tubulointerstitial kidney disease.…”