There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum-Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct.

Autosomal dominant tubulointerstitial kidney disease caused by mutations in uromodulin gene (ADTKD-UMOD) is a spectrum of hereditary renal disorders, characterized by early-onset hyperuricemia, gout and progressive nephropathy. This study presented a novel UMOD mutation in an ADTKD pedigree and reviewed studies in Chinese population. The index patient is a 16-year-old girl with hypertension, hyperuricemia and normal serum creatinine level. Four affected and six unaffected members were available for genetic screen. The mutation analysis was performed by next-generation sequencing and direct sequencing. A literature research was conducted to review Chinese ADTKD-UMOD cases. MEDLINE and Chinese Biomedicine Databases were searched with \'uromodulin\', \'juvenile gout\' and their related terms. Genetic sequencing revealed a de novo mutation within exon 3 (Cys223Gly), which was co-segregating with phenotype in this pedigree. In the review, four studies and our study involving a total of 67 ADTKD patients from 11 families were identified. Of these patients, 27 were confirmed to carry UMOD mutations. Mutations occurred in exon 3 were commonly observed, while mutations within exon 4, 5 and 9 occurred less frequently in Chinese ADTKD-UMOD cases. Among these cases, median age of symptom onset was 26.5 years, median age of end-stage renal diseases (ESRD) or death by ESRD was 41.9 years without renal replacement treatment. Phenotype caused by mutations in D8C domain seemed to be severe than those in GPI domain. Compared with patients of other race, Chinese ADTKD-UMOD patients advanced more aggressively to ESRD.