Astley, Megan E

Introduction: Autosomal-dominant tubulointerstitial kidney disease (ADTKD) is characterized by chronic kidney disease (CKD) with an average age of end-stage renal disease (ESRD) of approximately 45 years, bland urinary sediment, the absence of proteinuria and autosomal dominant inheritance. While several causative genes have been found, there remain families in whom no molecular diagnosis has been identified (ADTKD-NMD). Methods: We identified BICC1 truncating variants in several families with ADTKD-NMD in the Wake Forest Rare Inherited Kidney Disease Registry and then screened families in our database and other referred families for BICC1 truncating variants. We performed segregation analysis and characterized affected individuals for clinical and histopathologic phenotypes. We analyzed oligomer formation of BICC1 mutants with wild-type BICC1-, ANKS3- and ANKS6 proteins through co-immunoprecipitation and Western blotting, and we tested for posttranscriptional regulation of the BICC1 target mRNA, Dand5, in a Luciferase reporter assay. Results: We found 6 heterozygous truncating mutations in BICC1 segregating with the ADTKD phenotype in 8 independent pedigrees worldwide. Affected individuals developed kidney failure in the 6th to 7th decade of life that was characterized pathologically by tubular atrophy and interstitial fibrosis. The truncated gene products localized to cytoplasmic bodies and demonstrated various degrees of self-association or binding to the known interaction partners, ANKS3 and ANKS6. While the wild-type BICC1 gene product acts as a posttranscriptional repressor of target mRNAs, all truncation variants exhibited increased expression of substrate mRNA. Conclusions: Truncating variants in BICC1 are a novel cause of ADTKD, segregating with the disease phenotype and upregulating BICC1 target gene expression through a dominant-negative- or a gain-of-function mode of action.

The extent to which eGFR varies across populations, in the absence of risk factors and comorbidities associated with kidney disease, remains uncertain. We aimed to develop eGFR reference values in healthy American adults and to compare them with previously described European eGFR reference values. This cross-sectional study compared newly described age-specific and sex-specific creatinine-based eGFR reference values from over 9000 healthy Americans from National Health and Nutrition Examination Survey with previously described eGFR reference values from over 1.5 million healthy individuals in the European CKD Burden Consortium. Health status was based on 14 criteria related to comorbidities, lifestyle factors, and medication use. eGFR was calculated using the European Kidney Function Consortium equation and modeled over the age span and by sex using a generalized additive model. The median eGFR in both 20-year-old American and European men was 98 ml/min per 1.73 m 2 . In both 20-year-old American and European women, the median eGFR was 101 ml/min per 1.73 m 2 . eGFR started to decrease at age 40 years, a result of the structure of the European Kidney Function Consortium equation. By age 79 years, the median eGFR in American and European men was 68 and 67 ml/min per 1.73 m 2 , respectively. The median eGFR in 79-year-old American and European women was 63 and 64 ml/min per 1.73 m 2 , respectively. When removing the effect of comorbidities, lifestyle factors and medication use associated with kidney function, achieved by restricting the analyses to individuals who did not have a presence or history of certain criteria, the distribution of eGFR was similar between healthy Americans and Europeans. This supports the notion that eGFR reference values may be generalizable to populations they were not derived from.