PURPOSE: Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis-related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes. METHODS: Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies. RESULTS: The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1, which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies. CONCLUSION: We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patientspecific CFRD risk to guide CFRD monitoring and treatment.

With increasing life expectancy and the need for lung transplantation in the cystic fibrosis (CF) population, there are increasing reports of chronic kidney disease (CKD). However, values for baseline or longitudinal glomerular filtration rate (GFR) as measured by exogenous clearance markers are lacking in this population. Retrospective cross-sectional study in 2 to 18-year-olds cared for at a single CF center who had a GFR measured by plasma disappearance of Technetium-99 m diethylenetriaminepentaacetic acid (mGFR). The primary outcome was evidence of renal dysfunction as defined by CKD stage II or below (mGFR <90 ml/min/1.73 m(2), persistent abnormalities in urinary sediment, abnormal renal imaging). Of 63 patients evaluated, four had apparent renal dysfunction, one demonstrated decreased mGFR, and three others had persistent microscopic hematuria. The mean mGFR was substantially higher (140 ± 24 ml/min/1.73 m(2)) than expected or previously reported for healthy children. We did not demonstrate the presence of significant renal impairment after limited aminoglycoside exposure in the first decade following diagnosis with CF. However, we did document the presence of glomerular hyperfiltration in a significant proportion of our CF patients.

Newborn screening for Cystic Fibrosis has been implemented in most programs worldwide, but the approach used varies, including combinations of immunoreactive trypsinogen (IRT) and CFTR mutation analysis on one or more specimens. The British Columbia (BC) newborn screening program tests ~45,000 infants per year in BC and the Yukon Territory, covering almost 1.5 million km2 in western Canada. CF screening was initiated using an IRT-DNA-IRT approach with a second bloodspot card at 21 days of age for all CFTR mutation heterozygotes and any non-carriers in the top 0.1% for IRT. This second IRT was implemented to avoid sweat testing of infants without persistent hypertrypsinemia, reducing the burden of travel for families. Over nine years (2010–2018), 401,977 infants were screened and CF was confirmed in 76, and a further 28 were deemed CF screen positive inconclusive diagnosis (CFSPID). Day 21 IRT was normal in 880 CFTR mutation carriers who were quoted a very low CF risk and offered optional sweat testing. Only 13% of families opted for sweat testing and a total of 1036 sweat tests were avoided. There were six false negative CF cases (and three CFSPID) due to a low initial IRT or no CFTR mutations. Although one CFSPID case had a normal repeat IRT result, the addition of the day 21 IRT did not contribute to any CF false negatives.

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