Heterozygosity for human polycystic kidney and hepatic disease 1 ( PKHD1) mutations was recently associated with cystic liver disease and radiographic findings resembling medullary sponge kidney (MSK). However, the relevance of these associations has been tempered by a lack of cystic liver or renal disease in heterozygous mice carrying Pkhd1 gene trap or exon deletions. To determine whether heterozygosity for a smaller Pkhd1 defect can trigger cystic renal disease in mice, we generated and characterized mice with the predicted truncating Pkhd1C642* mutation in a region corresponding to the middle of exon 20 cluster of five truncating human mutations (between PKHD1G617fs and PKHD1G644*). Mouse heterozygotes or homozygotes for the Pkhd1C642* mutation did not have noticeable liver or renal abnormalities on magnetic resonance images during their first weeks of life. However, when aged to ~1.5 yr, the Pkhd1C642* heterozygotes developed prominent cystic liver changes; tissue analyses revealed biliary cysts and increased number of bile ducts without signs of congenital hepatic fibrosis-like portal field inflammation and fibrosis that was seen in Pkhd1C642* homozygotes. Interestingly, aged female Pkhd1C642* heterozygotes, as well as homozygotes, developed radiographic changes resembling MSK. However, these changes correspond to proximal tubule ectasia, not an MSK-associated collecting duct ectasia. In summary, by demonstrating that cystic liver and kidney abnormalities are triggered by heterozygosity for the Pkhd1C642* mutation, we provide important validation for relevant human association studies. Together, these investigations indicate that PKHD1 mutation heterozygosity (predicted frequency 1 in 70 individuals) is an important underlying cause of cystic liver disorders and MSK-like manifestations in a human population.

Measurement of total kidney volume (TKV) using magnetic resonance imaging (MRI) is a valuable approach for monitoring disease progression in autosomal dominant polycystic kidney disease (ADPKD) and is becoming more common in preclinical studies using animal models. Manual contouring of kidney MRI areas (i.e., manual method (MM)) is a conventional, but time-consuming, way to determine TKV. We developed a template-based semi-automatic image segmentation method (SAM) and validated it in three commonly used PKD models, Cys1cpk/cpk mice, Pkd1RC/RC mice, and Pkhd1pck/pck rats (n=10 per model). We compared SAM-based TKV with those obtained by clinical alternatives including the ellipsoid formula-based method (EM) using three kidney dimensions, the longest kidney length method (LM), and the MM, which is considered the gold standard. Both SAM and EM presented high accuracy in TKV assessment in Cys1cpk/cpk mice (interclass correlation coefficient (ICC)≥0.94). SAM was superior to EM and LM in Pkd1RC/RC mice (ICC=0.87, 0.74, and <0.10 for SAM, EM, and LM, respectively) and Pkhd1pck/pck rats (ICC=0.59, <0.10, and <0.10, respectively). Also, SAM outperformed EM in processing time in Cys1cpk/cpk (3.6±0.6 vs 4.4±0.7 minutes per kidney)and Pkd1RC/RC mice (3.1±0.4 vs 7.1±2.6 minutes) (both p<0.001), but not in Pkhd1PCK/PCK rats (3.7±0.8 vs3.2±0.5 minutes). LM was the fastest (~1 min), but correlated most poorly with MM-based TKV in all studied models. Processing times by MM were longer for Cys1cpk/cpk mice, Pkd1RC/RC mice, and Pkhd1pck.pckrats (66.1±7.3, 38.3±7.5, and 29.2±3.5 minutes). In summary, SAM is a fast and accurate method to determine TKV in mouse and rat PKD models.