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Autosomal dominant polycystic kidney disease (ADPKD) is characterized by a variable renal disease progression, which is observed both between (inter-familial variability) and within (intra-familial variability) affected families. Inter-familial variability is primarily due to genetic heterogeneity (PKD1 vs. PKD2), although an influence of the nature/type of mutation may also interfere (at least for PKD1). The major factor influencing intra-familial variability is probably the occurrence of a somatic mutation in the intact allele within epithelial tubular cells (" second hit"). Studies of variability in siblings and twins, as well as in animal models, suggest that modifier genes also influence renal disease progression in ADPKD, in addition to environmental or toxic factors. These modifier loci could affect cystogenesis and/or cyst progression, but also more general factors such as blood pressure regulation or endothelial function. Substantiating the role of modifier genes will require large familial studies but will probably offer new perspectives to slow renal disease progression in ADPKD.