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Abstract: FR-PO316

Pharmacogenomics of Tolvaptan’s Inhibitory Effect on Kidney Volume Increase in Patients with Autosomal Dominant Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidney

  • 801 Cystic Kidney Diseases


  • Horie, Shigeo, Juntendo University, Tokyo, Japan
  • Masuda, Masatoshi, Otsuka Pharmaceutical Co., Ltd., Osaka, Japan
  • Neuber, Steffen, Bioscientia, Ingelheim, Germany
  • Muto, Satoru, Juntendo University, Tokyo, Japan
  • Okada, Tadashi, Otsuka Pharmaceutical Co., Ltd., Osaka, Japan
  • Bergmann, Carsten, Bioscientia, Ingelheim, Germany

We investigated the influence of genetic factors on tolvaptan treatment efficacy in patients with approved autosomal dominant polycystic kidney disease (ADPKD).


In the extension study of TEMPO 3:4 in Japan, DNA was collected from 100 patients. Germline variants of 116 genes (including all genes known for cystic/ polycystic kidney disease) were sequenced by targeted next generation sequencing and called with a custom variant analysis pipeline sensitive for variants in sequence homology regions. Genetic architecture of samples was modeled as binary factor, discriminating those samples carrying solely PKD1 or PKD2 pathogenic variants from samples that harbored additional likely pathogenic variants in any of the other 114 targeted genes. Kidney volume growth rate was used as a marker for tolvaptan efficacy. A two-way factorial ANOVA was applied to test for a correlation between genetic architecture, treatment / placebo group and treatment efficacy as outcome.


Sixty percent of our samples demonstrated multiple likely pathogenic variants in non-PKD genes. Statistical analysis revealed a significant main effect of treatment vs placebo group as expected (p<0.009), and a non-significant main effect when considering modifier variants only (p<0.29). The interaction term combining modifier cases with treatment group was non-significant as well (p<0.14). We carried out subgroup analysis assuming that low power is the cause for not reaching significance in the interaction model, and observed that the kidney growth rate in patients with modifier pathogenic variants was significantly lower in the tolvaptan group. This difference was not clear in patients with singleton PKD1 or PKD2 pathogenic variants. Therefore, we hypothesize that tolvaptan may be more effective in patients with modifier pathogenic variants.


Additional pathogenic variants in modifier genes other than PKD1 or PKD2 may potentially affect the efficacy of tolvaptan in patients with ADPKD.