Effectiveness of Tolvaptan in Patients with ADPKD

New Orleans—Researchers in Japan, led by Shigeo Horie, MD, recently conducted a study designed to examine the influence of genetic factors on the efficacy of treatment with tolvaptan in patients with approved autosomal dominant polycystic kidney disease (ADPKD). They reported results during a poster session at Kidney Week 2017 in a poster titled Pharmacogenomics of Tolvaptan’s Inhibitory Effect on Kidney Volume Increase in Patients with Autosomal Dominant Polycystic Kidney Disease.

DNA was collected from patients participating in the extension study of TEMPO 3:4 in Japan. 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.

Efficacy of tolvaptan was measured as growth rate in kidney volume. A two-way factorial ANOVA was applied to test for a correlation between genetic architecture, treatment/placebo group, and treatment efficacy as outcome.

Of the 114 samples of non-PKD genes, 60% demonstrated multiple likely pathogenic variants. Results of statistical analyses revealed a significant main effect of treatment versus placebo as expected (P<.009), and a non-significant main effect when considering modifier variants only (P<.29). Also non-significant was the interaction term combining modifier cases with the treatment group (P<.14).

Assuming low power to be the cause of not reaching significance in the interaction model, the researchers conducted subgroup analyses. Those results demonstrated that the kidney growth rate in patients with modifier pathogenic variants was significantly lower in the group treated with tolvaptan. There was no clear difference seen in patients with singleton PKD1 or PKD2 pathogenic variants. “Therefore, we hypothesize that tolvaptan may be more effective in patients with modifier pathogenic variants,” the researchers said.

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

Source: Horie S, Masuda M, Neuber S, Muto S, Okada T, Bergmann C. Pharmacogenomics of tolvaptan’s inhibitory effect on kidney volume increase in patients with autosomal dominant polycystic kidney disease. Abstract of a poster presented at the American Society of Nephrology 2017 Kidney Week, November 3, 2017, New Orleans, Louisiana.