Potential effect of tolvaptan on polycystic liver disease for patients with ADPKD meeting the Japanese criteria of tolvaptan use

Abstract

Polycystic liver disease (PLD) is a common extrarenal complication of autosomal dominant polycystic kidney disease (ADPKD), which causes compression-related syndrome and ultimately leads to liver dysfunction. Tolvaptan, a V2 receptor antagonist, is widely used to protect kidney function in ADPKD but its effect on PLD remains unknown. An observational cohort study was conducted to evaluate tolvaptan's effect on patients with PLD due to ADPKD. After screening 902 patients, we found the 107 ADPKD patients with PLD who met the criteria of tolvaptan use in Japan. Among them, tolvaptan was prescribed for 62 patients (tolvaptan group), while the other was defined as the non-tolvaptan group. Compared with the non-tolvaptan group, the tolvaptan group had larger height-adjusted total kidney volume (median 994(range 450-4152) mL/m, 513 (405-1928) mL/m, p = 0.01), lower albumin level (mean 3.9±SD 0.4 g/dL, 4.3±0.4g/dL, p<0.01), and higher serum creatinine level (1.2±0.4 mg/dL, 0.9±0.2 mg/dL, p<0.01). Although the median change in annual growth rate of total liver volume (TLV) was not statistically different between the tolvaptan group (-0.8 (-15.9, 16.7) %/year) and the non-tolvaptan group (1.7 (-15.6-18.7) %/year)(p = 0.52), 20 (43.5%) patients in the tolvaptan group experienced a decrease in the growth rate of TLV (responders). A multivariable logistic regression model adjusting for related variables showed that older age (odds ratio 1.15 [95% CI 1.01-1.32]) and a higher growth rate of TLV in the non-tolvaptan period (odds 1.45 95% CI 1.10-1.90) were significantly associated with responders. In conclusion, the change in annual growth rate of TLV in ADPKD patients taking tolvaptan was not statistically different compared with that in ADPKD patients without taking tolvaptan. However, tolvaptan may have the potential to suppress the growth rate of TLV in some PLD patients due to ADPKD, especially in older patients or those that are rapid progressors of PLD. Several limitations were included in this study, therefore well-designed prospective studies were required to confirm the effect of tolvaptan on PLD.

Fig 1. Flow chart of patients.

In total 902 patients, tolvaptan was prescribed for 295 patients. Among them, 46 patients were eligible for the tolvaptan group. In the other 607 patients, 16 patients were eligible for the non-tolvaptan group. PLD: polycystic liver disease, PKD: polycystic kidney disease, ADPKD: autosomal dominant polycystic kidney disease, TLV%: annual growth rate of total liver volume.

Fig 2. Comparison of the change in annual growth rate of total liver volume between the tolvaptan group and the non-tolvaptan group.

The median difference in the annual change in TLV was not statistically different between the tolvaptan group (-0.8 (-15.9, 16.7) %/year) and the non-tolvaptan group (1.7 (-15.6, 18.7)) (p = 0.52, Wilcoxon rank sum test). TLV; total liver volume, ΔTLV %; change in annual growth rate of TLV.

Fig 3. Comparison of the change in annual growth rate of total kidney volume between the tolvaptan group and the non-tolvaptan group.

The median difference in the annual change in TKV was not statistically different between the tolvaptan group (0.2 (range -30.3, 22.5)) and the non-tolvaptan group (2.0 (-15.6, 16.6)) (p = 0.39, Wilcoxon rank sum test). TKV: total kidney volume, ΔTKV%: the change in growth rate of TKV.

Fig 4. The spaghetti plotting of the annual liver growth rate before and after tolvaptan use.

In the tolvaptan group, the median growth rate of TLV before tolvaptan use was 1.23 (range -6.9, 16.3) %/year and that after tolvaptan use was 2.4 (-8.6, 17.6) %/year. Although, the growth rate of TLV did not statistically change after tolvaptan use (p = 0.78, Wilcoxon test for paired observations), 20 out of 46 patients (43.5%) experienced a decline in the change in annual growth rate of TLV (ΔTLV%) after taking tolvaptan, we defined them as responders (red circle). The other 26 patients (56.5%), who experienced an increase in ΔTLV% after taking tolvaptan, were categorized as non-responders (blue circle). TLV: total liver volume, ΔTLV%: change in annual liver growth rate of TLV.