Genetics May Predict Effectiveness of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cystic kidney disease, affecting 1 in 1,000–2,500 people worldwide [1]. ADPKD has been linked to mutations in 2 genes: polycystic kidney disease 1 (PKD1) gene (chromosome 16; 16p13.3) and polycystic kidney disease 2 (PKD2) gene (chromosome 4; 4q21); the former mutation was found in 78% of patients and the latter, in 15% [1]. Approximately 7% of patients with ADPKD appear not to have a PKD1/2 mutation [2, 3]. Among ADPKD patients, the severity of the effects of these mutations on renal survival was reported to be as follows: PKD1 truncating mutation > PKD1 non-truncating mutation > PKD2 mutation > no PKD1 or PKD2 mutation [4, 5].

The only therapeutic drug for patients with ADPKD is tolvaptan, a vasopressin V2-receptor antagonist that slows the rate of decline of the estimated glomerular filtration rate (eGFR). The efficacy of tolvaptan was investigated in the randomized, double-blind, placebo-controlled, multicenter, phase 3 TEMPO 3:4 trial [6] and its long-term extension, TEMPO 4:4 [7], and the efficacy in patients with later-stage ADPKD was investigated in the randomized, double-blind, placebo-controlled, multicenter, phase 3 REPRISE trial [8]. A post hoc analysis of TEMPO 4:4 data found statistically significant treatment effects of tolvaptan in the PKD1 truncating group [7]. However, the treatment effects of tolvaptan in the other groups (PKD1 non-truncating, PKD2, and no PKD1/2 mutation) and the change in clinical course before and after tolvaptan therapy in each group were unclear. Therefore, in the present study, we evaluated the relation between genetic characteristics and treatment effects of tolvaptan by analyzing clinical variables in patients with ADPKD before and after tolvaptan therapy. To our knowledge, this is the first report of the evaluation of the effectiveness of tolvaptan in patients with ADPKD who do not have a PKD1/2 mutation.

This study included 21 patients with ADPKD who had been treated with tolvaptan at Toranomon Hospital and undergone genetic testing between April 2016 and February 2020. We previously reported on 14 of these patients [9]. Eligibility requirements included a diagnosis of ADPKD according to the protocol of REPRISE trial modified Pei-Ravine criteria [10-12], with an eGFR >15 mL/min/1.73 m², a total kidney volume (TKV) ≥750 mL, and a TKV growth rate of 5% per year or more. All patients were started on 60 mg of tolvaptan in a split-dose regimen (45 mg in the morning and 15 mg in the evening). The dose was modified according to patients’ tolerance; the maximum dose was 120 mg/day.

As an indicator of the decline of renal function, we obtained the eGFR 3–12 times at intervals of a few months (including 1 interval of at least 6 months) both before and after treatment with tolvaptan. The eGFR was calculated with the Japanese eGFR equation [13]. Then, we used the eGFR data to draw an approximate curve and estimated the decline in renal function from the slope of the curve (ΔeGFR/y) for each patient before and after treatment with tolvaptan. As an indicator of the percentage increase in TKV (%ΔTKV/y), we assessed TKV twice before treatment with tolvaptan (at least 6 months between measurements; median time between measurements: 2 years) and twice after starting treatment with tolvaptan (almost 1.5–3 years between measurements; median time between measurements: 2.3 years). TKV was calculated from CT scans or MR images by the modified ellipse method with the following formula: volume = π/6 × length × width × depth [14].

Most of the patients were seen at our hospital at least 3 times before and after treatment with tolvaptan, and we were able to collect the required data. However, we were not able to confirm the diachronic data on renal function before tolvaptan therapy in 3 patients and, therefore, excluded them from the study. This study was performed in accordance with the Declaration of Helsinki and was approved by the research Ethics Committees of Toranomon Hospital and Tokyo Medical and Dental University Hospital. Written informed consent was obtained from all patients.

Genetic analysis was performed with capture-based next-generation sequencing according to the method reported previously [9, 15, 16]. The next-generation sequencing panel provided good coverage of the exonic regions of both PKD1 and PKD2, except for exon 1 of PKD1. This approach detected no mutations of 6 pseudogenes.

We analyzed the data of the 18 patients with ADPKD and tabulated the clinical characteristics by the type of mutation. Categorical variables were summarized as the number (percentage) and continuous variables as the mean with the standard deviation or median with the interquartile range (IQR). The association between genotype (4 groups: PKD1 truncating, PKD1 non-truncating, PKD2, and no PKD1/2) and the clinical data was analyzed by the Kruskal-Wallis test; and the association between each of the 4 groups (PKD1 truncating vs. PKD1 non-truncating, PKD1 truncating vs. PKD2, PKD1 truncating vs. no PKD1/2, PKD1 non-truncating vs. PKD2, PKD1 non-truncating vs. no PKD1/2, and PKD2 vs. no PKD1/2) or the existence of a PKD1/2 mutation and the change in ΔeGFR/y or %ΔTKV/y before and after tolvaptan therapy were analyzed by the Wilcoxon rank-sum (Mann-Whitney U) test. For all analyses, p < 0.05 was taken to indicate statistical significance. Analyses were conducted with STATA® SE version 14.0 (StataCorp, College Station, TX, USA).

On the basis of the probable genetic cause of ADPKD, the 18 patients were classified into the following 4 groups: PKD1 truncating group (4 patients), PKD1 non-truncating group (7 patients), PKD2 group (4 patients), and no PKD1/2 group (3 patients). Data on the clinical and laboratory characteristics of these groups at the start of tolvaptan therapy are displayed in Table 1. The mean dose of tolvaptan was 54 mg in the PKD1 truncating group, 77 mg in the PKD1 non-truncating group, 60 mg in the PKD2 group, and 60 mg in the no PKD1/2 group. The dose was reduced in 3 patients (2 in the PKD1 truncating group and 1 in the PKD2 group) because of polyuria. No other additional adverse events including liver enzyme elevation, hypernatremia, and volume depletion were observed. The median follow-up period after starting treatment with tolvaptan was 3.8 years (IQR, 2.6–4.5 years) in the PKD1 truncating group, 4.5 years (3.5–5 years) in the PKD1 non-truncating group, 2.8 years (2.4–3.1 years) in the PKD2 group, and 2.5 years (2–2.8 years) in the no PKD1/2 group. We found no significant differences in age, BMI, mean atrial pressure, height-adjusted TKV, the number of cysts (in a middle section of the left kidney), or the follow-up period after starting treatment with tolvaptan between the groups. The patients with PKD1 truncating mutations had significantly decreased eGFR than the other patients (Kruskal-Wallis, p = 0.04). Detailed information on the variants detected in the patients is presented in online suppl. Tables 1–4 (or all online suppl. material, see www.karger.com/doi/10.1159/000509817 f).

Figure 1 shows the change in eGFR before and after tolvaptan therapy. We found no changes in variables that may have influenced eGFR, including the use of an angiotensin 2 receptor blocker, before and after tolvaptan therapy. Urine osmolarity, a surrogate of the efficacy of tolvaptan, did not differ between the groups before and after treatment (Table 2). The annual change in eGFR (ΔeGFR/y) from before to after tolvaptan therapy was from a median of −5.5 (IQR, −5.7 to −4.4) to −2.5 (−3.1 to −1.9) mL/min/1.73 m² in the PKD1 truncating group, −3.3 (−4.6 to −2.4) to −2.4 (−3.9 to −2.0) mL/min/1.73 m² in the PKD1 non-truncating group, −3.1 (−3.5 to −2.4) to −1.6 (−2.4 to −0.5) mL/min/1.73 m² in the PKD2 group, and −1.9 (−2.6 to −1.2) to −2.6 (−3.3 to −1.8) mL/min/1.73 m² in the no PKD1/2 group (Table 2). The median degree of improvement of ΔeGFR/y was 2.5 (45%) (IQR, 1.8–2.9) mL/min/1.73 m² in the PKD1 truncating group, 0.4 (10%) (−0.2–1.6) mL/min/1.73 m² in the PKD1 non-truncating group, 0.6 (28%) (0.5–1.7) mL/min/1.73 m² in the PKD2 group, and −0.7 (−37%) (−0.7 to −0.6) mL/min/1.73 m² in the no PKD1/2 group (Fig. 2a). Compared with the PKD1 truncating group, the no PKD1/2 group showed significantly less improvement of ΔeGFR/y with tolvaptan (p = 0.03). Compared with the PKD1 non-truncating group, the no PKD1/2 group showed significantly less improvement of ΔeGFR/y with tolvaptan (p = 0.04). Compared with the PKD2 group, the no PKD1/2 group showed significantly less improvement of ΔeGFR/y with tolvaptan (p = 0.03). We found no significant differences in the changes in ΔeGFR/y before and after tolvaptan therapy between the groups with a PKD1 truncating, PKD1 non-truncating, or PKD2 mutation. The no PKD1/2 group showed significantly less improvement of ΔeGFR/y than the group of patients with any PKD1/2 mutation (−0.7 vs. 0.6 mL/min/1.73 m², respectively; p = 0.01, Fig. 2b).

The annual rate of TKV increase (%ΔTKV/y) improved significantly less in the no PKD1/2 group than in the group of patients with any PKD1/2 mutation (−1.1 vs. −6.7%, respectively; p = 0.02, Fig. 2c). The median %ΔTKV/y in each of the 4 mutation groups from before to after tolvaptan therapy was as follows: PKD1 truncating group, 5.9% (IQR, 5.6–6.0%) to 0.2% (−3.4 to 3.1%); PKD1 non-truncating group, 7.1% (5.6–7.2%) to 0.3% (−0.4 to 2.8%); in the PKD2 group, 7.8% (7.2–9.0%) to −1.1% (−5.5 to 3.3%); and in the no PKD1/2 group, 5.3% (5.2–6.7%) to 4.3% (3.5–5.7%) (Table 2). The median degree of improvement of %ΔTKV/y was −5.9% (IQR, −2.9 to −9.2%) in the PKD1 truncating group, −5.4% (−3.8 to −6.9%) in the PKD1 non-truncating group, −10.7% (−6.6 to −13.6%) in the PKD2 group, and −1.1% (−1.0 to −1.9%) in the no PKD1/2 group (Fig. 2d). We found no significant differences between the groups in the changes in %ΔTKV/y before and after tolvaptan therapy.

In the current study of 18 patients with ADPKD, ΔeGFR/y and %ΔTKV/y improved less with tolvaptan therapy in the group without any variants in PKD1 or PKD2 than in the group with a mutation in one of these genes (PKD1 truncating, PKD1 non-truncating, or PKD2). The efficacy of tolvaptan therapy was investigated in several randomized, double-blind, placebo-controlled, multicenter, phase 3 trials, including the TEMPO 3:4 trial [6]; its long-term extension, the TEMPO 4:4 trial [7]; and the trial in later-stage ADPKD, REPRISE [8]. A post hoc analysis of data from TEMPO 4:4 found statistically significant treatment effects of tolvaptan in the PKD1 truncating group but not in the PKD1 non-truncating or PKD2 group [7]. Unlike the TEMPO 4:4 study, which compared tolvaptan-treated with placebo-treated patients, the current study analyzed the change in ΔeGFR/y and %ΔTKV/y before to after tolvaptan within patients. For this reason, our results are not directly comparable with those of the TEMPO 4:4 study. However, our study showed efficacy of tolvaptan not only in the PKD1 truncating group but also in the PKD1 non-truncating and PKD2 groups. The important finding of our study is that the patients with ADPKD who had no PKD1/2 mutation showed significantly less improvement of ΔeGFR/y and %ΔTKV/y before to after tolvaptan therapy.

The vasopressin V2-receptor antagonist tolvaptan was effective in a Pkd1-deletion mouse model and Pkd2-deletion mouse model of ADPKD [17, 18], so its efficacy may be associated with the PKD1/2 mutations found in patients with ADPKD. At present, PKD1/2 mutations are not considered when administering tolvaptan therapy, but our findings suggest that in the future, physicians may need to test for them. In fact, the ERA-EDTA Working Group already recommended adding a PKD1 truncating mutation to the criteria for selecting tolvaptan therapy to treat patients with ADPKD [19].

The current study has some limitations. It was a retrospective, single-center study with a small sample size. Furthermore, it may have a selection bias because we included only patients who underwent genetic testing. Genetic testing is not commonly performed in Japan, but it is often performed in patients without an apparent family history. Thus, approximately 200 patients were treated with tolvaptan in our hospital, but genetic testing was performed in only 21 of them. Therefore, our findings need to be confirmed in a large, prospective, multicenter study. Despite these limitations, the study still led to the interesting finding that the efficacy of tolvaptan seems to differ between patients with ADPKD with no PKD1/PKD2 mutation and typical ADPKD patients with a PKD1/PKD2 mutation.

In conclusion, ΔeGFR/y and %ΔTKV/y improved significantly less with tolvaptan therapy in the group without any detectable PKD1/PKD2 mutation than in the group of patients with a mutation in one of these genes (PKD1 truncating, PKD1 non-truncating, or PKD2). Accordingly, determining whether or not patients with ADPKD have a PKD1/PKD2 mutation may help predict the efficacy of tolvaptan therapy.

The manuscript was checked by a native English-speaking medical editor from Yamada Translation Bureau, Inc. (Tokyo, Japan).

This study was carried out in accordance with the Declaration of Helsinki and was approved by the research Ethics Committees of Toranomon Hospital and Tokyo Medical and Dental University Hospital. Written informed consent was obtained from all of the patients.

J.H. has received a research grant from Otsuka Pharmaceutical Co. All other authors have no competing financial interests to declare.

This work was supported by a Grant-in-Aid for Scientific Research (JSPS KAKENHI Grant Nos. 18K08227 and 19K17758), a research grant from Otsuka Pharmaceutical Co., and a research grant from the Okinaka Memorial Institute to J.H., and by a research grant from the Okinaka Memorial Institute to Y.U. This work was also supported in part by Grants-in-Aid for Scientific Research (S) (25221306) to S.U., Scientific Research (B) (16H05314) to E.S., Challenging Exploratory Research to S.U. (15K15327) and E.S. (16K15467), and Research Activity Start-up (17H06657) to T.M. from the Japan Society for the Promotion of Science; a Health Labor Science Research Grant from the Ministry of Health, Labor and Welfare; and grants from the Salt Science Research Foundation (1422 and 1629) to S.U., the Takeda Science Foundation to E.S., and the Banyu Foundation Research Grant from the Banyu Life Science Foundation International to E.S. None of the funding bodies had any role in the study design, data analysis, decision to publish, or preparation of the manuscript.

A.S., J.H., K.T., and Y.U. designed the study; A.S., J.H., T.S., H.M., M.K., R.H., E.H., M.Y., N.H., and N.S. managed the patients and collected clinical data; A.S., J.H., and Y.U. analyzed the genetic and clinical data; T.F., S.M., M.C., H.K., F.A., T.M., E.S., and S.U. analyzed gene mutations; A.S. made the figures and tables; and all authors approved the final version of the manuscript.