We conducted a retrospective case series to evaluate the efficacy and safety of combination therapy with tolvaptan and dapagliflozin in patients with ADPKD. Between January 2017 and April 2024, we identified four patients (one male, three females: Case A, B, C, D) who received concurrent treatment with both medications at our institution. For comparison, we included two control patients with ADPKD (one male, one female: Case E, F) who received tolvaptan monotherapy for at least three years during the same period. All patients met the diagnostic criteria outlined in the Evidence-based clinical practice guideline for polycystic kidney disease (PKD) 2020 [6]. Baseline characteristics included demographic data and initial clinical measurements (Table 1). We analyzed eGFR trajectories (mL/min/1.73 m2) across three periods: pre-tolvaptan, post-tolvaptan, and post-dapagliflozin initiation (the period from December 2021 to April 2024 in the control group). The clinical course is presented in Figs. 1 and 2. The eGFR decline rate was determined using linear regression analysis, excluding the initial adaptation period (Table 2). The initial decline was specifically defined as the difference between baseline eGFR and the lowest eGFR value recorded within the first two months of dapagliflozin therapy, expressed both as an absolute value and percentage change from baseline. Additional monitoring included blood pressure (BP, mmHg), body mass index (BMI, kg/m2), Urinary protein-to-creatinine ratio (UPCR, mg/gCr), urinary osmolality (Uosm, mOsm/L), serum hemoglobin (Hb, g/dL), serum uric acid level (UA, mg/dL), and height-adjusted total kidney volume (htTKV, mL/m) (Table 3, 4, Fig. 3, 4). TKV measurements were derived from computed tomography scans using Ziostation2 volume measurement software (Ziosoft, Japan).

The progression in eGFR pre- and post- administration of tolvaptan, and post- administration of dapagliflozin (in the dapagliflozin group). eGFR estimated glomerular filtration rate, Dis discontinuation

The progression in eGFR pre- and post- administration of tolvaptan and the period from December 2021 to April 2024 (in the control group). eGFR estimated glomerular filtration rate

The progression of height adjusted TKV in the dapagliflozin group

The progression of height adjusted TKV in the control group

For statistical analysis, we compared mean laboratory values before and after dapagliflozin administration using paired t-tests. The pre-dapagliflozin period was defined as the year preceding treatment initiation, while the post-dapagliflozin period encompassed the first year of treatment. All laboratory values are presented as mean ± standard deviation, with statistical significance set at p < 0.05. Statistical analyses were performed using EZR, a modified version of R commander [7].

Case A: A 74-year-old Japanese woman with CKD stage 4 and sporadic Mayo Class 1D ADPKD showed an improvement in her eGFR decline rate from − 2.81 to − 1.39 mL/min/1.73m2/year with tolvaptan, further improving to − 0.66 mL/min/1.73m2/year after 854 days of combination therapy. HtTKV increased from 3508 to 3946 cc, representing an annual growth rate of 4.03%. One-year follow-up revealed an increase in Uosm, along with improvements in both Hb and UA. Her BP increased, while BMI and UPCR decreased.

Case B: A 62-year-old Japanese woman with CKD stage 3b and Mayo Class 1B ADPKD, with a documented family history of the condition, showed an improvement in her eGFR decline rate from − 2.30 to − 1.02 mL/min/1.73m2/year with tolvaptan, further improving to − 0.66 mL/min/1.73 m2/year after 854 days of combination therapy. HtTKV decreased from 1207 to 1196 cc, representing a reduction of 0.45%/year. One-year follow-up revealed a slight decrease in Uosm, improvements in Hb, and a slight decrease in UA. Her BP and BMI showed a downward trend.

Case C: A 39-year-old man, the son of Case B, with CKD stage 3a and Mayo Class 1C ADPKD showed eGFR decline from − 2.96 to − 5.00 mL/min/1.73m2/year with tolvaptan. Over the subsequent 826 days of combination therapy, his eGFR decline rate improved to -1.35 mL/min/1.73 m2/year. HtTKV increased from 596 to 632 cc, representing an annual growth rate of 3.65%. One-year follow-up revealed increase in Uosm, slight improvements in Hb, a notable decrease in UA.

Case D: A 45-year-old Japanese woman presented with CKD stage3b and sporadic Mayo Class 1D ADPKD. Five months after initiating tolvaptan, she developed liver dysfunction, leading to the discontinuation of tolvaptan. After her liver dysfunction improved, tolvaptan was resumed one month after dapagliflozin administration, with dose escalations to 90 mg at five months and 120 mg at 25 months. At 19 months after dapagliflozin initiation, the patient developed type 2 diabetes and began semaglutide treatment, which resulted in a 10-kg reduction in body weight. Her eGFR decline rate almost unchanged with tolvaptan. After 846 days of dapagliflozin treatment, her eGFR decline rate improved to − 0.22 mL/min/1.73 m2/year. HtTKV decreased from 905 to 821 cc, representing a reduction of 3.65%/year. One-year follow-up revealed an increase in Uosm, improvement in Hb, a slight decrease in UA. Her BP showed a downward trend,

Case E: A 50-year-old woman with CKD stage 3b and familial Mayo Class 1C ADPKD, who received tolvaptan monotherapy, showed eGFR decline improvement from − 6.53 to − 2.19 mL/min/1.73m2/year. After 847 days from December 2021, the eGFR decline rate was − 1.86 mL/min/1.73 m2/year. HtTK remained stable (Fig. 4). One-year follow-up revealed a slight increase in Uosm, improvements in Hb, a slight increase in UA.

Case F: A 74-year-old man with CKD stage 4 and familial Mayo Class 1C ADPKD, who received tolvaptan monotherapy showed eGFR decline improvement from − 10.29 to − 2.48 mL/min/1.73m2/year. After 839 days from December 2021, the eGFR decline rate was − 2.23 mL/min/1.73 m2/year. HtTK was not assessed. One-year follow-up revealed an increase in Uosm, a slight decrease in Hb, and decrease in UA.

Adverse events after initiation of dapagliflozin included the development of pyelonephritis in Cases A and B, both of whom achieved complete resolution following antibiotic therapy.