Tolvaptan, a vasopressin V2 receptor antagonist, is the only pharmaceutical treatment for ADPKD. The phase 3 Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 study showed that tolvaptan could reduce the rates of total kidney volume (TKV) increase (49% reduction in rate of change of TKV at the end of 3 years; P=.001) and kidney function decline (26% reduction in rate of kidney function decline; P=.001) in patients with ADPKD.
Toshio Mochizuki and colleagues conducted a post hoc analysis of data from the TEMPO 3:4 study to examine whether the initial changes in eGFR between baseline and week 3 after tolvaptan administration were predictive of the longer-term effects of tolvaptan on TKV and eGFR in patients with ADPKD. Their results were published in Kidney360.
TEMPO 3:4 was a phase 3, multicenter, double-blind, placebo-controlled study of the safety and efficacy of tolvaptan in patients aged 18-50 years with ADPKD. All participants had a TKV of ≥750 mL and creatinine clearance of ≥60 mL/min. The subjects were randomized 2:1 to tolvaptan or placebo. Those in the tolvaptan group (n=961; 51.51% male; mean age, 38.56 years) received the drug twice daily for 36 months at the maximum tolerated dose after a 3-week titration period. During the first week of the titration period, patients in the tolvaptan group received 45 mg in the morning and 15 mg in the afternoon, with the dose increasing to 60/30 mg and 90/30 mg each week as tolerated.
In the post hoc assessment, Mochizuki et al assessed the effects of tolvaptan on kidney function and kidney volume using the eGFR mean rate of change calculated from week 3 of tolvaptan administration up to 36 months and the TKV rate of percentage growth calculated from baseline up to 36 months. They estimated GFR using the creatinine-based Chronic Kidney Disease Epidemiology Collaboration equation at baseline, week 3, weekly during tolvaptan dose escalation, and every 4 months during treatment up to month 36 after tolvaptan initiation.
Reciprocal serum creatinine provided a more accurate assessment of change in kidney function. This was calculated using the formula 1/Pcr, where Pcr equals serum creatinine concentration (mg/dL). The researchers evaluated TKV using standardized kidney magnetic resonance imaging at baseline and at months 12, 24, and 36 after tolvaptan initiation. They assessed blood urea nitrogen (BUN) and fasting urine osmolality (uOsm) at baseline.
At baseline, mean eGFR was 81.35 mL/min/1.73 m2 and mean TKV was 1,704.82 mL. At 3 weeks after starting tolvaptan, mean ± SD eGFR was (76.58±21.13) mL/min/1.73 m2, with a mean decrease from baseline of (4.42±8.81) mL/min/1.73 m2. The change in eGFR from baseline to 3 weeks was significantly associated with the mean rate of change per year in eGFR, and the larger the initial change in eGFR, the smaller the mean rate of change per year.
Univariate regression analysis identified the baseline characteristics of eGFR, age, body mass index (BMI), TKV, BUN, and fasting uOsm as significant factors for predicting eGFR at 3 weeks. Multivariate regression analysis identified eGFR, age, TKV, and BUN as significant factors. However, no association was found between initial change in eGFR and the rate of percent growth in TKV per year. Univariate regression analysis found that male sex, lower age, higher baseline BMI, and higher baseline TKV had a significant association with greater percent growth in TKV per year; these factors were significantly associated with TKV rate of change on multivariate analysis.
The authors acknowledged certain limitations. The TEMPO 3:4 study only included a few patients with more advanced kidney dysfunction, so their findings may not apply to such patients. The race-free eGFR equation was not used, so the interpretation of results may be limited. The authors recommended using the race-free calculation for future research.
“In conclusion,” they wrote, “this post hoc analysis of the TEMPO 3:4 study demonstrated that initial changes in eGFR 3 weeks after initiation of tolvaptan treatment, which can be easily measured in clinical practice, are predictive of the long-term
effects of tolvaptan.”
Source: Kidney360
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