Pro: Tolvaptan delays the progression of autosomal dominant polycystic kidney disease

Abstract

No treatment until now has directly targeted the mechanisms responsible for the development and growth of cysts in autosomal dominant polycystic kidney disease (ADPKD). Strong rationale and preclinical studies using in vitro and in vivo models justified the launching of two large phase 3 clinical trials of tolvaptan in early and later stages of ADPKD. Their design was based on preliminary studies informing on the pharmacokinetics, pharmacodynamics, short-term safety and self-reported tolerability in patients with ADPKD. Tolvaptan slowed kidney growth in the early stage and estimated glomerular filtration rate decline in early and later stages of the disease. All participants had the opportunity to enroll in open-label extension trials to ascertain long-term safety and efficacy. In a single-center analysis of long-term outcomes, the effect of tolvaptan was sustained and cumulative over time supporting a disease-modifying effect of tolvaptan in ADPKD. In the countries where tolvaptan has been approved by regulatory agencies, patients with rapidly progressive ADPKD should be informed about the option of treatment including possible benefits and risks. If a decision to initiate treatment is made, prescribing physicians should educate the patients on the prevention of aquaresis-related adverse events and should be vigilant in the surveillance and management of the potential tolvaptan hepatotoxicity. Other vasopressin V2 receptor antagonists, possibly without potential hepatotoxicity, alternative strategies targeting vasopressin and combination with other drugs able to enhance the efficacy or reduce the aquaresis associated with tolvaptan, deserve further study.

FIGURE 1

Imaging classification of ADPKD as a prognostic biomarker: this classification is applicable to ∼95% of patients with ADPKD with typical renal involvement characterized by bilateral and diffuse distribution of cysts (see reference for criteria used to identify atypical cases where the classification cannot be used). (Left) Typical ADPKD cases are divided according to the estimated annual rate of kidney growth [derived from the age of the patient, height-adjusted TKV (HtTKV) and a theoretical starting HtTKV of 150 mL/m] into class 1A (≤1.5%), 1B (> 1.5–3%), 1C (> 3–4.5%), 1D (> 4.5–6%) or 1E (>6%). Class 1A patients have a very low risk for end-stage renal disease during their lifetimes and should not be included in clinical trials or subjected to treatments with potential side effects to slow down cyst growth. Patients in class 1C–1E, who have rapidly progressive disease, are most informative in clinical trials and most likely to benefit from an effective therapy. Patients in class 1B have an intermediate risk and could be re-evaluated at yearly intervals to more precisely determine their risk for progression. (Right) Coronal abdominal magnetic resonance images of three 41-year-old male patients with ADPKD class 1A (HtTKV 229 mL/m, eGFR 83 mL/min/1.73 m²), 1C (HtTKV 736 mL/m, eGFR 48 mL/min/1.73 m²) and 1E (HtTKV 2, 765 mL/m, eGFR 26 mL/min/1.73 m²). Other prognostic models such as genetic information (gene and type of mutation), PROPKD score that combines genetic and clinical information, and image texture analysis can be used in combination or independently from the image classification.

FIGURE 2

Changes in eGFR during the TEMPO 3:4, TEMPO 4:4 and REPRISE clinical trials. (A) Change in eGFR from the TEMPO 3:4 baseline to the Month 24 visit of TEMPO 4:4. TEMPO 3:4 participants from Japan were not enrolled in TEMPO 4:4 and they are not included in the figure. Open circles and triangles represent off-treatment time points. Note the small, acute reduction in eGFR when tolvaptan was started in TEMPO 3:4 and TEMPO 4:4 and its reversal when it was discontinued in the tolvaptan group at the end of TEMPO 3:4. The eGFR benefit accumulated by tolvaptan compared with placebo-treated patients at the end of TEMPO 3:4 (3.34 mL/min/1.73 m², P < 0.001) was maintained 2 years later (3.15 mL/min/1.73 m², P < 0.001) in TEMPO 4:4 when all patients were treated with tolvaptan. (B) Illustration of the results of REPRISE showing the changes from baseline (i) in eGFR that were due to the renal hemodynamic effect of tolvaptan during the single-blind tolvaptan period (ii) and the rapid reversal of these changes after randomization into the placebo group (iii) and after discontinuation of the drug in the tolvaptan group (iv); the vertical lines indicate these four time periods [(i)–(iv)]. The red bar along the X axis indicates the period during which patients received placebo, and the blue bar the period during which patients received tolvaptan. Plus signs on the X axis indicate trial visits at which the eGFR was assessed. The annualized mean change in eGFR (± SE) from pre-treatment baseline to post-treatment follow-up in the intention-to-treat population was −2.34 ± 0.24 with tolvaptan versus −3.61 ± 0.24 mL/min/1.73 m² with placebo (treatment effect 1.27 mL/min/1.73 m², 95% CI 0.86–1.68, P < 0.001). Panels (A) and (B) are modified from published papers [23, 24].