Clinical Utility and Tolerability of Tolvaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Abstract

Autosomal dominant polycystic kidney disease, also known as ADPKD, is the most common hereditary kidney disease, affecting different age groups. ADPKD can eventually lead to end-stage renal disease. The etiology of ADPKD is genetic, resulting in the formation of cysts containing fluids on the kidneys. Patients with ADPKD present a range of symptoms following a decline in kidney function. Pain, stones, proteinuria and osteoporosis are few of the many symptoms, resulting from decreased kidney function. Tolvaptan, a selective V2 receptor antagonist, is the etiological treatment used for ADPKD. In this paper, we conducted a systematic review of the literature between 2011 and 2021 to gather data regarding the tolerability and efficacy of tolvaptan use in ADPKD. A total of 22 trials were reviewed. Tolvaptan efficacy in the trials was measured using changes in eGFR or changes in total kidney volume. Results showed that tolvaptan use in ADPKD was associated with a slower decline in kidney function and a decrease in total kidney volume. Side effects of this drug include polyuria, nocturia and polydipsia along with hepatotoxicity. The two biggest trials, TEMPO and REPRISE, change in eGFR from pre-treatment baseline to post-treatment was 1.3 mL/min/1.73 for REPRISE and 1 mL/min/1.73 for TEMPO 3:4. A mean decrease of 49% in total kidney volume from baseline to post-treatment was found in the TEMPO 3:4 study.

Recent updates in therapeutic approach using tolvaptan for autosomal dominant polycystic kidney disease

“…Aquaretic symptoms, including thirst, polydipsia, polyuria, nocturia, and pollakiuria, are the most common side effects of tolvaptan [11,12]. These symptoms were detected as a significant side effect of tolvaptan in most trials, and the incidence was variable [31]. These symptoms are unavoidable responses associated with the mechanism of V2R blockade.…”

“…The association between tolvaptan use and hepatic adverse events has been reported with the idiosyncratic and reversible elevation of blood aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. The prevalence was reported to be < 2% to 10.9% of patients in clinical trials, and severe and potentially life-threatening liver injury is rare and reversible [31,41]. Nevertheless, there was a case that required liver transplantation due to fulminant hepatic failure after using tolvaptan [42].…”

Clinical findings, underlying pathogenetic processes and treatment of vascular dysfunction in autosomal dominant polycystic kidney disease

“…Due to renal vascular lesions causing renal damage, kidney function may gradually decline, and pain, stones, proteinuria, and osteoporosis are some of the many symptoms caused by the decline in kidney function, eventually leading to ESRD [ 4 , 44 ].…”

Recent advances in the understanding of cilia mechanisms and their applications as therapeutic targets

“…However, it is plausible that some of the drugs act on ciliary GPCRs because agonists/antagonists of certain GPCRs, which are also distributed in primary cilia, have been developed (e.g., β2AR agonists and antagonists, PTHR agonist teriparatide, EP4 antagonist grapiprant). Interestingly, tolvaptan, a selective vasopressin V 2 receptor (V 2 R) antagonist, is an FDA-approved ADPKD drug ( Raina et al, 2022 ). It slows the decline in estimated glomerular filtration rate of ADPKD ( Torres, 2019 ).…”