Tolvaptan Delays the Onset of End-Stage Renal Disease in a Polycystic Kidney Disease Model by Suppressing Increases in Kidney Volume and Renal Injury

Aihara, Miki; Fujiki, Hiroyuki; Mizuguchi, Hiroshi; Hattori, Katsuji; Ohmoto, Koji; Ishikawa, Makoto; Nagano, Kenichi; Yamamura, Yoshitaka

doi:10.1124/jpet.114.213256

Cited by 52 publications

(41 citation statements)

References 48 publications

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“…Genetic elimination of circulating vasopressin markedly inhibits the development of PKD in PCK rats, an effect that was reversed by the administration of DDAVP (28). Treatment with selective V2 receptor antagonists (mozavaptan or tolvaptan) inhibits renal cyst development in cpk mice (8) and in orthologous models of ARPKD (7,26), PKD1 (10,14), PKD2 (24,25), and juvenile nephronophthisis (2,7). A phase 3 randomized, double-blind clinical trial has shown that tolvaptan administered over 3 yr slows kidney growth and renal function decline in patients with ADPKD (20).…”

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Effects of hydration in rats and mice with polycystic kidney disease

Hopp

Wang

et al. 2015

American Journal of Physiology-Renal Physiology

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Hopp K, Wang X, Ye H, Irazabal MV, Harris PC, Torres VE. Effects of hydration in rats and mice with polycystic kidney disease. Am J Physiol Renal Physiol 308: F261-F266, 2015. First published December 10, 2014 doi:10.1152/ajprenal.00345.2014.-Vasopressin and V2 receptor signaling promote polycystic kidney disease (PKD) progression, raising the question whether suppression of vasopressin release through enhanced hydration can delay disease advancement. Enhanced hydration by adding 5% glucose to the drinking water has proven protective in a rat model orthologous to autosomal recessive PKD. We wanted to exclude a glucose effect and explore the influence of enhanced hydration in a mouse model orthologous to autosomal dominant PKD. PCK rats were assigned to normal water intake (NWI) or high water intake (HWI) groups achieved by feeding a hydrated agar diet (HWI-agar) or by adding 5% glucose to the drinking water (HWI-glucose), with the latter group used to recapitulate previously published results. Homozygous Pkd1 R3277C (Pkd1 RC/RC ) mice were assigned to NWI and HWI-agar groups. To evaluate the effectiveness of HWI, kidney weight and histomorphometry were assessed, and urine vasopressin, renal cAMP levels, and phosphodiesterase activities were measured. HWI-agar, like HWI-glucose, reduced urine vasopressin, renal cAMP levels, and PKD severity in PCK rats but not in Pkd1 RC/RC mice. Compared with rat kidneys, mouse kidneys had higher phosphodiesterase activity and lower cAMP levels and were less sensitive to the cystogenic effect of 1-deamino-8-D-arginine vasopressin, as previously shown for Pkd1 RC/RC mice and confirmed here in Pkd2 WS25/Ϫ mice. We conclude that the effect of enhanced hydration in rat and mouse models of PKD differs. More powerful suppression of V2 receptor-mediated signaling than achievable by enhanced hydration alone may be necessary to affect the development of PKD in mouse models. polycystic kidney disease; vasopressin; cAMP; cyclic nucleotide phosphodiesterase; hydration POLYCYSTIC KIDNEY DISEASES (PKDs) are characterized by the development and growth of cysts arising from renal tubules and associated with enlargement of the kidneys and destruction of the renal parenchyma. Autosomal dominant PKD (AD-PKD), the fourth leading cause of end-stage kidney disease in adults, is caused by mutations to either of two genes, PKD1 or PKD2. Autosomal recessive PKD (ARPKD), an important cause of end-stage renal disease and mortality in infants and children, is caused by mutations to polycystic kidney and hepatic disease 1 (PKHD1) (9,23).A large body of evidence indicates that vasopressin and V2 receptor signaling promote the progression of PKD via cAMP and PKA (22). Administration of the V2 receptor agonist 1-deamino-8-D-arginine vasopressin (DDAVP) aggravates the disease in orthologous models of ARPKD and PKD1 (10,28). Genetic elimination of circulating vasopressin markedly inhibits the development of PKD in PCK rats, an effect that was reversed by the administration of DDAVP (28). Treatment with select...

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Effects of hydration in rats and mice with polycystic kidney disease

Hopp

Wang

et al. 2015

American Journal of Physiology-Renal Physiology

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“…4 Vasopressin promotes kidney-cyst cell proliferation and fluid secretion by means of up-regulation of adenosine-3′,5′-cyclic monophosphate (cAMP). 5,6 The suppression of vasopressin production, release, or action by means of hydration, 7,8 V 2 -receptor blockade, [9][10][11][12][13][14] or genetic mutation 15 has been shown to reduce cyst burden, protect kidney function, and prolong survival in rodent models.…”

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Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

et al. 2017

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BACKGROUNDIn a previous trial involving patients with early autosomal dominant polycystic kidney disease (ADPKD; estimated creatinine clearance, ≥60 ml per minute), the vasopressin V 2 -receptor antagonist tolvaptan slowed the growth in total kidney volume and the decline in the estimated glomerular filtration rate (GFR) but also caused more elevations in aminotransferase and bilirubin levels. The efficacy and safety of tolvaptan in patients with later-stage ADPKD are unknown. METHODSWe conducted a phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial. After an 8-week prerandomization period that included sequential placebo and tolvaptan run-in phases, during which each patient's ability to take tolvaptan without dose-limiting side effects was assessed, 1370 patients with ADPKD who were either 18 to 55 years of age with an estimated GFR of 25 to 65 ml per minute per 1.73 m 2 of body-surface area or 56 to 65 years of age with an estimated GFR of 25 to 44 ml per minute per 1.73 m 2 were randomly assigned in a 1:1 ratio to receive tolvaptan or placebo for 12 months. The primary end point was the change in the estimated GFR from baseline to follow-up, with adjustment for the exact duration that each patient participated (interpolated to 1 year). Safety assessments were conducted monthly. RESULTSThe change from baseline in the estimated GFR was −2.34 ml per minute per 1.73 m 2 (95% confidence interval [CI], −2.81 to −1.87) in the tolvaptan group, as compared with −3.61 ml per minute per 1.73 m 2 (95% CI, −4.08 to −3.14) in the placebo group (difference, 1.27 ml per minute per 1.73 m 2 ; 95% CI, 0.86 to 1.68; P<0.001). Elevations in the alanine aminotransferase level (to >3 times the upper limit of the normal range) occurred in 38 of 681 patients (5.6%) in the tolvaptan group and in 8 of 685 (1.2%) in the placebo group. Elevations in the aminotransferase level were reversible after stopping tolvaptan. No elevations in the bilirubin level of more than twice the upper limit of the normal range were detected. CONCLUSIONSTolvaptan resulted in a slower decline than placebo in the estimated GFR over a 1-year period in patients with later-stage ADPKD. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; REPRISE ClinicalTrials.gov number, NCT02160145.)

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“…Health insurance adaptation of tolvaptan has been accepted in Japan since 2014, and it has been considered as a new therapeutic drug for ADPKD [9,11]. However, its effect in patients with severe renal dysfunction is not clear because large-scale clinical intervention studies were intended for cases with a GFR of more than 60 ml/min/ 1.73 m 2 .…”

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Two autosomal dominant polycystic kidney (ADPKD) cases with advanced renal dysfunction, effectively treated with tolvaptan

et al. 2015

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We report here two cases of autosomal dominant polycystic kidney disease (ADPKD) with renal dysfunction that were treated with tolvaptan. Case 1 was a 47-year-old man with a glomerular filtration rate (GFR) of 17.0 ml/min/1.73 m 2 who received tolvaptan treatment (30 mg/day). After treatment, kidney pain was alleviated, and the estimated GFR (eGFR) decline improved from -9.84 ml/min/1.73 m 2 per year to -4.08 ml/min/1.73 m 2 per year, respectively. The rate of increase in total kidney volume was reduced from 18 % per year before treatment to 4 % per year following tolvaptan administration. Case 2 was a 44-year-old man with a GFR of 22.6 ml/min/ 1.73 m 2 , and the eGFR decline improved from -5.76 ml/ min/1.73 m 2 per year before treatment to -3.12 ml/min/ 1.73 m 2 per year following tolvaptan treatment (30 mg/day). The rate of increase in total kidney volume was also decreased from 10 % per year before treatment to -7 % per year following tolvaptan administration. These results suggested that tolvaptan may be effective in impeding kidney function aggravation and kidney volume increase in ADPKD patients with advanced renal dysfunction.

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Tolvaptan Delays the Onset of End-Stage Renal Disease in a Polycystic Kidney Disease Model by Suppressing Increases in Kidney Volume and Renal Injury

Cited by 52 publications

References 48 publications

Effects of hydration in rats and mice with polycystic kidney disease

Effects of hydration in rats and mice with polycystic kidney disease

Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

Two autosomal dominant polycystic kidney (ADPKD) cases with advanced renal dysfunction, effectively treated with tolvaptan

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