Tolvaptan inhibits ERK-dependent cell proliferation, Cl<sup>−</sup>secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin

Reif, Gail A.; Yamaguchi, Tomohiro; Nivens, Emily; Fujiki, Hiroyuki; Pinto, Cibele S.; Wallace, Darren P.

doi:10.1152/ajprenal.00243.2011

Cited by 139 publications

(138 citation statements)

References 49 publications

Supporting

Mentioning

132

Contrasting

Unclassified

Order By: Relevance

“…The effect on kidney volume in the first year was likely due to deflation caused by slowing fluid secretion, while the effect during the second and third years was likely due to decreased cell proliferation as secretion is maintained at a reduced level. This is supported by studies in cultured ADPKD cystic cells in which low concentrations of tolvaptan inhibited arginine vasopressinstimulated, chloride-driven fluid secretion and cell proliferation (24) and by clinical studies that demonstrated acute decreases in TKV as early as 1 and 3 weeks of treatment, which are probably not to be explained by effects on cell proliferation (17,25).…”

Section: Discussionmentioning

confidence: 82%

Effect of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease by CKD Stage: Results from the TEMPO 3:4 Trial

Torres¹,

Higashihara²,

Devuyst³

et al. 2016

CJASN

133

106

View full text Add to dashboard Cite

Background and objectives The Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 study demonstrated a significant beneficial effect of the vasopressin V2 receptor antagonist tolvaptan on rates of kidney growth and eGFR decline in autosomal dominant polycystic kidney disease (ADPKD). This post hoc analysis was performed to reassess the primary and secondary efficacy endpoints by CKD stage at baseline.Design, setting, participants, & measurements In a phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, 1445 patients with ADPKD (age 18-50 years), with total kidney volume (TKV) $750 ml and estimated creatinine clearance $60 ml/min, were randomly assigned 2:1 to split-dose tolvaptan (45/15, 60/30, or 90/30 mg daily as tolerated) or placebo. The primary endpoint was annualized rate of TKV change. Secondary endpoints included a composite endpoint of time to multiple composite ADPKD-related events (worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney function decline.Results Tolvaptan reduced annualized TKV growth by 1.99%, 3.12%, and 2.61% per year (all P,0.001; subgrouptreatment interaction, P=0.17) and eGFR decline by 0.40 in CKD1 (P=0.23), 1.13 in CKD2 (P,0.001) and 1.66 ml/min per 1.73 m 2 per year in CKD3 (P,0.001) with a trend for a positive subgroup-treatment interaction (P=0.07) across CKD1, CKD2 and CKD3. ADPKD-related events were less frequent in tolvaptan recipients than in placebo recipients among those with CKD1 (hazard ratio [HR], 0.83; 95% confidence interval [95% CI], 0.70-0.98; P=0.03) and those with CKD 3 (HR, 0.71; 95% CI, 0.57-0.89; P=0.003), but not among those with CKD2 (HR, 1.02; 95% CI, 0.85-1.21; P=0.86). Aquaresis-related adverse events (more frequent in the tolvaptan group) and ADPKD-related adverse events (more frequent in the placebo group) were not associated with CKD stage. Hypernatremia events in tolvaptan-treated patients with CKD3 and plasma aminotransferase elevations in tolvaptan-treated patients across CKD stages 1-3 occurred more frequently than in placebo recipients.Conclusions This post hoc analysis suggests clinically similar beneficial effects of tolvaptan in ADPKD across CKD stages 1-3.

show abstract

Section: Discussionmentioning

confidence: 82%

Effect of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease by CKD Stage: Results from the TEMPO 3:4 Trial

Torres¹,

Higashihara²,

Devuyst³

et al. 2016

CJASN

133

106

View full text Add to dashboard Cite

show abstract

“…138 Tolvaptan also inhibits vasopressin-induced cell proliferation, chloride secretion, and in vitro cyst growth of human ADPKD cells. 139 …”

Section: V2 Receptor Antagonists: Rationale and Preclinical Trialsmentioning

confidence: 99%

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

Torres

Harris

2014

Journal of the American Society of Nephrology

244

218

View full text Add to dashboard Cite

Polycystic kidney disease (PKD) is a leading cause of ESRD worldwide. In PKD, excessive cell proliferation and fluid secretion, pathogenic interactions of mutated epithelial cells with an abnormal extracellular matrix and alternatively activated interstitial macrophages, and the disruption of mechanisms controlling tubular diameter contribute to cyst formation. Studies with animal models suggest that several diverse pathophysiologic mechanisms, including dysregulation of intracellular calcium levels and cAMP signaling, mediate these cystogenic mechanisms. This article reviews the evidence implicating calcium and cAMP as central players in a network of signaling pathways underlying the pathogenesis of PKD and considers the therapeutic relevance of treatment strategies targeting cAMP signaling.

show abstract

“…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.…”

mentioning

confidence: 99%

Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

et al. 2017

View full text Add to dashboard Cite

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.)

show abstract

Tolvaptan inhibits ERK-dependent cell proliferation, Cl⁻secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin

Cited by 139 publications

References 49 publications

Effect of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease by CKD Stage: Results from the TEMPO 3:4 Trial

Effect of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease by CKD Stage: Results from the TEMPO 3:4 Trial

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

Contact Info

Product

Resources

About

Tolvaptan inhibits ERK-dependent cell proliferation, Cl−secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin

Cited by 139 publications

References 49 publications

Effect of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease by CKD Stage: Results from the TEMPO 3:4 Trial

Effect of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease by CKD Stage: Results from the TEMPO 3:4 Trial

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

Contact Info

Product

Resources

About

Tolvaptan inhibits ERK-dependent cell proliferation, Cl⁻secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin