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

Torres, Vicente E.; Higashihara, Eiji; Devuyst, Olivier; Chapman, Arlene B.; Gansevoort, Ronald; Grantham, Jared J.; Perrone, Ronald D.; Ouyang, John; Blais, Jaime D.; Czerwiec, Frank S.

doi:10.2215/cjn.06300615

Cited by 129 publications

(121 citation statements)

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“…that information cannot be determined from the present trial, a post hoc analysis of data from patients with chronic kidney disease of stage 3 in the TEMPO 3:4 trial showed a treatment effect of 1.67 ml per minute per 1.73 m 2 per year, which was incremental over the 3 years of that trial. 26 In the present trial, the baseline estimated GFR was 41.1 ml per minute per 1.73 m 2 and declined over a 1-year period by 4.17 ml per minute per 1.73 m 2 with placebo. If one assumes that tolvaptan treatment would continue to slow the decrement in the estimated GFR by 1.27 ml per minute per 1.73 m 2 per year, the time to chronic kidney disease of stage 5 would be extended from 6.2 years to 9.0 years.…”

mentioning

confidence: 43%

“…19,26 (Data from the Japanese patients in the TEMPO 3:4 trial were not included in the power calculations because the present trial [REPRISE] was not planned to include Japanese patients.) The analyses of all the efficacy end points were performed according to the intention-to-treat principle.…”

Section: Discussionmentioning

confidence: 99%

“…These estimated GFR measurements were not affected by the acute hemodynamic effect of tolvaptan, which is rapidly reversible when the drug is not being taken. [24][25][26] Vasopressin acting on V 2 -receptors increases the glomerular filtration rate by means of the activation of tubuloglomerular feedback and afferent vasodilation and by means of renin release and efferent vasoconstriction 27,28 ; tolvaptan counteracts these effects.…”

Section: Primary End Pointmentioning

confidence: 99%

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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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confidence: 43%

Section: Discussionmentioning

confidence: 99%

Section: Primary End Pointmentioning

confidence: 99%

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Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

et al. 2017

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“…They exhibit a hyper-proliferative and pro-apoptotic phenotype 5 , eventually leading to end-stage renal disease. Tolvaptan, a v2-specific vasopressin receptor antagonist, is the first drug approved for the treatment of ADPKD, however additional therapeutic targets are needed because tolvaptan is not curative and side effects preclude treatment in some patients 6 .…”

Section: Introductionmentioning

confidence: 99%

STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease

Fragiadaki

Lannoy

Themanns

et al. 2017

Kidney International

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Article available under the terms of the CC-BY-NC-ND licence (https://creativecommons.org/licenses/by-nc-nd/4.0/) eprints@whiterose.ac.uk https://eprints.whiterose.ac.uk/ Reuse Unless indicated otherwise, fulltext items are protected by copyright with all rights reserved. The copyright exception in section 29 of the Copyright, Designs and Patents Act 1988 allows the making of a single copy solely for the purpose of non-commercial research or private study within the limits of fair dealing. The publisher or other rights-holder may allow further reproduction and re-use of this version -refer to the White Rose Research Online record for this item. Where records identify the publisher as the copyright holder, users can verify any specific terms of use on the publisher's website. TakedownIf you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request. Autosomal dominant polycystic kidney disease (ADPKD) leads to renal failure. The hallmark of ADPKD is increased epithelial proliferation, which has been proposed to be due to atypical signalling including abnormal JAK-STAT activity. However, the relative contribution of JAK-STAT family members in promoting proliferation in ADPKD is unknown. Here we present an siRNA JAK-STAT focused screen revealing a previously unknown proliferative role for multiple JAK-STAT components (including STAT1, STAT2, STAT4, STAT5a, STAT5b). Amongst these we selected to study the GH-GHR-STAT5-axis because of its known role as a regulator of growth in non-renal tissues. We show that STAT5 loss of function, facilitated by pharmacological inhibition or siRNAs, significantly reduced proliferation with an associated reduction in cyst growth in vitro. To study whether STAT5 is abnormally activated in vivo, we analyzed its expression using two independent mouse models of ADPKD. STAT5 was nuclear, thus activated, in renal epithelial cyst lining cells in both. To test whether forced activation of STAT5 can modulate proliferation of renal cells in vivo, irrespective of Pkd1 status, we overexpressed growth hormone (GH). GH mice showed increased STAT5 activity in renal epithelial cells, correlating with de-novo expression of cyclin D1, a STAT5 target gene. Chromatin immunoprecipitations, revealed that STAT5 transcriptionally activated cyclin D1 in GH-stimulated renal epithelial but not control cells, thus providing a mechanism into how STAT5 enhances proliferation. Finally, we provide evidence of elevated GH in Pkd1 nl/nl mice. Collectively, our data identify the GH-STAT5 signalling axis as a novel therapeutic target in ADPKD.

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“…Goals and limits for safe correction are similar to those described above in the treatment of chronic hyponatraemia. Hepatotoxicity with tolvaptan is a concern based on the TEMPO trial (this trial examined the effect of tolvaptan, at high dose, on the progression of polycystic kidney disease); 57 it is therefore recommended to check liver enzymes in patients taking tolvaptan. Another potential limitation to the use of vaptan therapy is that its cost may be prohibitive.…”

Section: Vaptansmentioning

confidence: 99%

Hyponatraemia – presentations and management

2017

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Hyponatraemia is the most common electrolyte disturbance encountered in clinical practice. It is associated with signifi cant morbidity and mortality, thus appropriate investigation and treatment is essential. Hyponatraemia presents with a spectrum of clinical presentations ranging from no symptoms to life-threatening neurological sequelae. Hyponatraemia has multiple aetiologies and distinguishing the underlying aetiology facilitates appropriate treatment. This review provides an overview of the presentations and approaches to management of this common clinical condition. IntroductionHyponatraemia (defined as serum sodium <135 mmol/L) is the most common electrolyte abnormality and is encountered in all areas of clinical practice.1 Hyponatraemia is associated with increased morbidity and mortality.2 The assessment of patients with hyponatraemia can pose a clinical challenge and strategies for its management are often suboptimal. In recent years, expert guidance and recommendations have been published that provide an evidence-based approach to diagnosis and treatment of hyponatraemia 3,4 although it should be highlighted that highquality evidence is lacking for many aspects of hyponatraemia management. Additionally, new therapies have emerged promising a more targeted approach to regulating body water and sodium balance in certain patients with hyponatraemia. EpidemiologyHyponatraemia occurs in approximately 15-30% of hospitalised patients, with 1-2% of patients having a serum sodium level <125 mmol/L. 5,6 In addition, hyponatraemia is often underreported in the hospital setting. 7 In the intensive care unit, approximately 25-30% of patients will have a serum sodium <134 mmol/L. 8,9 In neurosurgical units, hyponatraemia is reported in up to 50% of patients with subarachnoid haemorrhage in retrospective 2 and prospective studies.10 Hyponatraemia is also a common occurrence in ABSTRACT Hyponatraemia -presentations and management heart failure with an incidence of approximately 20% in patients hospitalised for heart failure. 11 Age-related changes and chronic diseases are often associated with abnormalities in water homeostasis. Miller et al 12 have reported that more than 50% of nursing home residents had at least one episode of hyponatraemia over a 12-month study period. Morbidity and mortality associated with hyponatraemiaHyponatraemia is associated with increased morbidity and mortality. Acute severe symptomatic hyponatraemia is a medical emergency that carries a high mortality rate if not addressed acutely. A recent prospective observational study found a positive correlation of serum sodium and mortality, with a serum sodium <125 mmol/L associated with a substantial 1-year mortality, recurrence of hyponatraemia and rehospitalisation rate.13 'Asymptomatic' chronic mild hyponatraemia has previously been thought to be clinically insignificant; however, recent evidence shows that mild chronic 'asymptomatic' hyponatraemia, particularly in an older population, may contribute to impaired cognition, 14 increased risk o...

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

Cited by 129 publications

References 24 publications

Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease

Hyponatraemia – presentations and management

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