A Practical Guide for Treatment of Rapidly Progressive ADPKD with Tolvaptan

Chebib, Fouad T.; Perrone, Ronald D.; Chapman, Arlene B.; Dahl, Neera K.; Harris, Peter C.; Mrug, Michal; Mustafa, Reem A.; Rastogi, Anjay; Watnick, Terry; Yu, Alan; Torres, Vicente E.

doi:10.1681/asn.2018060590

Cited by 175 publications

(196 citation statements)

References 55 publications

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“…Vaptans that antagonize V2 receptors in the kidney have been used clinically to treat chronic hyponatremia (Schrier et al, 2006). In addition, one of the vaptans, namely tolvaptan, has been shown to slow the progression of autosomal dominant polycystic kidney disease (Torres et al, 2012) and has recently been approved by the US FDA for this purpose (Chebib et al, 2018).…”

Section: Mol#119602mentioning

confidence: 99%

Phosphoproteomic Identification of Vasopressin/cAMP/Protein Kinase A–Dependent Signaling in Kidney

et al. 2020

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Water excretion by the kidney is regulated by the neurohypophyseal peptide hormone vasopressin through actions in renal collecting duct cells to regulate the water channel protein, aquaporin-2. Vasopressin signalling is initiated by binding to a G-protein coupled receptor V2R, which signals through Gsα, adenylyl cyclase 6, and activation of the cAMP-regulated protein kinase (PKA). Signaling events coupling PKA activation and aquaporin-2 regulation were largely unknown until the advent of modern protein mass spectrometry techniques that allow proteomewide quantification of protein phosphorylation changes (phosphoproteomics). This short review documents phosphoproteomic findings in collecting duct cells describing the response to V2selective vasopressin agonists and antagonists, the response to CRISPR-mediated deletion of PKA, results from in vitro phosphorylation studies using recombinant PKA, the response to the broad spectrum kinase inhibitor H89, and the responses underlying lithium-induced nephrogenic diabetes insipidus. These phosphoproteomic datasets have been made available online for modelling vasopressin signalling and signalling downstream from other Gsα-coupled receptors.

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Section: Mol#119602mentioning

confidence: 99%

Phosphoproteomic Identification of Vasopressin/cAMP/Protein Kinase A–Dependent Signaling in Kidney

et al. 2020

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“…Moreover, effective management of increasing comorbidities with advancing disease stage, including heart failure and hyperkalemia, may offer further potential for cost reductions. Novel treatments for ADPKD are currently the subject of several clinical trials, and, in 2018, one treatment received regulatory approval in the US for the treatment of ADPKD in patients at risk of rapidly progressing disease [52][53][54][55][56][57]. These treatments have the potential help alleviate the burden of ADPKD for both individuals living with this disease, and their caregivers.…”

Section: Discussionmentioning

confidence: 99%

The societal economic burden of autosomal dominant polycystic kidney disease in the United States

Cloutier

Manceur

Guérin

et al. 2020

BMC Health Serv Res

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Background: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited kidney diseases characterized by progressive development of renal cysts and numerous extra-renal manifestations, eventually leading to kidney failure. Given its chronic and progressive nature, ADPKD is expected to carry a substantial economic burden over the course of the disease. However, there is a paucity of evidence on the impact of ADPKD from a societal perspective. This study aimed to estimate the direct and indirect costs associated with ADPKD in the United States (US). Methods: A prevalence-based approach using data from scientific literature, and governmental and nongovernmental organizations was employed to estimate direct healthcare costs (i.e., medical services, prescription drugs), direct non-healthcare costs (i.e., research and advocacy, donors/recipients matching for kidney transplants, transportation to/from dialysis centers), and indirect costs (i.e., patient productivity loss from unemployment, reduced work productivity, and premature mortality, caregivers' productivity loss and healthcare costs). The incremental costs associated with ADPKD were calculated as the difference between costs incurred over a one-year period by individuals with ADPKD and the US population. Sensitivity analyses using different sources and assumptions were performed to assess robustness of estimates and account for variability in published estimates. Results: The estimated total annual costs attributed to ADPKD in 2018 ranged from $7.3 to $9.6 billion in sensitivity analyses, equivalent to $51,970 to $68,091 per individual with ADPKD. In the base scenario, direct healthcare costs accounted for $5.7 billion (78.6%) of the total $7.3 billion costs, mostly driven by patients requiring renal replacement therapy ($3.2 billion; 43.3%). Indirect costs accounted for $1.4 billion (19.7%), mostly driven by productivity loss due to unemployment ($784 million; 10.7%) and reduced productivity at work ($390 million; 5.3%). Total excess direct non-healthcare costs were estimated at $125 million (1.7%). Conclusions: ADPKD carries a considerable economic burden, predominantly attributed to direct healthcare costs, the majority of which are incurred by public and private healthcare payers. Effective and timely interventions to slow down the progression of ADPKD could substantially reduce the economic burden of ADPKD.

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“…Determination of TKV may not be appropriate to monitor the efficacy of tolvaptan. Indeed, a recently published review, which contains a practical guide for treatment of rapidly progressive ADPKD with tolvaptan, does not recommend annual TKV measurements to monitor efficacy of the therapy [15]. Further cohort studies of ADPKD patients who undergo tolvaptan treatment for a long period are needed to determine whether annual TKV measurements can predict eGFR decline and would also be informative in regard to other factors.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Effects of High-Dose Tolvaptan for Autosomal Dominant Polycystic Kidney Disease Patients

Nakatani

Ishimura

Machiba

et al. 2020

Case Rep Nephrol Dial

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Tolvaptan, a vasopressin V2 receptor antagonist, was initially approved in Japan for treatment of autosomal dominant polycystic kidney disease (ADPKD). Recently, a retrospective study showed that the effect of tolvaptan on kidney function could be sustained for a long period. However, the long-term efficacy and safety of high-dose tolvaptan (120 mg/day) in individual cases remain unknown. We report here 2 Japanese ADPKD patients (males, 36 and 29 years old) treated with tolvaptan (120 mg/day) for 9 years, during which time determinations of estimated glomerular filtration rate (eGFR) and total kidney volume (TKV) were performed. In these 2 patients, eGFR prior to therapy was 57.3 and 76.3 mL/min/1.73 m 2 , respectively, and 30.2 and 43.5 mL/min/1.73 m 2 , respectively, after 9 years of tolvaptan treatment, for a relatively constant annual decline of -3.01 and -3.64 mL/min/1.73 m 2 , respectively. As compared to the predicted (calculated) eGFR without tolvaptan treatment, eGFR actually measured was higher Case Rep Nephrol Dial Nakatani et al.: Long-Term Effects of High-Dose Tolvaptan for Autosomal Dominant Polycystic Kidney Disease Patients 10by 15.3 and 12.6 mL/min/1.73 m 2 , respectively, after the 9-year therapy period. In addition, the rate of TKV increase was gradual, 2.4 and 4.7%, respectively, per year during the initial 3-year period, to 6.5 and 12.5%, respectively, per year in the following 6-year period. During the 9 years of treatment, neither patient showed tolvaptan-related adverse events. Our findings suggest that long-term administration of tolvaptan at a high dose is both safe and effective to preserve kidney function, though a gradual increase in TKV was seen in both of the present cases, particularly during the later phase.

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A Practical Guide for Treatment of Rapidly Progressive ADPKD with Tolvaptan

Cited by 175 publications

References 55 publications

Phosphoproteomic Identification of Vasopressin/cAMP/Protein Kinase A–Dependent Signaling in Kidney

Phosphoproteomic Identification of Vasopressin/cAMP/Protein Kinase A–Dependent Signaling in Kidney

The societal economic burden of autosomal dominant polycystic kidney disease in the United States

Long-Term Effects of High-Dose Tolvaptan for Autosomal Dominant Polycystic Kidney Disease Patients

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