Short-term Effects of Tolvaptan in Individuals With Autosomal Dominant Polycystic Kidney Disease at Various Levels of Kidney Function

Boertien, Wendy E.; Meijer, Esther; Jong, Paul E. de; Horst, Gert J. Ter; Renken, Remco; Jagt, Eric J. van der; Kappert, Peter; Ouyang, John; Engels, Gerwin E.; Oeveren, Willem van; Struck, Joachim; Czerwiec, Frank S.; Oberdhan, Dorothee; Krasa, Holly B.; Gansevoort, Ron T.

doi:10.1053/j.ajkd.2014.11.010

Cited by 72 publications

(76 citation statements)

References 22 publications

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“…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: 81%

“…Tolvaptan and enhanced hydration are known to exert an acute, reversible renal hemodynamic effect, likely through inhibition of tubuloglomerular feedback (17)(18)(19)25). Because this could have affected the eGFR slopes on treatment, a sensitivity analysis comparing the change in eGFR values from pretreatment baseline to post-treatment visits after discontinuation of the study drug was performed.…”

Section: Discussionmentioning

confidence: 99%

“…Although these are legitimate concerns, other considerations may be reassuring. A recent study in patients with ADPKD who had a GFR .60, 30-60, and ,30 ml/min per 1.73 m 2 showed that the pharmacodynamic efficacy of tolvaptan is maintained in patients with advanced CKD, as reflected by a greater fractional free water clearance and a similar absolute change in TKV (17). Several experimental and clinical studies in various kidney diseases, hypertension, diabetes, and the metabolic syndrome support a role for vasopressin, via V2 receptors, in the progression of CKD in general and raise the possibility that the blockade of vasopressin V2 receptors may slow its progression (18,19).…”

Section: Introductionmentioning

confidence: 99%

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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

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133

106

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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.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

Self Cite

133

106

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“…Interestingly, in the Tolvaptan Efficacy and Safety in Managment of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 trial, urinary excretion of the inflammation marker monocyte chemoattractant protein-1 increased after 3 weeks of treatment with tolvaptan, whereas after longer treatment a gradual and significant decrease occurred. Another study showed that 3 weeks treatment with tolvaptan already led to a decrease in urinary excretion of kidney injury markers (except kidney injury molecule-1) (27). These data indicate that there may be differences between short-term and long-term effects of this medication and that there may be differences in the outcome parameter under investigation.…”

Section: Discussionmentioning

confidence: 93%

Urinary EGF Receptor Ligand Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease and Response to Tolvaptan

Harskamp¹,

Gansevoort²,

Boertien³

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Recent animal experiments suggest that dysregulation of the EGF receptor pathway plays a role in the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD). Research on EGF receptor ligands in humans with ADPKD is lacking. EGF receptor ligands were measured in patients with ADPKD at baseline and after treatment with a vasopressin V2 receptor antagonist (V2RA) because this information might provide a rationale for future V2RA combination therapy.Design, setting, participants, & measurements Blood and urine concentrations of the EGF receptor ligands heparin-binding (HB)-EGF, EGF, and TGF-a were measured by ELISAs in 27 patients with ADPKD who participated in a single-center study investigating a V2RA in 2011-2013 and in 27 controls who were selected from a general population-based observational study. Cyst fluid concentrations were also measured. In patients with ADPKD, ligands were measured at baseline, after 3-week treatment with a V2RA, and 3 weeks after drug withdrawal. The measured GFR (mGFR) was determined by iothalamate infusion, and total kidney volume was measured by magnetic resonance imaging.Results Urinary HB-EGF excretion and plasma concentration were higher in patients with ADPKD than in controls (median, . In contrast, urinary EGF excretion and plasma EGF concentration were lower in patients with ADPKD, whereas TGF-a did not differ between patients and controls. Higher HB-EGF excretion was correlated with more severe disease, assessed as lower mGFR (r=20.39; P=0.05), higher total kidney volume (r=0.39; P=0.05), and higher urinary excretion of albumin and heart-type fatty acid-binding protein, whereas higher EGF excretion and TGF-a excretion were negatively correlated with disease severity. During V2RA treatment, HB-EGF excretion increased (from 1.4 [1.2-1.9] to 2.4 [2.1-3.1] mg/24 hours; P,0.001).1 ConclusionIn patients with ADPKD, higher urinary HB-EGF excretion is correlated with more severe disease. Whether this association is causal needs to be investigated in intervention studies.

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“…Infine un altro aspetto significativo da prendere in considerazione nell'utilizzo clinico di tolvaptan in ADPKD è l'effetto di rapida e reversibile perdita di funzione renale che si osserva nelle prime settimane di trattamento (13). Questa iniziale perdita funzionale è limitata (circa il 5% del valore basale (13)) e reversibile al momento della sospensione di tolvaptan.…”

Section: Introduzioneunclassified

Tolvaptan: Clinical Evidence for Slowing the Progression of Autosomal Dominant Polycystic Kidney Disease

Magistroni

2017

Giornale di Tecniche Nefrologiche e Dialitiche

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Short-term Effects of Tolvaptan in Individuals With Autosomal Dominant Polycystic Kidney Disease at Various Levels of Kidney Function

Cited by 72 publications

References 22 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

Urinary EGF Receptor Ligand Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease and Response to Tolvaptan

Tolvaptan: Clinical Evidence for Slowing the Progression of Autosomal Dominant Polycystic Kidney Disease

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