TY - JOUR
T1 - Effect of tolvaptan in autosomal dominant polycystic kidney disease by CKD stage
T2 - Results from the TEMPO 3:4 trial
AU - TEMPO 3:4 Trial Investigators
AU - Torres, Vicente E.
AU - Higashihara, Eiji
AU - Devuyst, Olivier
AU - Chapman, Arlene B.
AU - Gansevoort, Ronald T.
AU - Grantham, Jared J.
AU - Perrone, Ronald D.
AU - Ouyang, John
AU - Blais, Jaime D.
AU - Czerwiec, Frank S.
N1 - Publisher Copyright:
© 2016 by the American Society of Nephrology.
PY - 2016
Y1 - 2016
N2 - 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; subgroup– treatment 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 m2 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 tolvaptaninADPKD across CKD stages 1–3.
AB - 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; subgroup– treatment 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 m2 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 tolvaptaninADPKD across CKD stages 1–3.
KW - ADPKD
KW - Albuminuria
KW - Chronic kidney disease
KW - Glomerular filtration rate
KW - Humans
KW - Pain
KW - Polycystic kidney, autosomal dominant
KW - Receptors, vasopressin
KW - Renal insufficiency, chronic
KW - Tolvaptan
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U2 - 10.2215/CJN.06300615
DO - 10.2215/CJN.06300615
M3 - Article
C2 - 26912543
AN - SCOPUS:85013000324
SN - 1555-9041
VL - 11
SP - 803
EP - 811
JO - Clinical Journal of the American Society of Nephrology
JF - Clinical Journal of the American Society of Nephrology
IS - 5
ER -