Plasma copeptin levels predict disease progression and tolvaptan efficacy in autosomal dominant polycystic kidney disease

Abstract

In the TEMPO 3:4 Trial, treatment with tolvaptan, a vasopressin V2 receptor antagonist, slowed the increase in total kidney volume and decline in estimated glomerular filtration rate (eGFR) in autosomal dominant polycystic kidney disease (ADPKD). We investigated whether plasma copeptin levels, a marker of plasma vasopressin, are associated with disease progression, and whether pre-treatment copeptin and treatment-induced change in copeptin are associated with tolvaptan treatment efficacy. This post hoc analysis included 1,280 TEMPO 3:4 participants (aged 18-50 years, estimated creatinine clearance ≥60 ml/min and total kidney volume ≥750 mL) who had plasma samples available at baseline for measurement of copeptin using an automated immunofluorescence assay. In placebo-treated subjects, baseline copeptin predicted kidney growth and eGFR decline over 3 years. These associations were independent of sex, age, and baseline eGFR, but were no longer statistically significant after additional adjustment for baseline total kidney volume. In tolvaptan-treated subjects, copeptin increased from baseline to week 3 (6.3 pmol/L versus 21.9 pmol/L, respectively). In tolvaptan-treated subjects with higher baseline copeptin levels, a larger treatment effect was noted with respect to kidney growth rate and eGFR decline. Tolvaptan-treated subjects with a larger percentage increase in copeptin from baseline to week 3 had a better disease outcome, with less kidney growth and eGFR decline after three years. Copeptin holds promise as a biomarker to predict outcome and tolvaptan treatment efficacy in ADPKD.

Keywords: ADPKD; AVP; copeptin; polycystic kidney disease; tolvaptan; vasopressin.

Figure 1 |

Annual change (mean and 95% confidence interval) in total kidney volume (TKV, left panel) and estimated glomerular filtration rate (eGFR, right panel) in placebo-treated subjects according to sex-adjusted quartiles of baseline copeptin.

Figure 2 |

Tolvaptan treatment effect on annual change in total kidney volume (TKV, left panel) and estimated glomerular filtration rate (eGFR, right panel) according to sex-adjusted quartile of baseline copeptin (means and interquartile ranges).

Figure 3 |. Median copeptin levels in tolvaptan-(dark gray) and placebo- (light gray) treated subjects at baseline, during 36 months of treatment, and after withdrawal of treatment (follow-up).

*P < 0.05, **P < 0.001 versus baseline.

Figure 4 |. Short-term change in copeptin (week 3 vs. baseline) in tolvaptan-treated subjects versus annual TKV growth rate (left panel) and annual eGFR decline (right panel).

Data are shown per quartile of change in copeptin (QΔC1: <119%; QΔC2: 119%−230%; QΔC3: 230%−390%; QΔC4:F ≥ 390%).