Background: A recent study showed that tolvaptan, a vasopressin V-2 receptor antagonist, decreased total kidney volume (TKV) growth and estimated glomerular filtration rate (GFR) loss in autosomal dominant polycystic kidney disease (ADPKD) with creatinine clearance >= 60 mL/min. The aim of our study was to determine whether the renal hemodynamic effects and pharmacodynamic efficacy of tolvaptan in ADPKD are dependent on GFR.
Study Design: Clinical trial with comparisons before and after treatment.
Setting & Participants: Patients with ADPKD with a wide range of measured GFRs (mGFRs; 18-148 mL/min) in a hospital setting.
Intervention: Participants were studied at baseline and after 3 weeks of treatment with tolvaptan given in increasing dosages, if tolerated (doses of 60, 90, and 120 mg/d in weeks 1, 2, and 3, respectively).
Outcomes: Change in markers for aquaresis (free-water clearance, urine and plasma osmolality, 24-hour urine volume, and plasma copeptin) and kidney injury (TKV and kidney injury biomarkers).
Measurements: GFR was measured by 125 I-iothalamate clearance; TKV, by magnetic resonance imaging; biomarker excretion, by enzyme-linked immunosorbent assay; and osmolality, by freezing point depression.
Results: In 27 participants (52% men; aged 46 +/- 10 years; mGFR, 69 +/- 39 mL/min; TKV, 2.15 [IQR, 1.10-2.77] L), treatment with tolvaptan led to an increase in urine volume and free-water clearance and a decrease in urine osmolality, TKV, and kidney injury marker excretion. Changes in urine volume and osmolality with treatment were less in participants with lower baseline mGFRs (both P <0.01). However, change in fractional free-water clearance was greater at lower baseline mGFRs (P = 0.001), suggesting that participants with decreased GFRs responded more to tolvaptan per functioning nephron.
Limitations: Limited sample size, no control group.
Conclusions: In patients with ADPKD with decreased kidney function, response to tolvaptan is lower for TKV, urinary volume, and osmolality, but larger for fractional free-water clearance. This latter finding suggests that patients with ADPKD with lower GFRs might benefit from long-term treatment with tolvaptan, as has been observed for patients with preserved GFRs. (C) 2015 by the National Kidney Foundation, Inc.
- Autosomal dominant polycystic kidney disease (ADPKD)
- vasopressin V-2 receptor antagonist
- drug efficacy
- disease progression
- kidney function
- glomerular filtration rate (GFR)
- V2 RECEPTOR ANTAGONIST