Wendy E Boertien1, Esther Meijer1, Paul E de Jong1, Gert J ter Horst2, Remco J Renken2, Eric J van der Jagt3, Peter Kappert3, John Ouyang4, Gerwin E Engels5, Willem van Oeveren5, Joachim Struck6, Frank S Czerwiec4, Dorothee Oberdhan4, Holly B Krasa4, Ron T Gansevoort7. 1. Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 2. Department of Neuroscience, Neuroimaging Center, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 3. Department of Radiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 4. Otsuka Pharmaceutical Development & Commercialization, Inc, Rockville, MD. 5. Haemoscan bv, Groningen, the Netherlands. 6. AdrenoMed AG, Hennigsdorf, Germany. 7. Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Electronic address: r.t.gansevoort@umcg.nl.
Abstract
BACKGROUND: A recent study showed that tolvaptan, a vasopressin V2 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≥60mL/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 120mg/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±39mL/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.
BACKGROUND: A recent study showed that tolvaptan, a vasopressin V2 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≥60mL/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 120mg/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±39mL/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.
Authors: Vicente E Torres; Eiji Higashihara; Olivier Devuyst; Arlene B Chapman; Ronald T Gansevoort; Jared J Grantham; Ronald D Perrone; John Ouyang; Jaime D Blais; Frank S Czerwiec Journal: Clin J Am Soc Nephrol Date: 2016-02-23 Impact factor: 8.237
Authors: Manal Mazloum; Jordan Jouffroy; François Brazier; Christophe Legendre; Antoine Neuraz; Nicolas Garcelon; Dominique Prié; Dany Anglicheau; Frank Bienaimé Journal: J Am Soc Nephrol Date: 2019-06-19 Impact factor: 10.121
Authors: A Lianne Messchendorp; Edwin M Spithoven; Niek F Casteleijn; Wendy A Dam; Jacob van den Born; Wouter F Tonnis; Carlo A J M Gaillard; Esther Meijer Journal: BMC Nephrol Date: 2018-12-19 Impact factor: 2.388
Authors: Ron T Gansevoort; Maatje D A van Gastel; Arlene B Chapman; Jaime D Blais; Frank S Czerwiec; Eiji Higashihara; Jennifer Lee; John Ouyang; Ronald D Perrone; Katrin Stade; Vicente E Torres; Olivier Devuyst Journal: Kidney Int Date: 2019-03-09 Impact factor: 10.612
Authors: A Lianne Messchendorp; Esther Meijer; Folkert W Visser; Gerwin E Engels; Peter Kappert; Monique Losekoot; Dorien J M Peters; Ron T Gansevoort Journal: Am J Nephrol Date: 2019-10-10 Impact factor: 3.754
Authors: Marie E Edwards; Fouad T Chebib; Maria V Irazabal; Troy G Ofstie; Lisa A Bungum; Andrew J Metzger; Sarah R Senum; Marie C Hogan; Ziad M El-Zoghby; Timothy L Kline; Peter C Harris; Frank S Czerwiec; Vicente E Torres Journal: Clin J Am Soc Nephrol Date: 2018-07-19 Impact factor: 8.237
Authors: Debbie Zittema; Irina B Versteeg; Ron T Gansevoort; Harry van Goor; Emile de Heer; Kimberley A M Veraar; Dorien J M Peters; Esther Meijer Journal: Am J Nephrol Date: 2016-08-31 Impact factor: 3.754
Authors: Yong Wu; Jen X Xu; Wassim El-Jouni; Tzongshi Lu; Suyan Li; Qingyi Wang; Mei Tran; Wanfeng Yu; Maoqing Wu; Ivan E Barrera; Joseph V Bonventre; Jing Zhou; Bradley M Denker; Tianqing Kong Journal: J Cell Sci Date: 2016-08-05 Impact factor: 5.285