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

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.

• Authors: Wendy E Boertien, Esther Meijer, Paul E de Jong, Gert J ter Horst, Remco J Renken, Eric J van der Jagt, Peter Kappert, John Ouyang, Gerwin E Engels, Willem van Oeveren, Joachim Struck, Frank S Czerwiec, Dorothee Oberdhan, Holly B Krasa, Ron T Gansevoort
• Journal: American journal of kidney diseases : the official journal of the National Kidney Foundation (Am J Kidney Dis) Vol. 65 Issue 6 Pg. 833-41 (Jun 2015) ISSN: 1523-6838 [Electronic] United States
• PMID: 25600953 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antidiuretic Hormone Receptor Antagonists
• Benzazepines
• Biomarkers
• Glycopeptides
• copeptins
• Tolvaptan

Topics

• Acute Kidney Injury (metabolism)
• Adult
• Antidiuretic Hormone Receptor Antagonists (therapeutic use)
• Benzazepines (therapeutic use)
• Biomarkers (metabolism)
• Cohort Studies
• Disease Progression
• Enzyme-Linked Immunosorbent Assay
• Female
• Glomerular Filtration Rate
• Glycopeptides (blood)
• Humans
• Kidney (pathology)
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Organ Size
• Osmolar Concentration
• Polycystic Kidney, Autosomal Dominant (complications, drug therapy, metabolism)
• Prospective Studies
• Renal Insufficiency, Chronic (drug therapy, etiology, metabolism)
• Severity of Illness Index
• Tolvaptan
• Treatment Outcome