Tolvaptan was associated with a lower response on urinary volume, urinary osmolality, and decreased total kidney volume (TKV), and with a greater response for fractional free-water clearance in patients with autosomal dominant polycystic kidney disease (ADPKD). That was among the findings of a trial conducted recently by Wendy E. Boertien, MD, PhD, and colleagues. The researchers reported trial results in the American Journal of Kidney Diseases [2015;65(6):833-841].
ADPKD is a hereditary disease leading to formation of cysts, particularly in the kidney, and results in enlargement of the kidneys and loss of kidney function. Of patients with ADPKD, half require renal replacement therapy in their sixties. A study reported in 2011 demonstrated that tolvaptan, a vasopressin V2 receptor antagonist, decreased TKV growth and estimated glomerular filtration rate (eGFR) loss in ADPKD with creatinine clearance ≥60 mL/min. The current study investigated whether the renal hemodynamic effects and pharmacodynamics efficacy of tolvaptan in ADPKD are dependent on GFR.
Patients 18 to 70 years of age with ADPKD and measured GFRs (mGFR) ranging from 18 to 148 mL/min/1.73 m2 were stratified (using estimated GFR) into three groups: eGFR >60 mL/min/1.73 m2; 30 to 60 mL/min/1.73 m2; and <30 mL/min/1.73 m2. The researchers used eGFR only for inclusion; in all analyses, they used mGFR.
Exclusion criteria were diuretic use, pregnancy or breast-feeding, previous exposure to tolvaptan, risk factors for decreased renal function other than ADPKD, recent renal surgery, diabetes mellitus, contraindications to magnetic resonance imaging (MRI), critical electrolyte imbalances, and uncontrolled hypertension.
Participants were studied at baseline and following 3 weeks of treatment with tolvaptan, which was given in increasing dosages if tolerated: 60 mg/d in week one, 90 mg/d in week two, and 120 mg/d in week three. The outcomes of interest were change in markers for aquaresis, defined as free-water clearance, urine and plasma osmolality, 24-hour urine volume, and plasma copeptin; and kidney injury, defined as TKV and kidney injury biomarkers.
GFR was measured by 125I-iothalamate clearance; TVK was measured by MRI; biomarker excretion was measured by enzyme-linked immunosorbent assay; and osmolality was measured by freezing point depression.
Of the 29 patients included, 27 completed the study (nine per eGFR stratum). One patient withdrew after 3 days of treatment due to polyuria and the other after 13 days due to xerostomia.
Following 3 weeks of treatment, there was a significant decrease in TKV and mGFR, as well as in other measured variables. There was no decrease seen in urinary monocyte chemotactic protein 1 (MCP-1) and kidney injury molecule-1 (KIM-1) concentrations; they were essentially unchanged. In contrast, there were significant increases in plasma osmolality, copeptin concentration, and urine volume. All the changes were reversible after 3 weeks’ withdraw of tolvaptan (TKV remained slightly but significantly lower than the baseline value).
Some changes in study variables during treatment were associated with baseline mGFR. The lower the baseline mGFR, the lower the increase in urine volume and the lower the decrease in urine osmolality and mGFR. Lower mGFR was also associated with less decrease in TKV when expressed as percentage (P=.06), but not when expressed as absolute change.
Free-water clearance also increased less in participants with lower mGFRs. However, when free-water clearance was expressed normalized for mGFR (fractional free-water clearance), the change in free-water clearance per single nephron was stronger in those with lower mGFRs. With the exception of IgG and MCP-1, that was no association with baseline mGFR and changes in excretion of urinary biomarkers during treatment with tolvaptan. Finally, there was no significant association between baseline mGFR and maximal tolvaptan concentration or area under the curve.
The researchers cited the small sample size and the lack of a control group as limitations to the study.
“In conclusion, response to tolvaptan on urinary volume, urinary osmolality, and TKV is lower in patients with ADPKD with decreased kidney function, when using relative changes. In contrast, in patients with lower kidney function, the effect of tolvaptan on fractional free-water clearance is more distinct. Based on these latter results, we hypothesize that the lower relative response on urinary volume, urinary osmolality, and TKV in patients with decreased kidney function is not due to decreased sensitivity for tolvaptan, but could be due to less functioning renal mass or structural renal abnormalities. In addition, we found that absolute changes in TKV, plasma copeptin, and urinary biomarker excretion were not associated with baseline GFR, suggesting that patients with ADPKD with lower GFRs also might benefit from long-term treatment with tolvaptan, as has been observed for those with relatively preserved GFRs,” the researchers said.
- This study investigated whether the renal hemodynamic effects and pharmacodynamics efficacy of tolvaptan in ADPKD are dependent on GFR.
- The outcomes of interest were change in markers for aquaresis, defined as free-water clearance, urine and plasma osmolality, 24-hour urine volume, and plasma copeptin; and kidney injury, defined as TKV and kidney injury biomarkers.
- Following 3 weeks of treatment, there was a significant decrease in TKV and mGFR, as well as in other measured variables, and significant increases in plasma osmolality, copeptin concentration, and urine volume.