Tolvaptan decreases albuminuria over time in patients with autosomal dominant polycystic kidney disease (ADPKD), independent of blood pressure (BP), according to a post-hoc analysis of the TEMPO 3:4 Trial. The finding contrasts with the initial trial report, which concluded that tolvaptan had no effect on albuminuria.
The trial was a 3-year prospective, randomized, placebo-controlled study that included 1,375 ADPKD patients randomized to receive the V2 receptor antagonist tolvaptan or placebo. Researchers measured albuminuria in a spot morning urine sample prior to tolvaptan dosing and expressed as albumin-to-creatinine ratio (ACR). The investigators who conducted the post-hoc analysis noted that the initial TEMPO 3:4 Trial looked at categorical “albuminuria events,” which may have resulted in a loss of sensitivity to detect changes. The post-hoc analysis, led by Ron T. Gansevoort, MD, of University Medical Center Groningen in The Netherlands, examined the effect of tolvaptan on albuminuria as a continuous variable.
At baseline, the patients had a median ACR of 3.2 mg/mmol, and 47.9%, 48.7%, and 3.4% of patients had normal, moderately increased, and severely increased ACR, respectively, Dr. Gansevoort and his colleagues reported online in Nephrology Dialysis Transplantation. Patients with a higher baseline ACR had higher BP and total kidney volume (TKV) and lower estimated glomerular filtration rate (eGFR).
Over 3 years, ACR rose in the placebo arm and decreased in the tolvaptan arm (+23 vs. −0.40 mg/mmol). The difference in ACR increased over time, reaching a maximum of 24% at month 36. At that time, the researchers observed only a minor difference in blood pressure (BP). The decrease in ACR was similar in all subgroups and remained after withdrawal of tolvaptan. During follow-up, higher baseline ACR was associated with more rapid eGFR loss, but not TKV growth rate. Compared with placebo, tolvaptan was associated with a significant beneficial effect on TKV growth in all ACR subgroups, but was stronger in patients with a higher ACR, Dr. Gansevoort’s team reported.
“In our opinion, the gradual onset of the ACR lowering response that remains after drug withdrawal indicates that the reduction in albuminuria with V2 receptor antagonists is a reflection of structural benefits that have obtained, such as less growth in TKV during tolvaptan treatment,” the authors wrote.
ADPKD is a relatively low albuminuria disease, so the effect of tolvaptan on albuminuria per se is of limited clinical relevance, the authors pointed out. The new findings are particularly important because they indicate that, in ADPKD patients, tolvaptan induces structural renal benefits and assessing albuminuria status in this disease may help to identify ADPKD patients who may benefit more from tolvaptan treatment, according to the researchers.