CLINICAL RESEARCH www.jasn.org The Effect of Tolvaptan on BP in Polycystic Kidney Disease: A Post Hoc Analysis of the TEMPO 3:4 Trial Judith E. Heida ,1 Ron T. Gansevoort,1 Vicente E. Torres,2 Olivier Devuyst ,3,4 Ronald D. Perrone ,5 Jennifer Lee,6 Hui Li,6 John Ouyang,6 and Arlene B. Chapman7 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Background The V2 receptor antagonist tolvaptan is prescribed to patients with autosomal dominant polycystic kidney disease to slow disease progression. Tolvaptan may alter BP via various acute and chronic effects. Methods To investigate the magnitude and time course of the effect of tolvaptan use on BP, we conducted a post hoc study of the TEMPO 3:4 trial, which included 1445 patients with autosomal dominant polycystic kid- ney disease randomized 2:1 to tolvaptan or placebo for 3 years. We evaluated systolic and diastolic BP, mean arterial pressure, hypertension status, and use and dosing of antihypertensive drugs over the course of the trial. Results At baseline, BP did not differ between study arms. After 3 weeks of tolvaptan use, mean body weight had decreased from 79.7 to 78.8 kg, and mean plasma sodium increased from 140.4 to 142.6 mmol/L (both P,0.001), suggesting a decrease in circulating volume. We observed none of these changes in the placebo arm. Nonetheless, BP remained similar in the study arms. After 3 years of treatment, however, mean systolic BP was significantly lower in participants receiving tolvaptan versus placebo (126 versus 129 mm Hg, respec- tively; P50.002), as was mean diastolic BP (81.2 versus 82.6 mm Hg, respectively; P50.01). These differences leveled off at follow-up 3 weeks after discontinuation of the study medication. Use of antihypertensive drugs remained similar in both study arms during the entire study. Conclusions Long-term treatment with tolvaptan gradually lowered BP compared with placebo, which may be attributed to a beneficial effect on disease progression, a continued natriuretic effect, or both. Clinical Trial registry name and registration number: TEMPO 3:4, NCT00428948 JASN 32: 1801–1812, 2021. doi: https://doi.org/10.1681/ASN.2020101512 Vasopressin and antidiuretic hormone are names V2 receptor, although indispensable for water that refer to the pleiotropic effects of this peptide. homeostasis, can also be damaging in a variety of Although the former name is most often used, the kidney disorders, including autosomal dominant latter may be more appropriate because decreasing polycystic kidney disease (ADPKD).7 The V2 urinary output is the principal function of vaso- receptor regulates water permeability of the tubular pressin. Effects of vasopressin are facilitated by cell membrane via an intracellular second three types of receptors, the V1a, V1b, and V2 1 receptors, present on various cell types. The V2 Received October 27, 2020. Accepted March 01, 2021. receptor, responsible for the antidiuretic effect, is Published online ahead of print. Publication date available at activated by a minimal change in vasopressin sig- www.jasn.org. nal.2,3 In contrast, activation of the V1a receptor, 4–6 Correspondence: Dr. Ron T. Gansevoort, Department of responsible for vasoconstriction, requires con- Nephrology, University Medical Center Groningen, Hanzeplein siderably higher vasopressin levels.3 1, PO Box 30.001, 9700 RB Groningen, The Netherlands. Not all of the effects of vasopressin are benefi- Email: [email protected] cial. It has been recognized that activation of the Copyright ß 2021 by the American Society of Nephrology JASN 32: 1801–1812, 2021 ISSN : 1046-6673/3207-1801 1801 CLINICAL RESEARCH www.jasn.org messenger, cAMP.8 In patients with ADPKD, growth of kid- Significance Statement ney cysts is stimulated by an increase in intracellular cAMP, leading to loss of kidney function and ultimately, resulting Patients with autosomal dominant polycystic kidney disease are in ESKD.9 Patients with ADPKD are therefore treated with treated with tolvaptan, a V2 receptor antagonist, to slow progres- tolvaptan, a selective V2 receptor antagonist, which has been sion toward ESKD. In theory, tolvaptan could have both BP-increasing and BP-decreasing effects. To investigate the mag- shown to slow the rate of disease progression in patients at nitude and time course of the effect of tolvaptan use on BP, the 10,11 risk of rapid kidney function decline. By preventing bind- authors conducted a post hoc analysis of data from the TEMPO ing of vasopressin to the V2 receptor, tolvaptan induces neph- 3:4 trial, which randomized 1445 patients with autosomal domi- rogenic diabetes insipidus, which causes a compensatory rise nant polycystic kidney disease to tolvaptan or placebo. Their anal- in plasma vasopressin.12 It is important to note that tolvaptan ysis shows that directly after start of tolvaptan therapy, BP does not change, but in the long term, BP gradually becomes lower has a high selectivity for the V2 receptor and does not block the in patients with tolvaptan compared with placebo. This observa- 13 effect of vasopressin on the V1a receptor. Consequently, tion might be attributed to the beneficial effect of tolvaptan on given the higher levels of vasopressin induced by treatment, disease progression, a sustained natriuretic effect, or both. the V1a receptor is activated more than usual. This could have undesired off-target effects, of which a change in BP summary, 1445 patients were enrolled for 2:1 randomization could be one. to either treatment with tolvaptan or placebo between 2007 Tolvaptan could theoretically have several effects on BP. In and 2009. Inclusion criteria were age between 18 and 50 years, the short term, via increased V1a receptor activation, one total kidney volume (TKV) measured by magnetic resonance could expect an increase in vascular resistance and thus, an imaging .750 ml, and Cockcroft–Gault-calculated creatinine 14,15 increase in BP. However, as mentioned above, V1a recep- clearance of 60 ml/min or greater. Exclusion criteria included tor activation has a variety of effects. It also increases sodium but were not limited to concomitant diseases that were likely 16 excretion, thereby potentially decreasing BP. In addition, to confound study end points, such as poorly controlled diabe- preventing vasopressin binding to the V2 receptor could result tes mellitus. Participants allocated to the treatment arm were – in a reduction of BP because of loss of V2 receptor mediated started on a dosage regimen of 45 mg in the morning and 15 ENaC channel activation and therefore, sodium reabsorption, mg in the late afternoon, which was increased to 60/30 mg loss of renin angiotensin aldosterone system (RAAS) activa- after 1 week and thereafter, to 90/30 mg in the third week if tol- – tion due to a decrease of V2 receptor dependent renin pro- erated. Participants remained on the highest tolerated dose for 17,18 duction, and loss of circulating volume due to aquaresis. 36 months. Primary outcome was the annual rate of change in Finally, in the long term, tolvaptan ameliorates the rate of TKV, and secondary outcomes included annual rate of change disease progression, possibly also reducing the develop- in eGFR. Tolvaptan efficacy was studied on top of standard ment of secondary symptoms of kidney disease, such as clinical care, which included optimal BP control. Study rec- hypertension. ommendations defined in 2007, at the start of the trial, consid- The original publication of the TEMPO 3:4 trial disclosed 10 ered optimal control to start antihypertensive treatment at a only limited information on the effect of tolvaptan on BP. systolic BP of 130 mm Hg or a diastolic BP of 85 mm Hg. Change in BP was expressed as worsening hypertension, Adjustments in antihypertensive therapy could be made dur- defined as a change in BP category, or as worsening of hyper- ing the entire study period in case BP exceeded the limits on tension requiring an increase in hypertensive treatment. No two consecutive visits. RAAS inhibitors were recommended effect was found. However, the use of a categorical variable as first-line antihypertensive drug. The choice for second- as outcome measure may have resulted in a loss of power to line therapy was left to the discretion of the treating physician. find differences between the two study groups. Therefore, Long-term use of diuretics was discouraged for safety reasons. this study investigates the magnitude and time course of the This study was approved by all local ethics committees of effect of tolvaptan on BP expressed as a continuous variable, the participating sites and was conducted according to the not only taking into account measured values but also, use International Conference of Harmonization Good Clinical of BP-lowering medication. Practice Guidelines. Written informed consent was obtained from all participants. METHODS Data Collection Study Population and Design Data were collected at baseline, during treatment at week 3, at This study is a post hoc analysis of the TEMPO 3:4 trial, a pro- month 3, and thereafter, after every 4 months for 36 months. A spective, multicenter, double-blinded, randomized, con- follow-up visit was scheduled between 1 and 3 weeks after the trolled trial to assess the efficacy of tolvaptan in patients last dose of study medication. At every visit, a physical exam- with early-stage ADPKD (ClinicalTrials.gov identifier ination was performed, including BP measurement. Systolic NCT00428948). A detailed study protocol of this randomized, BP and diastolic BP were measured at the brachial artery after controlled trial has been published previously.10,19 In 5 minutes of rest in seated position, either manually or with a 1802 JASN JASN 32: 1801–1812, 2021 www.jasn.org CLINICAL RESEARCH validated oscillometric device. BP was measured twice, and if by baseline disease severity–related characteristics (sex, these values varied by .5 mm Hg, they were repeated two median age, Mayo htTKV class, median eGFR, and median more times.