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 kidney 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, respectively; 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: ccc–ccc, 2021. doi: https://doi.org/10.1681/ASN.2020101512 Vasopressin and antidiuretic hormone are names receptor, although indispensable for water homeo- that refer to the pleiotropic effects of this peptide. stasis, can also be damaging in a variety of kidney Although the former name is most often used, the disorders, including autosomal dominant poly- latter may be more appropriate because decreasing cystic kidney disease (ADPKD).7 The V2 receptor urinary output is the principal function of vaso- regulates water permeability of the tubular cell pressin. Effects of vasopressin are facilitated by three types of receptors, the V1a, V1b, and V2 re- ceptors, present on various cell types.1 The V2 re- Received October 27, 2020. Accepted March 1, 2021. ceptor, 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, Correspondence: Dr. Ron T. Gansevoort, Department of Ne- 4–6 responsible for vasoconstriction, requires con- phrology, University Medical Center Groningen, Hanzeplein 1, siderably higher vasopressin levels.3 PO Box 30.001, 9700 RB Groningen, The Netherlands. Email: r.t. Not all of the effects of vasopressin are beneficial. [email protected] It has been recognized that activation of the V2 Copyright © 2021 by the American Society of Nephrology JASN 32: ccc–ccc, 2021 ISSN : 1046-6673/3207-ccc 1 CLINICAL RESEARCH www.jasn.org membrane via an intracellular second messenger, cAMP.8 In Significance Statement patients with ADPKD, growth of kidney cysts is stimulated by an increase in intracellular cAMP, leading to loss of kidney Patients with autosomal dominant polycystic kidney disease are function and ultimately, resulting in ESKD.9 Patients with treated with tolvaptan, a V2 receptor antagonist, to slow pro- ADPKD are therefore treated with tolvaptan, a selective V2 gression toward ESKD. In theory, tolvaptan could have both BP-increasing and BP-decreasing effects. To investigate the mag- receptor antagonist, which has been shown to slow the rate nitude and time course of the effect of tolvaptan use on BP, the of disease progression in patients at risk of rapid kidney func- authors conducted a post hoc analysis of data from the TEMPO 3:4 tion decline.10,11 By preventing binding of vasopressin to the trial, which randomized 1445 patients with autosomal dominant V2 receptor, tolvaptan induces nephrogenic diabetes insipidus, polycystic kidney disease to tolvaptan or placebo. Their analysis which causes a compensatory rise in plasma vasopressin.12 It is shows that directly after start of tolvaptan therapy, BP does not change, but in the long term, BP gradually becomes lower in patients important to note that tolvaptan has a high selectivity for the with tolvaptan compared with placebo. This observation might be V2 receptor and does not block the effect of vasopressin on the attributed to the beneficial effect of tolvaptan on disease progres- V1a receptor.13 Consequently, given the higher levels of vaso- sion, a sustained natriuretic effect, or both. pressin induced by treatment, the V1a receptor is activated more than usual. This could have undesired off-target effects, summary, 1445 patients were enrolled for 2:1 randomization of which a change in BP 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 increase in BP.14,15 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 excretion, thereby potentially decreasing BP.16 In addition, to confound study end points, such as poorly controlled di- preventing vasopressin binding to the V2 receptor could result abetes mellitus. Participants allocated to the treatment arm in a reduction of BP because of loss of V2 receptor–mediated ENaC channel activation and therefore, sodium reabsorption, were started on a dosage regimen of 45 mg in the morning loss of renin angiotensin aldosterone system (RAAS) activa- and 15 mg in the late afternoon, which was increased to tion due to a decrease of V2 receptor–dependent renin pro- 60/30 mg after 1 week and thereafter, to 90/30 mg in the third duction, and loss of circulating volume due to aquaresis.17,18 week if tolerated. Participants remained on the highest toler- Finally, in the long term, tolvaptan ameliorates the rate of ated dose for 36 months. Primary outcome was the annual rate disease progression, possibly also reducing the develop- of change in TKV, and secondary outcomes included annual fi ment of secondary symptoms of kidney disease, such as rate of change in eGFR. Tolvaptan ef cacy was studied on top hypertension. of standard clinical care, which included optimal BP control. fi The original publication of the TEMPO 3:4 trial disclosed Study recommendations de ned in 2007, at the start of the trial, only limited information on the effect of tolvaptan on BP.10 considered optimal control to start antihypertensive treatment Change in BP was expressed as worsening hypertension, de- at a systolic BP of 130 mm Hg or a diastolic BP of 85 mm Hg. fined as a change in BP category, or as worsening of hyperten- Adjustments in antihypertensive therapy could be made during sion requiring an increase in hypertensive treatment. No effect the entire study period in case BP exceeded the limits on two was found. However, the use of a categorical variable as out- consecutive visits. RAAS inhibitors were recommended as first- come measure may have resulted in a loss of power to find line antihypertensive drug. The choice for second-line therapy differences between the two study groups. Therefore, this was left to the discretion of the treating physician. Long-term study investigates the magnitude and time course of the effect use of diuretics was discouraged for safety reasons. of tolvaptan on BP expressed as a continuous variable, not This study was approved by all local ethics committees of only taking into account measured values but also, use of the participating sites and was conducted according to the BP-lowering medication. International Conference of Harmonization Good Clinical 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 month 3, and thereafter, after every 4 months for 36 months. A prospective, 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 2 JASN JASN 32: ccc–ccc,2021 www.jasn.org CLINICAL RESEARCH validated oscillometric device. BP was measured twice, and if baseline disease severity–related characteristics (sex, median these values varied by .5 mm Hg, they were repeated two age, Mayo htTKV class, median eGFR, and median copeptin more times.