Block Geoffrey A, Rosenbaum David P, Leonsson-Zachrisson Maria, Stefansson Bergur V, Rydén-Bergsten Tina, Greasley Peter J, Johansson Susanne A, Knutsson Mikael, Carlsson Björn C
Denver Nephrology, Denver, Colorado.
Ardelyx Inc., Fremont, California; and.
Clin J Am Soc Nephrol. 2016 Sep 7;11(9):1597-1605. doi: 10.2215/CJN.09050815. Epub 2016 Jun 23.
Interdialytic weight gain in patients on hemodialysis is associated with adverse cardiovascular outcomes and increased mortality. The degree of interdialytic weight gain is influenced by sodium intake. We evaluated the effects of tenapanor (AZD1722 and RDX5791), a minimally systemically available inhibitor of the sodium/hydrogen exchanger isoform 3, on interdialytic weight gain in patients with CKD stage 5D treated with hemodialysis.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This phase 2, randomized, double-blind study (NCT01764854; conducted January to September of 2013) enrolled adults on maintenance hemodialysis with interdialytic weight gain ≥3.0% of postdialysis weight and ≥2 kg. Patients were randomly assigned (1:1) to receive tenapanor or placebo. The primary end point was change in mean interdialytic weight gain (percentage of baseline postdialysis weight) from baseline (mean across a 2-week run-in period) to week 4. In a subgroup of inpatients, 24-hour stool sodium and stool weight were assessed for 1 week.
Sixteen patients received 1 week of inpatient treatment (tenapanor, eight; placebo, eight), and 72 patients received 4 weeks of treatment in an outpatient setting (tenapanor, 37; placebo, 35; completers: tenapanor, 31; placebo, 33). In the outpatient cohort, no significant effect on interdialytic weight gain was detected; least squares mean changes in relative interdialytic weight gain from baseline to week 4 were tenapanor, -0.26% (95% confidence interval, -0.57% to 0.06%) and placebo, -0.23% (95% confidence interval, -0.54% to 0.07%; P=0.46). During week 1 (inpatient cohort only), compared with placebo, tenapanor treatment resulted in higher stool sodium content (mean [±SD]: tenapanor, 36.6 [±21.8] mmol/d; placebo, 2.8 [±2.7] mmol/d; P<0.001) and higher stool weight (tenapanor, 172.5 [±68.1] g/d; placebo, 86.3 [±30.0] g/d; P<0.01). A similar safety profile was observed across treatment groups with the exception of diarrhea, which occurred more frequently with tenapanor treatment.
Tenapanor treatment increased stool sodium and weight over placebo in patients undergoing hemodialysis. However, over 4 weeks of treatment, there was no difference in interdialytic weight gain between patients treated with tenapanor and those receiving placebo.
血液透析患者透析间期体重增加与不良心血管结局及死亡率增加相关。透析间期体重增加的程度受钠摄入的影响。我们评估了钠/氢交换体3型的最小全身可用抑制剂替那帕诺（AZD1722和RDX5791）对接受血液透析的5D期慢性肾脏病患者透析间期体重增加的影响。
设计、地点、参与者及测量：这项2期随机双盲研究（NCT01764854；于2013年1月至9月进行）纳入维持性血液透析的成年人，其透析间期体重增加≥透析后体重的3.0%且≥2 kg。患者被随机分配（1:1）接受替那帕诺或安慰剂。主要终点是从基线（2周导入期的平均值）到第4周平均透析间期体重增加的变化（透析后体重基线的百分比）。在住院患者亚组中，评估1周的24小时粪便钠含量和粪便重量。
16例患者接受了1周的住院治疗（替那帕诺组8例；安慰剂组8例），72例患者在门诊接受了4周的治疗（替那帕诺组37例；安慰剂组35例；完成治疗者：替那帕诺组31例；安慰剂组33例）。在门诊队列中，未检测到对透析间期体重增加有显著影响；从基线到第4周相对透析间期体重增加的最小二乘均值变化在替那帕诺组为-0.26%（95%置信区间，-0.57%至0.06%），在安慰剂组为-0.23%（95%置信区间，-0.54%至0.07%；P=0.46）。在第1周（仅住院患者队列），与安慰剂相比，替那帕诺治疗导致粪便钠含量更高（均值[±标准差]：替那帕诺组，36.6[±21.8]mmol/d；安慰剂组，2.8[±2.7]mmol/d；P<0.001）且粪便重量更高（替那帕诺组，172.5[±68.1]g/d；安慰剂组，86.3[±30.0]g/d；P<0.01）。除腹泻外各治疗组观察到相似的安全性概况，腹泻在替那帕诺治疗时更频繁发生。
在接受血液透析的患者中，替那帕诺治疗使粪便钠含量和重量高于安慰剂。然而，在4周的治疗期间，接受替那帕诺治疗的患者与接受安慰剂的患者在透析间期体重增加方面没有差异。
