Departments of Renal Medicine and Biomedical Engineering, Centro di Ricerche Cliniche per le Malattie Rare "Aldo e Cele Daccò," Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.
Department of Management, Information and Production Engineering, University of Bergamo, Dalmine, Italy.
Clin J Am Soc Nephrol. 2023 Feb 1;18(2):223-233. doi: 10.2215/CJN.0000000000000049.
Tolvaptan and octreotide-long-acting release (LAR) have renoprotective effects in autosomal dominant polycystic kidney disease (ADPKD) that are partially mediated by amelioration of compensatory glomerular hyperfiltration. We compared the effects of tolvaptan and octreotide-LAR combination therapy versus those of tolvaptan monotherapy in patients with ADPKD.
This pilot, randomized, placebo-controlled, cross-over trial primarily compared the effects of 1- and 4-week treatments with octreotide-LAR (two 20-mg i.m. injections) or placebo (two i.m. 0.9% saline solution injections) added-on tolvaptan (up to 90 and 30 mg/d) on GFR (iohexol plasma clearance) in 19 consenting patients with ADPKD referred to a clinical research center in Italy. Analyses were intention-to-treat. The local ethical committee approved the study.
At 4 weeks, GFR significantly decreased by a median (interquartile range) of 3 (-1 to 5) ml/min per 1.73 m2 with tolvaptan and placebo (P=0.01) and by 7 (3-14) ml/min per 1.73 m2 with tolvaptan and octreotide-LAR (P=0.03). GFR changes during the two treatment periods differed by 2 (-5 to 14) ml/min per 1.73 m2 (P=0.28). At 1 week, GFR significantly decreased by 3 (0-7) ml/min per 1.73 m2 with tolvaptan and placebo (P=0.006) and by 10 (-6 to 16) ml/min per 1.73 m2 with tolvaptan and octreotide-LAR add-on therapy (P<0.001). GFR changes during the two treatment periods significantly differed by 3 (0-12) ml/min per 1.73 m2 (P=0.012). Total kidney volume nonsignificantly changed by 4 (-48 to 23) ml with tolvaptan and placebo (P=0.74), whereas it decreased significantly by 41 (25-77) ml with tolvaptan and octreotide-LAR (P=0.001). Changes during the two treatment periods differed by 36 (0-65) ml (P=0.01). Octreotide-LAR also attenuated (P=0.02) the aquaretic effect of tolvaptan. Treatments were well tolerated.
In patients with ADPKD, octreotide-LAR added-on tolvaptan reduced GFR more effectively than octreotide-LAR and placebo. Octreotide-LAR also reduced total and cystic kidney volumes and attenuated the acquaretic effect of tolvaptan.
Tolvaptan-Octreotide LAR Combination in ADPKD (TOOL), NCT03541447.
托伐普坦和奥曲肽长效释放（LAR）在常染色体显性多囊肾病（ADPKD）中具有肾脏保护作用，部分作用机制是通过改善代偿性肾小球高滤过来实现的。我们比较了托伐普坦和奥曲肽-LAR 联合治疗与托伐普坦单药治疗在 ADPKD 患者中的疗效。
这是一项试点、随机、安慰剂对照、交叉试验，主要比较了在意大利临床研究中心纳入的 19 例 ADPKD 患者中，1 周和 4 周的治疗中，奥曲肽-LAR（两次 20mg 肌肉注射）或安慰剂（两次 0.9%生理盐水肌肉注射）联合托伐普坦（最高 90 和 30mg/d）对 GFR（碘海醇血浆清除率）的影响。分析采用意向治疗。当地伦理委员会批准了这项研究。
在 4 周时，托伐普坦和安慰剂使 GFR 中位数（四分位距）分别降低 3（-1 至 5）ml/min/1.73m2（P=0.01）和 7（3-14）ml/min/1.73m2（P=0.03）。两个治疗期的 GFR 变化差异为 2（-5 至 14）ml/min/1.73m2（P=0.28）。在 1 周时，托伐普坦和安慰剂使 GFR 中位数（四分位距）分别降低 3（0-7）ml/min/1.73m2（P=0.006）和 10（-6 至 16）ml/min/1.73m2（P<0.001）。两个治疗期的 GFR 变化差异为 3（0-12）ml/min/1.73m2（P=0.012）。托伐普坦和安慰剂使总肾体积中位数（四分位距）无显著变化（4（-48 至 23）ml，P=0.74），而托伐普坦和奥曲肽-LAR 使总肾体积中位数（四分位距）显著减少 41（25-77）ml（P=0.001）。两个治疗期的体积变化差异为 36（0-65）ml（P=0.01）。奥曲肽-LAR 还减弱了托伐普坦的水合作用（P=0.02）。治疗均耐受良好。
在 ADPKD 患者中，奥曲肽-LAR 联合托伐普坦比奥曲肽-LAR 和安慰剂更有效地降低 GFR。奥曲肽-LAR 还降低了总肾和囊性肾体积，并减弱了托伐普坦的水合作用。
Tolvaptan-Octreotide LAR 联合在 ADPKD（TOOL）中，NCT03541447。
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