Labonté Eric D, Carreras Christopher W, Leadbetter Michael R, Kozuka Kenji, Kohler Jill, Koo-McCoy Samantha, He Limin, Dy Edward, Black Deborah, Zhong Ziyang, Langsetmo Ingrid, Spencer Andrew G, Bell Noah, Deshpande Desiree, Navre Marc, Lewis Jason G, Jacobs Jeffrey W, Charmot Dominique
Ardelyx, Inc., Fremont, California.
Ardelyx, Inc., Fremont, California
J Am Soc Nephrol. 2015 May;26(5):1138-49. doi: 10.1681/ASN.2014030317. Epub 2014 Nov 17.
In CKD, phosphate retention arising from diminished GFR is a key early step in a pathologic cascade leading to hyperthyroidism, metabolic bone disease, vascular calcification, and cardiovascular mortality. Tenapanor, a minimally systemically available inhibitor of the intestinal sodium-hydrogen exchanger 3, is being evaluated in clinical trials for its potential to (1) lower gastrointestinal sodium absorption, (2) improve fluid overload-related symptoms, such as hypertension and proteinuria, in patients with CKD, and (3) reduce interdialytic weight gain and intradialytic hypotension in ESRD. Here, we report the effects of tenapanor on dietary phosphorous absorption. Oral administration of tenapanor or other intestinal sodium-hydrogen exchanger 3 inhibitors increased fecal phosphorus, decreased urine phosphorus excretion, and reduced [(33)P]orthophosphate uptake in rats. In a rat model of CKD and vascular calcification, tenapanor reduced sodium and phosphorus absorption and significantly decreased ectopic calcification, serum creatinine and serum phosphorus levels, circulating phosphaturic hormone fibroblast growth factor-23 levels, and heart mass. These results indicate that tenapanor is an effective inhibitor of dietary phosphorus absorption and suggest a new approach to phosphate management in renal disease and associated mineral disorders.
在慢性肾脏病（CKD）中，肾小球滤过率降低导致的磷潴留是引发甲状腺功能亢进、代谢性骨病、血管钙化和心血管死亡的病理级联反应中的关键早期步骤。替那帕诺是一种全身利用度极低的肠道钠-氢交换体3抑制剂，目前正在临床试验中评估其潜力，包括（1）降低胃肠道钠吸收，（2）改善CKD患者与液体超负荷相关的症状，如高血压和蛋白尿，以及（3）减少终末期肾病（ESRD）患者透析间期体重增加和透析中低血压。在此，我们报告替那帕诺对膳食磷吸收的影响。口服替那帕诺或其他肠道钠-氢交换体3抑制剂可增加大鼠粪便磷含量，减少尿磷排泄，并降低大鼠[（33）P]正磷酸盐摄取。在CKD和血管钙化大鼠模型中，替那帕诺减少钠和磷吸收，并显著降低异位钙化、血清肌酐和血清磷水平、循环中磷尿激素成纤维细胞生长因子-23水平以及心脏重量。这些结果表明，替那帕诺是膳食磷吸收的有效抑制剂，并为肾病及相关矿物质紊乱的磷管理提供了一种新方法。
