Johnson Ali C M, Zager Richard A
Fred Hutch Cancer Center, Seattle, Washington.
Renibus Therapeutics, Dallas, Texas.
Kidney360. 2025 May 1;6(5):696-706. doi: 10.34067/KID.0000000743. Epub 2025 Mar 3.
Veverimer, a nonabsorbed gastrointestinal tract HCl binder, increases bicarbonate generation, causes bicarbonaturia, and thus decreases renal ammoniagenesis. Decreases in ammoniagenesis can suppress kidney disease–induced alternative complement pathway activation. As a result of the above changes, decreases in renal injury, as induced by nephrotoxic serum injection, can occur.
Increased tubular ammoniagenesis is an adaptive response to progressive kidney disease, facilitating net acid excretion. However, excess ammonia production can also exacerbate kidney disease progression, in part, by activating the alternative complement cascade. Oral Na bicarbonate therapy can decrease the systemic H burden, limiting ammonia production. However, poor compliance limits bicarbonate's efficacy. Veverimer is an oral, Na-free, nonabsorbed polymer that binds H within the gastrointestinal (GI) tract. This stimulates GI carbonic anhydrase-mediated bicarbonate production and systemic bicarbonate uptake. Hence, the goals of this study were to test whether GI HCl binding decreases renal tubular ammoniagenesis, to assess whether complement activation decreases, and to determine whether these changes can mitigate nephrotoxic serum (NTS) nephritis, in which complement activation may play a role.
A normal diet± veverimer (4.5% w/w) was fed to normal mice for approximately 1 week. Veverimer's effect on plasma bicarbonate; blood/urinary pH; urinary ammonia excretion; and tubular H transporter, NHE3, density was assessed. Additional mice were fed the normal or veverimer diet after NTS injection. Urine protein, albumin, ammonia, C5b-9 excretion, and plasma C3a levels were measured 1 week and/or 2 weeks after NTS injection. Renal histologic changes (hematoxylin and eosin stain; C5b-9, CD45 immunohistochemistry), and selected injury mediators/biomarkers (NGAL, IL-6, MCP-1, TGF1, and endothelin-1 mRNAs) were also assessed.
Veverimer increased plasma bicarbonate/urinary pH, reduced urinary ammonia, and decreased NHE3 in normal mice. Veverimer also reduced NTS-induced proteinuria/albuminuria, urinary ammonia, and C5b-9 excretion (by approximately 60%, 75%, and 50%, respectively). Significant reductions in NTS-induced glomerular/tubulointerstitial injury, inflammatory/profibrotic gene expression, renal C5b-9 deposition, and suppressed plasma C3a levels were observed. Oral bicarbonate also conferred protection, implicating bicarbonate's role in veverimer's beneficial effect.
Veverimer-mediated bicarbonate generation can suppress renal ammoniagenesis and complement activation. These findings suggest a potential benefit of veverimer/bicarbonate therapy in selected complement-mediated kidney diseases.
维利美（veverimer）是一种不被吸收的胃肠道盐酸结合剂，可增加碳酸氢盐生成，导致尿中出现碳酸氢盐，从而减少肾脏氨生成。氨生成减少可抑制肾病诱导的替代补体途径激活。由于上述变化，可减轻注射肾毒性血清所致的肾损伤。
肾小管氨生成增加是对进行性肾病的一种适应性反应，有助于净酸排泄。然而，过量氨生成也可部分通过激活替代补体级联反应而加剧肾病进展。口服碳酸氢钠治疗可减轻全身酸负荷，限制氨生成。然而，依从性差限制了碳酸氢盐的疗效。维利美是一种口服、无钠、不被吸收的聚合物，可在胃肠道内结合盐酸。这刺激胃肠道碳酸酐酶介导的碳酸氢盐生成和全身碳酸氢盐摄取。因此，本研究的目的是测试胃肠道盐酸结合是否会减少肾小管氨生成，评估补体激活是否会减少，并确定这些变化是否可减轻补体激活可能起作用的肾毒性血清（NTS）肾炎。
给正常小鼠喂食正常饮食±维利美（4.5% w/w）约1周。评估维利美对血浆碳酸氢盐、血液/尿液pH值、尿氨排泄以及肾小管氢离子转运体NHE3密度的影响。在注射NTS后，给另外的小鼠喂食正常或维利美饮食。在注射NTS后1周和/或2周测量尿蛋白、白蛋白、氨、C5b - 9排泄以及血浆C3a水平。还评估了肾脏组织学变化（苏木精和伊红染色；C5b - 9、CD45免疫组化）以及选定的损伤介质/生物标志物（中性粒细胞明胶酶相关脂质运载蛋白、白细胞介素 - 6、单核细胞趋化蛋白 - 1、转化生长因子 - 1和内皮素 - 1 mRNA）。
维利美可增加正常小鼠的血浆碳酸氢盐/尿液pH值，减少尿氨，并降低NHE3水平。维利美还可减少NTS诱导的蛋白尿/白蛋白尿、尿氨以及C5b - 9排泄（分别减少约60%、75%和50%）。观察到NTS诱导的肾小球/肾小管间质损伤、炎症/纤维化基因表达、肾脏C5b - 9沉积显著减少，且血浆C3a水平受到抑制。口服碳酸氢盐也具有保护作用，提示碳酸氢盐在维利美有益作用中发挥作用。
维利美介导的碳酸氢盐生成可抑制肾脏氨生成和补体激活。这些发现提示维利美/碳酸氢盐治疗在某些补体介导的肾病中可能有益。
