{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:58:54Z","timestamp":1790740734265,"version":"4.1.0"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T00:00:00Z","timestamp":1740960000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Kidney360"],"published-print":{"date-parts":[[2025,5]]},"abstract":"\n Key Points<\/jats:title>\n \n \n \n Veverimer, a nonabsorbed gastrointestinal tract HCl binder, increases bicarbonate generation, causes bicarbonaturia, and thus decreases renal ammoniagenesis.<\/jats:p>\n <\/jats:list-item>\n \n Decreases in ammoniagenesis can suppress kidney disease\u2013induced alternative complement pathway activation.<\/jats:p>\n <\/jats:list-item>\n \n As a result of the above changes, decreases in renal injury, as induced by nephrotoxic serum injection, can occur.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n \n 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\n +<\/jats:sup>\n burden, limiting ammonia production. However, poor compliance limits bicarbonate's efficacy. Veverimer is an oral, Na\n +<\/jats:sup>\n -free, nonabsorbed polymer that binds H\n +<\/jats:sup>\n 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.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n A normal diet\u00b1 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\n +<\/jats:sup>\n 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, TGF\n \u03b2<\/jats:italic>\n 1, and endothelin-1 mRNAs) were also assessed.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>","DOI":"10.34067\/kid.0000000743","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T12:02:29Z","timestamp":1741003349000},"page":"696-706","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":3,"title":["Veverimer, a Nonabsorbed Gastrointestinal Tract HCl Binder, Decreases Renal Ammoniagenesis and Mitigates Nephrotoxic Serum Nephritis"],"prefix":"10.34067","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4667-4580","authenticated-orcid":false,"given":"Ali C.M.","family":"Johnson","sequence":"first","affiliation":[{"name":"Fred Hutch Cancer Center, Seattle, Washington"},{"name":"Renibus Therapeutics, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2067-2395","authenticated-orcid":false,"given":"Richard A.","family":"Zager","sequence":"additional","affiliation":[{"name":"Fred Hutch Cancer Center, Seattle, Washington"},{"name":"Clinical Research Division, The University of Washington, Seattle, Washington"},{"name":"Renibus Therapeutics, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2025,3,3]]},"reference":[{"issue":"2","key":"B1-20250530","doi-asserted-by":"crossref","first-page":"29","DOI":"10.5049\/EBP.2021.19.2.29","article-title":"Metabolic acidosis in chronic kidney disease: pathogenesis, clinical consequences, and treatment","volume":"19","author":"Kim","year":"2021","journal-title":"Electrolyte Blood Press."},{"issue":"4","key":"B2-20250530","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.semnephrol.2019.04.009","article-title":"Acid base balance and progression of kidney disease","volume":"39","author":"Chen","year":"2019","journal-title":"Semin Nephrol."},{"issue":"10","key":"B3-20250530","doi-asserted-by":"crossref","first-page":"5187","DOI":"10.3390\/ijms25105187","article-title":"Metabolic acidosis in CKD: pathogenesis, adverse effects, and treatment effects","volume":"25","author":"Raphael","year":"2024","journal-title":"Int J Mol Sci."},{"issue":"3","key":"B4-20250530","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1681\/ASN.2019070677","article-title":"Mechanisms of metabolic acidosis\u2013induced kidney injury in chronic kidney disease","volume":"31","author":"Wesson","year":"2020","journal-title":"J Am Soc Nephrol."},{"issue":"6","key":"B5-20250530","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1097\/01.ASN.0000127865.26968.36","article-title":"Kidney protein dynamics and ammoniagenesis in humans with chronic metabolic acidosis","volume":"15","author":"Garibotto","year":"2004","journal-title":"J Am Soc Nephrol."},{"issue":"2","key":"B6-20250530","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1172\/JCI112020","article-title":"Pathophysiology of chronic tubulo-interstitial disease in rats. 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