Veverimer, a Non-Absorbed Gastrointestinal Tract HCl Binder, Decreases Renal Ammoniagenesis and Mitigates Nephrotoxic Serum Nephritis.

Abstract

Background: 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, non-absorbed 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; assess whether decreased complement activation results; and determine whether these changes can mitigate nephrotoxic serum (NTS) nephritis in which complement activation may play a role.

Methods: A normal diet ± veverimer (4.5% w/w) was fed to normal mice for ∼1 week. Veverimer's impact on plasma bicarbonate, blood/urinary pH, urinary ammonia excretion, and tubular H+ transporter, NHE3, density were assessed. Additional mice were fed the normal or veverimer diet following NTS injection. Urine protein, albumin, ammonia, C5b-9 excretion, and plasma C3a levels were measured at 1 and/or 2 weeks post NTS injection. Renal histologic changes (H/E stain; C5b-9, CD45 immunohistochemistry), and selected injury mediators/biomarkers (NGAL, IL-6, MCP-1, TGF beta 1, endothelin-1 mRNAs) were also assessed.

Results: Veverimer increased plasma bicarbonate/urinary pH, reduced urinary ammonia, and decreased NHE3 in normal mice. Veverimer also reduced NTS-induced proteinuria/albuminura, urinary ammonia, and C5b-9 excretion (by ∼60%, ∼75%, ∼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 in veverimer's beneficial effect.

Conclusions: 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 renal diseases.