Sevelamer reverses liver fibrosis by deactivation of hepatic stellate cells.

Liver fibrosis is a chronic liver disease characterized by a progressive wound healing response caused by chronic liver injury. Currently, there are no approved clinical treatments for liver fibrosis. Sevelamer is used clinically to treat hyperphosphatemia and has shown potential therapeutic effects on liver diseases. However, there have been few studies evaluating the therapeutic effects of sevelamer on liver fibrosis, and the specific mechanisms are still unclear. In this study, we investigated the antifibrotic effects of sevelamer-induced low inorganic phosphate (Pi) stress in vitro and in vivo and analyzed the detailed mechanisms. We found that low Pi stress could inhibit the proliferation of activated hepatic stellate cells (HSCs) by promoting apoptosis, effectively suppressing the migration and epithelial-mesenchymal transition (EMT) of hepatic stellate cells. Additionally, low Pi stress significantly increased the antioxidant stress response. It is worth noting that low Pi stress indirectly inhibited the activation and migration of HSCs by suppressing transforming growth factor ß (TGF-ß) expression in macrophages. In a rat model of liver fibrosis, oral administration of sevelamer significantly decreased blood phosphorus levels, improved liver function, reduced liver inflammation, and increased the antioxidant stress response in the liver. Our study revealed that the key mechanism by which sevelamer inhibited liver fibrosis involved binding to gastrointestinal phosphate, resulting in a decrease in blood phosphorus levels, the downregulation of TGF-ß expression in macrophages, and the inhibition of HSC migration and fibrosis-related protein expression. Therefore, our results suggest that sevelamer-induced low Pi stress can attenuate hepatic stellate cell activation and inhibit the progression of liver fibrosis, making it a potential option for the treatment of liver fibrosis and other refractory chronic liver diseases.

Effectiveness of sucroferric oxyhydroxide in patients on on-line hemodiafiltration in real-world clinical practice: A retrospective study / Eficácia do oxihidróxido sucroférrico em pacientes em hemodiafiltração on-line na realidade da prática clínica: um estudo retrospectivo

Abstract Introduction: Hyperphosphatemia is a serious consequence of chronic kidney disease and has been associated with an increased risk for cardiovascular disease. Controlling serum phosphorus levels in patients on dialysis is a challenge for the clinicians and implies, in most cases, the use of phosphate binders (PB). Part of the reason for this challenge is poor adherence to treatment because of the high pill burden in this patient group. Objective: To assess the real-world effectiveness of sucroferric oxyhydroxide (SO) in controlling serum phosphorus levels and determine the associated pill burden. Methods: A multicenter, quantitative, retrospective, before-after study was conducted with patients receiving online hemodiafiltration. Patients who switched to SO as a part of routine care were included in the study. PB treatment, number of pills, serum phosphorus levels, and intravenous iron medication and dosage were collected monthly during the six months of treatment with either PB or SO. Results: A total of 42 patients were included in the study. After switching from a PB to SO, the prescribed pills/day was reduced 67% from 6 pills/day to 2 pills/day (p < 0.001) and the frequency of pill intake was lowered from 3 times/day to 2 times/day (p < 0.001). During the treatment with SO, the proportion of patients with serum phosphorus ≤ 5.5 mg/dL increased from 33.3% at baseline to 45% after six months of treatment. Conclusion: During the six-month follow-up with SO, serum phosphorus levels were controlled with one third of the pills/day compared to other PB.

Resumo Introdução: A hiperfosfatemia é uma grave consequência da doença renal crônica associada a risco aumentado de doença cardiovascular. O controle dos níveis séricos de fósforo dos pacientes em diálise é um desafio que requer, na maioria dos casos, o uso de quelantes de fosfato (QF). Parte da dificuldade se deve à baixa adesão ao tratamento oriunda do grande número de medicamentos receitados para esse grupo de pacientes. Objetivo: Avaliar a real eficácia do oxihidróxido sucroférrico (OHS) no controle dos níveis séricos de fósforo e determinar a carga de comprimidos associada. Métodos: Estudo multicêntrico, quantitativo, retrospectivo, antes e depois conduzido com pacientes em hemodiafiltração on-line. Pacientes remanejados para OHS como parte dos cuidados de rotina foram incluídos no estudo. Tratamento com QF, número de comprimidos, níveis séricos de fósforo, reposição férrica endovenosa e dosagens foram registrados mensalmente durante seis meses de tratamento com QF ou OHS. Resultados: Foram incluídos 42 pacientes no estudo. Após a mudança de QF para OHS, o número de comprimidos prescritos por dia caiu em 67%, de seis para duas unidades diárias (p < 0,001). A frequência de ingestão de comprimidos caiu de três para duas vezes ao dia (p < 0,001). Durante o tratamento com OHS, o percentual de pacientes com fósforo sérico ≤ 5,5 mg/dL aumentou de 33,3% no início para 45% após seis meses de tratamento. Conclusão: Durante os seis meses de seguimento com OHS, os níveis séricos de fósforo foram controlados com um terço dos comprimidos por dia em relação aos tratamentos com outros QF.

Cómo estimar la eficacia de un captor del fósforo / How to assess the efficacy of phosphate binders

Antecedentes y objetivos: Es difícil estimar clínicamente la eficacia de los captores de fósforo (CP). Este estudio analiza los cambios que se producen en la fosfatemia y excreción urinaria de fósforo tras la administración de CP a pacientes con enfermedad renal crónica, y la utilidad de la relación entre la excreción urinaria de fósforo y la tasa de catabolismo proteico (Po/TCP) en la estimación de la eficacia de estos fármacos. Métodos: Estudio retrospectivo de observación en una cohorte de pacientes adultos con enfermedad renal crónica en estadios 4-5. Se compararon parámetros bioquímicos basales y 45-60 días después de un tratamiento con dieta baja en fósforo más CP (subgrupo «captor»=260 pacientes) o solo con los consejos dietéticos (subgrupo «control»=79 pacientes). Resultados: La carga de fósforo (excreción urinaria total) por unidad de función renal (Po/GFR) fue el parámetro mejor relacionado con la fosfatemia (R2=0,61). La cifra media de Po/TCP fue de 8,2±2,3mg de fósforo por gramo de proteína. Tras la administración de CP, la fosfatemia descendió un 11%, la fosfaturia un 22%, la tasa de catabolismo proteico un 7% y la Po/TCP un 15%. En el subgrupo control la Po/TCP se incrementó un 20%. La excreción urinaria de fósforo y de nitrógeno ureico se correlacionaron fuertemente de forma lineal antes y después del tratamiento con CP o tras los consejos dietéticos en el subgrupo control. Conclusiones: La Po/TCP es un parámetro que podría reflejar la absorción intestinal de fósforo y, por tanto, sus variaciones tras la administración de CP podrían servir para estimar la eficacia de estos fármacos (AU)

Background and aims: The efficacy of phosphate binders is difficult to be estimated clinically. This study analyzes the changes in serum phosphate and urinary phosphate excretion after the prescription of phosphate binders (PB) in patients with chronic kidney disease stage 4-5 pre-dialysis, and the usefulness of the ratio between total urinary phosphate and protein catabolic rate (Pu/PCR) for estimating the efficacy of PB. Methods: This retrospective observational cohort study included adult chronic kidney disease patients. Biochemical parameters were determined baseline and after 45-60 days on a low phosphate diet plus PB (‘binder’ subgroup=260 patients) or only with dietary advice (‘control’ subgroup=79 patients). Results: Phosphate load (total urinary excretion) per unit of renal function (Pu/GFR) was the best parameter correlated with serum phosphate levels (R2=0.61). Mean±SD level of Pu/PCR was 8.2±2.3mg of urinary phosphate per each g of estimated protein intake. After treatment with PB, serum phosphate levels decreased by 11%, urinary phosphate 22%, protein catabolic rate 7%, and Pu/PCR 15%. In the control subgroup, Pu/PCR increased by 20%. Urinary phosphate and urea nitrogen excretion correlated strongly, both baseline and after PB or dietary advice. Conclusions: The proposed parameter Pu/PCR may reflect the rate of intestinal phosphate absorption, and therefore, its variations after PB prescription may be a useful tool for estimating the pharmacological efficacy of these drugs (AU)