Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.
Department of Cardiovascular, Respiratory, Nephrologic, Anesthetic and Geriatric Sciences, Sapienza University of Rome, Rome, Italy.
Am J Kidney Dis. 2019 Sep;74(3):338-350. doi: 10.1053/j.ajkd.2019.01.029. Epub 2019 Apr 23.
RATIONALE & OBJECTIVE: Hyperphosphatemia is associated with increased risk for chronic kidney disease (CKD) progression and reduced antiproteinuric effects of renin-angiotensin system (RAS) blockers. We investigated whether the phosphate binder sevelamer carbonate may enhance the antiproteinuric effect of RAS inhibitors in patients with CKD.
Phase 2, randomized, controlled, open-label, crossover trial.
SETTING & PARTICIPANTS: Between November 2013 and December 2014, we enrolled 53 patients with CKD with estimated glomerular filtration rates (eGFRs)>15mL/min/1.73m and residual proteinuria with protein excretion≥0.5g/24h despite maximal tolerated ramipril and/or irbesartan therapy from 2 nephrology units in Italy.
After stratification by serum phosphate level, ≤4 or>4mg/dL, patients were randomly assigned to 3 months of sevelamer (1,600mg thrice daily) treatment followed by 3 months without sevelamer separated by a 1-month washout period or 3 months without sevelamer followed by 3 months with sevelamer, also separated by a 1-month washout period.
The primary outcome was 24-hour proteinuria (n=49patients). Secondary outcomes included measured GFR (using iohexol plasma clearance), office blood pressure (BP), serum lipid levels, levels of inflammation and bone metabolism biomarkers, urinary electrolyte levels, and arterial stiffness.
Changes in proteinuria during the 3-month treatment with (from 1.36 [IQR, 0.77-2.51] to 1.36 [IQR, 0.77-2.60] g/24h) or without (from 1.36 [IQR, 0.99-2.38] to 1.48 [IQR, 0.81-2.77] g/24h) sevelamer were similar (P=0.1). Sevelamer reduced urinary phosphate excretion without affecting serum phosphate levels. Sevelamer reduced C-reactive protein (CRP), glycated hemoglobin, and total and low-density lipoprotein cholesterol levels and increased high-density lipoprotein cholesterol levels without affecting levels of office BP, measured GFR, fibroblast growth factor 23, klotho, intact parathyroid hormone, serum vitamin D, or other urinary electrolytes. Results were similar in the low- and high-phosphate groups. Sevelamer was well tolerated. Adverse events were comparable between treatment periods. One case of transient hypophosphatemia was observed during treatment with sevelamer.
Short treatment duration, lower pretreatment proteinuria than expected.
3-month sevelamer treatment did not reduce proteinuria in patients with CKD on maximal RAS blockade. Amelioration of inflammation and dyslipidemia with sevelamer treatment raises the possibility that it may confer benefit in patients with CKD beyond reduction of proteinuria.
Sanofi (Milan, Italy).
Registered at ClinicalTrials.gov with study number NCT01968759.
高磷血症与慢性肾脏病（CKD）进展风险增加以及肾素-血管紧张素系统（RAS）抑制剂的降蛋白尿作用降低有关。我们研究了磷结合剂碳酸钙司维拉姆是否可以增强 RAS 抑制剂在 CKD 患者中的降蛋白尿作用。
这是一项 2 期、随机、对照、开放标签、交叉试验。
2013 年 11 月至 2014 年 12 月，我们从意大利的 2 个肾脏病单位招募了 53 名估计肾小球滤过率（eGFR）>15mL/min/1.73m 且尽管接受了最大耐受剂量雷米普利和/或厄贝沙坦治疗仍有蛋白尿残留（蛋白排泄≥0.5g/24h）的 CKD 患者。
根据血清磷水平分层，≤4 或>4mg/dL，患者被随机分配接受 3 个月的碳酸钙司维拉姆（每日 3 次，每次 1600mg）治疗，然后无碳酸钙司维拉姆治疗 3 个月，其间有 1 个月洗脱期，或无碳酸钙司维拉姆治疗 3 个月，然后有碳酸钙司维拉姆治疗 3 个月，其间也有 1 个月洗脱期。
24 小时蛋白尿（n=49 名患者）。次要结局包括测量肾小球滤过率（使用 iohexol 血浆清除率）、诊室血压（BP）、血清脂质水平、炎症和骨代谢生物标志物水平、尿电解质水平以及动脉僵硬度。
接受碳酸钙司维拉姆治疗 3 个月期间（从 1.36[IQR，0.77-2.51]降至 1.36[IQR，0.77-2.60]g/24h）或无碳酸钙司维拉姆治疗 3 个月期间（从 1.36[IQR，0.99-2.38]降至 1.48[IQR，0.81-2.77]g/24h）的蛋白尿变化相似（P=0.1）。碳酸钙司维拉姆降低了尿磷排泄，而不影响血清磷水平。碳酸钙司维拉姆降低了 C 反应蛋白（CRP）、糖化血红蛋白以及总胆固醇和低密度脂蛋白胆固醇水平，并增加了高密度脂蛋白胆固醇水平，而不影响诊室血压、测量肾小球滤过率、成纤维细胞生长因子 23、klotho、完整甲状旁腺激素、血清维生素 D 或其他尿电解质水平。在低磷组和高磷组中结果相似。碳酸钙司维拉姆耐受良好。治疗期间的不良事件相似。在接受碳酸钙司维拉姆治疗期间观察到 1 例短暂性低磷血症。
治疗时间短，预处理蛋白尿低于预期。
3 个月的碳酸钙司维拉姆治疗不能降低最大 RAS 阻断治疗的 CKD 患者的蛋白尿。碳酸钙司维拉姆治疗改善炎症和血脂异常，提示其可能除了降低蛋白尿外，还能在 CKD 患者中带来益处。
赛诺菲（意大利米兰）。
ClinicalTrials.gov 注册，编号为 NCT01968759。
