Oral Sodium Bicarbonate to Slow Chronic Kidney Disease Progression

口服碳酸氢钠可减缓慢性肾脏病的进展

• 批准号: 8586209
• 负责人: Alfred K Cheung
• 金额: $ 30.57万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586209
• 关键词: Acidosis; Acids; Adverse effects; Albumins; Alkalies; Ancillary Study; Animals; Bicarbonates; Biological Markers; Blood Pressure; Body Weight; Calcium; Catabolism; Chronic; Chronic Kidney Failure; Clinical; Clinical Data; Clinical Research; Clinical Trials; Complement Activation; Coronary artery; Disease Progression; Dose; Endothelin-1; Excretory function; Future; Generations; Glomerular Filtration Rate; Glucosaminidase; Injury; Intervention; Intervention Trial; Kidney; Kidney Diseases; Kidney Failure; Literature; Measures; Mediator of activation protein; Metabolic acidosis; National Institute of Diabetes and Digestive and Kidney Diseases; Oral; Outcome; Patients; Pilot Projects; Placebos; Practice Guidelines; Production; Proteins; Public Health; Randomized; Renal function; Safety; Scanning; Serum; Sodium Bicarbonate; Staging; Subgroup; Suggestion; Testing; Texas; Urine; Utah; Vascular calcification; Weight; X-Ray Computed Tomography; activation product; arm; base; blind; bone; clinical care; clinical practice; clinically significant; coronary artery calcification; demineralization; design; follow-up; pill; premature; prevent; public health relevance; randomized trial; symposium; urinary

DESCRIPTION (provided by applicant): The decline in kidney function is unrelenting in many patients with chronic kidney disease (CKD) despite current therapies. Animal studies show that a systemic acid load induces kidney generation of pro-fibrotic mediators and kidney injury. Single-center clinical studies have further found that chronic alkali treatment, such as with oral sodium bicarbonate, is renoprotective in people with low, or even normal, serum bicarbonate concentrations. These promising results are underscored by the emphasis of this therapy as a potential clinical trial intervention in a 2011 NIDDK Conference and the specific suggestion by the present RFA. Before a large definitive trial can be undertaken, however, it is important to examine carefully the tolerability, compliance and safety features of various doses of oral bicarbonate. The present application for a pilot study is designed precisely for this purpose. In a two-center, single-blind pilot study, 140 patients with albuminuric stage 3-4 CKD and low-to-normal serum bicarbonate concentrations (20 - 26 meq/L) will be randomly assigned to one of three treatment arms: (i) low- dose oral sodium bicarbonate (0.4 meq/kg lean body weight/day; n = 52), (ii) high-dose oral sodium bicarbonate (0.7 meq/kg lean body weight/day; n = 52), or (iii) placebo for one-year. The major objectives are to assess: (i) the tolerability and compliance of low-dose and high-dose sodium bicarbonate by performing pill counts and measuring changes in urinary net acid excretion (NAE), (ii) the safety profile of low-dose and high- dose sodium bicarbonate using clinical parameters, such as blood pressure, and coronary artery calcium score assessed by computed tomography scan, and (iii) the efficacy of low-dose and high-dose sodium bicarbonate on two kidney-injury biomarkers (albumin and N-acetyl-¿-D-glucosaminidase) in the urine. Built into this parallel design is an initial one-month period to determine the relationship between various bicarbonate doses (0.2 - 0.7 meq/kg lean body weight/day) and urinary NAE in a pragmatic setting. The results from this pilot study will help to design the large, definitive trial by delineating the tolerability, compliance, and safety featuresof two rational doses of chronic oral sodium bicarbonate therapy. While the intermediate efficacy (urinary biomarker) results of this pilot study will also be informative, inconclusive efficacy results will not preclude the planning of a large trial, since positive results using glomerular filtration rate as an outcome have already been demonstrated in previous small trials. Chronic oral sodium bicarbonate is a promising adjunct therapy to slow CKD. If its renoprotective effects can be demonstrated in a large definitive trial, the broad applicability of this inexpensive therap will significantly transform clinical practice and have major public health implications.

描述（由申请人提供）：尽管采用了目前的治疗方法，但许多慢性肾病（CKD）患者的肾功能衰退仍在持续。动物研究表明，全身酸负荷会诱导肾脏产生促纤维化介质和肾损伤。单中心临床研究进一步发现，慢性碱治疗（例如口服碳酸氢钠）对于血清碳酸氢盐浓度低甚至正常的人具有肾脏保护作用。 2011 年 NIDDK 会议强调该疗法作为潜在的临床试验干预措施，以及当前 RFA 的具体建议，强调了这些有希望的结果。然而，在进行大规模的确定性试验之前，仔细检查各种剂量的口服碳酸氢盐的耐受性、依从性和安全性特征非常重要。本试点研究申请正是为此目的而设计的。在一个 两中心、单盲试点研究，140 名蛋白尿 3-4 期 CKD 和血清碳酸氢盐浓度低至正常 (20 - 26 meq/L) 的患者将被随机分配至三个治疗组之一：(i) 低剂量口服碳酸氢钠（0.4 meq/kg 去脂体重/天；n = 52），(ii) 高剂量口服碳酸氢钠 （0.7 meq/kg 去脂体重/天；n = 52），或 (iii) 安慰剂一年。主要目标是评估：（i）通过进行药丸计数和测量尿净酸排泄（NAE）的变化来评估低剂量和高剂量碳酸氢钠的耐受性和依从性，（ii）使用临床参数（例如血压和通过计算机断层扫描评估的冠状动脉钙评分）来评估低剂量和高剂量碳酸氢钠的安全性，以及（iii） 低剂量和高剂量碳酸氢钠对尿液中两种肾损伤生物标志物（白蛋白和 N-乙酰-¿-D-氨基葡萄糖苷酶）的功效。该并行设计中包含初始一个月的时间，以确定在务实环境中各种碳酸氢盐剂量（0.2 - 0.7 meq/kg 去脂体重/天）与尿 NAE 之间的关系。这项试点研究的结果将通过描述两种合理剂量的慢性口服碳酸氢钠疗法的耐受性、依从性和安全性特征，将有助于设计大型、明确的试验。虽然这项试点研究的中间功效（尿液生物标志物）结果也将提供信息，但不确定的功效结果不会妨碍大型试验的计划，因为使用肾小球滤过率作为结果的积极结果已经在之前的小型试验中得到证实。长期口服碳酸氢钠是一种很有前景的减缓 CKD 的辅助疗法。如果其肾脏保护作用能够在大型确定性试验中得到证实，那么这种廉价疗法的广泛适用性将显着改变临床实践，并对公共卫生产生重大影响。