Metabolic acidosis is common in kidney transplant recipients and is associated with declining graft function. Sodium bicarbonate treatment effectively corrects metabolic acidosis, but no prospective studies have examined its effect on graft function. Therefore, we aimed to test whether sodium bicarbonate treatment would preserve graft function and slow the progression of estimated glomerular filtration rate (GFR) decline in kidney transplant recipients. The Preserve-Transplant Study was a multicentre, randomised, single-blind, placebo-controlled, phase 3 trial at three University Hospitals in Switzerland (Zurich, Bern, and Geneva), which recruited adult (aged ≥18 years) male and female long-term kidney transplant recipients if they had undergone transplantation more than 1 year ago. Key inclusion criteria were an estimated GFR between 15 mL/min per 1·73 m and 89 mL/min per 1·73 m, stable allograft function in the last 6 months before study inclusion (<15% change in serum creatinine), and a serum bicarbonate of 22 mmol/L or less. We randomly assigned patients (1:1) to either oral sodium bicarbonate 1·5–4·5 g per day or matching placebo using web-based data management software. Randomisation was stratified by study centre and gender using a permuted block design to guarantee balanced allocation. We did multi-block randomisation with variable block sizes of two and four. Treatment duration was 2 years. Acid-resistant soft gelatine capsules of 500 mg sodium bicarbonate or matching 500 mg placebo capsules were given at an initial dose of 500 mg (if bodyweight was <70 kg) or 1000 mg (if bodyweight was ≥70 kg) three times daily. The primary endpoint was the estimated GFR slope over the 24-month treatment phase. The primary efficacy analyses were applied to a modified intention-to-treat population that comprised all randomly assigned participants who had a baseline visit. The safety population comprised all participants who received at least one dose of study drug. The trial is registered with , . Between June 12, 2017, and July 10, 2019, 1114 kidney transplant recipients with metabolic acidosis were assessed for trial eligibility. 872 patients were excluded and 242 were randomly assigned to the study groups (122 [50%] to the placebo group and 120 [50%] to the sodium bicarbonate group). After secondary exclusion of two patients, 240 patients were included in the intention-to-treat analysis. The calculated yearly estimated GFR slopes over the 2-year treatment period were a median –0·722 mL/min per 1·73 m (IQR –4·081 to 1·440) and mean –1·862 mL/min per 1·73 m (SD 6·344) per year in the placebo group versus median –1·413 mL/min per 1·73 m (IQR –4·503 to 1·139) and mean –1·830 mL/min per 1·73 m (SD 6·233) per year in the sodium bicarbonate group (Wilcoxon rank sum test p=0·51; Welch -test p=0·97). The mean difference was 0·032 mL/min per 1·73 m per year (95% CI –1·644 to 1·707). There were no significant differences in estimated GFR slopes in a subgroup analysis and a sensitivity analysis confirmed the primary analysis. Although the estimated GFR slope did not show a significant difference between the treatment groups, treatment with sodium bicarbonate effectively corrected metabolic acidosis by increasing serum bicarbonate from 21·3 mmol/L (SD 2·6) to 23·0 mmol/L (2·7) and blood pH from 7·37 (SD 0·06) to 7·39 (0·04) over the 2-year treatment period. Adverse events and serious adverse events were similar in both groups. Three study participants died. In the placebo group, one (1%) patient died from acute respiratory distress syndrome due to SARS-CoV-2 and one (1%) from cardiac arrest after severe dehydration following diarrhoea with hypotension, acute kidney injury, and metabolic acidosis. In the sodium bicarbonate group, one (1%) patient had sudden cardiac death. In adult kidney transplant recipients, correction of metabolic acidosis by treatment with sodium bicarbonate over 2 years did not affect the decline in estimated GFR. Thus, treatment with sodium bicarbonate should not be generally recommended to preserve estimated GFR (a surrogate marker for graft function) in kidney transplant recipients with chronic kidney disease who have metabolic acidosis. Swiss National Science Foundation.

中文翻译：

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碳酸氢钠治疗瑞士肾移植受者代谢性酸中毒：一项多中心、随机、单盲、安慰剂对照的 3 期试验

代谢性酸中毒在肾移植受者中很常见，并且与移植物功能下降有关。碳酸氢钠治疗可有效纠正代谢性酸中毒，但尚无前瞻性研究探讨其对移植物功能的影响。因此，我们的目的是测试碳酸氢钠治疗是否会保留肾移植受者的移植物功能并减缓估计肾小球滤过率（GFR）下降的进展。保存-移植研究是在瑞士三所大学医院（苏黎世、伯尔尼和日内瓦）进行的一项多中心、随机、单盲、安慰剂对照 3 期试验，招募了成年（年龄≥18 岁）男性和女性- 足月肾移植受者，如果他们在一年多前接受过移植。主要纳入标准是估计 GFR 介于每 1·73 m 15 mL/min 和每 1·73 m 89 mL/min 之间、研究纳入前最后 6 个月的同种异体移植功能稳定（血清肌酐变化 <15%），以及血清碳酸氢盐为 22 mmol/L 或更低。我们使用基于网络的数据管理软件将患者随机分配（1:1），每天口服碳酸氢钠 1·5–4·5 g 或匹配安慰剂。使用置换区组设计按研究中心和性别对随机化进行分层，以保证平衡分配。我们使用可变块大小为 2 和 4 进行多块随机化。治疗时间为2年。500 mg 碳酸氢钠耐酸软明胶胶囊或配套的 500 mg 安慰剂胶囊，初始剂量为 500 mg（如果体重<70 kg）或 1000 mg（如果体重≥70 kg），每日 3 次。主要终点是 24 个月治疗阶段的估计 GFR 斜率。主要疗效分析适用于修改后的意向治疗人群，其中包括所有随机分配的基线访视参与者。安全人群包括接受至少一剂研究药物的所有参与者。该试验已在 , 注册。2017年6月12日至2019年7月10日期间，对1114名患有代谢性酸中毒的肾移植受者进行了试验资格评估。872 名患者被排除，242 名患者被随机分配到研究组（122 名 [50%] 分配到安慰剂组，120 名 [50%] 分配到碳酸氢钠组）。二次排除两名患者后，240 名患者被纳入意向治疗分析。在 2 年治疗期间计算出的每年估计 GFR 斜率中位数为 –0·722 mL/min 每 1·73 m（IQR –4·081 至 1·440），平均值为 –1·862 mL/min 每 1安慰剂组每年 73 m (SD 6·344)，而中位数为每 1·73 m –1·413 mL/min（IQR –4·503 至 1·139），平均值为每 1·830 mL/min碳酸氢钠组每年 1·73 m (SD 6·233)（Wilcoxon 秩和检验 p=0·51；Welch 检验 p=0·97）。平均差异为每年每 1·73 m 0·032 mL/min（95% CI –1·644 至 1·707）。亚组分析中估计的 GFR 斜率没有显着差异，敏感性分析证实了主要分析。尽管估计的 GFR 斜率在治疗组之间没有显示出显着差异，但碳酸氢钠治疗通过将血清碳酸氢盐从 21·3 mmol/L (SD 2·6) 增加至 23·0 mmol/L (2 ·7) 和血液 pH 值在 2 年治疗期间从 7·37 (SD 0·06) 降至 7·39 (0·04)。两组的不良事件和严重不良事件相似。三名研究参与者死亡。在安慰剂组中，一名 (1%) 患者死于 SARS-CoV-2 引起的急性呼吸窘迫综合征，一名 (1%) 患者因腹泻伴低血压、急性肾损伤和代谢性酸中毒后严重脱水而导致心脏骤停。在碳酸氢钠组中，一名（1%）患者出现心源性猝死。在成年肾移植受者中，通过碳酸氢钠治疗纠正代谢性酸中毒超过 2 年不会影响估计 GFR 的下降。因此，对于患有慢性肾病且患有代谢性酸中毒的肾移植受者，一般不建议使用碳酸氢钠治疗来保留估计的 GFR（移植物功能的替代标志物）。瑞士国家科学基金会。