Scholtes Rosalie A, Muskiet Marcel H A, van Baar Michiel J B, Hesp Anne C, Greasley Peter J, Hammarstedt Ann, Karlsson Cecilia, Hallow Karen M, Danser A H Jan, Heerspink Hiddo J L, van Raalte Daniël H
Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VU University Medical Center, Amsterdam, The Netherlands.
Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Kidney Int Rep. 2022 Mar 4;7(5):1084-1092. doi: 10.1016/j.ekir.2022.02.023. eCollection 2022 May.
Proximal tubule sodium uptake is diminished following sodium glucose cotransporter 2 (SGLT2) inhibition. We previously showed that during SGLT2 inhibition, the kidneys adapt by increasing sodium uptake at distal tubular segments, thereby maintaining body sodium balance. Despite continuous glycosuria, we detected no increased urine volumes. We therefore assessed the adaptive renal responses to prevent excessive fluid loss.
We conducted a mechanistic open-label study in people with type 2 diabetes mellitus with preserved kidney function, who received a standardized sodium intake (150 mmol/d) to evaluate the effects of dapagliflozin on renin-angiotensin-aldosterone system (RAAS) hormones, volume-related biomarkers, urinary albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR), at start of treatment (day 4), end of treatment (day 14), and follow-up (day 18).
A total of 14 people were enrolled. Plasma renin and angiotensin II and urinary aldosterone and angiotensinogen were acutely and persistently increased during treatment with dapagliflozin. Plasma copeptin level was numerically increased after 4 days (21%). Similarly, fractional urea excretion was significantly decreased at start of treatment (-17%). Free water clearance was significantly decreased after 4 days (-74%) and 14 days (-41%). All changes reversed after dapagliflozin discontinuation.
Dapagliflozin-induced osmotic diuresis triggers kidney adaptive mechanisms to maintain volume and sodium balance in people with type 2 diabetes and preserved kidney function. ClinicalTrials.gov (identification: NCT03152084).
钠葡萄糖协同转运蛋白2（SGLT2）受抑制后，近端肾小管对钠的摄取减少。我们之前发现，在SGLT2受抑制期间，肾脏会通过增加远端肾小管段对钠的摄取来进行适应性调节，从而维持机体钠平衡。尽管持续存在糖尿，但我们并未检测到尿量增加。因此，我们评估了肾脏的适应性反应以防止过多液体流失。
我们对肾功能正常的2型糖尿病患者进行了一项开放标签的机制性研究，这些患者接受标准化钠摄入量（150 mmol/d），以评估达格列净在治疗开始时（第4天）、治疗结束时（第14天）和随访时（第18天）对肾素-血管紧张素-醛固酮系统（RAAS）激素、容量相关生物标志物、尿白蛋白与肌酐比值（UACR）以及估计肾小球滤过率（eGFR）的影响。
共纳入14人。在使用达格列净治疗期间，血浆肾素、血管紧张素II以及尿醛固酮和血管紧张素原均急性且持续升高。4天后血浆 copeptin 水平在数值上有所升高（21%）。同样，治疗开始时尿素排泄分数显著降低（-17%）。4天后（-74%）和14天后（-41%）自由水清除率显著降低。停用达格列净后所有变化均逆转。
达格列净诱导的渗透性利尿触发肾脏适应性机制，以维持2型糖尿病且肾功能正常患者的容量和钠平衡。ClinicalTrials.gov（标识符：NCT03152084）
