Wu Aihua, Wolley Martin J, Vesey David, Terker Andrew S, Welling Paul A, Fenton Robert A, Stowasser Michael
Endocrine Hypertension Research Centre, The University of Queensland Frazer Institute, Greenslopes and Princess Alexandra Hospitals, Brisbane, Australia.
Department of Medicine, Vanderbilt University Medical Centre, Nashville, Tennessee, USA.
Nephrology (Carlton). 2025 Mar;30(3):e70017. doi: 10.1111/nep.70017.
Using urinary extracellular vesicles (uEVs), we have demonstrated the functional 'renal-K switch' mechanism (the WNK-SPAK-NCC pathway) in both healthy subjects and those with primary aldosteronism. The close relationship between blood pressure and CKD has led to the hypothesis that high potassium intake may be reno-protective through the same mechanism. This study used uEVs to evaluate whether plasma potassium negatively correlates with NCC and its phosphorylation (pNCC) in patients with CKD.
Morning blood and second morning urine were collected on a single occasion between 8 and 11 AM from patients with various CKD stages. Plasma potassium levels were assessed by a local pathology laboratory. uEVs were obtained by progressive ultracentrifugation, and NCC and pNCC were analysed by western blotting.
Correlation analyses among 23 patients with CKD revealed the abundance of NCC (R = 0.46, p = 0.0003) and pNCC (R = 0.30, p = 0.0067) strongly and negatively correlate with plasma potassium. The negative correlations persist among 18 patients who did not receive SGLT2 inhibitors or K-binders (NCC: R = 0.5, p = 0.002; pNCC: R = 0.30, p = 0.03) and the negative trends remain among 5 patients who received either SGLT2 inhibitors or K-binders (NCC: R = 0.64, p = 0.11; pNCC: R = 0.42, p = 0.24).
In patients with CKD, there are negative correlations between NCC and pNCC in uEVs and plasma potassium, which appear independent of eGFR. This suggests that the mechanism at play is distinct from the overall kidney function, and potassium supplement within a safe level may assist in natriuresis and improve cardiovascular outcomes.
通过尿细胞外囊泡（uEVs），我们已在健康受试者和原发性醛固酮增多症患者中证实了功能性“肾-钾开关”机制（WNK-SPAK-NCC途径）。血压与慢性肾脏病（CKD）之间的密切关系引发了这样的假设，即高钾摄入可能通过相同机制对肾脏起到保护作用。本研究使用uEVs来评估CKD患者血浆钾水平是否与NCC及其磷酸化（pNCC）呈负相关。
在上午8点至11点之间一次性收集处于不同CKD阶段患者的晨尿和次日晨尿。血浆钾水平由当地病理实验室评估。通过逐步超速离心获得uEVs，并用蛋白质免疫印迹法分析NCC和pNCC。
对23例CKD患者的相关性分析显示，NCC丰度（R = 0.46，p = 0.0003）和pNCC丰度（R = 0.30，p = 0.0067）与血浆钾呈强负相关。在未接受钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂或钾结合剂的18例患者中，这种负相关仍然存在（NCC：R = 0.5，p = 0.002；pNCC：R = 0.30，p = 0.03），而在接受SGLT2抑制剂或钾结合剂的5例患者中，负相关趋势仍然存在（NCC：R = 0.64，p = 0.11；pNCC：R = 0.42，p = 0.24）。
在CKD患者中，uEVs中的NCC和pNCC与血浆钾之间存在负相关，且这一关系似乎独立于估算肾小球滤过率（eGFR）。这表明所涉及的机制与整体肾功能不同，在安全水平内补充钾可能有助于利钠并改善心血管结局。
