這篇發表於排尿障礙權威期刊的 2025 年國際禁尿學會研究學社（ICI-RS）智庫前瞻報告，針對臨床上極具挑戰性的特發性夜尿症（Idiopathic Nocturia），基於「腦—腎—膀胱軸」的創新概念，系統性地剖析了三大具備臨床轉化潛力的前沿治療方向，為泌尿科醫師、護理師與技術員等專業同仁，提供了突破現行治療瓶頸的學術思維。

現行的夜尿症常規藥物治療，如去氨加壓素（Desmopressin），雖能減少夜間尿量，但在改善高齡患者的實質睡眠品質上往往未達預期，且面臨高達 11% 的低鈉血症風險，臨床應用受限。為此，醫學界開始探討調節「睡眠—覺醒週期」的介入成效。文獻實證顯示，褪黑激素受體激動劑（如 Ramelteon）或新型雙食慾素受體拮抗劑（如 Lemborexant、Daridorexant）能大幅延長第一段不間斷睡眠時間（Time to first nocturia episode）。在非藥物領域，特定波長的定時光照療法（如調控藍光暴露），正被研究用於恢復視交叉上核的中央時鐘節律，以期引導自主神經降低夜間膀胱的敏感度。

在「腎外水分重吸收」的機制探討上，本篇研究打破了傳統認為膀胱壁完全不透水的醫學既定印象。臨床 3D 超音波與微觀磁振造影證實，人類膀胱在夜間能透過副細胞擴散與移行上皮內的水通道蛋白（如 AQP3），主動將尿液中的水分重吸收入體循環，以維持血容積穩定。當此通道失調時，便可能引發夜間多尿。更受矚目的臨床進展是小分子 vasopressin V2 受體激動劑 Fedovapagon，臨床試驗已證實其能減少 50% 的夜尿次數。其多靶點機制不僅能作用於腎集合管減少尿液形成，更能直接作用於膀胱壁的 V2 受體，啟動膀胱水分重吸收，同時放鬆逼尿肌平滑肌、抑制由 acrolein 誘發的膀胱過動症狀，在單一藥物中同時解決了夜間多尿與夜間尿急的雙重難題。

最後，針對膀胱周邊時鐘與時間生物學的臨床介入，更是未來精準醫療的核心。研究發現，膀胱黏膜與逼尿肌具有獨立於大腦的自主時鐘基因節律，控制著夜間機械感覺通道（如 Piezo1、TRPV4）的敏感度以及自發性收縮，使健康人在夜間的傳入神經活動與 ATP 釋放自然降低。當此周邊節律因高血壓或高鹽飲食而紊亂時，便會造成夜間膀胱儲尿功能障礙。未來透過針對膀胱組織特異性的「時辰療法（Chronotherapies）」，如利用特定時間給予糖皮質激素或局部受體調節劑來重置盆腔器官時鐘，將可望根治因節律失調引起的難治性夜尿。這些奠基於分子生物學與臨床轉化的新興療法，正逐步建立起多學科合作的診治新地平線。

Background: Nocturia is a prevalent condition with systematic etiologies which require multidisciplinary collaborations during diagnosis and management. Here we evaluate current evidence and present unresolved research questions regarding the three key pathophysiological domains of nocturia with respect to a conceptual brain-kidney-bladder axis, namely sleep enhancement, extra-renal water reabsorption and circadian regulation of bladder tissue.

Methods: A Think Tank was convened at the 12th International Consultation on Incontinence Research Society meeting in June 2025, looking at novel therapeutic targets for nocturia. This article synthesizes key deliberations from this meeting session.

Results: The discussion was mainly focused on idiopathic nocturia with an overactive bladder symptom complex or nocturnal polyuria. Firstly, medications and conservative nondrug measures targeting sleep that could potentially improve nocturia were considered. Secondly, investigation of water reabsorption mechanisms within the bladder and the role of small molecule vasopressin receptor type-2 agonists were examined that may provide novel therapeutic options to rectify nocturnal polyuria. Finally, to address circadian misalignments, organ specific chronotherapies, based on abnormal circadian features of bladder tissues that can be curative for nocturia, were discussed.

Conclusions: The evidence indicates that promising therapeutic modalities targeting the regulation of sleep-wake cycles, intravesical water transport mechanisms, and circadian patterns of detrusor activity may offer alternative strategies for managing nocturnal polyuria. However, further mechanistic investigations and randomized controlled trials are required to advance these approaches toward clinical translation.