原發性高醛固酮症接受腎上腺切除的臨床預後:探討KCNJ5基因組突變和三甲胺氧化物在單側分泌原發性高醛固酮症所扮演的角色

Abstract

腎素-血管張力素-醛固酮系統（renin-angiotensin-aldosterone system, RAAS）在調節血容量、血中鈉濃度和血壓方面扮演著重要角色。高血壓影響全球超過14億成年人，且會影響人體全身的器官功能，是很重要的健康議題。醛固酮是RAAS的一部分，對維持血中鈉濃度、血容量和血壓的穩定性至關重要。 原發性高醛固酮症（primary aldosteronism, PA）首次由Jerome Conn於1954年發現，是次發性高血壓主要的原因之一，其特徵是不受腎素調控的醛固酮分泌過多。這種情況會導致鈉滯留、血容量增加、高血壓和低鉀血症。PA在嚴重或難治性高血壓以及伴有心房顫動或糖尿病的患者中發病率較高。 人體內高醛固酮血症與多種器官的不良影響有關，它會影響心臟、血管、大腦和腎臟等功能。PA還與胰島素敏感性降低和代謝綜合群及第2型糖尿病的風險增加有關。通過單側腎上腺切除術治療單側分泌PA (uPA)或使用礦物皮質素受體拮抗劑治療雙側分泌PA，可以有效降低血壓以及心血管、腦血管和腎臟併發症的風險。雖然單側腎上腺切除術目前是uPA患者的標準治療方法，但一些患者在腎上腺切除術後仍然患有高血壓或需要高血壓藥物的治療。因此，目前仍需更多的研究來闡明uPA患者在腎上腺切除術後未能完全緩解高血壓的原因並找出可能的預測因子來制定不同的術後追蹤計畫。同時，目前對於uPA患者術後長期預後的資料仍很缺乏，這也是很值得研究的主題。 我們的研究希望能找出uPA患者術後血壓控制和長期預後的預測因子以其制定個別化的追蹤計畫並對PA的病生理機轉有更進一步的了解。我們假設PA患者的不同基因變異可能會影響uPA患者的臨床表現以及在單側腎上腺切除術後的治療結果（血壓控制）和長期預後（心血管疾病和代謝症候群的發生）。我們進一步假設，uPA患者不同的基因變異可能通過消化道微生物相與其代謝產物 [三甲胺氧化物，Trimethylamine-N-oxide (TMAO)]來影響uPA患者的臨床表現，並可能與uPA患者術後的血壓控制以及心血管疾病和糖尿病的發生有關。 我們研究分析了358名接受單側腎上腺切除術的uPA患者，分析了他們臨床特徵和手術後的長期預後，同時也分析了他們的消化道微生物相及其TMAO血中濃度。我們的患者平均年齡為51.3±11.3歲，其中46.7%為男性，52.5%的患者帶有KCNJ5突變。與未有KCNJ5突變的患者相比，攜帶KCNJ5突變的患者年齡較小，有較低的糖尿病、代謝綜合群和高脂血症的患病率。同時，他們的血漿腎素活性和血中鉀離子濃度較低，但有較高的血中醛固酮濃度、腎絲球濾過率和蛋白尿的嚴重度。 在平均5.4±3.5年的追蹤時間中，攜帶KCNJ5突變的uPA患者在腎上腺切除術後一年內達到血壓良好控制的比例較高，且其死亡率和心腦血管疾病及新發糖尿病的發生率也較低。在多變量邏輯回歸分析中，我們也發現年齡、身體質量指數、血中鉀離子濃度和腫瘤大小是有否攜帶KCNJ5突變的預測因子。而與術後血壓控制成功與否的預測因子包括是否攜帶KCNJ5突變、高eGFR、較低的身體質量指數、較低的收縮壓和血中鉀離子濃度以及較短的高血壓患病時程。同時，在多變量回歸分析中也發現，攜帶KCNJ5突變的患者在長期追蹤中也有較佳的長期預後，包括有較低的死亡風險，較低的心血管疾病和新發生糖尿病的發生率。 在消化道微生物相的分析中，我們的研究結果發現uPA患者和原發性高血壓患者之間不論是在菌叢的豐富性或多樣性的部分都存在顯著差異。我們的研究也發現，uPA患者中的血中TMAO濃度比原發性高血壓族群高，且在uPA患者中，血中TMAO濃度也與心血管風險相關。腎上腺切除術似乎可以降低攜帶KCNJ5突變的uPA患者血中TMAO濃度，但在非攜帶KCNJ5突變的uPA患者中，TMAO的濃度在術後並沒有顯著的降低。 在這個研究中，我們發現攜帶KCNJ5突變的uPA患者在術後也更好的血壓控制與長期預後，包括較低的死亡率與較低的心腦血管疾病和新發糖尿病的發生率。根據我們的研究結果，我們建議非攜帶KCNJ5突變的uPA患者和具有特定臨床特徵的uPA患者在腎上腺切除術後可能需要更頻繁評估心腦血管的功能和追蹤血糖。我們的研究也發現，未來需要更進一步的研究來闡明消化道微生物相和血中TMAO濃度與uPA患者心血管風險與基因變異之間的關係。

The renin-angiotensin-aldosterone system is pivotal in regulating blood volume, plasma sodium levels, and mean arterial pressure. As a result, it is a central component in managing arterial hypertension (HTN). Affecting over 1.4 billion adults worldwide and contributing to 7% of global disability-adjusted life years, HTN represents a significant global health challenge. Aldosterone is part of the RAAS, which is important for maintaining homeostasis of plasma sodium concentration, blood volume, and mean arterial blood pressure. Primary aldosteronism (PA), first identified by Jerome Conn in 1954, is a leading form of secondary HTN characterized by excessive aldosterone production independent of renin. This condition increases sodium retention, volume expansion, elevated blood pressure, and hypokalemia. The incidence of PA is higher among patients with severe or resistant HTN and those with comorbid conditions such as atrial fibrillation or diabetes mellitus (DM). Elevated aldosterone levels in PA are associated with adverse effects on various organs, including the heart, blood vessels, brain, and kidneys. PA is also linked to reduced insulin sensitivity and a higher risk of metabolic syndrome and type 2 diabetes. Effective treatment of PA, through either adrenalectomy for unilateral cases or MRAs for bilateral cases, can reduce the risk of cardiovascular, cerebrovascular, and renal complications. Although adrenalectomy is currently the standard treatment for patients with unilateral PA (uPA), some patients remain hypertensive or require antihypertensive medications after adrenalectomy. Further investigation is essential to elucidate the predisposing factors and underlying pathophysiology that contribute to the variable rates of complete remission observed among patients with uPA following adrenalectomy. This investigation assessed the extended-term consequences linked with predictive factors in PA. Our hypothesis posited that the interplay among genetic variants may influence the clinical presentations, treatment outcomes (blood pressure control), and long-term consequences (cardiovascular/metabolic outcomes) in pre- and post-unilateral adrenalectomy patients with uPA. Additionally, we proposed that genetic variants could modulate the formation of gut microbiome-related metabolites, specifically trimethylamine-N-oxide (TMAO), via the gut microbiome and may be associated with cardiovascular and metabolic comorbidities in patients with uPA. This study analyzed the baseline characteristics and outcomes of 358 uPA patients who underwent adrenalectomy. The cohort's mean age was 51.3±11.3 years, with 46.7% male and 52.5% carrying KCNJ5 mutations. Individuals carrying the KCNJ5 mutation were observed to be younger, with a lower prevalence of DM, metabolic syndrome, and hyperlipidemia. Additionally, they exhibited lower plasma renin activity and serum potassium but higher plasma aldosterone concentration, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio compared to non-KCNJ5 carriers. The uPA patients with KCNJ5 mutations exhibited a higher rate of complete clinical success (odds ratio [OR]=1.98; 95% confidence interval [CI], 1.14-3.46; P=0.016) six months to one-year post-adrenalectomy and a lower incidence of mortality and major adverse cardiac and cerebrovascular events (MACCEs) (hazard ratio [HR]=0.46; 95% CI, 0.22-0.98; P=0.044) during a mean follow-up of 5.4±3.5 years. They also had a lower incidence of new-onset DM (HR=0.36; 95% CI, 0.14-0.97; P=0.04). Multivariable logistic regression identified age, body mass index (BMI), potassium, and tumor size as predictors of KCNJ5 mutations. Factors associated with complete clinical success included KCNJ5 mutations, high eGFR, lower BMI, systolic blood pressure, serum potassium level, and shorter HTN duration. Patients with KCNJ5 mutations exhibited a reduced risk of MACCEs and mortality during long-term follow-up. Additionally, carriers of the KCNJ5 mutation showed a lower incidence of new-onset DM. In gut microbiome analysis, our results revealed significant differences between uPA and essential HTN patients, with specific bacteria associated with each condition. The study found that circulating TMAO levels were linked to cardiovascular risks in uPA cohorts. Adrenalectomy reduced TMAO levels in uPA patients with KCNJ5 mutations but not in non-KCNJ5 mutation carriers. In conclusion, uPA patients with KCNJ5 mutations are more likely to achieve complete clinical success and have better long-term outcomes post-adrenalectomy. Our findings suggest that uPA patients with non-KCNJ5 mutations and those with specific clinical characteristics may require more frequent monitoring for cardiovascular events and new-onset DM post-adrenalectomy. Further research is required to elucidate the relationship between TMAO levels and cardiovascular risk in uPA patients.