Background and aims

The cardiovascular hormones renin/angiotensin/aldosterone (RAA), brain-type natriuretic peptide (BNP)and arginine-vasopressin (AVP) are key regulators of systemic circulatory homeostasis in portal hypertension (PH). We assessed (i) the activation of renin, BNP and AVP across distinct stages of PH and (ii) whether activation of these hormones correlates with clinical outcomes.

Methods

Plasma levels of renin, proBNP and copeptin (AVP biomarker) were determined in 663 patients with advanced chronic liver disease (ACLD) undergoing hepatic venous pressure gradient (HVPG) measurement at the Vienna General Hospital between 11/2011 and 02/2019. We stratified for Child stage (A–C), HVPG (6–9 mmHg, 10–15 mmHg, ≥ 16 mmHg) and compensated vs. decompensated ACLD.

Results

With increasing PH, hyperdynamic state was indicated by higher heart rates (6–9 mmHg: median 71.0 [IQR 18.0] bpm, 10–15 mmHg: 76.0 [19.0] bpm, ≥ 16 mmHg: 80.0 [22.0] bpm; p < 0.001), lower mean arterial pressure (6–9 mmHg: 103.0 [13.5] mmHg, 10–15 mmHg: 101.0 [19.5] mmHg, ≥ 16 mmHg: 99.0 [21.0] mmHg; p = 0.032) and lower serum sodium (6–9 mmHg: 139.0 [3.0] mmol/L, 10–15 mmHg: 138.0 [4.0] mmol/L, ≥ 16 mmHg: 138.0 [5.0] mmol/L; p < 0.001). Across HVPG strata (6–9 mmHg vs. 10–15 mmHg vs ≥ 16 mmHg), median plasma levels of renin (21.0 [50.5] vs. 25.1 [70.9] vs. 65.4 [219.6] µIU/mL; p < 0.001), proBNP (86.1 [134.0] vs. 63.6 [118.0], vs. 132.2 [208.9] pg/mL; p = 0.002) and copeptin (7.8 [7.7] vs. 5.6 [8.0] vs. 10.7 [18.6] pmol/L; p = 0.024) increased with severity of PH. Elevated renin levels independently predicted first hepatic decompensation (adjusted hazard ratio [aHR]: 1.69; 95% confidence interval [95% CI] 1.07–2.68; p = 0.025) and mortality in compensated patients (aHR: 3.15; 95% CI 1.70–5.84; p < 0.001) and the overall cohort aHR: 1.42; 95% CI 1.01–2.01; p = 0.046). Elevated copeptin levels predicted mortality in decompensated patients (aHR: 5.77; 95% CI 1.27–26.33; p = 0.024) and in the overall cohort (aHR: 3.29; 95% CI 1.36–7.95; p = 0.008). ProBNP levels did not predict clinical outcomes.

Conclusions

The cardiovascular hormones renin, proBNP and AVP are activated with progression of ACLD and PH. Renin activation is a risk factor for hepatic decompensation and mortality, especially in compensated patients. Increased plasma copeptin is a risk factor for mortality, in particular in decompensated patients.

中文翻译：

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门静脉高压症不同阶段心血管激素的差异激活可预测临床结果

背景和目标

心血管激素肾素/血管紧张素/醛固酮 (RAA)、脑型利钠肽 (BNP) 和精氨酸加压素 (AVP) 是门静脉高压症 (PH) 全身循环稳态的关键调节因子。我们评估了 (i) 肾素、BNP 和 AVP 在不同 PH 阶段的激活，以及 (ii) 这些激素的激活是否与临床结果相关。

方法

2011 年 11 月至 2019 年 2 月期间，在维也纳总医院接受肝静脉压力梯度 (HVPG) 测量的 663 名晚期慢性肝病 (ACLD) 患者中测定了肾素、proBNP 和和肽素 (AVP 生物标志物) 的血浆水平。我们对儿童阶段 (A-C)、HVPG (6-9 mmHg、10-15 mmHg、≥ 16 mmHg) 和代偿性与失代偿性 ACLD 进行分层。

结果

随着 PH 的增加，心率加快（6-9 mmHg：中位数 71.0 [IQR 18.0] bpm，10-15 mmHg：76.0 [19.0] bpm，≥ 16 mmHg：80.0 [22.0] bpm；p  < 0.001 )、降低平均动脉压 (6–9 mmHg: 103.0 [13.5] mmHg, 10–15 mmHg: 101.0 [19.5] mmHg, ≥ 16 mmHg: 99.0 [21.0] mmHg; p  = 0.032) 和降低血清钠 (6– 9 mmHg：139.0 [3.0] mmol/L，10–15 mmHg：138.0 [4.0] mmol/L，≥ 16 mmHg：138.0 [5.0] mmol/L；p  < 0.001）。跨 HVPG 层（6–9 mmHg vs. 10–15 mmHg vs ≥ 16 mmHg），肾素的中位血浆水平（21.0 [50.5] vs. 25.1 [70.9] vs. 65.4 [219.6] µIU/mL；p  < 0.001） , proBNP (86.1 [134.0] vs. 63.6 [118.0], vs. 132.2 [208.9] pg/mL; p = 0.002）和和肽素（7.8 [7.7] vs. 5.6 [8.0] vs. 10.7 [18.6] pmol/L；p  = 0.024）随着 PH 的严重程度而增加。肾素水平升高独立预测首次肝脏失代偿（调整后的风险比 [aHR]：1.69；95% 置信区间 [95% CI] 1.07–2.68；p  = 0.025）和代偿患者的死亡率（aHR：3.15；95% CI 1.70– 5.84；p  < 0.001）和整个队列 aHR：1.42；95% CI 1.01–2.01；p  = 0.046）。和肽素水平升高可预测失代偿患者（aHR：5.77；95% CI 1.27-26.33；p  = 0.024）和整个队列（aHR：3.29；95% CI 1.36-7.95；p  = 0.008）的死亡率。ProBNP 水平不能预测临床结果。

结论

心血管激素肾素、proBNP 和 AVP 随着 ACLD 和 PH 的进展而被激活。肾素激活是肝脏失代偿和死亡的危险因素，尤其是在代偿期患者中。血浆和肽素增加是死亡的危险因素，尤其是在失代偿患者中。