Hartleif Steffen, Baier Hannah, Kumpf Matthias, Handgretinger Rupert, Königsrainer Alfred, Nadalin Silvio, Sturm Ekkehard
Pediatric Gastroenterology and Hepatology (SH, HB, ES), University Hospital Tübingen, Tübingen, Germany.
Pediatric Cardiology, Pulmonology and Pediatric Intensive Care Medicine (MK), University Hospital Tübingen, Tübingen, Germany.
J Pediatr Pharmacol Ther. 2022;27(5):428-435. doi: 10.5863/1551-6776-27.5.428. Epub 2022 Jul 6.
Arterial hypertension (AH) is the most common toxic effect of calcineurin inhibitor (CNI)-based immunosuppression in children after liver transplantation (LT). Activation of the renal sodium chloride cotransporter (NCC) by CNIs has been described as a major cause of CNI-induced AH. Thiazides, for example, hydrochlorothiazide (HCTZ), can selectively block the NCC and may ameliorate CNI-induced AH after pediatric LT.
From 2005 thru 2015 we conducted a retrospective, single-center analysis of blood pressure in 2 pediatric cohorts (each n = 33) with or without HCTZ in their first year after LT. All patients received CNI-based immunosuppression. According to AAP guidelines, AH was defined as stage 1 and stage 2. Cohort 1 received an HCTZ-containing regimen to target the CNI-induced effect on the NCC, leading to AH. Cohort 2 received standard antihypertensive therapy without HCTZ.
In children who have undergone LT and been treated with CNI, AH overall was observed less frequently in cohort 1 vs cohort 2 (31% vs 44%; ns). Moreover, severe AH (stage 2) was significantly lower in cohort 1 vs 2 (1% vs 18%; p < 0.001). Multivariate analysis revealed HCTZ as the only significant factor with a protective effect on occurrence of severe stage 2 AH. While monitoring safety and tolerability, mild asymptomatic hypokalemia was the only adverse effect observed more frequently in cohort 1 vs 2 (27% vs 3%; p = 0.013).
Targeting NCC by HCTZ significantly improved control of severe CNI-induced AH and was well tolerated in children who underwent LT. This effect may reduce the risk of long-term end-organ damage and improve quality of life.
动脉高血压（AH）是儿童肝移植（LT）后基于钙调神经磷酸酶抑制剂（CNI）的免疫抑制最常见的毒性作用。CNI对肾氯化钠协同转运蛋白（NCC）的激活被认为是CNI诱导AH的主要原因。噻嗪类药物，如氢氯噻嗪（HCTZ），可选择性阻断NCC，并可能改善小儿肝移植后CNI诱导的AH。
2005年至2015年，我们对两个儿科队列（每组n = 33）进行了一项回顾性单中心血压分析，这两个队列在肝移植后的第一年使用或未使用HCTZ。所有患者均接受基于CNI的免疫抑制治疗。根据美国儿科学会（AAP）指南，AH被定义为1期和2期。队列1接受含HCTZ的方案，以针对CNI对NCC的诱导作用，从而导致AH。队列2接受不含HCTZ的标准抗高血压治疗。
在接受肝移植并接受CNI治疗的儿童中，队列1中AH的总体发生率低于队列2（31%对44%；无显著性差异）。此外，队列1中重度AH（2期）显著低于队列2（1%对18%；p < 0.001）。多变量分析显示，HCTZ是对严重2期AH发生具有保护作用的唯一显著因素。在监测安全性和耐受性时，轻度无症状低钾血症是队列1中比队列2更频繁观察到的唯一不良反应（27%对3%；p = 0.013）。
HCTZ靶向NCC可显著改善严重CNI诱导的AH的控制，并且在接受肝移植的儿童中耐受性良好。这种作用可能降低长期终末器官损害的风险并改善生活质量。
