Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, the Netherland; Department of Internal Medicine and Paediatrics, Laboratory of Gastroenterology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; VIB-UGent Center for Inflammation Research, Ghent, Belgium.
The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya; KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya.
EBioMedicine. 2022 May;79:103991. doi: 10.1016/j.ebiom.2022.103991. Epub 2022 Apr 7.
While fluid flows in a steady state from plasma, through interstitium, and into the lymph compartment, altered fluid distribution and oedema can result from abnormal Starling's forces, increased endothelial permeability or impaired lymphatic drainage. The mechanism of oedema formation, especially the primary role of hypoalbuminaemia, remains controversial. Here, we explored the roles of albumin and albumin-independent mechanisms in oedema formation among children with severe malnutrition (SM).
We performed secondary analysis of data obtained from two independent clinical trials in Malawi and Kenya (NCT02246296 and NCT00934492). We then used an unconventional strategy of comparing children with kwashiorkor and marasmus by matching (discovery cohort, n = 144) and normalising (validation cohort, n = 98, 2 time points) for serum albumin. Untargeted proteomics was used in the discovery cohort to determine plausible albumin-independent mechanisms associated with oedema, which was validated using enzyme-linked immunosorbent assay and multiplex assays in the validation cohort.
We demonstrated that low serum albumin is necessary but not sufficient to develop oedema in SM. We further found that markers of extracellular matrix (ECM) degradation rather than markers of EG degradation distinguished oedematous and non-oedematous children with SM.
Our results show that oedema formation has both albumin-dependent and independent mechanisms. ECM integrity appears to have a greater role in oedema formation than EG shedding in SM.
Research Foundation Flanders (FWO), Thrasher Foundation (15122 and 9403), VLIR-UOS-Ghent University Global Minds Fund, Bill & Melinda Gates Foundation (OPP1131320), MRC/DfID/Wellcome Trust Global Health Trials Scheme (MR/M007367/1), Canadian Institutes of Health Research (156307), Wellcome Trust (WT083579MA).
尽管液体在稳定状态下从血浆流经间质进入淋巴间隙，但异常的 Starling 力、内皮通透性增加或淋巴引流受损可导致液体分布和水肿改变。水肿形成的机制，尤其是低白蛋白血症的主要作用，仍存在争议。在这里，我们探讨了白蛋白和白蛋白独立机制在严重营养不良（SM）儿童水肿形成中的作用。
我们对来自马拉维和肯尼亚的两项独立临床试验的数据进行了二次分析（NCT02246296 和 NCT00934492）。然后，我们通过匹配（发现队列，n=144）和标准化（验证队列，n=98，2 个时间点）血清白蛋白的方法，比较了 kwashiorkor 和 marasmus 患儿，使用非传统策略比较两种疾病。发现队列中使用无靶向蛋白质组学来确定与水肿相关的可能的白蛋白独立机制，然后在验证队列中使用酶联免疫吸附测定法和多重分析进行验证。
我们证明低血清白蛋白是 SM 发生水肿的必要条件，但不是充分条件。我们进一步发现，区分 SM 伴水肿和非水肿患儿的是细胞外基质（ECM）降解标志物，而不是 EG 降解标志物。
我们的结果表明，水肿形成既有白蛋白依赖性机制，也有独立机制。在 SM 中，ECM 完整性在水肿形成中的作用似乎大于 EG 脱落。
弗兰德斯研究基金会（FWO）、撒切尔基金会（15122 和 9403）、VLIR-UOS-根特大学全球思维基金、比尔和梅琳达盖茨基金会（OPP1131320）、医学研究委员会/国际发展部/惠康信托全球健康试验计划（MR/M007367/1）、加拿大卫生研究院、惠康信托基金会（WT083579MA）。
