The role of albumin and the extracellular matrix on the pathophysiology of oedema formation in severe malnutrition
Gerard Bryan Gonzales,
James M. Njunge,
Bonface M Gichuki,
Bijun Wen,
Moses Ngari,
Isabel Potani,
Johnstone Thitiri,
Debby Laukens,
Wieger Voskuijl,
Robert Bandsma,
Jill Vanmassenhove,
James A Berkley
Affiliations
Gerard Bryan Gonzales
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; Corresponding author at: Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, the Netherland.
James M. Njunge
The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya; KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya; Corresponding author at: The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya.
Bonface M Gichuki
The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya; KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya
Bijun Wen
Centre for Global Child Health, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Canada
Moses Ngari
The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya; KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya
Isabel Potani
The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya; Centre for Global Child Health, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Canada; Kamuzu University of Health Sciences (Former College of Medicine), Blantyre, Malawi
Johnstone Thitiri
The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya; KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya
Debby Laukens
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
Wieger Voskuijl
The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya; Kamuzu University of Health Sciences (Former College of Medicine), Blantyre, Malawi; Amsterdam Centre for Global Child Health, Emma Children's Hospital, Amsterdam University Medical Centres, Amsterdam, the Netherland; Department of Global Health, Amsterdam Institute for Global Health and Development, Amsterdam University Medical Centres, Amsterdam, the Netherland
Robert Bandsma
The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya; Centre for Global Child Health, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Canada; Kamuzu University of Health Sciences (Former College of Medicine), Blantyre, Malawi
Jill Vanmassenhove
Department of Internal Medicine and Paediatrics, Renal Division, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
James A Berkley
The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya; KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya; Nuffield Department of Medicine, Centre for Tropical Medicine & Global Health, University of Oxford, Oxford, UK
Summary: Background: 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). Methods: 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. Findings: 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. Interpretation: 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. Funding: 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).
