Albumin-dependent and independent mechanisms in the syndrome of kwashiorkor

The syndrome of kwashiorkor is a striking phenotype of childhood severe malnutrition (SM) comprising oedema, fatty liver, and skin and hair changes. Despite high fatality, the aetiology and pathophysiology of kwashiorkor remain enigmatic, including the role of serum albumin on oedema development. Here, we demonstrate that serum albumin is associated with the presence and severity of oedema among severely malnourished children. Further, in two independent cohorts of children in Malawi and Kenya, we show albumin-independent mechanisms are associated with oedema in SM, including oxidative stress and extracellular matrix (ECM) remodelling. Plasma concentrations of ECM-related proteins: lumican, podoplanin, lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) and matrix metalloproteinase (MMP)2 were associated with kwashiorkor. We therefore conclude that the pathophysiology of kwashiorkor has both albumin-dependent and independent mechanisms. We discuss the ways in which albumin-independent mechanisms may explain the clinical features observed in kwashiorkor. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT02246296 and [NCT00934492][1] ### Funding Statement GBG was a postdoctoral fellow of the Research Foundation Flanders (FWO) and received financial support from the Thrasher Foundation Early Career Award (15122) and VLIR-UOS-Ghent University Global Minds Fund. JMN, MN, IP, JT, WV, RB, and JAB received support from CHAIN: Bill & Melinda Gates Foundation (OPP1131320). JAB is also supported by MRC/DfID/Wellcome Trust Global Health Trials Scheme (MR/M007367/1). The F75 reformulation trial was funded by Thrasher Research Fund (9403) while the co-trimoxazole trial was funded by the Wellcome Trust (WT083579MA), both awarded to JAB. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The F75 reformulation trial was approved by KEMRI Ethical Review Committee (SCC 2799), College of Medicine Research Ethics Boards of the University of Malawi (P.03/14/1540), Oxford Tropical Research Ethics Committee (OXTREC 58 14) and the Hospital for Sick Children Research Ethics Board, Toronto (1000046559), including the secondary analysis in this manuscript. The co-trimoxazole trial was approved by Kenya National Ethical Review Committee (SSC 1562) and Oxford Tropical Research Ethics Committee (reference number 18‐09), including the secondary analysis in this manuscript. This paper is published with the permission of the Director of the Kenya Medical Research Institute. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The processed data and codes (STATA and R) will be deposited in the KEMRI-Wellcome data repository on the Harvard Dataverse under the Biosciences Dataverse subtheme () and issued with Digital Object Identifiers (DOI) at the time of deposit. The data will be titled: Albumin-dependent and independent mechanisms in the syndrome of kwashiorkor. The anonymised mass spectrometry raw files generated and analysed in the current study will be deposited to The ProteomeXchange Consortium: and assigned a unique identifier. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00934492&atom=%2Fmedrxiv%2Fearly%2F2021%2F06%2F01%2F2021.05.31.21257914.atom