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.