Obesity-related glomerulopathy: Current approaches and future perspectives

Abstract

Obesity-related glomerulopathy (ORG) is a silent comorbidity which is increasing in incidence as the obesity epidemic escalates. ORG is associated with serious health consequences including chronic kidney disease, end-stage renal disease (ESRD), and increased mortality. Although the pathogenic mechanisms involved in the development of ORG are not fully understood, glomerular hemodynamic changes, renin-angiotensin-aldosterone system (RAAS) overactivation, insulin-resistance, inflammation and ectopic lipid accumulation seem to play a major role. Despite albuminuria being commonly used for the non-invasive evaluation of ORG, promising biomarkers of early kidney injury that are emerging, as well as new approaches with proteomics and metabolomics, might permit an earlier diagnosis of this disease. In addition, the assessment of ectopic kidney fat by renal imaging could be a useful tool to detect and evaluate the progression of ORG. Weight loss interventions appear to be effective in ORG, although large-scale trials are needed. RAAS blockade has a renoprotective effect in patients with ORG, but even so, a significant proportion of patients with ORG will eventually progress to ESRD despite therapeutic efforts. It is noteworthy that certain antidiabetic agents such as sodium-glucose cotransporter 2 inhibitors (SGLT2i) or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) could be useful in the treatment of ORG through different pleiotropic effects. In this article, we review current approaches and future perspectives in the care and treatment of ORG.

Keywords: albuminuria; kidney; nephroprotection; obesity.

FIGURE 1

Pathogenic mechanisms involved in obesity‐related glomerulopathy (ORG). In obesity, glomerular hyperfiltration and RAAS overactivation lead to podocyte injury and fibrogenesis. Inflammatory agents promote different glomerular changes, favoring fibrosis and proteinuria. Ectopic lipid accumulation prompts glomerular damage through lipotoxicity and mechanical compression; synthesized adipokines also have pro‐inflammatory and vasoconstrictive properties. Hyperinsulinemia and insulin resistance can induce podocyte dysfunction and glomerulosclerosis directly and via stimulation of hemodynamic changes and pro‐inflammatory cytokine production. RAAS, renin‐angiotensin‐aldosterone system; IL, interleukin; TNF‐α, tumor necrosis factor α; TGF‐β, transforming growth factor β; MCP ‐1, monocyte chemoattractant protein‐1; PAI‐1, plasminogen activator inhibitor‐1

FIGURE 2

Histopathology of ORG. Two glomeruli at the same magnification (40×). The one on the left (HE) corresponds to a normal glomerulus of a patient without glomerular disease. The one on the right (Masson) corresponds to a patient with obesity with glomerulomegaly; a clear difference in size can be seen. Also, the glomerulus on the right shows a perihilar segmental sclerosing lesion (red circle; the hilum red arrow). Glomerulomegaly is defined as a glomerulus that is more than 1.5 times the size of a normal glomerulus (approx. 250 microns) or as a glomerulus that occupies more than half of a 40× field

FIGURE 3

Potential mechanisms explaining the effect of sodium‐glucose cotransporter 2 inhibitors (SGLT2i) on ameliorating the progression of obesity‐related glomerulopathy (ORG). eGFR, estimated glomerular filtration rate