Clinical, Morphometric and Biochemical Effects on Adiposopathy Associated With the Use of GLP-1RA in CKD

Chronic kidney disease (CKD) is defined as an irreversible abnormality of kidney structure and/or function lasting for more than three months. CKD is a major global health burden, affecting over 10% of the worldwide population and representing a leading cause of morbidity and mortality. Its progression to end-stage kidney disease (ESKD) drastically increases cardiovascular risk and is associated with a five-year survival rate of only approximately 50%. The principal risk factors for CKD-hypertension, obesity and type 2 diabetes (T2DM) in particular-are intrinsically linked through the dysfunction of fat/adipose tissue (AT), also known as adiposopathy. Adiposopathy is a key driver of cardiorenal risk in CKD. Evidence from bioimpedance, imaging techniques (CT, MRI), and molecular biology studies confirm that alterations in adipose tissue-including its quantity, distribution (e.g., perirenal, epicardial), radiodensity, and the secretion of pro-inflammatory adipokines-are powerful triggers of cardiorenal damage and mortality in these patients. This understanding frames obesity, T2DM, cardiovascular diseases (CVDs), and CKD as different manifestations of a shared spectrum, now termed adiposity-based chronic disease (ABCD), necessitating an "adipocentric" therapeutic approach. One hallmark feature of adiposopathy is the reprogramming and increase in size of certain region-specific adipose tissue. Perivisceral adipose tissue plays a pivotal role in adiposity-based chronic diseases as it releases adipokines and cytokines that not only contribute to the systemic pro-inflammatory and oxidative stress processes but may also influence the function of the organs surrounded by this tissue. GLP-1RA stimulates the receptor for glucagon-like peptide-1 (GLP-1), an incretin-like hormone released in the large intestine that reduces serum glucose concentrations by stimulating the glucose-dependent release of insulin, inhibiting the hypersecretion of glucagon (except in hypoglycemia periods) and promoting satiety. GLP-1RA reduced the incidence of cardiovascular death in patients with T2DM compared with placebo and decreased the incidence of major kidney events, also reducing the progression of kidney dysfunction and the risk of death. In animals, the observed morphological changes generated by GLP-1RA could be underlined by potential actions on adipose tissue remodeling, as these drugs upregulated the expression of AT-browning related genes in perivisceral white adipose tissue from murine models, although the transcriptomic effects from GLP-1RA on the adiposopathy process are still unknown.