RAASi, MRA and FGF-23 in CKD progression: the usual suspects?

Chronic kidney disease (CKD) affects almost 10% of the global population and is a significant health issue. The presence of CKD increases the risk of fatal and non-fatal cardiovascular events, overall mortality, and progression of renal damage leading to kidney failure. Inhibiting the renin-angiotensin-aldosterone system (RAAS) through angiotensin-converting enzyme inhibitor or angiotensin II receptor blockers reduces proteinuria and slows eGFR decline in CKD patients. Several factors can reduce the effect of inhibition RAAS, such as individual variations, drug intolerance, and adverse effects like hyperkalemia. Moreover, the aldosterone breakthrough phenomenon, where aldosterone levels rebound during RAAS therapy, limits treatment efficacy in reducing proteinuria and slowing the progression of CKD and is associated with poor cardiovascular and renal outcomes. Similarly, FGF23 attenuates RAAS blockade effectiveness through, in fact, enhancing the expression of angiotensin-converting enzyme 2 and reducing degradation of angiotensin I to angiotensin 1-9 and angiotensin II to angiotensin 1-7 inducing a reduced efficacy in controlling RAAS-mediated effects and an increase of cardiovascular risk and CKD progression. New therapeutic strategies to reduce the progression of CKD, such as SGLT-2 inhibitors, GLP-1 receptor agonists, and mineralocorticoid receptor antagonists (MRAs), are recommended in CKD patients to reduce the risk of progression and cardiovascular events. Furthermore, these therapies may reduce FGF-23 levels and regulate aldosterone breakthrough. This review aims to clarify the mechanisms underlying CKD progression, with a focus on aldosterone breakthrough, FGF-23, and activins, in order to identify new therapeutic approaches for better management of CKD and its complications.