The Pillars for Renal Disease Treatment in Patients with Type 2 Diabetes

Abstract

The diabetes epidemic and the increasing number of patients with diabetic chronic vascular complications poses a significant challenge to health care providers. Diabetic kidney disease is a serious diabetes-mediated chronic vascular complication and represents a significant burden for both patients and society in general. Diabetic kidney disease not only represents the major cause of end stage renal disease but is also paralleled by an increase in cardiovascular morbidity and mortality. Any interventions to delay the development and progression of diabetic kidney disease are important to reduce the associated cardiovascular burden. In this review we will discuss five therapeutic tools for the prevention and treatment of diabetic kidney disease: drugs inhibiting the renin-angiotensin-aldosterone system, statins, the more recently recognized sodium-glucose co-transporter-2 inhibitors, glucagon-like peptide 1 agonists, and a novel non-steroidal selective mineralocorticoid receptor antagonist.

Keywords: diabetes; kidney disease; therapeutics.

Figure 1

The treatment “pillars” for renal protection in diabetes.

Figure 2

Proposed renoprotective mechanisms of action of SGLT2 inhibitors, GLP1 receptor agonists, non-steroidal MRAs, statins, and inhibitors of the RAAS (see text for detailed explanation).

Figure 3

Steroidal and nonsteroidal MRAs mechanisms of action. Aldosterone binds to mineralocorticoid receptors (MR) and by translocating into the nucleus and binding to specific nuclear hormone response elements (HRE), recruits transcriptional cofactors and then initiates the transcription of target genes (e.g., NfKB, nuclear factor kappa-light-chain-enhancer of activated B cell; AP-1, activator protein-1; TGFβ1, transforming growth factor β1; ET-1, endothelin-1; CTGF, connective tissue growth factor; PAI-1, plasminogen activator inhibitor 1). Increased activation of the MR promotes proinflammatory and profibrotic processes that drive renal disease. Both steroidal and non-steroidal MRAs bind to MR inhibiting aldosterone from binding to MRs. This prevents the downstream activation of proinflammatory and profibrotic mechanisms. Steroidal MRAs, by interacting with cofactors that affect gene transcription, function as partial MR agonists. Conversely, non-steroidal MRA (e.g., finerenone) anti-inflammatory and anti-fibrotic effects are more pronounced than those of steroidal MRAs (see text for detailed explanation).