Optimization of guideline-directed medical therapies in patients with diabetes and chronic kidney disease

Figures

• 

  Figure 1:. Diagram showing the interrelation of mechanistic drivers in early though advanced stages of kidney damage and disease progression in diabetes. AGE, advanced glycation end product; CKD, chronic kidney disease; CTGF, connective tissue growth factor; DKD, diabetic kidney disease; ICAM-1, intracellular adhesion molecule 1; IL, interleukin; MCP-1, monocyte chomoattractant protein-1; MMP-9, matric metalloproteinase 9; MR, mineralocorticoid receptor; PAI-1, plasminogen activator inhibitor; RAGE, receptor for advanced glycation end product; ROS, reactive oxygen species; SAA, serum amyloid A; TGF-β, transforming growth factor beta; TLR-4, toll-like preceptor-4; TNF-α, tumor necrosis factor alpha. From: Tuttle KR, Agarwal R, Alpers CE et al. Molecular mechanisms and therapeutic targets for diabetic kidney disease. Kidney Int 2022;102:248–60.

• 

  Figure 2:. Mechanisms of kidney protection with SGLT2 inhibitors, GLP-1RAs, and a nonsteroidal MRA. A. Hemodynamic changes in the diabetic kidney are reversed with SGLT2 inhibition. In diabetes, the resorptive capacity for glucose in the proximal tubule is increased via upregulation of SGLT2 and SGLT1. As a result of enhanced glucose and sodium chloride uptake in the proximal tubule, solute delivery to the macula densa cells of the juxtaglomerular apparatus is diminished resulting in altered tubuloglomerular feedback. Adenosine release is subsequently decreased resulting in vasodilation of afferent arteriole, glomerular hyperfiltration, and hypertension. SGLT2 inhibition deceases glucose and sodium reabsorption, thus increasing solute delivery to the distal tubule. These effects help restore tubuloglomerular feedback with a resulting increase in production of adenosine leading to vasoconstriction of the afferent arteriole, and possibly vasodilation of the efferent arteriole, with improvement of glomerular hyperfiltration and hypertension. B. Structural changes observed in patients with diabetes and CKD include glomerular hypertrophy, thickening of the glomerular basement membrane, podocyte…

• 

  Figure 3:. Proposed mechanisms of kidney protection for guideline-directed medical therapies. Current guideline-directed medical therapies, inclusive of RAS inhibitors, SGLT2 inhibitors, GLP-1RAs, and the ns-MRA finerenone address multiple pathophysiological drivers of DKD. DKD, diabetic kidney disease; GLP-1, glucagon-like peptide-1; ns-MRA, nonsteroidal mineralocorticoid receptor antagonist; RAS, renin-angiotensin system; SGLT2, sodium-glucose cotransporter-2. Created with Biorender.com.

• 

  Figure 4:. Holistic approach for improving outcomes in patients with diabetes and chronic kidney disease (CKD). Icons presented indicate the following benefits: blood pressure (BP) cuff, BP-lowering; glucometer, glucose-lowering; heart, cardioprotection; kidney, kidney protection; scale, weight management. Estimated glomerular filtration rate (eGFR) is presented in units of ml/min/1.73 m2. *Angiotensin converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) (at maximal tolerated doses) should be first-line therapy for hypertension (HTN) when albuminuria is present. Otherwise, dihydropyridine calcium channel blocker (CCB) or diuretic can also be considered; all three classes are often needed to attain BP targets. †Finerenone is currently the only nonsteroidal mineralocorticoid receptor antagonist (ns-MRA) with proven clinical kidney and cardiovascular benefits. ACR, albumin-to-creatinine ratio; ASCVD, atherosclerotic cardiovascular disease; CVD, cardiovascular disease; GLP-1 RA, GLP-1 receptor agonist; MRA, mineralocorticoid receptor antagonist; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitor; RAS, renin-angiotensin system; SGLT2i, sodium–glucose…