Slowing the Progression of Diabetic Kidney Disease

Abstract

Diabetes is the most frequent cause of kidney disease that progresses to end-stage renal disease worldwide, and diabetic kidney disease is significantly related to unfavorable cardiovascular outcomes. Since the 1990s, specific therapies have emerged and been approved to slow the progression of diabetic kidney disease, namely, renin–angiotensin–aldosterone system blockers (including angiotensin-converting enzyme inhibitors (ACEi) angiotensin receptor blockers (ARBs), the non-steroidal mineralocorticoid receptor antagonist (NS-MRA), finerenone, and sodium–glucose cotransporter-2 (SGLT2) inhibitors). Mechanistically, these different classes of agents bring different anti-inflammatory, anti-fibrotic, and complementary hemodynamic effects to patients with diabetic kidney disease such that they have additive benefits on slowing disease progression. Within the coming year, there will be data on renal outcomes using the glucagon-like peptide-1 receptor agonist, semaglutide. All the aforementioned medications have also been shown to improve cardiovascular outcomes. Thus, all three classes (maximally dosed ACEi or ARB, low-dose SGLT-2 inhibitors, and the NS-MRA, finerenone) form the “pillars of therapy” such that, when used together, they maximally slow diabetic kidney disease progression. Ongoing studies aim to expand these pillars with additional medications to potentially normalize the decline in kidney function and reduce associated cardiovascular mortality.

Role of Uremic Toxins, Oxidative Stress, and Renal Fibrosis in Chronic Kidney Disease

“…Figure 3 shows the effects of SGLT2 inhibitors on inflammation and oxidative stress [82]. A study in mice with type 2 diabetes showed that SGLT2 inhibitors prevented renal tubular fibrosis [80]. Other studies show that these drugs can reduce abnormal cell remodeling by decreasing endothelial markers.…”

“…An increase in the eNOS enzyme has been shown to inhibit pathological remodeling in diabetic kidney disease by restoring proper NO utilization and having a protective effect on both the renal endothelium and the cardiovascular system [83]. One of the main pro-fibrotic factors is growth factor 1 (TGF-1), which has potent profibrotic effects through the deposition of the extramesenchymal matrix, re- A study in mice with type 2 diabetes showed that SGLT2 inhibitors prevented renal tubular fibrosis [80]. Other studies show that these drugs can reduce abnormal cell remodeling by decreasing endothelial markers.…”

“…SGLT2 inhibitors, via proximal tubules, prevent the absorption of both glucose and sodium chloride. Reabsorption of Na+ in the renal tubules, decreases intraglomerular pressure which directly translates into decreased glomerular hyperfiltration, reduced oxidative stress and slowed progression of chronic kidney disease and nephropathy [ 80 , 81 ]. This group of drugs has potent anti-inflammatory effects, due to the down-regulation of the nucleotide-binding domain, or NLRP3.…”

“…In addition, SGLT2 inhibitors reduce the concentration of pro-inflammatory factors and contribute to the beneficial phenomenon of autophagy. SGLT2 inhibitors reduce hyperglycemia, hypertension, albuminuria, fibrosis, hypoxia, obesity, lipotoxicity and inflammation [ 80 ]. Figure 3 shows the effects of SGLT2 inhibitors on inflammation and oxidative stress [ 82 ].…”

Emerging role of antidiabetic drugs in cardiorenal protection

“…The driving factors for cardiovascular complications in diabetic patients including glucotoxicity, lipotoxicity, and hypertension ( Kenny and Abel, 2019 ). Meanwhile, diabetic kidney disease (DKD) is the most common cause of death among microvascular complications of diabetes and is closely associated with cardiovascular outcomes ( Blazek and Bakris, 2023 ). Currently, there has been a paradigm shift in the management of diabetes and its complications, with a focus on not only controlling blood glucose levels but also addressing the associated cardiovascular and renal risks.…”