Recent Advances in the Management of Diabetic Kidney Disease: Slowing Progression

Abstract

Diabetic kidney disease (DKD) is a major cause of chronic kidney disease (CKD), and it heightens the risk of cardiovascular incidents. The pathogenesis of DKD is thought to involve hemodynamic, inflammatory, and metabolic factors that converge on the fibrotic pathway. Genetic predisposition and unhealthy lifestyle practices both play a significant role in the development and progression of DKD. In spite of the recent emergence of angiotensin receptors blockers (ARBs)/angiotensin converting enzyme inhibitor (ACEI), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid receptors antagonists (NS-MRAs), current therapies still fail to effectively arrest the progression of DKD. Glucagon-like peptide 1 receptor agonists (GLP-1RAs), a promising class of agents, possess the potential to act as renal protectors, effectively slowing the progression of DKD. Other agents, including pentoxifylline (PTF), selonsertib, and baricitinib hold great promise as potential therapies for DKD due to their anti-inflammatory and antifibrotic properties. Multidisciplinary treatment, encompassing lifestyle modifications and drug therapy, can effectively decelerate the progression of DKD. Based on the treatment of heart failure, it is recommended to use multiple drugs in combination rather than a single-use drug for the treatment of DKD. Unearthing the mechanisms underlying DKD is urgent to optimize the management of DKD. Inflammatory and fibrotic factors (including IL-1, MCP-1, MMP-9, CTGF, TNF-a and TGF-β1), along with lncRNAs, not only serve as diagnostic biomarkers, but also hold promise as therapeutic targets. In this review, we delve into the potential mechanisms and the current therapies of DKD. We also explore the additional value of combing these therapies to develop novel treatment strategies. Drawing from the current understanding of DKD pathogenesis, we propose HIF inhibitors, AGE inhibitors, and epigenetic modifications as promising therapeutic targets for the future.

Keywords: biomarkers; chronic kidney disease; diabetic kidney disease; molecular mechanisms; therapies.

Figure 1

Metabolic, inflammatory, and hemodynamic perturbation pathways in the pathogenesis of DKD. Hyperglycemia, activation of RAAS, and inflammatory responses can lead to hyperfiltration. Increased levels of AGEs/RAGE, ROS, and activated PKC pathway can trigger the accumulation of macrophage and the release of inflammatory factors, eventually leading to kidney fibrosis. The interaction between dietary AGEs and gut microbiota has the potential to trigger an inflammatory response through NF-κB pathway. Hyperglycemia, AGEs, and hyperfiltration can induce macrophage accumulation through upregulating TGF-β and MR. RAAS: renin angiotensin aldosterone system; AGEs: advanced glycation end products; RAGEs: receptors for AGEs; ROS: reactive oxygen species; PKC: polyol and protein kinase C; NF-κB: nuclear factor κ light-chain enhancer of activated B cell; LPS: lipopolysaccharide; SCFAs: short-chain fatty acids; TNF-α: tumor necrosis factor α; IL-1: interleukin-1;IL-6: interleukin-6; IL-18: interleukin-18; MCP-1: monocyte chemoattractant protein-1; MMP-9: matrix metalloproteinase-9; Na: sodium; MD: macula densa; ET: endothelin; TGF-β: transforming growth factor; MR: mineralocorticoid receptor; M1: M1 macrophage; M2: M2 macrophage.

Figure 2

The timeline of major therapy targeting precise molecular processes of DKD. Since 2007, numerous clinical trials of therapies targeting precise molecular processes have been attempted, yet they consistently failed to achieve success due to inefficiency or severe side effects. As a result, these agents failed to be adopted for the treatment of DKD. PKC: polyol and protein kinase C; TGF-β: transforming growth factor; MR: mineralocorticoid receptor; Nrf2: nuclear 1 factor (erythroid-derived 2)-related factor 2; ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blockers.

Figure 3

Recent advances in the therapy and potential mechanisms for slowing the progression of DKD. Multidisciplinary treatment including lifestyle modification with RAS blockers, SGLT2 inhibitors, Ns-MRAs, and GLP-1RA are recommended to be adopted for DKD. Meanwhile, the clinical trials of PTF, selonsertib, and baricitinib have exhibited potential for the treatment of DKD. However, more RCTs are required to further evaluate their effectiveness. RAS: renin-angiotensin/aldosterone system; SGLT2: sodium-glucose cotransporter 2; Ns-MRAs: nonsteroidal mineralocorticoid receptors antagonists; GLP-1RAs: glucagon-like peptide 1 receptor agonists; ASK1: apoptosis signal -regulating kinase 1; JAK: Janus kinase.