Diabetic Kidney Disease: From Pathophysiology to Treatment Perspectives

Chronic kidney disease (CKD) presents an extensive healthcare burden globally. Diabetes mellitus (DM) is the most prevalent cause of CKD and end-stage kidney disease, requiring renal replacement therapy. Type II DM remains the most prevalent subtype, as it is closely related to metabolic syndrome, whose prevalence is also rising with a sedentary lifestyle and with consumption of energy-dense, highly processed foods, including excess sodium, high-fat dairy products, added sugars, saturated fats, and processed meats. Therefore, understanding the pathophysiology of diabetic kidney disease (DKD), its early recognition and early initiation of the currently available therapy remains an important measure to slow the progression of the disease.

Pathophysiology of DKD is a complex process, where all the mechanisms are still being elucidated on preclinical animal and in vitro models as well as in clinical studies. Changes in glomerular hemodynamics, glomerular and tubular hypertrophy, hyperfiltration, overactivation of the renin-angiotensin-aldosterone system, podocyte injury, inflammation, oxidative stress, renal hypoxia, mitochondrial injury, and epigenetic changes are the main mechanisms leading to albuminuria, glomerulosclerosis, and fibrosis. In the latter years, the importance of gut microbiota in DKD has also been shown. Understanding the mechanisms behind DKD is important, especially for researching current and possibly future pharmacological treatment of DKD. While angiotensin convertase enzyme inhibitors and angiotensin receptor blockers alongside nonpharmacological measures have been the pillars of DKD treatment and reduction of albuminuria for many decades, novel pharmacological agents are emerging, starting with sodium-glucose transporter 2 (SGLT2) inhibitors, which have been proven to affect many of the pathophysiological mechanisms, continuing with novel non-steroidal mineralocorticoid receptor antagonists, which are a new anti-inflammatory and antifibrotic possibility, and finishing with glucagon-like peptide 1 receptor antagonists (GLP1RAs), which have recently joined the therapeutic options for DKD.

This comprehensive review focuses on the main pathophysiological mechanisms of DKD and current available pharmacological and non-pharmacological possibilities.