Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease, including end-stage kidney disease, and increases the risk of cardiovascular mortality. Although the treatment options for DKD, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid receptor antagonists, have advanced, their efficacy is still limited. Thus, a deeper understanding of the molecular mechanisms of DKD onset and progression is necessary for the development of new and innovative treatments for DKD. The complex pathogenesis of DKD includes various different pathways, and the mechanisms of DKD can be broadly classified into inflammatory, fibrotic, metabolic, and hemodynamic factors. Here, we summarize the recent findings in basic research, focusing on each factor and recent advances in the treatment of DKD. Collective evidence from basic and clinical research studies is helpful for understanding the definitive mechanisms of DKD and their regulatory systems. Further comprehensive exploration is warranted to advance our knowledge of the pathogenesis of DKD and establish novel treatments and preventive strategies.

Protease-activated receptor 2 (PAR2) is a seven-transmembrane, G-protein-coupled receptor that is activated by coagulation proteases such as factor VIIa and factor Xa and other serine proteases. It is a potential therapeutic target for kidney injury, as it enhances inflammatory and fibrotic responses via the nuclear factor-kappa B and mitogen-activated protein kinase cascades. The body of knowledge regarding the role of PAR2 in kidney disease is currently growing, and its role in various kidney disease models, such as acute kidney injury, renal fibrosis, diabetic kidney disease, aging, and thrombotic microangiopathy, has been reported. Here, we review the literature to better understand the various aspects of PAR2 in kidney disease.

Background: The prognosis of chronic kidney disease (CKD) typically requires longitudinal estimated glomerular filtration rate (eGFR) data, making risk stratification difficult at initial consultation. Furthermore, eGFR-based clinical decisions often overlook the critical factor of patient age. This study aimed to establish a simplified predictive model for progressive CKD and quantify the impact of clinical interventions. Methods: Utilizing a historical dataset (1988–2003) from the pre-renin-angiotensin system inhibitor (RASi) and pre-sodium-glucose cotransporter 2 inhibitor (SGLT2i) era, we developed heatmaps to predict the probability of reaching eGFR < 30 mL/min/1.73 m² by age 80 years. The model also estimated the risk reduction from smoking cessation and pharmacological therapies. The predictive performance for age + eGFR was assessed using standard calibration and discrimination metrics, and clinical utility was evaluated using decision curve analysis across a range of threshold probabilities. Risk reclassification analyses compared age +eGFR-based categories with conventional eGFR-based stratification. Results: Regarding the risk of eGFR < 30 mL/min/1.73 m² by age 80 years, simulations confirmed a correlation between age and eGFR. At age 40 years, an eGFR of ~57 mL/min/1.73 m² indicated a 50% probability of progressing to CKD stage 4 by age 80 years. This threshold decreases to 53 and 48 mL/min/1.73 m² at 50 and 60 years of age, respectively. Calibration and discrimination analyses demonstrated acceptable agreement between predicted and observed risks. Decision curve analysis showed that an age + eGFR threshold of approximately 115 primarily provided a net benefit at lower threshold probabilities, supporting intensified surveillance strategies, whereas an age +eGFR of 100 showed a positive net benefit across a broader range of thresholds, comparable to the conventional eGFR < 45 mL/min/1.73 m² criterion. While proteinuria markedly increased risk, smoking cessation provided a 9.4–11.2% risk reduction. Combined RASi and SGLT2i treatment showed the greatest impact, reducing progression probability by 31.2–40.0% (e.g., reducing a 50.0% baseline risk to 32.1% in 40-year-old men). Conclusions: The age + eGFR rule represents a simple, clinically interpretable heuristic for age-adjusted risk stratification based on a single eGFR measurement and may offer potential clinical utility for guiding surveillance intensity and consideration of earlier intervention strategies. However, external validation is required before clinical application.