Abstract
Over decades, substantial progress has been achieved in understanding the pathogenesis of proteinuria in diabetic kidney disease (DKD), biomarkers for DKD screening, diagnosis, and prognosis, as well as novel hypoglycemia agents in clinical trials, thereby rendering more attention focused on the role of renal tubules in DKD. Previous studies have demonstrated that morphological and functional changes in renal tubules are highly involved in the occurrence and development of DKD. Novel tubular biomarkers have shown some clinical importance. However, there are many challenges to transition into personalized diagnosis and guidance for individual therapy in clinical practice. Large-scale clinical trials suggested the clinical relevance of increased proximal reabsorption and hyperfiltration by sodium-glucose cotransporter-2 (SGLT2) to improve renal outcomes in patients with diabetes, further promoting the emergence of renal tubulocentric research. Therefore, this review summarized the recent progress in the pathophysiology associated with involved mechanisms of renal tubules, potential tubular biomarkers with clinical application, and renal tubular factors in DKD management. The mechanism of kidney protection and impressive results from clinical trials of SGLT2 inhibitors were summarized and discussed, offering a comprehensive update on therapeutic strategies targeting renal tubules.
Highlights
Along with the disease spectrum that evolved around the world over the past 30 years, diabetic kidney disease (DKD) has become the leading cause of end-stage kidney disease (ESKD) at daunting rates in both developed and developing countries [1, 2]
This review aimed to summarize the latest updates on the pathogenesis of renal tubular dysfunction in DKD, potential applications of tubular biomarkers, and renal tubule-targeting therapeutics based on evidence from recent trials in DKD
Another study from the United States population at relatively late stages of biopsy-proven DKD showed that interstitial fibrosis and tubular atrophy were of univariate significance for their ability to predict clinical prognosis [25]
Summary
Along with the disease spectrum that evolved around the world over the past 30 years, diabetic kidney disease (DKD) has become the leading cause of end-stage kidney disease (ESKD) at daunting rates in both developed and developing countries [1, 2]. Plasma tubular markers, which may reflect inflammatory and fibrotic responses, oxidative stress, and capacity of reabsorption in DKD, were reported to be associated with early renal function decline and DKD progression [9, 10]. Estimated glomerular filtration rate (eGFR) and albuminuria are only modestly useful for risk prediction in type 2 diabetes mellitus (T2DM) patients with preserved renal function, and DKD progresses even in the absence of albuminuria [12, 13]. By investigating the mechanism of the newest disease-modifying treatments for DKD, an accumulating body of research had documented the vital role of tubule function in regulating glomerular filtration through tubuloglomerular feedback. The tubuloglomerular feedback mechanism begins with the theory that diabetic hyperfiltration and glomerular capillary hypertension are significant treatable stressors contributing to the progression of DKD [16,17,18,19]. This review aimed to summarize the latest updates on the pathogenesis of renal tubular dysfunction in DKD, potential applications of tubular biomarkers, and renal tubule-targeting therapeutics based on evidence from recent trials in DKD
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