Current Challenges and Future Perspectives of Renal Tubular Dysfunction in Diabetic Kidney Disease

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.

Exfoliated Kidney Cells from Urine for Early Diagnosis and Prognostication of CKD: The Way of the Future?

“…There are promising urinary biomarkers (e.g., KIM-1, monocyte chemoattractant protein-1 and neutrophil gelatinase-associated lipocalin) which reflect proximal tubule injury, inflammation and fibrosis in CKD, although it remains uncertain whether these biomarkers could be reliably expressed in urinary exfoliated PTCs [ 65 , 66 ]. Further work needs to be undertaken to determine if these biomarkers could be extracted from urinary exfoliated PTCs, and the extent to which they are useful for prognosticating the diverse etiologies of CKD.…”

Targeted drug delivery strategy: a bridge to the therapy of diabetic kidney disease

“…The renal tubules consist of the proximal tubules, collecting tubules and distal tubules. The morphological and functional changes of the renal tubules are involved in the pathogenesis and progression of DKD (Duan et al., 2021 ). Most renal tubular targeted systems are directed at the proximal tubules (Christensen et al., 2012 ).…”

Transcriptomic signatures responding to PKM2 activator TEPP-46 in the hyperglycemic human renal proximal epithelial tubular cells

“…Due to its physiologic role, PTECs are susceptible to nutritional stress such as in the diabetic context. Increased reabsorption of glucose and sodium in PTECs under chronic hyperglycemic stress triggers renal hyperfiltration and exacerbates hypoxia, playing a crucial role in preserving the diabetic state and renal injury ( 10 , 11 ). Compared with other metabolically active cells such as cardiomyocytes or skeletal muscle cells, PTECs show a relatively low metabolic flexibility toward glycolysis and mainly rely on fatty acids as energy source ( 12 ).…”