Treatment of Diabetic Kidney Disease: Current and Future

Abstract

Diabetic kidney disease (DKD) is the major cause of end-stage kidney disease. However, only renin-angiotensin system inhibitor with multidisciplinary treatments is effective for DKD. In 2019, sodium-glucose cotransporter 2 (SGLT2) inhibitor showed efficacy against DKD in Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, adding a new treatment option. However, the progression of DKD has not been completely controlled. The patients with transient exposure to hyperglycemia develop diabetic complications, including DKD, even after normalization of their blood glucose. Temporary hyperglycemia causes advanced glycation end product (AGE) accumulations and epigenetic changes as metabolic memory. The drugs that improve metabolic memory are awaited, and AGE inhibitors and histone modification inhibitors are the focus of clinical and basic research. In addition, incretin-related drugs showed a renoprotective ability in many clinical trials, and these trials with renal outcome as their primary endpoint are currently ongoing. Hypoxia-inducible factor prolyl hydroxylase inhibitors recently approved for renal anemia may be renoprotective since they improve tubulointerstitial hypoxia. Furthermore, NF-E2–related factor 2 activators improved the glomerular filtration rate of DKD patients in Bardoxolone Methyl Treatment: Renal Function in chronic kidney disease/Type 2 Diabetes (BEAM) trial and Phase II Study of Bardoxolone Methyl in Patients with Chronic Kidney Disease and Type 2 Diabetes (TSUBAKI) trial. Thus, following SGLT2 inhibitor, numerous novel drugs could be utilized in treating DKD. Future studies are expected to provide new insights.

Activated Histone Acetyltransferase p300/CBP-Related Signalling Pathways Mediate Up-Regulation of NADPH Oxidase, Inflammation, and Fibrosis in Diabetic Kidney

“…Over the past two decades, multiple molecular triggers and signalling pathways of glomerular capillary dysfunction contributing to kidney failure have been determined [ 1 , 2 , 3 ]. Yet, despite the significant advances in clinical and experimental research in diabetes and its complications, the diagnosis and effective treatment of DKD remains challenging [ 4 , 5 , 6 , 7 , 8 ]. Noteworthy, due to the metabolic memory in diabetes (an emergent and rapidly evolving epigenetic-related mechanistic concept) and in spite of the therapeutic control of hyperglycaemia, diabetes pathological long-lasting effects persist and continue to promote systemic cellular detrimental effects [ 44 , 45 , 46 , 47 ].…”

“…Diabetic kidney disease (DKD), the major microvascular complication of both type I and type II diabetes, is a complex multifactorial renal disorder having a detrimental impact on the patient’s quality of life and life-span expectation [ 1 , 2 , 3 ]. Dysfunction of glomerular endothelial cells and podocytes, thickening of the glomerular basement membrane, mesangial cells hypertrophy and proliferation, progressive accumulation of mesangial extracellular matrix (ECM) components, podocyte damage, and disruption of glomerular endothelium fenestrations are the main structural alterations ultimately leading to glomerulosclerosis; a pathological condition that is further responsible for increased intraglomerular capillary pressure, hyperfiltration, and eventually kidney failure [ 4 , 5 , 6 ].…”

HIF-α Prolyl Hydroxylase Inhibitors and Their Implications for Biomedicine: A Comprehensive Review

“…Anemia caused primarily by renal failure is defined as renal anemia [ 104 , 105 , 106 ]. REP cells are localized in the interstitium of normal kidneys [ 43 , 107 ].…”

Pleiotropic Effects of Sodium-Glucose Cotransporter-2 Inhibitors: Renoprotective Mechanisms beyond Glycemic Control

“…Hence, the concept of DKD has emerged owing to this recent shift in the clinical presentation of kidney disease caused by diabetes mellitus [ 6 ]. That is, DKD is defined as CKD with diabetes-associated pathogenesis [ 7 ]. Considering that kidney dysfunction may latently progress in patients with DKD, it is important to improve the management of diabetes mellitus to prevent end-stage renal disease.…”