For example, it was found that loss of endothelial glucocorticoid receptors accelerates diabetic nephropathy in mice. New insights into the pathophysiology of DKD are also being obtained. New potential treatment targets are continuously being recognized, such as N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), sirtuin 3 (SIRT3), glycolysis inhibitors, pyruvate kinase M2 type (PKM2) activators, etc. Baricitinib, a JAK1 and 2 inhibitor, was also shown to reduce albuminuria in DKD patients. Recently, a selective endothelin A receptor antagonist atrasentan was shown to lower the risk of renal events in carefully selected patients with DKD.
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Therefore, novel treatments are being developed that target inflammation, fibrosis, oxidative stress, renal hemodynamics, glomerular hyperfiltration, the endothelin system, janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, etc.
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Despite all these treatment options, current management of DKD still leaves a substantial residual risk for kidney disease progression, morbidity and mortality.
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Other hypoglycemic agents with potential benefit in DKD are dipeptidyl peptidase 4 (DPP4) inhibitors, but further research needs to be conducted. Glucagon-like peptide-1 (GLP1) agonists also improve glycemic control, decrease cardiovascular outcomes and moderately decrease kidney outcomes. Since 2019, SGLT2 inhibitors have been part of the recommended treatment of DKD by the American Diabetes Association. In the last few years, sodium-glucose co-transporter-2 (SGLT2) inhibitors made it to the forefront by lowering blood sugar, blood pressure, reducing kidney function decline and improving cardiovascular outcomes. However, they do not reduce the number of cardiovascular events. The cornerstone of therapy in patients with albuminuria are angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), which slow down the rate of kidney function decline. Therefore, treatment of DKD encompasses appropriate lifestyle changes (i.e., weight reduction, physical activity, appropriate diet, smoking cessation), glycemic and blood pressure control. Risk factors for DKD are various (sex, age, ethnicity, hyperglycemia, arterial hypertension, obesity, smoking, etc.), but the leading ones are hyperglycemia and arterial hypertension. Albuminuria is also an important risk marker it is associated with kidney disease progression, risk of end-stage kidney disease, cardiovascular morbidity and mortality. Clinical identification of DKD is based upon at least 3 months of decreased estimated glomerular filtration rate (eGFR < 60 mL/min/1.73 m 2) and/or presence of albuminuria (urinary albumin–creatinine ratio (UACR) ≥ 30 mg/g) in a patient with DM. Although the gold standard for DKD confirmation is kidney biopsy, it is mostly not performed because of its invasive nature. DM and its complications present not only a personal, but also a major economic burden. Patients with DM have a 10-year life span loss while those with DKD have a 16-year life span loss.
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Cardiovascular and all-cause mortality is further increased by the presence of chronic kidney disease. DM patients suffer from excess morbidity, cardiovascular and all-cause mortality. Up to forty percent of these patients have diabetic kidney disease (DKD), making it the most common cause of chronic kidney disease. Diabetes mellitus (DM) is a worldwide health issue and it is estimated that it affected 463 million adults in 2019.