Therapeutic Considerations for Antihyperglycemic Agents in Diabetic Kidney Disease.

Diabetic kidney disease is among the most frequent complications of diabetes, with approximately 50% of patients with ESRD attributed to diabetes in developed countries. Although intensive glycemic management has been shown to delay the onset and progression of increased urinary albumin excretion and reduced GFR in patients with diabetes, conservative dose selection and adjustment of antihyperglycemic medications are necessary to balance glycemic control with safety. A growing body of literature is providing valuable insight into the cardiovascular and renal safety and efficacy of newer antihyperglycemic medications in the dipeptidyl peptidase-4 inhibitor, glucagon-like peptide-1 receptor agonist, and sodium-glucose cotransporter 2 inhibitor classes of medications. Ongoing studies will continue to inform future use of these agents in patients with diabetic kidney disease

Urinary excretion of RAS, BMP, and WNT pathway components in diabetic kidney disease.

Abstract The renin-angiotensin system (RAS), bone morphogenetic protein (BMP), and WNT pathways are involved in pathogenesis of diabetic kidney disease (DKD). This study characterized assays for urinary angiotensinogen (AGT), gremlin-1, and matrix metalloproteinase 7 (MMP-7), components of the RAS, BMP, and WNT pathways and examined their excretion in DKD. We measured urine AGT, gremlin-1, and MMP-7 in individuals with type 1 diabetes and prevalent DKD (n = 20) or longstanding (n = 61) or new-onset (n = 10) type 1 diabetes without DKD. These urine proteins were also quantified in type 2 DKD (n = 11) before and after treatment with candesartan. The utilized immunoassays had comparable inter- and intra-assay and intraindividual variation to assays used for urine albumin. Median (IQR) urine AGT concentrations were 226.0 (82.1, 550.3) and 13.0 (7.8, 20.0) μg/g creatinine in type 1 diabetes with and without DKD, respectively (P < 0.001). Median (IQR) urine gremlin-1 concentrations were 48.6 (14.2, 254.1) and 3.6 (1.7, 5.5) μg/g, respectively (P < 0.001). Median (IQR) urine MMP-7 concentrations were 6.0 (3.8, 10.5) and 1.0 (0.4, 2.9) μg/g creatinine, respectively (P < 0.001). Treatment with candesartan was associated with a reduction in median (IQR) urine AGT/creatinine from 23.5 (1.6, 105.1) to 2.0 (1.4, 13.7) μg/g, which did not reach statistical significance. Urine gremlin-1 and MMP-7 excretion did not decrease with candesartan. In conclusion, DKD is characterized by markedly elevated urine AGT, MMP-7, and gremlin-1. AGT decreased in response to RAS inhibition, suggesting that this marker reflects therapeutic response. Urinary components of the RAS, BMP, and WNT pathways may identify risk of DKD and aid development of novel therapeutics

Effects of amino acids and glucose on mesangial cell aminopeptidase a and angiotensin receptors

Effects of amino acids and glucose on mesangial cell aminopeptidase a and angiotensin receptors.BackgroundHigh protein diets and diabetes increase renal renin angiotensin system (RAS) activity, which is associated with glomerular injury. Aminopeptidase A (APA) is a cell surface metalloprotease that degrades angiotensin II (AII) in the mesangium. Mesangial cells (MC) also possess receptors for AII; the type 1 (AT1 receptor) promotes proliferation and fibrosis, while the type 2 (AT2 receptor) opposes these effects. We evaluated whether amino acids and glucose alter expression of APA, AT1 receptor and AT2 receptor in a manner that further augments RAS activity.MethodsConfluent rat MC were grown in serum-free media for 48 hours prior to exposing to experimental conditions: control (C), high amino acids (HA, mixed amino acid solution added to raise concentrations 5- to 6-fold over C), high glucose (HG 30, mM glucose). Semi-quantitative RT-PCR was used to assess mRNA for APA, AT1 receptor, AT2 receptor, and β-actin. Values are expressed relative to βbgr; actin.ResultsBoth HA and HG reduced APA mRNA (HG 1.13 ± 0.19, HA 1.12 ± 0.16 versus C 1.27 ± 0.16 P < 0.05, N = 8). HA increased AT1 receptor mRNA (HA 2.11 ± 0.43 versus C 1.14 ± 0.28 P < 0.05, N = 8). HG increased AT2 receptor mRNA (HG 1.31 ± 0.43 versus C 0.82 ± 0.33 P < 0.05, N = 6).ConclusionsA reduction of APA, in response to high levels of amino acids or glucose, could contribute to increased AII as a result of decreased degradation in MC. The effect of amino acids to increase AT1 receptor expression may further enhance adverse hemodynamic and pro-fibrotic actions of AII. Conversely, glucose increased AT2 receptor expression, which could modulate responses mediated by the AT1 receptor

Current and projected burden of heart failure in the Australian adult population: A substantive but still ill-defined major health issue

Background: Comprehensive epidemiological data to describe the burden of heart failure (HF) in Australia remain lacking despite its importance as a major health issue. Herewith, we estimate the current and future burden of HF in Australia using best available data

New strategies to improve clinical outcomes for diabetic kidney disease

BACKGROUND: Diabetic kidney disease (DKD), the most common cause of kidney failure and end-stage kidney disease worldwide, will develop in almost half of all people with type 2 diabetes. With the incidence of type 2 diabetes continuing to increase, early detection and management of DKD is of great clinical importance. MAIN BODY: This review provides a comprehensive clinical update for DKD in people with type 2 diabetes, with a special focus on new treatment modalities. The traditional strategies for prevention and treatment of DKD, i.e., glycemic control and blood pressure management, have only modest effects on minimizing glomerular filtration rate decline or progression to end-stage kidney disease. While cardiovascular outcome trials of SGLT-2i show a positive effect of SGLT-2i on several kidney disease-related endpoints, the effect of GLP-1 RA on kidney-disease endpoints other than reduced albuminuria remain to be established. Non-steroidal mineralocorticoid receptor antagonists also evoke cardiovascular and kidney protective effects. CONCLUSION: With these new agents and the promise of additional agents under clinical development, clinicians will be more able to personalize treatment of DKD in patients with type 2 diabetes