A New Clinical Utility for Tubular Markers to Identify Kidney Responders to Saxagliptin Treatment in Adults With Diabetic Nephropathy.

OBJECTIVES: In recent clinical studies, saxagliptin exhibited nephroprotective potential by lowering albuminuria. In this study, we aimed to determine whether these kidney effects of saxagliptin were mediated by changes in markers of kidney tubular damage, including urinary neutrophil gelatinase-associated protein (uNGAL) and liver-type fatty acid-binding protein (uL-FABP). METHODS: Our study included 80 patients with type 2 diabetes, hypertension and mild to moderate diabetic kidney disease (DKD) with prevalent albuminuria. Patients were either randomly assigned to saxagliptin as add-on therapy or remained unchanged on their stable antidiabetic therapy as a control arm. RESULTS: Saxagliptin significantly reduced uNGAL with a median change of -25.4% (interquartile range [IQR], -35.6% to -12.2%) compared with the control group (median change, -0.91%; IQR, -12% to 11.88%; p<0.001) after 3 months. Similarly, patients given saxagliptin had a highly significant reduction in uL-FABP (median change, -24.4%; IQR, -30.5% to -15.1%) compared with controls (median change, -3.8%; IQR -10% to 12.5%; p<0.001). Median estimated glomerular filtration rate (eGFR) values after 3 months in the saxagliptin arm were significantly higher (76.5 mL/min per 1.73 m2; IQR, 70 to 92.75 mL/min per 1.73 m2) in the low-risk uNGAL group compared with controls (59.8 mL/min per 1.73 m2; IQR, 51 to 76.2 mL/min per 1.73 m2; p=0.002). Also, higher-although not significantly-posttreatment eGFR levels were observed in patients with low risk of uL-FABP (73 mL/min per 1.73 m2; IQR, 58 to 91.3 mL/min per 1.73 m2) compared with controls (57.3 mL/min per 1.73 m2; IQR, 49.5 to 72.6 mL/min per 1.73 m2; p=0.06). No significant increase was observed in high-risk patients for either marker when compared with controls. CONCLUSIONS: The albuminuria-lowering effect of saxagliptin may be due to inhibition of kidney tubular damage. Use of tubular markers may be a promising approach to identifying kidney responders to gliptins.

Patterns of Toll-Like Receptor Expressions and Inflammatory Cytokine Levels and Their Implications in the Progress of Insulin Resistance and Diabetic Nephropathy in Type 2 Diabetic Patients.

Background: Diabetic nephropathy (DNP) is a type 2 diabetes mellitus (T2DM) chronic complication, which is the largest single cause of end-stage kidney disease. There is an increasing evidence of the role of inflammation and Toll-like receptors (TLRs) as part of innate immune system in its development and progression. In addition, Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) downward signaling causes the production of proinflammatory cytokines, which can induce insulin (INS) resistance in T2DM. Objective: The goal of this study was to estimate the expression of TLRs (TLR2 and TLR4) in relation to inflammation and INS resistance in nephrotic type 2 diabetic patients with or without renal failure and to discuss the role of these TLRs in DNP progression. Patients and Methods: In this study, blood samples were obtained from type 2 diabetic patients with or without renal failure, and patients with non-diabetic renal failure were compared to healthy controls. All participants were tested for analysis of fasting plasma glucose and serum insulin, kidney function tests, C-reactive protein (CRP), and proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), and interleukin 6 (IL-6) as well as expression of TLR2 and TLR4 in peripheral blood (PB). Statistical analysis of data was done by using SPSS. Results: Diabetic patients with renal failure exhibited significant increase in TLR2, TLR4 mRNA expression in PB in comparison with normal subjects, diabetic patients without renal failure and non-diabetic patients with renal failure. Both diabetic patients with or without kidney failure and non-diabetic patients with renal failure had increased TLR2 and TLR4 mRNA expression in association with increased levels of proinflammatory cytokines (TNF-α, IFN-γ, and IL-6) compared to normal subjects. The diabetic patients with kidney failure exhibited the highest elevation of TLRs, Th1 cytokines and CRP in association the highest record of insulin resistance. Conclusion: Toll-like receptor 2 and Toll-like receptor 4 increased expression and Th2 cytokines may have an important role in the progression of DNP and deteriorations in insulin resistance in type 2 diabetic patients. Therefore, TLR2 and TLR4 may be a promising therapeutic target to prevent or retard DNP in type 2 diabetic patients.