Effects of the SGLT2 inhibitor canagliflozin on plasma biomarkers TNFR-1, TNFR-2 and KIM-1 in the CANVAS trial

Aims/hypothesis Higher plasma concentrations of tumour necrosis factor receptor (TNFR)-1, TNFR-2 and kidney injury molecule-1 (KIM-1) have been found to be associated with higher risk of kidney failure in individuals with type 2 diabetes in previous studies. Whether drugs can reduce these biomarkers is not well established. We measured these biomarkers in samples of the CANVAS study and examined the effect of the sodium–glucose cotransporter 2 inhibitor canagliflozin on these biomarkers and assessed whether the early change in these biomarkers predict cardiovascular and kidney outcomes in individuals with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS). Methods Biomarkers were measured with immunoassays (proprietary multiplex assay performed by RenalytixAI, New York, NY, USA) at baseline and years 1, 3 and 6. Mixed-effects models for repeated measures assessed the effect of canagliflozin vs placebo on the biomarkers. Associations of baseline levels and the early change (baseline to year 1) for each biomarker with the kidney outcome were assessed using multivariable-adjusted Cox regression. Results In total, 3523/4330 (81.4%) of the CANVAS participants had available samples at baseline. Each doubling in baseline TNFR-1, TNFR-2 and KIM-1 was associated with a higher risk of kidney outcomes, with corresponding HRs of 3.7 (95% CI 2.3, 6.1; p < 0.01), 2.7 (95% CI 2.0, 3.6; p < 0.01) and 1.5 (95% CI 1.2, 1.8; p < 0.01), respectively. Canagliflozin reduced the level of the plasma biomarkers with differences in TNFR-1, TNFR-2 and KIM-1 between canagliflozin and placebo during follow-up of 2.8% (95% CI 3.4%, 1.3%; p < 0.01), 1.9% (95% CI 3.5%, 0.2%; p = 0.03) and 26.7% (95% CI 30.7%, 22.7%; p < 0.01), respectively. Within the canagliflozin treatment group, each 10% reduction in TNFR-1 and TNFR-2 at year 1 was associated with a lower risk of the kidney outcome (HR 0.8 [95% CI 0.7, 1.0; p = 0.02] and 0.9 [95% CI 0.9, 1.0; p < 0.01] respectively), independent of other patient characteristics. The baseline and 1 year change in biomarkers did not associate with cardiovascular or heart failure outcomes. Conclusions/interpretation Canagliflozin decreased KIM-1 and modestly reduced TNFR-1 and TNFR-2 compared with placebo in individuals with type 2 diabetes in CANVAS. Early decreases in TNFR-1 and TNFR-2 during canagliflozin treatment were independently associated with a lower risk of kidney disease progression, suggesting that TNFR-1 and TNFR-2 have the potential to be pharmacodynamic markers of response to canagliflozin. Graphical abstract

Humoral and cellular indices of immunity in newborns with early realization of the allergically changed reactivity

The complex immunologic examination in 39 children aged 2 to 28 days with early realization of the allergically changed reactivity in boys 61,5%, in girls 38,5% is performed. The peculiarities of immunologic reactivity in children with early realization of the allergically changed reactivity (the increase of the immune regulatory index due to the deficiency of CD 8+ lymphocytes, the increased expression of activation markers, the increase of Ig E) show the prevalence of the atopic response type. Uniformity of changes of the immune status indices in early and late neonatal period testifies the intrauterine and/or early change of immunocompetent cell phenotype under the influence of perinatal development factors of a child

Association Between Kidney Function Decline and Baseline TNFR Levels or Change Ratio in TNFR by Febuxostat Chiefly in Non-diabetic CKD Patients With Asymptomatic Hyperuricemia

Background: The levels of circulating tumor necrosis factor receptor (TNFR) 1 and 2 help predict the future decline of estimated glomerular filtration rate (eGFR) chiefly in patients with diabetes. It has been recently reported that the change ratio in TNFR1 by SGLT2 inhibitor treatment is also related with future GFR decline in patients with diabetes. The aims of this study are to investigate the association between baseline TNFR levels and early change in TNFR levels by the non-purine selective xanthine oxidase inhibitor, febuxostat, and future eGFR decline chiefly in chronic kidney disease (CKD) patients without diabetes.Methods: We conducted a post-hoc analysis of the FEATHER study on patients with asymptomatic hyperuricemia and CKD stage 3, who were randomly assigned febuxostat 40 mg/day or matched placebo. This analysis included 426 patients in whom baseline stored samples were available. Serum TNFR levels at baseline were measured using enzyme-linked immunosorbent assay. Those levels were also measured using 12-week stored samples from 197 randomly selected patients.Results: Compared with placebo, short-term febuxostat treatment significantly decreased the median percent change from baseline in serum uric acid (−45.05, 95% CI −48.90 to −41.24 mg/dL), TNFR1 (1.10, 95% CI−2.25 to 4.40), and TNFR2 (1.66, 95% CI −1.72 to 4.93), but not TNFR levels. Over a median follow-up of 105 weeks, 30 patients (7.0%) experienced 30% eGFR decline from baseline. In the Cox multivariate model, high levels of baseline TNFR predicted a 30% eGFR decline, even after adjusting for age, sex, systolic blood pressure, high sensitivity C-reactive protein, uric acid, and presence or absence of febuxostat treatment and diabetes, in addition to baseline albumin to creatinine ratio and eGFR.Conclusion: Early change in circulating TNFR levels failed to predict future eGFR decline; however, regardless of febuxostat treatment, the elevated baseline level of TNFR was a strong predictor of 30% eGFR decline even in chiefly non-diabetic CKD patients with asymptomatic hyperuricemia.

Beneficial Effect of Left Ventricular Remodeling after Early Change of Sacubitril/Valsartan in Patients with Nonischemic Dilated Cardiomyopathy

Background and Objectives: Evidence for effectiveness of early change from angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs) to sacubitril/valsartan is lacking. We aimed to investigate whether early changes to sacubitril/valsartan could improve outcomes in patients with nonischemic dilated cardiomyopathy (DCM) in real-world practice. Materials and Methods: A total of 296 patients with nonischemic DCM who were treated with ARB or ACEI continuously (group A, n = 150) or had their medication switched to sacubitril/valsartan (group S, n = 146) were included. The sacubitril/valsartan group was divided into early change (within 60 days, group S/E, n = 59) and late change (group S/L, n = 87) groups. Changes in echocardiographic parameters from the time of initial diagnosis to the last follow-up were analyzed. Results: Patients in group S showed greater left ventricular (LV) end-diastolic dimension (EDD) (group A vs. S, 61.7 ± 7.4 vs. 66.5 ± 8.0, p < 0.001) and lower LV ejection fraction (LVEF) (28.9 ± 8.2% vs. 23.9 ± 7.5%, p < 0.001) than those in group A at initial diagnosis. During a median follow-up of 76 months, patients in group S/E, ∆ LVEF (%) and ∆ LVESD (mm) were significantly improved compared with those in patients in group A (group A vs. S/E, ∆ LVEF, p = 0.036; ∆ LVESD, p = 0.023) or S/L (group S/E vs. S/L, ∆ LVEF, p = 0.05; ∆ LVESD, p = 0.005). Among patients whose medications were switched to sacubitril/valsartan, those with an earlier change showed a significant correlation with greater LVEF improvement (r = −0.367, p < 0.001) and LV reverse remodeling (r = 0.277, p < 0.001). Conclusions: in patients with nonischemic DCM, an early switch to sacubitril/valsartan was associated with greater improvement in LV function. Patients might benefit in terms of LV function by early switching to sacubitril/valsartan.

Circulating miR-145 as a marker of therapeutic response to anti-TNF therapy in patients with ankylosing spondylitis

Circulating miRNAs appear promising therapeutic and prognostic biomarkers. We aimed to investigate the predictive value of circulating miRNAs on the disease outcome following anti-TNF therapy in patients with ankylosing spondylitis (AS). Our study included 19 AS patients assessed at baseline (M0), after three (M3) and twelve months (M12) of therapy. Total RNA was isolated from plasma. A comprehensive analysis of 380 miRNAs using TaqMan Low Density Array (TLDA) was followed by a single assay validation of selected miRNAs. All AS patients had high baseline disease activity and an excellent response to anti-TNF therapy at M3 and M12. TLDA analysis revealed the dysregulation of 17 circulating miRNAs, including miR-145. Single assay validation confirmed that miR-145 is significantly downregulated at M3 compared to baseline. The decrease in the levels of miR-145 from M0 to M3 negatively correlated with the change in BASDAI from M0 to M3; and positively correlated with disease activity improvement from M3 to M12 as per BASDAI and ASDAS. The predictive value of the early change in miR-145 and levels of miR-145 at M3 were further validated by Receiver operating curves analysis. We show that the early change in circulating miR-145 may be a predictor for the future outcome of AS patients treated with TNF inhibitors. Patients with a more significant decrease in miR-145 levels may show further significant improvement of disease activity after 12 months. Monitoring the expression of miR-145 in plasma in AS patients may, therefore, influence our therapeutic decision-making.