The pathophysiology of sepsis involves inflammation and hypercoagulability, which lead to microvascular thrombosis and compromised organ perfusion. Dipeptidyl peptidase (DPP)-4 inhibitors, e.g., linagliptin, are commonly used anti-diabetic drugs known to exert anti-inflammatory effects. However, whether these drugs confer an anti-thrombotic effect that preserves organ perfusion in sepsis remains to be investigated. In the present study, human umbilical vein endothelial cells (HUVECs) were treated with linagliptin to examine its anti-inflammatory and anti-thrombotic effects under tumor necrosis factor (TNF)-α treatment. To validate findings from in vitro experiments and provide in vivo evidence for the identified mechanism, a mouse model of lipopolysaccharide (LPS)-induced systemic inflammatory response syndrome was used, and pulmonary microcirculatory thrombosis was measured. In TNF-α-treated HUVECs and LPS-injected mice, linagliptin suppressed expressions of interleukin-1β (IL-1β) and intercellular adhesion molecule 1 (ICAM-1) via a nuclear factor-κB (NF-κB)–dependent pathway. Linagliptin attenuated tissue factor expression via the Akt/endothelial nitric oxide synthase pathway. In LPS-injected mice, linagliptin pretreatment significantly reduced thrombosis in the pulmonary microcirculation. These anti-inflammatory and anti-thrombotic effects were independent of blood glucose level. Together the present results suggest that linagliptin exerts protective effects against endothelial inflammation and microvascular thrombosis in a mouse model of sepsis.

Pneumonia is a leading cause of mortality. Severity-assessment scores in pneumonia guide treatment crucially, but the ones currently in existence are limited in their use. Community-based studies demonstrated the association between pre-existing low estimated glomerular filtration rate (eGFR) and outcomes in pneumonia. However, whether a single emergency department-eGFR measurement could predict outcomes in pneumonia remains unclear. This retrospective cohort study included 1554 patients hospitalized with pneumonia. The predictor was the first eGFR measurement. Outcomes included mortality, intensive care unit (ICU) admission, durations of hospital and ICU stay, and ventilator use. Receiver operating characteristic curves was used to determine optimal cutoff values to predict mortality. Of 1554 patients, 263 had chronic kidney disease, demonstrated higher C-reactive protein and SMART-COP scores, and had more multilobar pneumonia, acute kidney injury, ICU admission, and mortality. Patients with higher pneumonia severity scores tended to have lower eGFR. For predicting in-hospital mortality, the optimal eGFR cutoff value was 56 mL/min/1.73 m². eGFR < 56 mL/min/1.73 m² had an odds ratio of 2.5 (95% confidence interval, 1.6–4.0) for mortality by multivariate logistic regression. In Conclusion, eGFR < 56 mL/min/1.73 m² is an independent predictor of mortality, indicating that even mild renal impairment affects the outcome of pneumonia adversely.

Sacubitril/valsartan is a combined neprilysin inhibitor/angiotensin II receptor blocker designed for treatment of heart failure (HF). Nonetheless, its renal protective effect remained an issue of debate. This retrospective cohort study investigated the renal protective effect of sacubitril/valsartan in HF patients. HF patients on sacubitril/valsartan or valsartan for > 30 days were matched for gender, age, estimated glomerular filtration rate (eGFR), and left ventricular ejection fraction (LVEF) to be enrolled into analysis. The follow-up period was 18 months. The outcomes included end eGFR, renal function decline defined as 20% reduction of eGFR, mortality, and HF-related hospitalization. Each group had 137 patients after matching. The mean age was 72.7 years and 65.7% were male. Mean eGFR was 70.9 mL/min/1.73 m² and LVEF was 54.0% at baseline. Overall, the eGFR of sacubitril/valsartan groups was significantly higher than valsartan group at the end (P < 0.01). Subgroup analysis showed that the difference in eGFR was significant in subgroups with LVEF ≥ 40% or eGFR ≥ 60 mL/min/1.73 m². Multivariate Cox regression model showed that sacubitril/valsartan group had significantly reduced risk for renal function decline (hazard ratio: 0.5, 95% confidence interval: 0.3–0.9). Kaplan–Meier curve showed no difference in the risk for cardiovascular mortality, all-cause mortality or HF-related hospitalization. We showed renal protective effect of neprilysin inhibition in HF patients and specified that subgroups with LVEF ≥ 40% or eGFR ≥ 60 mL/min/1.73 m² were sensitive to this effect, suggesting an optimal subgroup of this treatment.

Acute kidney injury (AKI) is a sudden episode of kidney damage that commonly occurs in patients admitted to hospitals. To date, no ideal treatment has been developed to reduce AKI severity. Oligo-fucoidan (FC) interferes with renal tubular cell surface protein cluster of differentiation 44 (CD44) to prevent renal interstitial fibrosis; however, the influence of oligosaccharides on AKI remains unknown. In this study, FC, galacto-oligosaccharide (GOS), and fructo-oligosaccharide (FOS) were selected to investigate the influence of oligosaccharides on AKI. All three oligosaccharides have been proven to be partially absorbed by the intestine. We found that the oligosaccharides dose-dependently reduced CD44 antigenicity and suppressed the hypoxia-induced expression of CD44, phospho-JNK, MCP-1, IL-1β, and TNF-α in NRK-52E renal tubular cells. Meanwhile, CD44 siRNA transfection and JNK inhibitor SP600125 reduced the hypoxia-induced expression of phospho-JNK and cytokines. The ligand of CD44, hyaluronan, counteracted the influence of oligosaccharides on CD44 and phospho-JNK. At 2 days post-surgery for ischemia–reperfusion injury, oligosaccharides reduced kidney inflammation, serum creatine, MCP-1, IL-1β, and TNF-α in AKI mice. At 7 days post-surgery, kidney recovery was promoted. These results indicate that FC, GOS, and FOS inhibit the hypoxia-induced CD44/JNK cascade and cytokines in renal tubular cells, thereby ameliorating AKI and kidney inflammation in AKI mice. Therefore, oligosaccharide supplementation is a potential healthcare strategy for patients with AKI.

Atrial fibrillation (AF) is highly prevalent, occurring in 1%–2% of the adult population, increasing the risk of stroke, and resulting in considerable healthcare costs. While stroke is a major complication of AF, end-stage renal disease (ESRD) patients also have a high risk of stroke, suggesting that AF is a possible risk factor for mortality of ESRD patients. However, whether the existence of AF at the initiation of hemodialysis predicts higher mortality risk of incident ESRD patients remains to be defined. This retrospective cohort study was performed at Wanfang Hospital from January 2004 to May 2018. The end points were mortality of patients or the end of the study. Incident ESRD patients who were on maintenance hemodialysis for more than 3 months were eligible for inclusion. Cox proportional regression and Kaplan–Meier survival curves were used to determine the association between predictors and mortality. The association between AF and echocardiographic parameters, causes of death were also investigated. Of the 393 incident ESRD patients at initiation of hemodialysis, 57 (14.5%) had AF and the median age was 71 years. Patients with AF were significantly older; showed significantly higher C-reactive protein levels, more heart failure, chronic obstructive pulmonary disease and mortality. Multivariate Cox regression showed that AF had a hazard ratio of 4.1 (95% confidence interval: 2.4–7.0) for mortality. Age-specific analysis showed that AF was significantly associated with mortality in all age groups. Echocardiography measurements including ejection fraction and left ventricular hypertrophy (LVH) were similar in AF and non-AF patients. Cause-specific analysis showed that AF significantly associated with overall cardiovascular death and death due to acute myocardial infarction/coronary artery disease and sepsis. AF at the initiation of hemodialysis predicts higher mortality risk of incident ESRD patients regardless of age. The systolic function and degree of LVH were similar in AF and non-AF patients. The association between AF and sepsis-related death suggested the role of systemic inflammation on the pathogenesis of AF.

While the patency of vascular access is essential for hemodialysis patients, optimal pharmaceutical treatment to maintain arteriovenous fistula (AVF) patency remains lacking. As cardiovascular diseases are highly prevalent in patients with end-stage renal disease, various cardiovascular medications have also been used to maintain AVF patency. However, previous studies revealed inconsistent therapeutic effects and a comprehensive evaluation of this issue is needed. The present retrospective, longitudinal cohort study included patients receiving successful AVF creation. The evaluated cardiovascular medications included antiplatelet agents, antihypertensive agents, nitrates and nitrites, statins, dipyridamole, and pentoxifylline. The outcome was AVF primary patency. All laboratory data and medication profiles were recorded at baseline and followed at 3-month interval, until the end of the 2-year study period. Cox proportional regression model with time-dependent covariates was used to evaluate the risk for AVF patency loss. A total of 349 patients were included in the present study, in which 57% were men and the mean age was 65 ± 14 years. Among the included patients, 40% used antiplatelet agents, 27% used dipyridamole and 36% used statins at baseline. Of all the evaluated cardiovascular medications, only dipyridamole showed significant association with a higher risk for loss of AVF patency. To evaluate the effect of combination of antiplatelet agents and dipyridamole, the patients were classified into four groups, I: combine use of antiplatelet agents and dipyridamole, II: antiplatelet only, III: dipyridamole only; IV: none of both were used. Of the four groups, group IV exhibited highest AVF patency (52.4%), which was followed by group III (42.7%), group II (40%), and group I (28.6%), respectively. Compared with group IV, only group I showed a significantly higher risk for AVF patency loss. None of the cardiovascular medications evaluated in the present study showed a beneficial effect on AVF patency. Furthermore, dipyridamole showed an association with a higher risk of AVF patency loss. We do not suggest a beneficial effect of dipyridamole on maintaining AVF patency, particularly in combination with antiplatelet agents.