Intravitreal ranibizumab injection is associated with an increased risk of chronic kidney disease: a population-based study in Taiwan.

Systemic vascular endothelial growth factor (VEGF) blockade has been the top adjunctive chemotherapy since 1990. Anti-VEGF therapy has also been associated with worsened renal function in some patients. However, the association between patient outcomes and use of intravitreal VEGF inhibitors remains controversial. Thus, it is necessary to determine the action mechanism and long-term renal effects of ranibizumab. The National Health Insurance Research Database (NHIRD) is one of the largest global databases that are extensively used for epidemiological research. NHIRD contains the medical information of all insureds, such as inpatient, outpatient, emergency, and traditional Chinese medicine records. We selected subjects aged ≥ 20 years who recently administered ranibizumab for the ranibizumab cohort. Non-ranibizumab cohort consisted of subjects who did not receive ranibizumab, and the index date was a random date between 2008 and 2018. We excluded subjects with missing sex and age records and those in which the date of primary outcome was before the index date. The two cohorts were matched via 1:1 propensity score matching based on sex, age, index year, hypertension, diabetes mellitus, hyperlipidemia, stroke, coronary artery disease, alcoholism, chronic obstructive pulmonary disease, and age-related macular degeneration, retinal vein occlusion, and diabetic macular edema. Medical confounders were angiotensin I-converting enzyme inhibitors, statins, corticosteroids, VEGF inhibitors including bevacizumab and aflibercept, lithium, amphotericin B, adefovir, NSAIDS, cisplatin, and calcineurin inhibitors. Among 48,248 participants aged ≥ 20 years, 24,136 (50%) received ranibizumab (13,565 male [56.20%] and 10,571 female [43.80%]). Moreover, 24,136 participants who did not receive ranibizumab were matched by age, sex, comorbidities, and medications. Subjects who received ranibizumab exhibited a significantly higher risk of CKD than those who did not receive ranibizumab (adjusted hazard ratio = 1.88, 95% CI = 1.79-1.96). Our findings revealed that exposure to intravitreal ranibizumab is an independent risk factor for CKD. Therefore, physicians and ophthalmologists should make the patients aware of such a correlation to increase patient safety and decrease the CKD burden.

Serum lipopolysaccharide-binding protein levels and cardiovascular events in hemodialysis patients: A prospective cohort study.

INTRODUCTION: Patients with end-stage kidney disease (ESKD) exhibit an elevated cardiovascular risk. Chronic inflammation is one of the main mechanisms of cardiovascular disease (CVD). Lipopolysaccharide has been proposed as a link between systemic inflammation and CVD. Herein, we evaluated whether lipopolysaccharide-binding protein (LBP), a surrogate marker of lipopolysaccharide and consequent inflammation, is associated with cardiovascular events in ESKD. METHODS: We performed a prospective cohort study of maintenance haemodialysis patients. Baseline serum LBP levels were categorized into tertiles and also modelled continuously for analyses. Cox regression methods were used to evaluate the association of serum LBP levels with cardiovascular events. RESULTS: A total of 360 haemodialysis patients were included in this analysis. During a median follow-up of 3.1 years, 90 (25.0%) patients had cardiovascular events. Patients in the upper tertile of serum LBP levels had a significantly greater risk of cardiovascular events [hazard ratio (HR) 4.87; 95% confidence intervals (CI), 2.12-11.15] than those in the lower tertile, independent of age, sex, hypertension, diabetes, CVD, dialysis vintage, body mass index, non-high-density lipoprotein cholesterol, albumin, phosphorus, high-sensitivity C-reactive protein, and interleukin-6. The association was consistent regardless of whether competing risk of death was accounted for (subdistribution HR 4.87; 95% CI, 1.96-12.11 for upper versus lower tertiles) or serum LBP was analysed as a continuous variable (HR 1.30; 95% CI, 1.02-1.66 per 1 SD increment). CONCLUSIONS: Serum LBP levels were independently associated with cardiovascular events in heomodialysis patients. LBP might serve as a novel biomarker for CVD in ESKD.

Extracts from guava fruit protect renal tubular endothelial cells against acetaminophen­induced cytotoxicity.

Acetaminophen (APAP) is an analgesic and antipyretic agent primarily used in the clinical setting. However, high doses of APAP can cause oxidative stress. Guavas have been reported to provide anti­inflammatory, anti­microbial, anti­oxidative and anti­diarrheal functions. In addition, guavas have been reported to prevent renal damage due to progression of diabetes mellitus. Therefore, the aim of the present study was to investigate whether guavas can reduce APAP­induced renal cell damage. In the present study, extracts from guavas were obtained and added to APAP­treated renal tubular endothelial cells. The present results demonstrated that APAP induces cytotoxicity in renal tubular endothelial cells, while guava extracts inhibited this cytotoxicity. In addition, the study demonstrated that the protective effects of guava extracts against APAP­induced cytotoxicity may be associated with inhibition of oxidative stress and caspase­3 activation.

Ascorbic acid inhibits TPA-induced HL-60 cell differentiation by decreasing cellular H2O2 and ERK phosphorylation.

Retinoic acid (RA), vitamin D and 12-O­tetradecanoyl phorbol-13-acetate (TPA) can induce HL-60 cells to differentiate into granulocytes, monocytes and macrophages, respectively. Similar to RA and vitamin D, ascorbic acid also belongs to the vitamin family. High­dose ascorbic acid (>100 µM) induces HL­60 cell apoptosis and induces a small fraction of HL­60 cells to express the granulocyte marker, CD66b. In addition, ascorbic acid exerts an anti­oxidative stress function. Oxidative stress is required for HL­60 cell differentiation following treatment with TPA, however, the effect of ascorbic acid on HL­60 cell differentiation in combination with TPA treatment remains to be fully elucidated. The aim of the present study was to investigate the cellular effects of ascorbic acid treatment on TPA-differentiated HL-60 cells. TPA-differentiated HL-60 cells were used for this investigation, this study and the levels of cellular hydrogen peroxide (H2O2), caspase activity and ERK phosphorylation were determined following combined treatment with TPA and ascorbic acid. The results demonstrated that low­dose ascorbic acid (5 µM) reduced the cellular levels of H2O2 and inhibited the differentiation of HL­60 cells into macrophages following treatment with TPA. In addition, the results of the present study further demonstrated that low­dose ascorbic acid inactivates the ERK phosphorylation pathway, which inhibited HL­60 cell differentiation following treatment with TPA.

Vitamin C attenuates the toxic effect of aristolochic acid on renal tubular cells via decreasing oxidative stress­mediated cell death pathways.

Aristolochic acid (AA) is a component of Chinese medicinal herbs, including asarum and aristolochia and has been used in Traditional Chinese Medicine for a long time. Recent studies found that AA has a cytotoxic effect resulting in nephropathy. These studies indicated that AA­induced cytotoxicity is associated with increases in oxidative stress and caspase­3 activation. The present study further demonstrated that AA mainly elevates the H2O2 ratio, leading to increases in oxidative stress. Furthermore, the results indicated that AA induces cell death can via caspase­dependent and ­independent pathways. It is desirable to identify means of inhibiting AA­induced renal damage; therefore, the present study applied an anti­oxidative nutrient, vitamin C, to test whether it can be employed to reduce AA­induced cell cytotoxicity. The results showed that vitamin C decreased AA­induced H2O2 levels, caspase­3 activity and cytotoxicity in renal tubular cells. In conclusion, the present study was the first to demonstrate that AA­induced increases of the H2O2 ratio resulted in renal tubular cell death via caspase­dependent and ­independent pathways, and that vitamin C can decrease AA­induced increases in H2O2 levels and caspase­3 activity to attenuate AA­induced cell cytotoxicity.