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.

Gout and the risk of epilepsy: A population-based cohort study.

Gout is a chronic disease related to uric acid metabolism. It involves crystals of uric acid accumulating in the joints, causing joint pain and releasing cytokines that trigger inflammation. Inflammation is a key component in the pathogenesis of epilepsy. Thus, we conducted a cohort study to investigate if epilepsy is associated with gout and determine the risk of epilepsy in patients with gout.The gout cohort was obtained from the Registry of Catastrophic Illnesses Patient Database (RCIPD). We identified 104,238 patients who were aged 20 years or more and newly diagnosed with gout between 2000 and 2011 and 3 outpatient visits or history of gout-specific hospitalization between 2000 and 2011. Patients without gout were frequency matched with the gout cohort at a 2:1 ratio according to age, sex, comorbidities, and year of gout diagnosis.The gout cohort showed a 1.27-fold higher overall crude hazard ratio (HR) for epilepsy compared with the control cohort. After we adjusted the analyses by age, sex, and comorbidities the gout patients displayed an increased risk of epilepsy compared with the control group (adjusted HR = 1.25, 95% confidence interval = 1.15-1.36).This study revealed a significantly higher risk of epilepsy in patients with gout. It provides further evidence for the debate around the effect of gout on brain health.

Impaired Gut Epithelial Tight Junction Expression in Hemodialysis Patients Complicated with Intradialytic Hypotension.

BACKGROUND: There is accumulating evidence pointing to uremia-induced impairment of the intestinal epithelial barrier structure in advanced chronic kidney disease (CKD) and hemodialysis (HD) patients. In this study, the impact of intradialytic hypotension on intestinal barrier integrity is being explored. METHODS: Immunohistochemical staining was used to detect the expression of 4 types of tight junction (TJ) proteins such as occludin, zonula occludens-1 (ZO-1), claudin-1, and claudin-4, in colonic samples of a group of patients receiving segmental colectomy. Five patients with nondialysis CKD (group 2), 5 HD patients with intradialytic hypotension (group 3), and 5 non-CKD subjects (group 1) were examined. RESULTS: Both patients' groups 2 and 3 demonstrated significantly reduced expression of occludin as compared to group 1 (p < 0.05 and p < 0.01, resp.). Except for claudin-4, expression of all markers of TJ proteins was significantly reduced in patients' group 3 as compared to control (p < 0.01). In addition, decreased expressions of claudin-1 and ZO-1 were also more pronounced in group 3 when compared to group 2. CONCLUSIONS: This study extends the earlier finding by demonstrating that dialysis-related hypotension caused even marked depletion of the key protein constituents of the epithelial TJ.

Proportions of Proinflammatory Monocytes Are Important Predictors of Mortality Risk in Hemodialysis Patients.

Despite the continuous progression in dialysis medicine, mortality and the burden of cardiovascular disease (CVD) among hemodialysis patients are still substantial. Substantial evidence suggests that proinflammatory (CD16+) monocytes contribute to the development of atherosclerosis. A cohort of 136 stable hemodialysis patients (follow-up: 6.25 year) was assessed to investigate the association between the proportion of CD16+ monocytes for all-cause and CVD mortalities. The CD16+ monocytes were associated with both mortalities after adjusting for a preexisting CVD history. Compared to the reference group (CD16+ monocytes within [15.6-18.6], the first and second quartile), patients with CD16+ monocytes above the highest quartile level (>21.5) had an adjusted hazard ratio (HR) of 30.85 (95% confidence interval [CI]: 7.12-133.8) for CVD mortality and 5.28 (2.07-13.49) for all-cause mortality, and those with CD16+ monocytes below the lowest quartile ≤15.6), had significantly elevated death risks after 3.5-year follow-up (HR [95% CI]: 10.9 [2.42-48.96] and 4.38 [1.45-13.24] for CV and all-cause mortalities, respectively). The hemodialysis patients with CD16+ monocyte level in a low but mostly covering normal range also portended a poor prognosis. The findings shed some light for nephrologists on future prospects of early recognizing immune dysfunction and improving early intervention outcomes.

A Practical Standardized Composite Nutrition Score Based on Lean Tissue Index: Application in Nutrition Screening and Prediction of Outcome in Hemodialysis Population.

OBJECTIVE: Rapid screening and monitoring of nutritional status is mandatory in hemodialysis population because of the increasingly encountered nutritional problems. Considering the limitations of previous composite nutrition scores applied in this population, we tried to develop a standardized composite nutrition score (SCNS) using low lean tissue index as a marker of protein wasting to facilitate clinical screening and monitoring and to predict outcome. DESIGN AND METHODS: This retrospective cohort used 2 databases of dialysis populations from Taiwan between 2011 and 2014. First database consisting of data from 629 maintenance hemodialysis patients was used to develop the SCNS and the second database containing data from 297 maintenance hemodialysis patients was used to validate this developed score. RESULTS: SCNS containing albumin, creatinine, potassium, and body mass index was developed from the first database using low lean tissue index as a marker of protein wasting. When applying this score in the original database, significantly higher risk of developing protein wasting was found for patients with lower SCNS (odds ratio 1.38 [middle tertile vs highest tertile, P < .0001] and 2.40 [lowest tertile vs middle tertile, P < .0001]). The risk of death was also shown to be higher for patients with lower SCNS (hazard ratio 4.45 [below median level vs above median level, P < .0001]). These results were validated in the second database. CONCLUSION: We developed an SCNS consisting of 4 easily available biochemical parameters. This kind of scoring system can be easily applied in different dialysis facilities for screening and monitoring of protein wasting. The wide application of body composition monitor in dialysis population will also facilitate the development of specific nutrition scoring model for individual facility.

Validating Body Fat Assessment by Bioelectric Impedance Spectroscopy in Taiwanese Hemodialysis Patients.

OBJECTIVE: Obesity is becoming increasingly common in hemodialysis (HD) patients and is associated with inflammation and increased mortality. The primary aim of the present study was to evaluate the accuracy and variability of the bioimpedance device in measuring body fat in Taiwanese dialysis patients. DESIGN: Cross-sectional study. SUBJECTS: One hundred twenty-two adult patients receiving HD in a single hospital in Taiwan. SETTING: We compared the results of fat mass (FM) measured by dual-energy x-ray absorptiometry (DEXA) and bioelectrical impedance spectroscopy device (Body composition monitor, BCM). MAIN OUTCOME MEASUREMENT: FM measured by BCM was calculated by subtracting fat-free mass (FFM) from body mass assuming fractional hydration of FFM of 0.73 or the proprietary prediction equations from the BCM model. RESULTS: Assessment of whole-body composition showed that percentage FM measured using the 2 techniques was highly correlated when using the BCM model or estimating from total body water using constant (0.73) hydration (r = 0.87, P < .001). There was no evident difference in measurement between patients gender. The Bland-Altman plot also showed good agreement of percentage of FM (t = 3.82; P < .001). In female patients, it was found that BCM significantly underestimated mean FM as compared to DEXA. However, the mean differences of the estimates between the methods were small (0.35 ± 3.00 kg) and with Bland-Altman plot the limits of agreements were -5.5 to 6.2 kg (P = .40) for FM in female patients. CONCLUSIONS: Using DEXA as the reference test, BCM is a valid tool for the assessment of total body fat in HD patients. Hence, it may provide a more accessible tool for early detection of changes in body composition in these high-risk patients.

Role of Cilostazol Therapy in Hemodialysis Patients with Asymptomatic Peripheral Arterial Disease: A Retrospective Cohort Study.

Background. Peripheral arterial disease (PAD) and its relevant complications are more common in hemodialysis (HD) patients, while the evidence regarding antiplatelet therapy in CKD patients is scarce. We retrospectively analyzed the efficacy of cilostazol on outcomes in HD patients with asymptomatic PAD (aPAD). Methods. This cohort study enrolled 217 HD patients (median follow-up time: 5.75 years). Associations between cilostazol use and the outcomes were evaluated by time-dependent Cox regression analysis. Results. During follow-up, 39.5% (47/119) patients used cilostazol for aPAD and 31.8% (69/217) patients died. Cilostazol users had significantly lower CVD and all-cause mortalities (adjusted HR [95% CI]: 0.11 [0.03, 0.51] and 0.2 [0.08, 0.52]) than nonusers. Both death risks were nonsignificantly higher in cilostazol users than in HD patients without aPAD. The unadjusted and adjusted HR [95% CI] of CVD death risk were 0.4 [0.07, 2.12] and 0.14 [0.02, 0.8] for patients with aPAD during follow-up and were 0.74 [0.16, 3.36] and 0.19 [0.04, 0.93] for those with aPAD at initial. Conclusions. In HD patients with aPAD, lower CVD and all-cause mortality rates were observed in low-dose cilostazol user. Further evidences from large-scale prospective study and randomization trial are desired to confirm the effect of cilostazol.

Proteinuria as a Therapeutic Target in Advanced Chronic Kidney Disease: a Retrospective Multicenter Cohort Study.

Current evidence of proteinuria reduction as a surrogate target in advanced chronic kidney disease (CKD) is incomplete due to lack of patient-pooled database. We retrospectively studied a multicenter cohort of 1891 patients who were enrolled in the nationwide multidisciplinary pre-end stage renal disease care program with a baseline glomerular filtration rate (GFR) <45 mL/min/1.73 m(2) and followed longitudinally to investigate the effect of the change in proteinuria on renal death (defined as composite of dialysis and death occurring before initiation of dialysis). The group with a change in proteinuria ≤0.30 g/g (n = 1261) had lower cumulative probabilities of renal death (p < 0.001). In a linear regression model, a higher baseline proteinuria and a greater increase in proteinuria were associated with faster annual GFR decline. Cox's analysis showed that every 1 unit increase in natural log(baseline proteinuria, 10 g/g) and every 0.1 g/g increase in the change in proteinuria resulted in 67% (HR = 1.67, 95% CI: 1.46-1.91) and 1% (HR = 1.01, 95% CI: 1.01-1.01) greater risk of renal death respectively after adjusting for the effects of the other covariates. Our study provided a patient-based evidence to support proteinuria as a therapeutic target in advanced CKD.

Association between Redox Status of Serum Albumin and Peritoneal Membrane Transport Properties in Patients on Peritoneal Dialysis.

BACKGROUND: Albumin, the most abundant protein in the extracellular fluid, displays an important antioxidant activity. Increased levels of oxidized albumin levels (high human non-mercaptoalbumin (HNA) level) have been reported in the serum of patients with end-stage renal disease. In this study, we attempted to identify the albumin redox status in the serum of patients on peritoneal dialysis (PD) and examined the relationship between these proteins and the transport type of the peritoneal membrane and other clinical and laboratory variables. METHODS: We performed a cross-sectional study of a cohort of 80 patients with end-stage renal disease receiving PD. Peritoneal transport characteristics were identified and after peritoneal equilibration test patients were grouped as high (high(H)/high-average (HA) group, n = 31) or low (low (L)/low-average (LA) group, n = 49) transporters. The redox state of human serum albumin was measured using high-performance liquid chromatography. RESULTS: The fraction of human mercaptoalbumin (HMA) showed significantly higher values in patients with high transport status than those with low transport status (f(HMA) 64.0 ± 5.4 and 52.7 ± 10.4%, respectively). Our data showed that the H/HA transport characteristic was associated with lower albumin (3.76 ± 0.48 vs. 4.00 ± 0.35, p < 0.05), and lower levels of advanced oxidized protein product (p = 0.008) when compared with the L/LA type. A correlation analysis showed that there was a positive correlation between dialysate/plasma (D/P) creatinine and f(HMA) levels (r = 0.511, p < 0.0001), as well as hemoglobin levels r = 0.231, p = 0.044 and a negative correlation between D/P creatinine and serum albumin, cholesterol and LDL levels (r = -0.236, p = 0.039; r = -0.237, p = 0.038; r = -0.272, p = 0.018, respectively). CONCLUSIONS: This study showed that higher serum levels of reduced albumin f(HMA) appear to be associated with high/high average peritoneal membrane transport characteristics in the incident PD patients.