The relationship between neutrophil‐to‐lymphocyte ratio and vascular calcification in end‐stage renal disease patients

Chronic inflammation was found to be correlated with coronary (CAC) and thoracic peri‐aortic calcification (TAC) in end‐stage renal disease (ESRD) patients. Neutrophil‐to‐lymphocyte ratio (NLR) was introduced as a potential marker to determine inflammation in cardiac and noncardiac disorders. Data regarding NLR and its association with TAC and CAC are lacking. We aimed to determine the relationship between NLR and vascular calcification in ESRD patients. This was a cross‐sectional study involving 56 ESRD patients (22 females, 34 males; mean age, 49.9 ± 14.2 years) receiving peritoneal dialysis or hemodialysis for ≥6 months in the Dialysis Unit of Necmettin Erbakan University. TAC and CAC scores were measured by using an electrocardiogram‐gated 64‐multidetector computed tomography. NLR was calculated as the ratio of the neutrophils and lymphocytes. There was a statistically significant correlation between NLR, TACS and CACS in ESRD patients (r = 0.43, P = 0.001 and r = 0.30, P = 0.02, respectively). The stepwise linear regression analysis revealed that age, as well as NLR were independent predictors of TACS. However, increased age was the only independent predictor of CACS according to linear regression analysis. Simple calculation of NLR can predict vascular calcification in ESRD patients.     

Monocyte/lymphocyte ratio as a better predictor of cardiovascular and all‐cause mortality in hemodialysis patients: A prospective cohort study

Introduction: Patients with chronic kidney disease, especially those with end‐stage renal disease, have an increased risk of death. Previous studies have suggested neutrophil/lymphocyte ratio (NLR) was related to worse outcome in patients undergoing hemodialysis (HD). However, monocyte/lymphocyte ratio (MLR) has not been evaluated in HD patients. In this study, we prospectively studied the predictive value of MLR for all‐cause and cardiovascular mortality in HD patients and compared it with NLR. Methods: Patients who had been on a HD treatment for at least 6 months were enrolled. MLR was calculated by dividing the monocyte count by the lymphocyte count. Survival outcomes were estimated using the Kaplan‐Meier method and compared by the log‐rank test. Univariate and multivariate analyses were performed to evaluate the prognostic impact of MLR and other clinical factors on all‐cause and cardiovascular mortality. Results: Mortality rates for the lowest, middle, and highest MLR tertile group were 3.65, 7.02, and 11.15, respectively per 100 patient‐years. The Kaplan‐Meier analysis revealed that survival rates were significantly different among three MLR groups (P < 0.001). In multivariate Cox regression analyses, MLR was independently associated with all‐cause mortality (HR 4.842; 95% CI, 2.091–11.214; P < 0.001) and cardiovascular mortality (HR 6.985, 95% CI 1.943–25.115, P = 0.003) as continuous variables. NLR was not an independent predictor of all‐cause nor cardiovascular mortality after adjusted with MLR. Conclusions: The main finding of the study suggest that higher MLR was a strong and independent predictor of all‐cause and cardiovascular mortality and overwhelmed NLR among HD patients.     

The neuroprotective effect of a traditional herbal (kyung‐ok‐ko) on transient middle cerebral artery occlusion‐Induced ischemic rat brain

Kyung‐ok‐ko (KOK) has been used for the treatment of central nervous system disorders such as amnesia, dementia, and cerebral ischemia. However, the effects of KOK on transient ischemic‐induced neuronal damage are still unclear. We examined whether KOK improves functional recovery and has a neuroprotective effect on infarction volume after transient middle cerebral artery occlusion (MCAO). KOK (50, 100, and 200 mg/kg) was administered orally following reperfusion and twice per day for 14 days post‐MCAO. Infarction volume was measured using 2% 2‐3‐5 triphenylterazolium (TTC) staining at 14 days post‐MCAO and alteration in regional cerebral blood flow (rCBF) after KOK treatment was monitored. Functional improvement was evaluated using adhesive removal and treadmill tests at 1, 7, and 14 days post‐MCAO. Also, apoptotic cell death was assessed by terminal deoxynucleotidyl‐transferase mediated d‐UTP‐biotin nick end (TUNEL) in the peri‐infarction region. The protein level of inflammatory cytokines such as tumor necrosis factor‐α (TNF‐α), interleukin‐1α (IL‐1α), and interleukin‐1β (IL‐1β) was measured in the ischemic core, ischemic border zone, and contralateral hemisphere regions. The KOK‐treated group showed both reduced infarction volume and behavior tests demonstrated a significant improvement as compared to the control. Also, in the KOK‐treated group, rCBF was recovered to near normal levels. The apoptotic cells were significantly decreased as compared with the control group in the ischemic peri‐infarction area. Furthermore, the level of TNF‐α, IL‐1β, and IL‐1α was decreased. These results suggest that KOK may improve functional outcome by inhibiting inflammatory cytokines (TNF‐α, IL‐1β, and IL‐1α) in neuronal injury such as ischemic stroke.     

Outcomes of patients with end‐stage renal disease (ESRD) under chronic hemodialysis requiring continuous renal replacement therapy (CRRT) and patients without ESRD in acute kidney injury requiring CRRT: A single‐center study

In most continuous renal replacement therapy (CRRT) studies, end‐stage renal disease (ESRD) patients were excluded and the outcomes of patients with ESRD treated with chronic hemodialysis (HD) were unknown. The purposes of this study were to (1) evaluate short‐term patient survival and (2) compare the survival of conventional HD patients needing CRRT with the survival of non‐ ESRD patients in acute kidney injury (AKI) requiring CRRT. We evaluated adults (>18 years) requiring CRRT who were treated in the intensive care unit (ICU) at Kosin University Gospel Hospital from January 1, 2009 to December 31, 2010. A total of 100 (24 ESRD, 76 non‐ESRD) patients underwent CRRT during the study period. Patients were divided into two major groups: patients with ESRD requiring chronic dialysis and patients without ESRD (non‐ESRD) with AKI. We compared the survival of conventional HD patients requiring CRRT with the survival of non‐ ESRD patients in AKI requiring CRRT. For non‐ESRD patients, the 90‐day survival rate was 41.6%. For ESRD patients, the 90‐day survival rate was 55.3%. Multivariate Cox proportional hazards analyses demonstrated that conventional HD was not a significant predictor of mortality (hazard ratio [HR]: 0.334, 95% confidence interval [CI]: 0.063–1.763, P = 0.196), after adjustment for age, gender, presence of sepsis, APACHE score, use of vasoactive drugs, number of organ failures, ultrafiltration rate, and arterial pH. The survival rates of non‐ESRD and ESRD patients requiring CRRT did not differ; ESRD with conventional HD patients may be not a significant predictor of mortality.     

Effect of hemodiafiltration with endogenous reinfusion on overt idiopathic chronic inflammation in maintenance hemodialysis patients: A multicenter longitudinal study

Chronic inflammation is widely diffuse in maintenance hemodialysis (MHD) patients and is associated with poor survival. Hemodiafiltration with endogenous reinfusion (HFR) is a dialysis technique, highly biocompatible, able to adsorb proinflammatory cytokines and to decrease amino acids and antioxidants loss. These features could be helpful in MHD patients affected by idiopathic chronic inflammation, but this issue remains to be elucidated. We performed a multicenter longitudinal study to assess the effect of the switching from bicarbonate HD to HFR in patients with serum C‐reactive Protein (CRP) > 5 mg/L coupled with albumin <4.0 g/dL in the last 6 months. We enrolled 24/176 (14%) patients, of which 20 patients were assessed at 4 months and 18 completed the study. We excluded 11 patients with evident causes of inflammation. At baseline, serum levels of CRP (18.7[7.0–39.4] mg/L) and albumin (3.5[3.3–3.7] g/dL) were significantly correlated (r = ?0.49; P = 0.028). The effect on CRP and albumin was almost evident in the first 4 months and remained stable until to eighth month. A strict correlation (R = ?0.49; 0.040) between percentage change of CRP (?35%) and albumin (+14%) after 8 months of HFR. These effects were associated with the reduction of IL‐6, IL‐1β, and TNF‐α and the increment of pre‐albumin and leptin, whereas the serum levels of Branched Chain Amino Acid (BCAA) remained unchanged. In MHD patients affected by idiopathic chronic inflammation the switching from BHD to HFR is associated with improvement of inflammation. Whether these favorable effects may modify the outcomes of these high‐risk patients needs to be confirmed by studies ad hoc.     

Plasma myeloperoxidase,NT‐proBNP,and troponin‐I in patients on CAPD compared with those on regular hemodialysis

Myeloperoxidase (MPO) is a hemoprotein that is released during inflammation and may lead to irreversible protein and lipid modification, increasing levels of oxidized low density lipoprotein, and promoting athrogenesis. Recently, it has been considered as a risk factor for cardiovascular diseases. Similarly, the measurement of carotid intima‐media thickness gives an indication about the degree of atherosclerosis and prediction of clinical cardiovascular events. Elevated white blood cells counts may indicate a state of acute inflammation and follow its progression. Dialysis patients are at a high risk of developing cardiovascular disease compared with healthy subjects. The role of N‐terminal pro‐brain natriuretic peptide and increased cardiac troponin in identification and prognostication of cardiovascular diseases in end‐stage renal disease patients has been investigated. The current study aimed to evaluate plasma MPO and its possible relationship with carotid intima‐media thickness, troponin I, N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), and insulin resistance as measured by homeostatic model assessment (HOMA index) in a cohort of Saudi patients who are undergoing hemodialysis (HD) vs. continuous ambulatory peritoneal dialysis for end‐stage renal disease. Plasma MPO was significantly higher in patients on continuous ambulatory peritoneal dialysis (CAPD) than in those on HD and in normal subjects (P<0.001). Conversely, NT‐proBNP plasma levels were significantly higher in patients on HD (both predialysis and postdialysis) than in those on CAPD (P<0.01) and than normal subjects. Similarly, plasma troponin‐I levels were significantly higher in patients on HD compared with those of CAPD and than normal subjects (P<0.001). Plasma troponin‐I and NT‐proBNP levels were positively correlated in the 3 groups namely those on CAPD, Pre‐HD, and post‐HD (r: 0.464 and P=0.047; r: 0.330 and P=0.013; and r: 0.452 and P=0.024), respectively. There was no correlation between the MPO level and carotid intima‐media thickness (P>0.05). However, plasma MPO level correlated positively with the white blood cell count in patients on CAPD and in those on HD (P<0.05). Our findings suggest an increased oxidative stress in CAPD patients compared with HD patients, while the reported difference in plasma NT‐proBNP and troponin‐I may be related to the rapid decline of residual renal function in HD and type of membrane used in the HD dialysis procedure itself.     

Malnutrition‐inflammation‐coronary calcification in pediatric patients receiving chronic hemodialysis

Malnutrition, inflammation, and renal osteodystrophy parameters with resultant coronary calcification (CC) are associated with increased cardiovascular mortality in adults. Previous pediatric studies demonstrated CC in children but none assessed for an association between inflammation, malnutrition, renal osteodystrophy, and CC. To assess CC, ultrafast computerized tomogram was obtained for 16 pediatric patients (6 females; median age 17.2 years; range 9.1–21.2 years) receiving hemodialysis for ≥2 months. Inflammation was assessed by serum IL‐6, IL‐8, and C‐reactive protein levels on the day of the computerized tomogram scan; nutrition parameters included serum albumin, cholesterol, the body mass index standard deviation score, and normalized protein catabolic rate. Renal osteodystrophy parameters included time‐averaged serum calcium, phosphorus, total PTH, and calcitriol/calcium dose. Patients received hemodialysis thrice‐weekly; mean single pool Kt/V 1.48±0.13; and mean normalized protein catabolic rate 1.27±0.17 g/kg/day. Five of 16 patients had CC. Patients with CC were older (19.1±2.1 vs. 15.4±3.1 months; P=0.03), had longer dialysis vintage (49.4±15.3 vs. 17.2±10.5 months, P=0.0002), lower serum cholesterol (122±17.7 vs. 160.4±10.6 mg/dL, P=0.02), and higher phosphorus (9.05±1.2 vs. 6.1±0.96 mg/dL, P=0.0001). Mean serum albumin and normalized protein catabolic rate did not differ for patients with CC. All patients had elevated IL‐6 and IL‐8 levels compared with healthy norms; the mean IL‐6, IL‐8, and C‐reactive protein levels were not different in patients with CC. Coronary calcification was prevalent in older children receiving maintenance hemodialysis with a longer dialysis vintage. Worse renal osteodystrophy control and malnutrition (low cholesterol) may contribute to CC development.     

Positive association between plasma levels of oxidized low‐density lipoprotein and myeloperoxidase after hemodialysis in patients with diabetic end‐stage renal disease

End‐stage renal disease (ESRD) patients undergoing hemodialysis (HD) have a high prevalence of cardiovascular events. Low‐density lipoprotein (LDL) in dialysis patients has been shown to be susceptible to in vitro peroxidation; therefore, oxidized‐LDL (ox‐LDL) could be generated in these patients. Moreover, myeloperoxidase (MPO) released from activated neutrophils may play a role in the induction of LDL oxidation. The purpose of this study was to investigate the relationship between plasma ox‐LDL levels, plasma MPO levels, and serum high‐sensitivity C‐reactive protein (hs‐CRP) levels during initial HD in patients with diabetic ESRD. Patients (n = 28) had serial venous blood samples drawn before and after HD at the initial, second, and third sessions. Plasma ox‐LDL levels were measured using a specific monoclonal antibody (DLH3), and plasma MPO levels were measured using an enzyme‐linked immunosorbent assay kit. Plasma ox‐LDL levels and MPO levels after a single HD session increased significantly (ox‐LDL, P < 0.005; MPO, P < 0.0001) compared with levels before that HD session. However, the increase was transient since the levels returned to pre‐HD session levels. Additionally, plasma MPO levels showed a positive correlation with plasma ox‐LDL levels during HD (R = 0.62, P = 0.0029). No significant change was observed in serum hs‐CRP levels before and after each HD session. This study demonstrates that plasma MPO levels are directly associated with plasma ox‐LDL levels in diabetic ESRD patients during initial HD. These findings suggest a pivotal role for MPO and ox‐LDL in the progression and acceleration of atherosclerosis in patients undergoing HD.     

Association between depression and inflammatory/anti‐inflammatory cytokines in chronic kidney disease and end‐stage renal disease patients: A review of literature

Depression is a common psychiatric disorder in patients with advanced chronic kidney diseases (CKDs). Strong correlation has been reported between depression and patients' morbidity and mortality among dialysis patients. On the contrary, chronic inflammation may be a major contributor to morbidity and mortality in these patients. Elevated plasma levels of proinflammatory cytokines, especially C‐reactive protein and interleukin (IL)‐6, have been correlated with cardiovascular events, hospitalization, and all‐cause and cardiovascular‐associated mortality in dialysis patients. Studies suggested that inflammation‐mediated atherosclerotic cardiovascular diseases are the possible reasons for depression‐induced mortality among patients without renal diseases. Several studies found significant elevations in circulating levels of proinflammatory cytokines, particularly IL‐6 and tumor necrosis factor‐α, in patients with major depression. Furthermore, depressive mood and behaviors, including sadness and suicidal ideation, were observed in patients who received repeated injections of recombinant cytokines. A thorough literature review indicates that while depressive symptoms and elevated inflammatory cytokine levels coexist in CKD and dialysis patients, their association is uncertain. Depression seems to be more associated with elevated serum levels of IL‐6 than other cytokines in these patients. Further studies are needed to clarify the possibility of a causal relationship between inflammation and depressive symptoms in CKD and dialysis patients.     

Confounding factors for early death in incident end‐stage renal disease patients: Role of emergency dialysis start

Hemodialysis (HD) has been associated with higher 1‐year mortality than peritoneal dialysis (PD) after dialysis start. Confounding effects of late referral, emergency dialysis start, or start with central venous catheter on this association have never been studied concomitantly. Survival was studied among the 495 incident dialysed patients in our department from 1995 to 2006 and followed at least 1 year until December 31, 2007. Nested Cox models adjusted on patient characteristics explored factors associated with 1‐year and ≥1‐year mortality. Hemodialysis patients were 332 (67.1%), 104 (21.0%) were late referred (<6 months), 167 (33.7%) started dialysis in emergency, and 144 (29.1%) started with central venous catheter. When adjusted only on age, sex, and comorbidities, HD was associated with poor 1‐year outcome: adjusted hazard ratio (aHR) for death in HD vs. PD was 1.77, P=0.02. In fully adjusted model, among first dialysis feature variables, only emergency dialysis start was significantly associated with 1‐year mortality: aHR 1.53, P=0.02. Dialysis modality was not associated with 1‐year mortality rates in this fully adjusted model: aHR in HD vs. PD became 1.03, P=0.91. In ≥1‐year period, HD was associated with lower mortality than PD (aHR 0.61, P=0.004), whereas other first dialysis features were not associated with death. Other factors associated with death were age, type 2 diabetes, peripheral vascular disease, heart failure, and hepatic failure. Negative association between HD and 1‐year survival on dialysis was explained by confounders. Emergency dialysis start was strongly associated with early mortality on dialysis. Its prevention may improve patient survival.     

Association between antiinflammatory cytokine,IL‐10, and sleep quality in patients on maintenance hemodialysis

Elevated proinflammatory cytokines have been attributed to poor sleep quality in patients receiving hemodialysis. This is the first investigation about the relationship between sleep quality and circulating levels of antiinflammatory markers in these patients. A total of 72 patients who were receiving maintenance hemodialysis were enrolled in this cross‐sectional study. The Pittsburgh Sleep Quality Index (PSQI) was used to measure sleep quality. Patients were divided into two groups: good sleepers (PSQI score < 5) and poor sleepers (PSQI score ≥ 5). Assessments were made for serum biochemical parameters (albumin, parathyroid hormone), inflammatory (interleukin [IL]‐6, tumor necrosis factor‐alpha [TNF‐α], and high‐sensitivity c‐reactive protein [hs‐CRP] ) and antiinflammatory (IL‐10) markers. Fifty‐four patients (75%) were classified as poor sleepers. Poor sleepers showed significantly lower levels of serum IL‐10 and higher serum triglyceride and parathyroid hormone concentrations. These patients were more likely to have more comorbidities. The global PSQI score was significantly correlated with serum IL‐10 (p = 0.03) and triglyceride levels (p = 0.01). Multivariate logistic regression analysis showed a direct correlation between PSQI and having comorbidities (p = 0.011, odds ratio [OR] = 3.918; confidence interval 95% [CI] = 2.742–19.031), between PSQI and serum triglyceride (p = 0.027, OR = 1.027 [95% CI = 1.007–1.048] ), and an inverse correlation between PSQI and serum IL‐10 level (p = 0.021, OR = 0.424 [95% CI = 0.195–0.922]). Reduced circulating levels of the antiinflammatory cytokine IL‐10 were significantly associated with poor sleep quality in hemodialysis patients. Factors including serum IL‐10 and triglyceride concentrations and having comorbidities may predict patients prone to poor sleep quality.     

Anti‐inflammatory effects of linagliptin in hemodialysis patients with diabetes

Inflammation and glycemic control are important prognosis‐related factors for hemodialysis (HD) patients; moreover, inflammation affects insulin secretion. Here, we evaluated the anti‐inflammatory effects of monotherapy with linagliptin—a dipeptidase‐4 inhibitor—in HD patients with type 2 diabetes. We examined 21 diabetic HD patients who were not receiving oral diabetes drugs or insulin therapy and with poor glycemic control (glycated albumin [GA] level, >20%). Linagliptin (5 mg) was administered to the patients daily. The levels of prostaglandin E2 (PGE2), interleukin‐6 (IL‐6), high‐sensitivity C‐reactive protein, GA, blood glucose, and active glucagon‐like peptide‐1 were determined before and 6 months after treatment. Body weight and serum levels of albumin, hemoglobin, total cholesterol, and low‐density lipoprotein cholesterol were also recorded before and after treatment. The levels of PGE2 and GA were significantly decreased 1 month after starting linagliptin therapy, whereas the IL‐6 levels were significantly decreased 6 months after starting linagliptin therapy. After 6 months of treatment, the PGE2 levels decreased from 188 ± 50 ng/mL to 26 ± 5 ng/mL; IL‐6 levels, from 1.5 ± 0.4 pg/mL to 0.6 ± 0.1 pg/mL; and GA levels, from 21.3% ± 0.6% to 18.0% ± 0.6%. Glucagon‐like peptide‐1 levels increased 2.5‐fold during the treatment. Over the 6‐month treatment period, body weight and levels of high‐sensitivity C‐reactive protein, blood glucose, albumin, hemoglobin, and cholesterol did not change; none of the patients exhibited hypoglycemia. The anti‐inflammatory effects of linagliptin monotherapy indicate that it may serve as a useful glucose control strategy for HD patients with diabetes.     

Long‐term effects of angiotensin II blockade with irbesartan on inflammatory markers in hemodialysis patients: A randomized double blind placebo controlled trial (SAFIR study)

Introduction: Low‐grade chronic inflammation is common in hemodialysis (HD) patients. Previous studies suggest an anti‐inflammatory effect of angiotensin II receptor blocker (ARB) treatment. The aim of this study was to compare the effect of ARB vs. placebo on plasma concentrations of inflammatory markers in HD patients. Methods: Adult HD patients were randomized for double‐blind treatment with the ARB irbesartan 150–300 mg/day or placebo. At baseline, 1 week, 3, 6, 9, and 12 months plasma high sensitivity C‐reactive protein (hsCRP), interleukin (IL)?1β, IL‐6, IL‐8, IL‐18, and transforming growth factor‐β (TGF‐β) were measured using Luminex and enzyme‐linked immunosorbent assay (ELISA) technology. Findings: Eighty‐two patients were randomized (placebo/ARB: 41/41). The groups did not differ in initial levels of any of the inflammatory markers (placebo/ARB median(range)): hsCRP 3.3(0.2–23.4)/2.7(0.2–29.6) μg/mL; IL‐1β 1.1(0.0–45.9)/1.1(0.0‐7.2) pg/mL; IL‐6 10(1–90)/12(1–84) pg/mL; IL‐8 31(9–134)/34(5–192) pg/mL; IL‐18 364(188–1343)/377(213–832) pg/mL; TGF‐β 3.2(0.8–13.9)/3.6(1.3–3.8) ng/mL. Overall, there was no significant difference in hsCRP, IL‐6, IL‐8, and TGF‐β between placebo and ARB‐treated patients during the study period, and hsCRP, IL‐6, IL‐8, and TGF‐β were relatively stable during the study period (P ≥ 0.18 in all tests for parallel curves, equal levels, and constant levels). The IL‐1β level was slightly different in the two groups over time, but not significantly (P = 0.09 in test for parallel curves) and it was also relatively stable during the study period (P ≥ 0.49 in tests for equal levels and constant level). IL‐18 was the only inflammatory marker which was not constant during the study period (P = 0.001 in test for constant level), but there was no significant difference between placebo and ARB‐treated (P ≥ 0.51 in tests for parallel curves and equal levels). Discussion: Inflammatory biomarkers were neither acutely, nor in the long‐term significantly affected by the ARB irbesartan. Our findings suggest that ARB treatment in HD patients does not offer protective anti‐inflammatory effects.     

Changes in circulating biomarkers during a single hemodialysis session

The hemodialysis (HD) procedure induces an inflammatory response potentially contributing to cardiovascular disease. Here we investigated the acute impact of HD on circulating biomarkers. Circulating biomarkers (small solutes, middle molecular‐sized peptides, and proteins) related to inflammation, oxidative stress, and vascular calcification (VC) were measured before and after a single session of HD in 45 clinically stable patients. Concentrations were corrected for ultrafiltration‐induced hemoconcentration. Among vascular calcification‐related biomarkers, osteoprotegerin and fetuin‐A remained unchanged while fibroblast growth factor‐23 (FGF23) decreased by ?19%. Changes of FGF23 and changes of phosphate correlated (ρ = 0.61, P < 0.001). While C‐reactive protein did not change, interleukin‐6 (IL‐6) increased by 14% and pentraxin 3 (PTX3) increased by 45%. IL‐6 and PTX3 appear to be valid biomarkers of the intradialytic inflammatory response. VC‐related markers were in general not affected by the single HD session; however, the observed correlation between acute changes of FGF‐23 and phosphate during HD warrants further studies.     

Template‐Mediated Assembly of DNA into Microcapsules for Immunological Modulation

There is a need for effective vaccine delivery systems and vaccine adjuvants without extraneous excipients that can compromise or minimize their efficacy. Vaccine adjuvants cytosine–phosphate–guanosine oligodeoxynucleotides (CpG ODNs) can effectively activate immune responses to secrete cytokines. However, CpG ODNs are not stable in serum due to enzymatic cleavage and are difficult to transport through cell membranes. Herein, DNA microcapsules made of CpG ODNs arranged into 3D nanostructures are developed to improve the serum stability and immunostimulatory effect of CpG. The DNA microcapsules allow encapsulation and co‐delivery of cargoes, including glycogen. The DNA capsules, with >4 million copies of CpG motifs per capsule, are internalized in cells and accumulate in endosomes, where the Toll‐like receptor 9 is engaged by CpG. The capsules induce up to 10‐fold and 20‐fold increases in tumor necrosis factor (TNF)‐α and interleukin (IL)‐6 secretion, respectively, in RAW264.7 cells compared with CpG ODNs. Furthermore, the microcapsules stimulate TNF‐α and IL‐6 secretion in a concentration‐ and time‐dependent manner. The immunostimulatory activity of the capsules correlates to their intracellular trafficking, endosomal confinement, and degradation, assessed by confocal and super‐resolution microscopy. These DNA capsules can serve as both adjuvants to stimulate an immune reaction and vehicles to encapsulate vaccine peptides/genes to achieve synergistic immune effects.     

End‐stage renal disease from hemolytic uremic syndrome in the United States, 1995–2010

Management of hemolytic uremic syndrome (HUS) has evolved rapidly, and optimal treatment strategies are controversial. However, it is unknown whether the burden of end‐stage renal disease (ESRD) from HUS has changed, and outcomes on dialysis in the United States are not well described. We retrospectively examined data for patients initiating maintenance renal replacement therapy (RRT) (n = 1,557,117), 1995–2010, to define standardized incidence ratios (SIRs) and outcomes of ESRD from HUS) (n = 2241). Overall ESRD rates from HUS in 2001–2002 were 0.5 cases/million per year and were higher for patients characterized by age 40–64 years (0.6), ≥65 years (0.7), female sex (0.6), and non‐Hispanic African American race (0.7). Standardized incidence ratios remained unchanged (P ≥ 0.05) between 2001–2002 and 2009–2010 in the overall population. Compared with patients with ESRD from other causes, patients with HUS were more likely to be younger, female, white, and non‐Hispanic. Over 5.4 years of follow‐up, HUS patients differed from matched controls with ESRD from other causes by lower rates of death (8.3 per 100 person‐years in cases vs. 10.4 in controls, P < 0.001), listing for renal transplant (7.6 vs. 8.6 per 100 person‐years, P = 0.04), and undergoing transplant (6.9 vs. 9 per 100 person‐years, P < 0.001). The incidence of ESRD from HUS appears not to have risen substantially in the last decade. However, given that HUS subtypes could not be determined in this study, these findings should be interpreted with caution.     

Relationship between Geriatric Nutritional Risk Index and total lymphocyte count and mortality of hemodialysis patients

We examined the relationships between Geriatric Nutritional Risk Index (GNRI), total lymphocyte count (TLC), and mortality in hemodialysis (HD) patients. We examined GNRI and TLC in 120 maintenance HD patients and followed these patients for 120 months. Predictors of all‐cause death were examined using life table analysis and the Cox proportional hazards model. TLC marginally correlated with GNRI (r = 0.176; p = 0.090) and significantly with phosphorus levels (r = 0.206; p = 0.026). Life table analysis revealed that subjects with a GNRI < 90 (n = 19) had lower survival rates than did those with a GNRI ≥ 90 (n = 101; Wilcoxon's test, p = 0.048), but subjects with a TLC < 1500/mm³ (n = 76) had similar survival rates compared with subjects with a TLC ≥ 1500/mm³ (n = 44; Wilcoxon's test, p = 0.500). Multivariate Cox proportional hazards analyses demonstrated that GNRI is a significant predictor of mortality (hazard ratio 9.315, 95% confidence interval 1.161–74.753, p = 0.036), after adjusting for age, sex, presence of type 2 diabetes mellitus, Kt/V, normalized protein catabolic rate, hematocrit, phosphorus, systolic blood pressure and TLC. Our findings suggest the TLC may be used as a simple nutritional tool, but may not be a predictor of mortality in HD patients. These findings require confirmation by further studies.     

Effects of l‐carnitine supplement on serum inflammatory cytokines,C‐reactive protein,lipoprotein (a), and oxidative stress in hemodialysis patients with Lp (a) hyperlipoproteinemia

Inflammation, oxidative stress, and high concentration of serum lipoprotein (a) [Lp (a)] are common complications in hemodialysis patients. The present study was designed to investigate the effects of l ‐carnitine supplement on serum inflammatory cytokines, C‐reactive protein (CRP), Lp (a), and oxidative stress in hemodialysis patients with Lp (a) hyperlipoproteinemia [hyper Lp (a)]. This was an unblinded, randomized clinical trial. Thirty‐six hyper Lp (a) hemodialysis patients (23 men and 13 women) were randomly assigned to either a carnitine or control group. Patients in the carnitine group received 1000 mg/d oral l ‐carnitine for 12 weeks, whereas patients in the control group did not receive any l ‐carnitine supplement. At baseline and the end of week 12, 5 mL of blood were collected after a 12‐ to 14‐hours fast and serum free carnitine, CRP, interleukin‐1β, interleukin‐6 (IL‐6), tumor necrosis factor‐α, Lp (a), and oxidized low‐density lipoprotein were measured. Serum free carnitine concentration increased significantly by 86% in the carnitine group at the end of week 12 compared with baseline (P<0.001), while serum CRP and IL‐6 showed a significant decrease of 29% (P<0.05) and 61% (P<0.001), respectively. No significant changes were observed in serum free carnitine, CRP, and IL‐6 in the control group. There were no significant differences between the two groups in mean changes of serum interleukin‐1β, tumor necrosis factor‐α, Lp (a), and oxidized low‐density lipoprotein concentrations. l ‐carnitine supplement reduces inflammation in hemodialysis patients, but has no effect on hyper Lp (a) and oxidative stress.     

Nervous system autoantibodies and vitamin D receptor gene polymorphisms in hemodialysis patients

Cognitive deficits are prevalent in hemodialysis (HD) patients. Vitamin D deficiency and vitamin D receptor (VDR) gene single nucleotide polymorphism (SNPs) have been linked to both neurodegeneration (ND) and neuroprotection, respectively. Autoantibodies (Ab) to myelin basic protein (MBP), glial fibrillary acidic protein (GFAP), and neurofilament (NF) triplet proteins arise secondary to nervous system (NS) damage providing a means to assess neurological injury. Characterization of Ab biomarkers of NS damage in HD patients, their association with VDR SNPs, and nutritional vitamin D (NVD) therapy was performed. VDR genotypes, cytokines, and Ab biomarkers to NS proteins in HD subjects receiving ergocalciferol (n = 40) were compared with nonusers (n = 71). Interleukin‐6 (IL‐6), tumor necrosis factor‐α (TNF‐α), and immunoglobulin G (IgG) titers against NFs, GFAP, and MBP were measured by immunoassay. Subjects were genotyped for VDR SNPs BsmI (rs1544410) and FokI (rs2228570). Subjects (age 63.3 ± 16.1 years, 66% male) who were C allele carriers of BsmI had higher values of NF‐68 antibody titers (p = 0.027). Ergocalciferol users (n = 40) compared with nonusers (n = 71) had lower Ab titers to NS proteins; however, only anti–NF‐160 and anti‐MBP titers were significantly (p < 0.05) higher. IgG against NS proteins in HD patients suggests neuronal and glial insult and a relationship with VDR alleles. NVD may provide some neuroprotection, indicated by anti–NF‐160 and anti‐MBP, which was markedly lowered in ergocalciferol patients. This preliminary study suggests that Ab detection may be useful in monitoring ND and the potential of NVD for neuroprotection in HD patients.     

High prevalence of subclinical hypothyroidism and nodular thyroid disease in patients on hemodialysis

Chronic kidney disease has been known to affect thyroid hormone metabolism. Low serum levels of T3 and T4 are the most remarkable laboratorial findings. A high incidence of goiter and nodules on thyroid ultrasonography has been reported in patients with end‐stage renal disease (ESRD). Our objective is to evaluate the prevalence of laboratorial and morphologic alterations in the thyroid gland in a cohort of patients with ESRD on hemodialysis (HD). Sixty‐one patients with ESRD on HD were selected and compared with 43 healthy subjects matched by age, gender, and weight. Patients were submitted to thyroid ultrasonography. T3, free T4 (FT4), thyroid‐stimulating hormone, antithyroglobulin, and antithyroperoxidase antibodies were measured. The mean age of patients with ESRD was 47.4 ± 12.3 and 61% were women. ESRD was mainly caused by hypertensive nephrosclerosis and diabetic nephropathy. Mean thyroid volume, as determined by ultrasonography, was similar in both groups. Patients with ESRD had more hypoechoic nodules when compared with the control group (24.1% vs. 7.9%, P = 0.056). Mean serum FT4 and T3 levels were significantly lower in patients with ESRD, and subclinical hypothyroidism was more prevalent in patients with ESRD (21.82% vs. 7.14% control group, P = 0.04). Titers of antithyroid antibodies were similar in both groups. ESRD was associated with a higher prevalence of subclinical hypothyroidism and lower levels of T3 and FT4. Almost a quarter of patients showed thyroid nodules >10 mm. Periodic ultrasound evaluation and assessment of thyroid function are recommended in patients with ESRD on HD.