Interleukin 1 gene polymorphism and susceptibility to disease.

The Interleukin 1 (IL-1) family plays a central role in the generation and regulation of inflammatory responses, in both innate and adaptive immunity. Although the IL-1 molecules are traditionally considered to be classical proinflammatory cytokines, their functions are not restricted to inflammation, and they have also been shown to play a key role in a wide range of additional physiological and pathological functions, including learning modulation, sleep, pregnancy, depression, appetite, hematopoiesis, metabolism, and many others. Since their effect as cytokines and regulators of inflammation is so pleiotropic, any shift of the biological balance between agonistic and antagonistic signals has the potential to cause disease. Here, we consider the genetic influence of interleukin-1 gene polymorphism in the context of susceptibility to human diseases. We review known single nucleotide polymorphisms (SNP) of IL-1 genes linked to human diseases, and suggest how exploring biological effects of IL-1 gene cluster polymorphism may lead to new directions in understanding and diagnostic of disease and effective treatment.

Free circulating active elastase contributes to chronic inflammation in patients on hemodialysis.

Atherosclerosis and cardiovascular complications are prevalent among patients undergoing chronic hemodialysis (HD). In this population, peripheral polymorphonuclear leukocytes (PMNLs) are primed, releasing proinflammatory mediators such as elastase. Elastase is normally inhibited by a specific inhibitor, avoiding undesirable degradation of cellular and extracellular components. This study tested the hypothesis that in states of noninfectious inflammation, elastase is released by PMNLs and acts in an uncontrolled manner to inflict vascular damage. Blood was collected from patients undergoing HD and healthy controls (HC). PMNL intracellular and surface expressions of elastase were determined by quantitative real-time PCR, Western blotting, and flow cytometry. The elastase activity was evaluated using a fluorescent substrate. The levels of serum α1-antitrypsin (α1-AT), the natural elastase inhibitor, were determined by Western blot. Free active elastase was elevated in HD sera, whereas the levels of α1-AT were decreased compared with HC. The levels of the intracellular elastase enzyme and its activity were lower in HD PMNLs despite similar expression levels of elastase mRNA. Elastase binding to PMNL cell surface was higher in HD compared with HC. The increased circulating levels of free active elastase released from primed HD PMNLs together with the higher cell surface-bound enzymes and the lower levels of α1-AT result in the higher elastase activity in HD sera. This exacerbated elastase activity could lead to the endothelial dysfunction, as hypothesized. In addition, it suggests that free circulating elastase can serve as a new biomarker and therapeutic target to reduce inflammation and vascular complications in patients on hemodialysis.

Primed polymorphonuclear leukocytes from hemodialysis patients enhance monocyte transendothelial migration.

Increased counts and priming of peripheral polymorphonuclear leukocytes (PMNLs) are associated with future or ongoing atherosclerosis; however, the role of PMNLs in enhancing monocyte transendothelial migration is still unclear. Our aims were to examine endothelial and monocyte activation, transmigration, and posttransmigration activation induced ex vivo by in vivo primed PMNLs and the effect of antioxidants on the activation. A unique ex vivo coculture system of three cell types was developed in this study, enabling interactions among the following: primary human umbilical vein endothelial cells (HUVECs), monocytes (THP-1 cell line), and in vivo primed PMNLs from hemodialysis (HD) patients and healthy control (HC) subjects. The interactions among these cells were examined, and an intervention with superoxide dismutase and catalase was performed. Preexposed HUVECs to HD/HC PMNLs showed a significant monocyte transmigration yield, 120-170% above HCs. Monocyte exposure to HD PMNLs induced pre- and posttransmigration activation. When the three cell types were cocultivated at the same time, monocyte chemoattractant protein-1 protein levels released from HUVECs, and activation markers on HUVECs [CD54 and chemokine (C-X3-C motif) ligand 1] and monocytes [chemokine (C-X3-C) receptor 1 and chemokine (C-C motif) receptor 2] were increased. Monocyte transmigration yield decreased to 70% (compared with HC subjects) due to adherence and accumulation of monocytes to HUVECs. When superoxide dismutase and catalase were used, reduced HUVEC and monocyte activation markers brought the transmigration yields to control levels and abolished accumulation of monocytes, emphasizing the role of superoxide in this process. We conclude that peripheral primed PMNLs play a pivotal role in enhancing monocyte transendotelial migration, the hallmark of the atherosclerotic process. Primed PMNLs can be used as a mediator and a biomarker of atherosclerosis even before plaque formation.NEW & NOTEWORTHY Primed polymorphonuclear leukocytes are key mediators in monocyte transendothelial migration, a new understanding of the initiation of endothelial dysfunction and monocyte activation, transmigration, and accumulation in the subendothelial layer.

[LEVEL AND OXIDATION OF BETA 2-MICROGLOBULIN IN HEMODIALYSIS PATIENTS TREATED WITH INTRAVENOUS IRON DURING DIALYSIS WITH HIGH-FLUX COMPARED TO LOW-FLUX DIALYZERS].

INTRODUCTION: Serum levels of ß2-microglobulin (b2M) are significantly higher in patients with end stage renal failure undergoing hemodialysis (HD) and its accumulation accelerates Dialysis Related Amyloidosis (DRA). In HD patients low-flux dialysis, intravenous (IV) iron (administered for the treatment of anemia) affects ß2M removal during dialysis. IV iron also affects the oxidation of plasma proteins, including b2M. AIMS: To examine the effect of intravenous iron therapy on ß2M levels and oxidation in HD patients treated with high-flux compared with low-flux dialyzers. METHODS: Sixteen HD patients on chronic maintenance IV iron therapy were studied. Half of the patients were allocated to high-flux and half to low-flux dialysis. After five weeks, each patient was assigned to the second dialyzer. After two weeks of treatment with each dialyzer, blood samples were taken and serum levels of ß2M were measured. In addition, the hematocrit and iron status were measured. Part of the samples were used to evaluate oxidized ß2M. RESULTS: A significant increase in ß2M levels was found with low-flux dialysis, which further increased during dialysis with IV iron administration. High-flux dialysis therapy significantly lowered the ß2M levels, with a clear decrease during the dialysis session, that was unaffected by IV iron administration. A significant decrease in ß2M oxidation was found during highflux, but not low-flux dialysis. CONCLUSIONS: High-flux dialysis is more effective than lowflux in decreasing the levels and oxidation of ß2M. These observations may have significance in improving iron therapy, aimed to decrease or attenuate the appearance of DRA.

Prevention of contrast-induced nephropathy with single bolus erythropoietin in patients with diabetic kidney disease: A randomized controlled trial.

AIM: Contrast-induced-nephropathy (CIN) is associated with poor outcomes, thus prevention of CIN may be of clinical value. Erythropoietin (EPO) has been shown to elicit tissue-protective effects in experimental models and in clinical studies of acute kidney injury. We therefore evaluated its effectiveness for prevention of CIN after coronary angiography (CA) ± percutaneous coronary intervention (PCI) in diabetic patients with chronic kidney disease. METHODS: A prospective, randomized, controlled trial was carried out in 138 diabetic patients with eGFR <60 mL/min who underwent non-urgent CA ± PCI. Patients received normal saline and n-acetyl cysteine before CA, with or without 50,000 U of EPO administered 30 min prior to CA. CIN was defined as an increase in serum creatinine of at least 0.5 mg/dL during the first 2 days after exposure to contrast media. Primary outcome was the incidence of CIN. Secondary outcomes were the sensitivity and positive predictive value (PPV) of Cystatin C (CC) and Neutrophil-gelatinase-associated-lipocalin (NGAL) for diagnosis of CIN. RESULTS: The observed incidence of CIN was 8.7%, significantly lower than the expected for such high-risk population. The administration of EPO prior to CA did not reduce the incidence of CIN (9.7% vs. 7.6%, P = 0.65). CC and NGAL demonstrated a low sensitivity (16.6%) and low PPV (6.7 and 33.3%, respectively) for detecting CIN. CONCLUSION: The administration of EPO prior to CA did not reduce the incidence of CIN. Additional prospective research with a larger sample size and in other patient categories is essential to further define the potential protective effect of EPO on prevention of CIN.

Does Pomegranate intake attenuate cardiovascular risk factors in hemodialysis patients?

BACKGROUND: Atherosclerotic cardiovascular disease (CVD) is the most common cause of morbidity and mortality among hemodialysis (HD) patients. It has been attributed, among other causes, to hypertension and dyslipidemia. The aim of the present study was to investigate the effect of a year-long consumption of Pomegranate juice (PJ), on two traditional cardiovascular (CV) risk factors: hypertension and lipid profile, as well as on cardiovascular events. METHODS: 101 HD patients were randomized to receive 100 cc of PJ (0.7 mM polyphenols) or matching placebo juice, three times a week for one year. The primary endpoints were traditional CV risk factors; blood pressure and lipid profile. Systolic, diastolic and pulse pressure, plasma levels of triglycerides (TG), high density lipoprotein (HDL), low density lipoprotein (LDL) and total cholesterol were monitored quarterly during the study year. Secondary endpoint was incidence of cardiovascular events. RESULTS: PJ consumption yielded a significant time response improvement in systolic blood pressure, pulse pressure, triglycerides and HDL level; an improvement that was not observed in the placebo intake group. These beneficial outcomes were more pronounced among patients with hypertension, high level of triglycerides and low levels of HDL. CONCLUSION: Regular PJ consumption by HD patients reduced systolic blood pressure and improved lipid profile. These favorable changes may reduce the accelerated atherosclerosis and high incidence of CVD among HD patients. TRIAL REGISTRATION: ClinicalTrials.gov registry, Identifier number: NCT00727519.

Oxidative modifications impair albumin quantification.

BACKGROUND: Hypoalbuminemia is a measure of malnutrition, inflammation and a predictor of mortality in uremia. It is controversial whether albumin levels per se are associated with the clinical outcomes in uremic patients. The co-occurrence of hypoalbuminemia and oxidative stress in hemodialysis (HD) patients led us to hypothesize that oxidative modifications of albumin decrease its detection and influence albumin quantification. METHODS: Albumin levels are determined in clinical laboratories mainly by the bromocresol green (BCG) spectrophotometric assay. The detection of serum albumin was investigated in HD patients and in healthy controls using an "albumin-detection index", defined as the ratio between BCG read-out (albumin-specific) to total albumin. The detection efficacy of albumin was also investigated in vitro, after glycoxidation, HOCl-mediated-oxidation, and metal-catalyzed-oxidation. Oncotic pressure was measured to assess albumin function. RESULTS: The albumin-detection index of patients was significantly lower compared with controls, correlating negatively with oxidative stress markers (serum advanced oxidation protein products-AOPP and glycoxidized serum albumin) and positively with serum albumin levels. The albumin-detection index was also decreased after in vitro oxidation. CONCLUSIONS: The study shows, both in vivo and in vitro, decreased detection of oxidized albumin by a commonly-used clinical assay, thus providing the molecular link between oxidative stress and hypoalbuminemia. Oxidative stress as reflected by hypoalbuminemia, rather than actual albumin levels, may be related to cardiovascular morbidity outcomes in HD patient.

Is anemia at hospital admission associated with in-hospital acute kidney injury occurrence?

BACKGROUND: The effect of acute kidney injury (AKI) on anemia has been well-documented. However, the effect of 'preexisting' anemia on AKI has been less addressed. The aims of the present study were to investigate (1) the association between anemia at hospital admission and AKI occurrence, and (2) the effect of 'preexisting' anemia on the clinical outcomes of AKI. METHODS: A retrospective cohort study was undertaken among patients aged > or =17 years who were admitted to our hospital during the year 2006 (n = 34,802). Anemia at hospital admission and AKI occurrences were determined using the WHO definition and the RIFLE criteria, respectively. A subgroup of patients with an estimated glomerular filtration rate > or =60 ml/min/1.73 m(2) was analyzed separately to control for the effect of chronic kidney disease on anemia. RESULTS: The cumulative incidence of AKI was 11.2% in anemic patients at hospital admission, compared to 5.5% in nonanemic subjects. The association between anemia at admission and AKI occurrence remained statistically significant after controlling for potential confounders (odds ratio 1.5, 95% CI 1.4-1.6). In addition, an association between anemia at hospital admission and clinical outcomes of AKI was observed. CONCLUSION: Anemia at hospital admission should be recognized as a potential risk factor for in-hospital AKI occurrence.

Contrast-induced nephropathy among Israeli hospitalized patients: incidence, risk factors, length of stay and mortality.

BACKGROUND: Radiological procedures utilizing intravascular contrast media are being widely applied for both diagnostic and therapeutic purposes. This has resulted in the increasing incidence of procedure-related contrast-induced nephropathy. In Israel, data on the incidence of CIN and its consequences are lacking. OBJECTIVES: To describe the epidemiology of CIN among hospitalized patients in the Western Galilee Hospital, Nahariya (northern Israel), and to explore the impact of CIN on mortality and length of stay. METHODS: The study group was a historical cohort of 1111 patients hospitalized during the year 2006 who underwent contrast procedure and whose serum creatinine level was measured before and after the procedure. Data were electronically extracted from different computerized medical databases and merged into a uniform platform using visual basic application. RESULTS: The occurrence of CIN among hospitalized patients was 4.6%. Different CIN rates were noticed among various high risk subgroups such as patients with renal insufficiency and diabetes mellitus (14.1%-44%). Average in-hospital length of stay was almost twice as long among patients with CIN compared to subjects without this condition. Furthermore, the in-hospital death rate among CIN patients was 10 times higher. A direct association was observed between severity of CIN based on the RIFLE classification and risk of mortality. CONCLUSIONS: Low CIN occurrence was demonstrated in general hospitalized patients (4.6%), and high rates (44%) in selected high risk subgroups of patients (with renal insufficiency or diabetes mellitus). Furthermore, prolonged length of stay and high in-hospital mortality were directly related to CIN severity.

Hospital-acquired acute kidney injury in Israel.

BACKGROUND: Acute kidney injury remains a common significant clinical problem. Yet there are scant data in Israel on the incidence of hospital-acquired AKI and on diagnosis validity. OBJECTIVES: To describe the epidemiology of AKI among hospitalized patients in the Western Galilee Hospital, Nahariya, compare discharge summaries to laboratory diagnosis, and investigate the impact of AKI on mortality and length of stay. METHODS: Computerized medical and laboratory data of 34,802 hospitalized subjects were collected. AKI was diagnosed according to three different definitions. We calculated the sensitivity and specificity of AKI based on ICD-9 diagnosis compared to patient's laboratory data as the gold standard. RESULTS: The overall AKI annual incidence rate was 1-5.1%, depending on the AKI definition used. The incidence of AKI based on ICD-9 diagnosis was significantly lower compared to the laboratory-based diagnosis. Average in-hospital length of stay was 2.4 times longer among patients with AKI compared to subjects without this condition. Furthermore, the in-hospital death rate among AKI patients was 14 times higher than among non-AKI hospitalized subjects, with a positive association between AKI severity and risk of death. CONCLUSIONS: Using AKI laboratory diagnosis as the gold standard revealed ICD-9 diagnosis to be 9.1% sensitive and 99.4% specific. Hospital-acquired AKI is a major contributor to prolonged length of stay and high mortality rates; therefore, interventions to reduce in-hospital disease incidence are required.

Malnutrition Risk in Hemodialysis Patients in Israel: Results of the Status of Nutrition In Hemodialysis Patients Survey Study.

BACKGROUND: Malnutrition is a frequently observed disorder in patients with chronic kidney disease (CKD) receiving hemodialysis (HD). While variously defined, malnutrition is a frequently observed condition among patients on HD. Prevalence estimates of malnutrition among Israeli HD patients have not been reported. OBJECTIVES: To survey nutrition intake in Israeli HD patients; estimate malnutrition risk prevalence; identify risk factors, and characterize malnutrition risk in HD patients. METHODS: A representative sample of 378 Israeli HD patients treated in hospital HD centers throughout the country were surveyed. Using the 24-h recall method, dietary intake was estimated and the chronologically corresponding biochemistry, anthropometric, and hemodynamic measures were recorded. Four categories of malnutrition risk were defined: "minimal": body mass index (BMI) > 23 kg/m2 and serum albumin > 3.8 g/dL; "mild": BMI < 23 kg/m2 and albumin > 3.8 g/dL; "moderate": BMI > 23 kg/m2 and albumin < 3.8 g/dL; "severe": BMI < 23 k/m2 and serum albumin < 3.8 g/dL. RESULTS: Elevated malnutrition risk was identified in 175 (46.3%) study participants, who were more likely to require feeding assistance, have major comorbidities, reduced hemoglobin, and elevated C-reactive protein. Oral nutrition supplementation was prescribed to only 14.3% of patients with elevated malnutrition risk. Intradialytic parenteral nutrition was recorded for 6 patients, all of whom had moderate or severe malnutrition risk. Less than one-third of patients met the guidelines for dietary intake of energy or protein, and this did not differ across malnutrition risk groups. DISCUSSION: Elevated malnutrition risk is a frequent finding in HD patients treated in hospital settings in Israel. Dietary intake does not meet guidelines but does not differ across malnutrition risk categories. Nutrition supplements are underused in HD patients with high malnutrition risk. There is a need to expand the survey to community HD centers.

Epoetin-alpha: preserving kidney function via attenuation of polymorphonuclear leukocyte priming.

BACKGROUND: Polymorphonuclear leukocyte priming and low grade inflammation are related to severity of kidney disease. Erythropoietin-receptor is present on PMNLs. OBJECTIVESxi: To evaluate the effect of 20 weeks of epoetin-alpha treatment on PMNL characteristics in relation to the rate of kidney function deterioration in patients with chronic kidney disease. METHODS: Forty anemic chronic kidney disease patients, stage 4-5, were assigned to EPO and non-EPO treatment for 20 weeks. A group of 20 healthy controls was also studied. PMNL priming and PMNL-derived low grade inflammation were estimated, in vivo and ex vivo, before and after EPO treatment: The rate of superoxide release, white blood cells and PMNL counts, serum alkaline phosphatase and PMNL viability were measured. EPO-receptor on PMNLs was assayed by flow cytometry. The effect of 20 weeks of EPO treatment on kidney function was related to the estimated glomerular filtration rate. esults: EPO treatment attenuated superoxide release ex vivo and in vivo and promoted PMNL survival ex vivo. Decreased low grade inflammation was reflected by reduced WBC and PMNL counts and ALP activity following treatment. EPO retarded the deterioration in GFR. The percent of PMNLs expressing EPO-R was higher before EPO treatment and correlated positively with the rate of superoxide release. After 20 weeks of EPO treatment the percent of PMNLs expressing EPO-R was down-regulated. CONCLUSIONS: These non-erythropoietic properties of EPO are mediated by EPO-R on PMNLs, not related to the anemia correction. A new renal protection effect of EPO via attenuation of PMNL priming that decreases systemic low grade inflammation and oxidative stress is suggested.

The polymorphonuclear leukocyte contributes to the development of hypertension in the Sabra rat.

BACKGROUND: We previously showed that priming of the polymorphonuclear leukocyte (PMNL), inflammation and oxidative stress antecede the development of hypertension in the Sabra rat model of hypertension. The actual role of PMNLs and PMNL-mediated oxidative stress and inflammation in the development of hypertension in this model has remained, however, unresolved. OBJECTIVE: The aim of our study was to test the hypothesis that PMNLs and that the PMNL-associated NADPH oxidase contribute to the development of hypertension in the Sabra rat model. METHODS: To determine the contribution of the PMNL to the development of hypertension, we depleted Sabra hypertension-prone (SBH/y) animals from PMNLs with an anti-PMNL antibody, salt-loaded them and monitored their blood pressure over a period of 30 days. To determine the contribution of the NADPH oxidase on the development of hypertension, we inhibited the activity of this enzyme with phenylarsine oxide or apocynin in SBH/y rats while salt-loading the animals and followed the course of their blood pressure over 60 days. RESULTS: PMNL depletion attenuated significantly the development of hypertension in SBH/y rats. Inhibition of NADPH oxidase with phenylarsine oxide and apocynin markedly inhibited the development of hypertension in SBH/y rats, as well as decreased the rate of superoxide release, the level of PMNL CD11b and the PMNL count. CONCLUSION: These data are consistent with a significant contribution of PMNLs to the development of hypertension, and suggest that the mechanism may be related, at least in part, to PMNL-mediated oxidative stress and inflammation.

In-vivo oxidized albumin- a pro-inflammatory agent in hypoalbuminemia.

Hypoalbuminemia of Hemodialysis (HD) patients is an independent cardiovascular risk factor, however, there is no mechanistic explanation between hypoalbuminemia and vascular injury. In the event of oxidative stress and inflammation to which HD patients are exposed, albumin is oxidized and undetected by common laboratory methods, rendering an apparent hypoalbuminemia. We wanted to show that these circulating modified oxidized albumin molecules cause direct vascular damage, mediating inflammation. Once these in-vivo albumin modifications were reduced in- vitro, the apparent hypoalbuminemia concomitantly with its inflammatory effects, were eliminated. Albumin modification profiles from 14 healthy controls (HC) and 14 HD patients were obtained by mass spectrometry (MS) analyses before and after reduction in- vitro, using redox agent 1,4 dithiothreitol (DTT). Their inflammatory effects were explored by exposing human umbilical endothelial cells (HUVEC) to all these forms of albumin. Albumin separated from hypoalbuminemic HD patients increased endothelial mRNA expression of cytokines and adhesion molecules, and augmented secretion of IL-6. This endothelial inflammatory state was almost fully reverted by exposing HUVEC to the in-vitro reduced HD albumin. MS profile of albumin modifications peaks was similar between HD and HC, but the intensities of the various peaks were significantly different. Abolishing the reversible oxidative modifications by DTT prevented endothelial injury and increased albumin levels. The irreversible modifications such as glycation and sulfonation show low intensities in HD albumin profiles and are nearly unobserved in HC. We showed, for the first time, a mechanistic link between hypoalbuminemia and the pro-inflammatory properties of in-vivo oxidized albumin, initiating vascular injury.

[Catheter lock solution--taurolock for prevention of catheter-related bacteremia in hemodialysis patients].

BACKGROUND: Bacteremia and thrombosis are the major complications of tunneled cuff central vein catheters (TCC) used for haemodialysis. Bacterial biofilm is the source of catheter related bacteremia (CRB). Instillation of catheter lock solution (CLS) containing antibiotic-anticoagulant solution can cure and prevent CRB. The aim of this publication is to report our experience with the use of CLS - TauroLock (Taurolidine and 4% citrate) in the prevention of catheter related bacteremia in hemodialysis patients. METHODS: Thirteen patients with TCC on chronic hemodialysis were included in the study. Group A: 5 patients with previous inserted catheters and history of at least one bacteremia episode before the study. Group B: 8 patients with new catheters. At the end of each dialysis the catheters were locked with TauroLock until the next dialysis session. RESULTS: In Group A, the catheter related bacteremia (CRB) was reduced from 9.5-episodes\1000 patients days prior to the study to 1.15 episodes\1000 patients days through 867 days of treatment. In Group B, there were not any CRB during 1179 treatment days in the 8 patients. Due to catheter patency problems, 2500 IU of heparin was added to the TauroLock solution in 3 patients (60%) of group A and in 7 patients (87.5%) of group B and Urokinase instillation in 1 and 3 patients of group A and B respectively. CONCLUSION: The catheter lock solution TauroLock significantly decreased the rate of CRB in HD patients with TCC, to complete prevention in new TCC. Addition of heparin to the TauroLock solution should be considered to maintain catheter patency.

[The significance of troponin T in hemodialysis patients].

INTRODUCTION: Troponin T and I are located in the myocardium. Monitoring blood Troponin levels is advantageous in evaluating unstable angina over measuring CPK-MB, previously serving as a "golden standard" for urgent evaluation of myocardial infarct. AIM: To measure blood troponin T levels in hemodialysis patients without severe cardiovascular events, following its distribution according to various risk factors. METHODS: Sera were collected from 68 hemodialysis (HD) patients before starting dialysis sessions and compared to 10 age- and gender-matched healthy volunteers (NC). Troponin T levels were measured using Troponin T STAT Elecsys-Roche kits. RESULTS: Blood Troponin T levels were significantly higher in HD patients compared to NC (0.126 +/- 0.016 vs. 0.005 +/- 0 ng/dL, respectively; P=0.026). HD patients with ischemic heart disease (IHD) showed significantly higher levels of Troponin T, compared to HD patients without IHD (0.17+/-0.036 vs. 0.081 +/- 0.015 ng/dL, respectively; P=0.012). Diabetic (DM) HD patients showed higher levels of Troponin T, compared to non-DM HD patients (0.168+/-0.034 vs. 0.068+/-0.012 ng/dL, respectively; P= 0.002). CONCLUSION: Troponin T may efficiently serve as a diagnostic, monitoring and prognostic parameter in HD patients.

[Polymorphonuclear leukocyte priming and counts are in correlation with blood pressure parameters].

BACKGROUND: In hypertensive patients, the polymorphonuclear leukocytes (PMNLs) are primed, concomitantly contributing to oxidative stress and chronic low-grade inflammation. Furthermore, in the Sabra rat model of salt-induced hypertension, priming of PMNLs, oxidative stress and inflammation antecede the development of hypertension. In the present study we tested the hypothesis that PMNL priming and PMNL and white blood cells (WBC) counts are interrelated with blood pressure values. Therefore, we have evaluated the correlation between WBC and PMNL counts, PMNL priming parameters and blood pressure in untreated essential hypertension patients (EH) and age and gender healthy controls. METHODS: Diastolic blood pressure (DBP), systolic blood pressure (SBP) and mean arterial pressure (MAP) values were correlated by linear regression analysis with the rates of superoxide release from separated PMNLs and with WBC and PMNL counts. RESULTS: The rate of superoxide release from PMNLs was higher in EH patients compared to their healthy controls. The rate of superoxide release from PMNLs correlated with SBP, DBP and MAP. WBC and PMNL counts were all significantly correlated with blood pressure values. CONCLUSION: The results of the study offer an additional mechanism involving primed PMNLs and elevated PMNL counts in the pathogenesis of hypertension and its late cardiovascular complications.

[The effect of calcium channel blocker lercanidipine on lowgrade inflammation parameters in essential hypertension patients].

INTRODUCTION: Oxidative stress (OS), inflammation and insulin resistance are among the mechanisms that have been recently implicated in pathogenesis of essential hypertension (EH). Peripheral polymorphonuclear leukocytes (PMNLs) are primed in EH patients, releasing uncontrolled superoxide anion contributing to OS and chronic low-grade inflammation in these patients. PMNL priming correlates with insulin resistance and with PMNL intracellular calcium ([Ca2+]i). Recent studies have attributed additional anti-oxidative characteristics to the anti-hypertensive drug Lercanidipine (Vasodip), a third generation calcium-channel blocker. AIM: To evaluate possible novel effects of two months of Lercanidipine treatment on systemic and PMNL-related inflammation and on insulin resistance in EH patients. METHODS: Fifteen non-smoking EH patients with untreated mild to moderate high blood pressure (BP) and age- and gender-matched healthy controls (HC) were included in the study. Low-grade inflammation was expressed by PMNL counts and apoptosis, by plasma fibrinogen, CRP and albumin (as a negative acute phase reactant) levels. Fasting serum insulin levels served as a marker of insulin resistance. RESULTS: Inflammation parameters and insulin levels were higher in EH compared to HC. PMNL counts, fibrinogen and insulin levels positively correlated with mean arterial blood pressure values. Two months of Lercanidipine treatment showed a significant decrease in BP, PMNL counts and apoptosis, CRP and serum insulin levels and a significant increase in serum albumin levels. CONCLUSION: The authors imply that the low-grade systemic inflammation and insulin resistance detected in EH patients may be attenuated by the use of Lercanidipine, adding new unknown anti-inflammatory properties to this calcium channel blocker.

Improving long-term outcomes in idiopathic membranous nephropathy using a distinctive cyclosporine regimen.

BACKGROUND: Patients with severe or progressive idiopathic membranous nephropathy (IMN) should receive immunosuppressive therapy (IST). Alkylating agents, corticosteroids and cyclosporine A (CsA) may be associated with substantial adverse effects and high relapse rates. To determine whether CsA is effective for long-term remission in the treatment of IMN with moderate to high risk for progression to renal failure, when given in a dosage of 3.5 mg/kg/day for 18 months, then tapered gradually to a maintenance dose of 0.35-0.70 mg/kg/day within 6 months and continued for 5.5 years. METHODS: The long-term effectiveness of our CsA regimen in 33 incident nephrotic IMN patients was determined retrospectively. Daily proteinuria, serum albumin and creatinine clearance were compared before starting therapy (time 0) and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 years. RESULTS: At the end of 18 months, 84.8% of patients treated with CsA were in remission; 78.8% maintained long-term remission for 10 years. All patients with complete remission (CR), 75% of those with partial remission (PR), 20% of non-responders (NR) and 14.3% of those who were treated with NIST, were free of chronic kidney disease (CKD) stage 3 at 10 years (P<0.001). Reduction in daily proteinuria by ≥50% at 6 months was the most powerful predictor for achievement of CR or PR (P=0.02). CONCLUSIONS: For most patients, CsA was effective in achieving sustained long-term remission without relapses, when gradually tapered to low maintenance dose given for 5.5 years.