Ronit Geron

Primed Peripheral Polymorphonuclear Leukocyte: A Culprit Underlying Chronic Low-Grade Inflammation and Systemic Oxidative Stress in Chronic Kidney Disease

This study characterizes the causal relationship between peripheral polymorphonuclear leukocyte (PMNL) priming, systemic oxidative stress (OS), and inflammation in patients with varying degrees of renal insufficiency (chronic kidney disease [CKD] not on renal replacement therapy [RRT]: continuous ambulatory peritoneal dialysis or hemodialysis [HD]) and healthy control subjects. Rate of superoxide release was measured after stimulation of PMNL with phorbol 12-myristate 13-acetate or zymosan. Priming was estimated by the rate of superoxide release after phorbol 12-myristate 13-acetate stimulation. Systemic OS was related to PMNL priming and intracellular myeloperoxidase activity. Inflammation was linked to peripheral white blood cells and PMNL counts, PMNL apoptosis, and PMNL ex vivo survival in autologous and heterologous sera. PMNL priming and counts were related to the severity of renal failure in CKD not on RRT. Compared with control subjects, PMNL from all CKD patients showed increased priming, highest in HD, with a significant decrease in their response to zymosan. PMNL myeloperoxidase activity and apoptosis were increased in all renal failure patients. Decreased ex vivo cell survival and elevated leukocyte counts were found in all patients, highest in HD. Both PMNL priming and counts correlated negatively with the GFR. A positive significant correlation was shown between PMNL counts and their priming in all groups, suggesting that the increased PMNL count in peripheral blood is an adaptive response to PMNL priming. Hence, PMNL priming is a key mediator of low-grade inflammation and OS associated with renal failure, occurring before the onset of RRT and further augmented in chronic HD.

One year of pomegranate juice intake decreases oxidative stress, inflammation, and incidence of infections in hemodialysis patients: a randomized placebo-controlled trial.

Increased systemic inflammation and oxidative stress are well established as nontraditional key players in the pathogenesis of atherosclerosis and are also involved in the innate immunity dysregulation in hemodialysis (HD) patients. The study aim was to investigate the effect of 1-year intake of pomegranate juice, an antioxidant source, on oxidative stress, inflammation, and long-term clinical outcomes. A randomized placebo controlled double-blind trial was designed, enrolling 101 chronic HD patients to receive during each dialysis 100 cc of pomegranate juice, or matching placebo, three times a week for 1 year. The primary endpoints were levels of oxidative stress and inflammation biomarkers. Secondary endpoints were hospitalization due to infections and the progression of atherosclerotic process based on a composite of variables of the carotid arteries: intima media thickness (IMT), number, and structure of plaques. Pomegranate juice intake yielded a significant time response reduction in polymorphonuclear leukocyte priming, protein oxidation, lipid oxidation, and inflammation biomarkers levels. These beneficial effects were abolished 3 months postintervention. Pomegranate juice intake resulted in a significantly lower incidence rate of the second hospitalization due to infections. Furthermore, 25% of the patients in the pomegranate juice group had improvement and only 5% progression in the atherosclerotic process, while more than 50% of patients in the placebo group showed progression and none showed any improvement. Prolonged pomegranate juice intake improves nontraditional CV risk factors, attenuates the progression of the atherosclerotic process, strengthens the innate immunity, and thus reduces morbidity among HD patients.

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 ≧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 ≧60 ml/min/1.73 m2 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.

Interaction between Erythropoietin and Peripheral Polymorphonuclear Leukocytes in Continuous Ambulatory Dialysis Patients

The effect of erythropoietin (EPO) on the oxidative stress (OS) and inflammation caused by polymorphonuclear leukocytes (PMNLs) in end-stage renal failure patients undergoing continuous ambulatory peritoneal dialysis (CAPD) was investigated in vivo and in vitro. The studies were performed on isolated PMNLs from peripheral blood of CAPD patients before and following 6 weeks of EPO treatment and from healthy controls. OS was expressed by the rate of superoxide release from phorbol 12-myristate 13-acetate (PMA) stimulated isolated PMNLs and the inflammatory state was evaluated by PMNL counts of the enrolled subjects. Following 6 weeks of EPO treatment in CAPD patients, both the rate of superoxide release from PMNLs and PMNL counts fell significantly when compared with the pretreatment values. In vitro incubation of PMNLs from CAPD patients with increasing amounts of EPO displayed a significant reduction in their rates of superoxide release. EPO, by direct interaction with PMNLs, attenuated their primed state, causing reduction in oxidative stress and inflammation.

Pomegranate juice intake attenuates the increase in oxidative stress induced by intravenous iron during hemodialysis.

The hemodialysis (HD) procedure induces oxidative stress (OS), which is further aggravated by intravenous (IV) iron administration, aimed at correcting anemia of patients with HD. We have recently shown that 1 year of pomegranate juice (PJ) intake attenuated OS and inflammation in patients with HD. In the current study, we hypothesized that a single dose of PJ can attenuate the enhanced OS and inflammation induced by both the dialysis procedure and IV iron administration during HD session. Twenty-seven patients with HD were randomized to receive PJ or placebo during 1 dialysis session with IV iron. Blood samples were drawn before and after the session to asses OS biomarkers such as advanced oxidation protein products and myeloperoxidase (MPO), whereas polymorphonuclear leukocyte (PMNL) counts served as an indirect measure of inflammation. At the end of the dialysis session, an increase in advanced oxidation protein products and MPO levels as well as a decrease in PMNLs counts were observed in the placebo group, whereas no significant changes occurred in the PJ group. The postdialysis increase in MPO levels in the placebo group is a direct result of PMNL degranulation, associated with postdialysis decrease in PMNL counts. Degranulation of PMNLs leads to the release of other cell moieties, such as inflammatory mediators and proteases that enhance inflammation. We conclude that PJ intake attenuated the increase in systemic OS and inflammation induced by IV iron administration during the dialysis session. These beneficial effects illuminate the previously observed attenuation in OS and inflammation in patients with HD on prolonged PJ intake.