Piotr Bartnicki

Effect of methoxy polyethylene glycol-epoetin beta on oxidative stress in predialysis patients with chronic kidney disease.

Background There is data in the literature indicating increased oxidative stress in chronic kidney disease (CKD). Erythropoiesis-stimulating agents (ESAs), which are commonly used to treat anemia in patients with CKD, seem to have an antioxidant action, which could be a part of nephroprotection. The aim of the current study was to investigate the effect of a long half-life ESA, methoxy polyethylene glycol-epoetin beta (Mircera), on some markers of oxidative stress in predialysis patients with CKD. Material/Methods Peripheral blood was collected from 28 predialysis CKD patients 2 times, before Mircera treatment and after achieving target hemoglobin (Hb), and 15 healthy subjects (control group). Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activity in erythrocytes were measured according to commonly used methods as a function of the antioxidant defense system. To assess reactive oxygen species (ROS) production, malondialdehyde (MDA) concentration in erythrocytes and in plasma was measured according to a commonly used method. Results SOD, GSH-Px, and CAT activity were similar, but plasma and erythrocyte MDA concentrations were significantly higher in CKD patients before ESA treatment in comparison to the control group. SOD, GSH-Px, and CAT activity was significantly higher, but plasma and erythrocyte MDA concentrations were significantly lower, in CKD patients after ESA treatment in comparison to these patients before treatment. We did not find a significant correlation between Hb concentration and SOD, GSH-Px, and CAT activity and plasma, as well as erythrocyte MDA concentrations. Analysis of all investigated groups showed a significant negative correlation between Hb concentration and plasma MDA concentration. Conclusions Our results suggest that treatment of anemia with methoxy polyethylene glycol-epoetin beta may inhibit oxidative stress in predialysis patients with CKD by enhancing the antioxidant defense system and reducing ROS production.

The influence of the pleiotropic action of erythropoietin and its derivatives on nephroprotection

Erythropoietin (EPO) is traditionally described as a hematopoietic cytokine or growth hormone regulating proliferation, differentiation, and survival of erythroid progenitors. The use of EPO in patients with chronic kidney disease (CKD) was a milestone achievement in the treatment of anemia. However, EPO involves some degree of risk, which increases with increasing hemoglobin levels. A growing number of studies have assessed the renoprotective effects of EPO in acute kidney injury (AKI) or CKD. Analysis of the biological effects of erythropoietin and pathophysiology of CKD in these studies suggests that treatment with erythropoiesis-stimulating agents (ESAs) may exert renoprotection by pleiotropic actions on several targets and directly or indirectly slow the progression of CKD. By reducing ischemia and oxidative stress or strengthening anti-apoptotic processes, EPO may prevent the development of interstitial fibrosis and the destruction of tubular cells. Furthermore, it could have a direct protective impact on the integrity of the interstitial capillary network through its effects on endothelial cells and promotion of vascular repair, or modulate inflammation response. Thus, it is biologically plausible to suggest that correcting anemia with ESAs could slow the progression of CKD. The aim of this article is to discuss these possible renoprotection mechanisms and provide a comprehensive overview of erythropoietin and its derivatives.

Are Markers of Cardiac Dysfunction Useful in the Assessment of Cardiovascular Risk in Dialysis Patients

BACKGROUND Cardiovascular morbidity and mortality of dialysis patients are major problems in this group of patients. METHODS The purpose of this study was also to evaluate whether any of the studied markers are better than troponin in early detection of the occurrence of ventricular arrhythmias and prolongation of QT interval. This study included 45 patients undergoing hemodialysis. ECG Holter and echocardiographic examination were performed before and after dialysis. The concentrations of markers: copeptin, GDF-15, HFABP and troponin were measured with the use of ELISA tests. RESULTS We observed significantly higher QT (p=0.004), QTc (0.018), right atrium volume (p=0.006) and concentrations of copeptin (p<0.0001) and H-FABP (p<0.0001) as well as smaller left atrium volume (p<0.0001) and width of inferior vena cava (p<0.0001) after dialysis than before it. Significantly longer QT and higher copeptin levels were seen in patients with ventricular arrhythmia. A trend between the increase in copeptin concentration and H-FABP level and the presence of ventricular arrhythmias was also noted. CONCLUSION Generally, we failed to find any strong predictor of post-dialysis ventricular arrhythmia or the prolongation of QT, however, it seems that copeptin may have prognostic value, but this has to be analyzed in large studies.

Combination drug versus monotherapy for the treatment of autosomal dominant polycystic kidney disease

ABSTRACT Introduction: Despite progress in the understanding of pathogenetic mechanisms of organ cyst formation in autosomal dominant polycystic kidney disease, current treatment methods are insufficient. Experimental studies and clinical trials target at inhibition of cysts development and to slowing CKD progression. Areas covered: The purpose of this analysis is to overview available literature regarding treatment of ADPKD. The most important recent events concerning ADPKD treatment are: the results of TEMPO 3/4 study and the registration of tolvaptan in the treatment of patients with CKD stage I-III and rapidly progressive ADPKD by EMA. ERA-EDTA recommendations for use of tolvaptan in ADPKD of 2016 will be useful for the identification of patients with rapid progression of disease who will benefit most from treatment. Clinical trials concerning inhibitors of mTOR and SSAs have not delivered convincing evidence of their effectiveness. Usefulness of statins in ADPKD require confirmation in adults. The HALT-PKD study confirmed that inhibition of RAA system slows progression of ADPKD. Expert opinion: Current treatment of ADPKD involves: the optimization of life style and combined pharmacological treatment with ACE inhibitors or angiotensin receptor blockers, statins (patients with lipid disorders and cardiovascular disease) and tolvaptan (patients with stage I-III CKD and rapidly progressive ADPKD).

Evaluation of Endothelial (dys)Function, Left Ventricular Structure and Function in Patients with Chronic Kidney Disease.

BACKGROUND Endothelial dysfunction is involved in the pathogenesis of atherosclerosis and cardiovascular complications in chronic kidney disease (CKD). Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), is considered as a marker of endothelial dysfunction. The aim of this study was to evaluate serum ADMA, eNOS concentration and left ventricular structure and function in CKD patients and to assess the impact of the type of dialyzer on serum ADMA and eNOS concentrations after a haemodialysis (HD) session. MATERIAL AND METHODS Peripheral blood was collected from 35 predialysis CKD patients, 40 CKD patients on HD and 15 healthy subjects. Patients on HD were divided into two groups according to the dialyzer used based on polynephron or cellulose membranes. Plasma ADMA and eNOS concentrations were assessed. All subjects underwent echocardiography and were evaluated for selected biochemical parameters. RESULTS We found significantly higher serum ADMA (p<0.05) and significantly lower eNOS (p<0.05) concentration in CKD patients compared with healthy subjects. Both dialyzers significantly reduced serum ADMA concentration (p<0.05) but none of the analysed dialyzers showed superiority when comparing the results. We showed that stage V CKD patients, who had the highest serum ADMA concentration had the lowest left ventricle ejection fraction (LVEF) and the highest left ventricle mass (LVM) and left ventricular end diastolic diameter (LVEDd). CONCLUSIONS Our results supports the presence of endothelial dysfunction in CKD patients. Correlation between elevated serum AMDA concentration and disadvantageous changes in left ventricular structure and function may indicate an important role of endothelial dysfunction in cardiovascular complications in CKD patients.

Impact of anemia treatment with methoxy polyethylene glycol-epoetin beta on polymorphonuclear cells apoptosis in predialysis patients with chronic kidney disease

BACKGROUND Some data in literature indicate increased apoptosis of polymorphonuclear cells (PMNs) in chronic kidney disease (CKD), what seems to be connected with anemia. Erythropoiesis-stimulating agents, used in anemia treatment in CKD may affect cells apoptosis. Aim of this study was to investigate impact of anemia treatment with methoxy polyethylene glycol-epoetin beta (CERA) on PMNs apoptosis in predialysis patients with CKD. METHODS Percentage of early and late apoptotic PMNs was measured by flow cytometry based on annexin V and propidium iodide binding. CD90 (Fas), CD95L (FasL), CD16 and CD11b expression on PMNs were evaluated by flow cytometry after incubation with respective monoclonal antibody. RESULTS Percentage of PMNs in early and late apoptosis in CKD patients before CERA treatment was significantly higher to control group, which was accompanied by significantly higher Fas and Fas-L expression and significantly lower expression of CD16. CERA treatment downregulated significantly percentage of early, apoptotic PMNs but percentage of late apoptotic cells did not change and was still significantly higher to control group. In all investigated groups we observed a significant negative correlation between hemoglobin concentration and percentage of apoptotic PMNs, as well as Fas and FasL expression and significant positive correlation between Hb and CD16 expression. CONCLUSIONS Our results indicate that PMNs apoptosis is increased in predialysis patients with CKD and anemia treatment with CERA may diminish readiness of PMNs to undergo apoptosis. This antiapoptotic impact of anemia treatment with CERA seems to concern early apoptotic PMNs before they undergo to late, irreversible stage of apoptosis.

Coronary artery atherosclerosis in patients with the initial and the early stage of chronic renal failure

The recent clinical data indicate that the initial and the early stages of chronic renal failure (CRF) may lead to increased incidence of cardiovascular complications and increased extent of coronary artery disease (CAD). This retrospective study was aimed to determine the effects of coexisting diabetes mellitus type 2 (DM-2) and the extent of atherosclerosis in coronary vessels in patients with mildly reduced kidney function (glomerular filtration rate GFR = 89–60 ml/min) and moderately reduced kidney function (GFR = 59–30 ml/min). The study patients included 53 subjects with creatinine concentration above 120 μmol/l as a cut-off level for the initial stage and compensated CRF. The distributions of coronary artery stenosis were also analysed with respect to DM-2 coexistence and levels of haemoglobin glikolised (HbA1c). The odds ratio of pathological changes in coronary arteries in patients with GFR = 44–30 ml/min, with respect to the number of affected vessels — only one, more than one or more than two — were 7.22, 4.90 and 3.55, respectively. In CRF patients with GFR = 60–89 ml/min the odds ratio of one, more than one and more than two vessels with stenosis and CAD was 1.93, 1.70 and 1.53, respectively. DM-2 was not related to the risk of significant coronary artery stenosis and did not enhance the pre-existing changes in the study setting. Our results demonstrate that the initial and the early stages of CRF were significant risk factors for coronary stenoses and for enhancing the pre-existing changes.

IL-2, IL-6 and IL-8 levels remain unaltered in the course of immunosuppressive therapy after renal transplantation

Cytokines regulate the immune reactions elicited by renal transplantation (RT). This study was designed to investigate the blood serum levels of IL-2, IL-6, IL-8 in 25 RT patients (10 female and 15 male, mean 5.4±2.7 yrs after RT) three times over a six-month period during standard immunosuppressive therapy with cyclosporine A, azathioprine and prednisolone. The levels of IL-2, IL-6 and IL-8 were tested with ELISA Quantikine Human Interleukin Immunoassay (R&D Systems, detection level 7,0.7 and 10 pg/cm3, respectively). There was no significant alternation of blood serum levels of IL-2, IL-6 and IL-8 in the study patients.

Basic inflammatory indices and chosen neutrophil receptors expression in chronic haemodialysed patients

Aim of the study End stage renal disease (ESRD) patients on chronic haemodialysis (HD) are immuno-compromised and prone to infection. Toll-like receptors (TLRs) play a role as both primary sensors of pathogen invasion and activators of inflammatory reaction. To test if the immune impairment in HD patients is connected with the defective expression of the neutrophil TLRs, we aimed to examine their expression and chosen inflammatory indices. Material and methods We tested CD14, TLR4, and TLR9 expressions on neutrophils using flow cytometry. Soluble CD14, C-reactive protein (CRP), and mannose-binding lectin (MBL) concentrations were tested using the ELISA method in 31 ESRD patients on chronic haemodialysis programs and in 17 healthy control subjects. Results Neutrophil TLR4 and TLR9 expressions did not differ significantly compared to the controls. The ESRD patients had markedly increased CRP and sCD14 levels alongside decreased MBL concentrations and neutrophil CD14 expression. The TLR4 expression correlated well with both TLR9 and CD14 neutrophil expressions; however, the increased CRP in the blood did not correlate with the MBL concentration or TLR expression. Conclusions The chronic program of haemodialysis and biochemical disorders in ESRD patients result in a low-grade chronic inflammation with no significant impact on the expression of neutrophil TLR4 and TLR9.

Hemodialysis Decreases the Concentration of Accumulated Plant Phenols in the Plasma of Patients on Maintenance Dialysis: Influence of Residual Renal Function

Plant phenols may accumulate in end‐stage kidney disease. The effect of hemodialysis on their plasma concentration remains poorly determined. Contingent on concentration, health‐promoting or noxious effects occur; therefore, we assessed plasma concentration in hemodialyzed patients. In total, 21 maintenance hemodialyzed patients with diuresis < 500 mL per day (with oliguria), nine hemodialyzed patients with diuresis ≥ 500 mL per day (without oliguria) and 31 healthy volunteers were included. Nine phenolic acids were identified with high‐performance liquid chromatography and total polyphenol concentration was determined with the Folin–Ciocalteu method in pre‐ or post‐hemodialysis plasma and pre‐ or intra‐hemodialysis dialysate. The concentration of total polyphenols was 27% higher in pre‐hemodialysis plasma than in that of controls (0.95 ± 0.18 mmol/L [P < 0.0001]). The concentration of total polyphenols was higher in patients with oliguria (1.01 ± 0.17) than in those without (0.84 ± 0.13 mmol/L), despite the former having more intense hemodialysis (Kt/V 1.29 ± 0.31 and 0.77 ± 0.25, respectively). Pre‐hemodialysis phenolic acid concentration in patients undergoing dialysis exceeded reference values by 3 to 34 times (3‐hydroxyphenylacetic acid and vanillic acid, respectively), from 0.69 (dihydrocaffeic acid) to 169.3 μmol/L (hippuric acid). The concentration of six phenolic acids (3‐hydroxyhippuric, caffeic, dihydrocaffeic, hippuric, homovanillic, and vanillic acid) was 1.1 (homovanillic) to 11.3 (3‐hydroxyhippuric) times higher in patients with oliguria than in those without. 4‐hydroxyhippuric acid occurred more in the plasma of patients with oliguria than in those without oliguria. A single hemodialysis session decreased total polyphenol concentration by 16% and phenolic acids from 30% (caffeic) to 58% (vanillic and 3‐hydroxyphenylacetic acid) and these compounds appeared in the dialysate. The percentage decrease (Δ%) of creatinine concentration correlated with the Δ% of total polyphenols and five phenolic acids (3‐hydroxyphenylacetic, dihydrocaffeic, hippuric, homovanillic, and vanillic acid). Urea Δ% and Kt/V correlated only with the Δ% of homovanilic acid. The results demonstrate that phenols accumulate variably in hemodialyzed patients and are differently eliminated during hemodialysis. Residual renal function ensures a lower concentration of plasma phenols.