CKD-5D Patients Research Articles

Relationship of CD4+ CD28null T cells with left ventricular hypertrophy in end-stage renal disease patients

Objective To determine CD4+ CD28null T cells and their relationship with the microinflammatory state and left ventricular hypertrophy in end-stage renal disease (ESRD) patients. Methods One hundred and twenty ESRD patients were selected, including sixty non-dialytic stage 5 chronic kidney disease patients(CKD5 stage) and thirty maintenance dialysis patients(CKD5D stage). In addition, thirty healthy adults from the hospital medical center were selected as the control group.Flow cytometry was used to detect the frequencies of T lymphocyte subsets in peripheral blood.All enrolled subjects underwent Doppler echocardiography investigations. Results (1)Compared with the control group, the high sensitivity C-reactive protein and the frequency of CD4+ CD28null T cells were significantly expanded in CKD5 and CKD5D paients (F=14.887, 9.659, all P<0.05). (2)In ninety ESRD patients, the incidence of LVH increased in CKD5 and CKD5D patients (76.67% vs.86.67%). (3)Linear correlation in CKD5 patients showed that: LVMI was positively correlated to duration of hypertension, SBP, P3+ , lg(CRP+ 1), lgiPTH, lg(CD4+ CD28null+ 1) (r=0.332, 0.291, 0.269, 0.310, 0.304, 0.396, all P<0.05), as well as negatively correlated to Hb(r=-0.285, P<0.05). Multiple linear regression analysis showed that LVMI was independently associated with lg(CD4+ CD28null+ 1) and duration of hypertension(F=6.589, P<0.000). Conclusion There is microinflammatory state in the ESRD patients regardless of whether or not they have dialysis treatment, and they have the high incidence of LVH and exhibit a substantially increased frequency of circulating CD4+ CD28null T cells.The frequency of CD4+ CD28null T cells and duration of hypertension are the independent predictors of LVH in non-dialytic stage 5 CKD patients, indicates that these cells may play a critical role in the development of cardiovascular disease. Key words: Kidney diseases; CD4+ CD28null T cells; Left ventricular hypertrophy

Differential Expression of Lipoprotein-Associated Phospholipase A2 in Monocyte Subsets: Impact of Uremia and Atherosclerosis

Background: Monocytic products, such as lipoprotein-associated phospholipase A2 (Lp-PLA2), may participate in the development of atherosclerosis. Heterogeneity of monocytes is widely acknowledged. Classical, intermediate, and non-classical subsets can be discerned. Recently, an inflammatory, pro-atherogenic monocyte population could be identified in hemodialysis patients. In this study, we investigated the expression of Lp-PLA2 on leucocytes and different monocyte subpopulations and their possible role in uremia, inflammation, and atherosclerosis. Methods: Chronic kidney disease stage 5-D (CKD5-D; n = 57), healthy control subjects with hs-C-reactive protein (CRP) levels ≤1 mg/L (CO-N, n = 22) and a control group with inflammatory activation (CRP levels >1 mg/L, CO-I, n = 29) were enrolled in this cross-sectional observation. The CKD5-D cohort was dichotomized into patients with (A+) and without subclinical atherosclerosis (A-) by carotid artery ultrasound measurement. Lp-PLA2 activity was determined in plasma samples, Lp-PLA2 mRNA expression analysis in leucocytes, and sorted monocyte subsets. Effects of Lp-PLA2 overexpression were studied in classical vs. intermediate and non-classical subsets. Results: The classical monocytes expressed the highest Lp-PLA2 mRNA levels as compared to other subpopulations. CKD5-D patients revealed significantly higher Lp-PLA2 transcripts, as well as higher Lp-PLA2 plasma activity as compared to healthy and “inflammatory” controls. In vitro data confirmed that uremia significantly contributes to Lp-PLA2 mRNA upregulation. Non-classical monocytes of A+ patients revealed significant higher Lp-PLA2 mRNA compared to A-. Conclusion: Uremic environment but not inflammation per se increases plasma Lp-PLA2 activity and upregulates monocytic Lp-PLA2 mRNA expression. The highest Lp-PLA2 levels were found in the classical and not in the inflammatory subsets. Atherosclerosis also contributes to a subset-specific increase in Lp-PLA2 mRNA expression.

Coronary artery calcification in CKD-5D patients is tied to adverse cardiac function and increased mortality .

Background: Coronary artery calcification (CAC) is common in patients with chronic kidney disease on hemodialysis (CKD-5D) and is an important predictor of mortality. However, cardiac functional links between CAC and mortality have not been well established. This study tested the hypothesis that CAC increases mortality by adversely affecting cardiac function. Methods: Patients were recruited from 37 regional dialysis centers. 2-D and Doppler echocardiographic analyses were performed, and CAC was measured using 64-slice computed tomography. Relationships between CAC and echocardiographic measures of left ventricular (LV) function were analyzed. Survival was assessed with median follow-up of 37 months. Results: There were 157 patients: 59% male, 46% Caucasian, 48% diabetic. Median age was 55 years, and median duration of CKD-5D was 45 months. Agatston CAC scores > 100 were found in 69% of patients, with 51% having a score > 400. CAC was associated with measures of LV systolic and diastolic function (global longitudinal strain (GLS; rho = 0.270, p = 0.004)), peak LV systolic velocity (rho = –0.259, p = 0.004), and estimate of LV filling pressure (E:E’; rho = 0.286, p = 0.001). Multivariate regression confirmed these relationships after adjustment for age, gender, LV ejection fraction, and coronary artery disease. Valvular calcification varied linearly with CAC (p < 0.05). Both LV diastolic and systolic functional measures were significant predictors of mortality, the strongest of which was LV diastolic dysfunction. Conclusions: These findings show a link between CAC, cardiac function, and mortality in CKD-5D. LV diastolic function (E:E’), peak LV systolic velocity, and GLS are independent predictors of mortality. Valvular calcification may be an important marker of CAC in CKD-5D. These effects on cardiac function likely explain the high mortality with CKD-5D and describe a potentially-valuable role for echocardiography in the routine management of these patients.

Modulation of circulating endothelial progenitor cells by erythropoiesis-stimulating agents in patients with chronic kidney disease stage G5 and 5D .

Circulating endothelial progenitor cells (EPCs) play a pivotal role in vasculogenesis and promote angiogenesis by secreting growth factors. Recent studies have suggested that erythropoietin (EPO) may accelerate not only angiogenesis but also vasculogenesis, beyond erythropoiesis. The aim of this study was to investigate whether two erythropoiesis-stimulating agents (ESAs) modulate vascular-related factors and EPC mobilization in patients with chronic kidney disease stage G5 and dialysis (CKD G5 and 5D). We conducted a 12-week prospective study in 63 patients; 21 patients received recombinant human erythropoietin (rhEPO) (EPO group, 4,565.5±1,994.4IU/week), 21 patients received darbepoetin (DA) (DA group, 40.1±13.8µg/week), and 21 patients received no ESAs (no-ESA group). Vascular mediators, including EPCs, vascular endothelial growth factor, matrix metalloproteinase-2 (MMP-2), high-sensitivity C-reactive protein, and asymmetric dimethyl arginine, were measured at 0 and 12 weeks. EPCs were measured by flow cytometry as CD45^lowCD34⁺CD133⁺ cells. We also performed a subanalysis of dialysis (5D) patients (n=32) in the three groups. In the EPO group, EPC count increased significantly from 0 to 12 weeks in a dose-dependent manner (r=0.62, p=0.005), and the increase was more conspicuous in the subgroup of dialysis 5D patients. In the DA group, the EPC number did not change at 12 weeks. Neither rhEPO nor DA affected the serum levels of the aforementioned biomarkers other than EPC. ;Conclusion: We speculate that the pleiotropic effects of rhEPO and DA beyond their hematopoietic effects may differ between CKD G5 and 5D patients. .

The CLOCK trial, a double-blinded randomized controlled trial: Trisodium citrate 30% and minocycline 3 mg/mL plus EDTA 30 mg/mL are effective and safe for catheter patency maintenance among CKD 5D patients on hemodialysis.

Poor blood flow rate (PF) is highly prevalent among CKD 5D patients with long-term central venous catheters. Heparin catheter lock solutions are commonly used to maintain catheter patency, however the incidence of PF remains high. The purpose of the CLOCK Trial was to evaluate two catheter lock solutions on reduction of PF incidence. Seventy-five CKD 5D patients on high-efficiency hemodialysis at the Integrated Centre of Nephrology (Guarulhos, Brazil) were randomized 1:1:1 to receive a lock solution combining minocycline 3 mg/mL with the anticoagulant/chelation agent EDTA 30 mg/mL (M-EDTA) or heparin 1000 IU/mL (H) or trisodium citrate 30% (TSC) vs. Hfor 15 weeks. A total of 68 patients completed the trial in which both investigators and patients were blinded to treatment allocation. The primary end-point was the occurrence of hydraulic resistance and secondary safety end-point was adverse drug reactions related to the lock solutions. At the beginning of the trial, 7 patients were excluded from this trial due to their poor catheter care. The incidence of hydraulic resistance was significantly higher among patients on H (18/23) compared to TSC (4/22) and M-EDTA (2/23) lock solutions, (P < 0.001). The CLOCK Trial suggests TSC and M-EDTA may preserve catheter patency better than H. TSC may be a better option due the lack of association with long-term antimicrobial resistance.

Reduced protein bound uraemic toxins in vegetarian kidney failure patients treated by haemodiafiltration.

Introduction Indoxyl sulfate (IS) and p cresyl sulfate (PCS) are protein bound toxins which accumulate with chronic kidney disease. Haemodiafiltration (HDF) increases middle molecule clearances and has been suggested to increase IS and PCS clearance. We therefore wished to establish whether higher convective clearances with HDF would reduce IS and PCS concentrations. Methods We measured total plasma IS and PCS in a cohort of 138 CKD5d patients treated by On-line HDF (Ol-HDF), by high pressure liquid chromatography. Findings Mean patient age was 64.6 ± 16.5 years, 60.1% male, 57.3% diabetic, median dialysis vintage 25.9 months (12.4-62.0). The mean ICS concentration was 79.8 ± 56.4 umol/L and PCS 140.3 ± 101.8 umol/L. On multivariate analysis, IS was associated with serum albumin (β 4.31,P < 0.001), and negatively with residual renal function (β-4.1,P = 0.02) and vegetarian diet(β-28.3, P = 0.048) and PCS negatively with log C reactive protein (β-75.8, P < 0.001) and vegetarian diet (β-109, P = 0.001). Vegetarian patients had lower IS and PCS levels (median 41.5 (24.2-71.9) vs. 78.1 (49.5-107.5) and PCS (41.6 (14.2-178.3) vs. 127.3 (77.4-205.6) µmol/L, respectively, P < 0.05. Vegetarian patients had lower preOl-HDF serum urea, and phosphate (13.8 ±3.8 vs. 18.4 ± 5.2 mmol/L, and 1.33 ± 0.21 vs. 1.58 ± 0.45 mmol/L), and estimated urea nitrogen intake (1.25 ± 0.28 vs. 1.62 ± 0.5 g/kg/day), respectively, all P < 0.05. Discussion Plasma IS and PCS concentrations were not lower with Ol-HDF compared to previous studies in haemodialysis patients. However those eating a vegetarian diet had reduced IS and PCS concentrations. Although this could be due to differences in dietary protein intake, a vegetarian diet may also potentially reduce IS and PCS production by the intestinal microbiome.

Rifampicin and anti-hypertensive drugs in chronic kidney disease: Pharmacokinetic interactions and their clinical impact

Patients on dialysis have an increased incidence of tuberculosis (TB). Rifampicin, a first-line antitubercular therapy (ATT) drug, is a potent inducer of hepatic cytochrome P450 (CYP). There is potential for pharmacokinetic interaction between rifampicin and anti-hypertensives that are CYP substrates: amlodipine and metoprolol. Therefore, hypertensive patients receiving rifampicin-based ATT are at risk for worsening of hypertension. However, this hypothesis has not yet been systematically studied. In this prospective study, hypertensive CKD 5D patients with TB were followed after rifampicin initiation. Blood pressure (BP) was ≤140/90 mmHg with stable anti-HT requirement at inclusion. Serum amlodipine, metoprolol, and prazosin levels were estimated by high-performance liquid chromatography at baseline and 3, 7, 10, and 14 days after rifampicin initiation. BP and anti-HT requirement were monitored for 2 weeks or until stabilization. All 24 patients in the study had worsening of hypertension after rifampicin and 83.3% required increase in drugs to maintain BP <140/90 mmHg. Serial amlodipine levels were estimated in 16 patients; metoprolol and prazosin in four patients each. Drug levels declined by >50% in all patients and became undetectable in 50-75%. Drug requirement increased from 4.5 ± 3.6 to 8.5 ± 6.4 units (P < 0.0001). Mean time to first increase in dose was 6.5 ± 3.6 days. Eleven (46%) patients experienced a hypertensive crisis at 9.1 ± 3.8 days. Three of them had a hypertensive emergency with acute pulmonary edema. In two patients, rifampicin had to be discontinued to achieve BP control. In conclusion, rifampicin caused a significant decrease in blood levels of commonly used anti hypertensives. This decrease in levels correlated well with worsening of hypertension. Thus, we suggest very close BP monitoring in CKD patients after rifampicin initiation.

Diagnosis of low bone mass in CKD-5D patients.

Background and objectives: Currently, there is no consensus whether dual-energy X-ray absorptiometry (DXA) or quantitative computed tomography (QCT) can be used to screen for osteoporosis or osteopenia in CKD-5D patients. This study uses iliac bone histology, the “gold standard” for bone volume evaluation, to determine the utility of DXA and QCT for low bone mass screening in CKD-5D patients. Patients and methods: A cross-sectional study of patients with CKD-5D employing iliac crest bone biopsies to assess bone volume by histology and comparing results to bone mineral density (BMD) measurements of the hip and spine by DXA and QCT. Pearson’s correlation, linear regression, and receiver operating characteristics curve analyses were performed. Results: 46 patients (mean age 51 years, 52% women, median dialysis vintage 46 months) had bone biopsies, DXA, and QCT scans. 37 patients (80%) had low bone volume by histology. DXA and QCT BMD values (g/cm2) were very highly correlated at the femoral neck (ρ = 0.97) and total hip (ρ = 0.97), and to a lesser degree at the spine (ρ = 0.65). DXA and QCT t-scores were also highly correlated, but QCT t-scores were systematically greater than DXA t-scores (1.1 S.D. on average at the femoral neck) leading to less recognition of osteopenia and osteoporosis by QCT. A t-score below –1 by DXA at the femoral neck (i.e., osteopenic or osteoporotic) showed 83% sensitivity and 78% specificity relative to low bone volume by histology. A QCT t-score below –1 did not reach acceptable diagnostic levels of sensitivity and specificity. Conclusions: DXA and QCT provide nearly identical areal BMD measures at the hip. However, QCT t-scores are consistently higher than DXA t-scores resulting in less diagnosis of osteoporosis or osteopenia. DXA results showed acceptable diagnostic sensitivity and specificity for low bone volume by histology and can be used for diagnosis of osteopenia and osteoporosis in patients with CKD-5D.

Role of the endogenous nitric oxide inhibitor asymmetric dimethylarginine (ADMA) and brain-derived neurotrophic factor (BDNF) in depression and behavioural changes: clinical and preclinical data in chronic kidney disease.

Patients with chronic kidney disease (CKD) exhibit a high prevalence of neuropsychiatric alterations, including depression and behavioural changes. CKD is also associated with decreased physical activity not fully explained by co-morbidities. In patients without CKD, the brain-derived neurotropic factor (BDNF) as well as the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) had been suspected to be involved in major depression. The aim of our study was to examine the role of ADMA and BDNF in the behaviour of haemodialysis patients (CKD5D) as well as in a rat model of 5/6 nephrectomy and chronic ADMA infusion alone. Eleven (5F/6M) CKD5D patients underwent Beck Depression Inventory (BDI) testing along with analysis of ADMA and BDNF. Male Sprague-Dawley rats were randomly assigned to four groups: (i) saline infusion; (ii) ADMA (250 µg/kg/day) infusion via osmotic mini pumps; (iii) 5/6 nephrectomy; (iv) untreated controls. After 28 days, the animals underwent behavioural tests measuring anxiety, locomotion and investigative behaviour. Animals were sacrificed, blood samples were drawn and analysed and hippocampal immunohistology for BDNF was performed. In CKD5D patients, decreased BDNF levels correlated with higher scores of depression (Pearson r = -0.8156, P = 0.002). ADMA infusion led to a significant decrease of BDNF while the decrease of BDNF in 5/6 nephrectomy was not significant. However, an attenuated hippocampal BDNF expression could be detected in 5/6 nephrecomized animals. Decreased spontaneous locomotor activity was shown in ADMA-infused rats [15.9 (13.5-26.1) lines crossed/min] and 5/6 nephrectomy [14.6 (6.1-20.2) lines crossed/min] when compared with controls [32.5 (15.3-42.4) lines crossed/min]. Anxiety-like behaviour tested by hole investigation time was significantly more pronounced in 5/6 nephrectomy [24 (6-44) s] when compared with ADMA infusion [64 (28-93) s] and controls [33 (26-65) s]. Progressive renal failure in rats is accompanied by a marked increase of ADMA and a decrease in BDNF. 5/6 nephrectomy leads to significantly decreased exploratory behaviour and locomotion. Both behaviours could be reproduced by ADMA infusion alone. Indicators of anxiety were more pronounced in ADMA-infused animals when compared with 5/6 nephrectomized rats. Furthermore, an inverse relationship of BDNF and BDI in 11 CKD5D patients was shown.

Randomized, Double-Blind, Placebo-Controlled, Withdrawal Study of Colestilan after Dose Titration in Chronic Kidney Disease Dialysis Patients with Hyperphosphatemia

Background/Aims: Colestilan is a new non-calcium-based phosphate binder licensed in Europe for the treatment of hyperphosphatemia in chronic kidney disease patients on dialysis (CKD 5D). This study was conducted to evaluate efficacy in a North American patient population and also to examine secondary actions of colestilan on lipid profile and glycated hemoglobin (HbA1c). Methods: This was a multicenter, randomized, double-blind, placebo-controlled withdrawal study, after an initial open-label titration period. Patients (n = 245) with stable phosphate control received 6-15 g/day colestilan during a 12-week, flexible titration period after which 169 were randomized to continue the same dose (n = 85) or switch to placebo (n = 84) for 4 weeks. The primary endpoint was the change in serum phosphorus level during the placebo-controlled withdrawal period. Results: A significant difference of -1.01 mg/dl (-0.33 mmol/l) in mean change in serum phosphorus, favoring colestilan, was seen during the placebo-controlled withdrawal period (p < 0.001). Colestilan reduced serum phosphorus significantly from baseline to week 12 (-1.54 mg/dl (-0.50 mmol/l); p < 0.001). Serum calcium levels were not affected. Colestilan significantly reduced and maintained reductions in calcium × phosphorus ion product (Ca × P), parathyroid hormone, total cholesterol, low-density lipoprotein cholesterol, uric acid and also HbA1c in patients with elevated baseline HbA1c. Colestilan was generally well tolerated; most adverse events were gastrointestinal. Conclusion: In this first clinical trial with colestilan in a North American patient population, colestilan demonstrated significant efficacy in controlling serum phosphorus levels in CKD 5D patients with hyperphosphatemia, without increasing calcium levels.

Improvement of mineral and bone metabolism markers is associated with better survival in haemodialysis patients: the COSMOS study.

Abnormalities in serum phosphorus, calcium and parathyroid hormone (PTH) have been associated with poor survival in haemodialysis patients. This COSMOS (Current management Of Secondary hyperparathyroidism: a Multicentre Observational Study) analysis assesses the association of high and low serum phosphorus, calcium and PTH with a relative risk of mortality. Furthermore, the impact of changes in these parameters on the relative risk of mortality throughout the 3-year follow-up has been investigated. COSMOS is a 3-year, multicentre, open-cohort, prospective study carried out in 6797 adult chronic haemodialysis patients randomly selected from 20 European countries. Using Cox proportional hazard regression models and penalized splines analysis, it was found that both high and low serum phosphorus, calcium and PTH were associated with a higher risk of mortality. The serum values associated with the minimum relative risk of mortality were 4.4 mg/dL for serum phosphorus, 8.8 mg/dL for serum calcium and 398 pg/mL for serum PTH. The lowest mortality risk ranges obtained using as base the previous values were 3.6-5.2 mg/dL for serum phosphorus, 7.9-9.5 mg/dL for serum calcium and 168-674 pg/mL for serum PTH. Decreases in serum phosphorus and calcium and increases in serum PTH in patients with baseline values of >5.2 mg/dL (phosphorus), >9.5 mg/dL (calcium) and <168 pg/mL (PTH), respectively, were associated with improved survival. COSMOS provides evidence of the association of serum phosphorus, calcium and PTH and mortality, and suggests survival benefits of controlling chronic kidney disease-mineral and bone disorder biochemical parameters in CKD5D patients.

Strategies for preserving residual renal function in peritoneal dialysis patients.

Although there have been many advancements in the treatment of patients with chronic kidney disease (CKD) over the last 50 years, in terms of reducing cardiovascular risk, mortality remains unacceptably high, particularly for those patients who progress to stage 5 CKD and initiate dialysis (CKD5d). As mortality risk increases exponentially with progressive CKD stage, the question arises as to whether preservation of residual renal function once dialysis has been initiated can reduce mortality risk. Observational studies to date have reported an association between even small amounts of residual renal function and improved patient survival and quality of life. Dialysis therapies predominantly provide clearance for small water-soluble solutes, volume and acid-base control, but cannot reproduce the metabolic functions of the kidney. As such, protein-bound solutes, advanced glycosylation end-products, middle molecules and other azotaemic toxins accumulate over time in the anuric CKD5d patient. Apart from avoiding potential nephrotoxic insults, observational and interventional trials have suggested that a number of interventions and treatments may potentially reduce the progression of earlier stages of CKD, including targeted blood pressure control, reducing proteinuria and dietary intervention using combinations of protein restriction with keto acid supplementation. However, many interventions which have been proven to be effective in the general population have not been equally effective in the CKD5d patient, and so the question arises as to whether these treatment options are equally applicable to CKD5d patients. As strategies to help preserve residual renal function in CKD5d patients are not well established, we have reviewed the evidence for preserving or losing residual renal function in peritoneal dialysis patients, as urine collections are routinely collected, whereas few centres regularly collect urine from haemodialysis patients, and haemodialysis dialysis patients are at risk of sudden intravascular volume shifts associated with dialysis treatments. On the other hand, peritoneal dialysis patients are exposed to a variety of hypertonic dialysates and episodes of peritonitis. Whereas blood pressure control, using an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), and low-protein diets along with keto acid supplementation have been shown to reduce the rate of progression in patients with earlier stages of CKD, the strategies to preserve residual renal function (RRF) in dialysis patients are not well established. For peritoneal dialysis patients, there are additional technical factors that might aggravate the rate of loss of residual renal function including peritoneal dialysis prescriptions and modality, bio-incompatible dialysis fluid and over ultrafiltration of fluid causing dehydration. In this review, we aim to evaluate the evidence of interventions and treatments, which may sustain residual renal function in peritoneal dialysis patients.

Absolute quantification of endogenous angiotensin II levels in human plasma using ESI-LC-MS/MS.

BackgroundAngiotensin II acts as a peptide hormone and component of renin-angiotensin- system (RAS) regulating the blood pressure, and seems to be involved in renal and vascular disorders. There is no reliable quantification method for angiotensin II available until now and the angiotensin II plasma levels described in the literature are correspondingly strongly divergent. Therefore, we developed and validated a sensitive, selective and reliable LC-ESI-MS/MS method for absolute quantification of angiotensin II concentration in human plasma based on the AQUA strategy.MethodsPlasma samples were extracted using MAX Oasis cartridges and were subjected to a further immunoaffinity-purification using immobilized anti-angiotensin II antibodies in order to isolate endogenous angiotensin II. Stable isotope (13C- and 15 N-) labeled angiotensin II was used as an internal standard. The fractionated samples were analysed using LC-ESI-MS/MS.ResultsThe calibration curve was established in plasma in the concentration range 6–240 pM (r2 > 0.999). The developed and validated method was successfully applied for quantification of endogenous angiotensin II in human plasma of healthy volunteers and chronic kidney disease (CKD-5D) patients. The mean plasma angiotensin II levels were found to be 18.4 ± 3.3 pM in healthy subjects and 64.5 ± 32.4 pM in CKD-5D patients (each n =9).ConclusionThe LC-ESI-MS/MS-based method for quantification of angiotensin II levels in human plasma was successfully evaluated within the study. This method is applicable for clinical applications aiming at the validation of the impact of highly physiologically and pathophysiologically active angiotensin II.

Omega-3 fatty acids inhibit the up-regulation of endothelial chemokines in maintenance hemodialysis patients.

Chronic systemic inflammation is common in patients with chronic kidney disease on dialysis (CKD5D) and has been considered a key mediator of the increased cardiovascular risk in this patient population. In this study, we tested the hypothesis that supplementation of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) will attenuate the systemic inflammatory process in CKD5D patients. The design was a randomized, double-blinded, placebo controlled pilot trial (NCT00655525). Thirty-eight patients were randomly assigned in a 1 : 1 fashion to receive 2.9 g of eicosapentaenoic acid (C20:5, n-3) plus docosahexaenoic acid (C22:6, n-3) versus placebo for 12 weeks. The primary outcome was change in pro-inflammatory chemokines measured by lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs). Secondary outcomes were changes in systemic inflammatory markers. Analysis of covariance was used to compare percent change from baseline to 12 weeks. Thirty-one patients completed 12 weeks and three patients completed 6 weeks of the study. Median age was 52 (interquartile range 45, 60) years, 74% were African-American and 79% were male. Supplementation of ω-3 PUFAs effectively decreased the LPS-induced PBMC expression of RANTES (Regulated upon Activation, Normal T cell Expressed and Secreted) and MCP-1 (Monocyte Chemotactic Protein-1; unadjusted P = 0.04 and 0.06; adjusted for demographics P = 0.02 and 0.05, respectively). There was no significant effect of the intervention on serum inflammatory markers (C-reactive protein, interleukin-6 and procalcitonin). The results of this pilot study suggest that supplementation of ω-3 PUFAs is beneficial in decreasing the levels of endothelial chemokines, RANTES and MCP-1. Studies of larger sample size and longer duration are required to further evaluate effects of ω-3 PUFAs on systemic markers of inflammation, other metabolic parameters and clinical outcomes, particularly cardiovascular outcomes in CKD5D patients.

The duration of hepatitis B vaccine immunity in pediatric dialysis patients.

Dialysis patients are at risk for hepatitis B infection, a serious but preventable disease. Long-term hepatitis B protection has not been defined in pediatric patients with chronic kidney disease stage 5 on dialysis (CKD 5D) who were vaccinated as infants or children. Annual hepatitis B antibody surveillance data were collected retrospectively on a cohort of pediatric CKD 5D patients (n = 202) at a single institution and analyzed by survival analysis to assess hepatitis B immunity duration. Median duration of immunity by Kaplan-Meier analysis since primary vaccination was 106.3 [95 % confidence interval (CI) 93.9, 124.4] months. After the initiation of dialysis, the median duration of hepatitis B immunity was 37.1 (95 % CI 24.2, 72.3) months. Multivariate adjusted analysis showed that there was a significant difference in the duration of hepatitis immunity based on the timing of hepatitis B vaccination (p < 0.001). Patients immunized after starting dialysis had a hazard ratio of 6.13 (95 % CI 2.87, 13.08) for hepatitis B immunity loss compared to patients immunized as infants (p < 0.001). After dialysis initiation, protective hepatitis B antibody levels wane rapidly, with a shortened duration of immunity. In our cohort of pediatric patients with CKD 5D, this decline was more pronounced in children who were immunized after starting dialysis than in those who received hepatitis B immunizations during childhood. Both groups of patients should be monitored with serial antibody titers.

Clinical Efficacy, Safety and Anti-Inflammatory Activity of Two Sevelamer Tablet Forms in Patients on Low-Flux Hemodialysis

Sevelamer hydrochloride is an ionic exchange resin with high affinity for phosphate. This phosphate-binding agent has few serious adverse reactions with the advantage of reducing total and low density lipoprotein (LDL) cholesterol levels. However, it is controversial as to whether sevelamer hydrochloride can modulate the inflammatory response via endotoxin reduction. Therefore, a single-center, open-label, prospective and randomized study was performed to compare the clinical efficacy, safety and anti-inflammatory activity of two sevelamer hydrochloride tablet forms a branded tablet form, Renagel (Genzyme manufacturer) and its generic equivalent (EMS manufacturer). Twenty-eight chronic kidney disease volunteer patients at stage 5 (CDK 5D), on chronic low-flux hemodialysis carried out in 4-hour sessions, three times a week, were studied. The serum phosphorus, ionic calcium, total cholesterol and fractions, bicarbonate, blood pH, interleukin (IL)-6, IL-10, IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) levels were collected prior to dialysis at mid-week. The incidence of gastrointestinal adverse effects were determined at the end of the phosphate-binder washout period as well as at the end of the fourth and eighth weeks of use of both tablet forms. The same magnitude of reduction in serum phosphorus was observed with both sevelamer tablet forms. Only the Renagel group showed lower total cholesterol and lower LDL cholesterol levels at the fourth and eighth week versus baseline. No significant differences in serum cytokine levels were identified in either drug group. However, the incidence of intestinal obstipation was higher among patients who used the generic equivalent form. In conclusion, Renagel and its EMS generic equivalent tablet forms have a similar clinical efficacy in reducing phosphorus in CKD 5D patients on low-flux hemodialysis and a similar safety profile.

The reversible part of cognitive impairment in chronic kidney disease: can mice help men break the TEMPOLimit?

Discussing the non-adherence to diet or medication with chronic haemodialysis patients can be an utterly frustrating experience, especially if one does this thrice a week. It is also a reflection of the fact that for more than half a century, nephrologists have been focusing on cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. Over the last decade, however, burgeoning evidence has accumulated to show that CKD also affects the patient’s brain. CKD is accompanied by severe cognitive impairment as recently reviewed by Elias et al. [1]. Kurella et al. [2] could show that decreased estimated glomerular filtration rate (GFR) in postmenopausal women is significantly associated with impairment in global cognition, executive function, language and memory. A community-based cross-sectional study found that global performance and specific cognitive functions are negatively affected early in CKD [3]. Interestingly, not only decreases in GFR but also elevated urinary albumin/creatinine ratios are independently associated with faster decline in cognitive function [4]. In a 5-year longitudinal community-based study, change in renal functioning over time was related to change observed in global cognitive ability, verbal episodic memory and abstract reasoning [5]. Moreover, moderate renal impairment has been shown to be associated with an excess risk of incident dementia among individuals in good to excellent health [6]. Naturally, cognitive impairment cannot be revealed during the discussions about phosphate binders and anti-hypertensives. The backbone for detection of cognitive impairment are psychometric tests, first introduced in 1944 by the US Army in the Army Individual Test Battery—Manual of Directions and Scoring. Part of this test battery was the trail making test (TMT), a neuropsychological test of visual attention and task switching. It consists of two parts in which the subject is instructed to connect a set of 25 dots as fast as possible while still maintaining accuracy (TMT A) [7]. It can provide information about visual search speed, scanning, speed of processing, mental flexibility as well as executive functioning that are evaluated in the TMT B [7]. It is more sensitive to detecting decline in cognitive function in different stages of CKD than the Modified Mini-Mental State Examination (3MS) [8]. The severity of cognitive impairment is best epitomized by the fact that a high school educated 50-yearold person is able to finish the TMT B in ∼1 min, whereas ∼20% of dialysis patients in the same age group are not able to finish the TMT B in 5 min [9]. The pathophysiological mechanisms leading to cognitive impairment in CKD are still not clearly understood. They may range from effects of urea to the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA [10, 11]). Of note, there is an irreversible and a reversible component of cognitive impairment in CKD (Figure 1). The underlying diseases causing CKD, mostly arterial hypertension and diabetes, go along with structural cerebral changes. This is best epitomized by the facts that CKD5D patients have a 6-fold age-adjusted relative risk of stroke when compared with the general population [12]. Also, the prevalence of asymptomatic silent cerebral infarction is four to five times higher in dialysis patients than in ageand sex-matched controls [13]. A recent systematic review of structural neuroimaging findings in CKD came to the conclusion that cerebral atrophy and cerebral density changes in patients with CKD are frequently seen along with cerebral vascular disease, including deep white matter

18F-fluoride Positron Emission Tomography Measurements of Regional Bone Formation in Hemodialysis Patients with Suspected Adynamic Bone Disease

18F-fluoride positron emission tomography (18F-PET) allows the assessment of regional bone formation and could have a role in the diagnosis of adynamic bone disease (ABD) in patients with chronic kidney disease (CKD). The purpose of this study was to examine bone formation at multiple sites of the skeleton in hemodialysis patients (CKD5D) and assess the correlation with bone biopsy. Seven CKD5D patients with suspected ABD and 12 osteoporotic postmenopausal women underwent an 18F-PET scan, and bone plasma clearance, K i, was measured at ten skeletal regions of interest (ROI). Fifteen subjects had a transiliac bone biopsy following double tetracycline labeling. Two CKD5D patients had ABD confirmed by biopsy. There was significant heterogeneity in K i between skeletal sites, ranging from 0.008 at the forearm to 0.028 mL/min/mL at the spine in the CKD5D group. There were no significant differences in K i between the two study groups or between the two subjects with ABD and the other CKD5D subjects at any skeletal ROI. Five biopsies from the CKD5D patients had single tetracycline labels only, including the two with ABD. Using an imputed value of 0.3 μm/day for mineral apposition rate (MAR) for biopsies with single labels, no significant correlations were observed between lumbar spine K i corrected for BMAD (K i/BMAD) and bone formation rate (BFR/BS), or MAR. When biopsies with single labels were excluded, a significant correlation was observed between K i/BMAD and MAR (r = 0.81, p = 0.008) but not BFR/BS. Further studies are required to establish the sensitivity of 18F-PET as a diagnostic tool for identifying CKD patients with ABD.

Cinacalcet: the chemical parathyroidectomy?

The existing body of evidence suggests that cinacalcet isan effective drug for secondary hyperparathyroidism(SHPT) control in patients undergoing maintenance dialy-sis (CKD-5D) [1–10]. Indeed, available evidence suggeststhat by modulating the parathyroid calcium-sensing re-ceptor affinity to serum calcium, cinacalcet lowers by40–50% (250–350 pg/mL) serum parathyroid hormone(PTH) (Table 1). A consensual reduction in calcium [∼0.5–0.8 mg/dL (0.125–0.200 mmol/L); 5–8%] (Table 1) is alsoreported and expected due to the calcium-PTH set pointchange induced by this drug [11, 12]. However, some,albeit not all, reports (Table 1) have described a consen-sual reduction in serum phosphorus, which is more com-plicated to explain and often confounded by theconcomitant use of other agents such as vitamin D andphosphate binders that significantly affect phosphorousmetabolism [13, 14].Serum phosphorous represents a minimal part (∼1%) ofthe total body pool and is regulated by the net amount ab-sorbed in the intestine, the quota excreted by the kidneysand the net amount exchanged by the bones in the timeunit [13]. Notably, serum phosphorous does not alwaysclosely mirror the total body pool and phosphorousbalance in CKD, since different hormones regulate renaltubular (i.e. FGF-23, FGF-7, PTH) and bone (i.e. PTH) phos-phate handling to avoid excessive fluctuations of serumphosphorous concentration [13–15]. However, in CKD-5Dpatients the amount excreted by the kidneys is minimal ifnot absent. Hence, the reported tendency of cinacalcet toreduce serum phosphorous cannot be explained bya ‘renalcompensation’, but rather by the PTH effect on bones.We read with interest the manuscript by Zitt et al. [16].The aim of their study was to elucidate the mechanismsby which cinacalcet may lower serum phosphorous. Inthis observational study (ECHO study) [16], the authorsreport an overall tendency towards phosphate reduction(median change −9.1%, interquartile range: −25% to+10%), after 12 months of cinacalcet therapy [16]. Each10% serum PTH reduction correlates with a 3% decreasein serum phosphorous in the ECHO study cohort [16].However, at least 25% of the study population experi-enced an increase in serum phosphorous (median change−9.1%, interquartile range: −25% to +10%) [16] in spiteof the treatment with cinacalcet. The use of othercompounds such as vitamin D or phosphate binders aswell as the lack of diet control might explain why not allpatients treated with cinacalcet exhibit a consensualserum phosphorous reduction, but authors documentthat among 45% of patients in which serum phosphorousdecreases [defined as a change of at least 0.1 mg/dL(0.0323 mmol/L)], the use of concomitant medicationscannot explain this trend (vitamin D either increased orremained unchanged and phosphate binders were eitherreduced or left unchanged during follow-up). Finally, thelack of association between cinacalcet dose and serumphosphorous corroborates the hypothesis that bonemetabolism may playa role at least in some patients whoexperience a phosphate reduction while on cinacalcettreatment, similarly to what was seen after surgical para-thyroidectomy [17]. The role of bone metabolism couldalso be hypothesized by the multivariable-adjusted andsensitivity analyses. Adjustment for factors associatedwith serum phosphorus in CKD-5D patients documentsthat baseline serum phosphorous, dialysis vintage andPTH change from baseline to month 12 are the major de-terminants of phosphorus reduction at follow-up [16].However, sensitivity analyses document that a significantserum phosphate reduction is noted in all but the lowestbaseline PTH quartile and PTH change at Month 12 [17],suggesting that the quota of phosphate removed fromthe bone is relevant among subjects with severe SHPT oramong patients with parathyroid gland tissue still respon-sive to a calcimimetic drug (i.e. greater PTH reduction).The findings reported by Zitt et al. are consistent withprevious reports (Table 1 ). Though all studies recruited sub-jects with on average a poorly controlled PTH (in the rangeof 500–700 pg/mL), not all patients experienced a de-crease in serum phosphate. However, no study has con-trolled the use of phosphate binders and vitamin Dchanges during follow-up. In this regard, Zitt et al. furtherexpand the body of knowledge showing this trend amongpatients who did not decrease vitamin D or increase phos-phate binder usage at follow-up. Nonetheless, the obser-vational nature and the potential of imbalance amongdifferent groups (data not reported) and the lack of phos-phate intake evaluation at baseline and during follow-up,caution against definitive conclusions about the role ofPTH and the generalizability of the authors’ results.

Asymptomatic Pulmonary Congestion and Physical Functioning in Hemodialysis Patients

Poor physical performance is common in patients with kidney failure on dialysis (CKD-5D). Whether lung congestion, a predictable consequence of cardiomyopathy and fluid overload, may contribute to the low physical performance of CKD-5D patients has not been investigated in hemodialysis patients. This study investigated the relationship between the physical functioning scale of the Kidney Disease Quality of Life Short Form and a validated ultrasonographic measure of lung water in a multicenter survey of 270 hemodialysis patients studied between 2009 and 2010. Moderate to severe lung congestion by lung ultrasonography was observed in 156 (58%) patients; among these, 60 (38%) were asymptomatic (New York Heart Association [NYHA] class I). On univariate analysis, physical functioning was inversely associated with lung water in the whole group (r=-0.22; P<0.001) and in the subgroup of asymptomatic patients (r=-0.40; P=0.002). Age (r=-0.45; P<0.001) and past cardiovascular events (r=-0.22; P=0.002) were also inversely associated with physical functioning, whereas albumin (r=0.23; P<0.001) was directly associated with the same parameter. NYHA class correlated strongly with physical functioning (r=-0.52; P<0.001). In a multiple regression analysis, both NYHA class and lung water maintained an independent association with physical functioning, whereas albumin and background cardiovascular events failed to independently relate with the same outcome. Symptomatic and asymptomatic lung congestion is associated with poor physical functioning in hemodialysis patients. This association is independent of NYHA, suggesting that this measurement and NYHA may have complementary value to explain the variability in physical performance in hemodialysis patients.