Inflammation,high ferritin,and erythropoietin resistance in indigenous maintenance hemodialysis patients from the Top End of Northern Australia

Use of erythropoiesis‐stimulating agents (ESAs) has improved the management of anemia in patients on maintenance hemodialysis (MHD). Iron deficiency and inflammation cause ESAs resistance and are both common among indigenous people of Northern Australia. As part of quality assurance in our Renal Anaemia Management program, we observed that there was use of higher doses of ESAs and adjuvant iron therapy in our MHD patients. This study aimed to explore the relationship among iron studies, inflammation, ESA responsiveness, and ESAs and iron requirements in indigenous patients on MHD from the Top End of Northern Australia. We performed a retrospective cohort analysis of anemia management in a cohort of our patients on MHD. We extracted data for 178 indigenous and 19 non‐indigenous patients from 1 March 2009 to 28 February 2010 from the Renal Anaemia Management database, which collects data prospectively in MHD patients. Ninety‐nine percent of the whole sample had a ferritin level above the international guidelines threshold of >500 µg/L. Indigenous patients had higher ferritin (1534 ± 245.5 µg/L vs. 1013 ± 323.3 µg/L, P = 0.002). C‐reactive protein (CRP) was high in 56.9% of the total cohort. One hundred percent of those with normal CRP had high ferritin (>500 µg/L). C‐reactive protein was higher in indigenous than in non‐indigenous patients. Erythropoiesis‐stimulating agents hyporesponsiveness was higher in indigenous patients (P < 0.0001). There was no significant difference in ESAs hyporesponsiveness among different levels of CRP (P = 0.116), ferritin (P = 0.408), and transferrin saturation (P = 0.503). Indigenous patients required higher total iron dose (2820.30 [2000–4350] vs. 2336.12 [1912–2900], P = 0.02). There was no significant relationship between the high ferritin and CRP. In indigenous dialysis patients, iron therapy and ESAs use are higher. The high iron use is due to a lack of published evidence to guide the administration of iron in patients with high ferritin. The high ferritin and ESAs resistance could not be fully explained by inflammation and need further evaluation. Further studies are required to determine the safe use of iron and management of ESAs resistance in our hemodialysis population.     

Erythrocyte folate status and serum iron levels in patients undergoing hemodialysis

The present study was aimed to evaluate erythrocyte folate and the iron levels in diabetes and hypertension patients treated with/without hemodialysis. The effects of erythropoietin and iron treatment as well as vitamin supplementation on measured parameters were considered. The 67 controls consisted of healthy subjects (n = 22), hypertensive subjects (n = 22), and diabetic subjects (n = 23) without any renal disorder. According to primary renal disorders, the patients undergoing hemodialysis (n = 68) were classified into four groups as diabetic nephropathy, hypertensive nephropathy, reflux nephropathy or interstitial nephritis, and renal insufficiency depending on other causative factors. The mean value of erythrocyte folate levels of all patients undergoing hemodialysis was higher than the healthy control group (P < 0.05). Erythrocyte folate levels in hypertensive and diabetic nephropathy patients were higher than their own hypertensive or diabetic controls and also healthy controls (both, P < 0.05). Serum iron levels of all subgroups in hemodialysis patients were found to be similar with healthy controls (all, P > 0.05). The only significance observed within the subgroups was between diabetic controls and diabetic nephropathy patients (P < 0.05). None of the treatment or supplementation of erythropoietin, iron and vitamin affected erythrocyte folate levels (all, P > 0.05). The increase in erythrocyte folate status of patients with end stage renal diseases might be the result of sum or individual effects of causative factors such as renal pathology, compensation mechanism against renal anemia, or routine folate supplementation.     

Pharmacologic adjuvants to epoetin in the treatment of anemia in patients on hemodialysis

Anemia is a common complication of chronic kidney disease, particularly in patients who are on dialysis. The use of recombinant human erythropoietin has led to the eradication of severe anemia in the dialysis population. Correction of anemia in these patients has been associated with better quality of life and clinical outcomes. Some hemodialysis patients have anemia that either is relatively refractory to epoetin therapy or requires very high doses of epoetin (i.e., hyporesponsiveness), despite having adequate iron stores, and are thus unable to achieve or maintain target hemoglobin levels. Several pharmacologic agents have been studied for effects on improving response to epoetin, either to counter hyporesponsiveness or simply to reduce epoetin use for purely economic reasons. This review examines the available literature regarding the efficacy of these potential pharmacologic adjuvants to epoetin in the treatment of anemia in patients on maintenance hemodialysis, with special emphasis on androgens, vitamin C (ascorbic acid), and L-carnitine. A review of published guidelines and recommendations for use of these agents in hemodialysis patients is provided.     

Naturally nonanemic dialysis patients: Who are they?

Introduction Not only anemia, but also erythropoiesis stimulating agent (ESA)s for treating anemia may adversely affect prognosis of chronic hemodialysis patients. Various features of naturally (with no ESA usage) nonanemic patients may be useful for defining several factors in the pathogenesis of anemia. Methods Data, retrieved from the European Clinical Database (EuCliD)‐Turkey on naturally nonanemic prevalent chronic hemodialysis patients (n: 201) were compared with their anemic (those who required ESA treatment) counterparts (n: 3948). Findings Mean hemoglobin values were 13.5 ± 0.8 and 11.5 ± 0.9 g/dL in nonanemic and anemic patients, respectively (P < 0.001). Nonanemia status was associated with younger age, male gender, longer dialysis vintage, nondiabetic status, more frequent hepatitis‐C virus seropositivity and more frequent arteriovenous fistula usage. Serum ferritin and CRP levels and urea reduction ratio were higher in ESA‐requiring patients. One (99%) and two (95.3%) years survival rates of the “naturally nonanemic” patients were superior as compared to anemics (91.0% and 82.6%, respectively), (P < 0.001). Discussion “Naturally nonanemic” status is associated with better survival in prevalent chronic hemodialysis patients; underlying mechanisms in this favorable outcome should be investigated by randomized controlled trials including large number of patients.     

Statin use is associated with lower inflammation and erythropoietin responsiveness index in hemodialysis patients

Patients with end-stage renal disease are prone to inflammation and inflammation is related to erythropoietin-stimulating agent hyporesponsiveness and mortality in this population. Statins have been demonstrated to reduce cardiovascular mortality in selected populations of end-stage renal disease patients. These drugs have pleiotrophic effects such as anti-inflammation. In this retrospective analysis, we determined whether the use of statins improves inflammation and inflammation-related anemia in a cohort of hemodialysis patients. Data were analyzed from Fresenius Medical Care Dialysis Clinics in Turkey between 2005 and 2007. Seventy prevalent hemodialysis patients who were on statins at the start of the study and have been on statins during follow-up (statin users) and 1293 patients who were not on statin at the start of the study and had never been prescribed any lipid-modifying drugs during follow-up (statin nonusers) were included in the study. High-sensitive C-reactive protein levels were significantly decreased in statin users (1.50±1.49 vs. 1.33±1.11 mg/L, P=0.05) compared with nonusers (1.93±3.22 vs. 2.05±2.77 mg/L). Hemoglobin levels and the rate of erythropoietin-stimulating agent users were similar. However, the prescribed erythropoietin-stimulating agent dose (31.6±27.5 vs. 47.3±45.2 U/kg/week, P<0.05) and the erythropoietin response index (2.90±2.73 vs. 4.51±4.48 U/kg/week/Hb, P=0.001) were lower in statin users compared with statin nonusers. On stepwise multiple regression analysis, gender, high-sensitive C-reactive protein, duration of hemodialysis, serum ferritin, and statin use were independent determinants of the erythropoietin responsiveness index. Our results suggest that statin treatment leads to lower inflammation and improves hematopoiesis in hemodialysis patients.     

Plasma vitamin C levels in ESRD patients and occurrence of hypochromic erythrocytes

Introduction: The achievement of erythropoiesis in hemodialysis (HD) patients is typically managed with erythropoiesis‐stimulating‐agents (ESA's) and intravenous iron (IV‐iron). Using this treatment strategy, HD patients frequently show an elevated fraction of red blood cells (RBC) with hemoglobin (Hb) content per cell that is below the normal range, called hypochromic RBC. The low Hb content per RBC is the result of the clinical challenge of providing sufficient iron content to the bone marrow during erythropoiesis. Vitamin C supplements have been used to increase Hb levels in HD patients with refractory anemia, which supports the hypothesis that vitamin C mobilizes iron needed for Hb synthesis. Methods: We conducted a cross‐sectional survey in 149 prevalent HD patients of the percent hypochromic RBC, defined as RBC with Hb < 300 ng/uL of packed RBC, in relation to plasma vitamin C levels. We also measured high‐sensitivity CRP, (hs‐CRP), iron, and ferritin levels. and calculated ESA dose. Findings: High plasma levels of vitamin C were negatively associated with hypochromic RBC (P < 0.003), and high ESA doses were positively associated (P < 0.001). There was no significant association of hs‐CRP with percent hypochromic RBC. Discussion: This finding supports the hypothesis that vitamin C mobilizes iron stores, improves iron delivery to the bone marrow, and increase the fraction of RBC with normal Hb content. Further research is warranted on development of protocols for safe and effective use of supplemental vitamin C for management of renal anemia.     

Orally administrated Juzen-taiho-to/TJ-48 ameliorates erythropoietin (rHuEPO)-resistant anemia in patients on hemodialysis

Maintenance of the red blood cell volume is a fundamental aspect of ensuring oxygen supply to the tissue. Recombinant human erythropoietin (rHuEPO) was approved for marketing in Japan in 1990 for the treatment of anemia in patients on dialysis. Recombinant human erythropoietin caused a significant increase in hemoglobin (Hb) levels in patients on dialysis. However, not all have a good response to rHuEPO therapy; the causes of rHuEPO failure include iron deficiency, infection, uremia, and interaction of some drugs. Juzen-taiho-to (TJ-48), a mixture of extracts from 10 medicinal herbs, has been used traditionally to treat patients with anemia, anorexia, or fatigue. To clarify the effect of TJ-48 on erythropoietin-resistant anemia, we studied the effect of TJ-48 in patients on hemodialysis with erythropoietin-resistant anemia. We divided 42 end-stage renal disease patients on hemodialysis with erythropoietin-resistant anemia (Hb<10.0 g/dL with rHuEPO 9000 U/wk or 15 U/kg/wk treatment) into 2 groups as follows: a TJ-48-treated group (TJ-48 group, 7.5 g/d, n=22) and a TJ-48 nontreated (control group, n=20). At the beginning of this study, there was no significant difference between the groups in age, sex, serum creatinine, blood urea nitrogen, serum iron, and ferritin. After 12 weeks of treatment, the Hb level had significantly increased from 8.4 +/- 1.1 to 9.5 +/- 1.3 g/dL (P=0.0272) in the TJ-48 group. C-reactive protein (CRP) had significantly decreased from 1.4 +/- 1.7 to 0.6 +/- 0.8 mg/dL (P=0.0438). There was a significant negative correlation between Hb and CRP in the TJ-48 group (r(2)=0.121, P=0.0066). In contrast, in the control group, Hb and CRP showed no significant changes throughout this study. Nor was there a significant correlation between Hb and CRP in the control group. In conclusion, TJ-48 was effective in improving erythropoietin-resistant anemia in end-stage renal disease patients. This effect was, at least in part, due to the anti-inflammatory effect of TJ-48 in patients on hemodialysis.     

TSAT is a better predictor than ferritin of hemoglobin response to Epoetin alfa in US dialysis patients

Clinical guidelines recommend concurrent treatment of anemia in end‐stage renal disease with erythropoiesis‐stimulating agents (ESAs) and iron. However, there are mixed data about optimal iron supplementation. To help address this gap, the relationship between iron markers and hemoglobin (Hb) response to ESA (Epoetin alfa) dose was examined. Electronic medical records of 1902 US chronic hemodialysis patients were analyzed over a 12‐month period between June 2009 and June 2010. The analysis included patients who had at least one Hb value during each 4‐week interval for four consecutive intervals (k ? 2, k ? 1, k, and k + 1; k is the index interval), received at least one ESA dose during intervals k ? 1 or k, had at least one transferrin saturation (TSAT) value at interval k, and at least one ferritin value during intervals k ? 2, k ? 1, or k. Effect modification by TSAT and ferritin on Hb response was evaluated using the generalized estimating equations approach. Patients had a mean (standard deviation) age of 62 (15) years; 41% were Caucasian, 34% African American, 65% had hypertension, and 39% diabetes. Transferrin saturation, but not ferritin, had a statistically significant (P < 0.05) modifying effect on Hb response. Maximum Hb response was achieved when TSAT was 34%, with minimal incremental effect beyond these levels. Of the two standard clinical iron markers, TSAT should be used as the primary marker of the modifying effect of iron on Hb response to ESA. Long‐term safety of iron use to improve Hb response to ESA warrants further study.     

Causes and consequences of inflammation on anemia management in hemodialysis patients

Inflammation is common among hemodialysis patients, and evidence is accumulating to suggest that inflammation is a major contributor to morbidity and mortality. Several factors have been suggested as potential causes of inflammation, including infections and the atherosclerosis process, as well as etiologies directly related to kidney disease such as reduced renal function and dialysis. Among several inflammatory biomarkers investigated, serum C-reactive protein (CRP) is the most widely used. In hemodialysis patients, raised CRP levels have been shown to be predictive of cardiovascular events, hospitalization, and all-cause and cardiovascular mortality. Elevated CRP levels may correlate with comorbidities and intercurrent events, all of which may impact the response to erythropoiesis-stimulating agents (ESAs) and lead to higher ESA doses. Most dialysis facilities do not routinely measure CRP, despite recommendations by the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative. Regular measurement of CRP levels may help providers to understand change in ESA dosing and identify patients at risk for cardiovascular events. This review explores the inter-relationships between inflammation, CRP levels, and anemia management in patients receiving hemodialysis.     

Is hepcidin‐25 a predictor of atherosclerosis in hemodialysis patients?

Atherosclerotic cardiovascular disease is an important cause of mortality and morbidity in hemodialysis patients. Iron accumulation in arterial wall macrophages is increased in atherosclerotic lesions. Hepcidin is a key hepatic hormone regulating iron balance. It inhibits iron release from macrophages and iron absorption from enterocytes by binding and inactivating the cellular iron exporter ferroportin. The aim of this study is to investigate the relation of hepcidin‐25, iron parameters, and atherosclerosis measured by carotid intima media thickness (CIMT) in hemodialysis patients. Eighty‐two hemodialysis patients were enrolled in this cross‐sectional study. Predialysis blood samples were centrifuged at 1500 g and 4°C for 10 minutes and stored at ?80°C for the measurement of hepcidin‐25. DRG hepcidin enzyme‐linked immunosorbent assay kit was used for the measurement of hepcidin‐25. Ultrasonographical B‐mode imaging of bilateral carotid arteries was performed with a high‐resolution real‐time ultrasonography (Mindray DC7). Mean age of the study population was 57.90 ± 16.08 years and 43.9% were men. Total study population was grouped into two according to median value of hepcidin‐25. There was no difference between groups with respect to age, dialysis vintage, and C‐reactive protein. CIMT was found to be statistically significantly higher in low hepcidin‐25 group. In correlation analysis, CIMT was found to be correlated with age (P < 0.01, R = 0.33) and hepcidin‐25 (P < 0.01, R = 0.46). In linear regression analysis, age (β = 0.31) and hepcidin‐25 (β = 0.44) were found to be the determinants of CIMT in hemodialysis patients. Our results implicate that hepcidin may take part in pathophysiology of atherosclerosis and cardiovascular disease in hemodialysis patients.     

Monthly continuous erythropoietin receptor activator treatment maintains stable hemoglobin levels in routine clinical management of hemodialysis patients

Once-monthly administration of CERA, a continuous erythropoietin receptor activator, has shown equivalent efficacy to shorter-acting erythropoiesis-stimulating agents (ESAs) that require more frequent dosing, but data on routine use of once-monthly CERA in hemodialysis patients are lacking. Study on Efficacy, Safety and Applicability of Mircera (SESAM) was a prospective, multicenter, noninterventional trial with a duration of up to 9 months (month 0-5 "titration phase"; month 6-8 "evaluation phase") to test the stability of Hb control in hemodialysis patients under routine conditions. Patient selection, Hb targets and CERA dosing were at the discretion of the local nephrologist. 918 patients from 92 German nephrology centers were included. Ninety-three percent were on ESA treatment prior to study entry. The mean number of CERA dose changes during the study was 1.9 ± 1.9 per patient. Mean Hb level was 11.4 ± 1.2 g/dL at baseline and 11.7 ± 1.4 g/dL at the end of the 8-month study. During the evaluation phase (months 6-8), 15.6%, 40.3%, and 66.0% of patients had stable Hb (i.e., at least two values) in the ranges 11-12, 10-12, and 10-13 g/dL, respectively. The mean intra-individual fluctuation in Hb was 1.4 ± 0.7 g/dL during the study (0.5 ± 0.4 g/dL during the 3-month evaluation phase). More than 90% of patients, and > 80% of physicians, rated CERA therapy as "very good" or "good" throughout the study. Four patients (0.4%) discontinued prematurely due to adverse drug reactions. Once-monthly CERA therapy maintains stable Hb values with low intra-individual variability and few dose adaptations in hemodialysis patients when administered entirely according to local practice, and the regimen was well-tolerated.     

Erythropoietin‐stimulating agents in the management of anemia of end‐stage renal disease patients on regular hemodialysis: A prospective randomized comparative study from Qatar

Despite extensive use, to the best of our knowledge, no trial has simultaneously compared the three currently used erythropoietin‐stimulating agents (ESAs) in a prospective manner in the treatment of anemia of end‐stage renal disease patients. All hemodialysis patients in Qatar who were treated with short‐acting epoetin alfa or beta have been screened. Eligible patients had been prospectively randomized, either to continue on the previous regimen of epoetin or to receive darbepoetin alfa or continuous erythropoietin receptor activator (CERA) for a total period of 40 weeks. All groups were assessed at the end of the study for safety and efficacy parameters. A total of 327 eligible patients were randomized. Mean hemoglobin concentration remained constant within the recommended target range (11–12 g/dL) throughout the study in the three studied groups. The percentage of patients who reached the target range was constantly above 50% in the second half of the study among CERA group patients who also had significantly lower mean number of dose adjustments as compared with the other two groups (P = 0.001). Similarly, the number of discontinuations of ESA among epoetin, darbepoetin, and CERA groups was 17, 19, and 9, respectively (P = 0.042). The frequencies of adverse events were similar in all groups. This study has specifically compared the effect of ESA type on the variability of serum hemoglobin levels in hemodialysis patients. Furthermore, it confirmed the efficacy and safety of once monthly CERA for maintaining tight hemoglobin control within recommended target ranges.     

Predictors of anemia in patients on hemodialysis

Even though the use of erythropoietin and intravenous iron has improved the treatment of anemia in hemodialysis patients, a considerable proportion of these patients still have anemia. The aim of this study was to identify predictors of anemia in a hemodialysis population. In a single-center hemodialysis unit, all patients were studied with blood tests and their medication recorded during a period of 22 months. Correlations with hemoglobin (Hb) were performed with a simple regression or a t test. Variables that reached 5% significance were entered in a multiple regression analysis. Selected variables were presented in quartiles with levels of Hb. Mean Hb was 11.3 g/dL, and 53 patients (40%) had Hb<11.0 g/dL. In the simple regression analysis Hb correlated positively with s-iron, CHr, s-albumin, and doses of sevelamer, and negatively with sedimentation rate (SR), ferritin, base excess, and doses of erythropoietin. In the multiple regression analysis erythrocytes SR was the only variable that remained significant. Elevated SR is the strongest predictor of anemia in hemodialysis patients receiving adequate treatment with erythropoietin and intravenous iron. Patients using high doses of sevelamer had higher Hb levels than patients using low doses.     

Hypomagnesemia as a predictor of mortality in hemodialysis patients and the role of proton pump inhibitors: A cross‐sectional, 1‐year,retrospective cohort study

Introduction This study aimed to evaluate the association between proton pump inhibitor (PPI) use and serum magnesium levels, and the role of hypomagnesemia and PPI use as a risk factor for mortality in hemodialysis patients. Methods An observational study, including a cross‐sectional and 1‐year retrospective cohort study. The study comprised 399 hemodialysis patients at a single center, and was conducted from January to September 2014. Multiple linear regression analysis was used to investigate the independent relationship between serum magnesium levels and baseline demographic and clinical variables, including PPI and histamine‐2 receptor antagonist use. Cox regression model was used to identify lower serum magnesium level and PPI as a predictor of 1‐year mortality. Findings Serum magnesium levels were lower with PPI use than non‐PPI use (2.39 ± 0.36 vs. 2.56 ± 0.39 mg/dL, P < 0.001). Multiple linear regression analysis showed that PPI use, low serum albumin levels, and low serum potassium and high‐sensitivity C‐reactive protein (hs‐CRP) levels were significantly associated with low serum magnesium levels. A total of 29 deaths occurred during the follow‐up period. According to Cox regression analysis stratified by hs‐CRP, only high serum hs‐CRP levels (>4.04 mg/L) in association with low serum magnesium levels was an independent risk factor for 1‐year mortality (hazard ratio: 2.92; 95% CI: 1.53–6.40, P < 0.001). Discussion Serum magnesium levels are lower in PPI use. In the inflammatory state, a low serum magnesium level is a significant predictor of mortality in hemodialysis patients.     

HFE gene mutation is a risk factor for tissue iron accumulation in hemodialysis patients

Introduction: HFE gene mutations are responsible from iron overload in general population. Studies in hemodialysis patients investigated the effect of presence of HFE gene mutations on serum ferritin and transferrin saturation (TSAT) with conflicting results. However effect of HFE mutations on iron overload in hemodialysis patients was not previously extensively studied. Methods: 36 hemodialysis patients (age 51.3 ± 15.6, (18/18) male/female) and 44 healthy control subjects included in this cross sectional study. Hemoglobin, ferritin, TSAT in the preceding 2 years were recorded. Iron and erythropoietin (EPO) administered during this period were calculated. Iron accumulation in heart and liver was detected by MRI. Relationship between HFE gene mutation, hemoglobin, iron parameters and EPO doses, and tissue iron accumulation were determined. Findings: Iron overload was detected in nine (25%) patients. Hemoglobin, iron parameters, weekly EPO doses, and monthly iron doses of patients with and without iron overload were similar. There was no difference between control group and hemodialysis patients with respect to the prevalence of HFE gene mutations. Iron overload was detected in five of eight patients who had HFE gene mutations, but iron overload was present in 4 of 28 patients who had no mutations (P = 0.01). Hemoglobin, iron parameters, erythropoietin, and iron doses were similar in patients with and without gene mutations. HFE gene mutations remained the main determinant of iron overload after multivariate logistic regression analysis (P = 0.02; OR, 11.6). Discussion: Serum iron parameters were not adequate to detect iron overload and HFE gene mutation was found to be an important risk factor for iron accumulation.     

Clinical Consequences of Intermittent Elevation of C-Reactive Protein Level in Hemodialysis Patients

The presence of persistently high C‐reactive protein (CRP) levels is well known to be associated with a state of inflammation, malnutrition, and erythropoietin resistance in hemodialysis (HD) population. Meanwhile, a substantial group of patients present with intermittent elevations of CRP levels, and its clinical consequences are unclear. We designed this study to compare the inflammatory and nutritional parameters and erythropoietin requirements in HD patients with persistent or intermittent CRP elevation and those with CRP levels in without. We included 100 HD patients [age: 48.4 ± 14.3 years; HD duration: 69.3 ± 49.0 months (minimum 12 months)]. The 6‐month retrospective clinical and laboratory data were retrieved from the patient records, and those with chronic inflammatory disease, malignancy, infectious complications, and surgery were excluded. The monthly determined CRP levels (at least 6 for each patient) were reviewed, and the patients were grouped according to their CRP levels as those with persistent (group 1), intermittent (at least one level of CRP 10 mg/L) (group 2), and those with CRP in normal ranges set by the laboratory (group 3). We compared the fibrinogen, ICAM‐1, VCAM‐1, albumin, prealbumin, normalized protein catabolic rate (nPCR), interdialytic weight gain (IDWG), and rHuEPO/kg/Hct results of the patient groups. The patient groups revealed significant differences in terms of fibrinogen (p < 0.001), albumin (p < 0.0001), prealbumin (p < 0.007), ICAM‐1 (p < 00.2) levels and nPCR (p < 0.03), IDWG (p < 0.02), and rHuEPO/kg/Hct (p < 0.03) values. Group 2 presented to be in risk of inflammation and malnutrition with a decrease in albumin levels and nPCR and presence of rHUEpo resistance when compared to patients in group 3. We conclude that, similar to HD patients with persistently high CRP levels, those with intermittent elevation of CRP must also be considered to be in a state of chronic inflammatory response associated with malnutrition and erythropoietin resistance. This signifies the importance of regulatory monitoring of CRP in HD population.     

Endotoxins and inflammation in hemodialysis patients

Long‐term endotoxin challenge may promote frequent complications in dialysis patients, namely malnutrition, chronic inflammation, and atherosclerosis, which are recognized as the so‐called MIA syndrome. Circulating soluble vascular cell adhesion molecule‐1 (sVCAM‐1) levels may be used to determine the stage of atherosclerosis. This study aimed to assess endotoxin level in hemodialysis (HD) patients and its role in inducing inflammation. The study was conducted on 50 HD patients, chosen from four dialysis centers in Alexandria. Serum blood samples were collected for the determination of albumin and C‐reactive protein (CRP), and whole blood samples were used for the measurement of hemoglobin level. A heparinized whole blood sample was taken postdialysis for endotoxin assay by limulus amebocyte lysate test, and in addition to sVCAM‐1 was estimated using enzyme‐linked immunosorbent assay. The mean endotoxin level was 76.30 pg/mL;80% exhibited values higher than 60 pg/mL. Half the studied patients had CRP values that exceeded the upper limit of the laboratory reference range (<6.0 mg/L). A statistically significant correlation was found between endotoxin and CRP levels (r = 0.47, P = 0.001). The mean pre‐HD level of VCAM was 1851.00 ng/mL, while the mean post‐HD level was 2829.00 ng/mL with statistically significant correlation (r = 0.354, P = 0.012) and it also correlated significantly with endotoxin as well as CRP levels. Endotoxemia may play an important role in the aggravation of endothelial dysfunction in HD patients as indicated by the post‐HD rise in sVCAM‐1.     

Determinants of C-reactive protein in chronic hemodialysis patients: relevance of dialysis catheter utilization

Biomarkers of inflammation, especially C-reactive protein (CRP), have been consistently shown to predict poor outcomes in chronic hemodialysis (CHD) patients. However, the determinants of CRP and the value of its monitoring in CHD patients have not been well defined. We conducted a retrospective cohort study to evaluate possible determinants of the inflammatory response in CHD patients with a focus on dialysis catheter utilization. Monthly CRP were measured in 128 prevalent CHD patients (mean age 56.6 years [range 19-90], 68% African Americans, 39% diabetics [DM]) over a mean follow-up of 12 months (range 2-26 months). There were a total of 2405 CRP measurements (median 5.7 mg/L; interquartile range [IQR] 2.4-16.6 mg/L). The presence of a dialysis catheter (p<0.002), cardiovascular disease (p=0.01), male gender (p=0.005), higher white blood cell count (p<0.0001), elevated phosphorus (p=0.03), and lower cholesterol (p=0.02) and albumin (p<0.0001) concentrations were independent predictors of elevated CRP in the multivariate analysis. Additionally, CRP levels were significantly associated with the presence of a catheter, when comparing the levels before and after catheter insertion (p=0.002) as well as before and after catheter removal (p=0.009). Our results indicate that the presence of a hemodialysis catheter is an independent determinant of an exaggerated inflammatory response in CHD patients representing a potentially modifiable risk factor.     

A Comparative Study of C‐Reactive Protein Plasma Levels in Patients on Hemodialysis and Peritoneal Dialysis

In dialysis patients, C‐reactive protein (CRP), a well‐recognized marker of inflammation, predicts mortality. Higher levels have been described in hemodialysis (HD) patients as compared with peritoneal dialysis (PD) patients. Our aim was to determine, based on CRP plasma levels, the degree of inflammation in HD patients using low‐permeability polysulfone membranes and relatively pure dialysate, and that in PD patients. A secondary objective was to study factors associated with hypoalbuminemia and inflammation in both populations. We studied 69 stable patients on dialysis (32 on HD and 37 on PD). The mean age was 69.9 ± 8.2 years, and the mean time on dialysis was 27 months. The two populations were comparable for overall and cardiovascular comorbidities. Nephelometry was used to measure CRP plasma levels (normal levels < 0.6 mg/dL). The Kt/V_urea, corrected for residual renal clearance, and the equivalent of protein nitrogen appearance (PNA) were also calculated. Of the patients studied, 53% showed CRP plasma levels higher than 0.6 mg/dL; in 36%, the levels were higher than 1 mg/dL. No significant differences in these percentages were noted between the two dialysis groups. Patients with CRP levels higher than 1 mg/dL showed lower serum albumin, iron, hemoglobin, and transferrin levels, and higher ferritin values and leukocyte counts. Under logistic regression analysis, CRP levels higher and lower than 1 mg/dL were significantly associated with serum albumin [p = 0.01; odds ratio (OR): 0.15], iron (p = 0.006; OR: 0.96), transferrin (p = 0.004; OR: 0.97), and hemoglobin (p = 0.02; OR: 0.67). Serum albumin levels were significantly lower in PD patients. Under regression analysis, serum albumin levels correlated with cholesterol (r: 0.25; p = 0.04), serum iron (r: 0.5; p = 0.0001), transferrin (r: 0.3; p = 0.015), ultrafiltration capacity (r: 0.42; p = 0.008), and CRP values above 0.6 mg/dL (r: –0.65; p = 0.001). In conclusion, the frequent elevation of CRP plasma levels observed in both HD and PD patients suggests the presence of a silent inflammatory state. Hemodialysis performed with biocompatible, low‐permeability membranes is not associated with higher CRP plasma levels than those seen in PD. In both groups, hypoalbuminemia is related to CRP level. Levels of serum albumin, slightly lower in PD patients, are also related to peritoneal ultrafiltration capacity.     

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

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