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.     

Hemochromatosis gene mutations and treatment of anemia in patients on hemodialysis

Hemochromatosis causes iron overload by enhanced intestinal absorption. This study examined erythropoietin and intravenous (IV) iron requirements in hemodialysis (HD) patients with HFE mutations. Patients on HD for >90 days with no cause of anemia except chronic kidney disease were tested for HFE mutations (H63D and C282Y). Intravenous iron and erythropoietin doses were adjusted to achieve recommended targets. Monthly hemoglobin (Hb), ferritin, mean corpuscular volume, mean cell hemoglobin, erythropoietin, and IV iron doses for 3 consecutive months were averaged. Of 172 patients, 71 (41.3%) had ≥1 HFE mutation: 24 (14%) C282Y heterozygotes, 40 (23.3%) H63D heterozygotes, 5 compound heterozygotes, and 2 homozygotes. Comparing patients with ≥1 HFE mutation to those without mutations showed no significant difference in Hb or serum ferritin. There was a trend toward lower median weekly erythropoietin dose in patients with ≥1 HFE mutation (94.0 vs. 135.4 U/kg body weight; P=0.13). There was no difference in median weekly IV iron dose (1.0 vs. 0.9 mg/kg body weight; P=0.56). Comparing the 30 patients with a C282Y mutation to patients without HFE mutations produced similar results. Comparing the 47 patients with an H63D mutation, with those without HFE mutations, no discernable trend was observed. In this study, patients with HFE gene mutations on HD for established renal failure do not require less iron supplementation to achieve recommended Hb targets. We observed a trend toward lower erythropoietin requirement in patients possessing C282Y mutations. Larger studies may clarify the role of HFE mutations, regulators of iron metabolism and erythropoiesis in chronic kidney disease.     

Sleep apnea in hemodialysis patients: risk factors and effect on survival

Sleep disorders are common in patients with end-stage renal disease (ESRD). Using a simple questionnaire, we estimate the probability of sleep apnea in ESRD patients, determine the factors associated with a higher probability of sleep apnea, and determine the association between the probability of sleep apnea and cardiovascular and all-cause mortality. Study design: Prospective cohort study. Setting and participants: prevalent hemodialysis patients (n=270) in 7 urban outpatient hemodialysis units. Predictor: Probability of sleep apnea as quantified by the Flemons questionnaire. Outcomes and measurements: Clinical, demographic, and dialysis-related characteristics were obtained at baseline. Total and cardiovascular mortality was ascertained after a median follow-up of 34 months. The probability of sleep apnea was low in 79 (29%) patients, moderate in 116 (43%) patients, and high in 75 (28%) patients. Male gender (odds ratio [OR] 5.13, p<0.001), obesity (BMI >30, OR 7.58, p<0.01), and interdialytic weight gain (OR 1.72/kg change, p<0.004) were independently associated with a high probability of sleep apnea. A high probability of sleep apnea at baseline did not predict total (hazard ratio [HR] 0.81, p=NS) or cardiovascular mortality (HR 0.9, p=NS). The Flemons questionnaire is validated in the general population, but has not been tested specifically in hemodialysis patients. The study may not be adequately powered to detect a difference in mortality. A high proportion of hemodialysis patients are likely to have sleep apnea; a simple bedside questionnaire can be used for screening to identify these patients. Excessive interdialytic weight gain is a potentially modifiable factor that increases the likelihood of sleep apnea. Despite the presence of a strong association between sleep apnea and mortality in the general population, a similar association could not be demonstrated in ESRD patients with a high prevalence of this condition.     

Adiponectin and atherosclerosis risk factors in African hemodialysis patients: a population at low risk for atherosclerotic cardiovascular disease

Atherosclerotic cardiovascular disease (CVD) is the major cause of morbidity and mortality in hemodialysis (HD) patients. Adiponectin (ADPN), a recently discovered collagen-like protein, is secreted exclusively by adipocytes. It has anti-atherogenic properties and reduced serum ADPN levels have been shown to be predictive of cardiovascular events. In this study, we determined the atherosclerotic risk and the significance of ADPN levels in our HD patients and also examined its relationship to other traditional CVD risk factors. A cross-sectional study of 84 patients on maintenance HD (58 Blacks and 26 non-Blacks) and 63 healthy controls matched for age, sex and race (35 Blacks and 28 non-Blacks) was undertaken. Serum ADPN levels and other risk factors, including blood pressure, serum lipid, and C-reactive protein, were studied in HD patients and were compared with the controls. Carotid artery intima-media thickness and plaque occurrence was measured by B-mode ultrasonography while echocardiography was done according to American Society of Echocardiography guidelines. Serum ADPN levels were higher in the HD group compared with the control subjects (22.19 ± 0.98 mg/mL vs. 9.93 ± 0.68 mg/mL; P < 0.001). Higher ADPN levels in HD patients were associated with lower triglyceride levels. ADPN correlated positively (r = 0.49, P < 0.0001) with left ventricular mass index (LVMI) in the total study population. ADPN levels were raised in HD patients and correlated with LVMI, possibly because of the confounding effect of low glomerular filtration rate. ADPN levels were inversely related to risk factors for atherosclerosis and may provide possible targets for therapeutic interventions.     

IL-6 is an independent risk factor for resistance to erythropoiesis-stimulating agents in hemodialysis patients without iron deficiency

Anemia is a common complication in dialysis patients because of their relative erythropoietin deficiency. Despite treatment with erythropoiesis-stimulating agents (ESAs), some patients experienced ESA hyporesponsiveness. We evaluated the clinical and laboratory factors that affect ESA hyporesponsiveness and investigated the relationships between hepcidin, inflammatory markers, and the iron profiles of hemodialysis patients. Sixty-eight patients receiving hemodialysis at a single institution were evaluated in a cross-sectional study. The patients were divided into tertiles based on the ESA hyporesponsiveness index (EHRI), defined as the weekly ESA dose per kilogram of body weight divided by the hemoglobin level. The mean EHRI values for each tertile were 3.3 ± 1.2 (T1), 10.2 ± 2.9 (T2), and 24.5 ± 11.6 (T3). The mean serum erythropoietin levels were significantly higher in the Q3 and Q4 groups. Thus, patients with ESA hyporesponsiveness showed relative resistance to erythropoietin therapy. In univariate and multivariate analyses, patients in the third tertile of EHRI showed significantly higher mean interleukin-6 (IL-6) levels. Serum C-reactive protein (CRP) levels showed a similar trend, but the differences were not significant. Serum hepcidin levels tended toward lower mean values in the third tertile of EHRI. No relationship was observed between hepcidin and inflammatory markers or iron status. In conclusion, IL-6, but not CRP, is a strong predictor of ESA hyporesponsiveness in hemodialysis patients who have sufficient iron. It may be difficult to use hepcidin as an independent clinical marker because of the many factors that influence it and their interactions.     

Genotyping of two mutations in the HFE gene using single-base extension and high-performance liquid chromatography

Currently, a major focus of human genetics is the utilization of single-nucleotide polymorphisms for clinical diagnostics, whole-genome linkage disequilibrium screens to identify common disease genes such as Alzheimer disease, determination of the recent evolutionary history of a species, and the process of speciation. We have examined single-nucleotide extension coupled with high-performance liquid chromatography as a method to simultaneously genotype two SNPs occurring in the coding region of the HFE gene that produce clinical effects. This assay allows concurrent genotyping of the C282Y and H63D mutations in 11 min and is 100% concordant with current testing methods for both of these mutations.     

Functional iron deficiency in hemodialysis patients with high ferritin

Although functional iron deficiency (FID) may be present in hemodialysis (HD) patients with high serum ferritin levels (>800 ng/mL), current protocols often preclude the use of intravenous (IV) iron in these patients. However, it has not been demonstrated that iron supplementation during erythropoietin therapy is ineffective or unsafe in increasing hemoglobin (Hb) levels in patients with high serum ferritin. This report describes the hematologic efficacy and safety of ferric gluconate (FG) therapy in patients with serum ferritin >800 ng/mL. A retrospective analysis was performed on HD patients at a single California dialysis center from January 1 to December 31, 2003. Patients classified as having high ferritin levels (serum ferritin >800 ng/mL on at least 66% of routine monthly measurements and transferrin saturation [TSAT] <25% on at least 1 occasion) were stratified as follows: patients in Group I were suspected of having FID and received FG > or =250 mg IV over a 3-month period when Hb was <11 g/dL, and patients in Group II were thought not to have FID and received <250 mg FG over a 3-month period. Both groups received standard recombinant human erythropoietin therapy as per the unit's protocol. Of 496 patients, 95 exhibited high ferritin and of these, 39 patients had sufficient data for analysis. Group I patients (n=14) showed a significant increase in Hb levels compared with Group II (n=25). There was no increase in ferritin levels in response to iron administration. No significant differences in hospitalizations or infections were observed between groups. Hemodialysis patients with high ferritin levels may have FID, and IV iron therapy safely improves FID in some patients. A larger randomized trial examining the optimal management of iron administration in HD patients with high ferritin levels is warranted.     

Statins are associated with a reduced risk of bone fracture in hemodialysis (HD) patients

The Dialysis Outcomes and Practice Patterns Study reported a statistically non-significant protective effect of HMG-co reductase inhibitors (statins) on bone fracture risk in hemodialysis (HD) patients. We sought to determine whether statin exposure was associated with reduced risk of bone fracture in our HD population. This was a retrospective cohort study of 174 prevalent HD patients. Fracture data are abstracted from the medical record. Subjects were considered to be on a statin if they were exposed at any time since the date of dialysis initiation. The subjects were 174 HD patients (68.4% male) with a median age of 69.1 and age range from 25.2 to 96.3 years. The median age at initiation of HD was 62.5, ranging from 15.2 to 90.5 years. The mean (SD) dialysis vintage was 7.3 (4.5) years. Seventy-seven subjects (44.3%) had statin exposure. There were a total of 54 first bone fractures. There was a positive correlation between bone fracture and dialysis vintage (p=0.023) and a negative association between bone fracture and statin exposure (p=0.044). Those with statin exposure had a higher prevalence of CAD (p=0.030) compared with those not exposed. Logistic regression analysis (stepwise, alpha=0.05) was performed with dependent variable bone fracture and independent variables age at HD initiation (forced), dialysis vintage, gender (forced), prednisone use (forced), and statin exposure. The significant predictors of bone fracture (R2=0.14, p=0.004) were age at HD initiation (p=0.016), dialysis vintage (p=0.007), and absence of statin exposure (p=0.019). Statin exposure appears to be associated with a reduced frequency of bone fracture in HD patients. Future studies evaluating the potential anabolic effect of statins on bone are required.     

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.     

Doctors are not pilots and patients are not airplanes: Quality improvement in medicine

Abstract

The Institute of Medicine of the National Academy of Science issued a report in 1999 entitled “To Err Is Human.” It described errors in hospitals which led to between 44,000 and 99,000 deaths per year. This was the “tipping point” toward self-evaluation and quality improvement. Medicine has slowly developed quality improvement methodologies that seem to work. Surgery leads the way. This article will go through some of the history of quality improvement with the difficulty comparing patients and defining outcomes, along with the difficulties changing physician behavior. The challenges of implementing quality improvement across an entire hospital will be demonstrated.     

Heparin albumin priming in a clinical setting for hemodialysis patients at risk for bleeding

Introduction: Intermittent hemodialysis (IHD) is sometimes necessary in patients with a bleeding risk, i.e., before/after surgery or brain hemorrhage. In such case IHD has to be modified to limit the conventional anticoagulation used to avoid clotting of the extracorporeal circuit (ECC). We evaluated if priming using a heparin and albumin (HA) mixture could minimize the exposure to heparin. Methods: Retrospective data from 1995 to 2013 were collected from 1408 acute dialysis treatment protocols that included 321 patients. Comparisons were made between IHD patients that had increased risk for bleeding and were treated by standard anticoagulation (Group‐S), and patients at increased risk of bleeding (Group‐HA). The ECC in Group‐HA was primed with a solution of unfractioned heparin (UFH) (5000 Units/L) and albumin (1 g/L) in saline that was discarded after priming. There were 16 different dialyzers in the material. Findings: Comparing Group‐S (n = 883) with Group‐HA (n = 221), the mean age was 61.6 vs. 62.2 years (P = 0.8), dialysis time was 197 vs. 190 minutes (P = 0.002), and total dose of intravenous anticoagulant/IHD was at median 5000 Units vs. 1200 Units (P = 0.001). Twenty‐four percent of patients were treated without any additional heparin. Clotting resulting in interrupted dialysis was similar in both groups (0.8% for Group‐S vs. 1.0% for Group‐HA, P = 0.8). No secondary bleeding was reported in either group. Discussion: HA priming minimized the risk of clotting and enabled acute IHD in vulnerable patients without increased bleeding, thus allowing completion of IHD to the same extent as for standard HD.     

Predialysis volume overload and patient‐reported sleep duration and quality in patients receiving hemodialysis

Introduction: Previous studies of patients with end‐stage renal disease have examined the role of fluid shifts on apnea‐hypopnea episodes, but the association between volume overload and patient‐reported sleep quality or duration has not been well‐established. Methods: We studied the association between predialysis bioimpedance spectroscopy‐derived volume estimates and self‐reported sleep quality and duration in 638 patients in the United States Renal Data System ACTIVE/ADIPOSE study receiving hemodialysis from 2009 to 2011. We used questionnaires to assess self‐reported sleep duration and quality. We used relative hydration status (fluid overload/extracellular water; FO/ECW) as the primary predictor and examined associations with hours of sleep duration using linear regression. We used multivariable ordinal logistic regression to determine the association between categories of relative hydration status (normal hydration [FO/ECW < 6.8%], mild overhydration [FO/ECW 6.8%–15%], and hyperhydration [FO/ECW > 15%]) and four levels of difficulty with falling asleep, waking, and returning to sleep. Findings: Higher relative hydration status was associated with fewer hours of sleep (?0.31 hours per 10%, 95% confidence interval (CI) ?0.49 to ?0.13). Compared to the normal hydration group, there was a statistically significant association between higher relative hydration status category and more frequent nighttime waking (OR: mild overhydration 1.92 [95% CI 1.23–2.99], hyperhydration 1.87 [95% CI 1.16–2.99]), a trend toward more difficulty returning to sleep (OR: mild overhydration 1.46 [95% CI 0.94–2.27], hyperhydration 1.52 [95% CI 0.95–2.43]), and no association between relative hydration category and difficulty falling asleep. Discussion: Hydration status was associated with self‐reported sleep duration in patients on dialysis. Future studies should prospectively examine the effects of optimizing fluid status on sleep duration and quality.     

Increased leukocyte aggregates are associated with atherosclerosis in patients with hemodialysis

Little data are available on the role of blood rheology in atherosclerosis in hemodialysis (HD) patients. This study sought to assess the relationship between leukocytes conjugated with platelets (leukocyte aggregates [LA]) and atherosclerosis in patients with HD. The present study included 118 patients on HD. As surrogate markers of atherosclerosis, aortic stiffness measured by brachial-ankle pulse wave velocity, and carotid intima-media thickness (IMT) were measured. As an assessment of LA, a method, microchannel array flow analyzer, which makes it possible to directly observe the flow of blood cell elements through the microchannel, was used. We measured a number of LA during 50 μL flow of whole blood through microchannels. In 12 age-matched healthy individuals, a number of LA during 50 μL flow of whole blood was 25.7±5.4, whereas in HD patients it was significantly increased up to 48.2±16.4 (P<0.001). Flow cytometry demonstrated that LA were predominantly monocytes. Leukocyte aggregates were positively associated with plasma levels of fibrinogen (P<0.01), or serum high-sensitive C-reactive protein (P<0.01). Moreover, LA had highly significant associations with brachial-ankle pulse wave velocity (P<0.001) and IMT (P<0.001). In conclusion, we demonstrated hemorheologically that monocyte-platelet conjugates play an important role in aortic stiffness and IMT in HD patients.