Serum Ascorbic Acid in Patients Undergoing Chronic Hemodialysis

ABSTRACT Serum presupplementation ascorbic acid levels were subnormal in 8 out of 10 patients undergoing chronic hemodialysis with capillary film and capillary flow dialyzers, the mean duration of treatment being 11 months. Supplementation with 100 mg ascorbic acid daily for two weeks raised the ascorbic acid values to normal in 9 out of 10 patients. After supplementation with 500 mg daily, all patients had ascorbic acid levels exceeding the normal upper limit, and 3 of them had gastrointestinal side-effects. The mean blood pH value, measured in 24 patients on chronic hemodialysis, showed a significant, though slight, decrease during supplementation with 500 mg daily as compared with the mean presupplementation value, but no statistically significant changes were observed in blood bicarbonate, base excess or Pco₂ values.     

HFE Haemochromatosis Gene Mutations in Liver Transplant Patients

Background: The majority of patients with inherited haemochromatosis carry two mutant alleles of the recently discovered HFE gene. Individuals heterozygous for the HFE mutation could be predisposed to end-stage liver disease due to other causes. Methods: The frequencies of the HFE gene mutations C282Y and H63D were determined in DNA samples obtained from 189 liver transplant patients and 225 healthy Finnish blood donors. Results: 5% of the 189 liver transplant recipients were heterozygotes and 0.5% homozygotes for the C282Y mutation, while 16% were heterozygotes and 0.5% homozygotes for the H63D mutation. These figures were not increased in comparison to controls, of whom 11% were C282Y heterozygotes, 16% H63D heterozygotes and 0.9% H63D homozygotes. Among recipients with acute non-A-E hepatitis (n = 31), the frequency of the H63D allele was higher than in controls (21% versus 9.1%, P < 0.01). Perls' stain for iron in explanted liver specimens was positive in 28% of recipients with alcoholic cirrhosis, 26% of patients with acute non-A-E hepatitis and 14% in the rest of the recipients. The HFE genotypes did not correlate with the iron status. Conclusion: Individuals heterozygous for either the C282Y or H63D mutation of the HFE gene are not at increased risk of developing chronic endstage liver disease. However, subjects heterozygous for the H63D mutation may have an increased risk to develop fulminant non-A-E hepatitis.     

25 Frequent Low‐Dose Iron Supplementation To Hemodialysis Patients

Outline Regular iron supplementation to most hemodialysis (HD) patients is necessary to ensure adequate response to epoetin (Epo). As enteral absorption of ferric compounds is insufficient in uremia, parenteral application is often needed. Usually, a dose of elementary iron is injected intraveneously at the end of an HD session once weekly to monthly according to the individual patient's needs. Doses range from usual 100 mg to several hundred mg. A surplus of iron immediately after application is transported to physiologic stores but might also be deposited at other sites in the body where it becomes inaccessible. In the long term, deposition of iron might lead to hemosiderosis and organ malfunction. Increased oxidative stress and acute toxic effects might supervene along with the increased susceptibility to infection, becoming fatal. Patients and methods In 59 patients on regular iron supplementation, we examined the effects of frequent low‐dose (25 mg) in comparison to usual regime of 100 mg post‐dialysis i.v. iron on Hb concentration and the required Epo dose to maintain the Hb target (120 g/L). Results (see Table A25 )

Effect of Alfacalcidol Therapy on the Survival of Chronic Hemodialysis Patients

The aim of this study was to determine the relationship between alfacalcidol therapy and the outcomes of chronic hemodialysis (HD) patients. We collected demographic and clinical baseline data from 190 prevalent HD patients in a regional Japanese cohort. A 5‐year survival analysis was performed according to whether the patients were receiving calcitriol analog therapy. Alfacalcidol therapy at a mean dose of 5.2 ± 1.8 µg/week was performed in 89 (46.8%) of the 190 patients. We recorded 38 deaths during the follow‐up period, including 19 deaths from cardiovascular events. A Kaplan–Meier analysis demonstrated that the alfacalcidol users had a significantly lower rate of all‐cause mortality and cardiovascular mortality than the non‐users. According to a multivariate Cox proportional hazards model, in addition to the use of alfacalcidol (HR=0.347 [0.155–0.714]; P = 0.0035), serum CRP levels (HR= 1.746 [1.184–2.442]; P = 0.0071) and non‐HDL‐cholesterol levels (HR=1.012 [1.001–1.022]; P = 0.0267) were identified as independent predictors of all‐cause mortality, and the presence of diabetes mellitus (HR=3.720 [1.182–12.398]; P = 0.0246) was identified as an independent predictor of cardiovascular mortality. These findings suggest that low‐dose alfacalcidol therapy provides a survival advantage to chronic HD patients.     

Serum Iron Markers in Patients With Chronic Hepatitis C Infection

Background

Patients with chronic hepatitis C (CHC) often have elevated serum iron markers, which may worsen liver injury.

Objectives

The aim of this study was to investigate the possible correlations between iron metabolism serum markers, HCV viral load, and liver disease severity in treatment-naive patients with chronic hepatitis C infection.

Patients and Methods

Eighty five patients with untreated hepatitis C chronic infection were investigated.

Results

Twenty one patients (24.7%) had elevated serum iron levels, and 29 subjects (34.1%) had severe liver fibrosis. Significantly elevated levels of serum iron (P < 0.05) and ferritin (P < 0.001), associated with lower levels of TIBC (P < 0.05) were detected in patients with severe fibrosis compared to no/mild fibrosis. Severe necroinflammatory activity was also significantly correlated with serum iron (P < 0.001), TIBC (P < 0.05), and ferritin levels (P < 0.001). Using multiple linear regression analysis, serum levels of ferritin and transferrin were the independent variables selected as being good predictors for advanced fibrosis and severe necroinflammatory activity. No significant correlations were detected between HCV viral load and iron markers.

Conclusions

This study revealed that serum iron markers (especially ferritin and transferrin) might be used as surrogate markers for both liver fibrosis and necroinflammatory activity.Patients with chronic hepatitis C (CHC) often have elevated serum iron markers, which may worsen liver injury.     

Labile Plasma Iron Generation After Intravenous Iron is Time-dependent and Transitory in Patients Undergoing Chronic Hemodialysis

Iron supplementation in hemodialysis patients is fundamental to erythropoiesis, but may cause harmful effects. We measured oxidative stress using labile plasma iron (LPI) after parenteral iron replacement in chronic hemodialysis patients. Intravenous iron saccharate (100 mg) was administered in patients undergoing chronic hemodialysis (N = 20). LPI was measured by an oxidant-sensitive fluorescent probe at the beginning of dialysis session (T0), at 10 min (T1), 20 min (T2), and 30 min (T3) after the infusion of iron and at the subsequent session; P < 0.05 was significant. The LPI values were significantly raised according to the time of administration and were transitory: −0.02 ± 0.20 µmol/L at the beginning of the first session, 0.01 ± 0.26 µmol/L at T0, 0.03 ± 0.23 µmol/L at T1, 0.09 ± 0.28 µmol/L at T2, 0.18 ± 0.52 µmol/L at T3, and −0.02 ± 0.16 µmol/L (P = 0.001 to 0.041) at the beginning of the second session. The LPI level in patients without iron supplementation was −0.06 ± 0.16 µmol/L. Correlations of LPI according to time were T1, T2, and T3 vs. serum iron (P = 0.01, P = 0.007, and P = 0.0025, respectively), and T2 and T3 vs. transferrin saturation (P = 0.001 and P = 0.0003, respectively). LPI generation after intravenous saccharate administration is time-dependent and transitorily detected during hemodialysis. The LPI increment had a positive correlation to iron and transferrin saturation.     

Intravenous Iron Exposure and Mortality in Patients on Hemodialysis

Background and objectives

Clinical trials assessing effects of larger cumulative iron exposure with outcomes are lacking, and observational studies have been limited by assessment of short-term exposure only and/or failure to assess cause-specific mortality. The associations between short- and long-term iron exposure on all-cause and cause-specific mortality were examined.

Design, setting, participants, & measurements

The study included 14,078 United States patients on dialysis initiating dialysis between 2003 and 2008. Intravenous iron dose accumulations over 1-, 3-, and 6-month rolling windows were related to all-cause, cardiovascular, and infection-related mortality in Cox proportional hazards models that used marginal structural modeling to control for time-dependent confounding.

Results

Patients in the 1-month model cohort (n=14,078) were followed a median of 19 months, during which there were 27.6% all-cause deaths, 13.5% cardiovascular deaths, and 3% infection-related deaths. A reduced risk of all-cause mortality with receipt of >150–350 (hazard ratio, 0.78; 95% confidence interval, 0.64 to 0.95) or >350 mg (hazard ratio, 0.79; 95% confidence interval, 0.62 to 0.99) intravenous iron compared with >0–150 mg over 1 month was observed. There was no relation of 1-month intravenous iron dose with cardiovascular or infection-related mortality and no relation of 3- or 6-month cumulative intravenous iron dose with all-cause or cardiovascular mortality. There was a nonstatistically significant increase in infection-related mortality with receipt of >1050 mg intravenous iron in 3 months (hazard ratio, 1.69; 95% confidence interval, 0.87 to 3.28) and >2100 mg in 6 months (hazard ratio, 1.59; 95% confidence interval, 0.73 to 3.46).

Conclusions

Among patients on incident dialysis, receipt of ≤1050 mg intravenous iron in 3 months or 2100 mg in 6 months was not associated with all-cause, cardiovascular, or infection-related mortality. However, nonstatistically significant findings suggested the possibility of infection-related mortality with receipt of >1050 mg in 3 months or >2100 mg in 6 months. Randomized clinical trials are needed to assess the safety of exposure to greater cumulative intravenous iron doses.     

Dialyzability of Faropenem in Infected Patients on Chronic Hemodialysis

The aim of this study was to evaluate the profile of dialyzability of an oral penem antibiotic, faropenem (FRPM), in hemodialysis (HD) patients with infections. Eight patients took one tablet of FRPM (200 mg) every 12 h during an inter‐dialysis period, and another tablet at 1–5 h before the beginning of the HD session. Blood samples were obtained during the HD session (3–4 h). Plasma FRPM concentrations in the arterial side were 4.8 ± 2.5 and 2.8 ± 1.0 µg/mL before and at the end of HD session, respectively, which are above the 50% minimal inhibitory concentrations of FRPM against the major pathogen (0.015–2 µg/mL). Dialyzer clearance and elimination fraction of FRPM were 14.9 ± 6.8 mL/min per m² and 20.4 ± 9.9%, respectively. About 2% of FRPM was removed from the body during a single HD session. The infection‐related symptoms, the white blood cell count and the level of C‐reactive protein were improved by FRPM without any adverse effects. These data suggest that the dialyzability of FRPM is relatively low, and the amount of the drug removed by a single HD session is small. FRPM 200 mg twice daily might provide an effective and safe dosage regimen without additional dosing at the end of the HD session.     

Hypoglycemia in Diabetic Patients Undergoing Chronic Hemodialysis

The aim of our study was to determine if different hypoglycemic therapies are associated with more frequent episodes of hypoglycemia in diabetes patients undergoing long-term hemodialysis. We conducted a prospective cohort study that included 102 diabetes patients who were undergoing long-term hemodialysis. The frequency of symptomatic hypoglycemic episodes, intradialytic hypotension, antihypertension medication, hypoglycemic therapy regimens, dialysate contents, and laboratory data were reviewed. The duration of follow-up was three months. Fifty-four (52.9%) patients were categorized as hypoglycemic and 48 (47.1%) patients as non-hypoglycemic. The serum albumin levels of the hypoglycemic and non-hypoglycemic patients were 3.18 ± 0.34 g/dL and 3.44 ± 0.33 g/dL respectively (P < 0.001). The prevalence of intradialytic hypotension is significantly higher in the hypoglycemic patients (44.4%) than in the non-hypoglycemic patients (20.8%) (P = 0.012). The risk of hypoglycemia differed significantly between the patients taking oral hypoglycemic agents (OHAs) and those receiving purely insulin therapy (P = 0.035). Multivariate analysis revealed that the serum albumin (odds ratio [OR] 0.093, 95% confidence interval [CI] 0.021–0.409), intradialytic hypotension (OR 2.755, 95% CI 1.048–7.228), and OHA therapy (OR 0.337, 95% CI 0.128–0.888) were independent factors of hypoglycemia. The patients treated only with meglitinides as hypoglycemic therapy had a significantly lower risk of hypoglycemia than those receiving mixed insulin therapy (P = 0.016). Frequent episodes of intradialytic hypotension and hypoalbuminemia are powerful clinical predictors of hypoglycemia in diabetes patients undergoing hemodialysis. It was also found that OHAs do not pose a higher risk of hypoglycemia than insulin in diabetic patients undergoing hemodialysis.     

Combined High Serum Ferritin and Low Iron Saturation in Hemodialysis Patients: The Role of Inflammation

Background: Serum ferritin, frequently used as a marker of iron status in individuals with chronic kidney disease, is also an inflammatory marker. The concurrent combination of high serum ferritin and low iron saturation ratio (ISAT) usually poses a diagnostic dilemma. We hypothesized that serum ferritin ≥500 ng/ml, especially in the seemingly paradoxical presence of ISAT level <25%, is more strongly associated with inflammation than with iron in maintenance hemodialysis (MHD) patients.Design, setting, and participants: In 789 MHD patients in the Los Angeles area, the association of serum ferritin ≥500 ng/ml with inflammatory markers, including IL-6 (IL-6) and C-reactive protein levels, and malnutrition-inflammation score (MIS) was examined.Results: After multivariate adjustment for case-mix and other measures of malnutrition-inflammation complex, MHD patients with serum ferritin ≥500 ng/ml and ISAT <25% had higher odds ratio for serum C-reactive protein ≥10 mg/L. The area under the receiver operating characteristic curves for the continuum of ISAT and IL-6 in detecting a serum ferritin ≥500 ng/ml were identical (0.57 versus 0.56, P = 0.7). The combination of IL-6 with ISAT yielded a higher area under the receiver operating characteristic curve (0.61) than either ISAT or IL-6 alone (P = 0.03 and P = 0.02, respectively).Conclusion: In MHD patients, ferritin values above 500 ng/ml, especially in paradoxical conjunction with low ISAT, are associated with inflammation. Strategies to dissociate inflammation from iron metabolism to mitigate the confounding impact of inflammation on iron and to improve iron treatment responsiveness may improve anemia management in chronic kidney disease.Anemia is common in individuals with chronic kidney disease (CKD), including those undergoing maintenance hemodialysis (MHD) treatment and may be associated with poor outcome, including higher death risk (1). With widespread administration of erythropoiesis stimulating agent (ESA) since the early 1990s, anemia management has become one of the core components of the nephrology practice striving to achieve an adequate and stable hemoglobin level. Not infrequently, however, anemia is hyporesponsive to ESA resulting from various conditions, especially iron deficiency (2,3) and inflammation (4), leading to hemoglobin variability and adverse outcomes (5).The most commonly used markers of iron management in CKD patients are iron saturation ratio (ISAT), also known as transferrin saturation ratio, and serum ferritin (6). Whereas serum ferritin is the main storage molecule for iron (7), it also is an acute phase reactant; i.e., its serum concentration tends to increase moderately in the presence of inflammation (3,7,8), which occurs commonly in MHD patients (9). Moreover, inflammation is closely related to protein-energy wasting in dialysis patients (10) and the simultaneous combination of these two conditions, also referred to as malnutrition-inflammation-cachexia syndrome (MICS), is observed frequently in CKD patients (9). Concurrent to the poor clinical outcomes, MICS may also lead to moderate hyperferritinaemia and refractory anemia in the form of ESA hyporesponsiveness (4). Hence, the latest update of the National Kidney Foundation Kidney Disease and Dialysis Outcome Quality Initiative guidelines removed the upper limit of serum ferritin of 800 ng/ml to withhold iron supplementation and suggested to individualize iron treatment strategies if serum ferritin is >500 ng/ml (6). Nevertheless, the mention of 500 ng/ml cutoff levels in the said guidelines has led to some confusion among nephrologists who may not be sure whether iron treatment should be withheld in patients with such moderately high ferritin levels (11). One of the challenging areas of this decision-making process is dealing with MHD patients with serum ferritin ≥500 ng/ml but relatively low ISAT, e.g., ISAT <25%. Even though a recent randomized controlled trial showed that such patients may still benefit from intravenous iron supplementation (12), the conditions that may lead to such a seemingly paradoxical combination have not been well studied. We hypothesized that, in MHD patients, moderately high ferritin levels, especially if combined with low ISAT, is more strongly associated with inflammation than with iron stores. Therefore, in the present study, we examined the relative contribution of inflammation and iron stores to high serum ferritin in a large and contemporary cohort of MHD patients, in that we first compared various clinical and paraclinical characteristics of the paradoxical high-ferritin/low-ISAT group with other MHD patients. Then, using several inflammatory markers and pro-inflammatory cytokines, we examined the extent to which inflammation is responsible for the moderately high serum ferritin concentrations ≥500 ng/ml, especially when combined with ISAT <25%.     

Serum Ferritin as an Index of Body Iron Stores in Patients on Chronic Haemodialysis*

Summary: Serum ferritin concentrations have been measured serially over a 12 month period in 35 patients on chronic haemodialysis. All patients on haemodialysis received oral iron and vitamin supplements during the period of study. In 28 of the patients simultaneous bone marrow iron was also estimated. A significant correlation was found between serum ferritin concentration and bone marrow iron content. In all but two patients, oral iron supplements were sufficient to prevent a fall in the serum ferritin concentration during the period of observation. Chronic renal failure per se did not appear to affect the serum ferritin concentration.     

Skin Autofluorescence Predicts Cardiovascular Mortality in Patients on Chronic Hemodialysis

Tissue accumulation of advanced glycation end products (AGE) is thought to contribute to the progression of cardiovascular disease (CVD). Skin autofluorescence, a non‐invasive measure of AGE accumulation using autofluorescence of the skin under ultraviolet light, has been reported to be an independent predictor of mortality associated with CVD in Caucasian patients on chronic hemodialysis. The aim of this study was to assess the predictive value of skin autofluorescence on all‐cause and cardiovascular mortality in non‐Caucasian (Japanese) patients on chronic hemodialysis. Baseline skin autofluorescence was measured with an autofluorescence reader in 128 non‐Caucasian (Japanese) patients on chronic hemodialysis. All‐cause and cardiovascular mortality was monitored prospectively during a period of 6 years. During the follow‐up period, 42 of the 128 patients died; 19 of those patients died of CVD. Skin autofluorescence did not have a significant effect on all‐cause mortality. However, age, carotid artery intima‐media thickness (IMT), serum albumin, high‐sensitivity C‐reactive protein (hsCRP), skin autofluorescence and pre‐existing CVD were significantly correlated with cardiovascular mortality. Multivariate Cox regression analysis showed skin autofluorescence (adjusted hazard ratio [HR] 3.97; 95% confidence interval [CI]1.67–9.43), serum albumin (adjusted HR 0.05; 95% CI 0.01–0.32), and hsCRP (adjusted HR 1.55; 95% CI 1.18–2.05) to be independent predictors of cardiovascular mortality. The present study suggests that skin autofluorescence is an independent predictor of cardiovascular mortality in non‐Caucasian (Japanese) patients on chronic hemodialysis.