Relationship between bone marrow iron load and liver iron concentration in dialysis-associated haemosiderosis.

BACKGROUND: Iron overload due to the excessive use of parenteral iron in haemodialysis is now an increasingly recognised clinical issue. Before erythropoiesis-stimulating agents (ESA) were introduced, a specific feature of patients treated by dialysis and having iron overload was that iron levels in the bone marrow were paradoxically low in most of them, despite severe hepatosplenic siderosis. Whether or not this paradox persists in the actual ESA era was unknown until recently, when an autopsy study in 21 patients treated by haemodialysis revealed similarities between liver and bone marrow iron content. The aim of this study was to further explore these recent findings in a cohort of alive patients on dialysis and to analyse the determinants of iron bone marrow. METHODS: Liver iron concentration (LIC) and vertebral T2∗ (a surrogate marker of bone marrow iron) were analysed retrospectively in 152 alive patients on dialysis (38.8% female) of whom 47.4% had iron overload by quantitative magnetic resonance imaging (MRI). FINDINGS: Vertebral T2∗ differed significantly between patients classified according to liver iron content at MRI: those with mild or moderate and severe liver iron overload had increased vertebral iron content at R2∗ relaxometry MRI (mild: vertebral T2∗ = 9.9 ms (4-24.8); moderate and severe: vertebral T2∗ = 8.5 ms (4.9-22.8)) when compared to patients with normal LIC (vertebral T2∗ = 13.2 ms (6.6-30.5) (p < 0.0001 Kruskal-Wallis test)). INTERPRETATION: The paradoxical discrepancy between bone marrow and liver iron-storage compartments observed in the pre-ESA era has disappeared today, as shown by a recent autopsy study and the present study in a cohort of alive patients treated by dialysis. FUNDING: None.

Differential Pharmacokinetics of Liver Tropism for Iron Sucrose, Ferric Carboxymaltose, and Iron Isomaltoside: A Clue to Their Safety for Dialysis Patients.

Anemia is a major complication of end-stage kidney disease (ESKD). Erythropoiesis-stimulating agents and intravenous (IV) iron are the current backbone of anemia treatment in ESKD. Iron overload induced by IV iron is a potential clinical problem in dialysis patients. We compared the pharmacokinetics of liver accumulation of iron sucrose, currently used worldwide, with two third-generation IV irons (ferric carboxymaltose and iron isomaltoside). We hypothesized that better pharmacokinetics of newer irons could improve the safety of anemia management in ESKD. Liver iron concentration (LIC) was analyzed in 54 dialysis patients by magnetic resonance imaging under different modalities of iron therapy. LIC increased significantly in patients treated with 1.2 g or 2.4 g IV iron sucrose (p < 0.001, Wilcoxon test), whereas no significant increase was observed in patients treated with ferric carboxymaltose or iron isomaltoside (p > 0.05, Wilcoxon-test). Absolute differences in LIC reached 25 µmol/g in the 1.2 g iron sucrose group compared with only 5 µmol/g in the 1 g ferric carboxymaltose and 1 g iron isomaltoside groups (p < 0.0001, Kruskal−Wallis test). These results suggest the beneficial consequences of using ferric carboxymaltose or iron isomaltoside on liver structure in ESKD due to their pharmacokinetic ability to minimize iron overload.

Histological Scores Validate the Accuracy of Hepatic Iron Load Measured by Signal Intensity Ratio and R2* Relaxometry MRI in Dialysis Patients.

Almost all haemodialysis patients are treated with parenteral iron to compensate for blood loss and to allow the full therapeutic effect of erythropoiesis-stimulating agents. Iron overload is an increasingly recognised clinical situation diagnosed by quantitative magnetic resonance imaging (MRI). MRI methods have not been fully validated in dialysis patients. We compared Deugnier's and Turlin's histological scoring of iron overload and Scheuer's classification (with Perls' stain) with three quantitative MRI methods for measuring liver iron concentration (LIC)-signal intensity ratio (SIR), R2* relaxometry, and R2* multi-peak spectral modelling (Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL-IQ®)) relaxometry-in 16 haemodialysis patients in whom a liver biopsy was formally indicated for medical follow-up. LIC MRI with these three different methods was highly correlated with Deugnier's and Turlin's histological scoring (SIR: r = 0.8329, p = 0.0002; R2* relaxometry: r = -0.9099, p < 0.0001; R2* relaxometry (IDEAL-IQ®): r = -0.872, p = 0.0018). Scheuer's classification was also significantly correlated with these three MRI techniques. The positive likelihood ratio for the diagnosis of abnormal LIC by Deugnier's histological scoring was > 62 for the three MRI methods. This study supports the accuracy of quantitative MRI methods for the non-invasive diagnosis and follow-up of iron overload in haemodialysis patients.

Liver Iron Load Influences Hepatic Fat Fraction in End-Stage Renal Disease Patients on Dialysis: A Proof of Concept Study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a spectrum of diseases including steatosis, nonalcoholic steatohepatitis (NASH), cirrhosis, and end-stage liver failure. Hepatic iron accumulation has been linked to hepatic fibrosis severity in NASH and NAFLD. Iron overload induced by parenteral (IV) iron therapy is a potential clinical problem in dialysis patients. We analyzed the hypothetical triggering and aggravating role of iron on NAFLD in patients on dialysis. METHODS: Liver iron concentration (LIC) and hepatic proton density fat fraction (PDFF) were analyzed prospectively in 68 dialysis patients by magnetic resonance imaging (MRI). Follow up of LIC and PDFF was performed in 17 dialysis patients during iron therapy. FINDINGS: PDFF differed significantly among dialysis patients classified according to LIC: patients with moderate or severe iron overload had increased fat fraction (PDFF: 7.9% (0.5-14.8%)) when compared to those with normal LIC (PDFF: 5% (0.27-11%)) or mild iron overload (PDFF: 5% (0.30-11.6%); P = 0.0049). PDFF correlated with LIC, and ferritin and body mass index. In seven patients monitored during IV iron therapy, LIC and PDFF increased concomitantly (PDFF: initial 2.5%, final 8%, P = 0.0156; LIC: initial 20 µmol/g, final 160 µmol/g: P = 0.0156), whereas in ten patients with iron overload, PDFF decreased after IV iron withdrawal or major dose reduction (initial: 8%, final: 4%; P = 0.0098) in parallel with LIC (initial: 195 µmol/g, final: 45 µmol/g; P = 0.002). INTERPRETATION: Liver iron load influences hepatic fat fraction in dialysis patients. Iron overload induced by iron therapy may aggravate or trigger NAFLD in dialysis patients. TRIAL REGISTRATION NUMBER (ISRCTN): 80100088.

Reassessment of Iron Biomarkers for Prediction of Dialysis Iron Overload: An MRI Study.

BACKGROUND AND OBJECTIVES: Iron overload among hemodialysis patients was previously considered rare but is now an increasingly recognized clinical situation. We analyzed correlations between iron biomarkers and the liver iron concentration (LIC) measured by magnetic resonance imaging (MRI), and examined their diagnostic accuracy for iron overload. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: We performed a prospective cross-sectional study from 31 January 2005 to 31 August 2013 in the dialysis centre of a French community-based private hospital. A cohort of 212 hemodialysis patients free of overt inflammation or malnutrition, were treated for anemia with parenteral iron-sucrose and an erythropoesis-stimulating agent, in keeping with current clinical guidelines. Blinded measurements of hepatic iron stores were performed by T1 and T2* contrast MRI, and relationships were analysed using Spearman's coefficient, logistic regression and receiver-operator characteristic (ROC) curves. RESULTS: Among the biological markers, only serum ferritin showed a strong correlation with LIC (rho= 0.52, 95% CI: 0.41-0.61, p< 0.0001, Spearman test). In logistic analysis, only serum ferritin correctly classified the overall cohort into patients with normal liver iron stores (LIC ≤ 50 µmol/g) and those with elevated liver iron stores (LIC > 50 µmol/g) (odds ratio 1.007; 95% CI: 1.004-1.010). Serum ferritin was the iron biomarker with the best discriminatory capacity in ROC curves analysis (area under the curve (AUC) = 0.767; 95% CI: 0.698-0.835). The optimal serum ferritin cutoffs were 160 µg/L for LIC > 50 µmol/g (mild iron overload) and 290 µg/L for LIC > 200 µmol/g (severe iron overload). CONCLUSIONS: For clinical purposes, serum ferritin correctly reflects liver iron stores, as assessed by MRI, in hemodialysis patients without overt inflammation or malnutrition. These results strongly suggest that current ferritin target values should be lowered to avoid iron overload. TRIAL REGISTRATION: ISRCTN Registry 80100088.

Maximal standard dose of parenteral iron for hemodialysis patients: an MRI-based decision tree learning analysis.

BACKGROUND AND OBJECTIVES: Iron overload used to be considered rare among hemodialysis patients after the advent of erythropoesis-stimulating agents, but recent MRI studies have challenged this view. The aim of this study, based on decision-tree learning and on MRI determination of hepatic iron content, was to identify a noxious pattern of parenteral iron administration in hemodialysis patients. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: We performed a prospective cross-sectional study from 31 January 2005 to 31 August 2013 in the dialysis centre of a French community-based private hospital. A cohort of 199 fit hemodialysis patients free of overt inflammation and malnutrition were treated for anemia with parenteral iron-sucrose and an erythropoesis-stimulating agent (darbepoetin), in keeping with current clinical guidelines. Patients had blinded measurements of hepatic iron stores by means of T1 and T2* contrast MRI, without gadolinium, together with CHi-squared Automatic Interaction Detection (CHAID) analysis. RESULTS: The CHAID algorithm first split the patients according to their monthly infused iron dose, with a single cutoff of 250 mg/month. In the node comprising the 88 hemodialysis patients who received more than 250 mg/month of IV iron, 78 patients had iron overload on MRI (88.6%, 95% CI: 80% to 93%). The odds ratio for hepatic iron overload on MRI was 3.9 (95% CI: 1.81 to 8.4) with >250 mg/month of IV iron as compared to <250 mg/month. Age, gender (female sex) and the hepcidin level also influenced liver iron content on MRI. CONCLUSIONS: The standard maximal amount of iron infused per month should be lowered to 250 mg in order to lessen the risk of dialysis iron overload and to allow safer use of parenteral iron products.

Hemodialysis-associated hemosiderosis in the era of erythropoiesis-stimulating agents: a MRI study.

BACKGROUND: Most dialysis patients receiving erythropoesis-stimulating agents (ESA) also receive parenteral iron supplementation. There are few data on the risk of hemosiderosis in this setting. METHODS: We prospectively measured liver iron concentration by means of T1 and T2* contrast magnetic resonance imaging (MRI) without gadolinium, in a cohort of 119 fit hemodialysis patients receiving both parenteral iron and ESA, in keeping with current guidelines. RESULTS: Mild to severe hepatic iron overload was observed in 100 patients (84%; confidence interval, [CI] 76%-90%), of whom 36% (CI, 27%-46%) had severe hepatic iron overload (liver iron concentration >201 µmol/g of dry weight). In the cross-sectional study, infused iron, hepcidin, and C-reactive protein values correlated with hepatic iron stores in both univariate analysis (P<.05, Spearman test) and binary logistic regression (P <.05). In 11 patients who were monitored closely during parenteral iron therapy, the iron dose infused per month correlated strongly with both the overall increase and the monthly increase in liver iron concentration (respectively, rho=0.66, P=.0306 and rho=0.85, P=0.0015, Spearman test). In the 33 patients with iron overload, iron stores fell significantly after iron withdrawal or after a major reduction in the iron dose (first MRI: 220 µmol/g (range: 60-340); last MRI: 50 µmol/g (range: 5-210); P <.0001, Wilcoxon's paired test). CONCLUSIONS: Most hemodialysis patients receiving ESA and intravenous iron supplementation have hepatic iron overload on MRI. These findings call for a revision of guidelines on iron therapy in this setting, especially regarding the amount of iron infused and noninvasive methods for monitoring iron stores.

Modulation of oxidative stress and microinflammatory status by colloids in refractory dialytic hypotension.

BACKGROUND: Intradialytic hypotension may adversely affect the outcome of chronic hemodialysis. Therapeutic albumin has powerful anti-oxidant and anti-inflammatory properties. We have recently shown that systematic colloid infusion during hemodialysis sessions improves hemodynamic parameters in most dialysis hypotension-prone patients unresponsive to usual of preventive measures.We postulated that frequent hypotensive episodes may lead to a noxious inflammatory response mediated by oxidative stress induced by ischemia-reperfusion. The aim of this study was therefore to analyze the effect of 20% albumin and 4% gelatin infusions on oxidative stress and microinflammatory status in hypotension-prone patients unresponsive to usual preventive measures. METHODS: Prospective cross-over study (lasting 20 weeks) of routine infusion of 200 ml of 20% albumin versus 200 ml of 4% gelatin in 10 patients with refractory intradialytic hypotension. We analyzed the effect of 20% albumin and 4% gelatin on microinflammatory status, oxidative stress, serum nitrite and nitrate levels by analysis of variance. RESULTS: A significant decrease in serum ceruloplasmin and serum C3 was observed during the albumin period (p < 0.05, repeated measure ANOVA). A significant decrease in serum hydrogen peroxide was seen during albumin and gelatin administration (p < 0.01, repeated measure ANOVA) and a very large decrease in serum lipid peroxides was observed during the albumin period only (p < 0.01, Friedman test). Serum lactoferrin, serum proinflammatory cytokines and serum nitrite and nitrate levels remained stable during the different periods of this pilot trial. CONCLUSIONS: We conclude that the improvement in microinflammatory status observed during colloid infusion in hypotension-prone dialysis patients may be related to a decrease in ischemia-reperfusion of noble organs, together with a specific reduction in oxidative stress by albumin. TRIAL REGISTRATION: ISRCTN 20957055.

A pilot study of routine colloid infusion in hypotension-prone dialysis patients unresponsive to preventive measures.

BACKGROUND AND AIMS: Intradialytic hypotension may adversely affect the outcome of chronic hemodialysis. The aim of this study was to assess the effects of routine infusion of 20% albumin and 4% gelatin in dialysis hypotension-prone patients unresponsive to prevention measures. METHODS: This was a prospective crossover study (lasting 20 weeks) of routine infusion of 200 mL of these colloids in 10 patients. We analyzed the effect of these colloids by n-of-1 trial methodology (Wilcoxon test) and analysis of variance. RESULTS: Twenty percent albumin increased systolic blood pressure (SBP) in 6 patients (p<0.05), whereas 4% gelatin improved SBP in only 2 patients (p<0.05). Albumin infusions increased diastolic blood pressure (DBP) in 4 patients (p<0.05), whereas gelatin improved DBP in only 1 patient (p<0.05). Weight gain between dialysis sessions was generally similar during the periods in most patients. An increase in the ultrafiltration rate was observed in 4 of the 6 patients whose blood pressure was improved by colloids (p<0.005). Kt/V and the fall in relative blood volume remained stable during the study, whereas ionic dialysance at the end of the dialysis sessions was improved only by albumin infusion (p<0.05, repeated measures ANOVA). CONCLUSIONS: Systematic colloids infusion during hemodialysis sessions improves hemodynamic parameters in most dialysis hypotension-prone patients unresponsive to usual measures of prevention. Prospective controlled trials are warranted to confirm these preliminary results.

Left-ventricular diastolic dysfunction as a risk factor for dialytic hypotension.

OBJECTIVES: Intradialytic hypotension may adversely affect the outcome of chronic hemodialysis and thus reduce the patients' life expectancy. The aim of this study was to assess the link between left-ventricular diastolic dysfunction and dialytic hypotension. METHODS: We performed a prospective cross-sectional study of 72 hemodialysis patients with a low dialysis vintage, 36 of whom had dialysis hypotension, based on echocardiography and brain natriuretic peptide (BNP) assay. RESULTS: There was no difference between normotensive patients and those with dialysis-associated chronic hypotension as regards BNP level, cardiac index, left-ventricular ejection fraction, or myocardial fractional shortening. Both hypotension-prone patients requiring dialysate sodium profiling and chronic refractory hypotensive patients requiring macromolecule infusion had cardiac diastolic dysfunction as shown by a similarly abnormal E/A ratio <1 in 89-91% of cases, associated with a significant decrease in color M-mode diastolic flow propagation velocity (V(p), p < 0.05 nonparametric ANOVA). The area under the ROC curve for V(p) was 0.69. A V(p) cutoff of 39.5 cm/s was optimal for predicting dialysis-associated hypotension. CONCLUSIONS: We conclude that diastolic dysfunction is associated with dialytic hypotension and that a low V(p)--a preload-independent index--is predictive of dialysis-associated hypotension.

Improving the efficiency of short-term single-needle hemodialysis.

It is widely believed that single-needle (SN) hemodialysis is inferior to conventional double-needle (DN) hemodialysis. The purpose of this study was to compare two SN dialysis regimens using different blood flow rates with conventional DN hemodialysis. The primary outcome measure was ionic dialysance. We studied eight patients (two women, six men) undergoing chronic intermittent DN bicarbonate hemodialysis three times per week on a Cimino-Brescia fistula for at least three months. The study had a prospective four-period design and lasted four weeks. During weeks 1 and 3, the participants had standard DN hemodialysis sessions, with Wallace needles at a blood flow rate of 250-300 mL/min. During week 2, they had single-needle dialysis sessions with a short 15-gauge stainless-steel needle, an effective blood flow rate of 180 mL/min (360 mL/min for each of the two pumps), and venous pressure below 200 mmHg. During week 4, they had SN dialysis sessions with a short 15-gauge stainless-steel needle, an effective blood flow rate of 250 mL/min (500 mL/min for each of the two pumps), and a venous pressure below 200 mmHg. Ionic dialysance recorded 45 minutes after the beginning of the dialysis session and 30 minutes before the end of the session were used for statistical analysis. The effective blood flow target of 250 mL/min was achieved in six of the eight patients. Ionic dialysance 45 minutes after the beginning of the session differed among the four periods (p < 0.001, Friedman test). Ionic dialysance was better during each DN dialysis period than during the 180 mL/min SN period (p < 0.01, Dunn's multiple comparison tests), but there was no difference with the 250 mL/min SN period. Ionic dialysance 30 minutes before the end of the dialysis session differed among the four periods (p < 0.001, Friedman test). Ionic dialysance was far better during each DN period than during the 180 mL/min SN period (p < 0.001, Dunn's multiple comparison test) and slightly better than during the 250 mL/min SN period (p < 0.05, Dunn's multiple comparison test). The single-pool Kt/V ratio differed among the four periods (p < 0.0001, Friedman test). The Kt/V ratios were far better during each DN period than during the 180 mL/min SN period (p < 0.001, Dunn's multiple comparison test) and slightly better than during the 250 mL/min SN period (p < 0.01, Dunn's multiple comparison test). The Kt/v provided by the dialysis monitor gave identical results to single pool Kt/v. We conclude that single-needle dialysis with an effective blood flow rate of 180 mL/min delivers an inadequate dialysis dose, which may be harmful. In contrast, an effective blood flow rate of 250 mL/min appears acceptable for brief periods of single-needle dialysis lasting one or two weeks. Otherwise, an increase in the length of the dialysis session and/or the use of a larger membrane surface area and even higher blood flow is required to obtain the same quality of dialysis as with conventional double-needle hemodialysis. Careful monitoring of the dialysis dose delivered is mandatory during single-needle dialysis.