About 2.5% of the world population, corresponding to about 177 million individuals, are infected by hepatitis C virus (HCV), a small, single-stranded RNA virus. The prevalence of HCV infection among dialysis patients in Japan, Europe, and North America during the 2012 to 2015 period was found to be 8.7% in the DOPPS study. Nosocomial HCV spread in hemodialysis facilities still occurs. Increased hepatic tissue iron has been shown to play a deleterious role in the course of hepatitis C, favor development of fibrosis and cirrhosis and possibly increase the risk of liver cancer in the general population. Regular loss of blood in the hemodialysis circuit, in routine blood sampling for laboratory tests (for uremia monitoring), and in gut due to uremic enteropathy, invariably results in iron deficiency for which patients are commonly treated with intravenous (IV) iron preparations. Data on the effects of IV iron in hemodialysis patients with hepatitis C are limited (2 studies) and strongly suggest that parenteral iron may contribute to hepatocellular injury. Iatrogenic iron overload is extremely prevalent among hemodialysis population worldwide. Iron overload and toxicity has emerged as one of the most controversial topic in the management of anemia in dialysis patients. Given the known impact of iron in promoting growth and virulence of HCV and the associated liver disease, it is necessary to use iron therapy cautiously and closely monitor plasma markers of iron metabolism and liver iron stores non-invasively by means of MRI to avoid iron overload in this vulnerable population.

Iron overload was considered rare in hemodialysis patients until recently, but its clinical frequency is now increasingly recognized. The liver is the main site of iron storage and the liver iron concentration (LIC) is closely correlated with total iron stores in patients with secondary hemosiderosis and genetic hemochromatosis. Magnetic resonance imaging (MRI) is now the gold standard method for estimating and monitoring LIC. Studies of LIC in hemodialysis patients by magnetic susceptometry thirteen years ago and recently by quantitative MRI have demonstrated a relation between the risk of iron overload and the use of intravenous (IV) iron products prescribed at doses determined by the iron biomarker cutoffs contained in current anemia management guidelines. These findings have challenged the validity of both iron biomarker cutoffs and current clinical guidelines, especially with respect to recommended IV iron doses. Moreover, three recent long-term observational studies suggested that excessive IV iron doses might be associated with an increased risk of cardiovascular events and death in hemodialysis patients. It has been hypothesized that iatrogenic iron overload in the era of erythropoiesis-stimulating agents might silently increase complications in dialysis patients without creating obvious, clinical signs and symptoms. High hepcidin-25 levels were recently linked to fatal and nonfatal cardiovascular events in dialysis patients. It has been postulated that the main pathophysiological pathway leading to these events might involve the pleiotropic master hormone hepcidin, which regulates iron metabolism, leading to activation of macrophages in atherosclerotic plaques and then to clinical cardiovascular events. Thus, the potential iron overload toxicity linked to chronic administration of IV iron therapy is now becoming one of the most controversial topics in the management of anemia in hemodialysis patients.

The routine use of recombinant erythropoiesis-stimulating agents (ESA) over the past three decades has enabled the partial correction of anaemia in most patients with end-stage renal disease (ESRD). Since ESA use frequently leads to iron deficiency, almost all ESA-treated haemodialysis patients worldwide receive intravenous iron (IV) to ensure sufficient available iron during ESA therapy. Patients with inflammatory bowel disease (IBD) are also often treated with IV iron preparations, as anaemia is common in IBD. Over the past few years, liver magnetic resonance imaging (MRI) has become the gold standard method for non-invasive diagnosis and follow-up of iron overload diseases. Studies using MRI to quantify liver iron concentration in ESRD have shown a link between high infused iron dose and risk of haemosiderosis in dialysis patients. In September 2017, the Pharmacovigilance Committee (PRAC) of the European Medicines Agency (EMA) considered convergent publications over the last few years on iatrogenic haemosiderosis in dialysis patients and requested that companies holding marketing authorization for iron products should investigate the risk of iron overload, particularly in patients with end-stage renal disease on dialysis and, by analogy, patients with IBD. We present a narrative review of data supporting the views and decision of the EMA, and then give our expert opinion on this controversial field of anaemia therapeutics.

Iron overload used to be considered rare in hemodialysis patients but its clinical frequency is now increasingly realized. The liver is the main site of iron storage and the liver iron concentration (LIC) is closely correlated with total iron stores in patients with secondary hemosideroses and genetic hemochromatosis. Magnetic resonance imaging is now the gold standard method for LIC estimation and monitoring in non-renal patients. Studies of LIC in hemodialysis patients by quantitative magnetic resonance imaging and magnetic susceptometry have demonstrated a strong relation between the risk of iron overload and the use of intravenous (IV) iron products prescribed at doses determined by the iron biomarker cutoffs contained in current anemia management guidelines. These findings have challenged the validity of both iron biomarker cutoffs and current clinical guidelines, especially with respect to recommended IV iron doses. Three long-term observational studies have recently suggested that excessive IV iron doses may be associated with an increased risk of cardiovascular events and death in hemodialysis patients. We postulate that iatrogenic iron overload in the era of erythropoiesis-stimulating agents may silently increase complications in dialysis patients without creating frank clinical signs and symptoms. High hepcidin-25 levels were recently linked to fatal and nonfatal cardiovascular events in dialysis patients. It is therefore tempting to postulate that the main pathophysiological pathway leading to these events may involve the pleiotropic master hormone hepcidin (synergized by fibroblast growth factor 23), which regulates iron metabolism. Oxidative stress as a result of IV iron infusions and iron overload, by releasing labile non-transferrin-bound iron, might represent a 'second hit' on the vascular bed. Finally, iron deposition in the myocardium of patients with severe iron overload might also play a role in the pathogenesis of sudden death in some patients.

Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects.

Background

Coronavirus disease 2019 (COVID-19)-related short-term mortality is high in dialysis patients, but longer-term outcomes are largely unknown. We therefore assessed patient recovery in a large cohort of dialysis patients 3 months after their COVID-19 diagnosis.

Methods

We analyzed data on dialysis patients diagnosed with COVID-19 from 1 February 2020 to 31 March 2021 from the European Renal Association COVID-19 Database (ERACODA). The outcomes studied were patient survival, residence and functional and mental health status (estimated by their treating physician) 3 months after COVID-19 diagnosis. Complete follow-up data were available for 854 surviving patients. Patient characteristics associated with recovery were analyzed using logistic regression.

Results

In 2449 hemodialysis patients (mean ± SD age 67.5 ± 14.4 years, 62% male), survival probabilities at 3 months after COVID-19 diagnosis were 90% for nonhospitalized patients (n = 1087), 73% for patients admitted to the hospital but not to an intensive care unit (ICU) (n = 1165) and 40% for those admitted to an ICU (n = 197). Patient survival hardly decreased between 28 days and 3 months after COVID-19 diagnosis. At 3 months, 87% functioned at their pre-existent functional and 94% at their pre-existent mental level. Only few of the surviving patients were still admitted to the hospital (0.8-6.3%) or a nursing home (∼5%). A higher age and frailty score at presentation and ICU admission were associated with worse functional outcome.

Conclusions

Mortality between 28 days and 3 months after COVID-19 diagnosis was low and the majority of patients who survived COVID-19 recovered to their pre-existent functional and mental health level at 3 months after diagnosis.

Background

Patients on kidney replacement therapy (KRT) are at very high risk of coronavirus disease 2019 (COVID-19). The triage pathway for KRT patients presenting to hospitals with varying severity of COVID-19 illness remains ill-defined. We studied the clinical characteristics of patients at initial and subsequent hospital presentations and the impact on patient outcomes.

Methods

The European Renal Association COVID-19 Database (ERACODA) was analysed for clinical and laboratory features of 1423 KRT patients with COVID-19 either hospitalized or non-hospitalized at initial triage and those re-presenting a second time. Predictors of outcomes (hospitalization, 28-day mortality) were then determined for all those not hospitalized at initial triage.

Results

Among 1423 KRT patients with COVID-19 [haemodialysis (HD), n = 1017; transplant, n = 406), 25% (n = 355) were not hospitalized at first presentation due to mild illness (30% HD, 13% transplant). Of the non-hospitalized patients, only 10% (n = 36) re-presented a second time, with a 5-day median interval between the two presentations (interquartile range 2-7 days). Patients who re-presented had worsening respiratory symptoms, a decrease in oxygen saturation (97% versus 90%) and an increase in C-reactive protein (26 versus 73 mg/L) and were older (72 vs 63 years) compared with those who did not return a second time. The 28-day mortality between early admission (at first presentation) and deferred admission (at second presentation) was not significantly different (29% versus 25%; P = 0.6). Older age, prior smoking history, higher clinical frailty score and self-reported shortness of breath at first presentation were identified as risk predictors of mortality when re-presenting after discharge at initial triage.

Conclusions

This study provides evidence that KRT patients with COVID-19 and mild illness can be managed effectively with supported outpatient care and with vigilance of respiratory symptoms, especially in those with risk factors for poor outcomes. Our findings support a risk-stratified clinical approach to admissions and discharges of KRT patients presenting with COVID-19 to aid clinical triage and optimize resource utilization during the ongoing pandemic.