End-stage renal disease (ESRD) patients often present impaired intestinal absorption of dietary iron, blood losses, and low-grade chronic inflammation, which can lead to difficulties in achieving adequate iron status. This is one of the main causes of hyporesponsiveness to therapy involving erythropoiesis-stimulating agents (ESA), e.g., erythropoietin.
However, iron supplementation is associated with gastrointestinal discomfort, may impair the absorption of other medication, and can alter the gut microbiota and systemic metabolome.
A recent study from the team behind the current report outlined the positive effects of resistance training (RT) on iron deficiency in ESRD patients, suggesting this training model as an adjunct treatment for anaemia. But it raised two fundamental questions: (I) Does RT enhance the treatment with erythropoietin (EPO) and iron sulfate in ESRD older individuals? (II) Is RT an effective treatment on its own to improve iron status?
The current study therefore sought to investigate the effects of RT combined with EPO and iron sulfate on the hemoglobin, hepcidin, ferritin, iron status, and inflammatory profile in older individuals with ESRD. The team hypothesised that RT would enhance the effects of EPO and iron sulfate in this population.
The study
This study is part of a large trial in which end-stage renal disease patients (N: 157, age: 66.8 ± 3.6; body mass: 73 ± 15 body mass index:27 ± 3), were assigned to control (CTL n: 76) and exercise groups (RT n: 81). RT consisted of 24 weeks/3 days per week of a moderate intensity. Venous blood samples were obtained at baseline, and after 24 weeks of training, to measure the iron metabolism status and inflammatory profile. The participants were randomised into two groups: the control group (CTL; n = 76) and the resistance training group (RT; n = 81).
For the current study, the researchers stratified the patients into six subgroups according to the iron treatment received. The CTL group: without iron treatment (CTL—none; n = 19), treated only with iron sulfate or EPO (CTL—EPO or IRON; n = 19), and treated with both iron sulfate and EPO (CTL—EPO + IRON; n = 38). The RT groups followed the same pattern (RT—none; n = 20), (RT—EPO or IRON; n = 18), (RT—EPO + IRON; n = 43).
The resulting data reveals patients from the CTL group did not display changes in iron, haemoglobin, ferritin, and hepcidin after this six-month assessment in all iron treatment groups (p > 0.05). RT increased haemoglobin from baseline in all groups. Only the RT group treated with EPO + IRON presented higher haemoglobin in relation to the CTL group treated with EPO + IRON. Serum iron increased in relation to baseline and the CTL groups. Ferritin only decreased from baseline.
The RT group presented a decrease in hepcidin in relation to baseline and in relation to the CTL group that received the same iron therapy. Patients from the RT groups displayed an improvement in the inflammatory profile, presenting a decrease in TNF and IL6 and an increase in IL10 when compared to baseline and to the CTL groups.
Overall, the results show that regardless of the treatment, the RT group showed modulated haemoglobin, iron, ferritin, hepcidin, and cytokine levels. However, RT—IRON + EPO presented a lower decrease in hepcidin in relation to RT—none.
The researchers say these results may point to two important insights: (1) that RT is an effective treatment for improving serum iron parameters in elderly patients with ESRD and (2) that conventional use of ESA + iron in this population is more effective in combination with RT.
The report states: "Interestingly, as RT alone improved serum iron availability, it may provide the opportunity to remove ferrous sulfate and its associated disturbances from the treatment in this population. This would limit iron accumulation and, in theory, further reduce hepcidin, as suggested by the greater reduction in hepcidin in the RT—none group compared to the RT—IRON + EPO group.
"Furthermore, although the small sample size did not allow us to perform this analysis, the combination of RT + ESA is probably the most promising treatment for lowering hepcidin levels. This combination would reduce the activation of the two main pathways of hepcidin synthesis: the JAK/STAT3 pathway, by lowering inflammation (RT effects), and the BMP/SMAD pathway, by increasing erythropoiesis activity and sequestering erythroferrone BMP2/6 ligands."
Limitations to this study are noted in the report, including: Lack of control for the time of iron supplementation or EPO, study not initially designed for this subgroup analysis, leading to low sample size for each iron treatment group, and lack of analysis related to nutritional markers and electrolytes.However, to date, this is the first study to demonstrate that RT is capable of inducing changes in iron metabolism regardless of iron treatment.
Source: Nutrients
Corrêa, H.D.L.; Alfaro-Magallanes, V.M.; Moura, S.R.G.; Neves, R.V.P.; Deus, L.A.; Honorato, F.S.; Silva, V.L.; Raab, A.T.O.; Maia, B.C.H.; Padula, I.A.; Gusmão Alves, L.S.D.; Machado, R.A.; Reis, A.L.; Prestes, J.; Ferreira, C.E.S.; Neto, L.S.D.S.; Tavares, F.S.; Andrade, R.V.; Rosa, T.D.S.
"Does the Combined Effect of Resistance Training with EPO and Iron Sulfate Improve Iron Metabolism in Older Individuals with End-Stage Renal Disease?"
https://doi.org/10.3390/nu13093250 (registering DOI)