Síndrome de anemia cardio-renal: CRAS. Aspectos básicos y clínicos

Abstract

Introduction Iron deficiency is extremely common and, in fact, it may be present in more than 80% of the world´s population, this making it perhaps the commonest disease known in clinical practice. Only about 1 in 4 patients with iron deficiency will have anaemia but many more will develop it over time as the iron stores continue to become more and more depleted. People with anaemia may suffer greatly from iron deficiency anaemia with fatigue, tiredness, lack of concentration, memory defects, reduced cognitive function and depression. Perhaps, in the whole field of medicine there is not a disease which is so common, so disabling, yet so eminently open to simple, safe and effective treatment. Iron deficiency due to nutritional causes Nutritional iron deficiency in animal and human studies may cause many alterations, with or even without associated anaemia 1. These defects include: · Reduced exercise capacity and physical performance. · Diturbance in thermoregulation with defects in the ability to maintain body temperature in response to cold stress. · Defects in the cognitive function of babies, children and adults. Restless legs syndrome, a condition characterized by discomfort in the legs which worsens as the day goes by, is worst at night, and is relieved by moving the legs or walking. Defects in the immune function, with abnormalities in the function of neutrophils, macrophages and lymphocytes, with increased susceptibility to infection. These defects can often be corrected by oral or intravenous (IV) iron therapy 1. The fact that these defects can occur even without anaemia and be improved, in some cases, even without a change in Haemoglobin (Hb) suggests that iron may also be working to improve cellular function, regardless of Hb concentration. Iron deficiency in chronic disease In chronic diseases in which anaemia is frequently present, such as cancer, chronic renal failure (CRF), ulcerative colitis, Chron´s disease and rheumatoid arthritis, the percentage of transferrin saturation is usually low, a sign suggestive of iron deficiency. However, serum ferritin is often increased in these cases. Will IV iron improve anaemia in these conditions as well? The answer is yes 2. In all these situations, IV iron alone has been shown to improve anaemia. To this list of IV iron-responsive anaemia in chronic disease, we can now add Congestive Heart Failure (CHF). Iron deficiency in Congestive Heart Failure The possibility that iron deficiency is common in anaemic CHF patients has been raised by two recent studies 3,4. One 3 showed that microcytosis, low % transferrin saturation and high Transferrin Receptor Protein levels, all of them signs of iron deficiency anaemia, were common in these anaemic CHF patients. The other study 4 showed that iron staining was absent in about three quarters of the bone marrow of anaemic patients with severe CHF. This is probably the most sensible iron deficiency test. However, the only way to actually prove that iron deficiency really plays a role in CHF is to treat it and see if anaemia and CHF improve. Recently, it has been shown in a randomized, double-blind, placebo-controlled study that anaemic CHF patients with signs of iron deficiency respond to IV iron (Iron Sucrose Complex), compared to the control group receiving placebo injections 5. In that study, there was an excellent Hb response and this was accompanied by an improvement in every studied CHF aspect including: improved New York Heart Association (NYHA) functional class, lower NT-pro-brain natriuretic peptide (NT-proBNP) (a crucial marker of severity and survival in CHF), lower heart rate, improved Left Ventricular Ejection Fraction (LVEF) and renal function, improved quality of life, increased exercise capacity, reduced need for diuretics, a reduction in inflammation, as judged by reduced C Reactive Protein (CRP) and reduced hospitalization. In a prospective uncontrolled open-label study with a three months follow-up using the same iron sucrose complex as above, Bolger et al 6 also found a significant increase in Hb level and a substantial improvement in NYHA functional class, quality of life and exercise capacity. In a 6-month study of severe CHF patients (NYHA III-IV) with marked cardiomegaly and Left Ventricular Hypertrophy (LVH), Usamov RI et al 7 found that weekly treatment with the same IV iron preparation caused a marked improvement in Hb, NYHA functional class and LVEF, and a marked reduction in cardiac size and LVH. May IV iron improve cardiac function even without increasing Hb? In a preliminary study of anaemic CHF patients with iron deficiency with or without anaemia 8, the same iron preparation as above failed to cause a significant increase in Hb over 16 weeks but caused an increase in oxygen consumption (an important sign of improved cardiac function), NYHA functional class and self-assessed quality of life. This, again, suggests that part of the improvement with IV iron in CHF may be unrelated to Hb levels but it might be due to improved functioning of body cellular function (including the mitochondria) as a result of the correction of iron deficiency. Furthermore, the mitochondria are known to be particularly susceptible to damage from iron deficiency. Uncertainty about the-long term safety of Erythropoiesis Stimulating Agents (ESA) and IV iron. All these findings take on an added importance now that there is concern about the safety of Erythropoietin (EPO) and other Erythropoiesis Stimulating Agents (ESAs) in Chronic Renal Failure (CRF). Although these agents along with oral or IV iron have been shown to improve all aspects of CHF in anaemic CHF patients 9-16, there is some concern about the side effects of ESAs in CRF such as arterial hypertension, thrombocytosis, thrombotic complications and increased cardiovascular events 17-19. Since many CHF patients also have some degree of CRF, this concern holds true for CHF as well. A large randomized, double-blind, placebo-controlled study of Darbepoetin, a long acting ESA, called the RED-HF study (Reduction of Events with Darbepoetin in Heart Failure) has now been started 20 and until more data are available, we will not know for sure about the safety of ESAs in anaemic CHF patients. The same holds true for IV iron in CHF. Large randomized, double-blind placebo- controlled studies are required to truly assess the safety and efficacy of this agent in CHF. Such studies are not available for CRF, even less for CHF. The use of IV iron is appealing because, as mentioned earlier, it may correct anaemia without ESAs, it is much less expensive than ESAs, corrects iron deficiency anaemia (while an ESA without oral or IV iron would worsen iron deficiency) and allows for the use of lower ESA doses when they are needed. Lower ESA doses would clearly be safer than higher doses, reducing the chances of possible side effects. The use of new IV iron products 21,22, which allow the rapid and safe administration of up to 1000 mg IV iron all at once instead of the 125 and 200 mg currently recommended for iron gluconate or iron sucrose complex respectively, will make the treatment even easier with fewer visits needed for treatment. Thus we may be on the way to a change in the treatment of anaemia of CHF, with the first treatment in many patients being IV iron and, only if this failed to achieve the target Hb of 12 g/dl would an ESA be added. In the last years, due to a better understanding of the pathophysiology of CHF and CRF, there has been an increased interest in anaemia as a key participant in the complex scenario of patients with Cardio Renal Anemia Syndrome (CRAS), in which each component (anaemia, CRF and CHF) may be a cause or a consequence of the other.