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ARC Journal of Nephrology Volume 3, Issue 2, 2018, PP 6-8 www.arcjournals.org

Brief Review of Studies on Oral Martial Therapy Compared to the Administration of Intravenous in Nephrology and

Ennio Duranti1*, Diletta Duranti2 1Consultant Nephrologist, Arezzo, Italy 2DepartmentPathology and ClinicalLaboratories AUO Novara, Italy

*Corresponding Author: Ennio Duranti, Consultant Nephrologist, Arezzo, Italy, Email: [email protected]

Anemia is a frequent and early complication of 20% of the administered iron is absorbed Chronic Kidney Disease (CKD), and its [10,11]. The sophisticated technology of natural prevalence increases with the worsening of renal phospholipids mounting makes the highly function, involving over 50% of patients in bioavailable iron, well tolerated and rapidly predialysis (stage 4 - 5) and practically almost absorbed. The presence of liposomal wrapper, 100% of patients in [1]. The in fact, protecting the iron by contact with the anemic state depends on an inadequate gastric mucosa avoids the pro-oxidant effect of production of , however a free iron. Liposomal protection allows the fundamental importance is represented by the micro-nutrient to overcome harmless the gastric alterations of the martial state or due to an iron environment to be absorbed directly in the small deficiency, as a consequence of inadequate intestine and not only in duodenum. intestinal absorption, or due to reduced technology delivery corresponds, in our body, , linked to the systemic to the transport of various substances from the inflammatory state, characteristic of these chylomicrons. These vehicles are few crowded patients or for uremic toxicity [2]. The natural and voluminous lipoproteins that administration of oral or intravenous iron and represent the mode of transport of dietary fats erythropoietin (Epo) is a key element for the from the intestine to the various tissues. This correction of both in patients with CKD similarity between and chylomicrons and in patients on chronic hemodialysis [3,4]. enables liposomal molecules to exploit same The martial therapy, administered orally is metabolic pathways that the body usually enacts preferred in patients in the conservative phase, to chylomicrons. In the intestinal lumen, the but presents frequent side effects especially of liposome is absorbed directly from M cells gastrointestinal type. In contrast, hemodialysis (enterocytes) that originate from the lymphatic patients use almost exclusively the intravenous system and are located on all the small intestine. route that can promote even serious allergic Then the liposome is incorporated for phenomena, and can lead to an increase in the endocytosis by macrophages and through the systemic inflammation with consequent lymphatic stream reaches, intact hepatocytes functional anemia due to a reduced use of the [8,13]. Within the hepatocytes, liposomes are iron by the marrow [3,4]. The possibility of opened by lysosomal enzymes, making iron having a particular oral iron preparation, the available to the organism. So in patients with liposomaliron, based on ferric pyrophosphate conservative CKD oral iron administration is carried within a phospholipid membrane, preferred, but sometimes for intestinal appears to have a lower incidence of malabsorption or the appearance of side effects, gastrointestinal side effects, without increasing such as abdominal pain, gastralgia, nausea, the inflammation of the patient [5]. Ionic iron , , we are forced to pass to the absorption takes place predominantly in administration via intravenous [6]. As duodenal level and is mediated by specific mentioned early, in patients on chronic carriers: ionic iron enters the intestinal cells by hemodialysis, intravenous iron during dialysis means of a divalent metal transporter. The session, is preferred for practical reasons. transition to the stream is then mediated However, allergic phenomena may occur up to by ferroportin at the basolateral membrane of severe anaphylactic reactions, potential the enterocyte; in normalconditions only 15- cytotoxicity, hepatic disease with iron ARC Journal of Nephrology Page | 6 Brief Review of Studies on Oral Martial Therapy Compared to the Administration of Intravenous Iron in Nephrology and Dialysis accumulation in various forms of liposomal microencapsulation, for which iron hemochromatosis, an increased risk of does not come into contact with mucous developing cirrhosis with levels of ferritin > membranes with better intestinal absorption 1000 ng / ml and an increase in the systemic bypassing the block induced by hepcidin, inflammation with a decrease in antioxidant moreover the absorbed pyrophosphate iron has a defenses [7]. The increased production of greater affinity for the transferrin and is directly inflammatory markers, such as CRP, IL-6, TNF- transferred to the [5]. In this alpha, promotes the release of hepcidin, a regard we have conducted a study [12], on a protein produced by the liver that acts by small number of patients in chronic daily home binding to another protein, called ferroportin, hemodialysis (8 pts) and on a group in which regulates the escape of iron from cells , conservative therapy with chronic renal failure blocking the passage of iron from cells to blood Stage 3b-4 (16pts) who were on treatment for resulting in functional iron deficiency, so-called sideropenic anemia: all pts belonging to the two inflammatory anemia [8,9,15]. Furthermore, groups had been earlier treated for at least 6 recently they have been emphasized the medico- months, with carboxymaltose iron iv (500 legal issues related to intravenous iron mg/month) and after they were passed to : a recent note dated 25 October liposomal iron. The protocol lasted 6 months for 2013 from the Italian Medicines Agency (AIFA) home hemodialys is pts and 12 months for CKD (www.agenzia droga.gov.it) underlined the risk pts. The study showed the equivalent efficacy of of intravenous administration with potentially oral liposomal iron, compared to intravenous fatal reactions, especially in patients with known iron, with the maintenance and in many cases allergies and in patients with inflammatory favoring the increment of hemoglobin values diseases, including the immune system, as well and reducing or keeping the same as in patients with , eczema, atopic Erythropoietin dosages. These results confirmed allergies [1, 10]. Therefore, according to these previously performed nephrological works notes, hemodialysis patients undergoing including a previous our work performed in 10 intravenous therapy should be monitored closely patients on three weekly dialysis treatment [10- during and at least 30 minutes after 14]. Differently from the precedent study the os administration in the presence of a doctor, in iron period was compared to an iv gluconate addition to the staff, and all this could iron period. The period (3months) of liposomal create organizational problems of considerable iron intake showed a significant increase in complexity especially if such indications should terms of Hb concentration, transferrin saturation be extended to the Dialysis Centers for limited and a significant decrease regarding CRP values and / or decentralized assistance, where the and weekly consumption of Epo. While the presence of the doctor is notoriously returning to iv gluconate iron administration circumscribed at times that do not cover all the period showed a significant reduction of Hb, a dialysis sessions of the day. Although on one significant increase in the weekly consumption hand, among the various preparations, iron of Epo and increase of CRP. The conclusion of gluconate and carboxymaltose seem to be the these two our studies [12, 14] was that one with fewer side effects, the Work Group liposomal iron seems to be a valid alternative to KDIGO 2012 did not show a definite benefit of intravenous iron therapy (iron gluconate o the intravenous route compared to the oral [1]. carboxymaltose). A particularly interesting On the other hand, as already mentioned, the use aspect of these studies is the reduction of PCR: of old oral iron compounds has not had much statistically significant in the first experience development until now due to their low efficacy and not statistically significant in the second and to the gastroenteric side effects linked to the experience of these two different works. This compound which usually contains iron sulphate, positive effect is explained by a lower activation which can be used only for a limited range of / production of inflammatory markers that patients, certainly not affected by Chronic Renal increase with the use of intravenous iron Insufficiency, since in these patients gastritis through the production of the species of reactive and gastralgia are constant [6]. So recently, the oxygen that exacerbate systemic inflammation, possibility of having a particular oral iron with decreased antioxidant defenses and preparation, the liposomal iron, based on ferric increased TNF and IL-6 release [15]. The pyrophosphate carried within a phospholipid absence of these inflammation effects in the membrane, showed a lower incidence of case of the use of liposomal iron, also explains gastrointestinal side effects, thanks to the the maintenance of weekly doses of ARC Journal of Nephrology Page | 7 Brief Review of Studies on Oral Martial Therapy Compared to the Administration of Intravenous Iron in Nephrology and Dialysis erythropoietin, recalling that 7 patients out of 16 trattamento dell’anemia nell’insufficienza in conservative therapy, throughout the period renale cronica. G ItalNefrol 2013; 30 (5) of observation, did not use erythropoietin and [6] Auerbach M, Goodnough LT, Picard D, this has certainly contributed to a reduction in ManiatisA. The role of intravenous iron in the costs of managing the anemia of patients in anemia management and transfusion avoidance. conservative treatment with chronic renal failure Transfusion. 2008 May;48(5):988-1000 and in dialysis schedule [12]. Another argument [7] ZagerRA, Johnson AC, Hanson SY.Parenteral iron in favor of liposomal iron is the reliability of nephrotoxicity: potential mechanisms and oral iron also on the appearance of its intestinal consequences. Kidney Int. 2004 Jul; 66(1):144-56. absorption in an almost constant percentage [8] Zager RA, Johnson AC, Hanson SY.Parenteral (20%) compared to the intravenously iron therapy exacerbates experimental . administered iron of which the percentage of use Kidney Int. 2004 Jun; 65(6):2108-12. is not certain, with an amount that it certainly [9] Chertow GM, Mason PD, Vaage-Nilsen O, precipitates at the tissue level, once the AhlménJ.Update on adverse events transferrin is saturated. In conclusion, our associated with parenteral iron. Nephrol Dial Transplant. 2006 Feb; 21(2):378-82. experience and that of many other authors demonstrates the possibility of replacing [10] Van Wyck DB, Roppolo M, Martinez CO et al. intravenous iron administration with liposomal A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with oral iron, well tolerated, effective, and with nondialysis-dependent CKD. Kidney significant economic savings in maintaining or international 2005 Dec;68(6):2846-56 reducing periodic doses of erythropoietin. [11] Charytan C, Qunibi W, Bailie GR et al. Furthermore, we would like to underline the Comparison of intravenous iron sucrose to oral important relapse also on the medico-legal level, iron in the treatment of anemic patients with due to the lower clinical risk in the use of chronic kidney disease not on dialysis. liposomal oral iron compared to intravenous Nephron. Clinical practice 2005;100(3):c55-62 iron. [12] DurantiE,DurantiD,PanzaF,RalliC. Efficacy of administration of oral liposomal iron after a REFERENCES period of intravenous iron carboxymaltose in [1] KDIGO clinical practice guidelines for anemia two groups of chronic kidney disease patients: in chronic kidney disease. Kidney IntSuppl home hemodialysis and conservative therapy. 2012; 2:288 ClinNephrol Res Vol.2 No.1 2018 June : 33-35 [2] Bregman DB, Morris D, Koch TA, He A, [13] Agarwal R, Rizkala AR, Bastani B et al. A Goodnough LT.Hepcidin levels predict randomized controlled trial of oral versus nonresponsiveness to oral iron therapy in intravenous iron in chronic kidney disease. patients with iron deficiency anemia. Am J American journal of nephrology 2006; 26(5): Hematol. 2013 Feb;88(2):97-101 445-54 [3] Taylor JE, Peat N, Porter C, Morgan [14] DurantiE. Comparative study between AG.Regular low-dose intravenous iron therapy liposomal iron (SideralForte) and intravenous improves response to erythropoietin in iron in chronic kidney disease. 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Citation: Ennio Duranti, Diletta Duranti. Brief Review of Studies on Oral Martial Therapy Compared to the Administration of Intravenous Iron in Nephrology and Dialysis. ARC Journal of Nephrology. 2018; 3(2):6-8. Copyright: ©2018 Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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