**4.4 Aluminum toxicity**

Although rarely seen nowadays, aluminum intoxication could be encountered with high content in the dialysis water source or with technical issues related to its treatment system [27, 28]. The resulting anemia is of microcytic hypochromic or normochromic pattern, which reflects ESA hyporesponsiveness associated with affected enzymes required for heme synthesis. Treatment requires gradual, incremental dosing of desferrioxamine infusion during hemodialysis sessions to avoid irreversible neurological damage. Other sources of aluminum exposure are aluminum-containing phosphate binders and antacids. The wide availability of-aluminum-containing phosphate binders led to very limited use of aluminum-containing phosphate binders for short periods and in certain occasions; for example, refractory hyperphosphatemia and hypercalcemia related to nonaluminum-containing phosphate binders. Combined use of sodium citrate with aluminum-containing phosphate binders promotes aluminum intoxication. Through increment of intestinal absorption. A concern was raised regarding the intake of ferric citrate as a phosphate binder due to the possible increase of aluminum absorption from food, water drinking, and concurrent medication use. Additional medications considered sources of aluminum are iron and calcium-containing medications, calcitriol vitamin B complex acetylsalicylic acid, clonidine, vitamins calcium carbonate, and iron sulfate. Injectable medications including iron, erythropoietin, and insulin have been found markedly more aluminum contaminated than oral formulations. Abnormal serum aluminum levels are those exceeding 20 mcg/L. According to Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, serum aluminum levels should be tested at least annually in hemodialysis patients and every 3 months in those who are taking aluminum-containing medications.

The Association for the Advancement of Medical Instrumentation (AAMI) recommendation is to perform periodic chemical monitoring for dialysis water at least annually, more frequently when indicated. The maximum allowed aluminum concentration is 0.01 mg/L [29–32].

## **4.5 Malnutrition**

Protein-energy wasting and inflammation are closely associated. Malnutritioninflammation complex is considered a predisposing factor for an impaired response to ESA therapy [33]. Moreover, vitamin deficiencies can be considered a contributing factor. Folic acid is involved in erythroid proliferation. Vitamin C, with its antioxidative effect, downregulates cytokine synthesis and increases iron utilization. Copper increases iron absorption. Alpha-lipoic acid is needed for ATP synthesis, and it has a lowering effect on symmetric-dimethyl arginine, reducing oxidative stress. l-Carnitine has an antioxidative stress effect by stimulating heme-oxygenase 1. There is no available data to support a relation between vitamin six and ESA hyporesponsiveness [34–37].

### **4.6 Pure red cell aplasia (PRCA)**

As a consequence of epoetin-induced polyclonal antibodies, neutralization of exogenous ESA and cross-reaction with endogenous EPO occur [38]. So, erythropoiesis becomes defective with undetectable EPO levels in serum. The resulting rare condition is called pure red cell aplasia (PRCA). It is manifested by a rapid drop of Hb and undetectable reticulocytes with normal counts of white blood cells and platelets. PRCA is suspected with a monthly decrease of Hb level by 2 gm/dl or more r if reticulocyte count is less than 20,000/microL. It is usually thought of when hyporesponsiveness is preceded by a reasonable response to ESA therapy. For PRCA to occur, at least 3–4 weeks of EPO therapy must be there, with the typical presentation following 6–18 months of intake [39]. According to Kidney Disease Improving Global Outcomes (KDIGO) 012 guidelines, screening for PRCA due to anti-EPO antibodies in patients on EPO therapy for at least 4 weeks was suggested with absolute reticulocyte count less than 10,000/microL, normal platelet and white blood cell count, in addition, to drop of Hb level more than 0.5–1.0 g/dl weekly or need for 1–2 transfusions per week [40].

All PRCA cases induced by anti-EPO antibodies were reported after subcutaneous ESA administration, with a duration of treatment ranging from 1 month to 5 years [41]. PRCA mandates blood transfusion and immunosuppression, sometimes with rituximab [42]. Following the disappearance of EPO antibodies, IV ESA administration can be restarted with strict monitoring of anti-EPO antibody titers and Hb levels. Renal transplantation is the definitive solution.
