Effects of carnitine on oxidative stress response to intravenous iron administration to patients with CKD: impact of haptoglobin phenotype

Zaher Armaly, Amir Abd El Qader, Adel Jabbour, Kamal Hassan, Rawi Ramadan, Abdalla Bowirrat, Bishara Bisharat, Zaher Armaly, Amir Abd El Qader, Adel Jabbour, Kamal Hassan, Rawi Ramadan, Abdalla Bowirrat, Bishara Bisharat

Abstract

Background: Anemia is a common disorder in CKD patients. It is largely attributed to decreased erythropoietin (EPO) production and iron deficiency. Therefore, besides EPO, therapy includes iron replenishment. However, the latter induces oxidative stress. Haptoglobin (Hp) protein is the main line of defense against the oxidative effects of Hemoglobin/Iron. There are 3 genotypes: 1-1, 2-1 and 2-2. Hp 2-2 protein is inferior to Hp 1-1 as antioxidant. So far, there is no evidence whether haptoglobin phenotype affects iron-induced oxidative stress in CKD patients. Therefore, the present study examines the influence of carnitine treatment on the intravenous iron administration (IVIR)-induced oxidative stress in CKD patients, and whether Hp phenotype affects this response.

Trial registration: Current Controlled Trials ISRCTN5700858. This study included 26 anemic (Hb = 10.23 ± 0.28) CKD patients (stages 3-4) that were given a weekly IVIR (Sodium ferric gluconate, [125 mg/100 ml] for 8 weeks, and during weeks 5-8 also received Carnitine (20 mg/kg, IV) prior to IVIR. Weekly blood samples were drawn before and after each IVIR for Hp phenotype, C-reactive protein (CRP), advanced oxidative protein products (AOPP), neutrophil gelatinase-associated lipocalin (NGAL), besides complete blood count and biochemical analyses.

Results: Eight percent of CKD patients were Hp1-1, 19 % Hp2-1, and 73 % Hp2-2. IVIR for 4 weeks did not increase hemoglobin levels, yet worsened the oxidative burden as was evident by elevated plasma levels of AOPP. The highest increase in AOPP was observed in Hp2-2 patients. Simultaneous administration of Carnitine with IVIR abolished the IVIR-induced oxidative stress as evident by preventing the elevations in AOPP and NGAL, preferentially in patients with Hp2-2 phenotype.

Conclusions: This study demonstrates that Hp2-2 is a significant risk factor for IVIR-induced oxidative stress in CKD patients. Our finding, that co-administration of Carnitine with IVIR preferentially attenuates the adverse consequences of IVIR, suggests a role for Carnitine therapy in these patients.

Trial registration: ClinicalTrials.gov NCT02312414.

Figures

Fig. 1
Fig. 1
Selection of anemic CKD patients for examination of the effects of carnitine on oxidative stress response to intravenous iron administration and the impact of haptoglobin phenotype
Fig. 2
Fig. 2
Effects of Carnitine therapy on AOPP levels in patients with CKD treated with intravenous administration of iron. AOPP levels were determined in blood samples drawn 1 and 8 weeks prior and post iron administration (Sodium ferric gluconate, 125 mg/100 ml) During weeks 5–8, these patients received carnitine (20 mg/kg, IV) prior to IVIR
Fig. 3
Fig. 3
Effects of Carnitine therapy on plasma NGAL levels in patients with CKD treated with intravenous administration of iron. NGAL levels were determined in blood samples drawn 1 and 8 weeks prior and post iron administration (Sodium ferric gluconate, 125 mg/100 ml) During weeks 5–8, these patients received carnitine (20 mg/kg, IV) prior to IVIR
Fig. 4
Fig. 4
Distribution of haptoglobin phenotype among the studied CKD patients
Fig. 5
Fig. 5
Effect of Haptoglobin phenotype on a) AOPP and b) NGAL levels in patients with CKD treated with intravenous administration of iron. AOPP and NGAL levels were determined in blood samples drawn 1 and 8 weeks prior and post iron administration (Sodium ferric gluconate, 125 mg/100 ml). During weeks 5–8, these patients received Carnitine (20 mg/kg, IV) prior to IVIR administration

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