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


METHODS



BACKGROUND
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.
Department of Nephrology, Nazareth Hospital-EMMS, Nazareth, 16100, Israel. ZaherArmaly@NAZHOSP.com.|Galilee Faculty of Medicine - Bar Ilan University, Zafed, Israel. ZaherArmaly@NAZHOSP.com.
Zaher
Z
Armaly
Department of Nephrology, Nazareth Hospital-EMMS, Nazareth, 16100, Israel. amirabed@gmail.com.|Galilee Faculty of Medicine - Bar Ilan University, Zafed, Israel. amirabed@gmail.com.
Amir
A
Abd El Qader
Department of Laboratory Medicine, Nazareth Hospital-EMMS, Nazareth, Israel. adeljabour@nazhosp.com.|Galilee Faculty of Medicine - Bar Ilan University, Zafed, Israel. adeljabour@nazhosp.com.
Adel
A
Jabbour
Department of Nephrology, Western Galilee Hospital, Nahariya, Israel. drkamalh@hotmail.com.
Kamal
K
Hassan
Department of Nephrology, Rambam Health Campus, Haifa, Israel. r_ramadan@rambam.health.gov.il.
Rawi
R
Ramadan
Department of Nephrology, Nazareth Hospital-EMMS, Nazareth, 16100, Israel. bowirrat@gmail.com.|Galilee Faculty of Medicine - Bar Ilan University, Zafed, Israel. bowirrat@gmail.com.
Abdalla
A
Bowirrat
Department of Nephrology, Nazareth Hospital-EMMS, Nazareth, 16100, Israel. Bishara@nazhosp.com.|Galilee Faculty of Medicine - Bar Ilan University, Zafed, Israel. Bishara@nazhosp.com.
Bishara
B
Bisharat
D000209:Acute-Phase Proteins; D062107:Advanced Oxidation Protein Products / Q000097:blood; D000368:Aged; D018798:Anemia, Iron-Deficiency / Q000188:drug therapy* / Q000209:etiology; D002097:C-Reactive Protein / Q000378:metabolism; D002331:Carnitine / Q000494:pharmacology*; D018592:Cross-Over Studies; D005260:Female; D005290:Ferric Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D005838:Genotype; D006242:Haptoglobins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000071068:Lipocalin-2; D054834:Lipocalins / Q000097:blood; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D010641:Phenotype; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000097:blood; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000235:genetics*
D000209:Acute-Phase Proteins; D062107:Advanced Oxidation Protein Products; D005290:Ferric Compounds; D006242:Haptoglobins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D002097:C-Reactive Protein; D002331:Carnitine; C035552:ferric gluconate