Background: Chronic kidney disease (CKD) patients develop metabolic acidosis when approaching stages 3 and 4, a period in which accelerated atherogenesis may ensue. Studies in vitro show that low pH may increase low-density lipoprotein (LDL) oxidation, suggesting a role for chronic metabolic acidosis in atherosclerosis. The present study attempted to evaluate the effects of conservative care using oral sodium bicarbonate (NaHCO3) supplementation on the electronegative LDL [LDL(-)], a minimally oxidized LDL, plasma levels in CKD patients. Methods: Thirty-one CKD patients were followed by a multidisciplinary team during 15 months of care in which 1.0 mmol/kg/day oral NaHCO3 supplementation was first given in the third month. Blood samples were collected 3 months before the initiation of oral NaHCO3 supplementation (T1), at the time of the beginning of supplementation (T2), and thereafter, each 4 months (T3, T4 and T5) until month 15 of care. Blood parameters and LDL(-) were measured from these collections. Results: After 12 months of conservative care, creatinine clearance (MDRD) was kept stable, and serum bicarbonate (HCO3-) increased from 20.5 ± 2.9 to 22.6 ± 1.1 mM (p < 0.003). LDL(-) plasma levels declined from 4.5 ± 3.3 to 2.1 ± 0.9 U/L (p < 0.007) after reaching mean serum HCO3- levels of 22.6 ± 1.1 mM. Conclusions: Conservative care using oral NaHCO3 supplementation was able to stabilize renal function and decrease serum levels of LDL(-), a modified proatherogenic lipoprotein, only when mean serum HCO3- levels approached 22 mM. This study constitutes evidence that alkali therapy, in addition to its beneficial effect on renal disease progression, might serve as a preventive strategy to attenuate atherogenesis in CKD patients.

Keywords:
Chronic kidney disease, Alkali therapy, Electronegative LDL, Cardiovascular diseases
1.
Lobo J, Santos F, Grosso D, Lima R, Barreira AL, Leite M Jr, Mafra D, Abdalla DS: Electronegative LDL and lipid abnormalities in patients undergoing hemodialysis and peritoneal dialysis. Nephron Clin Pract 2008;108:298-304.
2.
Holvoet P, Collen D: Oxidation of low-density lipoproteins in the pathogenesis of atherosclerosis. Atherosclerosis 1998;137:33-38.
3.
Asatryan L, Ziouzenkova O, Duncan R, Sevanian A: Heme and lipid peroxides in hemoglobin-modified low-density lipoprotein mediate cell survival and adaptation to oxidative stress. Blood Purif 2003;102:1732-1739.
4.
Molavi B, Mehta JL: Oxidative stress in cardiovascular disease: molecular basis of its deleterious effects, its detection, and therapeutic considerations. Curr Opin Cardiol 2004;19:488-493.
5.
Cofan F, Vela E, Cléries M: Collaborative Study Group for Dyslipidemia. Analysis of dyslipidemia in patients on chronic hemodialysis in Catalonia. Atherosclerosis 2006;184:94-102.
6.
Tertov VV, Orekhov AN: Metabolism of native and naturally occurring multiple low density lipoprotein in smooth muscle cells of human aortic intima. Exp Mol Pathol 1997;64:127-145.
7.
Avogaro P, Bon GB, Cazzolato G: Presence of a modified low density lipoprotein in humans. Arteriosclerosis 1988;8:79-87.
8.
Demuth K, Myara I, Chappey B, Vedie B, Pech-Amsellem MA, Haberland ME, Moatti N: A cytotoxic electronegative LDL subfraction is present in human plasma. Arterioscler Thromb Vasc Biol 1996;16:773-783.
9.
Vedie B, Jeunemaitre X, Megnien JL, Myara I, Trebeden H, Simon A, Moatti N: Charge heterogeneity of LDL in asymptomatic hypercholesterolemic men is related to lipid parameters and variations in the ApoB and CIII genes. Arterioscler Thromb Vasc Biol 1998;18:1780-1789.
10.
Tertov VV, Kaplun VV, Sobenin IA, Orekhov AN: Low-density lipoprotein modification occurring in human plasma. Possible mechanism of in vivo lipoprotein desialylation as a primary step of atherogenic modification. Atherosclerosis 1998;138:183-195.
11.
Moro E, Alessandrini P, Zambo C, Pianetti S, Pais M, Gazzolato G, Bon GB: Is glycation of low density lipoproteins in patients with type 2 diabetes mellitus a LDL pre-oxidative condition? Diabet Med 1999;16:663-669.
12.
Ziounzenkova O, Sevanian A: Oxidative modification of low-density lipoprotein (LDL) in HD patients: role of electronegative LDL formation. Blood Purif 2000;18:169-176.
13.
Hirowatari Y, Homma Y, Yoshizawa J, Homma K: Increase of electronegative-LDL-fraction ratio and IDL-cholesterol in chronic kidney disease patients with hemodialysis treatment. Lipids Health Dis 2012;11:111.
14.
Chang CT, Wang GJ, Kuo CC, Hsieh JY, Lee AS, Chang CM, Wang CC, Shen MY, Huang CC, Sawamura T, Yang CY, Stancel N, Chen CH: Electronegative low-density lipoprotein increases coronary artery disease risk in uremia patients on maintenance hemodialysis. Medicine (Baltimore) 2016;95:e2265.
15.
Ivanova EA, Bobryshev YV, Orekhov AN: LDL electronegativity index: a potential novel index for predicting cardiovascular disease. Vasc Health Risk Manag 2015;11:525-532.
16.
De Castelarnau C, Sanchez-Quesada JL, Bernitez S, Rosa R, Caveda L, Vila L, Ordonez-Llanos J: Electronegative LDL from normolipemic subjects induces IL-8 and monocyte chemotactic protein secretion by human endothelial cells. Arterioscler Thromb Vasc Biol 2000;20:2281-2287.
17.
Morgan J, Leake DS: Acidic pH increases the oxidation of LDL by macrophages. FEBS Lett 1993;333:275-279.
18.
Satchell L, Leake DS: Oxidation of low-density lipoprotein by iron at lysosomal pH: implications for atherosclerosis. Biochemistry 2012;51:3767-3775.
19.
Brito-Ashurst I, Varagunam M, Raftery MJ, Yaqoob MM: Bicarbonate supplementation slows progression of CKD and improves nutritional status. J Am Soc Nephrol 2009;20:2075-2084.
20.
Mahajan A, Simoni J, Sheather SJ, Broglio KR, Rajab MH, Wesson DE: Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy. Kidney Int 2010;78:303-309.
21.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D: A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999;16;130:461-470.
22.
Faulin TES, Sena KCM, Telles AER, Grosso DM, Faulin EJB, Adalla SP: Validation of a novel ELISA for measurement of electronegative low-density lipoprotein. Clin Chem Lab Med 2008;46:1769-1775.
23.
Leal VO, Delgado AG, Leite M Jr, Mitch WE, Mafra D: Influence of renal function and diet on acid-base status in chronic kidney disease patients. J Renal Nutr 2009;19:178-118.
24.
Jeong J, Kwon SK, Kim HY: Effect of bicarbonate supplementation on renal function and nutritional indices in predialysis advanced chronic kidney disease. Electrolyte Blood Press 2014;12:80-87.
25.
Tovar AMF, Pecly IMD, Rangel EP, Melo-Filho NM, Mourão PAS, Leite M Jr: Experimentally induced metabolic acidosis in rabbits modulates the interaction of aortic glycosaminoglycan with plasma low-density lipoprotein - an interesting observation about the association of acidosis and atherosclerosis. Atherosclerosis 2007;192:33-39.
26.
Leake DS: Does an acidic pH explain why low density lipoprotein is oxidized in atherosclerotic lesions? Atherosclerosis 1997;129:149-157.
27.
Hassan W, Ibrahim M, Rocha JB: Low pH does not modulate antioxidant status of diphenyl ditelluride but exacerbates Fe (II)-induced lipid peroxidation in liver preparation. Drug Chem Toxicol 2009;32:438-442.
28.
Rajamäki K, Nordström T, Nurmi K, Åkerman KE, Kovanen PT, Öörni K, Eklund KK: Extracellular acidosis is a novel danger signal alerting innate immunity via the NLRP3 inflammasome. J Biol Chem 2013;288:13410-13419.
29.
Ori Y, Zingerman B, Bergman M, Bessler H, Salman H: The effect of sodium bicarbonate on cytokine secretion in CKD patients with metabolic acidosis. Biomed Pharmacother 2015;71:98-101.
30.
Hansson GK, Libby P, Schönbeck U, Yan ZQ: Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res 2002;91:281-291.
31.
Ziouzenkova O, Asatryan L, Akmal M, Tetta C, Wratten ML, Heinecke J, Loseto-Wich G, Jürgens G, Sevanian A: Oxidative cross-linking of ApoB100 and hemoglobin results in low density lipoprotein modification in blood: relevance to atherogenesis caused by hemodialysis. J Biol Chem 1999;274:18916-18924.
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2017
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