Oral supplement of six selective amino acids arrest progression renal failure in uremic patients
Cite this article as: Yatzidis, H. Int Urol Nephrol (2004) 36: 591. doi:10.1007/s11255-004-8782-2 Abstract
Certain amino acids such as glycine,
L-aspartic acid, L-glutamic acid, L-glutamine, L-histidine and L-arginine taken orally by normal adults or patients with renal failure increase glomerular filtration rate (GFR). Twelve nondiabetic patients suffering from glomerulonephritis confirmed by renal biopsy previously, with creatinine clearances ranging from 15 to 24 ml minute/1.73, and on low protein diet 0.6 g/kg/day, received an amino acid supplement daily in 2 or 3 doses for 1 year. At 4, 8 and 12 months creatinine clearance increased slightly (NS, NS, NS), 24 hour urine volume increased ( P ≤ 0.001, 001, 0.001), 24 hour albuminuria decreased ( P<0.001, 0.001, 0.001), serum urea increased (NS, NS, NS) serum albumin increased (NS, 0.05, 0.05), total cholesterol decreased slightly (NS, NS, 0.01), HDL increased slightly (0.05, 0.05, 0.05), LDL decreased (NS, 0.001, 0.001) triglycerides decreased (0.001, 0.001, 0.001), Apo B remained unchanged (NS, NS, NS), ROS/H 2O 2 decreased (0.001, 0,001, 0.001), Hct increased (NS, 0.01, 0.01) Hb increased (0.05, 0.05, 0.05) and serum phosphate decreased (0.01, 0.01, 0.01). After removal of supplements at the end of the year all parameters remained unchanged. We believe that a large controlled study should be undertaken to confirm these most encouraging findings. Keywords Chronic kidney disease Glycine Essential amino acids L-Arginine L-Aspartic acid L-Glutamine L-Glutamine acid Prevention of renal disease References
Modification of Diet in Renal Disease (MDRD) study group (prepared by Beck GJ, Beck RL, Coggins CH, Gassman JJ, Hunsicker LG, Schluter MD, Williams GW). Design and studistical issues of the Modication of Diet in Renal Disease Trial. Controlled Clin Trials 1991; 12: 566–586.
Levey, AS, Greene, T, Schluchter, MD, et al. 1993 The modification of diet in renal disease (mdrd) study and the diabetes control and complications trial (dcct) research group: glomerular filtration rate measurement in clinical trials. J Am Soc Nephrol 3 1159 1171 Google Scholar
Modification of Diet in Renal Disease (MDRD) study group (prepared by Greene T, Bourgoignie JJ, Habwe VQ, Kusec JW, Snetsellaar L, Soucie JM, Yamamoto M). Baseline characteristics in the Modification of Diet in Renal Disease Study. J Am Soc Nephrol 1993; 3: 1819–1834 (original version); 1993; 4: 1221–1236 (corrected version).
Klahr, S, Levey, AS, Berk, GJ, et al. 1994 The modification of diet in renal disease (MDRD) Study Group.The effects of dietary protein restriction and blood pressure control on the progression of chronic renal disease. N Engl J Med 330 877 884 Google Scholar Peterson, J, Adler, S, Burkart, J, et al. 1995 For The modification of diet in renal disease (MDRD) study group.Blood pressure control, proteinuria, and the progression of renal disease: the Modification of Diet in Renal Disease Study. Annal Intern Med 123 754 762 Google Scholar The Modification of Diet in Renal Disease (MDRD) Study Group Klahr, S, Breyer, JA, Beck, GJ, Dennis, VW, Hartman, JA, Roth, D, Steinman, TI, Wang, S-R, Yamamoto, ME 1995 Dietary protein restriction, blood pressure control, and the progression of polycystic kidney disease. J Am Soc Nephrol 5 2037 2047 Google Scholar Levey, A, Adler, S, Caggiula, A, et al. 1996 For The MDRD Study Group.Effects of dietary protein restriction on the progression of advanced renal disease in the Modification of Diet in Renal Disease (MDRD) Study. Am J Kidney Dis 27 652 663 Google Scholar The Modification of Diet in Renal Disease (MDRD) Study Group Hunsicker, LG, Adler, S, Caggiula, A, England, BK, Green, T, Kusek, JW, Rogers, NL, Teschan, PE 1997 Predictors of the progression of renal disease in the modification of diet in renal disease study. Kidney Int 51 1908 1919 Google Scholar Lazarus, JM, Bourcoignie, JJ, Buckalew, VM, et al. 1997 For the Modification of Diet in Renal Disease Study Group.Achievement of safety of a low blood pressure goal in chronic renal disease in the Modification of Diet in Renal Disease Study. Hypertension 29 641 650 Google Scholar Klahr, S 1997 Prevention of progression of nephropathy. Nephrol Dial Transplant 12 63 66 Google Scholar Hebert, La, Kusek, Jw, Greene, T, et al. 1997 Effects of blood pressure control on progressive renal disease in blacks and whites.Modification of Diet in Renal Disease Study Group. Hypertension 30 428 435 Google Scholar Wanner, C, Greiber, S, Kramer-Guth, A, et al. 1997 Lipid and progression of renal disease: role of modified low density lipoprotein and lipoprotein (A). Kidney Int 52 S-102 S-106 Google Scholar Eddy, Aa, Liu, E, Me Culloch, L 1998 Interstitial fibrosis in hypercholesterolemic rats: role of oxidation, matrix synthesis, and proteolytic cascades. Kidney Int 53 1182 1189 Google Scholar Keane, Wf 2000 The role of lipid in renal disease: future challenges. Kidney Int 57 S-27 S-31 Google Scholar Campese, Vm, Romoff, Ms, Levitan, D, Massry, Sg 1981 Mechanisms of autonomic nervous system dysfunction in uremia. Kidney Int 20 246 253 Google Scholar Izzo, Zl, Izzo, Ms, Sterns, Rh, Freeman, Rb 1982 Sympathetic nervous system-hyperactivity in maintenance hemodialysis patients. Trans Am Soc Artif Organs 28 604 606 Google Scholar Katholi, Re, Whitlow Pl Hageman, Gr, Woods, T 1984 Intrarenal adenosine produces hypertension by activating the sympathetic nervous system via the renal nerves. J Hypertension 2 349 359 Google Scholar Converce, Rl, Jacobsen, Tn, Toto, Rd, et al. 1992 Sympathetic overactivity in patients with chronic renal failure. N Engl J Med 327 1912 1918 Google Scholar Campese, Vm, Kogosov, E, Koss, M 1995 Renal afferent denervation prevents the progression of renal disease ablation model of chronic renal failure in the rat. Am J Kidney Dis 26 861 865 Google Scholar Herzog, Ca, Ma, Jz, Collins, Aj 1998 Poor long-term surival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med 339 799 805 CrossRef PubMed Google Scholar Cambese, Vm 2000 Neurogenic factors and hypertension in renal disease. Kidney Int 57 S-2 S-6 Google Scholar Rump, Lc, Amann, K, Orth, S, Ritz, E 2000 Sympathetic overactivity in renal disease: a window to understand progression and cardiovascular complications of uremia? Nephrol Dial Transplant 15 1735 1738 Google Scholar Ibrahim, Hn, Rosenberg, Me, Greene, El, et al. 1997 Aldosterone is a major factor in the progression of renal disease. Kidney Int 52 S-115 S-l19 Google Scholar Klahr, S, Morrissey, Jj 2000 The role of vasoactive compounds, growth factors and citokines in the progression of renal disease. Kidney Int 57 S-7 S-14 Google Scholar Fogo, A. 2000 Glomerular hypertension, abnormal glomerular growth, and progression of renal diseases Kidney Int 57 S-15 S-21 Google Scholar D’Amico, G 1999 Tubulointerstitium as predictor of progression of glomerular disease. Nephron 83 289 295 CrossRef PubMed Google Scholar Ter Wee, Pm, Donker, Ajm 1992 Clinical strategies for arresting progression of renal disease Kidney Int 42 S-114 S-120 Google Scholar Tarif, N, Bakris, Gl 1997 Preservation of renal function: the spectrum of effects by calcium-channel blockers. Nephrol Dial Transplant 12 2244 2250 Google Scholar Romero, F, Rodriguez-Iturbe, B, Parra, G, et al. 1999 Mycophenolate mofetil prevents the progressive renal failure induced by 5/6 renal ablation in rats. Kidney Int 55 945 955 Google Scholar Barsotti, G, Cupisti, A, Gervasi, Gb, et al. 1999 Effects floral administration of heparan sulfate in the rat remmant kidney model. Nephron 81 310 318 Google Scholar Miller, Sb, Martin, Dr, Kissane, J, Hammrman, Mr. 1994 Hepatocyte growth factor accelerate recovery from acute ischemic renal injury in rat. Am J Physiol 35 F 129 F 134 Google Scholar Liu, Y, Tolber, Em, Lin, L, et al. 1999 Up-regulation of hepatocyte growth factor receptor: amplication and targeting mecanisms for hepatocyte growth factor action in acute renal failure. Kidney Int 55 442 453 Google Scholar Liu, Y, Rajur, K, Tolber, E, Drorkin, Ld 2000 Endogenous hepatocyte growth factor ameliorates chronic renal injury by activating matrix degradation pathways. Kidney Int 58 2028 2043 Google Scholar Matsumoto, K, Nakamura, T 2001 Hepatocyte growth factor: renotropic role and potential therapeutics for renal diseases. Kidney Iit 59 2023 2038 Google Scholar Breeders, N, Knoop, C, Antoine, M, et al. 2000 Fibrate-induced increase in blood urea and creatinine: is gemfibrozil the only inncuous agent? Nephrol Dial Transplant 15 1993 1999 Google Scholar Chapman, Ab, Gabow, Pa, Schrier, Pm 1991 Reversible renal failure associated with angiotensine-converting-enzyme inhibitors in polycystic kidney disease Ann Int Med 115 769 773 Google Scholar Devoy, Ma, Tomson, Cr, Edmunds, Me, et al. 1992 Deterioration in renal function associated with angiotensive converting enzyme inhibitor therapy is not always reversible. J Intern Med 232 493 498 Google Scholar Akone, D, Cante, D, Cillo, F, et al. 1996 Blood pressure and progression of failure in the elderly. Kidney Lit 49 S75 S77 Google Scholar Essen, Gg, Rensma, P1, De Zeeuw, D, et al. 1996 Association between angiotensine-converting-enzyme gene polymorphism and failure of renoprotective therapy. Lancet 347 94 95 Google Scholar Tanner, Ga 1998 Potassium citrate/citric acid intake improves renal function in rats with polycystic kidney disease. J Am Soc Nephrol 9 1242 1248 Google Scholar Tanner, Ga, Tanner, Ja 2000 Citrate therapy for polycystic kidney disease in rats. Kidney Int 58 1859 1869 Google Scholar Katholi, Re, Winternitz, Sr, Oraril, S 1982 Decrease in peripheral sympathetic nervous system activity following renal denervation or unclipping in the one-kidney one-clip Goldblatt hypertensive rat. J Clin Invest 69 55 62 Google Scholar Fellstrom, B, Backman, U, Larsson, E, Zezina, L 1993 Immunologic and nonimmunologic factors of chronic rejection. Transplant Proc 31 1304 1305 Google Scholar Remuzzi, G, Ruggenenti, B, Benigni, A 1997 Understanding the nature of renal disease progression. Kidney Int 51 2 15 PubMed Google Scholar Remuzzi, G, Perico, N 1998 Protecting single-kidney allografts from long-term functional Deterioration. J Am Soc Nephrol 9 1321 1332 Google Scholar Ponticelli, C 2000 Progression of renal damage in chronic rejection Kidney Int 57 S-62 S-70 Google Scholar Ritz, E, Schomic, M, Wagner, J 2000 ounteracting progression of renal disease: A look into the future C. Kidney Int 57 S-71 S-76 Google Scholar Ojo, Ad, Hanson, Ja, Wolfe, Ra, et al. 2000 Long-term survival in renal transplant recipients with graft function. Kidney Int 57 307 313 Google Scholar Solez K And 27 Other Investigators 1993 International standardization of criteria for the histologic diagnosis of renal allograft rejection. The Banff workin classification of kidney transplant pathology. Kidney Int 44 411 422 Google Scholar Wright, Jr, Duggal, Ad, Thomas, R, et al. 2001 Clinicopathological correlation in biopsy-proven atherosclerotic nephropathy: implications for renal functional outcome in atherosclerotic removascular disease. Nephrol Dial Transphant 16 765 770 Google Scholar Laidlaw, Sa, Kopple, Jd 1987 Newer concepts of the indispensable amino acids. Am J Clin Nutr 46 593 605 Google Scholar Yatzidis, H, Dombros, Nv, Digenis, Ge 1996 On the usefulness of glycylglycine in hemodialysis and peritoneal dialysis solutions. ASAIO J 42 984 992 Google Scholar Newberger, A 1981 The metabolism of glycine and serine. Comprehensive Biochem 19(A) 257 303 Google Scholar Jackson, Aa 1991 The glycine story. Eur J Clin Nutr 45 59 65 Google Scholar Pitts, R 1944 The effect of infusing glycine and of varying the dietary protein on renal hemodynamics in dog. Am J Physiol 142 355 365 Google Scholar Doolan, Pd, Harper, Ha, Hutchin, Me, Shreeve, Ww 1955 Renal clearance of eighteen individual amino acids in human subjects. J Clin Invest 34 1247 1255 Google Scholar Doolan, Pd, Harper, Ha, Hutchin, Me, Alpen, El 1956 The renal tubular response to amino acid loading. J Clin Invest 35 888 896 Google Scholar Graham, Lt, Shank, Rp, Werman, R, Aprison, Mh 1967 Distribution of some synaptic transmiter suspects in cat spinal cord. Glutamic acid, aspartic acid, γ-aminobuturic acid, glycine, and glutamine. J Neurochem 14 465 472 Google Scholar Johnson, Jl, Aprison, Mh 1971 The distribution of glutamate and free amino acids in thirteen specific regions of the eat central nervous system. Brain Res 26 141 148 Google Scholar Yatzidis, H 2002 A new, superior, single and stable, amino acid and bicarbonate-based, glucose-free solution for peritoneal dialysis. Dialysis and Transplantation 31 143 150 Google Scholar Bolus, N, Cersomino, E, Chisham, F, Abumrad, Nn 1982 Physiology importance of glutamine. Metabolism. 38(Suppl 1) 1 5 Google Scholar Souba, Ww, Klimberg, U, Plumbey, Da, et al. 1990 The role of glutamine in maintaining a healthy gut and supporting the metabolic response to injury and infection. J Surg Res 98 383 391 Google Scholar Smith, R 1990 Glutamine metabolism and its physiology importance. IPEN 14 405 445 Google Scholar Perriello, G, Jorde, R, Nurjhan, N, et al. 1995 Estimation of the glucose-alanine-lactate-glutamine cycles in post absorptive man: role of skeletal muscle. Am J Physiol 269 E-443 E-450 Google Scholar Stumvoll, M, Perriello, G, Meyer, C, Cerich, J 1999 Role of glutamine in human carbohydrate metabolism in kidney and other tissues. Kidney Int 55 778 792 Google Scholar Nurjhan, N, Bucci, A, Perriello, G, et al. 1995 Clutamine: A major gluconeogenic precursor and vehicle for interorgan carbon transport in man. J Clin Invest 95 272 277 Google Scholar Hankard, Rg, Darmaun, D, Sager, Bk, et al. 1995 Response of glutamine metabolism to exogenous glutamine in human Am J Physiol 269 E663 E670 Google Scholar Varnier, M, Leese, Gp, Thompson, J, Rennie, Mj 1995 Stimulatory effect of glutamine on glycogen accumulation in human skeletal muscle. Am J Physiol 269 E309 E315 Google Scholar Kreider, M, Stumvoll, M, Mever, C, et al. 1997 Steady strate and non steady measurement of plasma glutamine turnover in humans. Am J Physiol 272 E621 E627 Google Scholar Perriello, G, Nurjhan, N, Stumvoll, M, et al. 1997 Regulation of gluconeogenesis by glutamine in normal postabsorptive humans. Am J Physiol 272 E437 E445 Google Scholar Stumvoll, M, Meyer, C, Kreider, M, et al. 1998 Effects of glucagon on renal and hepatic glutamine gluconeogenesis in normal postabsorptive humans. Metabolism 47 1227 1232 Google Scholar Lavoinne, A, Baquet, A, Hue, L 1987 Stimulation of glucogen synthesis and lipogenesis by glutamine in isolated rat hepatocytes. Biochem J 248 429 437 Google Scholar Cercosimo, E, Williams, P, Hoxworth, B, et al. 1989 Glutamine blocks lipolysis and ketogenesis of fasting. Am J physiol 250 E248 E252 Google Scholar Vu, G, Thompson, Jr 1990 The effect of glutamine on protein turnover in chich sceletal muscle in vitro. Biochem J 265 593 598 Google Scholar
Garrison R. Lysine, Tryprophan and other amino acids. Copyright 1982 by Keats. Publishing, hie Printed in United States of America, 27 pine street.
Decker, EA, Ivanov, V, Zhu, BJ, Frei, B 2001 Inhibition of low- density lipoprotein oxidation by carnosine. J Agric Food Chem 49 511 516 Google Scholar Moncada, S, Palmer, RM, Higgs, EA 1991 Nithric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol Rev 43 109 142 PubMed Google Scholar Reyes, AA, Karl, IE, Klahr, S 1994 Role of arginine in health and in renal diseases. Am J Physiol 267 F331 F346 Google Scholar Rossitch, E, Alexander, E, Black, PM, Cooke, JP 1991 L-arginine normalizes endothelium function in cerebral vessels from hypercholesteremic rabbits. J Clin Invest 87 1295 1299 Google Scholar Cooke, JP, Singer, AH, Tsao, PS, et al. 1992 Antitherogentic effects of L-arginine in the hypercolesterolemic rabbit. J Clin Invest 90 1168 1172 PubMed Google Scholar Tsao, PS, McEvoy, LM, Drexler, H, et al. 1994 Enhanced endothelial adhesivess is attenuated by L-arginine. Circulation 89 23176 2182 Google Scholar Boger, RH, Bode-Boger, SM, Mugge, A, et al. 1995 Supplementation of hypercholesterolemic rabbits with L-arginine reduces the vascular release of superoxide anions and restores No production. Atherosclerosis 117 273 284 CrossRef PubMed Google Scholar Drexler, H, Zeiher, AM, Meinzer, K, Just, H 1991 Connection of endothelial dysfaction in coronary microcirculation of hypercholesterolemic patients by L-arginine. Lancet 338 1546 1550 CrossRef PubMed Google Scholar
Boger RH, Bode-Boger SM, Kienke et al. Dietary
L-arginine decrease myointimal cell proliferation and vascular monocyte accumulation in cholesterol -fed rappits. Atherosclerosis 998; 136: 67–77. Bode-Bager, SM, Boger, RH, Kienk, S, et al. 1998 Chronic dietary supplementation with L-arginine inhabits plately aggregation and thromboxane. A synthesis in hypercholesterolemic rabbits in vivo. Cardiovasc Res 17 756 764 Google Scholar Clarkson, P, Adams, MR, Powe, AJ, et al. 1996 Oral L-arginine improves endothelium -dependent dilation in hypercholesterolemic young adult. J Clin Invest 97 1989 1994 PubMed Google Scholar Tome, LA, Yu, L, deCastro, L, et al. 1999 Beneficial and harmful effects of L-arginine on renal ischaemia. Nephrol Dial Transplant 14 1139 1145 Google Scholar Arfeen, S, Goodship, THJ, Kirkwood, A, Ward, MK 1990 The nutritional /metabolic and hormonal effects of 8 weeks of continuous ambulatory peritoneal dialysis with a 1% amino acid solution. Clin Nephrol 33 192 199 Google Scholar Attman, Po, Alaupovic, P, Samuelson, O 1999 Lipoprotein abnormalities as a risk factor for progressive nondiabetic renal disease. Kidney Int 56(Suppl 71) S14 S17 Google Scholar Kerne, Wf 1994 Lipid and the kidney. Kidney Int 46 910 920 Google Scholar Samuelsson, O, Attman, Po, Knight-Gibson, C, et al. 1998 Complex apolipoprotein b-containing lipoprotein particles are associated with a higher rate of progression of human chronic renal insufficiency. J Am Soc Nephrol 9 1482 1488 Google Scholar Friedman, M, Byers, So, Rosenman, Rh 1957 Resolution of aortic atherosclerotic infiltration in the rabbit by phosphatide infusion. Proc Soc Exp Biol Med 95 586 588 Google Scholar Armstrong, Ml, Warner, Ed, Connor, We 1970 Regression of coronary atheromatosis in monkeys. Circ Res 27 59 67 Google Scholar Armstrong, Me, Megan, Mb 1975 Arterial fibrous protein in cynomologous monkeys after atherogenic and regression diets. Circ Res 36 256 261 Google Scholar Malinow, Mr 1983 Experimental models of atherosclerosis regression. Atherosclerosis 48 105 118 Google Scholar Small, D, Bond, M, Waugh, D, et al. 1984 Physicochemical and histological changes in the arterial wall of monhuman primates during progression and regression of atherosclerosis. J Clin Invest 73 1590 1605 Google Scholar Willams, Kj, Werth, Vp, Wolff, Ja 1984 Intravesously administered lecithin liposome: A synthetic antiatherogenic lipid particle. Perspect Biol Med 27 417 431 Google Scholar Radimon, Jj, Badimon, L, Fuster, V 1990 Regression of atherosclerotic lessions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit. J Clin Invest 85 1234 1241 Google Scholar Arnezenious, Ac 1991 Regression of atherosclerosis benefit can be expected from low LDL-C and high HDL-C levels (Editorial). Acta Cardiologica 46 431 438 Google Scholar Defevier, P, Serruys, P, Davies, M, et al. 1991 Quantitative coronary angiography to measure progression and regression of coronary atherosclerosis. Value, limitations and implications for clinicals. Circulation 84 412 423 Google Scholar Oliver, Mf 1992 Clinical perspective of trial of regression of coronary atherosclerosis. Cardiovasc Risk Factors 2 234 238 Google Scholar Davies, Mj, Woolf, N 1993 Atherosclerosis: What is it and why does it occur? Heart J 69(Suppl) S3 S1l Google Scholar Brown, Bg, Zhao, Xo, Sacco, De, Albers, Jj 1993 Lipid lowering and plaque regression: New insights into prevention of plaque disruption and clinical events in coronary disease. Circulation 87 1781 1791 Google Scholar Moncada, S, Martin, Je, Higgs, A 1993 Symposium on regression of atherosclerosis. Europ J Clin Invest 23 385 398 Google Scholar Schell, Wd, Myers, Jn 1997 Regression of atherosclerosis: a review. Prog. Cardiovasc Dis 39 483 496 Google Scholar Fogo, Ab 2001 Progression and potential regression of glomerulosclerosis (Nephrology Forum-Eds: JJ Cohen, JJ Harrington and NE Madias). Kidney Int 59 804 819 Google Scholar Mercer, LP, Dodds, S J, Veber, MD, Dunn, JD 1990 Histidine, histamine, and neuroregulation of food intake: a review and hypothesis. Nutrition 6 273 277 Google Scholar Patterson, Ra, Leake, Ds 1998 Human serum cysteine and histidine inhibit the oxidation of low density lipoprotein less at acidic pH. FEES Lett 434 317 321 Google Scholar Klebanov, GI, Teselkin, YuO, Balenkova, IV, et al. 1998 Effect of carnosine and its components on free-radical react. Member Cell Biol 12 89 99 Google Scholar Peterson, JW, Boldogh, I, Popov, VL, et al. 1998 Anti-inflammatory and antisecretory potential of histidine in salmonella -challenged mouse small intesting. Lap Investig 78 623 534 Google Scholar Copyright information
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