Journal of Renal Nutrition
Volume 11, Issue 4 , Pages 183-193, October 2001

Protective effects of dietary phytoestrogens in chronic renal disease☆☆

Assistant Professor of Medicine, Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University Medical Center, Washington, DC

Article Outline

Abstract 

Phytoestrogens are naturally occuring plant compounds that are present primarily in soybeans as isoflavones and in flaxseed as lignans. Because of their structural similarity to endogenous estrogens, phytoestrogens bind to both estrogen receptors (ER)-α and β (but more strongly to ER-β) and exert estrogen-like effects. There is increasing evidence that dietary phytoestrogens have a beneficial role in chronic renal disease. Nutritional intervention studies have shown that consumption of soy-based protein and flaxseed reduces proteinuria and attenuates renal functional or structural damage in animals and humans with various forms of chronic renal disease. It is not clear which component(s) of the soybean or flaxseed is (are) responsible for the protective effects observed in experimental animals and in limited studies in humans. Vegetable protein has been shown to have a beneficial effect on renal disease in animals and humans. Thus, the role of soy and flaxseed cannot be ruled out. Isoflavones and lignans are readily absorbed from the gut and converted to active metabolites, which may be partly responsible for the beneficial renal effects of soy protein and flaxseed. In addition, an interaction between type of protein and phytoestrogens is also possible. The biological actions of isoflavones and lignans have been well defined in different cell types in vitro and also in vivo, but how these compounds might reduce renal injury remains to be elucidated. Possible mechanisms include inhibition of cell growth and proliferation via ER-mediated mechanisms or non–ER-mediated pathways through inhibition of tyrosine protein kinases, modulation of growth factors involved in extracellular matrix synthesis and fibrogenesis, inhibition of cytokine-induced activation of transcription factors, inhibition of angiogenesis, antioxidative action, suppression of platelet activating factor and platelet aggregation, and immunomodulatory activity. To date, clinical trials in humans are few, of relatively short duration, and involve a small number of patients. Prospective randomized trials are needed to evaluate the long-term safety and effectiveness of dietary phytoestrogens on renal disease progression in patients with chronic renal failure. © 2001 by the National Kidney Foundation, Inc.

No full text is available. To read the body of this article, please view the PDF online.

 

Back to Article Outline

References 

  1. Giovanetti S, Maggiore Q. A low nitrogen diet with protein of high biological value for severe chronic uremia. Lancet. 1964;1:1000–1003
  2. Berlyne GM, Shaw AB, Nilwarangkur S. Dietary treatment of chronic renal failure. Experience with a modified Giovanetti diet. Nephron. 1965;2:129–147
  3. Kopple JD, Coburn JW. Metabolic studies of low protein diets in uremia. I. Nitrogen and potassium. Medicine. 1973;52:583–595
  4. Barsotti G. Effects of dietary therapy on urmeic symptoms and complications. In:  Giovannetti S editors. Nutritional Therapy of Chronic Renal Failure. Boston, MA: Kluwer Academic; 1989;p. 235–240
  5. Mitch WE, Walser M. Nutritional therapy of the uremic patient. In: ed 5.  Brenner BM editors. The Kidney. Philadelphia, PA: Saunders; 1996;p. 2382–2423
  6. Walser M, Mitch WE, Maroni BJ, et al.  Should protein intake be restricted in pre dialysis patients. Kidney Int. 1999;55:771–779
  7. Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease: The role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis of aging, renal ablation, and intrinsic renal disease. N Engl J Med. 1982;307:652–659
  8. Klahr S, Buerkert J, Purkerson ML. Role of dietary factors in the progression of chronic renal disease. Kidney Int. 1983;24:579–587
  9. Rosman JB, ter Wee PM, Meijer S, et al.  Prospective randomized trial of early dietary protein restriction in chronic renal failure. Lancet. 1984;2:1291–1296
  10. Mitch WE, Walser M, Steinman TL, et al.  The effect of a ketoacid-amino acid supplement to a restricted diet on the progression of chronic renal failure. N Engl J Med. 1984;311:623–629
  11. Ihle BU, Becker GJ, Whitworth JA, et al.  The effect of protein restriction on the progression of renal insufficiency. N Engl J Med. 1989;321:1773–1777
  12. Walker JD, Dodds RA, Murrells TJ, et al.  Restriction of dietary protein and progression of renal failure in diabetic nephropathy. Lancet. 1989;2:1411–1414
  13. Zeller KR. Low protein diets in renal disease. Diabetes Care. 1991;14:856–866
  14. Fouque D, Laville M, Boissel JP, et al.  Controlled low protein diets in chronic renal insufficiency: Meta-analysis. BMJ. 1992;304:216–220
  15. Pedrini MT, Levey AS, Lau J, et al.  The effects of dietary protein restriction on the progression of diabetic and non-diabetic renal disease: A meta-analysis. Ann Intern Med. 1996;124:627–632
  16. Williams AJ, Walls J. Metabolic consequences of differing protein diets in experimental renal disease. Eur J Clin Invest. 1987;17:117–122
  17. Williams AJ, Baker F, Walls J. Effect of varying quantity and quality of dietary protein intake in experimental renal disease in rats. Nephron. 1987;46:83–90
  18. Barsotti G, Navalesi R, Giampietro O, et al.  Effects of a vegetarian, supplemented diet on renal function, proteinuria, and glucose metabolism in patients with “overt” diabetic nephropathy and renal insufficiency. Contrib Nephrol. 1988;65:87–94
  19. Jibani MM, Bloodworth LL, Foden E, et al.  Predominantly vegetarian diet in patients with incipient and early clinical diabetic nephropathy: Effects on albumin excretion rate and nutritional status. Diabet Med. 1991;8:949–953
  20. Wardle EN. Soy protein diet therapy in renal disease. Nephron. 1998;78:328–331
  21. Iwasaki K, Gleiser CA, Masoro EJ, et al.  The influence of dietary protein source on longevity and age-related disease processes of Fischer rats. J Gerontol. 1988;43:B5–B12
  22. Shimokawa I, Higami Y, Hubbard GB, et al.  Diet and the suitability of the male Fischer 343 rat as a model for aging research. J Gerontol. 1993;48:B27–B32
  23. Tomobe K, Philbrick DJ, Ogborn MR, et al.  Effect of dietary soy protein and genistein on disease progression in mice with polycystic kidney disease. Am J Kidney Dis. 1998;31:55–61
  24. Aukema HM, Housini I, Rawling JM. Dietary soy protein effects on inherited polycystic kidney disease are influenced by gender and protein level. J Am Soc Nephrol. 1999;10:300–308
  25. Ogborn MR, Bankovic-Calic N, Shoesmith C, et al.  Soy protein modification of rat polycystic kidney disease. Am J Physiol. 1998;274(3Pt2):F541–F549
  26. Ogborn MR, Nitschmann E, Weiler HA, et al.  Modification of polycystic kidney disease and fatty acid status by soy protein diet. Kidney Int. 2000;57:159–166
  27. D'Amico G, Gentile MG, Manna G, et al.  Effect of vegetarian soy diet on hyperlipidaemia in nephrotic syndrome. Lancet. 1992;339:1131–1134
  28. Gentile MG, Fellin G, Cofano F, et al.  Treatment of proteinuric patients with a vegetarian soy diet and fish oil. Clin Nephrol. 1993;40:315–320
  29. Soroka N, Silverberg DS, Greemland M, et al.  Comparison of a vegetable-based (soya) and an animal-based low-protein diet in predialysis chronic renal failure patients. Nephron. 1998;79:173–180
  30. Anderson JW, Blake JE, Turner J, et al.  Effects of soy protein on renal function and proteinuria in patients with type 2 diabetes. Am J Clin Nutr. 1998;68(Suppl 6):1347S–1353S
  31. Hall AV, Parbtani A, Clark WF, et al.  Abrogation of MRL/lpr lupus nephritis by dietary flaxseed. Am J Kidney Dis. 1993;22:326–332
  32. Theofilopolous AN, Dixon FJ. Murine models of systemic lupus erythematosus. Adv Immunol. 1985;37:269–290
  33. Ingram AJ, Parbtani A, Clark WF, et al.  Effects of flaxseed and flax oil diets in a rat-5/6 renal ablation model. Am J Kidney Dis. 1995;25:320–329
  34. Ogborn MR, Nitschmann E, Weiler H, et al.  Flaxseed ameliorates interstitial nephritis in rat polycystic kidney disease. Kidney Int. 1999;55:417–423
  35. Clark WF, Parbtani A, Huff MW, et al.  Flaxseed: A potential treatment for lupus nephritis. Kidney Int. 1995;48:475–480
  36. Martin PM, Horwitz KB, Ryan DS, et al.  Phytoestrogen interaction with estrogen receptors in human breast cancer cells. Endocrinology. 1978;103:1860–1867
  37. Miksicek RJ. Interaction of naturally occurring non-steroidal estrogens with expressed with recombinant human estrogen receptor. J Steroid Biochem Mol Biol. 1994;49:153–160
  38. Ros Barcelo A. Lignification in plant cell walls. In:  Jeon KW editors. International Review of Cytology. vol 176:San Diego, CA: Academic; 1997;p. 87–132
  39. Axelson M, Sjovall J, Gustafsson B, et al.  Soya—A dietary source of the non-steroidal oestrogen equol in humans and animals. J Endocrinol. 1984;102:49–56
  40. Coward L, Barnes NC, Setchell KDR, et al.  Genistein and daidzein, and their β-glycoside conjugates: Anti-tumor isoflavones in soy bean foods from American and Asian diets. J Agric Food Chem. 1993;41:1961–1967
  41. Wang H-J, Murphy PA. Isoflavone content in commercial soybean foods. J Agric Food Chem. 1994;42:1666–1673
  42. Wang H-J, Murphy PA. Isoflavone composition of American and Japanese soybean in Iowa: Effects of variety, crop year, and location. J Agric Food Chem. 1994;42:1674–1677
  43. Haytowitz DB, Matthews RH. Legumes and Legume Products. In: Washington, DC: United States Department of Agriculture; 1986;p. 1–156
  44. Young VR. Soy protein in relation to human protein and amino acid nutrition. J Am Diet Assoc. 1991;91:828–835
  45. Thompson LU, Robb P, Serraino M, et al.  Mammalian lignan production from various foods. Nutr Cancer. 1991;16:43–52
  46. Thompson LU, Rickard SE, Cheung F, et al.  Variability in anticancer lignan levels in flaxseed. Nutr Cancer. 1997;27:26–30
  47. Mazur W, Fotsis T, Wahala K, et al.  Isotope dilution gas chromatographic-mass spectrometric method for the determination of isoflavonoids, coumestrol, and lignans in food samples. Anal Biochem. 1996;233:169–180
  48. Slavin JL, Jacobs D, Marquart L. Grain processing and nutrition. Crit Rev Food Sci Nutr. 2000;40:309–326
  49. Setchell KDR, Adlercreutz H. Mammalian lignans and phyto-estrogens. Recent studies on their formation, metabolism and biologic role in health and disease. In:  Rowland I editors. Role of the Gut Flora in Toxicity and Cancer. Basel, Switzerland: Karger; 1988;p. 315–345
  50. Borriello SP, Setchel KDR, Axelson M. Production and metabolism of lignans by the human faecal flora. J Appl Bacteriol. 1985;58:37–43
  51. Axelson M, Setchell KDR. The excretion of lignans in rats: evidence for an intestinal bacterial source for this new group of compounds. FEBS Lett. 1981;123:337–342
  52. Rowland IR, Wiseman H, Sanders TA, et al.  Interindividual variation in metabolism of soy isoflavones and lignans: Influence of habitual diet on equol production by the gut microflora. Nutr Cancer. 2000;36:27–32
  53. Morton MS, Wilcox G, Wahlgvist ML, et al.  Determination of lignans and isoflavonoids in human female plasma following dietary supplementation. J Endocrinol. 1994;142:251–259
  54. Adlercreutz H, Fotsis T, Lampe J, et al.  Quantitative determination of lignans and isoflavones in plasma of omnivorous and vegetarian women by isotope-dilution gas chromatography-mass spectrometry. Scand J Clin Lab Invest. 1993;53(suppl 215):5–18
  55. Adlercreutz H, Markkanen H, Watanabe S. Plasma concentrations of phyto-oestrogens in Japanese men. Lancet. 1993;342:1209–1210
  56. Nesbitt PD, Lam Y, Thompson LU. Human metabolism of mammalian lignan precursors in raw and processed flaxseed. Am J Clin Nutr. 1999;69:549–555
  57. Lampe JW, Martini MC, Kurzer MS, et al.  Urinary lignan and isoflavonoid excretion in premenopausal women consuming flaxseed powder. Am J Clin Nutr. 1994;60:122–128
  58. Cunnane SC, Hamadeh MJ, Liede AC, et al.  Nutritional attributes of traditional flaxseed in healthy young adults. Am J Clin Nutr. 1995;61:62–68
  59. Rickard SE, Orcheson LJ, Seidl MM, et al.  Dose-dependent production of mammalian lignans in rats and in vitro from the purified precursor secoisolariciresinol diglycoside in flaxseed. J Nutr. 1996;126:2012–2019
  60. Setchell KDR. Phytoestrogens: The biochemistry, physiology, and implications for human health of soy isoflavones. Am J Clin Nutr. 1998;68:1333S–1348S
  61. Tham DM, Gardner CD, Haskell WL. Potential health benefits of dietary phytoestrogens: A review of the clinical, epidemiological, and mechanistic evidence. J Clin Endocrinol Metab. 1998;83:2223–2235
  62. Markiewicz L, Garey J, Adlercreutz H, et al.  In vitro bioassays of non-steroidal phytoestrogens. J Steroid Biochem Mol Biol. 1993;45:399–405
  63. Kuiper GGJM, Lemmen JG, Carlsson B, et al.  Interaction of estrogenic chemicals and phytoestrogens with estrogen receptorβ. Endocrinology. 1998;139:4252–4263
  64. Taylor AH, Al-Azzawi F. Immunolocalisation of oestrogen receptor beta (ERβ) in human tissues. J Mol Endocrinol. 2000;24:145–155
  65. Hirano T, Fukuoka K, oka K, et al.  Antiproliferative activity of mammalian lignan derivatives against the human breast carcinoma cell line, ZR-75-1. Cancer Invest. 1990;8:595–601
  66. Serraino M, Thompson LU. The effect of flaxseed supplementation on the initiation and promotional stages of mammary tumorigenesis. Nutr Cancer. 1992;17:153–159
  67. Peterson G, Coward L, Barnes S. Isoflavones inhibit the growth of human prostate cancer cells in culture. Proc Am Assoc Cancer Res. 1992;33:57–64
  68. Yanajihara K, Ito A, Toge T, et al.  Antiproliferative effects of isoflavones on human cancer cell lines established from the gastrointestinal tract. Cancer Res. 1993;53:5815–5821
  69. Zava DT, Duwe G. Estrogenic and antiproliferative properties of genistein and other flavonoids in human breast cancer cells in vitro. Nutr Cancer. 1997;27:31–40
  70. Wang TTY, Sathyamoorthy N, Phang JM. Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis. 1996;17:271–275
  71. Fotsis T, Pepper M, Adlercreutz H, et al.  Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc Natl Acad Sci U S A. 1993;90:2690–2694
  72. Akiyama T, Ishida J, Nakagawa S, et al.  Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem. 1987;262:5592–5595
  73. Linassier C, Pierre M, LePecq JB, et al.  Mechanisms of action in NIH-3T3 cells of genistein, an inhibitor of EGF receptor tyrosine kinase activity. Biochem Pharmacol. 1990;39:187–193
  74. Okura A, Arakawa H, Oka H, et al.  Effect of genistein on topoisomerase activity and on the growth of [Val 12] Ha-ras-transformed NIH 3T3 cells. Biochem Biophys Res Commun. 1988;157:183–189
  75. Markovits J, Linassier C, Fosse P, et al.  Inhibitory effects of the tyrosine kinase inhibitor genistein on mammalian DNA topoisomerase II. Cancer Res. 1989;49:5111–5117
  76. Kim H, Peterson TG, Barnes S. Mechanisms of action of the soy isoflavone genistein: Emerging role for its effects via transforming growth factor β signaling pathways. Am J Clin Nutr. 1998;68(suppl):1418S–1425S
  77. Wei HC, Wei LH, Frenkel K, et al.  Inhibition of tumor promoter-induced hydrogen peroxide formation in vitro and in vivo by genistein. Nutr Cancer. 1993;20:1–12
  78. Wei HC, Bowen R, Cai Q, et al.  Antioxidant and antipromotional effects of the soybean isoflavone genistein. Proc Soc Exp Biol Med. 1995;208:124–130
  79. Record IR, Dreosti IE, McInerney JK. The antioxidant activity of genistein in vitro. J Nutr Biochem. 1995;6:481–485
  80. Kitts DD, Yuan YV, Wijewickreme AN, et al.  Antioxidant activity of the flaxseed lignan secoisolariciresinol diglycoside and its mammalian lignan metablites enterodiol and enterolactone. Mol Cell Biochem. 1999;202:91–100
  81. Vedavanam K, Srijayanta S, O'Reilly J, et al.  Antioxidant action and potential antidiabetic properties of an isoflavonoid-containing soyabean phytochemical extract (SPE). Phytother Res. 1999;13:601–608
  82. Nakashima S, Koike T, Nozawa Y. Genistein, a protein tyrosine kinase inhibitor, inhibits thromboxane A2-mediated human platelet responses. Mol Pharmacol. 1991;39:475–480
  83. Asahi M, Yanagi S, Ohta S, et al.  Thombin-induced human platelet aggregation is inhibited by protein tyrosine-kinase inhibitors, ST638 and genistein. FEBS Lett. 1992;309:10–14
  84. Rendu F, Eldor A, Grelac F, et al.  Inhibition of platelet activation by tyrosine kinase inhibitors. Biochem Pharmacol. 1992;44:881–888
  85. McNicol A. The effects of genistein on platelet function are due to thromboxane receptor antagonism rather than inhibition of tyrosine kinase. Prostaglandins Leukot Essent Fatty Acids. 1992;48:379–384
  86. Shen TY, Hussaini IM. Kadsurenone and other related lignans as antagonists of platelet-activating factor receptor. Methods Enzymol. 1990;187:446–454
  87. Krol W, Czuba ZP, Threadgill MD, et al.  Inhibition of nitric oxide (NO) production in murine macrophages by flavones. Biochem Pharmacol. 1995;50:1031–1035
  88. Atluru D, Gudapaty S. Inhibition of bovine mononuclear cell proliferation, interleukin-2 synthesis, protein-tyrosine kinase and leukotiene-B(4) production by a protein-tyrosine kinase inhibitor, genistein. Vet Immunol Immunopathol. 1993;38:113–122
  89. Hirakata M, Kaname S, Chung UG, et al.  Tyrosine kinase dependent expression of TGF-beta induced by stretch in mesangial cells. Kidney Int. 1997;51:1028–1036
  90. Kato H, Osajima A, Uezono Y, et al.  Involvement of PDGF in pressure-induced mesangial cell proliferation through PKC and tyrosine kinase pathways. Am J Physiol. 1999;277(1Pt2):F105–F112
  91. Ha H, Roh DD, Kirschenbaum MA, et al.  Atherogenic lipoproteins enhance mesangial cell expression of platelet-derived growth factor: role of protein tyrosine kinase and cyclic AMP-dependent protein kinase. J Lab Clin Med. 1998;131:456–465
  92. Yokoo T, Kitamura M. Dual regulation of IL-1β-mediated matrix metalloproteinase-9 expression in mesangial cells by NF-kB and AP-1. Am J Physiol. 1996;270(1 Pt 2):F123–F130
  93. Coyne DW, Morrison AR. Effect of tyrosine kinase inhibitor, genistein, on interleukin-1 stimulated PGE2 production in mesangial cells. Biochem Biophys Res Commun. 1990;73:718–724

 †Research Chemist, Phytonutrients Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, MD.

☆☆ ‡Professor of Medicine, Division of Renal Diseases and Hypertension, George Washington University Medical Center, Washington, DC.

 Address reprint requests to Manuel T. Velasquez, MD, Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University Medical Center, 2150 Pennsylvania Avenue, NW, Washington, DC 20037.

PII: S1051-2276(01)70036-2

doi:10.1016/S1051-2276(01)70036-2

Journal of Renal Nutrition
Volume 11, Issue 4 , Pages 183-193, October 2001