Skip to main content

Advertisement

SpringerLink
Log in

Low-Protein Diet for Diabetic Nephropathy

  • Microvascular Complications—Nephropathy (B Roshan, Section Editor)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Diabetic nephropathy is the leading cause of progressive kidney disease, leading to end-stage renal disease and renal replacement therapy. Angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers have been considered effective at slowing the progression of kidney function deterioration. However, these drugs cannot sufficiently halt the progression of nephropathy to the extent that is required. A low-protein diet (LPD) is believed to be a nutritional intervention that may slow kidney disease progression. In fact, preclinical animal experiments have demonstrated excellent renoprotective effects of an LPD. However, in human clinical trials, analyses of the effects of protein restriction on diabetic nephropathy have not yet revealed consistently positive outcomes of this nutritional intervention. In this review, we analyze the potential renoprotective effects of an LPD on diabetic nephropathy and summarize the outcomes of clinical trials that have systematically investigated the efficacy of an LPD in diabetic nephropathy. In addition, we discuss some potential approaches associated with nutritional interventions to combat progressive kidney disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Premen AJ. Protein-mediated elevations in renal hemodynamics: existence of a hepato-renal axis? Med Hypotheses. 1986;19:295–309.

    Article  CAS  PubMed  Google Scholar 

  2. Ueda J, Nakanishi H, Miyazaki M, Abe Y. Effects of glucagon on the renal hemodynamics in the dog. Jpn Circ J. 1977;41:991–8.

    Article  CAS  PubMed  Google Scholar 

  3. Fontana L, Weiss EP, Villareal DT, Klein S, Holloszy JO. Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell. 2008;7:681–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Tonshoff B, Kaskel FJ, Moore LC. Effects of insulin-like growth factor I on the renal juxtamedullary microvasculature. Am J Physiol. 1998;274:F120–8.

    CAS  PubMed  Google Scholar 

  5. Tsukahara H, Gordienko DV, Tonshoff B, Gelato MC, Goligorsky MS. Direct demonstration of insulin-like growth factor-I-induced nitric oxide production by endothelial cells. Kidney Int. 1994;45:598–604.

    Article  CAS  PubMed  Google Scholar 

  6. Martinez-Maldonado M, Benabe JE, Wilcox JN, Wang S, Luo C. Renal renin, angiotensinogen, and ANG I-converting-enzyme gene expression: influence of dietary protein. Am J Physiol. 1993;264:F981–8.

    CAS  PubMed  Google Scholar 

  7. Benabe JE, Fernandez-Repollet E, Tapia E, Luo C, Martinez-Maldonado M. Angiotensin II and catecholamines interaction in short-term low protein feeding. Kidney Int. 1993;44:285–93.

    Article  CAS  PubMed  Google Scholar 

  8. Benabe JE, Wang S, Wilcox JN, Martinez-Maldonado M. Modulation of ANG II receptor and its mRNA in normal rat by low-protein feeding. Am J Physiol. 1993;265:F660–9.

    CAS  PubMed  Google Scholar 

  9. Peters H, Border WA, Noble NA. Angiotensin II blockade and low-protein diet produce additive therapeutic effects in experimental glomerulonephritis. Kidney Int. 2000;57:1493–501.

    Article  CAS  PubMed  Google Scholar 

  10. 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 in aging, renal ablation, and intrinsic renal disease. N Engl J Med. 1982;307:652–9.

    Article  CAS  PubMed  Google Scholar 

  11. Gonska T, Hirsch JR, Schlatter E. Amino acid transport in the renal proximal tubule. Amino Acids. 2000;19:395–407.

    Article  CAS  PubMed  Google Scholar 

  12. Sallstrom J, Carlstrom M, Olerud J, Fredholm BB, Kouzmine M, Sandler S, et al. High-protein-induced glomerular hyperfiltration is independent of the tubuloglomerular feedback mechanism and nitric oxide synthases. Am J Physiol Regul Integr Comp Physiol. 2010;299:R1263–8.

    Article  PubMed  Google Scholar 

  13. Mino M, Nakamura J, Nakamuta N, Morioka H, Morikawa Y, Okada T. Effects of low protein intake on the development of the remaining kidney in subtotally nephrectomized immature rats: apoptosis and epidermal growth factor. J Vet Med Sci/ Jpn Soc Vet Sci. 2007;69:247–52.

    Article  CAS  Google Scholar 

  14. Okuda S, Nakamura T, Yamamoto T, Ruoslahti E, Border WA. Dietary protein restriction rapidly reduces transforming growth factor beta 1 expression in experimental glomerulonephritis. Proc Natl Acad Sci U S A. 1991;88:9765–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Fukui M, Nakamura T, Ebihara I, Nagaoka I, Tomino Y, Koide H. Low-protein diet attenuates increased gene expression of platelet-derived growth factor and transforming growth factor-beta in experimental glomerular sclerosis. J Lab Clin Med. 1993;121:224–34.

    CAS  PubMed  Google Scholar 

  16. Nakamura T, Fukui M, Ebihara I, Tomino Y, Koide H. Low protein diet blunts the rise in glomerular gene expression in focal glomerulosclerosis. Kidney Int. 1994;45:1593–605.

    Article  CAS  PubMed  Google Scholar 

  17. Cottini EP, Gallina DL, Dominguez JM. Urea excretion in adult humans with varying degrees of kidney malfunction fed milk, egg or an amino acid mixture: assessment of nitrogen balance. J Nutr. 1973;103:11–9.

    CAS  PubMed  Google Scholar 

  18. Hruska KA, Saab G, Mathew S, Lund R. Renal osteodystrophy, phosphate homeostasis, and vascular calcification. Semin Dial. 2007;20:309–15.

    Article  PubMed  Google Scholar 

  19. Ciavarella A, Di Mizio G, Stefoni S, Borgnino LC, Vannini P. Reduced albuminuria after dietary protein restriction in insulin-dependent diabetic patients with clinical nephropathy. Diabetes Care. 1987;10:407–13.

    Article  CAS  PubMed  Google Scholar 

  20. Walker JD, Bending JJ, Dodds RA, Mattock MB, Murrells TJ, Keen H, et al. Restriction of dietary protein and progression of renal failure in diabetic nephropathy. Lancet. 1989;2:1411–5.

    Article  CAS  PubMed  Google Scholar 

  21. Zeller K, Whittaker E, Sullivan L, Raskin P, Jacobson HR. Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus. N Engl J Med. 1991;324:78–84.

    Article  CAS  PubMed  Google Scholar 

  22. National Kidney F. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update. Am J Kidney Dis Off J Natl Kidney Found. 2012;60:850–86. These guidelines represent the most up-to-date recommendations on the management of diabetes and CKD.

    Article  Google Scholar 

  23. Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med. 1994;330:877–84.

    Article  CAS  PubMed  Google Scholar 

  24. Beck GJ, Berg RL, Coggins CH, Gassman JJ, Hunsicker LG, Schluchter MD, et al. Design and statistical issues of the Modification of Diet in Renal Disease Trial. The Modification of Diet in Renal Disease Study Group. Control Clin Trials. 1991;12:566–86.

    Article  CAS  PubMed  Google Scholar 

  25. Levey AS, Greene T, Sarnak MJ, Wang X, Beck GJ, Kusek JW, et al. Effect of dietary protein restriction on the progression of kidney disease: long-term follow-up of the Modification of Diet in Renal Disease (MDRD) Study. Am J Kidney Dis Off J Natl Kidney Found. 2006;48:879–88.

    Article  CAS  Google Scholar 

  26. Locatelli F, Alberti D, Graziani G, Buccianti G, Redaelli B, Giangrande A. Prospective, randomised, multicentre trial of effect of protein restriction on progression of chronic renal insufficiency. Northern Italian Cooperative Study Group. Lancet. 1991;337:1299–304.

    Article  CAS  PubMed  Google Scholar 

  27. Pijls LT, de Vries H, Donker AJ, van Eijk JT. The effect of protein restriction on albuminuria in patients with type 2 diabetes mellitus: a randomized trial. Nephrol Dial Transplant Off Publ Eur Dial Transp Assoc Eur Renal Assoc. 1999;14:1445–53.

    CAS  Google Scholar 

  28. Meloni C, Morosetti M, Suraci C, Pennafina MG, Tozzo C, Taccone-Gallucci M, et al. Severe dietary protein restriction in overt diabetic nephropathy: benefits or risks? J Renal Nutr Off J Coun Renal Nutr Natl Kidney Found. 2002;12:96–101.

    Article  Google Scholar 

  29. Raal FJ, Kalk WJ, Lawson M, Esser JD, Buys R, Fourie L, et al. Effect of moderate dietary protein restriction on the progression of overt diabetic nephropathy: a 6-mo prospective study. Am J Clin Nutr. 1994;60:579–85.

    CAS  PubMed  Google Scholar 

  30. Dullaart RP, Beusekamp BJ, Meijer S, van Doormaal JJ, Sluiter WJ. Long-term effects of protein-restricted diet on albuminuria and renal function in IDDM patients without clinical nephropathy and hypertension. Diabetes Care. 1993;16:483–92.

    Article  CAS  PubMed  Google Scholar 

  31. Dussol B, Iovanna C, Raccah D, Darmon P, Morange S, Vague P, et al. A randomized trial of low-protein diet in type 1 and in type 2 diabetes mellitus patients with incipient and overt nephropathy. J Renal Nutr Off J Coun Renal Nutr Natl Kidney Found. 2005;15:398–406.

    Article  Google Scholar 

  32. Hansen HP, Tauber-Lassen E, Jensen BR, Parving HH. Effect of dietary protein restriction on prognosis in patients with diabetic nephropathy. Kidney Int. 2002;62:220–8.

    Article  PubMed  Google Scholar 

  33. Meloni C, Tatangelo P, Cipriani S, Rossi V, Suraci C, Tozzo C, et al. Adequate protein dietary restriction in diabetic and nondiabetic patients with chronic renal failure. J Renal Nutr Off J Coun Renal Nutr Natl Kidney Found. 2004;14:208–13.

    Article  Google Scholar 

  34. Pijls LT, de Vries H, van Eijk JT, Donker AJ. Protein restriction, glomerular filtration rate and albuminuria in patients with type 2 diabetes mellitus: a randomized trial. Eur J Clin Nutr. 2002;56:1200–7.

    Article  CAS  PubMed  Google Scholar 

  35. Gross JL, Zelmanovitz T, Moulin CC, De Mello V, Perassolo M, Leitao C, et al. Effect of a chicken-based diet on renal function and lipid profile in patients with type 2 diabetes: a randomized crossover trial. Diabetes Care. 2002;25:645–51.

    Article  PubMed  Google Scholar 

  36. Kasiske BL, Lakatua JD, Ma JZ, Louis TA. A meta-analysis of the effects of dietary protein restriction on the rate of decline in renal function. Am J Kidney Dis Off J Natl Kidney Found. 1998;31:954–61.

    Article  CAS  Google Scholar 

  37. Pedrini MT, Levey AS, Lau J, Chalmers TC, Wang PH. The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: a meta-analysis. Ann Intern Med. 1996;124:627–32.

    Article  CAS  PubMed  Google Scholar 

  38. Nezu U, Kamiyama H, Kondo Y, Sakuma M, Morimoto T and Ueda S. Effect of low-protein diet on kidney function in diabetic nephropathy: meta-analysis of randomised controlled trials. 2013. BMJ Open 3:e002934. doi:10.1136/bmjopen-2013-002934. This meta-analysis found that an LPD significantly improved kidney function in patients with DN.

  39. Dunkler D, Dehghan M, Teo KK, Heinze G, Gao P, Kohl M, et al. Diet and kidney disease in high-risk individuals with type 2 diabetes mellitus. JAMA Intern Med. 2013;173:1682–92. This large-scale observational study trial found that an LPD increased the incidence or progression of CKD among individuals with type 2 diabetes.

    CAS  PubMed  Google Scholar 

  40. Robertson L, Waugh N, and Robertson A . Protein restriction for diabetic renal disease. 2007 Cochrane Database Syst Rev. CD002181.

  41. Pan Y, Guo LL, Jin HM. Low-protein diet for diabetic nephropathy: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2008;88:660–6.

    CAS  PubMed  Google Scholar 

  42. National Kidney F. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis Off J Natl Kidney Found. 2002;39:S1–266.

    Google Scholar 

  43. The National Collaborating Centre for Chronic Conditions (UK). In Chronic Kidney Disease: National Clinical Guideline for Early Identification and Management in Adults in Primary and Secondary Care, London; 2008.

  44. Andrassy KM. Comments on ‘KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease’. Kidney Int. 2013;84:622–3.

    Article  CAS  PubMed  Google Scholar 

  45. Levey AS, de Jong PE, Coresh J, El Nahas M, Astor BC, Matsushita K, et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int. 2011;80:17–28.

    Article  PubMed  Google Scholar 

  46. Arimura E, Horiuchi M, Kawaguchi H, Miyoshi N, Aoyama K, Takeuchi T. Low-protein diet improves blood and urinary glucose levels and renal manifestations of diabetes in C57BLKS-db/db mice. Eur J Nutr. 2013;52:813–24.

    Article  CAS  PubMed  Google Scholar 

  47. Walser M, Hill S, Tomalis EA. Treatment of nephrotic adults with a supplemented, very low-protein diet. Am J Kidney Dis Off J Natl Kidney Found. 1996;28:354–64.

    Article  CAS  Google Scholar 

  48. Wang X, Hu Z, Hu J, Du J, Mitch WE. Insulin resistance accelerates muscle protein degradation: activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling. Endocrinology. 2006;147:4160–8.

    Article  CAS  PubMed  Google Scholar 

  49. Merforth S, Osmers A, Dahlmann B. Alterations of proteasome activities in skeletal muscle tissue of diabetic rats. Mol Biol Rep. 1999;26:83–7.

    Article  CAS  PubMed  Google Scholar 

  50. Gougeon R, Pencharz PB, Sigal RJ. Effect of glycemic control on the kinetics of whole-body protein metabolism in obese subjects with non-insulin-dependent diabetes mellitus during iso- and hypoenergetic feeding. Am J Clin Nutr. 1997;65:861–70.

    CAS  PubMed  Google Scholar 

  51. Gougeon R, Styhler K, Morais JA, Jones PJ, Marliss EB. Effects of oral hypoglycemic agents and diet on protein metabolism in type 2 diabetes. Diabetes Care. 2000;23:1–8.

    Article  CAS  PubMed  Google Scholar 

  52. Mitch WE. Metabolic acidosis stimulates protein metabolism in uremia. Miner Electrolyte Metab. 1996;22:62–5.

    CAS  PubMed  Google Scholar 

  53. Kopple JD, Kalantar-Zadeh K, Mehrotra R. Risks of chronic metabolic acidosis in patients with chronic kidney disease. Kidney Int Supp. 2005;S21–27.

  54. Mitch WE. Metabolic and clinical consequences of metabolic acidosis. J Nephrol. 2006;19 Suppl 9:S70–5.

    CAS  PubMed  Google Scholar 

  55. Kopple JD, Mehrotra R, Suppasyndh O, Kalantar-Zadeh K. Observations with regard to the National Kidney Foundation K/DOQI clinical practice guidelines concerning serum transthyretin in chronic renal failure. Clin Chem Lab Med CCLM / FESCC. 2002;40:1308–12.

    CAS  Google Scholar 

  56. Blumenkrantz MJ, Kopple JD, Gutman RA, Chan YK, Barbour GL, Roberts C, et al. Methods for assessing nutritional status of patients with renal failure. Am J Clin Nutr. 1980;33:1567–85.

    CAS  PubMed  Google Scholar 

  57. Koya D, Haneda M, Inomata S, Suzuki Y, Suzuki D, Makino H, et al. Long-term effect of modification of dietary protein intake on the progression of diabetic nephropathy: a randomised controlled trial. Diabetologia. 2009;52:2037–45.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Maroni BJ, Steinman TI, Mitch WE. A method for estimating nitrogen intake of patients with chronic renal failure. Kidney Int. 1985;27:58–65.

    Article  CAS  PubMed  Google Scholar 

  59. Borah MF, Schoenfeld PY, Gotch FA, Sargent JA, Wolfsen M, Humphreys MH. Nitrogen balance during intermittent dialysis therapy of uremia. Kidney Int. 1978;14:491–500.

    Article  CAS  PubMed  Google Scholar 

  60. Gannon MC, Nuttall FQ, Westphal SA, Fang S, Ercan-Fang N. Acute metabolic response to high-carbohydrate, high-starch meals compared with moderate-carbohydrate, low-starch meals in subjects with type 2 diabetes. Diabetes Care. 1998;21:1619–26.

    Article  CAS  PubMed  Google Scholar 

  61. Solon-Biet SM, McMahon AC, Ballard JWO, Ruohonen K, Wu LE, Cogger VC, et al. The Ratio of Macronutrients, Not Caloric Intake, Dictates Cardiometabolic Health, Aging, and Longevity in Ad Libitum-Fed Mice. Cell Metab. 2014;19:418–30.

    Article  CAS  PubMed  Google Scholar 

  62. Levine ME, Suarez JA, Brandhorst S, Balasubramanian P, Cheng C-W, Madia F, et al. Low Protein Intake Is Associated with a Major Reduction in IGF-1, Cancer, and Overall Mortality in the 65 and Younger but Not Older Population. Cell Metab. 2014;19:407–17.

    Article  CAS  PubMed  Google Scholar 

  63. Fontana L, Partridge L, Longo VD. Extending healthy life span–from yeast to humans. Science. 2010;328:321–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124:471–84.

    Article  CAS  PubMed  Google Scholar 

  65. Fingar DC, Blenis J. Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene. 2004;23:3151–71.

    Article  CAS  PubMed  Google Scholar 

  66. Hara K, Yonezawa K, Weng QP, Kozlowski MT, Belham C, Avruch J. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem. 1998;273:14484–94.

    Article  CAS  PubMed  Google Scholar 

  67. Inoki K, Mori H, Wang J, Suzuki T, Hong S, Yoshida S, et al. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J Clin Invest. 2011;121:2181–96.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Yamahara K, Kume S, Koya D, Tanaka Y, Morita Y, Chin-Kanasaki M, et al. Obesity-mediated autophagy insufficiency exacerbates proteinuria-induced tubulointerstitial lesions. J Am Soc Nephrol JASN. 2013;24:1769–81.

    Article  CAS  Google Scholar 

  69. Sakaguchi M, Isono M, Isshiki K, Sugimoto T, Koya D, Kashiwagi A. Inhibition of mTOR signaling with rapamycin attenuates renal hypertrophy in the early diabetic mice. Biochem Biophys Res Commun. 2006;340:296–301.

    Article  CAS  PubMed  Google Scholar 

  70. Ohkawa S, Yanagida M, Uchikawa T, Yoshida T, Ikegaya N, Kumagai H. Attenuation of the activated mammalian target of rapamycin pathway might be associated with renal function reserve by a low-protein diet in the rat remnant kidney model. Nutr Res. 2013;33:761–71. This animal study suggests that the preventive effect of an LPD on the proggression of renal failure is associated with attenuation of the activated mTOR/p70S6k pathway.

    Article  CAS  PubMed  Google Scholar 

  71. Della Torre S, Rando G, Meda C, Stell A, Chambon P, Krust A, et al. Amino acid-dependent activation of liver estrogen receptor alpha integrates metabolic and reproductive functions via IGF-1. Cell Metab. 2011;13:205–14.

    Article  CAS  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Toshiki Otoda, Keizo Kanasaki, and Daisuke Koya declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Department of Diabetology & Endocrinology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, 920-0293, Japan

    Toshiki Otoda, Keizo Kanasaki & Daisuke Koya

Authors
  1. Toshiki Otoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keizo Kanasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daisuke Koya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daisuke Koya.

Additional information

This article is part of the Topical Collection on Microvascular Complications—Nephropathy

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Otoda, T., Kanasaki, K. & Koya, D. Low-Protein Diet for Diabetic Nephropathy. Curr Diab Rep 14, 523 (2014). https://doi.org/10.1007/s11892-014-0523-z

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11892-014-0523-z

Keywords

Search

Navigation