Renal Disease in Obesity, Metabolic Syndrome and Diabesity

  • Esteban Porrini
  • Maruja Navarro-Díaz
  • Rosa Rodríguez-Rodríguez
  • Eduardo Salido


The pandemic of metabolic syndrome (MS), obesity, and type 2 diabetes – diabesity – may portend severe consequences in renal disease. In patients with obesity and particularly in extreme obesity, obesity-related glomerulopathy (ORG) is the classical picture of renal damage. ORG is characterized by glomerulomegaly and a secondary form of focal and segmental glomerulosclerosis. Interestingly, 50% of the cases with ORG also have “diabetoid changes” including mesangial expansion mainly in the absence of overt diabetes. This clearly indicates a common link between obesity and diabetes in the pathogenesis of renal disease. On the other hand, little evidence is available regarding pathogenesis, clinical evolution, and renal histology of renal disease in overweight and MS. In this chapter we will review the available evidence on renal disease in extreme obesity, moderate obesity overweight and MS. Major factors involved in renal disease in diabesity include hemodynamic changes leading to glomerular hyperfiltration, inflammation and lipotoxicity.


Renal disease Obesity Metabolic syndrome Obesity-related glomerulopathy 



E.P. is a researcher of the Program Ramón y Cajal (RYC-2014-16573). We thank the Instituto de Salud Carlos III for the following grants, PI13/00342 and PI16/01814, and REDINREN RD16/0009/0031 and the IMBRAIN project for support (FP7-RE6-POT-2012-CT2012-31637-IMBRAIN). M.N.D is a researcher of the REMAR group (Recerca en Malalties d’Afectació Renal research on kidney diseases) 2017-SGR-301. We thank the Instituto de Salud Carlos III for the REDINREN RD16/0009/0032. The authors also thank the DIABESITY working group of the ERA-EDTA.


  1. 1.
  2. 2. Accessed Jan 2018.
  3. 3.
  4. 4.
    Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal. Joint statement from the American Diabetes Association and the European Association for the Study of diabetes. Diabetologia. 2005;48:1684–99.CrossRefGoogle Scholar
  5. 5.
    Hanson R, Imperatore G, Bennett P, et al. Components of the “metabolic syndrome” and the incidence of type 2 diabetes. Diabetes. 2002;51:3120–7.CrossRefGoogle Scholar
  6. 6.
    Soriguer F, Goday A, Bosch-Comas A, et al. Prevalence of diabetes mellitus and impaired glucose regulation in Spain: the Study. Diabetologia. 2012;55:88–93.CrossRefGoogle Scholar
  7. 7.
    Reaven GM. Role of insulin resistance in human disease. Diabetes. 1988;37:1595–607.CrossRefGoogle Scholar
  8. 8.
    Wilson P, D’Agostino R, Parise H, et al. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation. 2005;112:3066–72.CrossRefGoogle Scholar
  9. 9.
    Moore JB. Non-alcoholic fatty liver disease: the hepatic consequence of obesity and the metabolic syndrome. Proc Nutr Soc. 2010;69:211–20.CrossRefGoogle Scholar
  10. 10.
    Esposito K, Chiodini P, Colao A, et al. Metabolic syndrome and risk of cancer: a systematic review and meta-analysis. Diabetes Care. 2012;35:2402–11.CrossRefGoogle Scholar
  11. 11.
    Thomas G, Sehgal AR, Kashyap SR, et al. Metabolic syndrome and kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2011;6:2364–73.CrossRefGoogle Scholar
  12. 12.
    Weisinger JR, Kempson RL, Eldridge FL, et al. The nephrotic syndrome: a complication of massive obesity. Ann Intern Med. 1974;81:440–7.CrossRefGoogle Scholar
  13. 13.
    Cohen AH. Massive obesity and the kidney. Am J Pathol. 1975;81:117–30.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Kambham N, Markowitz GS, Valeri AM, Lin J, D’Agati VD. Obesity-related glomerulopathy: an emerging epidemic. Kidney Int. 2001;59:1498–509.CrossRefGoogle Scholar
  15. 15.
    Serra A, Romero R, Lopez D, et al. Renal injury in the extremely obese patients with normal renal function. Kidney Int. 2008;73:947–55.CrossRefGoogle Scholar
  16. 16.
    Pinto-Sietsma SJ, Navis G, Janssen WM, PREVEND Study Group, et al. A central body fat distribution is related to renal function impairment, even in lean subjects. Am J Kidney Dis. 2003;41(4):733–41.CrossRefGoogle Scholar
  17. 17.
    D’Agati VD, Chagnac A, de Vries AP, et al. Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis. Nat Rev Nephrol. 2016;12(8):453–71.CrossRefGoogle Scholar
  18. 18.
    Praga M, Hernández E, Morales E, et al. Clinical features and long-term outcome of obesity-associated focal segmental glomerulosclerosis. Nephrol Dial Transplant. 2001;16:1790–8.CrossRefGoogle Scholar
  19. 19.
    De Jong PE, Verhave JC, Pinto-Sietsma SJ, for the PREVEND study group, et al. Obesity and target organ damage: the kidney. Int J Obes. 2002;26:S21–4.CrossRefGoogle Scholar
  20. 20.
    Hsu C, Mc Culloch CE, Iribarren C, et al. Body mass index and risk for end-stage renal disease. Ann Intern Med. 2006;144:21–8.CrossRefGoogle Scholar
  21. 21.
    Navarro-Díaz M, Serra A, Romero R, Bonet J, Bayés B, Homs M, et al. Effect of drastic weight loss after bariatric surgery on renal parameters in extremely obese patients: long-term follow-up. J Am Soc Nephrol. 2006;17(12 suppl 3):S13–7.Google Scholar
  22. 22.
    Luis-Lima S, Porrini E. An overview of errors and flaws of estimated GFR versus true GFR in patients with diabetes mellitus. Nephron. 2017;136:287–91.CrossRefGoogle Scholar
  23. 23.
    Gaspari F, Ruggenenti P, Porrini E, GFR Study Investigators, et al. The GFR and GFR decline cannot be accurately estimated in type 2 diabetics. Kidney Int. 2013;84:164–73.CrossRefGoogle Scholar
  24. 24.
    Delanaye P, Radermecker RP, Rovire M, et al. Indexing glomerular filtration rate for body surface area in obese patients is misleading: concept and example. Nephrol Dial Transplant. 2015;20(10):2024–8.CrossRefGoogle Scholar
  25. 25.
    Chagnac A, Weinstein T, Herman M, Hirsh J, Gafter U, Ori Y. The effects of weight loss on renal function in patients with severe obesity. J Am Soc Nephrol. 2003;14:1480–6.CrossRefGoogle Scholar
  26. 26.
    Bolignano D, Zoccali C. Effects of weight loss on renal function in obese CKD patients: a systematic review. Nephrol Dial Transplant. 2013;28(Suppl 4):iv82–98.CrossRefGoogle Scholar
  27. 27.
    Serra A, Esteve A, Navarro-Díaz M, López D, Bancu I, Romero R. Long-term normal renal function after drastic weight reduction in patients with obesity-related glomerulopathy. Obes Facts. 2015;8:188–99.CrossRefGoogle Scholar
  28. 28.
    Ruggenenti P, Abbate M, Ruggiero B, C.RE.S.O. Study Group, et al. Renal and systemic effects of calorie restriction in patients with type 2 diabetes with abdominal obesity: a randomized controlled trial. Diabetes. 2017;66(1):75–86.CrossRefGoogle Scholar
  29. 29.
    Klag MJ, Whelton PK, Randall BL, et al. Blood pressure and end-stage renal disease in men. N Engl J Med. 1996;334:13–8.CrossRefGoogle Scholar
  30. 30.
    Hsu CY, McCulloch CE, Darbinian J, et al. Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease. Arch Intern Med. 2005;165:923–8.CrossRefGoogle Scholar
  31. 31.
    Stefansson V, Schei J, Solbu MD, et al. Metabolic syndrome but not obesity measures are risk factors for accelerated age-related glomerular filtration rate decline in the general population. Kidney Int. 2018;93(5):1183–90. Epub 2018 Feb 1.CrossRefGoogle Scholar
  32. 32.
    Melsom T, Schei J, Stefansson VT, et al. Prediabetes and risk of glomerular hyperfiltration and albuminuria in the general nondiabetic population: a prospective cohort study. Am J Kidney Dis. 2016;67(6):841–50.CrossRefGoogle Scholar
  33. 33.
    Eriksen BO, Stefansson VTN, Jenssen TG, et al. Elevated blood pressure is not associated with accelerated glomerular filtration rate decline in the general non-diabetic middle-aged population. Kidney Int. 2016;90:404–10.CrossRefGoogle Scholar
  34. 34.
    Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet. 2016;387:435–43.CrossRefGoogle Scholar
  35. 35.
    Kincaid-Smith P. Hypothesis: obesity and the insulin resistance syndrome play a major role in end-stage renal failure attributed to hypertension and labelled ‘hypertensive nephrosclerosis’. J Hypertens. 2004;22(6):1051–5.CrossRefGoogle Scholar
  36. 36.
    Munkhaugen J, Lydersen S, Widerøe TE, Hallan S. Prehypertension, obesity, and risk of kidney disease: 20-year follow-up of the HUNT I study in Norway. Am J Kidney Dis. 2009;54(4):638–46.CrossRefGoogle Scholar
  37. 37.
    Reaven G. All obese individuals are not created equal: insulin resistance is the major determinant of cardiovascular disease in overweight/obese individuals. Diab Vasc Dis Res. 2005;2(3):105–12.CrossRefGoogle Scholar
  38. 38.
    Hashimoto Y, Tanaka M, Okada H, et al. Metabolically healthy obesity and risk of incident CKD. Clin J Am Soc Nephrol. 2015;10(4):578–83.CrossRefGoogle Scholar
  39. 39.
    Kurella M, Lo JC, Chertow GM, et al. Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults. J Am Soc Nephrol. 2005;16:2134–40.CrossRefGoogle Scholar
  40. 40.
    Porrini E, Ruggenenti P, Mogensen CE, et al. ERA-EDTA diabesity working. Non-proteinuric pathways in loss of renal function in patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2015;3(5):382–91.CrossRefGoogle Scholar
  41. 41.
    Retnakaran R, Cull CA, Thorne KI, Adler AI, Holman RR, and the UKPDS Study Group. Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74. Diabetes. 2006;55:1832–9.CrossRefGoogle Scholar
  42. 42.
    Afghahi H, Cederholm J, Eliasson B, et al. Risk factors for the development of albuminuria and renal impairment in type 2 diabetes—the Swedish National Diabetes Register (NDR). Nephrol Dial Transplant. 2011;26:1236–43.CrossRefGoogle Scholar
  43. 43.
    Neugarten J, Acharya A, Silbiger SR. Effect of gender on the progression of nondiabetic renal disease: a meta-analysis. J Am Soc Nephrol. 2000;11:319–29.PubMedGoogle Scholar
  44. 44.
    Regitz-Zagrosek V, Lehmkuhl E, Weickert MO. Gender differences in the metabolic syndrome and their role for cardiovascular disease. Clin Res Cardiol. 2006;95:136–47.CrossRefGoogle Scholar
  45. 45.
    Szalat A, Raz I. Gender-specific care of diabetes mellitus: particular considerations in the management of diabetic women. Diabetes Obes Metab. 2008;10:1135–56.PubMedGoogle Scholar
  46. 46.
    Thorand B, Baumert J, Doring A, and the KORA Group, et al. Sex differences in the relation of body composition to markers of inflammation. Atherosclerosis. 2006;184:216–24.CrossRefGoogle Scholar
  47. 47.
    Thorand B, Baumert J, Kolb H, et al. Sex differences in the prediction of type 2 diabetes by inflammatory markers: results from the MONICA/KORA Augsburg case-cohort study, 1984–2002. Diabetes Care. 2007;30:854–60.CrossRefGoogle Scholar
  48. 48.
    Juutilainen A, Kortelainen S, Lehto S, et al. Gender difference in the impact of type 2 diabetes on coronary heart disease risk. Diabetes Care. 2004;27:2898–904.CrossRefGoogle Scholar
  49. 49.
    Lee C, Joseph L, Colosimo A, Dasgupta K. Mortality in diabetes compared with previous cardiovascular disease: a gender-specific meta-analysis. Diabetes Metab. 2012;38:420–7.CrossRefGoogle Scholar
  50. 50.
    Samuel T, Hoy WE, Douglas-Denton R, et al. Applicability of the glomerular size distribution coefficient in assessing human glomerular volume: the Weibel and Gomez method revisited. J Anat. 2007;210(5):578–82.CrossRefGoogle Scholar
  51. 51.
    Tsuboi N, Utsunomiya Y, Kanzaki G, et al. Low glomerular density with glomerulomegaly in obesity-related glomerulopathy. Clin J Am Soc Nephrol. 2012;7(5):735–41.CrossRefGoogle Scholar
  52. 52.
    Hughson M, Farris AB 3rd, Douglas-Denton R, et al. Glomerular number and size in autopsy kidneys: the relationship to birth weight. Kidney Int. 2003;63(6):2113–22.CrossRefGoogle Scholar
  53. 53.
    Chagnac A, Weinstein T, Korzets A, et al. Glomerular hemodynamics in severe obesity. Am J Physiol Renal Physiol. 2000;278(5):F817–22.CrossRefGoogle Scholar
  54. 54.
    Hostetter TH, Olson JL, Rennke HG, et al. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am J Phys. 1981;241:F85–93.Google Scholar
  55. 55.
    Wahba IM, Mak RH. Obesity and obesity-initiated metabolic syndrome: mechanistic links to chronic kidney disease. Clin J Am Soc Nephrol. 2007;2(3):550–62.CrossRefGoogle Scholar
  56. 56.
    Griffin KA, Kramer H, Bidani AK. Adverse renal consequences of obesity. Am J Physiol Renal Physiol. 2008;294(4):F685–96.CrossRefGoogle Scholar
  57. 57.
    Keller G, Zimmer G, Mall G, Ritz E, Amann K. Nephron number in patients with primary hypertension. N Engl J Med. 2003;348(2):101–8.CrossRefGoogle Scholar
  58. 58.
    D’Agati VD, Fogo AB, Bruijn JA, Jennette JC. Pathologic classification of focal segmental glomerulosclerosis: a working proposal. Am J Kidney Dis. 2004;43(2):368–82.CrossRefGoogle Scholar
  59. 59.
    Chen HM, Liu ZH, Zeng CH, et al. Podocyte lesions in patients with obesity-related glomerulopathy. Am J Kidney Dis. 2006;48(5):772–9.CrossRefGoogle Scholar
  60. 60.
    Alexander MP, Patel TV, Farag YM, Florez A, et al. Kidney pathological changes in metabolic syndrome: a cross-sectional study. Am J Kidney Dis. 2009;53:751–9.CrossRefGoogle Scholar
  61. 61.
    Kasiske BL, Crosson JT. Renal disease in patients with massive. Arch Intern Med. 1986;146:1105–9.CrossRefGoogle Scholar
  62. 62.
    Klessens CQ, Woutman TD, Veraar KA, et al. An autopsy study suggests that diabetic nephropathy is underdiagnosed. Kidney Int. 2016;90(1):149–56.CrossRefGoogle Scholar
  63. 63.
    Wolf G. After all those fat years: renal consequences of obesity. Nephrol Dial Transplant. 2003;18:2471–4.CrossRefGoogle Scholar
  64. 64.
    Tobar A, Ori Y, Benchetrit S, Milo G, Herman-Edelstein M, Zingerman B, et al. Proximal tubular hypertrophy and enlarged glomerular and proximal tubular urinary space in obese subjects with proteinuria. PlosOne. 2013;8(9):e75547.CrossRefGoogle Scholar
  65. 65.
    Henegar JR, Bigler SA, Henegar LK, et al. Functional and structural changes in the kidney in the early stages of obesity. J Am Soc Neprhol. 2001;12:1211–7.Google Scholar
  66. 66.
    Vallon V, Thomson SC. Renal function in diabetic disease models: the tubular system in the pathophysiology of the diabetic kidney. Annu Rev Physiol. 2012;74:351–75.CrossRefGoogle Scholar
  67. 67.
    Thomson SC, Vallon V, Blantz RC. Kidney function in early diabetes: the tubular hypothesis of glomerular filtration. Am J Physiol Renal Physiol. 2004;286:F8–F15.CrossRefGoogle Scholar
  68. 68.
    Guerre-Millo M. Adipose tissue and adipokines: for better or worse. Diabetes Metab. 2004;30:13–9.CrossRefGoogle Scholar
  69. 69.
    De Vries APJ, Ruggenenti P, Ruan XZ, ERA-EDTA Working Group Diabesity, et al. Fatty kidney: emerging role of ectopic lipid in obesity-related renal disease. Lancet Diabetes Endocrinol. 2014;2:417–26.CrossRefGoogle Scholar
  70. 70.
    Hutley L, Prins JB. Fat as an endocrine organ: relationship to the metabolic syndrome. Am J Med Sci. 2005;330(6):280–9.CrossRefGoogle Scholar
  71. 71.
    Fontana L, Eagon JC, Trujillo ME, Scherer PE, Klein S. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes. 2007;56:1010–3.CrossRefGoogle Scholar
  72. 72.
    El-Atat FA, Stas SN, McFarlane SI, Sowers JR. The relationship between hyperinsulinemia, hypertension and progressive renal disease. J Am Soc Nephrol. 2004;15(11):2816–27.CrossRefGoogle Scholar
  73. 73.
    Sharma K, Considine RV. The Ob protein (leptin) and the kidney. Kidney Int. 1998;53:1483–7.CrossRefGoogle Scholar
  74. 74.
    Wolf G, Hamann A, Han DC, et al. Leptin stimulates proliferation and TFG-β expression in renal glomerular endothelial cells: potential role in glomerulosclerosis. Kidney Int. 1999;56:860–72.CrossRefGoogle Scholar
  75. 75.
    Ix JH, Sharma K. Mechanisms linking obesity, chronic kidney disease and fatty liver disease: the roles of fetuin-A, adiponectin, and AMPK. J Am Soc Nephrol. 2010;21:406–12.CrossRefGoogle Scholar
  76. 76.
    Sharma K, Ramachandrarao S, Qiu G, et al. Adiponectin regulates albuminuria and podocyte function in mice. J Clin Invest. 2008;118(5):1645–56.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Nagase M, Fujita T. Aldosterone and glomerular podocyte injury. Clin Exp Nephrol. 2008;12(4):233–42.CrossRefGoogle Scholar
  78. 78.
    Galli G, Pinchera A, Piaggi P, et al. Serum insulin-like growth-factor -1 concentrations are reduced in severely obese women and rise after weight loss induced by laparoscopic adjustable gastric banding. Obes Surg. 2012;22:1276–80.CrossRefGoogle Scholar
  79. 79.
    Wu Y, Liu Z, Xiang Z, et al. Obesity-related glomerulopathy: insights from gene expression profiles of glomeruli derived from renal biopsy samples. Endocrinology. 2006;147:44–50.CrossRefGoogle Scholar
  80. 80.
    Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006;444:881–7.CrossRefGoogle Scholar
  81. 81.
    Benedict M, Zhang X. Non-alcoholic fatty liver disease: an expanded review. World J Hepatol. 2017;9(16):715–32.CrossRefGoogle Scholar
  82. 82.
    Ruan XZ, Varghese Z, Moorhead JF. An update on the lipid nephrotoxicity hypothesis. Nat Rev Nephrol. 2009;5:713–21.CrossRefGoogle Scholar
  83. 83.
    Berfield AK, Andress DL, Abrass CK. IGF-1-induced lipid accumulation impairs mesangial cell migration and contractile function. Kidney Int. 2002;62:1229–37.CrossRefGoogle Scholar
  84. 84.
    Ruan XZ, Varghese Z, Powis SH, Moorhead JF. Dysregulation of LDL receptor under the influence of inflammatory cytokines: a new pathway for foam cell formation. Kidney Int. 2001;60:1716–25.CrossRefGoogle Scholar
  85. 85.
    Godel M, Hartleben B, Herbach N, et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest. 2011;121:2197–209.CrossRefGoogle Scholar
  86. 86.
    Inoki K, Mori H, Wang J, 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.CrossRefGoogle Scholar
  87. 87.
    Welsh GI, Hale LJ, Eremina V, et al. Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metab. 2010;12:329–40.CrossRefGoogle Scholar
  88. 88.
    Lennon R, Pons D, Sabin MA, et al. Saturated fatty acids induce insulin resistance in human podocytes: implications for diabetic nephropathy. Nephrol Dial Transplant. 2009;24:3288–96.CrossRefGoogle Scholar
  89. 89.
    Nieth H, Schollmeyer P. Substrate-utilization of the human kidney. Nature. 1966;209:1244–5.CrossRefGoogle Scholar
  90. 90.
    Wirthensohn G, Guder W. Renal lipid metabolism. Miner Electrolyte Metab. 1983;9:203–11.PubMedGoogle Scholar
  91. 91.
    Thomas ME, Harris KPG, Walls J, et al. Fatty acids exacerbate tubulointerstitial injury in protein-overload proteinuria. Am J Physiol Renal Physiol. 2002;283:F640–7.CrossRefGoogle Scholar
  92. 92.
    Bobulescu I, Lotan Y, Zhan J, et al. Triglycerides in the human kidney cortex: relationship with body size. PLoS One. 2014;9(8):e101285.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  • Esteban Porrini
    • 1
  • Maruja Navarro-Díaz
    • 2
    • 3
    • 4
  • Rosa Rodríguez-Rodríguez
    • 5
  • Eduardo Salido
    • 1
    • 5
  1. 1.University of La Laguna, ITB (Instituto de Tecnología Biomédicas), Hospital Universitario de Canarias, Nephrology UnitTenerifeSpain
  2. 2.Nephrology DepartmentGermans Trias i Pujol University HospitalBadalonaSpain
  3. 3.REMAR Group, Health Science Research Institute Germans Trias i Pujol, Can Ruti CampusBadalonaSpain
  4. 4.Autonomous University of BarcelonaBellaterraSpain
  5. 5.University of La Laguna, Pathology DepartmentHospital Universitario de CanariasTenerifeSpain

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