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Obesity-related glomerulopathy: pathogenesis, pathologic, clinical characteristics and treatment

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Abstract

In light of the rapid increase in the number of obesity incidences worldwide, obesity has become an independent risk factor for chronic kidney disease. Obesity-related glomerulopathy (ORG) is characterized by glomerulomegaly in the presence or absence of focal and segmental glomerulosclerosis lesions. IgM and complement 3 (C3) nonspecifically deposit in lesions without immune-complex-type deposits during ORG immunofluorescence. ORG-associated glomerulomegaly and focal and segmental glomerulosclerosis can superimpose on other renal pathologies. The mechanisms under ORG are complex, especially hemodynamic changes, inflammation, oxidative stress, apoptosis, and reduced functioning nephrons. These mechanisms synergize with obesity to induce end-stage renal disease. A slow increase of subnephrotic proteinuria ( < 3.5 g/d) is the most common clinical manifestation of ORG. Several treatment methods for ORG have been developed. Of these methods, renin–angiotensin–aldosterone system blockade and weight loss are proven effective. Targeting mitochondria may offer a novel strategy for ORG therapy. Nevertheless, more research is needed to further understand ORG.

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References

  1. Jia W. Obesity in China: its characteristics, diagnostic criteria, and implications. Front Med 2015; 9(2): 129–133

    Article  PubMed  Google Scholar 

  2. Kambham N, Markowitz GS, Valeri AM, Lin J, D’Agati VD. Obesity-related glomerulopathy: an emerging epidemic. Kidney Int 2001; 59(4): 1498–1509

    Article  CAS  PubMed  Google Scholar 

  3. D’Agati VD, Chagnac A, de Vries AP, Levi M, Porrini E, Herman-Edelstein M, Praga M. Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis. Nat Rev Nephrol 2016; 12(8): 453–471

    Article  PubMed  Google Scholar 

  4. D’Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N Engl J Med 2011; 365(25): 2398–2411

    Article  PubMed  Google Scholar 

  5. Serra A, Romero R, Lopez D, Navarro M, Esteve A, Perez N, Alastrue A, Ariza A. Renal injury in the extremely obese patients with normal renal function. Kidney Int 2008; 73(8): 947–955

    Article  CAS  PubMed  Google Scholar 

  6. Hughson MD, Hoy WE, Douglas-Denton RN, Zimanyi MA, Bertram JF. Towards a definition of glomerulomegaly: clinicalpathological and methodological considerations. Nephrol Dial Transplant 2011; 26(7): 2202–2208

    Article  PubMed  Google Scholar 

  7. de Vries AP, Ruggenenti P, Ruan XZ, Praga M, Cruzado JM, Bajema IM, D’Agati VD, Lamb HJ, Pongrac Barlovic D, Hojs R, Abbate M, Rodriquez R, Mogensen CE, Porrini E; ERA-EDTA Working Group Diabesity. Fatty kidney: emerging role of ectopic lipid in obesity-related renal disease. Lancet Diabetes Endocrinol 2014; 2(5): 417–426

    Article  PubMed  Google Scholar 

  8. Praga M, Morales E. The fatty kidney: obesity and renal disease. Nephron 2016 Jul 15. [Epub ahead of print] doi:10.1159/000447674

    Google Scholar 

  9. Chagnac A, Weinstein T, Korzets A, Ramadan E, Hirsch J, Gafter U. Glomerular hemodynamics in severe obesity. Am J Physiol Renal Physiol 2000; 278(5): F817–F822

    Article  CAS  PubMed  Google Scholar 

  10. Fukuda A, Chowdhury MA, Venkatareddy MP, Wang SQ, Nishizono R, Suzuki T, Wickman LT, Wiggins JE, Muchayi T, Fingar D, Shedden KA, Inoki K, Wiggins RC. Growth-dependent podocyte failure causes glomerulosclerosis. J Am Soc Nephrol 2012; 23(8): 1351–1363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Liu Y. New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol 2010; 21(2): 212–222

    Article  CAS  PubMed  Google Scholar 

  12. Matsusaka T, Sandgren E, Shintani A, Kon V, Pastan I, Fogo AB, Ichikawa I. Podocyte injury damages other podocytes. J Am Soc Nephrol 2011; 22(7): 1275–1285

    Article  PubMed  PubMed Central  Google Scholar 

  13. Bobulescu IA, Lotan Y, Zhang J, Rosenthal TR, Rogers JT, Adams-Huet B, Sakhaee K, Moe OW. Triglycerides in the human kidney cortex: relationship with body size. PLoS One 2014; 9(8): e101285. doi: 10.1371/journal.pone.0101285

    Article  PubMed  PubMed Central  Google Scholar 

  14. Stefan N, Artunc F, Heyne N, Machann J, Schleicher ED, Häring HU. Obesity and renal disease: not all fat is created equal and not all obesity is harmful to the kidneys. Nephrol Dial Transplant 2016; 31(5): 726–730

    Article  PubMed  Google Scholar 

  15. Wu Y, Liu Z, **ang Z, Zeng C, Chen Z, Ma X, Li L. Obesity-related glomerulopathy: insights from gene expression profiles of the glomeruli derived from renal biopsy samples. Endocrinology 2006; 147(1): 44–50

    Article  CAS  PubMed  Google Scholar 

  16. Bonnet F, Deprele C, Sassolas A, Moulin P, Alamartine E, Berthezène F, Berthoux F. Excessive body weight as a new independent risk factor for clinical and pathological progression in primary IgA nephritis. Am J Kidney Dis 2001; 37(4): 720–727

    Article  CAS  PubMed  Google Scholar 

  17. D’Agati VD, Markowitz GS. Supersized kidneys: lessons from the preclinical obese kidney. Kidney Int 2008; 73(8): 909–910

    Article  PubMed  Google Scholar 

  18. Felizardo RJ, da Silva MB, Aguiar CF, Câmara NO. Obesity in kidney disease: a heavyweight opponent. World J Nephrol 2014; 3(3): 50–63

    Article  PubMed  PubMed Central  Google Scholar 

  19. Weisinger JR, Kempson RL, Eldridge FL, Swenson RS. The nephrotic syndrome: a complication of massive obesity. Ann Intern Med 1974; 81(4): 440–447

    Article  CAS  PubMed  Google Scholar 

  20. Kriz W, Lemley KV. A potential role for mechanical forces in the detachment of podocytes and the progression of CKD. J Am Soc Nephrol 2015; 26(2): 258–269

    Article  PubMed  Google Scholar 

  21. Wuerzner G, Pruijm M, Maillard M, Bovet P, Renaud C, Burnier M, Bochud M. Marked association between obesity and glomerular hyperfiltration: a cross-sectional study in an African population. Am J Kidney Dis 2010; 56(2): 303–312

    Article  PubMed  Google Scholar 

  22. 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(6): 1480–1486

    Article  PubMed  Google Scholar 

  23. Novikov A, Vallon V. Sodium glucose cotransporter 2 inhibition in the diabetic kidney: an update. Curr Opin Nephrol Hypertens 2016; 25(1): 50–58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373(22): 2117–2128

    Article  CAS  PubMed  Google Scholar 

  25. Zingerman B, Herman-Edelstein M, Erman A, Bar Sheshet Itach S, Ori Y, Rozen-Zvi B, Gafter U, Chagnac A. Effect of acetazolamide on obesity-induced glomerular hyperfiltration: a randomized controlled trial. PLoS One 2015; 10(9): e0137163

    Article  PubMed  PubMed Central  Google Scholar 

  26. Nishiyama A, Abe Y. Molecular mechanisms and therapeutic strategies of chronic renal injury: renoprotective effects of aldosterone blockade. J Pharmacol Sci 2006; 100(1): 9–16

    Article  CAS  PubMed  Google Scholar 

  27. Ribstein J, Du Cailar G, Fesler P, Mimran A. Relative glomerular hyperfiltration in primary aldosteronism. J Am Soc Nephrol 2005; 16(5): 1320–1325

    Article  PubMed  Google Scholar 

  28. Kawarazaki W, Nagase M, Yoshida S, Takeuchi M, Ishizawa K, Ayuzawa N, Ueda K, Fujita T. Angiotensin II-and salt-induced kidney injury through Rac1-mediated mineralocorticoid receptor activation. J Am Soc Nephrol 2012; 23(6): 997–1007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. De Cosmo S, Menzaghi C, Prudente S, Trischitta V. Role of insulin resistance in kidney dysfunction: insights into the mechanism and epidemiological evidence. Nephrol Dial Transplant 2013; 28(1): 29–36

    Article  PubMed  Google Scholar 

  30. Chen S, Chen Y, Liu X, Li M, Wu B, Li Y, Liang Y, Shao X, Holthöfer H, Zou H. Association of insulin resistance with chronic kidney disease in non-diabetic subjects with normal weight. PLoS One 2013; 8(9): e74058.doi: 10.1371/journal.pone.0074058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Redon J, Lurbe E. The kidney in obesity. Curr Hypertens Rep 2015; 17(6): 555

    Article  PubMed  Google Scholar 

  32. Ye J. Mechanisms of insulin resistance in obesity. Front Med 2013; 7(1): 14–24

    Article  PubMed  PubMed Central  Google Scholar 

  33. Szeto HH, Liu S, Soong Y, Alam N, Prusky GT, Seshan SV. Protection of mitochondria prevents high-fat diet-induced glomerulopathy and proximal tubular injury. Kidney Int 2016; 90(5): 997–1011

    Article  CAS  PubMed  Google Scholar 

  34. Tang C, Cai J, Dong Z. Mitochondrial dysfunction in obesity-related kidney disease: a novel therapeutic target. Kidney Int 2016; 90(5): 930–933

    Article  CAS  PubMed  Google Scholar 

  35. Herman-Edelstein M, Scherzer P, Tobar A, Levi M, Gafter U. Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J Lipid Res 2014; 55(3): 561–572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sharma K. Obesity, oxidative stress, and fibrosis in chronic kidney disease. Kidney Int Suppl (2011) 2014; 4(1): 113–117

    Article  CAS  Google Scholar 

  37. Declèves AE, Zolkipli Z, Satriano J, Wang L, Nakayama T, Rogac M, Le TP, Nortier JL, Farquhar MG, Naviaux RK, Sharma K. Regulation of lipid accumulation by AMP-activated kinase [corrected] in high fat diet-induced kidney injury. Kidney Int 2014; 85(3): 611–623

    Article  PubMed  Google Scholar 

  38. Dugan LL, You YH, Ali SS, Diamond-Stanic M, Miyamoto S, De Cleves AE, Andreyev A, Quach T, Ly S, Shekhtman G, Nguyen W, Chepetan A, Le TP, Wang L, Xu M, Paik KP, Fogo A, Viollet B, Murphy A, Brosius F, Naviaux RK, Sharma K. AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function. J Clin Invest 2013; 123(11): 4888–4899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Manabe I. Chronic inflammation links cardiovascular, metabolic and renal diseases. Circ J 2011; 75(12): 2739–2748

    Article  CAS  PubMed  Google Scholar 

  40. Nolan E, O’Meara YM, Godson C. Lipid mediators of inflammation in obesity-related glomerulopathy. Nephrol Dial Transplant 2013; 28(4 Suppl 4): iv22–iv29

    CAS  PubMed  Google Scholar 

  41. Young CN, Morgan DA, Butler SD, Mark AL, Davisson RL. The brain subfornical organ mediates leptin-induced increases in renal sympathetic activity but not its metabolic effects. Hypertension 2013; 61(3): 737–744

    Article  CAS  PubMed  Google Scholar 

  42. Nasrallah MP, Ziyadeh FN. Overview of the physiology and pathophysiology of leptin with special emphasis on its role in the kidney. Semin Nephrol 2013; 33(1): 54–65

    Article  CAS  PubMed  Google Scholar 

  43. Rutkowski JM, Wang ZV, Park AS, Zhang J, Zhang D, Hu MC, Moe OW, Susztak K, Scherer PE. Adiponectin promotes functional recovery after podocyte ablation. J Am Soc Nephrol 2013; 24(2): 268–282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Simonds SE, Pryor JT, Ravussin E, Greenway FL, Dileone R, Allen AM, Bassi J, Elmquist JK, Keogh JM, Henning E, Myers MG Jr, Licinio J, Brown RD, Enriori PJ, O’Rahilly S, Sternson SM, Grove KL, Spanswick DC, Farooqi IS, Cowley MA. Leptin mediates the increase in blood pressure associated with obesity. Cell 2014; 159(6): 1404–1416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ogna A, Forni Ogna V, Bochud M, Guessous I, Paccaud F, Burnier M, Wuerzner G. Association between obesity and glomerular hyperfiltration: the confounding effect of smoking and sodium and protein intakes. Eur J Nutr 2016; 55(3): 1089–1097

    Article  CAS  PubMed  Google Scholar 

  46. Tsuboi N, Utsunomiya Y, Kanzaki G, Koike K, Ikegami M, Kawamura T, Hosoya T. Low glomerular density with glomerulomegaly in obesity-related glomerulopathy. Clin J Am Soc Nephrol 2012; 7(5): 735–741

    Article  PubMed  Google Scholar 

  47. Praga M, Hernández E, Morales E, Campos AP, Valero MA, Martínez MA, León M. Clinical features and long-term outcome of obesity-associated focal segmental glomerulosclerosis. Nephrol Dial Transplant 2001; 16(9): 1790–1798

    Article  CAS  PubMed  Google Scholar 

  48. Chen HM, Chen Y, Zhang YD, Zhang PP, Chen HP, Wang QW, Li LS, Liu ZH. Evaluation of metabolic risk marker in obesity-related glomerulopathy. J Ren Nutr 2011; 21(4): 309–315

    Article  CAS  PubMed  Google Scholar 

  49. Tsuboi N, Koike K, Hirano K, Utsunomiya Y, Kawamura T, Hosoya T. Clinical features and long-term renal outcomes of Japanese patients with obesity-related glomerulopathy. Clin Exp Nephrol 2013; 17(3): 379–385

    Article  PubMed  Google Scholar 

  50. Praga M, Borstein B, Andres A, Arenas J, Oliet A, Montoyo C, Ruilope LM, Rodicio JL. Nephrotic proteinuria without hypoalbuminemia: clinical characteristics and response to angiotensinconverting enzyme inhibition. Am J Kidney Dis 1991; 17(3): 330–338

    Article  CAS  PubMed  Google Scholar 

  51. Praga M, Morales E, Herrero JC, Pérez Campos A, Domínguez-Gil B, Alegre R, Vara J, Martínez MA. Absence of hypoalbuminemia despite massive proteinuria in focal segmental glomerulosclerosis secondary to hyperfiltration. Am J Kidney Dis 1999; 33(1): 52–58

    Article  CAS  PubMed  Google Scholar 

  52. Sethi S, Zand L, Nasr SH, Glassock RJ, Fervenza FC. Focal and segmental glomerulosclerosis: clinical and kidney biopsy correlations. Clin Kidney J 2014; 7(6): 531–537

    Article  PubMed  PubMed Central  Google Scholar 

  53. Sethi S, Glassock RJ, Fervenza FC. Focal segmental glomerulosclerosis: towards a better understanding for the practicing nephrologist. Nephrol Dial Transplant 2015; 30(3): 375–384

    Article  CAS  PubMed  Google Scholar 

  54. Salvatore SP, Chevalier JM, Kuo SF, Audia PF, Seshan SV. Kidney disease in patients with obesity: It is not always obesity-related glomerulopathy alone. Obes Res Clin Pract 2017 Apr 22. [Epub ahead of print] doi: 10.1016/j.orcp.2017.04.003

    Google Scholar 

  55. Saiki A, Nagayama D, Ohhira M, Endoh K, Ohtsuka M, Koide N, Oyama T, Miyashita Y, Shirai K. Effect of weight loss using formula diet on renal function in obese patients with diabetic nephropathy. Int J Obes 2005; 29(9): 1115–1120

    Article  CAS  Google Scholar 

  56. 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–iv98

    Article  PubMed  Google Scholar 

  57. Friedman AN, Chambers M, Kamendulis LM, Temmerman J. Shortterm changes after a weight reduction intervention in advanced diabetic nephropathy. Clin J Am Soc Nephrol 2013; 8(11): 1892–1898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Morales E, Valero MA, León M, Hernández E, Praga M. Beneficial effects of weight loss in overweight patients with chronic proteinuric nephropathies. Am J Kidney Dis 2003; 41(2): 319–327

    Article  PubMed  Google Scholar 

  59. Afshinnia F, Wilt TJ, Duval S, Esmaeili A, Ibrahim HN. Weight loss and proteinuria: systematic review of clinical trials and comparative cohorts. Nephrol Dial Transplant 2010; 25(4): 1173–1183

    Article  PubMed  Google Scholar 

  60. 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(3): 188–199

    Article  PubMed  PubMed Central  Google Scholar 

  61. Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Brethauer SA, Navaneethan SD, Aminian A, Pothier CE, Kim ES, Nissen SE, Kashyap SR; STAMPEDE Investigators. Bariatric surgery versus intensive medical therapy for diabetes—3-year outcomes. N Engl J Med 2014; 370(21): 2002–2013

    Article  PubMed  PubMed Central  Google Scholar 

  62. MacLaughlin HL, Hall WL, Patel AG, Macdougall IC. Laparoscopic sleeve gastrectomy is a novel and effective treatment for obesity in patients with chronic kidney disease. Obes Surg 2012; 22(1): 119–123

    Article  PubMed  Google Scholar 

  63. Neff KJ, Frankel AH, Tam FW, Sadlier DM, Godson C, le Roux CW. The effect of bariatric surgery on renal function and disease: a focus on outcomes and inflammation. Nephrol Dial Transplant 2013; 28(Suppl 4): iv73–iv82

    PubMed  Google Scholar 

  64. Reid TJ, Saeed S, McCoy S, Osewa AA, Persaud A, Ahmed L. The effect of bariatric surgery on renal function. Surg Obes Relat Dis 2014; 10(5): 808–813

    Article  PubMed  Google Scholar 

  65. Saleh F, Kim SJ, Okrainec A, Jackson TD. Bariatric surgery in patients with reduced kidney function: an analysis of short-term outcomes. Surg Obes Relat Dis 2015; 11(4): 828–835

    Article  PubMed  Google Scholar 

  66. Lieske JC, Mehta RA, Milliner DS, Rule AD, Bergstralh EJ, Sarr MG. Kidney stones are common after bariatric surgery. Kidney Int 2015; 87(4): 839–845

    Article  PubMed  Google Scholar 

  67. Mallamaci F, Ruggenenti P, Perna A, Leonardis D, Tripepi R, Tripepi G, Remuzzi G, Zoccali C; REIN Study Group. ACE inhibition is renoprotective among obese patients with proteinuria. J Am Soc Nephrol 2011; 22(6): 1122–1128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Patil MR, Mishra A, Jain N, Gutch M, Tewari R. Weight loss for reduction of proteinuria in diabetic nephropathy: comparison with angiotensin-converting enzyme inhibitor therapy. Indian J Nephrol 2013; 23(2): 108–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Miyazaki Y, Cersosimo E, Triplitt C, De Fronzo RA. Rosiglitazone decreases albuminuria in type 2 diabetic patients. Kidney Int 2007; 72(11): 1367–1373

    Article  CAS  PubMed  Google Scholar 

  70. Zhang SQ, Sun YT, Xu TH, Zhang XF, Liu YZ, Ma MJ, Wang LN, Yao L. Protective effect of metformin on renal injury of C57BL/6J mouse treated with high fat diet. Pharmazie 2014; 69(12): 904–908

    CAS  PubMed  Google Scholar 

  71. Birk AV, Chao WM, Bracken C, Warren JD, Szeto HH. Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. Br J Pharmacol 2014; 171(8): 2017–2028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Pierine DT, Navarro ME, Minatel IO, Luvizotto RA, Nascimento AF, Ferreira AL, Yeum KJ, Corrêa CR. Lycopene supplementation reduces TNF-α via RAGE in the kidney of obese rats. Nutr Diabetes 2014; 4(11): e142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Stacchiotti A, Favero G, Giugno L, Lavazza A, Reiter RJ, Rodella LF, Rezzani R. Mitochondrial and metabolic dysfunction in renal convoluted tubules of obese mice: protective role of melatonin. PLoS One 2014; 9(10): e111141. DOI:10.1371/journal. pone. 0111141

    Article  PubMed  PubMed Central  Google Scholar 

  74. Wang C, Wu M, Arvapalli R, Dai X, Mahmood M, Driscoll H, Rice KM, Blough E. Acetaminophen attenuates obesity-related renal injury through ER-mediated stress mechanisms. Cell Physiol Biochem 2014; 33(4): 1139–1148

    Article  CAS  PubMed  Google Scholar 

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Xu, T., Sheng, Z. & Yao, L. Obesity-related glomerulopathy: pathogenesis, pathologic, clinical characteristics and treatment. Front. Med. 11, 340–348 (2017). https://doi.org/10.1007/s11684-017-0570-3

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