New Understanding on the Role of Proteinuria in Progression of Chronic Kidney Disease

  • Dan Liu
  • Lin-Li LvEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1165)


Proteinuria is identified as an important marker and risk factor of progression in chronic kidney disease. However, the precise mechanism of action in the progress of chronic kidney disease is still unclear. Mesangial toxicity from specific filtered compounds such as albumin-bound fatty acids and transferrin/iron, tubular overload and hyperplasia, and induction of proinflammatory molecules such as MCP-1 and inflammatory cytokines are some of the proposed mechanisms. Reversing intraglomerular hypertension with protein restriction or antihypertensive therapy may be beneficial both by diminishing hemodynamic injury to the glomeruli and by reducing protein filtration. Therefore, understanding proteinuria and its role in renal tubular interstitial inflammation and fibrosis is of great significance for the study of renal protective therapy, such as antiproteinuric treatments, and delaying the progression of chronic renal disease.


Proteinuria Chronic kidney disease End-stage renal disease 



This study was supported by grants from the National Key Research and Development Program of China (2018YFC1314004), the National Natural Science Foundation of China (No. 81720108007, 81670696, 81470922, 81600513 and 31671194), the Clinic Research Center of Jiangsu Province (No. BL2014080), and the Postgraduate Research and Practice Innovation Program of Jiangsu Province (No. KYCX18_0171).


  1. Abbate M, Zoja C, Remuzzi G (2006) How does proteinuria cause progressive renal damage? J Am Soc Nephrol 17:2974–2984CrossRefGoogle Scholar
  2. Alvarez V, Quiroz Y, Nava M, Pons H, Rodriguez-Iturbe B (2002) Overload proteinuria is followed by salt-sensitive hypertension caused by renal infiltration of immune cells. Am J Physiol Renal Physiol 283:F1132–F1141CrossRefGoogle Scholar
  3. Amsellem S, Gburek J, Hamard G, Nielsen R, Willnow TE, Devuyst O et al (2010) Cubilin is essential for albumin reabsorption in the renal proximal tubule. J Am Soc Nephrol 21:1859–1867CrossRefGoogle Scholar
  4. Anders HJ, Muruve DA (2011) The inflammasomes in kidney disease. J Am Soc Nephrol 22:1007–1018PubMedGoogle Scholar
  5. Atkins RC, Briganti EM, Lewis JB, Hunsicker LG, Braden G, Champion de Crespigny PJ et al (2005) Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy. Am J Kidney Dis 45:281–287CrossRefGoogle Scholar
  6. Baines RJ, Brunskill NJ (2011) Tubular toxicity of proteinuria. Nat Rev Nephrol 7:177–180CrossRefGoogle Scholar
  7. Biemesderfer D (2006) Regulated intramembrane proteolysis of megalin: linking urinary protein and gene regulation in proximal tubule? Kidney Int 69:1717–1721CrossRefGoogle Scholar
  8. Boor P, Ostendorf T, Floege J (2010) Renal fibrosis: novel insights into mechanisms and therapeutic targets. Nat Rev Nephrol 6:643–656CrossRefGoogle Scholar
  9. Borges FT, Melo SA, Ozdemir BC, Kato N, Revuelta I, Miller CA et al (2013) TGF-beta1-containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative responses and fibrosis. J Am Soc Nephrol 24:385–392CrossRefGoogle Scholar
  10. Burton C, Harris KP (1996) The role of proteinuria in the progression of chronic renal failure. Am J Kidney Dis 27:765–775CrossRefGoogle Scholar
  11. Cao W, Zhou QG, Nie J, Wang GB, Liu Y, Zhou ZM et al (2011) Albumin overload activates intrarenal renin-angiotensin system through protein kinase C and NADPH oxidase-dependent pathway. J Hypertens 29:1411–1421CrossRefGoogle Scholar
  12. Caruso-Neves C, Pinheiro AA, Cai H, Souza-Menezes J, Guggino WB (2006) PKB and megalin determine the survival or death of renal proximal tubule cells. Proc Natl Acad Sci U S A 103:18810–18815CrossRefGoogle Scholar
  13. Chang A, Ko K, Clark MR (2014) The emerging role of the inflammasome in kidney diseases. Curr Opin Nephrol Hypertens 23:204–210CrossRefGoogle Scholar
  14. Cravedi P, Ruggenenti P, Remuzzi G (2012) Proteinuria should be used as a surrogate in CKD. Nat Rev Nephrol 8:301–306CrossRefGoogle Scholar
  15. de Zeeuw D, Ramjit D, Zhang Z, Ribeiro AB, Kurokawa K, Lash JP et al (2006) Renal risk and renoprotection among ethnic groups with type 2 diabetic nephropathy: a post hoc analysis of RENAAL. Kidney Int 69:1675–1682CrossRefGoogle Scholar
  16. Eardley KS, Zehnder D, Quinkler M, Lepenies J, Bates RL, Savage CO et al (2006) The relationship between albuminuria, MCP-1/CCL2, and interstitial macrophages in chronic kidney disease. Kidney Int 69:1189–1197CrossRefGoogle Scholar
  17. Fernandez-Fernandez B, Izquierdo MC, Valino-Rivas L, Nastou D, Sanz AB, Ortiz A et al (2018) Albumin Downregulates Klotho in tubular cells. Nephrol Dial Transplant 33:1712–1722CrossRefGoogle Scholar
  18. Gorriz JL, Martinez-Castelao A (2012) Proteinuria: detection and role in native renal disease progression. Transplant Rev (Orlando) 26:3–13CrossRefGoogle Scholar
  19. Greka A, Mundel P (2012) Cell biology and pathology of podocytes. Annu Rev Physiol 74:299–323CrossRefGoogle Scholar
  20. Huxley VH, Williams DA (2000) Role of a glycocalyx on coronary arteriole permeability to proteins: evidence from enzyme treatments. Am J Physiol Heart Circ Physiol 278:H1177–H1185CrossRefGoogle Scholar
  21. Iseki K, Iseki C, Ikemiya Y, Fukiyama K (1996) Risk of developing end-stage renal disease in a cohort of mass screening. Kidney Int 49:800–805CrossRefGoogle Scholar
  22. Iwao Y, Nakajou K, Nagai R, Kitamura K, Anraku M, Maruyama T et al (2008) CD36 is one of important receptors promoting renal tubular injury by advanced oxidation protein products. Am J Physiol Renal Physiol 295:F1871–F1880CrossRefGoogle Scholar
  23. Jefferson JA, Shankland SJ, Pichler RH (2008) Proteinuria in diabetic kidney disease: a mechanistic viewpoint. Kidney Int 74:22–36CrossRefGoogle Scholar
  24. Keane WF, Zhang Z, Lyle PA, Cooper ME, de Zeeuw D, Grunfeld JP et al (2006) Risk scores for predicting outcomes in patients with type 2 diabetes and nephropathy: the RENAAL study. Clin J Am Soc Nephrol 1:761–767CrossRefGoogle Scholar
  25. Kim JH, Xie J, Hwang KH, Wu YL, Oliver N, Eom M et al (2017) Klotho may ameliorate proteinuria by targeting TRPC6 channels in podocytes. J Am Soc Nephrol 28:140–151CrossRefGoogle Scholar
  26. Ku E, Johansen KL, McCulloch CE (2018) Time-centered approach to understanding risk factors for the progression of CKD. Clin J Am Soc Nephrol 13:693–701CrossRefGoogle Scholar
  27. Lee D, Gleich K, Fraser SA, Katerelos M, Mount PF, Power DA (2013) Limited capacity of proximal tubular proteolysis in mice with proteinuria. Am J Physiol Renal Physiol 304:F1009–F1019CrossRefGoogle Scholar
  28. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB et al (2001) Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851–860CrossRefGoogle Scholar
  29. Li X, Pabla N, Wei Q, Dong G, Messing RO, Wang CY et al (2010) PKC-delta promotes renal tubular cell apoptosis associated with proteinuria. J Am Soc Nephrol 21:1115–1124CrossRefGoogle Scholar
  30. Liu BC, Gao J, Li Q, Xu LM (2009) Albumin caused the increasing production of angiotensin II due to the dysregulation of ACE/ACE2 expression in HK2 cells. Clin Chim Acta 403:23–30CrossRefGoogle Scholar
  31. Liu BC, Tang TT, Lv LL, Lan HY (2018) Renal tubule injury: a driving force toward chronic kidney disease. Kidney Int 93:568–579CrossRefGoogle Scholar
  32. Liu D, Wen Y, Tang TT, Lv LL, Tang RN, Liu H et al (2015) Megalin/cubulin-lysosome-mediated albumin reabsorption is involved in the tubular cell activation of NLRP3 inflammasome and tubulointerstitial inflammation. J Biol Chem 290:18018–18028CrossRefGoogle Scholar
  33. Liu D, Xu M, Ding LH, Lv LL, Liu H, Ma KL et al (2014) Activation of the Nlrp3 inflammasome by mitochondrial reactive oxygen species: a novel mechanism of albumin-induced tubulointerstitial inflammation. Int J Biochem Cell Biol 57:7–19CrossRefGoogle Scholar
  34. Luo S, Coresh J, Tin A, Rebholz CM, Appel LJ, Chen J et al (2019) Serum metabolomic alterations associated with proteinuria in CKD. Clin J Am Soc Nephrol 14:342–353CrossRefGoogle Scholar
  35. Lv LL, Feng Y, Wen Y, Wu WJ, Ni HF, Li ZL et al (2018) Exosomal CCL2 from tubular epithelial cells is critical for albumin-induced tubulointerstitial inflammation. J Am Soc Nephrol 29:919–935CrossRefGoogle Scholar
  36. Macconi D, Chiabrando C, Schiarea S, Aiello S, Cassis L, Gagliardini E et al (2009) Proteasomal processing of albumin by renal dendritic cells generates antigenic peptides. J Am Soc Nephrol 20:123–130CrossRefGoogle Scholar
  37. Morigi M, Macconi D, Zoja C, Donadelli R, Buelli S, Zanchi C et al (2002) Protein overload-induced NF-kappaB activation in proximal tubular cells requires H(2)O(2) through a PKC-dependent pathway. J Am Soc Nephrol 13:1179–1189PubMedGoogle Scholar
  38. Motoyoshi Y, Matsusaka T, Saito A, Pastan I, Willnow TE, Mizutani S et al (2008) Megalin contributes to the early injury of proximal tubule cells during nonselective proteinuria. Kidney Int 74:1262–1269CrossRefGoogle Scholar
  39. Nakajima H, Takenaka M, Kaimori JY, Hamano T, Iwatani H, Sugaya T et al (2004) Activation of the signal transducer and activator of transcription signaling pathway in renal proximal tubular cells by albumin. J Am Soc Nephrol 15:276–285CrossRefGoogle Scholar
  40. Nijenhuis T, Sloan AJ, Hoenderop JG, Flesche J, van Goor H, Kistler AD et al (2011) Angiotensin II contributes to podocyte injury by increasing TRPC6 expression via an NFAT-mediated positive feedback signaling pathway. Am J Pathol 179:1719–1732CrossRefGoogle Scholar
  41. Nishi Y, Satoh M, Nagasu H, Kadoya H, Ihoriya C, Kidokoro K et al (2013) Selective estrogen receptor modulation attenuates proteinuria-induced renal tubular damage by modulating mitochondrial oxidative status. Kidney Int 83:662–673CrossRefGoogle Scholar
  42. Peired A, Angelotti ML, Ronconi E, la Marca G, Mazzinghi B, Sisti A et al (2013) Proteinuria impairs podocyte regeneration by sequestering retinoic acid. J Am Soc Nephrol 24:1756–1768CrossRefGoogle Scholar
  43. Pitt JM, Kroemer G, Zitvogel L (2016) Extracellular vesicles: masters of intercellular communication and potential clinical interventions. J Clin Invest 126:1139–1143CrossRefGoogle Scholar
  44. Remuzzi G, Benigni A, Remuzzi A (2006) Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 116:288–296CrossRefGoogle Scholar
  45. Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M et al (1999) Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 354:359–364CrossRefGoogle Scholar
  46. Ruggenenti P, Perna A, Mosconi L, Matalone M, Pisoni R, Gaspari F et al (1997) Proteinuria predicts end-stage renal failure in non-diabetic chronic nephropathies. The “Gruppo Italiano di Studi Epidemiologici in Nefrologia” (GISEN). Kidney Int 63(Suppl):S54–S57Google Scholar
  47. Ruggenenti P, Perna A, Mosconi L, Pisoni R, Remuzzi G (1998) Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies. “Gruppo Italiano di Studi Epidemiologici in Nefrologia” (GISEN). Kidney Int 53:1209–1216CrossRefGoogle Scholar
  48. Ruggenenti P, Perna A, Remuzzi G, Investigators GG (2003) Retarding progression of chronic renal disease: the neglected issue of residual proteinuria. Kidney Int 63:2254–2261CrossRefGoogle Scholar
  49. Shimizu H, Maruyama S, Yuzawa Y, Kato T, Miki Y, Suzuki S et al (2003) Anti-monocyte chemoattractant protein-1 gene therapy attenuates renal injury induced by protein-overload proteinuria. J Am Soc Nephrol 14:1496–1505CrossRefGoogle Scholar
  50. Souma T, Abe M, Moriguchi T, Takai J, Yanagisawa-Miyazawa N, Shibata E et al (2011) Luminal alkalinization attenuates proteinuria-induced oxidative damage in proximal tubular cells. J Am Soc Nephrol 22:635–648CrossRefGoogle Scholar
  51. Storm T, Tranebjaerg L, Frykholm C, Birn H, Verroust PJ, Neveus T et al (2013) Renal phenotypic investigations of megalin-deficient patients: novel insights into tubular proteinuria and albumin filtration. Nephrol Dial Transplant 28:585–591CrossRefGoogle Scholar
  52. Strutz FM (2009) EMT and proteinuria as progression factors. Kidney Int 75:475–481CrossRefGoogle Scholar
  53. Thrailkill KM, Nimmo T, Bunn RC, Cockrell GE, Moreau CS, Mackintosh S et al (2009) Microalbuminuria in type 1 diabetes is associated with enhanced excretion of the endocytic multiligand receptors megalin and cubilin. Diab Care 32:1266–1268CrossRefGoogle Scholar
  54. Toblli JE, Bevione P, Di Gennaro F, Madalena L, Cao G, Angerosa M (2012) Understanding the mechanisms of proteinuria: therapeutic implications. Int J Nephrol 2012:546039CrossRefGoogle Scholar
  55. Tojo A, Onozato ML, Kitiyakara C, Kinugasa S, Fukuda S, Sakai T et al (2008) Glomerular albumin filtration through podocyte cell body in puromycin aminonucleoside nephrotic rat. Med Mol Morphol 41:92–98CrossRefGoogle Scholar
  56. Webster AC, Nagler EV, Morton RL, Masson P (2017) Chronic kidney disease. Lancet 389:1238–1252CrossRefGoogle Scholar
  57. Weyer K, Storm T, Shan J, Vainio S, Kozyraki R, Verroust PJ et al (2011) Mouse model of proximal tubule endocytic dysfunction. Nephrol Dial Transplant 26:3446–3451CrossRefGoogle Scholar
  58. Zhang L, Wang F, Wang L, Wang W, Liu B, Liu J et al (2012) Prevalence of chronic kidney disease in China: a cross-sectional survey. Lancet 379:815–822CrossRefGoogle Scholar
  59. Zoja C, Abbate M, Remuzzi G (2015) Progression of renal injury toward interstitial inflammation and glomerular sclerosis is dependent on abnormal protein filtration. Nephrol Dial Transplant 30:706–712CrossRefGoogle Scholar
  60. Zou Z, Chung B, Nguyen T, Mentone S, Thomson B, Biemesderfer D (2004) Linking receptor-mediated endocytosis and cell signaling: evidence for regulated intramembrane proteolysis of megalin in proximal tubule. J Biol Chem 279:34302–34310CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Institute of Nephrology, Zhong Da HospitalSoutheast University School of MedicineNanjingChina

Personalised recommendations