Skip to main content

Pathophysiology of Chronic Kidney Disease

  • Chapter
  • First Online:
Chronic Kidney Disease

Abstract

Chronic kidney disease (CKD), a general term for heterogeneous disorders, frequently occurs in association with a variety of factors including diabetes, nephritis, hypertension, and immune system disorder. As the etiologically distinct cause progresses, a common renal pathological manifestation including glomerulosclerosis and/or interstitial fibrosis develops regardless of the cause. Over the past several years, rapid progress in deciphering the cellular and molecular mechanisms have led to better understanding of pathophysiology of CKD and would make it possible to develop clinically effective anti-CKD therapies. This chapter summarizes and updates the pathophysiological knowledge of CKD from animal models and human studies, providing new insights into the complicated process of CKD.

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

Access this chapter

eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Levin A, et al. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3(1):1–150.

    Article  Google Scholar 

  2. Bello AK, et al. Assessment of global kidney health care status. JAMA. 2017;317(18):1864–81.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Breyer MD, Susztak K. The next generation of therapeutics for chronic kidney disease. Nat Rev Drug Discov. 2016;15(8):568–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. D’Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N Engl J Med. 2011;365(25):2398–411.

    Article  PubMed  Google Scholar 

  5. Fogo AB. Causes and pathogenesis of focal segmental glomerulosclerosis. Nat Rev Nephrol. 2015;11(2):76–87.

    Article  CAS  PubMed  Google Scholar 

  6. Liu Y. New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol. 2010;21(2):212–22.

    Article  CAS  PubMed  Google Scholar 

  7. Dai C, et al. Wnt/beta-catenin signaling promotes podocyte dysfunction and albuminuria. J Am Soc Nephrol. 2009;20(9):1997–2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Liu XL, et al. Characterization of the interactions of the nephrin intracellular domain. FEBS J. 2005;272(1):228–43.

    Article  CAS  PubMed  Google Scholar 

  9. Ichimura K, Kurihara H, Sakai T. Actin filament organization of foot processes in rat podocytes. J Histochem Cytochem. 2003;51(12):1589–600.

    Article  CAS  PubMed  Google Scholar 

  10. Blattner SM, et al. Divergent functions of the rho GTPases Rac1 and Cdc42 in podocyte injury. Kidney Int. 2013;84(5):920–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Soda K, et al. Role of dynamin, synaptojanin, and endophilin in podocyte foot processes. J Clin Invest. 2012;122(12):4401–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kaplan JM, et al. Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet. 2000;24(3):251–6.

    Article  CAS  PubMed  Google Scholar 

  13. Shankland SJ. The podocyte’s response to injury: role in proteinuria and glomerulosclerosis. Kidney Int. 2006;69(12):2131–47.

    Article  CAS  PubMed  Google Scholar 

  14. Chen HC, et al. Altering expression of alpha3beta1 integrin on podocytes of human and rats with diabetes. Life Sci. 2000;67(19):2345–53.

    Article  CAS  PubMed  Google Scholar 

  15. Tian X, et al. Podocyte-associated talin1 is critical for glomerular filtration barrier maintenance. J Clin Invest. 2014;124(3):1098–113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yu D, et al. Urinary podocyte loss is a more specific marker of ongoing glomerular damage than proteinuria. J Am Soc Nephrol. 2005;16(6):1733–41.

    Article  CAS  PubMed  Google Scholar 

  17. Niranjan T, et al. The notch pathway in podocytes plays a role in the development of glomerular disease. Nat Med. 2008;14(3):290–8.

    Article  CAS  PubMed  Google Scholar 

  18. Tanaka E, et al. Notch2 activation ameliorates nephrosis. Nat Commun. 2014;5:3296.

    Article  PubMed  CAS  Google Scholar 

  19. Kriz W, et al. The podocyte’s response to stress: the enigma of foot process effacement. Am J Physiol Renal Physiol. 2013;304(4):F333–47.

    Article  CAS  PubMed  Google Scholar 

  20. Eddy AA. Progression in chronic kidney disease. Adv Chronic Kidney Dis. 2005;12(4):353–65.

    Article  PubMed  Google Scholar 

  21. Kaissling B, Le Hir M. The renal cortical interstitium: morphological and functional aspects. Histochem Cell Biol. 2008;130(2):247–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. LeBleu VS, et al. Origin and function of myofibroblasts in kidney fibrosis. Nat Med. 2013;19(8):1047–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Duffield JS. Cellular and molecular mechanisms in kidney fibrosis. J Clin Invest. 2014;124(6):2299–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Schrimpf C, Duffield JS. Mechanisms of fibrosis: the role of the pericyte. Curr Opin Nephrol Hypertens. 2011;20(3):297–305.

    Article  PubMed  Google Scholar 

  25. Duffield JS, Humphreys BD. Origin of new cells in the adult kidney: results from genetic labeling techniques. Kidney Int. 2011;79(5):494–501.

    Article  PubMed  Google Scholar 

  26. Humphreys BD, et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol. 2010;176(1):85–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Iwano M, et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest. 2002;110(3):341–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li L, et al. Autophagy is a component of epithelial cell fate in obstructive uropathy. Am J Pathol. 2010;176(4):1767–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Grande MT, et al. Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat Med. 2015;21(9):989–97.

    Article  CAS  PubMed  Google Scholar 

  30. Lovisa S, et al. Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat Med. 2015;21(9):998–1009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pilling D, et al. Identification of markers that distinguish monocyte-derived fibrocytes from monocytes, macrophages, and fibroblasts. PLoS One. 2009;4(10):e7475.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Niedermeier M, et al. CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes. Proc Natl Acad Sci U S A. 2009;106(42):17892–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Roufosse C, et al. Bone marrow-derived cells do not contribute significantly to collagen I synthesis in a murine model of renal fibrosis. J Am Soc Nephrol. 2006;17(3):775–82.

    Article  CAS  PubMed  Google Scholar 

  34. Brinkkoetter PT, et al. Angiotensin II type 1-receptor mediated changes in heparan sulfate proteoglycans in human SV40 transformed podocytes. J Am Soc Nephrol. 2004;15(1):33–40.

    Article  CAS  PubMed  Google Scholar 

  35. Lee FT, et al. Interactions between angiotensin II and NF-kappaB-dependent pathways in modulating macrophage infiltration in experimental diabetic nephropathy. J Am Soc Nephrol. 2004;15(8):2139–51.

    Article  CAS  PubMed  Google Scholar 

  36. Zhang JD, et al. Type 1 angiotensin receptors on macrophages ameliorate IL-1 receptor-mediated kidney fibrosis. J Clin Invest. 2014;124(5):2198–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wada T, et al. The cyclin-dependent kinase inhibitor p21 is required for TGF-beta1-induced podocyte apoptosis. Kidney Int. 2005;68(4):1618–29.

    Article  CAS  PubMed  Google Scholar 

  38. Schiffer M, et al. Apoptosis in podocytes induced by TGF-beta and Smad7. J Clin Invest. 2001;108(6):807–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Eremina V, et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest. 2003;111(5):707–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. McGowan TA, et al. TGF-beta-induced Ca(2+) influx involves the type III IP(3) receptor and regulates actin cytoskeleton. Am J Physiol Renal Physiol. 2002;282(5):F910–20.

    Article  CAS  PubMed  Google Scholar 

  41. Xavier S, et al. Curtailing endothelial TGF-beta signaling is sufficient to reduce endothelial-mesenchymal transition and fibrosis in CKD. J Am Soc Nephrol. 2015;26(4):817–29.

    Article  CAS  PubMed  Google Scholar 

  42. Trachtman H, et al. A phase 1, single-dose study of fresolimumab, an anti-TGF-beta antibody, in treatment-resistant primary focal segmental glomerulosclerosis. Kidney Int. 2011;79(11):1236–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Surendran K, Schiavi S, Hruska KA. Wnt-dependent beta-catenin signaling is activated after unilateral ureteral obstruction, and recombinant secreted frizzled-related protein 4 alters the progression of renal fibrosis. J Am Soc Nephrol. 2005;16(8):2373–84.

    Article  CAS  PubMed  Google Scholar 

  44. Feng Y, et al. Wnt/beta-catenin-promoted macrophage alternative activation contributes to kidney fibrosis. J Am Soc Nephrol. 2018;29(1):182–93.

    Article  CAS  PubMed  Google Scholar 

  45. Shimobayashi M, Hall MN. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol. 2014;15(3):155–62.

    Article  CAS  PubMed  Google Scholar 

  46. Hagiwara A, et al. Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab. 2012;15(5):725–38.

    Article  CAS  PubMed  Google Scholar 

  47. Guertin DA, et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell. 2006;11(6):859–71.

    Article  CAS  PubMed  Google Scholar 

  48. Stylianou K, et al. Rapamycin induced ultrastructural and molecular alterations in glomerular podocytes in healthy mice. Nephrol Dial Transplant. 2012;27(8):3141–8.

    Article  CAS  PubMed  Google Scholar 

  49. Lui SL, et al. Rapamycin attenuates the severity of murine adriamycin nephropathy. Am J Nephrol. 2009;29(4):342–52.

    Article  CAS  PubMed  Google Scholar 

  50. Godel M, et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest. 2011;121(6):2197–209.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  51. Mao J, et al. Mammalian target of rapamycin complex 1 activation in podocytes promotes cellular crescent formation. Am J Physiol Renal Physiol. 2014;307(9):F1023–32.

    Article  CAS  PubMed  Google Scholar 

  52. Canaud G, et al. AKT2 is essential to maintain podocyte viability and function during chronic kidney disease. Nat Med. 2013;19(10):1288–96.

    Article  CAS  PubMed  Google Scholar 

  53. Jiang L, et al. Rheb/mTORC1 signaling promotes kidney fibroblast activation and fibrosis. J Am Soc Nephrol. 2013;24(7):1114–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Li J, et al. Rictor/mTORC2 signaling mediates TGFbeta1-induced fibroblast activation and kidney fibrosis. Kidney Int. 2015;88(3):515–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ren J, et al. Rictor/mammalian target of rapamycin complex 2 promotes macrophage activation and kidney fibrosis. J Pathol. 2017;242(4):488–99.

    Article  CAS  PubMed  Google Scholar 

  56. Kato M, Arce L, Natarajan R. MicroRNAs and their role in progressive kidney diseases. Clin J Am Soc Nephrol. 2009;4(7):1255–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Shi S, et al. Podocyte-selective deletion of dicer induces proteinuria and glomerulosclerosis. J Am Soc Nephrol. 2008;19(11):2159–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhdanova O, et al. The inducible deletion of Drosha and microRNAs in mature podocytes results in a collapsing glomerulopathy. Kidney Int. 2011;80(7):719–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sequeira-Lopez ML, et al. The microRNA-processing enzyme dicer maintains juxtaglomerular cells. J Am Soc Nephrol. 2010;21(3):460–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kriegel AJ, et al. MiR-382 targeting of kallikrein 5 contributes to renal inner medullary interstitial fibrosis. Physiol Genomics. 2012;44(4):259–67.

    Article  CAS  PubMed  Google Scholar 

  61. Ma L, Qu L. The function of microRNAs in renal development and pathophysiology. J Genet Genomics. 2013;40(4):143–52.

    Article  PubMed  CAS  Google Scholar 

  62. Chung AC, et al. Smad7 suppresses renal fibrosis via altering expression of TGF-beta/Smad3-regulated microRNAs. Mol Ther. 2013;21(2):388–98.

    Article  CAS  PubMed  Google Scholar 

  63. Chau BN, et al. MicroRNA-21 promotes fibrosis of the kidney by silencing metabolic pathways. Sci Transl Med. 2012;4(121):121ra18.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  64. Li R, et al. The microRNA miR-433 promotes renal fibrosis by amplifying the TGF-beta/Smad3-Azin1 pathway. Kidney Int. 2013;84(6):1129–44.

    Article  CAS  PubMed  Google Scholar 

  65. Chandrasekaran K, et al. Role of microRNAs in kidney homeostasis and disease. Kidney Int. 2012;81(7):617–27.

    Article  CAS  PubMed  Google Scholar 

  66. Weber JA, et al. The microRNA spectrum in 12 body fluids. Clin Chem. 2010;56(11):1733–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Freeburg PB, et al. Podocyte expression of hypoxia-inducible factor (HIF)-1 and HIF-2 during glomerular development. J Am Soc Nephrol. 2003;14(4):927–38.

    Article  CAS  PubMed  Google Scholar 

  68. Ding M, et al. Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice. Nat Med. 2006;12(9):1081–7.

    Article  CAS  PubMed  Google Scholar 

  69. Steenhard BM, et al. Deletion of von Hippel-Lindau in glomerular podocytes results in glomerular basement membrane thickening, ectopic subepithelial deposition of collagen {alpha}1{alpha}2{alpha}1(IV), expression of neuroglobin, and proteinuria. Am J Pathol. 2010;177(1):84–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kapitsinou PP, et al. Endothelial HIF-2 mediates protection and recovery from ischemic kidney injury. J Clin Invest. 2014;124(6):2396–409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kalucka J, et al. Kidney injury is independent of endothelial HIF-1alpha. J Mol Med (Berl). 2015;93(8):891–904.

    Article  CAS  Google Scholar 

  72. Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol. 2006;17(1):17–25.

    Article  CAS  PubMed  Google Scholar 

  73. Gucer S, et al. Focal segmental glomerulosclerosis associated with mitochondrial cytopathy: report of two cases with special emphasis on podocytes. Pediatr Dev Pathol. 2005;8(6):710–7.

    Article  PubMed  Google Scholar 

  74. Peng M, et al. Primary coenzyme Q deficiency in Pdss2 mutant mice causes isolated renal disease. PLoS Genet. 2008;4(4):e1000061.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  75. Kampe K, et al. Susceptibility of podocytes to palmitic acid is regulated by fatty acid oxidation and inversely depends on acetyl-CoA carboxylases 1 and 2. Am J Physiol Renal Physiol. 2014;306(4):F401–9.

    Article  CAS  PubMed  Google Scholar 

  76. Mayrhofer C, et al. Alterations in fatty acid utilization and an impaired antioxidant defense mechanism are early events in podocyte injury: a proteomic analysis. Am J Pathol. 2009;174(4):1191–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Abe Y, et al. Bioenergetic characterization of mouse podocytes. Am J Physiol Cell Physiol. 2010;299(2):C464–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ding H, et al. PDE/cAMP/Epac/C/EBP-beta signaling Cascade regulates mitochondria biogenesis of tubular epithelial cells in renal fibrosis. Antioxid Redox Signal. 2018;29(7):637–52.

    Article  CAS  PubMed  Google Scholar 

  79. Kang HM, et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat Med. 2015;21(1):37–46.

    Article  CAS  PubMed  Google Scholar 

  80. Chen KH, et al. The AMPK agonist AICAR inhibits TGF-beta1 induced activation of kidney myofibroblasts. PLoS One. 2014;9(9):e106554.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  81. Ding H, et al. Inhibiting aerobic glycolysis suppresses renal interstitial fibroblast activation and renal fibrosis. Am J Physiol Renal Physiol. 2017;313(3):F561–75.

    Article  CAS  PubMed  Google Scholar 

  82. Han SH, et al. Deletion of Lkb1 in renal tubular epithelial cells leads to CKD by altering metabolism. J Am Soc Nephrol. 2016;27(2):439–53.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Jiafa Ren or Chunsun Dai .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Ren, J., Dai, C. (2020). Pathophysiology of Chronic Kidney Disease. In: Yang, J., He, W. (eds) Chronic Kidney Disease. Springer, Singapore. https://doi.org/10.1007/978-981-32-9131-7_2

Download citation

  • DOI: https://doi.org/10.1007/978-981-32-9131-7_2

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-32-9130-0

  • Online ISBN: 978-981-32-9131-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics