Skip to main content

Advertisement

SpringerLink
Log in

A conceptual framework for the molecular pathogenesis of progressive kidney disease

  • Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

The data regarding the pathogenesis of progressive kidney disease implicate cytokine effects, physiological factors, and myriad examples of relatively nonspecific cellular dysfunction. The sheer volume of information being generated on this topic threatens to overwhelm our efforts to understand progression in chronic kidney disease or to derive rational strategies to treat it. Here, a conceptual framework is offered for organizing and considering these data. Disease is initiated by an injury that evokes a tissue-specific cellular response. Subsequent structural repair may be effective, or the new structure may be sufficiently changed that it requires an adaptive physiological response. If this adaptation is not successful, subsequent cycles of misdirected repair or maladaptation may lead to progressive nephron loss. To illustrate how this framework can be used to organize our approach to disease pathogenesis, the role of cytokines in proteinuria and progressive glomerular disease is discussed. Finally, this theoretical framework is reconsidered to examine its implications for the diagnosis and treatment of clinical conditions. Application of this schema could have significant relevance to both research inquiry and clinical practice.

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
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, Van Lente F, Levey AS (2007) Prevalence of chronic kidney disease in the United States. JAMA 298:2038–2047

    Article  CAS  PubMed  Google Scholar 

  2. Glassock RJ, Winearls C (2008) Screening for CKD with eGFR: doubts and dangers. Clin J Am Soc Nephrol 3:1563–1568

    Article  PubMed  Google Scholar 

  3. Thurau K, Boylan JW (1976) Acute renal success. The unexpected logic of oliguria in acute renal failure Am J Med 61:308–315

    CAS  Google Scholar 

  4. Ross R (1999) Atherosclerosis-an inflammatory disease. N Engl J Med 340:115–126

    Article  CAS  PubMed  Google Scholar 

  5. Bricker NS, Fine LG, Kaplan M, Epstein M, Bourgoignie JJ, Light A (1978) “Magnification phenomenon” in chronic renal disease. N Engl J Med 299:1287–1293

    Article  CAS  PubMed  Google Scholar 

  6. Barnes JL, Hastings RR, De la Garza MA (1994) Sequential expression of cellular fibronectin by platelets, macrophages, and mesangial cells in proliferative glomerulonephritis. Am J Pathol 145:585–597

    CAS  PubMed  Google Scholar 

  7. Shalhoub RJ (1974) Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 2:556–560

    Article  CAS  PubMed  Google Scholar 

  8. Schnaper HW (1989) The immune system in minimal change nephrotic syndrome. Pediatr Nephrol 3:101–110

    Article  CAS  PubMed  Google Scholar 

  9. Sahali D, Pawlak A, Valanciute A, Grimbert P, Lang P, Remy P, Bensman A, Guellaen G (2002) A novel approach to investigation of the pathogenesis of active minimal-change nephrotic syndrome using subtracted cDNA library screening. J Am Soc Nephrol 13:1238–1247

    CAS  PubMed  Google Scholar 

  10. Araya CE, Wasserfall CH, Brusko TM, Mu W, Segal MS, Johnson RJ, Garin EH (2006) A case of unfulfilled expectations. Cytokines in idiopathic minimal lesion nephrotic syndrome. Pediatr Nephrol 21:603–610

    Article  PubMed  Google Scholar 

  11. Lai KW, Wei CL, Tan LK, Tan PH, Chiang GS, Lee CG, Jordan SC, Yap HK (2007) Overexpression of interleukin-13 induces minimal-change-like nephropathy in rats. J Am Soc Nephrol 18:1476–1485

    Article  CAS  PubMed  Google Scholar 

  12. Heslan JM, Branellec AI, Pilatte Y, Lang P, Lagrue G (1991) Differentiation between vascular permeability factor and IL-2 in lymphocyte supernatants from patients with minimal-change nephrotic syndrome. Clin Exp Immunol 86:157–162

    Article  CAS  PubMed  Google Scholar 

  13. Garin EH, West L, Zheng W (1997) Effect of interleukin-8 on glomerular sulfated compounds and albuminuria. Pediatr Nephrol 11:274–279

    Article  CAS  PubMed  Google Scholar 

  14. Morales-Ruiz M, Fulton D, Sowa G, Languino LR, Fujio Y, Walsh K, Sessa WC (2000) Vascular endothelial growth factor-stimulated actin reorganization and migration of endothelial cells is regulated via the serine/threonine kinase Akt. Circ Res 86:892–896

    CAS  PubMed  Google Scholar 

  15. Sung SH, Ziyadeh FN, Wang A, Pyagay PE, Kanwar YS, Chen S (2006) Blockade of vascular endothelial growth factor signaling ameliorates diabetic albuminuria in mice. J Am Soc Nephrol 17:3093–3104

    Article  CAS  PubMed  Google Scholar 

  16. Moller CC, Flesche J, Reiser J (2009) Sensitizing the slit diaphragm with TRPC6 ion channels. J Am Soc Nephrol 20:950–953

    Article  CAS  PubMed  Google Scholar 

  17. Barisoni L, Schnaper HW, Kopp JB (2007) A proposed taxonomy for the podocytopathies: a reassessment of the primary nephrotic diseases. Clin J Am Soc Nephrol 2:529–542

    Article  PubMed  Google Scholar 

  18. Barisoni L, Schnaper HW, Kopp JB (2009) Advances in the biology and genetics of the podocytopathies: implications for diagnosis and therapy. Arch Pathol Lab Med 133:201–216

    PubMed  Google Scholar 

  19. Schiffer M, Bitzer M, Roberts IS, Kopp JB, ten Dijke P, Mundel P, Bottinger EP (2001) Apoptosis in podocytes induced by TGF-beta and Smad7. J Clin Invest 108:807–816

    CAS  PubMed  Google Scholar 

  20. Schnaper HW, Hayashida T, Hubchak SC, Poncelet AC (2003) TGF-beta signal transduction and mesangial cell fibrogenesis. Am J Physiol Renal Physiol 284:F243–F252

    CAS  PubMed  Google Scholar 

  21. Liu Y (2004) Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. J Am Soc Nephrol 15:1–12

    Article  CAS  PubMed  Google Scholar 

  22. Shimizu A, Yamanaka N (1993) Apoptosis and cell desquamation in repair process of ischemic tubular necrosis. Virchows Arch B Cell Pathol Incl Mol Pathol 64:171–180

    Article  CAS  PubMed  Google Scholar 

  23. Sato M, Muragaki Y, Saika S, Roberts AB, Ooshima A (2003) Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J Clin Invest 112:1486–1494

    CAS  PubMed  Google Scholar 

  24. Schiffer M, Schiffer LE, Gupta A, Shaw AS, Roberts IS, Mundel P, Bottinger EP (2002) Inhibitory Smads and TGF-beta signaling in glomerular cells. J Am Soc Nephrol 13:2657–2666

    Article  CAS  PubMed  Google Scholar 

  25. Wolf G, Chen S, Han DC, Ziyadeh FN (2002) Leptin and renal disease. Am J Kidney Dis 39:1–11

    Article  CAS  PubMed  Google Scholar 

  26. Qi W, Twigg S, Chen X, Polhill TS, Poronnik P, Gilbert RE, Pollock CA (2005) Integrated actions of transforming growth factor-beta1 and connective tissue growth factor in renal fibrosis. Am J Physiol Renal Physiol 288:F800–F809

    Article  CAS  PubMed  Google Scholar 

  27. Bassuk JA, Pichler R, Rothmier JD, Pippen J, Gordon K, Meek RL, Bradshaw AD, Lombardi D, Strandjord TP, Reed M, Sage EH, Couser WG, Johnson R (2000) Induction of TGF-beta1 by the matricellular protein SPARC in a rat model of glomerulonephritis. Kidney Int 57:117–128

    Article  CAS  PubMed  Google Scholar 

  28. Goumenos DS, Tsakas S, El Nahas AM, Alexandri S, Oldroyd S, Kalliakmani P, Vlachojannis JG (2002) Transforming growth factor-beta(1) in the kidney and urine of patients with glomerular disease and proteinuria. Nephrol Dial Transplant 17:2145–2152

    Article  CAS  PubMed  Google Scholar 

  29. Guo G, Morrissey J, McCracken R, Tolley T, Liapis H, Klahr S (2001) Contributions of angiotensin II and tumor necrosis factor-alpha to the development of renal fibrosis. Am J Physiol Renal Physiol 280:F777–F785

    CAS  PubMed  Google Scholar 

  30. Ophascharoensuk V, Giachelli CM, Gordon K, Hughes J, Pichler R, Brown P, Liaw L, Schmidt R, Shankland SJ, Alpers CE, Couser WG, Johnson RJ (1999) Obstructive uropathy in the mouse: role of osteopontin in interstitial fibrosis and apoptosis. Kidney Int 56:571–580

    Article  CAS  PubMed  Google Scholar 

  31. Ozawa Y, Kobori H, Suzaki Y, Navar LG (2007) Sustained renal interstitial macrophage infiltration following chronic angiotensin II infusions. Am J Physiol Renal Physiol 292:F330–F339

    Article  CAS  PubMed  Google Scholar 

  32. Floege J, Kriz W, Schulze M, Susani M, Kerjaschki D, Mooney A, Couser WG, Koch KM (1995) Basic fibroblast growth factor augments podocyte injury and induces glomerulosclerosis in rats with experimental membranous nephropathy. J Clin Invest 96:2809–2819

    Article  CAS  PubMed  Google Scholar 

  33. Terzi F, Burtin M, Hekmati M, Federici P, Grimber G, Briand P, Friedlander G (2000) Targeted expression of a dominant-negative EGF-R in the kidney reduces tubulo-interstitial lesions after renal injury. J Clin Invest 106:225–234

    Article  CAS  PubMed  Google Scholar 

  34. Haseley LA, Hugo C, Reidy MA, Johnson RJ (1999) Dissociation of mesangial cell migration and proliferation in experimental glomerulonephritis. Kidney Int 56:964–972

    Article  CAS  PubMed  Google Scholar 

  35. Oikawa T, Freeman M, Lo W, Vaughan DE, Fogo A (1997) Modulation of plasminogen activator inhibitor-1 in vivo: a new mechanism for the anti-fibrotic effect of renin-angiotensin inhibition. Kidney Int 51:164–172

    Article  CAS  PubMed  Google Scholar 

  36. Wang A, Ziyadeh FN, Lee EY, Pyagay PE, Sung SH, Sheardown SA, Laping NJ, Chen S (2007) Interference with TGF-beta signaling by Smad3-knockout in mice limits diabetic glomerulosclerosis without affecting albuminuria. Am J Physiol Renal Physiol 293:F1657–F1665

    Article  CAS  PubMed  Google Scholar 

  37. Singh P, Deng A, Blantz RC, Thomson SC (2009) Unexpected effect of angiotensin AT1 receptor blockade on tubuloglomerular feedback in early subtotal nephrectomy. Am J Physiol Renal Physiol 296:F1158–F1165

    Article  CAS  PubMed  Google Scholar 

  38. Ichikawa I, Fogo A (1996) Focal segmental glomerulosclerosis. Pediatr Nephrol 10:374–391

    CAS  PubMed  Google Scholar 

  39. Schlaich MP, Schmitt D, Ott C, Schmidt BM, Schmieder RE (2008) Basal nitric oxide synthase activity is a major determinant of glomerular haemodynamics in humans. J Hypertens 26:110–116

    Article  CAS  PubMed  Google Scholar 

  40. Ozeki M, Nagasu H, Satoh M, Namikoshi T, Haruna Y, Tomita N, Sasaki T, Kashihara N (2009) Reactive oxygen species mediate compensatory glomerular hypertrophy in rat uninephrectomized kidney. J Physiol Sci 59:397–404

    Article  CAS  PubMed  Google Scholar 

  41. Eberhardt W, Pfeilschifter J (2007) Nitric oxide and vascular remodeling: spotlight on the kidney. Kidney Int Suppl 106:S9–S16

    Google Scholar 

  42. Kriz W, LeHir M (2005) Pathways to nephron loss starting from glomerular diseases-insights from animal models. Kidney Int 67:404–419

    Article  PubMed  Google Scholar 

  43. Lovett DH, Johnson RJ, Marti HP, Martin J, Davies M, Couser WG (1992) Structural characterization of the mesangial cell type IV collagenase and enhanced expression in a model of immune complex-mediated glomerulonephritis. Am J Pathol 141:85–98

    CAS  PubMed  Google Scholar 

  44. Oktem F, Sirin A, Bilge I, Emre S, Agachan B, Ispir T (2004) ACE I/D gene polymorphism in primary FSGS and steroid-sensitive nephrotic syndrome. Pediatr Nephrol 19:384–389

    Article  PubMed  Google Scholar 

  45. Tesch GH (2008) MCP-1/CCL2: a new diagnostic marker and therapeutic target for progressive renal injury in diabetic nephropathy. Am J Physiol Renal Physiol 294:F697–F701

    Article  CAS  PubMed  Google Scholar 

  46. August P, Sharma V, Ding R, Schwartz JE, Suthanthiran M (2009) Transforming growth factor beta and excess burden of renal disease. Trans Am Clin Climatol Assoc 120:61–72

    PubMed  Google Scholar 

  47. Schnaper HW, Robson AM, Kopp JB (2006) Nephrotic syndrome: minimal change nephropathy, focal segmental glomerulosclerosis and collapsing glomerulopathy. In: Schrier RW (ed) Diseases of the kidney and urinary tract, 8th edn. Lippincott Williams & Wilkins, Philadelphia, pp 1585–1673

    Google Scholar 

  48. Kopp JB, Smith MW, Nelson GW, Johnson RC, Freedman BI, Bowden DW, Oleksyk T, McKenzie LM, Kajiyama H, Ahuja TS, Berns JS, Briggs W, Cho ME, Dart RA, Kimmel PL, Korbet SM, Michel DM, Mokrzycki MH, Schelling JR, Simon E, Trachtman H, Vlahov D, Winkler CA (2008) MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet 40:1175–1184

    Article  CAS  PubMed  Google Scholar 

  49. Motoyoshi Y, Matsusaka T, Saito A, Pastan I, Willnow TE, Mizutani S, Ichikawa I (2008) Megalin contributes to the early injury of proximal tubule cells during nonselective proteinuria. Kidney Int 74:1262–1269

    Article  CAS  PubMed  Google Scholar 

  50. Rossini M, Naito T, Yang H, Freeman M, Donnert E, Ma LJ, Dunn SR, Sharma K, Fogo AB (2010) Sulodexide ameliorates early but not late kidney disease in models of radiation nephropathy and diabetic nephropathy. Nephrol Dial Transplant. doi:10.1093/ndt/gfp724

    Google Scholar 

  51. Mauer M, Zinman B, Gardiner R, Suissa S, Sinaiko A, Strand T, Drummond K, Donnelly S, Goodyer P, Gubler MC, Klein R (2009) Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med 361:40–51

    Article  CAS  PubMed  Google Scholar 

  52. Fioretto P, Steffes MW, Sutherland DE, Goetz FC, Mauer M (1998) Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 339:69–75

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Supported in part by grants R01-DK049362 and R01-DK075663 from the National Institute of Diabetes, Digestive and Kidney Diseases.

Author information

Authors and Affiliations

  1. Division of Kidney Diseases, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    H. William Schnaper, Susan C. Hubchak, Constance E. Runyan, James A. Browne, Gal Finer, Xiaoying Liu & Tomoko Hayashida

  2. Children’s Memorial Hospital, 2300 Children’s Plaza, Chicago, IL, 60614-3363, USA

    H. William Schnaper, Susan C. Hubchak, Constance E. Runyan, James A. Browne, Gal Finer, Xiaoying Liu & Tomoko Hayashida

  3. Northwestern University, Pediatrics W-140, 310 E. Superior St., Chicago, IL, 60611-3008, USA

    H. William Schnaper

Authors
  1. H. William Schnaper
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susan C. Hubchak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Constance E. Runyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James A. Browne
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gal Finer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaoying Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tomoko Hayashida
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H. William Schnaper.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schnaper, H.W., Hubchak, S.C., Runyan, C.E. et al. A conceptual framework for the molecular pathogenesis of progressive kidney disease. Pediatr Nephrol 25, 2223–2230 (2010). https://doi.org/10.1007/s00467-010-1503-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-010-1503-4

Keywords

Search

Navigation